Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
−
{{#lst:Section editor transclusions|leuk}}
+
{{#lst:Section editor transclusions|peds}}
−
<big>'''Note: these are regimens specific to Ph+ B-cell ALL; please see the [[B-cell acute lymphoblastic leukemia|main B-cell ALL page]] for other regimens, including portions of a course of therapy that are not biomarker-specific (such as pre-phase prednisone and post-induction transplant).'''
+
<big>''This page contains studies that are specific to pediatric populations. For the more general B-cell acute lymphoblastic leukemia page, including regimens for adolescents and young adults, follow [[B-cell acute lymphoblastic leukemia|this link]].''</big>
−
</big><br>
 
−
<big>'''Note: certain regimens have been moved to dedicated pages:
 
−
*'''[[B-cell acute lymphoblastic leukemia,_Ph-positive,_pediatric|Pediatric B-cell ALL, Ph-positive]]
 
−
</big>
 
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
|}
 
|}
−
{{TOC limit|limit=3}}
+
{{TOC limit|limit=4}}
 
=Guidelines=
 
=Guidelines=
−
==[http://www.esmo.org/ ESMO]==
 
−
*'''2016:''' Hoelzer et al. [https://www.esmo.org/Guidelines/Haematological-Malignancies/Acute-Lymphoblastic-Leukaemia Acute lymphoblastic leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up]
 
 
=="How I Treat"==
 
=="How I Treat"==
−
*'''2020:''' Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. [https://doi.org/10.1182/blood.2019002477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31977001 PubMed]
+
*'''2020:''' Hunger & Raetz. [https://doi.org/10.1182/blood.2019004043 How I treat relapsed acute lymphoblastic leukemia in the pediatric population]
−
*'''2019:''' Ravandi F. How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019 Jan 10;133(2):130-136. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7042663/ link to PMC article]
 
−
*'''2015:''' Curran E, Stock W. How I treat acute lymphoblastic leukemia in older adolescents and young adults. Blood. 2015 Jun 11;125(24):3702-10. Epub 2015 Mar 24. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463735/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25805810 PubMed]
 
 
==[https://www.nccn.org/ NCCN]==
 
==[https://www.nccn.org/ NCCN]==
−
*[https://www.nccn.org/professionals/physician_gls/pdf/all.pdf NCCN Guidelines - Acute Lymphoblastic Leukemia]
+
*[https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia]
−
=Prephase=
+
=Upfront therapy=
−
==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
+
==COG AALL0932 protocol==
−
<div class="toccolours" style="background-color:#eeeeee">
+
'''For Standard Risk B-ALL'''
−
===Regimen {{#subobject:b1507b|Variant=1}}===
+
===Induction (Pegaspargase, Vincristine, Dexamethasone) {{#subobject:15hgu1|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
 +
|2005-2010
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
''Note: there are very minor differences in timing between protocols; see papers for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV once over 1 to 2 hours on day 4
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT once on day 0
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Initial Dose
 +
|-
 +
|1 - 1.99 years
 +
|30 mg
 +
|-
 +
|2 - 2.99 years
 +
|50 mg
 +
|-
 +
|≥ 3 years
 +
|70 mg
 +
|}
 +
CNS2 Patients will receive an additional dose of [[Cytarabine (Ara-C)]] IT on either day 4, 5, or 6, followed by [[Methotrexate (MTX)]] IT on day 8 and then another dose of [[Cytarabine (Ara-C)]] IT on either day 11 or 12 according to the following dosing.
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Subsequent Doses
 +
|-
 +
|1 - 1.99
 +
|20 mg
 +
|-
 +
|2 - 2.99
 +
|30 mg
 +
|-
 +
|≥ 3
 +
|40 mg
 +
|}
 +
*[[Methotrexate (MTX)]] IT once per day on days 8, 29
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Age
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Dose
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/118/25/6521 Foà et al. 2011 (GIMEMA LAL1205)]
+
|1 - 1.99
−
|style="background-color:#91cf61"|Phase 2
+
|8 mg
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ Chiaretti et al. 2016 (GIMEMA LAL 0904)]
+
|2 - 2.99
−
|style="background-color:#91cf61"|Phase 2
+
|10 mg
 
|-
 
|-
−
|[https://doi.org/10.1056/nejmoa2016272 Foà et al. 2020 (GIMEMA LAL2116)]
+
|3 - 8.99
−
| style="background-color:#91cf61" |Phase 2
+
|12 mg
 
|-
 
|-
 +
|≥ 9
 +
|15 mg
 
|}
 
|}
−
''Note: dosing details are as provided in the protocol for GIMEMA LAL2116.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Glucocorticoid therapy====
+
====DS Arm====
−
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/day PO on day -6, then 30 mg/m<sup>2</sup>/day PO on day -5, then 40 mg/m<sup>2</sup>/day PO on day -4, then 50 mg/m<sup>2</sup>/day PO on day -3, then 60 mg/m<sup>2</sup>/day PO on days -2 to 0
+
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 10, 11, 31, 32
−
'''7-day course'''
+
'''35-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*'''GIMEMA LAL1205 & GIMEMA LAL2116:''' [[#Dasatinib_.26_Prednisone|Dasatinib & Prednisone]] induction
+
*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
−
*'''GIMEMA LAL 0904:''' [[#Imatinib_.26_Prednisone|Imatinib & Prednisone]] induction
+
*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
−
</div></div>
 
−
===References===
 
−
# '''GIMEMA LAL1205:''' Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, Baccarani M; GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. Epub 2011 Sep 19. [http://www.bloodjournal.org/content/118/25/6521 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21931113 PubMed] NCT00391989
 
−
# '''GIMEMA LAL 0904:''' Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. [http://www.haematologica.org/content/101/12/1544.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27515250 PubMed] NCT00458848
 
−
# '''GIMEMA LAL2116:''' Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. [https://doi.org/10.1056/nejmoa2016272 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33085860/ PubMed] NCT02744768
 
−
=Upfront induction therapy=
 
−
==Dasatinib & Prednisone {{#subobject:41bc84|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, dasatinib 70 mg twice per day {{#subobject:5e3bf1|Variant=1}}===
+
===Protocol, Consolidation (Mercaptopurine & Vincristine) {{#subobject:171gc1|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Age
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====DS Arm====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3, 4, 10, 11, 17, 18.
 +
'''28-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 +
===Interim Maintenance I (Methotrexate & Vincristine) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
 +
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone_88|Mercaptopurine, MTX, Vincristine, Dexamethasone]]
 +
| style="background-color:#1a9850" |Superior EFS
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/118/25/6521 Foà et al. 2011 (GIMEMA LAL1205)]
+
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
−
|style="background-color:#91cf61"|Phase 2
+
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
 
|}
 
|}
 +
'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Prednisone_monotherapy|Pre-phase prednisone]]
+
*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 70 mg PO twice per day on days 1 to 84
+
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
−
====Glucocorticoid therapy====
+
**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day (maximum dose of 120 mg) PO on days 1 to 24, then tapered and stopped at day 32
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] (dose not specified) IT once per day on days 22 & 43
+
*[[Methotrexate (MTX)]] IT once on day 31
−
'''12-week course'''
+
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====DS Arm====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 33, 34
 +
'''8-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*Post-induction treatment is not specified
+
*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
−
</div></div><br>
+
===AALL0932 delayed intensification {{#subobject:17185g|Regimen=1}}===
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen variant #2, dasatinib 140 mg once per day {{#subobject:5e6da1|Variant=1}}===
 
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 33%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 33%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1056/nejmoa2016272 Foà et al. 2020 (GIMEMA LAL2116)]
+
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
−
|2017-2019
+
|2010-2018
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
 +
'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Prednisone_monotherapy|Pre-phase prednisone]]
+
*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 140 mg PO once per day on days 1 to 84
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 24, then 40 mg/m<sup>2</sup>/day PO on days 25 & 26, then 20 mg/m<sup>2</sup>/day PO on days 27 & 28, then 10 mg/m<sup>2</sup>/day PO on days 29 & 30, then 5 mg/m<sup>2</sup>/day PO on day 31
+
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup>/dose PO twice daily on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day)
−
'''12-week course'''
+
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====DS Arm====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 31 to 32
 +
'''8-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Dasatinib_.26_Blinatumomab|Dasatinib & Blinatumomab]] consolidation
+
*[[#Methotrexate_.26_Vincristine_2|MTX & Vincristine]] interim maintenance II
 +
===Interim Maintenance II (Methotrexate & Vincristine) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
 +
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone_88|Mercaptopurine, MTX, Vincristine, Dexamethasone]]
 +
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
'''For AR B-ALL patients, LR-C Arm, and B-LLy'''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 +
**Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on day 31
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====DS Arm====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> PO x 2 doses given 48 and 60 hours after the lumbar puncture on days 3 to 4, 33 to 34
 +
'''8-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
 +
===Maintenance Arm A and C (Vincristine/Dexamethasone Pulses) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
'''For AR B-ALL patients, and LR-C Arm'''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice daily on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m<sup>2</sup>/day)
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
 +
===Maintenance Arm B and D (Vincristine/Dexamethasone Pulses) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*Currently maintenance arm B and D are also treated with [[Methotrexate (MTX)]] PO at 20 mg/m<sup>2</sup> (decreased from the starting dose of 40 mg/m<sup>2</sup>) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice daily on days 1 to 5, 29 to 33, 57 to 61
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
 +
===Maintenance Arm DS (Vincristine/Dexamethasone) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
'''For DS AR B-ALL patients and DS B-LLy'''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice daily on days 1 to 5 (DO NOT TAPER)
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
 +
===Arm LR-M Consolidation {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV on days 8, 29, 50, 71, 92, 113
 +
Given as a 200 mg/m<sup>2</sup> bolus over 20 to 30 minutes followed by 800 mg/m<sup>2</sup> over 23.5 hours (initial bolus of 30 minutes) or 23 hours and 40 minutes (if initial bolus was over 20 minutes)
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 78, 85
 +
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day on days 1 to 33
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice daily on days 15 to 21, 78 to 84
 +
====Supportive therapy====
 +
*[[Folinic acid (Leucovorin)]] 10 mg/m<sup>2</sup> x 2 doses PO or IV (given 48 and 60 hours after the START of methotrexate infusion, continuing until methotrexate level < 0.2 μM) on days 9, 10, 30, 31, 51, 52, 72, 73, 93, 94, 114, 115
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on days 8, 29, 50, 71, 92,  113 (To be delivered within 6 hours of the beginning of the IV methotrexate infusion, -6hr to + 6 hr)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''19-week cycle'''
 +
===Arm LR-M Maintenance {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
Methotrexate (MTX) DATES CHANGE DEPENDING ON CYCLE NUMBER
 +
Cycles 1 and 4:
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78, 92, 99, 106
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
 +
Cycles 2 and 5:
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 1, 8, 15, 22, 29, 36, 43, 50, 64, 71, 78, 85, 92, 99, 106
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
 +
Cycles 3 and 6:
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 1, 8, 15, 22, 36, 43, 50, 57, 64, 71, 78, 85, 92, 99, 106
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 112 (NOTE: Higher 6-MP dose than in consolidation)
 +
Cycle 7:
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 1, 8, 15, 29, 22, 36, 43, 50, 57, 64
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 70 (NOTE: Higher 6-MP dose than in consolidation)
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice daily on days 1 to 7 (6 mg/m<sup>2</sup>/day, do not taper)
 +
====CNS therapy, prophylaxis====
 +
DATES CHANGE DEPENDING ON CYCLE NUMBER
 +
Cycles 1 and 4:
 +
*[[Methotrexate (MTX)]] IT once on day 1, 85
 +
Cycles 2 and 5:
 +
*[[Methotrexate (MTX)]] IT once on day 57
 +
Cycles 3 and 6:
 +
*[[Methotrexate (MTX)]] IT once on day 29
 +
Cycle 7:
 +
NO MTX IT on Cycle 7
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''16-week cycles until a total duration of therapy of 2.5 years from the date of diagnosis is reached for both boys and girls.'''
 +
===Maintenance Arm LLy (Vincristine/Dexamethasone) {{#subobject:0ae09f|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*COG AALL0932: [[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57 (4 Week Intervals)
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice daily on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m<sup>2</sup>/day) (DO NOT TAPER)
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once on day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GIMEMA LAL1205:''' Foà R, Vitale A, Vignetti M, Meloni G, Guarini A, De Propris MS, Elia L, Paoloni F, Fazi P, Cimino G, Nobile F, Ferrara F, Castagnola C, Sica S, Leoni P, Zuffa E, Fozza C, Luppi M, Candoni A, Iacobucci I, Soverini S, Mandelli F, Martinelli G, Baccarani M; GIMEMA Acute Leukemia Working Party. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2011 Dec 15;118(25):6521-8. Epub 2011 Sep 19. [http://www.bloodjournal.org/content/118/25/6521 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21931113 PubMed] NCT00391989
+
#'''COG CCG-1991:''' Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
−
# '''GIMEMA LAL2116:''' Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. [https://doi.org/10.1056/nejmoa2016272 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33085860/ PubMed] NCT02744768
+
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274746/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
−
==Daunorubicin, L-Asparaginase, Vincristine, Prednisone, Imatinib {{#subobject:d36b57|Regimen=1}}==
+
==COG AALL1131 protocol==
−
<div class="toccolours" style="background-color:#eeeeee">
+
===Induction (Daunorubicin, Pegaspargase, Vincristine, Dexamethasone) {{#subobject:98346f|Variant=1}}===
−
===Regimen {{#subobject:f3e30f|Variant=1}}===
 
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
−
''To our knowledge, this is the largest induction trial in adult ALL, N=1,646. CR rate was 91%. There are many local variants of this protocol, which begins with "Phase I." Note that, for simplicity, the flow from this phase to others does not include the imatinib; please check the original reference for further details on imatinib dosing.''
+
''Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Daunorubicin (Cerubidine)]] 65 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
−
*[[Asparaginase (Elspar)]] 10,000 units IM or IV once per day on days 17 to 28
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
−
*[[Vincristine (Oncovin)]] 1.4 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 28
+
Patients < 10 years ONLY:
−
====Targeted therapy====
+
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
−
*[[Imatinib (Gleevec)]] 400 mg PO once per day, increased to 600 mg PO once per day "wherever possible"
+
Patients ≥ 10 years ONLY:
−
**Note: Two variants have been tested: from 2003 to 2005, imatinib was added after induction; from 2005 onward, imatinib was added during induction. Various durations are proposed, see Fielding et al. 2013 for more details.
+
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 12 mg IT once on day 15
+
*[[Cytarabine (Ara-C)]] by the following criteria:
 +
**Ages 1 to 1.99: 30 mg IT once on day 1
 +
**Ages 2 to 2.99: 50 mg IT once on day 1
 +
**Age 3 and older: 70 mg IT once on day 1
 +
CNS2 Patients will receive an additional dose of [[Cytarabine (Ara-C)]] IT on either day 4, 5, or 6, and then another dose of [[Cytarabine (Ara-C)]] IT on either day 11 or 12 according to the following dosing.
 +
*[[Cytarabine (Ara-C)]] by the following criteria:
 +
**Ages 1 to 1.99: 20 mg IT once
 +
**Ages 2 to 2.99: 30 mg IT once
 +
**Age 3 and older: 40 mg IT once
 +
*[[Methotrexate (MTX)]] by the following criteria: (CNS3 also on Days 15 and 22)
 +
**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
 +
**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
 +
**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
 +
**Age 9 and older: 15 mg IT once per day on days 8 & 29
 
'''4-week course'''
 
'''4-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[B-cell acute lymphoblastic leukemia#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine|Cyclophosphamide, cytarabine, mercaptopurine induction ("Phase 2")]]
+
*See protocol for details of treatment beyond induction
 +
</div></div>
 +
===References===
 +
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
 +
==COG AALL1131 protocol for HR B-ALL==
 +
===Consolidation (Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine) {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Interim Maintenance with HD MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
 +
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56
 +
*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43
 +
**[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV infused over 30 minutes, then [[Methotrexate (MTX)]] 4,500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours
 +
ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose [[Methotrexate (MTX)]]
 +
*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT methotrexate within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
 +
'''63-Day course'''
 +
===Delayed Intensification {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29, 36
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Maintenance HR B-ALL {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
Cycles 1-4
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 to 4: 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
 +
**Cycle 5 onwards: 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 to 4: IT once per day on days 1, 29
 +
**Cycle 5 onwards: IT once per day on day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-Week Cycles repeated until the total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]  
+
==COG AALL1131 protocol for VHR B-ALL==
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]  
+
===Consolidation {{#subobject:98346f|Variant=1}}===
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+
{| class="wikitable" style="width: 40%; text-align:center;"
−
==Daunorubicin, Vincristine, Prednisolone, Nilotinib {{#subobject:2b1389|Regimen=1}}==
+
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 15, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 1, 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes once daily on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22 (Omit days 15 and 22 for CNS3 Patients)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Interim Maintenance I with HD MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 56
 +
*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43
 +
**[[Methotrexate (MTX)]]500 mg/m<sup>2</sup> IV infused over 30 minutes, then [[Methotrexate (MTX)]] 4,500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours
 +
ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate.
 +
*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''28-Day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Protocol, Delayed Intensification {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on day 1, 29, 36
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:e721b6|Variant=1}}===
+
===Protocol, Interim Maintenance II with Capizzi MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
 +
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2, 22
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 31
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Protocol, VHR Arm Maintenance {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
For Patients with CNS3 Disease
 +
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.'''
 +
</div></div>
 +
===References===
 +
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
 +
==COG AALL1131 protocol for Ph-like B-ALL (Dasatinib Arm)==
 +
===Consolidation {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes once daily on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 +
*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once daily on days 1 to 56
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Interim Maintenance with HD MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
 +
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56.
 +
*High Dose [[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43
 +
**[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV infused over 30 minutes, then [[Methotrexate (MTX)]] 4,500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours
 +
ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate
 +
*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose [[Methotrexate (MTX)]] infusion) on days 3, 4, 17, 18, 31, 32, 45, 46
 +
*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once daily on days 1 to 63
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
 +
'''63-Day course'''
 +
===Delayed Intensification {{#subobject:98346f|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 +
*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once daily on days 1 to 56
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29, 36
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Interim Maintenance II with Capizzi MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
 +
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m<sup>2</sup> on day 11, 200 mg/m<sup>2</sup> on day 21, 250 mg/m<sup>2</sup> on day 31, and 300 mg/m<sup>2</sup> on day 41
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 2, 22
 +
*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once daily on days 1 to 56
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 31
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===Maintenance {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015 (AMC-UUCM-2008-0310)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
For Patients with CNS3 Disease
 +
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Daunorubicin (Cerubidine)]] 90 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose: 270 mg/m<sup>2</sup>)
+
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 29, 57
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
−
*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61
−
**Alternate: 48 mg/m<sup>2</sup> IV once per day on days 1 to 14
 
 
====Targeted therapy====
 
====Targeted therapy====
−
*[[Nilotinib (Tasigna)]] 400 mg PO twice per day, starting on day 8
+
*[[Dasatinib (Sprycel)]] 60 mg/m<sup>2</sup> (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 84
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.'''
 +
</div></div>
 +
===References===
 +
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
 +
==COG AALL1131 protocol for DS HR B-ALL {{#subobject:088146|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Protocol, Induction (Daunorubicin, Pegaspargase, Vincristine, Dexamethasone) {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
''Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 +
RER - M1 Marrow at Day 15
 +
*Add [[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once on days 15
 +
====Glucocorticoid therapy====
 +
Patients < 10 years ONLY:
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
 +
Patients ≥ 10 years ONLY:
 +
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28 (DO NOT TAPER)
 +
====Supportive therapy====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10, 11, 31, 32 (CNS3 also on days 17, 18, 24, 25)
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 15 mg IT, mixed with [[Hydrocortisone (Cortef)]]
+
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
−
*[[Hydrocortisone (Cortef)]] 50 mg IT, mixed with [[Methotrexate (MTX)]]
+
**Ages 1 to 1.99: 30 mg IT once on day 1
−
*Up to 10 doses given during or after induction
+
**Ages 2 to 2.99: 50 mg IT once on day 1
−
'''14-day course, with ongoing nilotinib'''
+
**Age 3 and older: 70 mg IT once on day 1
 +
*[[Methotrexate (MTX)]] by the following age-based criteria:
 +
**Ages 1 to 1.99: 8 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
 +
**Ages 2 to 2.99: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
 +
**Ages 3 to 8.99: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
 +
**Age 9 and older: 15 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
 +
'''4-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Nilotinib-based_consolidation|Nilotinib-based]] consolidation or [[B-cell_acute_lymphoblastic_leukemia#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]]. Transplant regimen left to the discretion of the investigator
+
*See protocol for details of treatment beyond induction
 +
===Consolidation {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on days 1, 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 15, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
DS Arm
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25
 +
'''56-Day course'''
 +
===Interim Maintenance with ID MTX {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
 +
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup>/dose PO once per day on days 1 to 56
 +
*Intermediate Dose [[Methotrexate (MTX)]] 2000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43
 +
**[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV infused over 30 minutes, then [[Methotrexate (MTX)]] 1800 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours
 +
ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate
 +
*[[Folinic acid (Leucovorin)]] 15 mg/m<sup>2</sup> x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of intermediate dose methotrexate infusion) on days 2, 3, 17, 18, 31, 32, 45, 46
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).
 +
'''63-Day course'''
 +
===Delayed Intensification {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push over 1 to 15 minutes once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on days 4, 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 43, 50
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once on day 29 ONLY
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21
 +
====Supportive therapy====
 +
*[[Folinic acid (Leucovorin)]] 5 mg/m<sup>2</sup> x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3, 4, 31, 32, 38, 39
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 29, 36
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''56-Day course'''
 +
===DS HR Arm Maintenance {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
 +
| style="background-color:#91cf61" |Randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
For Patients with CNS3 Disease
 +
*[[External_beam_radiotherapy|Total body irradiation (TBI)]] 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance
 +
====Chemotherapy====
 +
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/dose PO once per day on days 1 to 84
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on day 1 ONLY
 +
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on days 8, 15, 22, (29), 36, 43, 50, 57, 64, 71, 78 (OMIT DAY 29 WHEN CNS RADIATION IS GIVEN, DUE TO IT MTX)
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup>/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 - 1.99
 +
|8 mg
 +
|-
 +
|2 - 2.99
 +
|10 mg
 +
|-
 +
|3 - 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
'''12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26065651 PubMed] NCT00844298
+
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
−
==Hyper-CVAD/MA & Dasatinib {{#subobject:7722d2|Regimen=1}}==
+
=Prephase=
−
Hyper-CVAD/MA & Dasatinib: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethorexate & '''<u>A</u>'''ra-C (Cytarabine) & Dasatinib
+
==Methylprednisolone monotherapy {{#subobject:5gh1bb|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:b88b6e|Variant=1}}===
+
===Regimen {{#subobject:88fgh7|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 33%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 33%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
+
|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
−
|2006-2009
+
|2005-2011
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321539/ Sasaki et al. 2016]
+
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
−
|NR
+
|2012-2015
−
|style="background-color:#1a9851"|Propensity score analysis
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|[[#Hyper-CVAD.2FMA_.26_Ponatinib|Hyper-CVAD/MA & Ponatinib]]
+
|-
−
|style="background-color:#fc8d59"|Seems to have inferior OS
+
|}
 +
''Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Glucocorticoid therapy====
 +
*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 1 to 3
 +
'''3-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*DFCI 05-001: [[#Doxorubicin.2C_L-Asparaginase.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_88|Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone]] versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
 +
*DFCI 11-001: [[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_88|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]] versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
 +
</div></div>
 +
===References===
 +
#'''DFCI 05-001:''' Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] NCT00400946
 +
##'''Pooled update:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed]
 +
#'''DFCI 11-001:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] NCT01574274
 +
## '''Update:''' Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. [https://doi.org/10.1200/jco.20.03692 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34228505/ PubMed]
 +
==Prednisone monotherapy {{#subobject:8ca13b|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:2fd1d7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ Ravandi et al. 2016 (SWOG S0805)]
+
|[http://www.bloodjournal.org/content/127/17/2101.long Möricke et al. 2016 (AIEOP-BFM ALL 2000)]
−
|2009-2013
+
|2000-2006
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
 
|-
 
|-
 
|}
 
|}
−
''Note #1: the dosing of dasatinib changed three times for this protocol. The initial protocol was 50 mg PO twice per day, which was then changed to 100 mg PO once per day after these were shown to be equivalent in a separate trial. Starting with patient #43, the protocol was further amended to 100 mg of dasatinib once per day in the first 14 days of the first cycle only, followed by 70 mg once per day continuously from the second cycle through completion of induction. These details are described in the references.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<br>''Note #2: Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial.''
+
====Glucocorticoid therapy====
−
====Chemotherapy, part A====
+
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 7
−
*[[Cyclophosphamide (Cytoxan)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
 
−
*[[Vincristine (Oncovin)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 2 mg IV once per day on days 4 & 11
 
−
*[[Doxorubicin (Adriamycin)]] as follows:
 
−
**Cycles 1, 3, 5, 7, by the following criteria:
 
−
***Normal EF: 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
 
−
***EF less than 50%: 25 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m<sup>2</sup>)
 
−
====Glucocorticoid therapy, part A====
 
−
*[[Dexamethasone (Decadron)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 40 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Supportive therapy, part A====
 
−
*[[Mesna (Mesnex)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]'''
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 1, 3, 5, 7: 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
*Cycle 1 also involved:
 
−
**Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
 
−
**[[Allopurinol (Zyloprim)]] to decrease likelihood of tumor lysis syndrome; [[Rasburicase (Elitek)]] could be used instead for patients with high white blood cell counts at initial presentation
 
−
**Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3
 
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens have used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====Chemotherapy, part B====
 
−
*[[Methotrexate (MTX)]] as follows:
 
−
**Cycles 2, 4, 6, 8: 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 
−
*[[Cytarabine (Ara-C)]] as follows:
 
−
**Cycles 2, 4, 6, 8, by the following age-based criteria:
 
−
***Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
 
−
***60 and older: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
 
−
====Supportive therapy, part B====
 
−
*[[Folinic acid (Leucovorin)]] as follows:
 
−
**Cycles 2, 4, 6, 8: 50 mg IV once on day 3; 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
 
−
**Leucovorin rescue with [[Folinic acid (Leucovorin)]] 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of [[Methotrexate (MTX)]]; greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
 
−
*[[Filgrastim (Neupogen)]] as follows:
 
−
**Cycles 2, 4, 6, 8: 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
*[[Acetazolamide (Diamox)]] as follows:
 
−
**Cycles 2, 4, 6, 8: (no dosage/schedule listed) used if urine pH less than 7 to promote excretion
 
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====Targeted therapy====
 
−
*[[Dasatinib (Sprycel)]] as follows:
 
−
**Cycle 1: 100 mg PO once per day on days 1 to 14
 
−
**Cycles 2 to 8: 70 mg PO once per day
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
+
*[[Methotrexate (MTX)]] 15 mg IT once on day 1
−
*[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
+
'''7-day course'''
−
'''Given each cycle for a total of 6 or 8 intrathecal treatments (i.e., 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%'''
 
−
====CNS therapy, for known CNS disease====
 
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Ara-C)]] 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
 
−
*Then [[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and [[Cytarabine (Ara-C)]] 100 mg IT, given weeks 2 & 4
 
−
*Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
 
−
**[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT once on day 2
 
−
**[[Cytarabine (Ara-C)]] 100 mg IT once on day 7
 
−
*Therapeutic external radiation is given to patients with CNS disease at presentation
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*Patients achieving a CR who had an available matched sibling or 10/10 matched unrelated donor: [[B-cell_acute_lymphoblastic_leukemia#Allogeneic_hematopoietic_stem_cell_transplant|allogeneic HSCT]]
+
*[[#DOLP|Daunorubicin, L-Asparaginase, Vincristine, Prednisone]] versus [[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Dexamethasone_99|Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone]] induction
−
*All others: [[#Dasatinib.2C_Vincristine.2C_Prednisone|Dasatinib, vincristine, and prednisone]] maintenance
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed] NCT00390793
+
#'''AIEOP-BFM ALL 2000:''' Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. [http://www.bloodjournal.org/content/127/17/2101.long link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/26888258 PubMed] NCT00430118; NCT00613457
−
## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
+
==Vincristine & Prednisone {{#subobject:663781|Regimen=1}}==
−
# '''Retrospective:''' Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, Daver NG, Kadia TM, Konopleva MY, Jain N, Issa GC, Jeanis V, Moore HG, Garris RS, Pemmaraju N, Cortes JE, O'Brien SM, Kantarjian HM. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. Cancer. 2016 Dec 1;122(23):3650-3656. [https://doi.org/10.1002/cncr.30231 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27479888 PubMed]
+
VP: '''<u>V</u>'''incristine & '''<u>P</u>'''rednisone
−
# '''SWOG S0805:''' Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. [http://www.bloodadvances.org/content/1/3/250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29046900 PubMed] NCT00792948
 
−
==Hyper-CVAD/MA & Imatinib {{#subobject:50d757|Regimen=1}}==
 
−
Hyper-CVAD/MA & Imatinib: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethorexate & '''<u>A</u>'''ra-C (Cytarabine) & Imatinib
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:38ce3d|Variant=1}}===
+
===Regimen {{#subobject:79fc67|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/51/3/425.long Sallan et al. 1978]
 +
|1973-1977
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 21
 +
'''21-day course'''
 +
</div></div>
 +
===References===
 +
#Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. [http://www.bloodjournal.org/content/51/3/425.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/272207 PubMed]
 +
=Upfront induction therapy=
 +
==Calaspargase, Daunorubicin, Vincristine, Prednisone {{#subobject:1abca2|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:cf26ce|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ Angiolillo et al. 2014 (COG AALL07P4)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
 +
|[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone_88|Daunorubicin, Pegaspargase, Vincristine, Prednisone]]
 +
| style="background-color:#1a9850" |Longer half-life
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
+
|}
−
|2001-2003
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|style="background-color:#91cf61"|Phase 2
+
====Chemotherapy====
−
| style="background-color:#d3d3d3" |
+
*[[Calaspargase (Asparlas)]] 2500 units/m<sup>2</sup> IV once on day 4
−
| style="background-color:#d3d3d3" |
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 +
'''5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See protocol for details of treatment beyond induction
 +
</div></div>
 +
===References===
 +
#'''COG AALL07P4:''' Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. [https://doi.org/10.1200/JCO.2014.55.5763 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239306/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25348002 PubMed] NCT00671034
 +
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:088146|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:98346f|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/125/24/3711.long Chalandon et al. 2015 (GRAAPH-2005)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ Burke et al. 2019 (COG AALL1131)]
−
|2006-2011
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Imatinib.2C_Vincristine.2C_Dexamethasone|Imatinib, Vincristine, Dexamethasone]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of MMR rate after cycle 2
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
+
====Chemotherapy====
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4
−
*[[Doxorubicin (Adriamycin)]] by the following criteria:
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
−
**Normal EF: 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
+
====Glucocorticoid therapy====
−
**EF less than 50%: 25 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m<sup>2</sup>)
+
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 14
−
====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
+
====CNS therapy, prophylaxis====
−
*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Targeted therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Imatinib (Gleevec)]] 400 mg PO once per day on days 1 to 14
 
−
====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]'''
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
*Cycle 1 also involved:
 
−
**Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
 
−
**[[Allopurinol (Zyloprim)]] to decrease likelihood of tumor lysis syndrome; [[Rasburicase (Elitek)]] could be used instead for patients with high white blood cell counts at initial presentation
 
−
**Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3
 
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 
 
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
−
**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+
**Ages 1 to 1.99: 30 mg IT once on day 1
−
**60 and older: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
**Ages 2 to 2.99: 50 mg IT once on day 1
−
====Targeted therapy, Part B (cycles 2, 4, 6, 8)====
+
**Age 3 and older: 70 mg IT once on day 1
−
*[[Imatinib (Gleevec)]] 400 mg PO once per day on days 1 to 14
+
*[[Methotrexate (MTX)]] by the following age-based criteria:
−
====Supportive therapy, Part B (cycles 2, 4, 6, 8)====
+
**Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
−
*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3; 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
+
**Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
−
**Leucovorin rescue with [[Folinic acid (Leucovorin)]] 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of [[Methotrexate (MTX)]]; greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
+
**Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
−
*ONE of the following antibiotics:
+
**Age 9 and older: 15 mg IT once per day on days 8 & 29
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
+
'''4-week course'''
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
*[[Acetazolamide (Diamox)]] (no dosage/schedule listed) used if urine pH less than 7 to promote excretion
 
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
 
−
*[[Cytarabine (Ara-C)]] 100 mg IT on day 7 '''OR''' 8
 
−
'''Given each cycle for a total of 6 or 8 intrathecal treatments (i.e. 3 each of methotrexate and cytarabine or 4 each of methotrexate and cytarabine), depending on risk for CNS relapse based serum lactate dehydrogenase (LDH) greater than 1400 IU/L and/or proliferative index percentage of S + G2M of at least 14%'''
 
−
====CNS therapy, for known CNS disease====
 
−
*[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT alternating with [[Cytarabine (Ara-C)]] 100 mg IT, with both given every week until cell count in CSF normalizes and cytology is negative for malignancy
 
−
*Then [[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT given weeks 1 & 3 and [[Cytarabine (Ara-C)]] 100 mg IT, given weeks 2 & 4
 
−
*Once those 4 weeks are complete, then intrathecal treatment is given similar to the prophylactic schedule, with each drug given once during every remaining cycle of induction therapy:
 
−
**[[Methotrexate (MTX)]] 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
 
−
**[[Cytarabine (Ara-C)]] 100 mg IT on day 7 '''OR''' 8
 
−
*Therapeutic [[External_beam_radiotherapy|external radiation]] is given to patients with CNS disease at presentation
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Imatinib.2C_Vincristine.2C_Prednisone|Imatinib, Vincristine, Prednisone]] maintenance
+
*See protocol for details of treatment beyond induction
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
+
#'''COG AALL1131:''' Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. [http://www.haematologica.org/content/104/5/986.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518909/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30545921 PubMed] NCT02883049
−
## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
+
==DOLP {{#subobject:3c9897|Regimen=1}}==
−
# '''GRAAPH-2005:''' Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. [http://www.bloodjournal.org/content/125/24/3711.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25878120 PubMed] NCT00327678
+
DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
−
==Hyper-CVAD/MA & Ponatinib {{#subobject:98f919|Regimen=1}}==
+
<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
−
Hyper-CVAD/MA & Ponatinib: '''<u>Hyper</u>'''fractionated '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>D</u>'''examethasone alternating with '''<u>M</u>'''ethorexate & '''<u>A</u>'''ra-C (Cytarabine) & Ponatinib
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:3c0426|Variant=1}}===
+
===Regimen variant #1, 25/1.5/6000/60 {{#subobject:3fe1a2|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
!style="width: 33%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 33%"|Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816046/ Jabbour et al. 2015 (MDACC 2011-0030)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ Seibel et al. 2008 (COG CCG-1961)]
−
|2011-2013
+
|1996-2002
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321539/ Sasaki et al. 2016]
+
|[https://doi.org/10.1002/pbc.24149 Termuhlen et al. 2012 (COG A5971)]
−
|NR
+
|2000-2005
−
|style="background-color:#1a9851"|Propensity score analysis
+
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
−
|[[#Hyper-CVAD.2FMA_.26_Dasatinib|Hyper-CVAD/MA & Dasatinib]]
 
−
|style="background-color:#91cf60"|Seems to have superior OS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: Sasaki et al. 2016 is a post-hoc analysis, not a randomized trial. Jabbour et al. 2015 refers to Thomas et al. 2004 (Hyper-CVAD & Imatinib) for regimen details; these are replicated here.''
+
''Note: COG A5971 was intended for patients with localized lymphoblastic lymphoma, of which 75% had B-cell immunophenotype. Exact days were not specified for the L-asparaginase; suggested days are similar to those used in other protocols. COG CCG-1961 did not specify a tapering schedule for prednisone, and did not cap vincristine.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, Part A (cycles 1, 3, 5, 7)====
+
====Chemotherapy====
−
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m<sup>2</sup>)
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 0, 7, 14, 21
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 4 & 11
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 0, 7, 14, 21
−
*[[Doxorubicin (Adriamycin)]] by the following criteria:
+
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
−
**Normal EF: 50 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 4
+
====Glucocorticoid therapy====
−
**EF less than 50%: 25 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 4 (total dose per cycle: 50 mg/m<sup>2</sup>)
+
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 0 to 27, then tapered from days 28 to 38 (see note)
−
====Glucocorticoid therapy, Part A (cycles 1, 3, 5, 7)====
+
====CNS therapy====
−
*[[Dexamethasone (Decadron)]] 40 mg IV or PO once per day on days 1 to 4, 11 to 14
 
−
====Targeted therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Ponatinib (Iclusig)]] as follows:
 
−
**Cycle 1: 45 mg PO once per day on days 1 to 14
 
−
**Cycles 3, 5, 7: 45 mg PO once per day
 
−
====Supportive therapy, Part A (cycles 1, 3, 5, 7)====
 
−
*[[Mesna (Mesnex)]] 600 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1, '''given 1 hour before [[Cyclophosphamide (Cytoxan)]] and completed 12 hours after the last dose of [[Cyclophosphamide (Cytoxan)]]'''
 
−
*ONE of the following antibiotics:
 
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
 
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
 
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day
 
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
 
−
*ONE of the following antivirals:
 
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
 
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
 
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
 
−
*Cycle 1 also involved:
 
−
**Hydration options included D5 water or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 50 to 100 mL/H
 
−
**[[Allopurinol (Zyloprim)]] to decrease likelihood of tumor lysis syndrome; [[Rasburicase (Elitek)]] could be used instead for patients with high white blood cell counts at initial presentation
 
−
**Oral sodium bicarbonate (no dosage or frequency listed) on days 1 to 3
 
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
 
−
====Chemotherapy, Part B (cycles 2, 4, 6, 8)====
 
−
*[[Methotrexate (MTX)]] 1000 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 
 
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
 
*[[Cytarabine (Ara-C)]] by the following age-based criteria:
−
**Younger than 60: 3000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 12,000 mg/m<sup>2</sup>)
+
**Age 1-1.99 years: 30 mg IT once on day 0
−
**60 and older: 1000 mg/m<sup>2</sup> IV over 2 hours every 12 hours on days 2 & 3 (total dose per cycle: 4000 mg/m<sup>2</sup>)
+
**Age 2-2.99 years: 50 mg IT once on day 0
−
====Targeted therapy, Part B (cycles 2, 4, 6, 8)====
+
**Age 3 or greater: 70 mg IT once on day 0
−
*[[Ponatinib (Iclusig)]] 45 mg PO once per day
+
*[[Methotrexate (MTX)]] by the following age-based criteria:
−
====Supportive therapy, Part B (cycles 2, 4, 6, 8)====
+
**Age 1-1.99 years: 8 mg IT once per day on days 7 & 28
−
*[[Folinic acid (Leucovorin)]] 50 mg IV once on day 3; 12 hours after [[Methotrexate (MTX)]] is complete, then 15 mg IV every 6 hours until serum methotrexate level less than 100 nmol/L
+
**Age 2-2.99 years: 10 mg IT once per day on days 7 & 28
−
**Leucovorin rescue with [[Folinic acid (Leucovorin)]] 50 mg IV every 6 hours if serum methotrexate levels were greater than 20,000 nmol/L at 0 hours after completion of [[Methotrexate (MTX)]]; greater than 1000 nmol/L at 24 hours; greater than 100 nmol/L at 48 hours
+
**Age 3 or greater: 12 mg IT once per day on days 7 & 28
−
*ONE of the following antibiotics:
+
'''5-week course'''
−
**[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day
+
</div>
−
**[[Levofloxacin (Levaquin)]] 500 mg PO once per day
+
<div class="toccolours" style="background-color:#cbd5e7">
−
**[[Trimethoprim-Sulfamethoxazole (Bactrim DS)]] 160/800 mg PO twice per day  
+
====Subsequent treatment====
−
*[[Fluconazole (Diflucan)]] 200 mg PO once per day
+
*COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
−
*ONE of the following antivirals:
+
*COG A5971: Consolidation (see paper for details)
−
**[[Acyclovir (Zovirax)]] 200 mg PO twice per day
+
</div></div><br>
−
**[[Valacyclovir (Valtrex)]] 500 mg PO once per day
+
<div class="toccolours" style="background-color:#eeeeee">
−
*D5W or 1/2 NS with 75 to 100 mEq sodium acetate per liter at 100 to 125 mL/H
+
===Regimen variant #2, 30/1.5/5000/60 ("Phase A" of ALL-BFM 95; "Phase 1" of ALL IC-BFM 2002) {{#subobject:020017|Variant=1}}===
−
*[[Filgrastim (Neupogen)]] 10 mcg/kg SC once per day, starting 24 hours after completion of intensive courses of chemotherapy (day 5 for part A, day 4 for part B), given until ANC greater than 1000/uL
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"
−
*[[Acetazolamide (Diamox)]] (no dosage/schedule listed) used if urine pH less than 7 to promote excretion
+
!style="width: 33%"|Study
−
'''Next cycle to start after count recovery. No definite criteria listed by the reference, but other Hyper-CVAD regimens used ANC greater than 1000/uL at least 24 hours off of G-CSF and platelet count greater than 60 x 10<sup>9</sup>/L'''
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/111/9/4477.long Möricke et al. 2008 (ALL-BFM 95)]
 +
|1995-2000
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[https://doi.org/10.1200/jco.2013.48.6522 Stary et al. 2013 (ALL IC-BFM 2002)]
 +
|2002-2007
 +
| style="background-color:#91cf61" |Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: see papers for details on dose adjustments based on risk. For example, in ALL IC-BFM 2002, days 22 & 29 of daunorubicin were omitted for standard risk B-cell precursor acute lymphoblastic leukemia.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
 +
*[[Asparaginase (Elspar)]] 5000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, tapered over 9 days
 +
====CNS therapy====
 +
*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 12, 33
 +
'''5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See papers for details
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 30/1.5/10,000/60 ("Protocol I") {{#subobject:0ccc82|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/95/11/3310.long Schrappe et al. 2000 (ALL-BFM 90)]
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|[https://doi.org/10.1038/sj.leu.2402489 Kamps et al. 2002 (DCLSG ALL-8)]
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''Note: see papers for details on dose adjustments based on risk.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 60 minutes once per day on days 8, 15, 22, 29
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
 +
*[[Asparaginase (Elspar)]] 10,000 units IV over 60 minutes once per day on days 12, 15, 18, 21, 24, 27, 30, 33
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
 +
====CNS therapy====
 +
*[[Methotrexate (MTX)]] 12 mg IT once per day on days 1, 15, 29
 +
'''5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See papers for details
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86) {{#subobject:6ad40d|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/84/9/3122.long Reiter et al. 1994 (ALL-BFM 86)]
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|[http://www.bloodjournal.org/content/94/4/1226.long Kamps et al. 1999 (DCLSG ALL-7)]
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 40 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
 +
*[[Asparaginase (Elspar)]] 10,000 units/m<sup>2</sup> IV once per day on days 19, 22, 25, 28, 31, 34, 37, 40
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28
 +
'''6-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Induction phase II (see papers for details)
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MDACC 2011-0030:''' Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, Pemmaraju N, Daver N, Garcia-Manero G, Sasaki K, Cortes J, Garris R, Yin CC, Khoury JD, Jorgensen J, Estrov Z, Bohannan Z, Konopleva M, Kadia T, Jain N, DiNardo C, Wierda W, Jeanis V, O'Brien S. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015 Nov;16(15):1547-55. Epub 2015 Sep 30. [https://doi.org/10.1016/S1470-2045(15)00207-7 link to original article] '''contains partial protocol details''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4816046/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26432046 PubMed] NCT01424982
+
#'''ALL-BFM 86:''' Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. [http://www.bloodjournal.org/content/84/9/3122.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7949185 PubMed]
−
## '''Retrospective:''' Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, Daver NG, Kadia TM, Konopleva MY, Jain N, Issa GC, Jeanis V, Moore HG, Garris RS, Pemmaraju N, Cortes JE, O'Brien SM, Kantarjian HM. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis. Cancer. 2016 Dec 1;122(23):3650-3656. [https://doi.org/10.1002/cncr.30231 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321539/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27479888 PubMed]
+
#'''DCLSG ALL-7:''' Kamps WA, Bökkerink JP, Hählen K, Hermans J, Riehm H, Gadner H, Schrappe M, Slater R, van den Berg-de Ruiter E, Smets LA, de Vaan GA, Weening RS, van Weerden JF, van Wering ER, den der Does-van den Berg A. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group protocol ALL-7 (1988-1991). Blood. 1999 Aug 15;94(4):1226-36. [http://www.bloodjournal.org/content/94/4/1226.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/10438710 PubMed]
−
==Imatinib & Prednisone {{#subobject:4f7d91|Regimen=1}}==
+
#'''ALL-BFM 90:''' Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H; German-Austrian-Swiss ALL-BFM Study Group. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000 Jun 1;95(11):3310-22. [http://www.bloodjournal.org/content/95/11/3310.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10828010 PubMed]
 +
##'''Pooled subgroup analysis:''' Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108 PubMed]
 +
#'''DCLSG ALL-8:''' Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. [https://doi.org/10.1038/sj.leu.2402489 link to original article] '''refers to ALL-BFM 90 protocol''' [https://pubmed.ncbi.nlm.nih.gov/12040440 PubMed]
 +
#'''COG CCG-1961:''' Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. [http://www.bloodjournal.org/content/111/5/2548.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2254538/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18039957 PubMed] NCT00002812
 +
#'''ALL-BFM 95:''' Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. [http://www.bloodjournal.org/content/111/9/4477.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18285545 PubMed]
 +
##'''Pooled subgroup analysis:''' Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. [https://doi.org/10.1200/JCO.2006.06.2679 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17179108 PubMed]
 +
#'''COG A5971:''' Termuhlen AM, Smith LM, Perkins SL, Lones M, Finlay JL, Weinstein H, Gross TG, Abromowitch M. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012 Dec 15;59(7):1229-33. Epub 2012 Apr 5. [https://doi.org/10.1002/pbc.24149 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/22488718/ PubMed] NCT00004228
 +
#'''ALL IC-BFM 2002:''' Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014 Jan 20;32(3):174-84. Epub 2013 Dec 16. [https://doi.org/10.1200/jco.2013.48.6522 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24344215/ PubMed] NCT00764907
 +
==DOLP (Prednisolone) {{#subobject:3c7jg7|Regimen=1}}==
 +
DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisolone
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:589c26|Variant=1}}===
+
===Regimen variant #1, 30/10,000/1.5/60 {{#subobject:087cg2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ de Moerloose et al. 2010 (EORTC CLG 58951)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Dexamethasone_99|Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|}
 +
''Note: see paper for details on CNS therapy and dose adjustments based on risk; these instructions include a 7-day pre-phase and are for AR1 patients.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV once per day on days 8, 15, 22, 29
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 8, 15, 22, 29
 +
*[[Asparaginase (Elspar)]] 10,000 units (route not specified) once per day on days 12, 15, 18, 22, 25, 29, 32, 35
 +
====Glucocorticoid therapy====
 +
*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, then tapered over 9 days
 +
'''5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See paper for details
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 45/6000/1.5/40 {{#subobject:b39731|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ Chiaretti et al. 2016 (GIMEMA LAL 0904)]
+
|[https://doi.org/10.1016/014067369292103M Chessells et al. 1992 (UK MRC ALLX)]
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
+
''Note: exact days for L-asparaginase were not specified in the protocol.''
−
====Preceding treatment====
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[B-cell acute lymphoblastic leukemia#Prednisone_monotherapy|Pre-phase prednisone]]
+
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup> IV once per day on days 1 & 2
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29
 +
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> SC once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
 +
====Glucocorticoid therapy====
 +
*[[Prednisolone (Millipred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 28
 +
'''29-day course'''
 
</div>
 
</div>
−
<div class="toccolours" style="background-color:#b3e2cd">
+
<div class="toccolours" style="background-color:#cbd5e7">
−
====Targeted therapy====
+
====Subsequent treatment====
−
*[[Imatinib (Gleevec)]] 600 mg PO once per day on days 1 to 50
+
*Intensification (randomized) or [[#Cyclophosphamide_.26_TBI.2C_then_allo_HSCT|Cy/TBI with allo HSCT]], depending on donor availability
 +
</div></div>
 +
===References===
 +
#'''UK MRC ALLX:''' Chessells JM, Bailey C, Wheeler K, Richards SM. Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X. Lancet. 1992 Sep 5;340(8819):565-8. [https://doi.org/10.1016/014067369292103M link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1355153 PubMed]
 +
##'''Update:''' Chessells JM, Bailey C, Richards SM; Medical Research Council Working Party on Childhood Leukaemia. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Lancet. 1995 Jan 21;345(8943):143-8. [https://doi.org/10.1016/S0140673695901647 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7823668 PubMed]
 +
#'''EORTC CLG 58951:''' De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. Epub 2010 Apr 20. [http://www.bloodjournal.org/content/116/1/36.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2904579/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20407035 PubMed] NCT00003728
 +
##'''Update:''' Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrand Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer. Dexamethasone (6 mg/m<sup>2</sup>/day) and prednisolone (60 mg/m<sup>2</sup>/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. [http://www.haematologica.org/content/99/7/1220.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4077084/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24727815 PubMed]
 +
##'''Update:''' Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group (CLG) of the European Organisation for Research and Treatment of Cancer. Prolonged versus standard native E coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. Epub 2017 Jul 27. [http://www.haematologica.org/content/102/10/1727.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622857/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28751566 PubMed]
 +
==Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone {{#subobject:127ca2|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:nc303e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.18.01877 Albertsen et al. 2019 (NOPHO ALL2008)]
 +
|2008-2016
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
''See protocol for initiation dependencies of 6-MP and pegaspargase.''
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 & 22
 +
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 30 to 35
 +
*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once on day 30
 +
*[[Vincristine (Oncovin)]] by the following age-based criteria:
 +
**Younger than 18: 2 mg/m<sup>2</sup> (maximum dose of 2.5 mg) IV once per day on days 1, 8, 15, 22, 29
 +
**18 or older: 2 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22, 29
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 24, then tapered and stopped at day 32
+
*[[Prednisolone (Millipred)]] 20 mg/m<sup>2</sup> PO three times per day on days 1 to 29, then 10 mg/m<sup>2</sup> PO three times per day on days 30 to 32, then 5 mg/m<sup>2</sup> PO three times per day on days 33 to 35, then 2.5 mg/m<sup>2</sup> PO three times per day on days 36 to 38
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 21 & 35
+
*[[Methotrexate (MTX)]] by the following age-based criteria:
−
'''50-day course'''
+
**Ages 1 to 1.9: 8 mg IT once per day on days 1, 8, 15, 29
 +
**Ages 2 to 2.9: 10 mg IT once per day on days 1, 8, 15, 29
 +
**Age 3 and older: 12 mg IT once per day on days 1, 8, 15, 29
 +
'''5-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#HAM_.26_Imatinib|HAM & imatinib]] consolidation
+
*See protocol for details of treatment beyond induction
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GIMEMA LAL 0904:''' Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. [http://www.haematologica.org/content/101/12/1544.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27515250 PubMed] NCT00458848
+
#'''NOPHO ALL2008:''' Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, Frandsen TL, Wolthers BO, Heyman M, Schmiegelow K. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol. 2019 Jul 1;37(19):1638-1646. Epub 2019 Apr 12. [https://doi.org/10.1200/JCO.18.01877 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/30978155 PubMed] NCT00819351
−
==Imatinib, Vincristine, Dexamethasone {{#subobject:7daa66|Regimen=1}}==
+
==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone {{#subobject:h1gtbb|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:afaf32|Variant=1}}===
+
===Regimen {{#subobject:hgu1h7|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 17%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 15%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 17%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 17%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 17%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
! style="width: 17%" |[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
 +
|2005-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin.2C_L-Asparaginase.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_88|Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone]]
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoint of DFS
 +
| style="background-color:#1a9850" |Less anxiety
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/125/24/3711.long Chalandon et al. 2015 (GRAAPH-2005)]
+
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
−
|2006-2011
+
|2012-2015
−
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Hyper-CVAD.2FMA_.26_Imatinib|Hyper-CVAD/MA & Imatinib]]
+
|[[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_99|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of MMR rate after cycle 2
+
| style="background-color:#d3d3d3" |Not reported
 +
|
 
|-
 
|-
 
|}
 
|}
 +
''Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001. Day numbering takes into account the pre-phase.''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[B-cell acute lymphoblastic leukemia#Prednisone_monotherapy|Pre-phase prednisone]]
+
*[[#Methylprednisolone_monotherapy|Methylprednisolone]] pre-phase
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Imatinib (Gleevec)]] 400 mg PO twice per day on days 1 to 28
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
+
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 5
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 6
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 7
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
 
====Glucocorticoid therapy====
 
====Glucocorticoid therapy====
−
*[[Dexamethasone (Decadron)]] 40 mg/day PO on days 1, 2, 8, 9, 15, 16, 22, 23
+
*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 4 to 32
 
====Supportive therapy====
 
====Supportive therapy====
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV or SC once per day from day 15 until ANC recovery
+
*[[Dexrazoxane (Zinecard)]] 300 mg/m<sup>2</sup> IV once per day on days 4 & 5
 
'''28-day course'''
 
'''28-day course'''
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT once per day on days 1 & 18
 +
**Day 18 dose is admixed with MTX and HC
 +
*[[Methotrexate (MTX)]] IT once per day on days 18 & 32
 +
**Day 18 dose is admixed with Ara-C and HC
 +
*[[Hydrocortisone (Cortef)]] IT once on day 18, admixed with Ara-C and MTX
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Doxorubicin.2C_Mercaptopurine.2C_Methotrexate.2C_Vincristine|Doxorubicin, Mercaptopurine, Methotrexate, Vincristine]] consolidation (IA)
 +
</div></div>
 +
===References===
 +
#'''DFCI 05-001:''' Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] NCT00400946
 +
##'''Pooled update:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed]
 +
#'''DFCI 11-001:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] NCT01574274
 +
## '''Update:''' Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. [https://doi.org/10.1200/jco.20.03692 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34228505/ PubMed]
 +
==Pegaspargase, Vincristine, Dexamethasone {{#subobject:15hgu1|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:e8uyt1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ Maloney et al. 2019 (COG AALL0331)]
 +
|2005-2010
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
|-
 +
|}
 +
''Note: there are very minor differences in timing between protocols; see papers for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT once at some point between days -2 and 1
 +
*[[Methotrexate (MTX)]] IT once per day on days 8 & 29
 +
'''35-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
 +
*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
 +
</div></div>
 +
===References===
 +
#'''COG AALL0331:''' Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. [https://doi.org/10.1200/jco.19.01086 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7030893/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31825704/ PubMed] NCT00103285
 +
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
 +
==Pegaspargase, Vincristine, Prednisone {{#subobject:158722|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:e8uhb3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://www.bloodjournal.org/content/99/6/1986.long Avramis et al. 2002 (CCG 1962)]
 +
|1997-1998
 +
| style="background-color:#1a9851" |Randomized (E-RT-switch-ic)
 +
|[[B-cell_acute_lymphoblastic_leukemia_-_historical#L-Asparaginase.2C_Vincristine.2C_Prednisone|L-Asparaginase, Vincristine, Prednisone]]
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoint of EFS
 +
|-
 +
|}
 +
''Note: the primary endpoint of CCG 1962 was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]]
 +
*[[Vincristine (Oncovin)]]
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]]
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#HAM_.26_Imatinib|HAM & imatinib]] consolidation
+
*See protocol for details of treatment beyond induction
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GRAAPH-2005:''' Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. [http://www.bloodjournal.org/content/125/24/3711.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25878120 PubMed] NCT00327678
+
#'''CCG 1962:''' Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep 1;100(5):1531. [http://www.bloodjournal.org/content/99/6/1986.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11877270 PubMed]
−
=Consolidation after upfront therapy (including post-remission therapy)=
+
=Early intensification therapy=
−
''Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.''
+
==Cyclophosphamide, Etoposide, Methotrexate {{#subobject:6ahzn6|Regimen=1}}==
−
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
 
−
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6ca28d|Variant=1}}===
+
===Regimen {{#subobject:16fxc9|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5145261/ Dreyer et al. 2014 (COG P9407)]
−
|1976-1977
+
|2001-2006
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.1994.12.12.2580 Sebban et al. 1994 (LALA 87)]
+
|[https://doi.org/10.1038/s41375-021-01177-6 Brown et al. 2021 (COG AALL0631)]
−
|1986-1991
+
|2008-2014
−
|style="background-color:#1a9851"|Phase 3 (E-esc)
+
| style="background-color:#1a9851" |Phase 3 (C)
−
|Chemotherapy or Auto HSCT
+
|[[#Cyclophosphamide.2C_Etoposide.2C_Lestaurtinib.2C_Methotrexate_77|Cyclophosphamide, Etoposide, Lestaurtinib, Methotrexate]]
−
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup>
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
−
|-
 
−
|[https://doi.org/10.1200/jco.2004.10.050 Thomas et al. 2004 (LALA-94)]
 
−
|1994-2002
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>While LALA 87 was a negative trial, the subgroup of high-risk ALL, including Ph+ ALL, appeared to have a superior outcome in the allo HSCT arm.''
+
<div class="toccolours" style="background-color:#fdcdac">
−
{{#lst:Allogeneic HSCT|6ca28d}}
+
====Biomarker eligibility criteria====
−
====Immunotherapy====
+
*COG AALL0631: KMT2A rearrangement
−
*[[Allogeneic stem cells]]
+
<div class="toccolours" style="background-color:#cbd5e8">
−
'''Stem cells transfused on day 0'''
+
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Preceding treatment====
 +
*Induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 300 mg/m<sup>2</sup> IV over 30 minutes once per day on days 15 to 19
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 2 hours once per day on days 15 to 19
 +
*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV over 20 minutes, then 3800 mg/m<sup>2</sup> IV continuous infusion over 23 hours and 40 minutes on days 1 & 8 (total dose: 8000 mg/m<sup>2</sup>)
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Reinduction
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
+
#'''COG P9407:''' Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, Harvey RC, Chen IM, Behm FG, Pullen J, Wood BL, Carroll AJ, Heerema NA, Felix CA, Robinson B, Reaman GH, Salzer WL, Hunger SP, Carroll WL, Camitta BM. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015 Mar;62(3):419-26. Epub 2014 Nov 14. [https://doi.org/10.1002/pbc.25322 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5145261/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25399948/ PubMed] NCT00002756
−
# '''LALA 87:''' Sebban C, Lepage E, Vernant JP, Gluckman E, Attal M, Reiffers J, Sutton L, Racadot E, Michallet M, Maraninchi D, Dreyfus F, Fiere D; French Group of Therapy of Adult Acute Lymphoblastic Leukemia. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. J Clin Oncol. 1994 Dec;12(12):2580-7. [https://doi.org/10.1200/JCO.1994.12.12.2580 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7989932 PubMed]
+
#'''COG AALL0631:''' Brown PA, Kairalla JA, Hilden JM, Dreyer ZE, Carroll AJ, Heerema NA, Wang C, Devidas M, Gore L, Salzer WL, Winick NJ, Carroll WL, Raetz EA, Borowitz MJ, Small D, Loh ML, Hunger SP. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631. Leukemia. 2021 May;35(5):1279-1290. Epub 2021 Feb 23. Erratum in: Leukemia. 2021 Apr 12. [https://doi.org/10.1038/s41375-021-01177-6 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33623141/ PubMed] NCT00557193
−
## '''Update:''' Thiebaut A, Vernant JP, Degos L, Huguet FR, Reiffers J, Sebban C, Lepage E, Thomas X, Fière D. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation: a follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am. 2000 Dec;14(6):1353-66. [https://doi.org/10.1016/s0889-8588(05)70190-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11147227 PubMed]
+
==Mercaptopurine & Methotrexate {{#subobject:6ad6d6|Regimen=1}}==
−
# '''LALA-94:''' Thomas X, Boiron JM, Huguet F, Dombret H, Bradstock K, Vey N, Kovacsovics T, Delannoy A, Fegueux N, Fenaux P, Stamatoullas A, Vernant JP, Tournilhac O, Buzyn A, Reman O, Charrin C, Boucheix C, Gabert J, Lhéritier V, Fiere D. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol. 2004 Oct 15;22(20):4075-86. Epub 2004 Sep 7. [https://doi.org/10.1200/jco.2004.10.050 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15353542 PubMed] NCT00002700
 
−
## '''Update:''' Vey N, Thomas X, Picard C, Kovascovicz T, Charin C, Cayuela JM, Dombret H, Dastugue N, Huguet F, Bastard C, Stamatoulas A, Giollant M, Tournilhac O, Macintyre E, Buzyn A, Bories D, Kuentz M, Dreyfus F, Delannoy A, Raynaud S, Gratecos N, Bordessoule D, de Botton S, Preudhomme C, Reman O, Troussard X, Pigneux A, Bilhou C, Vernant JP, Boucheix C, Gabert J; GET-LALA Group; Swiss Group for Clinical Cancer Research. Allogeneic stem cell transplantation improves the outcome of adults with t(1;19)/E2A-PBX1 and t(4;11)/MLL-AF4 positive B-cell acute lymphoblastic leukemia: results of the prospective multicenter LALA-94 study. Leukemia. 2006 Dec;20(12):2155-61. Epub 2006 Oct 12. [https://doi.org/10.1038/sj.leu.2404420 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17039234 PubMed]
 
−
==Dasatinib & Blinatumomab {{#subobject:9ljgc84|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5e6uyh8|Variant=1}}===
+
===Regimen {{#subobject:5b0ec9|Variant=1}}===
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 20%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1998.16.1.246 Mahoney et al. 1998 (POG 9005)]
 +
|1991-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Mercaptopurine_.26_Methotrexate|6-MP & MTX]]; LDMTX/IVMP
 +
| style="background-color:#91cf60" |Seems to have superior CCR
 
|-
 
|-
−
|[https://doi.org/10.1056/nejmoa2016272 Foà et al. 2020 (GIMEMA LAL2116)]
+
|[https://www.nature.com/articles/2402132 Lauer et al. 2001 (POG 9006)]
−
|2017-2019
+
|1991-1994
−
| style="background-color:#91cf61" |Phase 2
+
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Intensive chemotherapy
 +
| style="background-color:#fee08b" |Might have inferior EFS
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Dasatinib_.26_Prednisone|Dasatinib & Prednisone]] induction
+
*POG 9006: [[#DOLP|DOLP]] induction
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 140 mg PO once per day
+
*[[Mercaptopurine (6-MP)]]
−
====Immunotherapy====
+
*[[Methotrexate (MTX)]]
−
*[[Blinatumomab (Blincyto)]] 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
+
</div>
−
'''42-day cycle for at least 2 and up to 5 cycles'''
+
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*POG 9006: [[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]] maintenance
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GIMEMA LAL2116:''' Foà R, Bassan R, Vitale A, Elia L, Piciocchi A, Puzzolo MC, Canichella M, Viero P, Ferrara F, Lunghi M, Fabbiano F, Bonifacio M, Fracchiolla N, Di Bartolomeo P, Mancino A, De Propris MS, Vignetti M, Guarini A, Rambaldi A, Chiaretti S; GIMEMA Investigators. Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults. N Engl J Med. 2020 Oct 22;383(17):1613-1623. [https://doi.org/10.1056/nejmoa2016272 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33085860/ PubMed] NCT02744768
+
#'''POG 9005:''' Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B. Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol. 1998 Jan;16(1):246-54. [https://doi.org/10.1200/JCO.1998.16.1.246 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9440749 PubMed]
−
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
+
#'''POG 9006:''' Lauer SJ, Shuster JJ, Mahoney DH Jr, Winick N, Toledano S, Munoz L, Kiefer G, Pullen JD, Steuber CP, Camitta BM. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia. 2001 Jul;15(7):1038-45. [https://www.nature.com/articles/2402132 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11455971 PubMed]
 +
=Consolidation after upfront therapy (including post-remission therapy)=
 +
''Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.''
 +
==AALL0232 consolidation {{#subobject:065gg9|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:e4216b|Variant=1}}===
+
===Regimen {{#subobject:342b6d|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
 
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
−
{{#lst:Allogeneic HSCT|e4216b}}
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 29
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM or IV once per day on days 15 & 43
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 15, 22, 43, 50
 +
'''50-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*6-MP, Capizzi MTX, Pegaspargase, Vincristine interim maintenance versus [[#Mercaptopurine.2C_Methotrexate.2C_Vincristine_2|6-MP, HD-MTX, Vincristine interim]] maintenance
 +
</div></div>
 +
===References===
 +
#'''COG AALL0232:''' Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27114587 PubMed] NCT00075725
 +
==Augmented BFM consolidation {{#subobject:065ff9|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:687b6d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199806043382304 Nachman et al. 1998]
 +
|1991-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|Standard BFM consolidation
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|}
 +
''Unlikely to be completed, but of historic interest.''
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]]
 +
*[[Cytarabine (Ara-C)]]
 +
*[[Asparaginase (Elspar)]]
 +
*[[Mercaptopurine (6-MP)]]
 +
*[[Vincristine (Oncovin)]]
 +
</div></div>
 +
===References===
 +
#Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. [https://doi.org/10.1056/NEJM199806043382304 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9614257 PubMed]
 +
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
 +
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6ca28d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[http://www.bloodjournal.org/content/54/2/468.long Thomas et al. 1979]
 +
|1976-1977
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
{{#lst:Allogeneic HSCT|6ca28d}}
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Allogeneic stem cells]]
 
*[[Allogeneic stem cells]]
Line 623: Line 2,028:
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+
#Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. [http://www.bloodjournal.org/content/54/2/468.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/378292 PubMed]
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
 
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
 
−
==HAM & Imatinib {{#subobject:81dbe6|Regimen=1}}==
 
−
HAM & Imatinib: '''<u>H</u>'''igh-dose '''<u>A</u>'''ra-C (Cytarabine) & '''<u>M</u>'''itoxantrone & Imatinib
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:739821|Variant=1}}===
+
===Regimen {{#subobject:45f841|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S014067360566998X Balduzzi et al. 2005]
 +
|1995-2000
 +
| style="background-color:#1a9851" |Quasi-randomized
 +
|Chemotherapy
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/109/4/1408.long de Labarthe et al. 2006 (GRAAPH-2003)]
+
|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
−
|style="background-color:#91cf61"|Phase 2
+
|2003-2011
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ Chiaretti et al. 2016 (GIMEMA LAL 0904)]
+
|}
−
|style="background-color:#91cf61"|Phase 2
+
{{#lst:Allogeneic HSCT|45f841}}
 +
====Immunotherapy====
 +
*[[Allogeneic stem cells]]
 +
'''Stem cells transfused on day 0'''
 +
</div></div>
 +
===References===
 +
#Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. [https://doi.org/10.1016/S014067360566998X link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16112299 PubMed]
 +
#'''ALL-SCT-BFM-2003:''' Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. [https://doi.org/10.1200/jco.2014.58.9747 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25753432 PubMed] NCT01423747
 +
==Mercaptopurine & Vincristine {{#subobject:171gc1|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1ygvt1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Imatinib_.26_Prednisone|Imatinib & Prednisone]] induction
+
*[[#Pegaspargase.2C_Vincristine.2C_Dexamethasone|Pegaspargase, Vincristine, Dexamethasone]] induction
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1 to 4 (total dose: 24,000 mg/m<sup>2</sup>)
+
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup>/day PO on days 1 to 28
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 to 3
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once on day 1
−
====Targeted therapy====
 
−
*[[Imatinib (Gleevec)]] 600 mg PO once per day
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 15 mg IT repeated for a total of 14 doses (including all phases of treatment)
+
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15
−
'''4-day course; total duration of imatinib is not specified'''
+
'''28-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*GIMEMA LAL 0904, patients who did not achieve CR with induction: [[#Cytarabine.2C_Idarubicin.2C_Imatinib|Cytarabine, idarubicin, imatinib late intensification]]
+
*[[#Methotrexate_.26_Vincristine|MTX & Vincristine]] interim maintenance
−
*GIMEMA LAL 0904, patients who achieve CR after consolidation: allogeneic hematopoietic stem cell transplant, or autologous HSCT if no donor available (details not provided)
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GRAAPH-2003:''' de Labarthe A, Rousselot P, Huguet-Rigal F, Delabesse E, Witz F, Maury S, Réa D, Cayuela JM, Vekemans MC, Reman O, Buzyn A, Pigneux A, Escoffre M, Chalandon Y, MacIntyre E, Lhéritier V, Vernant JP, Thomas X, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study. Blood. 2007 Feb 15;109(4):1408-13. Epub 2006 Oct 24. [http://www.bloodjournal.org/content/109/4/1408.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/17062730 PubMed]
+
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
−
## '''Update:''' Tanguy-Schmidt A, Rousselot P, Chalandon Y, Cayuela JM, Hayette S, Vekemans MC, Escoffre M, Huguet F, Réa D, Delannoy A, Cahn JY, Vernant JP, Ifrah N, Dombret H, Thomas X. Long-term follow-up of the imatinib GRAAPH-2003 study in newly diagnosed patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: a GRAALL study. Biol Blood Marrow Transplant. 2013 Jan;19(1):150-5. Epub 2012 Sep 6. [https://www.bbmt.org/article/S1083-8791(12)00355-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22960387 PubMed]
+
=Interim maintenance=
−
# '''GIMEMA LAL 0904:''' Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. [http://www.haematologica.org/content/101/12/1544.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27515250 PubMed] NCT00458848
+
==Mercaptopurine, Methotrexate, Vincristine {{#subobject:72025a|Regimen=1}}==
−
==Nilotinib-based consolidation {{#subobject:2b1576|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol {{#subobject:e153b6|Variant=1}}===
+
===Regimen {{#subobject:b9e09c|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015 (AMC-UUCM-2008-0310)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ Larsen et al. 2016 (COG AALL0232)]
−
|style="background-color:#91cf61"|Phase 2
+
|2004-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Mercaptopurine.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine_88|6-MP, Capizzi MTX, Pegaspargase, Vincristine]]
 +
| style="background-color:#1a9850" |Superior EFS
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Daunorubicin.2C_Vincristine.2C_Prednisolone.2C_Nilotinib|Daunorubicin, Vincristine, Prednisolone, Nilotinib]] induction
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, consolidation A (Cycle 1)====
+
====Chemotherapy====
−
*[[Daunorubicin (Cerubidine)]] 45 mg/m<sup>2</sup>/day IV continuous infusion over 48 hours, started on day 1 (total dose: 90 mg/m<sup>2</sup>)
+
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1 & 8
+
*[[Methotrexate (MTX)]] 5000 mg/m<sup>2</sup> IV once per day on days 1, 15, 29, 43
−
====Glucocorticoid therapy, consolidation A (Cycle 1)====
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
−
*[[Prednisolone (Millipred)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14
+
====CNS therapy====
−
====Targeted therapy, consolidation A (Cycle 1)====
+
*[[Methotrexate (MTX)]] once per day on days 1 & 29
−
*[[Nilotinib (Tasigna)]] 400 mg PO twice per day
 
−
====Chemotherapy, consolidation B (Cycles 2 & 4)====
 
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 4
 
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 3 hours once per day on days 1 to 4
 
−
====Targeted therapy, consolidation B (Cycles 2 & 4)====
 
−
*[[Nilotinib (Tasigna)]] 400 mg PO twice per day
 
−
====Chemotherapy, consolidation C (Cycles 3 & 5)====
 
−
*[[Methotrexate (MTX)]] 220 mg/m<sup>2</sup> IV bolus once per day on days 1 & 15, then 60 mg/m<sup>2</sup>/hr IV continuous infusion over 36 hours (total dose per cycle: 2380 mg/m<sup>2</sup>)
 
−
====Targeted therapy, consolidation C (Cycles 3 & 5)====
 
−
*[[Nilotinib (Tasigna)]] 400 mg PO twice per day
 
−
====Supportive therapy, consolidation C (Cycles 3 & 5)====
 
−
*[[Folinic acid (Leucovorin)]] 50 mg/m<sup>2</sup> IV every 6 hours x 3 doses, then PO (frequency/dose not specified) until serum methotrexate level less than 0.05
 
−
'''Duration of each cycle of consolidation is not specified but is presumably based on toxicities and count recovery'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#Nilotinib_monotherapy|Nilotinib]] maintenance
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26065651 PubMed] NCT00844298
+
#'''COG AALL0232:''' Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. [https://doi.org/10.1200/JCO.2015.62.4544 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4981974/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27114587 PubMed] NCT00075725
−
=Late intensification=
+
==Methotrexate & Vincristine {{#subobject:0ae09f|Regimen=1}}==
−
==Cytarabine, Idarubicin, Imatinib {{#subobject:7c1f36|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:8578fe|Variant=1}}===
+
===Regimen {{#subobject:57f39d|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ Chiaretti et al. 2016 (GIMEMA LAL 0904)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ Matloub et al. 2011 (COG CCG-1991)]
−
|style="background-color:#91cf61"|Phase 2
+
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Dexamethasone_88|6-MP, MTX, Vincristine, Dexamethasone]]
 +
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
 +
|2010-2018
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
 
|}
 
|}
−
''This is for patients who did not achieve CHR with induction.''
 
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#HAM_.26_Imatinib|HAM & Imatinib]] consolidation
+
*COG AALL0932: [[#Mercaptopurine_.26_Vincristine|6-MP & Vincristine]] consolidation
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV once per day on days 1 to 5
+
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
−
*[[Idarubicin (Idamycin)]] 40 mg/m<sup>2</sup> IV once on day 3
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
−
====Targeted therapy====
 
−
*[[Imatinib (Gleevec)]] 600 mg PO once per day
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 15 mg IT repeated for a total of 14 doses (including all phases of treatment)
+
*[[Methotrexate (MTX)]] IT once on day 31
−
'''5-day course; total duration of imatinib is not specified'''
+
'''8-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*Patients who achieve CR: allogeneic hematopoietic stem cell transplant, or autologous HSCT if no donor available. Details not provided.
+
*COG AALL0932: [[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''GIMEMA LAL 0904:''' Chiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foà R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. [http://www.haematologica.org/content/101/12/1544.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5479612/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27515250 PubMed] NCT00458848
+
#'''COG CCG-1991:''' Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. [http://www.bloodjournal.org/content/118/2/243.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3138679/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21562038 PubMed] NCT00005945
−
=Maintenance after upfront therapy=
+
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
−
==Dasatinib monotherapy {{#subobject:0327e6|Regimen=1}}==
+
=Delayed intensification=
 +
==AALL0932 delayed intensification {{#subobject:17185g|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:2c1a45|Variant=1}}===
+
===Regimen {{#subobject:1y47gc|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 33%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
+
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
−
|style="background-color:#91cf61"|Phase 2
+
|2010-2018
−
|-
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ Ravandi et al. 2016 (SWOG S0805)]
 
−
|style="background-color:#91cf61"|Phase 2
 
 
|-
 
|-
 
|}
 
|}
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Dasatinib.2C_Vincristine.2C_Prednisone|Dasatinib, Vincristine, Prednisone]] x 2y
+
*[[#Methotrexate_.26_Vincristine|MTX & Vincristine interim]] maintenance
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 100 mg PO once per day
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once on day 29
−
'''Continued indefinitely'''
+
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup>/day SC or IV on days 29 to 32, 36 to 39
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 4
 +
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup>/day PO on days 29 to 42
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup>/day PO on days 1 to 7, 15 to 21
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1 & 29
 +
'''8-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Methotrexate_.26_Vincristine_2|MTX & Vincristine]] interim maintenance II
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed] NCT00390793
+
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
−
## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
+
=Interim maintenance II=
−
# '''SWOG S0805:''' Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. [http://www.bloodadvances.org/content/1/3/250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29046900 PubMed] NCT00792948
+
==Methotrexate & Vincristine {{#subobject:ajbz5g|Regimen=1}}==
−
==Dasatinib, Vincristine, Prednisone {{#subobject:71a41c|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:2efb7e|Variant=1}}===
+
===Regimen {{#subobject:18guaz|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 33%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ Ravandi et al. 2010 (MDACC 2006-0478)]
+
|[https://doi.org/10.1200/jco.20.00494 Angiolillo et al. 2021 (COG AALL0932)]
−
|style="background-color:#91cf61"|Phase 2
+
|2010-2018
−
|-
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ Ravandi et al. 2016 (SWOG S0805)]
 
−
|style="background-color:#91cf61"|Phase 2
 
 
|-
 
|-
 
|}
 
|}
−
''This is only offered to patients who achieved a CR. Maintenance therapy could be interrupted by provider's choice--typically only given to people with at least minimal residual disease (MRD) or more--in month 6 and 13 to give Hyper-CVAD Part A x 1 cycle.''
+
''Note: starting dose of the systemic MTX is 2/3 of the MTD from interim maintenance I; dosage below assumes that the final maximum dose was tolerated.''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Hyper-CVAD.2FMA_.26_Dasatinib|Hyper-CVAD/MA & Dasatinib]] x 8
+
*[[#AALL0932_delayed_intensification|AALL0932 delayed intensification]]
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Dasatinib (Sprycel)]] 100 mg PO once per day
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+
*[[Methotrexate (MTX)]] 200 mg/m<sup>2</sup> IV once on day 1, then 250 mg/m<sup>2</sup> IV once on day 11, then 300 mg/m<sup>2</sup> IV once on day 21, then 350 mg/m<sup>2</sup> IV once on day 31, then 400 mg/m<sup>2</sup> IV once on day 41
−
====Glucocorticoid therapy====
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
−
*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
+
====CNS therapy, prophylaxis====
−
'''28-day cycle for 26 cycles (2 years)'''
+
*[[Methotrexate (MTX)]] IT once per day on days 1 & 31
 +
'''8-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Dasatinib_monotherapy|Dasatinib]] maintenance
+
*Randomization to one of four maintenance arms; see paper for details.
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MDACC 2006-0478:''' Ravandi F, O'Brien S, Thomas D, Faderl S, Jones D, Garris R, Dara S, Jorgensen J, Kebriaei P, Champlin R, Borthakur G, Burger J, Ferrajoli A, Garcia-Manero G, Wierda W, Cortes J, Kantarjian H. First report of phase 2 study of dasatinib with hyper-CVAD for the frontline treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. Blood. 2010 Sep 23;116(12):2070-7. Epub 2010 May 13. [http://www.bloodjournal.org/content/116/12/2070.long link to original article] '''contains dosing details in manuscript'''--parts of the protocol were not explicitly listed in this reference, which instead referred to Thomas et al. 2004 and Kantarjian et al. 2004 [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081177/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20466853 PubMed] NCT00390793
+
#'''COG AALL0932:''' Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. [https://doi.org/10.1200/jco.20.00494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33411585/ PubMed] NCT01190930
−
## '''Update:''' Ravandi F, O'Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, Burger JA, Rytting ME, Ferrajoli A, Wierda WG, Verstovsek S, Champlin R, Kebriaei P, McCue DA, Huang X, Jabbour E, Garcia-Manero G, Estrov Z, Kantarjian HM. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015 Dec 1;121(23):4158-64. Epub 2015 Aug 26. [https://doi.org/10.1002/cncr.29646 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666803/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26308885 PubMed]
+
=Maintenance after upfront therapy=
−
# '''SWOG S0805:''' Ravandi F, Othus M, O’Brien SM, Forman SJ, Ha CS, Wong JY, Tallman MS, Paietta E, Racevskis J, Uy GL, Horowitz M, Takebe N, Little R, Borate U, Kebriaei P, Kingsbury L, Kantarjian HM, Radich JP, Erba HP, Appelbaum FR. US intergroup study of chemotherapy plus dasatinib and allogeneic stem cell transplant in Philadelphia chromosome positive ALL. Blood Adv. 2016;1(3):250-259. [http://www.bloodadvances.org/content/1/3/250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642915/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29046900 PubMed] NCT00792948
+
==Mercaptopurine & Methotrexate {{#subobject:6366a6|Regimen=1}}==
−
==Imatinib, Vincristine, Prednisone {{#subobject:50b727|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:7c2b3d|Variant=1}}===
+
===Regimen {{#subobject:e46d92|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/103/12/4396.long Thomas et al. 2003]
+
|[https://doi.org/10.1200/JCO.2001.19.7.1935 Millot et al. 2001 (EORTC 58881)]
−
|2001-2003
+
|1990-1996
−
|style="background-color:#91cf61"|Phase 2
+
| style="background-color:#1a9851" |Phase 3 (C)
−
| style="background-color:#d3d3d3" |
+
|[[#Mercaptopurine_.26_Methotrexate_2|6-MP & MTX]]; IV 6-MP & PO MTX
−
| style="background-color:#d3d3d3" |
+
| style="background-color:#1a9850" |Superior DFS<sup>1</sup>
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/125/24/3711.long Chalandon et al. 2015 (GRAAPH-2005)]
+
|[https://doi.org/10.1016/S0140-6736(07)60073-7 Conter et al. 2007 (I-BFM-SG IR ALL)]
−
|2006-2011
+
|1995-2000
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#Imatinib.2C_Vincristine.2C_Dexamethasone|Imatinib, Vincristine, Dexamethasone]]
+
|[[#D-OMP_99|D-OMP]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of MMR rate after cycle 2
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>Reported efficacy for EORTC 58881 is based on the 2005 update.''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#Hyper-CVAD.2FMA_.26_Imatinib|Hyper-CVAD/MA & Imatinib]] x 8
+
*I-BFM-SG IR ALL: BFM re-induction
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
 
−
*[[Imatinib (Gleevec)]] 600 mg PO once per day on days 1 to 28
 
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Vincristine (Oncovin)]] 2 mg IV once on day 1
+
*[[Mercaptopurine (6-MP)]] 50 mg/m<sup>2</sup> PO once per day
−
====Glucocorticoid therapy====
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO once on day 1
−
*[[Prednisone (Sterapred)]] 200 mg PO once per day on days 1 to 5
+
'''7-day cycle for 74 cycles or a total of 2 years from start of treatment'''
−
'''28-day cycle for 5 cycles, then Hyper-CVAD & Imatinib Part A x 1 cycle, then 28-day cycle for 6 cycles, then Hyper-CVAD & Imatinib Part A x 1 cycle'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Thomas DA, Faderl S, Cortes J, O'Brien S, Giles FJ, Kornblau SM, Garcia-Manero G, Keating MJ, Andreeff M, Jeha S, Beran M, Verstovsek S, Pierce S, Letvak L, Salvado A, Champlin R, Talpaz M, Kantarjian H. Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood. 2004 Jun 15;103(12):4396-407. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/12/4396.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14551133 PubMed]
+
#'''EORTC 58881:''' Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A, Lutz P, Mechinaud F, Robert A, Boutard P, Marguerite G, Ferster A, Plouvier E, Rialland X, Behard C, Plantaz D, Dresse MF, Philippet P, Norton L, Thyss A, Dastugue N, Waterkeyn C, Vilmer E, Otten J; Children's Leukemia Cooperative Group of the European Organiztaion for Research and Treatment of Cancer. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organisation for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol. 2001 Apr 1;19(7):1935-42. [https://doi.org/10.1200/JCO.2001.19.7.1935 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11283125 PubMed]
−
## '''Update:''' Daver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O' Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the frontline treatment of adult patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. Epub 2015 Feb 14. [http://www.haematologica.org/content/100/5/653 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420214/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25682595 PubMed]
+
##'''Update:''' Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002 Apr 15;99(8):2734-9. [http://www.bloodjournal.org/content/99/8/2734.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/11929760 PubMed]
−
# '''GRAAPH-2005:''' Chalandon Y, Thomas X, Hayette S, Cayuela JM, Abbal C, Huguet F, Raffoux E, Leguay T, Rousselot P, Lepretre S, Escoffre-Barbe M, Maury S, Berthon C, Tavernier E, Lambert JF, Lafage-Pochitaloff M, Lhéritier V, Chevret S, Ifrah N, Dombret H; Group for Research on Adult Acute Lymphoblastic Leukemia. Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia. Blood. 2015 Jun 11;125(24):3711-9. Epub 2015 Apr 15. Erratum in: Blood. 2015 Sep 3;126(10):1261. [http://www.bloodjournal.org/content/125/24/3711.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/25878120 PubMed] NCT00327678
+
##'''Update:''' van der Werff Ten Bosch J, Suciu S, Thyss A, Bertrand Y, Norton L, Mazingue F, Uyttebroeck A, Lutz P, Robert A, Boutard P, Ferster A, Plouvier E, Maes P, Munzer M, Plantaz D, Dresse MF, Philippet P, Sirvent N, Waterkeyn C, Vilmer E, Philippe N, Otten J. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005 May;19(5):721-6. [https://www.nature.com/articles/2403689 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15744348 PubMed]
−
==Nilotinib monotherapy {{#subobject:2a3276|Regimen=1}}==
+
#'''I-BFM-SG IR ALL:''' Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, Reiter A, Riehm H, Masera G, Schrappe M. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007 Jan 13;369(9556):123-31. [https://doi.org/10.1016/S0140-6736(07)60073-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17223475 PubMed] NCT00411541
 +
==Observation==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:f976b6|Variant=1}}===
+
===Regimen===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/126/6/746.long Kim et al. 2015 (AMC-UUCM-2008-0310)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416799/ Yang et al. 2021 (CCCG-ALL-2015)]
−
|style="background-color:#91cf61"|Phase 2
+
|2015-2020
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#Vincristine_.26_Dexamethasone_88|Vincristine & Dexamethasone]]
 +
| style="background-color:#eeee01" |Non-inferior EFS60
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
+
''No active maintenance treatment beyond 1 year. Patients in this study were required to be in continuous remission for 1 year after initial treatment.''
−
====Preceding treatment====
 
−
*[[#Nilotinib-based_consolidation|Nilotinib-based]] consolidation
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Targeted therapy====
 
−
*[[Nilotinib (Tasigna)]] 400 mg PO twice per day
 
−
'''2-year course'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''AMC-UUCM-2008-0310:''' Kim DY, Joo YD, Lim SN, Kim SD, Lee JH, Lee JH, Kim DH, Kim K, Jung CW, Kim I, Yoon SS, Park S, Ahn JS, Yang DH, Lee JJ, Lee HS, Kim YS, Mun YC, Kim H, Park JH, Moon JH, Sohn SK, Lee SM, Lee WS, Kim KH, Won JH, Hyun MS, Park J, Lee JH, Shin HJ, Chung JS, Lee H, Eom HS, Lee GW, Cho YU, Jang S, Park CJ, Chi HS, Lee KH; Adult Acute Lymphoblastic Leukemia Working Party of the Korean Society of Hematology. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Blood. 2015 Aug 6;126(6):746-56. Epub 2015 Jun 11. [http://www.bloodjournal.org/content/126/6/746.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26065651 PubMed] NCT00844298
+
#'''CCCG-ALL-2015:''' Yang W, Cai J, Shen S, Gao J, Yu J, Hu S, Jiang H, Fang Y, Liang C, Ju X, Wu X, Zhai X, Tian X, Wang N, Liu A, Jiang H, Jin R, Sun L, Yang M, Leung AWK, Pan K, Zhang Y, Chen J, Zhu Y, Zhang H, Li C, Yang JJ, Cheng C, Li CK, Tang J, Zhu X, Pui CH. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2021 Sep;22(9):1322-1332. Epub 2021 Jul 27. [https://doi.org/10.1016/s1470-2045(21)00328-4 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416799/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34329606/ PubMed] ChiCTR-IPR-14005706
 
=Relapsed or refractory=
 
=Relapsed or refractory=
 
==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
 
==Blinatumomab monotherapy {{#subobject:e7b2c6|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:2db105|Variant=1}}===
+
===Regimen {{#subobject:fd494b|Variant=1}}===
 
{| class="wikitable" style="width: 60%; text-align:center;"  
 
{| class="wikitable" style="width: 60%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 33%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 33%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2016.69.3531 Martinelli et al. 2017 (ALCANTARA)]
+
|[https://doi.org/10.1200/JCO.2016.67.3301 von Stackelberg et al. 2016 (MT103-205)]
−
|2014-2015
+
|2012-2014
−
|style="background-color:#91cf61"|Phase 2 (RT)
+
| style="background-color:#91cf61" |Phase 1/2 (RT)
 
|-
 
|-
 
|}
 
|}
 +
''Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Blinatumomab (Blincyto)]] as follows:
 
*[[Blinatumomab (Blincyto)]] as follows:
−
**Cycle 1: 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 651 mcg)
+
**Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
−
**Cycle 2 onwards: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
+
**Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)
−
'''6-week cycle for 2 to 5 cycles'''
+
'''42-day cycle for up to 5 cycles'''
−
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''ALCANTARA:''' Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, Fielding AK, Rambaldi A, Ritchie EK, Papayannidis C, Sterling LR, Benjamin J, Stein A. Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study. J Clin Oncol. 2017 Jun 1;35(16):1795-1802. Epub 2017 Mar 29. Erratum in: J Clin Oncol. 2017 Aug 10;35(23):2722. J Clin Oncol. 2017 Aug 20;35(24):2856. [https://doi.org/10.1200/JCO.2016.69.3531 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28355115 PubMed] NCT02000427
+
#'''MT103-205:''' von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. [https://doi.org/10.1200/JCO.2016.67.3301 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27998223 PubMed] NCT01471782
−
##'''Update:''' Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Rambaldi A, Ritchie EK, Papayannidis C, Tuglus CA, Morris JD, Stein A. Long-term follow-up of blinatumomab in patients with relapsed/refractory Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukaemia: Final analysis of ALCANTARA study. Eur J Cancer. 2021 Mar;146:107-114. Epub 2021 Feb 13. [https://doi.org/10.1016/j.ejca.2020.12.022 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33588145/ PubMed]
+
==CCE {{#subobject:f74969|Regimen=1}}==
−
==Bosutinib monotherapy {{#subobject:d66493|Regimen=1}}==
+
CCE: '''<u>C</u>'''lofarabine, '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''toposide
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:866932|Variant=1}}===
+
===Regimen {{#subobject:24f55b|Variant=1}}===
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916618/ Kantarjian et al. 2011 (Study 200)]
+
|[https://doi.org/10.1111/j.1365-2141.2009.07882.x Locatelli et al. 2009]
−
|style="background-color:#91cf61"|Phase 1/2
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
''Note: the dosing described is that reported for the phase 2 portion of the phase 1/2 study.''
+
''Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.''
−
<div class="toccolours" style="background-color:#b3e2cd">
+
====Chemotherapy====
−
====Targeted therapy====
+
*[[Clofarabine (Clolar)]] 40 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5, given first
−
*[[Bosutinib (Bosulif)]] 500 mg PO once per day, take with food
+
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
−
**If no grade 3 or higher drug-related toxicity occurs, dose can be escalated to 600 mg PO once per day if response is suboptimal. Suboptimal response defined as no complete hematologic response (CHR) by week 8 or complete cytogenetic response (CCyR) by week 12.
+
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
−
'''Continued indefinitely'''
+
====Supportive therapy====
 +
*Prophylactic [[:Category:Steroids|steroids]] used for patients with greater than 30 x 10<sup>9</sup> blasts/L in the peripheral blood prior to treatment
 +
'''5-day course'''
 +
''2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''Study 200:''' Cortes JE, Kantarjian HM, Brümmendorf TH, Kim DW, Turkina AG, Shen ZX, Pasquini R, Khoury HJ, Arkin S, Volkert A, Besson N, Abbas R, Wang J, Leip E, Gambacorti-Passerini C. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood. 2011 Oct 27;118(17):4567-76. Epub 2011 Aug 24. Erratum in: Blood. 2013 Oct 3;122(14):2524. [http://www.bloodjournal.org/content/118/17/4567.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916618/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21865346 PubMed] NCT00261846
+
#Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. [https://doi.org/10.1111/j.1365-2141.2009.07882.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19747360 PubMed]
−
## '''Update:''' Khoury HJ, Cortes JE, Kantarjian HM, Gambacorti-Passerini C, Baccarani M, Kim DW, Zaritskey A, Countouriotis A, Besson N, Leip E, Kelly V, Brümmendorf TH. Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure. Blood. 2012 Apr 12;119(15):3403-12. Epub 2012 Feb 27. [http://www.bloodjournal.org/content/119/15/3403.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916559/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22371878 PubMed]
+
==Clofarabine monotherapy {{#subobject:6befdc|Regimen=1}}==
−
## '''Update:''' Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brümmendorf TH, Porkka K, Martinelli G, Durrant S, Leip E, Kelly V, Turnbull K, Besson N, Gambacorti-Passerini C. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014 Feb 27;123(9):1309-18. Epub 2013 Dec 17. [http://www.bloodjournal.org/content/123/9/1309.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467890/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24345751 PubMed]
 
−
## '''Update:''' Gambacorti-Passerini C, Brümmendorf TH, Kim DW, Turkina AG, Masszi T, Assouline S, Durrant S, Kantarjian HM, Khoury HJ, Zaritskey A, Shen ZX, Jin J, Vellenga E, Pasquini R, Mathews V, Cervantes F, Besson N, Turnbull K, Leip E, Kelly V, Cortes JE. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. Epub 2014 Apr 28. [https://doi.org/10.1002/ajh.23728 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4173127/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24711212 PubMed]
 
−
## '''Update:''' Gambacorti-Passerini C, Kantarjian HM, Kim DW, Khoury HJ, Turkina AG, Brümmendorf TH, Matczak E, Bardy-Bouxin N, Shapiro M, Turnbull K, Leip E, Cortes JE. Long-term efficacy and safety of bosutinib in patients with advanced leukemia following resistance/intolerance to imatinib and other tyrosine kinase inhibitors. Am J Hematol. 2015 Sep;90(9):755-68. Epub 2015 Jun 1. [https://doi.org/10.1002/ajh.24034 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26040495 PubMed]
 
−
==Dasatinib monotherapy {{#subobject:e00998|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 70 mg twice per day {{#subobject:dd936a|Variant=1}}===
+
===Regimen {{#subobject:fc17b2|Variant=1}}===
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 33%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 33%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/110/7/2309.long Ottmann et al. 2007 (START-L)]
+
|[http://www.bloodjournal.org/content/103/3/784.long Jeha et al. 2003]
−
|2005
+
|2000-2002
−
|style="background-color:#91cf61"|Phase 2 (RT)
+
| style="background-color:#ffffbe" |Phase 1, <20 pts (RT)
−
|style="background-color:#d3d3d3"|
 
−
|style="background-color:#d3d3d3"|
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916944/ Kantarjian et al. 2009 (CA180-035)]
+
|[https://doi.org/10.1200/JCO.2005.03.8554 Jeha et al. 2006 (CLO212)]
−
|2005-2006
+
|2002-2004
−
|style="background-color:#1a9851"|Phase 3 (C)
+
| style="background-color:#91cf61" |Phase 2 (RT)
−
|[[#Dasatinib_monotherapy_2|Dasatinib]]; 140 mg once per day
 
−
|style="background-color:#ffffbf"|Inconclusive whether non-inferior MHR<sup>1</sup>
 
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for CA180-035 is based on the 2010 subgroup analysis.''
+
''Note: this dose was the MTD in Jeha et al. 2003.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 70 mg PO twice per day
+
*[[Clofarabine (Clolar)]] 52 mg/m<sup>2</sup> IV over 2 hours once per day on days 1 to 5
−
'''Continued indefinitely'''
+
'''2- to 6-week cycles, depending on response count recovery'''
−
</div></div><br>
+
</div></div>
 +
===References===
 +
#Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. [http://www.bloodjournal.org/content/103/3/784.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551141 PubMed]
 +
#'''CLO212:''' Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. [https://doi.org/10.1200/JCO.2005.03.8554 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16622268 PubMed] NCT00042341
 +
==DOLP {{#subobject:8804f2|Regimen=1}}==
 +
DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 140 mg/day {{#subobject:25da21|Variant=1}}===
+
===Regimen {{#subobject:a6fef6|Variant=1}}===
−
{| class="wikitable" style="color:white; background-color:#404040"
+
{| class="wikitable" style="width: 40%; text-align:center;"
−
|<small>'''FDA-recommended dose'''</small>
+
! style="width: 25%" |Study
 +
! style="width: 25%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM198607313150501 Rivera et al. 1986]
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Daunorubicin (Cerubidine)]]
 +
*[[Vincristine (Oncovin)]]
 +
*[[Asparaginase (Elspar)]]
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]]
 +
'''4-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See paper for details of treatment beyond induction
 +
</div></div>
 +
===References===
 +
#Rivera GK, Buchanan G, Boyett JM, Camitta B, Ochs J, Kalwinsky D, Amylon M, Vietti TJ, Crist WM; Pediatric Oncology Group. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group study. N Engl J Med. 1986 Jul 31;315(5):273-8. [https://doi.org/10.1056/NEJM198607313150501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3523250 PubMed]
 +
==Doxorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:1265yg|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:3gt03e|Variant=1}}===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 20%"|Study
+
! style="width: 20%" |Study
−
!style="width: 20%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 20%"|Comparator
+
! style="width: 20%" |Comparator
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916944/ Kantarjian et al. 2009 (CA180-035)]
+
|[https://doi.org/10.1182/blood.V96.5.1709 Abshire et al. 2000 (POG 9310)]
−
|2005-2006
+
|NR
−
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
+
| style="background-color:#91cf61" |Non-randomized
−
|[[#Dasatinib_monotherapy_2|Dasatinib]]; 70 mg twice per day
+
| style="background-color:#d3d3d3" |
−
|style="background-color:#ffffbf"|Inconclusive whether non-inferior MHR<sup>1</sup>
+
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ Raetz et al. 2008 (COG AALL01P2)]
 +
|2003-2005
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ Lew et al. 2021 (COG AALL0433)]
 +
|2007-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Doxorubicin, Pegaspargase, Vincristine, Prednisone]]; high-dose vincristine
 +
| style="background-color:#d3d3d3" |Not reported
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>Reported efficacy for CA180-035 is based on the 2010 subgroup analysis.''
+
''Note: This is "Block 1" of re-induction. Randomization in COG AALL0433 was discontinued early due to high rates of neuropathy in the experimental arm.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Dasatinib (Sprycel)]] 140 mg PO once per day
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
'''Continued indefinitely'''
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM once per day on days 2, 9, 16, 23
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 40 mg/m<sup>2</sup>/day PO on days 1 to 29
 +
====CNS therapy, prophylaxis (CNS-)====
 +
*[[Methotrexate (MTX)]] once per day on days 8 & 29
 +
====CNS therapy, treatment (CNS+)====
 +
*[[Methotrexate (MTX)]]
 +
*[[Cytarabine (Ara-C)]]
 +
*[[Hydrocortisone (Cortef)]]
 +
'''5-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See papers for details of treatment beyond induction block 1
 +
</div></div>
 +
===References===
 +
#'''POG 9310:''' Abshire TC, Pollock BH, Billett AL, Bradley P, Buchanan GR. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood. 2000 Sep 1;96(5):1709-15. [https://doi.org/10.1182/blood.V96.5.1709 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10961868/ PubMed]
 +
#'''COG AALL01P2:''' Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, Camitta BM, Gaynon PS, Carroll WL. Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]. J Clin Oncol. 2008 Aug 20;26(24):3971-8. Erratum in: J Clin Oncol. 2008 Oct 1;26(28): 4697. [https://doi.org/10.1200/jco.2008.16.1414 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2654313/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18711187/ PubMed] NCT00049569
 +
#'''COG AALL0433:''' Lew G, Chen Y, Lu X, Rheingold SR, Whitlock JA, Devidas M, Hastings CA, Winick NJ, Carroll WL, Wood BL, Borowitz MJ, Pulsipher MA, Hunger SP. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica. 2021 Jan 1;106(1):46-55. [https://doi.org/10.3324/haematol.2019.237230 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7776266/ link to PMC article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/32001530/ PubMed] NCT00381680
 +
==Inotuzumab ozogamicin monotherapy {{#subobject:d90806|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:8be9f9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
! style="width: 33%" |Study
 +
! style="width: 33%" |Years of enrollment
 +
! style="width: 33%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(11)70386-2 Kantarjian et al. 2012 (MDACC 2009-0872)]
 +
|2010-2011
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Antibody-drug conjugate therapy====
 +
*[[Inotuzumab ozogamicin (Besponsa)]] 0.8 mg/m<sup>2</sup> IV once on day 1, then 0.5 mg/m<sup>2</sup> IV once per day on days 8 & 15
 +
**For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m<sup>2</sup>
 +
'''21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''START-L:''' Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, Rege-Cambrin G, Radich J, Hochhaus A, Apanovitch AM, Gollerkeri A, Coutre S. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007 Oct 1;110(7):2309-15. Epub 2007 May 11. [http://www.bloodjournal.org/content/110/7/2309.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17496201 PubMed]
+
#'''MDACC 2009-0872:''' Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. [https://doi.org/10.1016/S1470-2045(11)70386-2 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22357140 PubMed] NCT01134575
−
<!-- Presented at ASH 2008 abstract 2926; 12th Congress of EHA 2007 abstract 859 -->
+
==Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone {{#subobject:910a81|Regimen=1}}==
−
# '''CA180-035:''' Kantarjian H, Cortes J, Kim DW, Dorlhiac-Llacer P, Pasquini R, DiPersio J, Müller MC, Radich JP, Khoury HJ, Khoroshko N, Bradley-Garelik MB, Zhu C, Tallman MS. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up. Blood. 2009 Jun 18;113(25):6322-9. Epub 2009 Apr 15. [http://www.bloodjournal.org/content/113/25/6322.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4916944/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19369231 PubMed] NCT00123487
 
−
## '''Subgroup analysis:''' Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, Müller MC, Charbonnier A, Bullorsky E, Dombret H, Brigid Bradley-Garelik M, Zhu C, Martinelli G. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010 Mar;85(3):164-70. [https://doi.org/10.1002/ajh.21615/pdf link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20131302 PubMed]
 
−
## '''Subgroup analysis:''' Saglio G, Hochhaus A, Goh YT, Masszi T, Pasquini R, Maloisel F, Erben P, Cortes J, Paquette R, Bradley-Garelik MB, Zhu C, Dombret H. Dasatinib in imatinib-resistant or imatinib-intolerant chronic myeloid leukemia in blast phase after 2 years of follow-up in a phase 3 study: efficacy and tolerability of 140 milligrams once daily and 70 milligrams twice daily. Cancer. 2010 Aug 15;116(16):3852-61. [https://doi.org/10.1002/cncr.25123 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4993589/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20564086 PubMed]
 
−
==Imatinib monotherapy {{#subobject:101df3|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:4bd0da|Variant=1}}===
+
===Regimen {{#subobject:ecb2e4|Variant=1}}===
−
{| class="wikitable" style="color:white; background-color:#404040"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
|<small>'''FDA-recommended dose'''</small>
+
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
 +
|2003-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Idarubicin.2C_Asparaginase_Erwinia_chrysanthemi.2C_Vincristine.2C_Dexamethasone_88|Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone]]
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
−
{| class="wikitable" style="width: 60%; text-align:center;"  
+
''Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.''
−
!style="width: 33%"|Study
+
<div class="toccolours" style="background-color:#b3e2cd">
−
!style="width: 33%"|Years of enrollment
+
====Chemotherapy====
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 20,000 units IM once per day on days 3, 5, 7, 9, 11, 13, 18, 20, 22, 24, 26, 28
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] by the following age-based criteria:
 +
**Age less than 2: 8 mg IT once per day on days 1 & 8
 +
**Age 2: 10 mg IT once per day on days 1 & 8
 +
**Age older than 2: 12 mg IT once per day on days 1 & 8
 +
'''4-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See paper for details of treatment beyond induction
 +
</div></div>
 +
===References===
 +
#'''CCLG ALL R3:''' Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. [https://doi.org/10.1016/S0140-6736(10)62002-8 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038 PubMed] NCT00967057
 +
==Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone {{#subobject:910a79|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:e3cbe4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/100/6/1965.long Ottmann et al. 2002]
+
|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
−
|1999-2000
+
|2003-2007
−
|style="background-color:#91cf61"|Phase 2 (RT)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Idarubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone_88|Idarubicin, Pegaspargase, Vincristine, Dexamethasone]]
 +
| style="background-color:#1a9850" |Superior OS
 
|-
 
|-
 
|}
 
|}
 +
''Note: per the protocol, this regimen is intended only for patients 18 and younger.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Chemotherapy====
−
*[[Imatinib (Gleevec)]] 600 mg PO once per day
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
'''Continued indefinitely'''
+
*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once per day on days 3 & 18
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] by the following age-based criteria:
 +
**Age less than 2: 8 mg IT once per day on days 1 & 8
 +
**Age 2: 10 mg IT once per day on days 1 & 8
 +
**Age older than 2: 12 mg IT once per day on days 1 & 8
 +
'''4-week course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See paper for details of treatment beyond induction
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# Ottmann OG, Druker BJ, Sawyers CL, Goldman JM, Reiffers J, Silver RT, Tura S, Fischer T, Deininger MW, Schiffer CA, Baccarani M, Gratwohl A, Hochhaus A, Hoelzer D, Fernandes-Reese S, Gathmann I, Capdeville R, O'Brien SG. A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood. 2002 Sep 15;100(6):1965-71. [http://www.bloodjournal.org/content/100/6/1965.long link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12200353 PubMed]
+
#'''CCLG ALL R3:''' Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. [https://doi.org/10.1016/S0140-6736(10)62002-8 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038 PubMed] NCT00967057
−
==Nilotinib monotherapy {{#subobject:fcb640|Regimen=1}}==
+
==Tisagenlecleucel monotherapy {{#subobject:d68f14|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a80f54|Variant=1}}===
+
===Regimen {{#subobject:60fc19|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
 
!style="width: 25%"|Study
 
!style="width: 25%"|Study
 +
!style="width: 25%"|Years of enrollment
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ Grupp et al. 2013 (Pedi CART19)]
 +
|2011-NR
 +
| style="background-color:#ffffbe" |Pilot
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ Maude et al. 2014 (UPCC04409)]
 +
|2012-2014
 +
| style="background-color:#91cf61" |Phase 1/2a
 +
|
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJMoa055104 Kantarjian et al. 2006 (A2101)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ Maude et al. 2018 (ELIANA)]
−
|style="background-color:#91cf61"|Phase 2
+
|2015-2017
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 +
|ORR: 81%
 
|-
 
|-
 
|}
 
|}
 +
''Note: dosing instructions are based on ELIANA.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Lymphodepleting therapy with [[Autologous_HSCT#FC|FC]] or [[Autologous_HSCT#CYVE|CYVE]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunotherapy====
−
*[[Nilotinib (Tasigna)]] 300 to 400 mg PO twice per day
+
*[[Tisagenlecleucel (Kymriah)]] by the following weight-based criteria:
−
'''Continued indefinitely'''
+
**Up to 50 kg: 2 to 5 x 10<sup>6</sup> CTL019 transduced viable T-cells per kg body weight IV once on day 0
 +
**Greater than 50 kg: 1.0 to 2.5 x 10<sup>8</sup> CTL019 transduced viable T-cells IV once on day 0
 +
'''One course'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''A2101:''' Kantarjian H, Giles F, Wunderle L, Bhalla K, O'Brien S, Wassmann B, Tanaka C, Manley P, Rae P, Mietlowski W, Bochinski K, Hochhaus A, Griffin JD, Hoelzer D, Albitar M, Dugan M, Cortes J, Alland L, Ottmann OG. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006 Jun 15;354(24):2542-51. [https://doi.org/10.1056/NEJMoa055104 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16775235 PubMed] NCT00109707
+
#'''Pedi CART19:''' Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1215134 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4058440/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23527958 PubMed] NCT01626495
−
==Ponatinib monotherapy {{#subobject:1ce5ae|Regimen=1}}==
+
#'''UPCC04409:''' Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. [https://doi.org/10.1056/NEJMoa1407222 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267531/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25317870 PubMed] NCT01029366
 +
#'''ELIANA:''' Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. [https://doi.org/10.1056/NEJMoa1709866 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1709866/suppl_file/nejmoa1709866_protocol.pdf link to supplementary protocol] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5996391/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29385370 PubMed] NCT02435849
 +
=Consolidation after salvage therapy=
 +
==Blinatumomab monotherapy {{#subobject:e7bh86|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:3d67eb|Variant=1}}===
+
===Regimen variant #1, 1 cycle {{#subobject:2db26g|Variant=1}}===
−
{| class="wikitable" style="width: 60%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 33%"|Study
+
! style="width: 20%" |Study
−
!style="width: 33%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1001/jama.2021.0987 Locatelli et al. 2021 (Amgen 20120215)]
 +
|2015-2019
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|Standard salvage consolidation chemotherapy
 +
| style="background-color:#1a9850" |Superior EFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Immunotherapy====
 +
*[[Blinatumomab (Blincyto)]] 15 mcg/m<sup>2</sup>/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m<sup>2</sup>)
 +
'''42-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic hematopoietic stem cell transplant]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 2 cycles {{#subobject:2db2g7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886799/ Cortes et al. 2013 (PACE)]
+
|[https://doi.org/10.1001/jama.2021.0669 Brown et al. 2021 (COG AALL1331)]
−
|2010-2011
+
|2014-2019
−
|style="background-color:#91cf61"|Phase 2 (RT)
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|Standard salvage consolidation chemotherapy
 +
| style="background-color:#d9ef8b" |Might have superior DFS
 
|-
 
|-
 
|}
 
|}
 +
''Note: insufficient dosing information was present in the abstract.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Targeted therapy====
+
====Immunotherapy====
−
*[[Ponatinib (Iclusig)]] 45 mg PO once per day; may be taken either with or without food
+
*[[Blinatumomab (Blincyto)]]
−
'''Continued indefinitely'''
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic hematopoietic stem cell transplant]]
 +
</div></div>
 +
===References===
 +
#'''COG AALL1331:''' Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. [https://doi.org/10.1001/jama.2021.0669 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33651090/ PubMed] NCT02101853
 +
#'''Amgen 20120215:''' Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. [https://doi.org/10.1001/jama.2021.0987 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/33651091/ PubMed] NCT02393859
 +
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9e6e8|Regimen=1}}==
 +
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1ba28d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM198110083051502 Johnson et al. 1981]
 +
|1976-1980
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1056/NEJM198708203170801 Kersey et al. 1987]
 +
|1982-1985
 +
| style="background-color:#1a9851" |Quasi-randomized
 +
|Auto HSCT
 +
| style="background-color:#1a9850" |Superior RFS
 +
|-
 +
|}
 +
{{#lst:Allogeneic HSCT|6ca28d}}
 +
====Immunotherapy====
 +
*[[Allogeneic stem cells]]
 +
'''Stem cells transfused on day 0'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!--
+
#Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. [https://doi.org/10.1056/NEJM198110083051502 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7024804 PubMed]
−
# Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, O'Hare T, Hu S, Narasimhan NI, Rivera VM, Clackson T, Turner CD, Haluska FG, Druker BJ, Deininger MW, Talpaz M. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012 Nov 29;367(22):2075-88. [https://doi.org/10.1056/NEJMoa1205127 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777383/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23190221 PubMed] -->
+
#Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. [https://doi.org/10.1056/NEJM198708203170801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3302708 PubMed]
−
# '''PACE:''' Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, Nicolini FE, Apperley JF, Khoury HJ, Talpaz M, DiPersio J, DeAngelo DJ, Abruzzese E, Rea D, Baccarani M, Müller MC, Gambacorti-Passerini C, Wong S, Lustgarten S, Rivera VM, Clackson T, Turner CD, Haluska FG, Guilhot F, Deininger MW, Hochhaus A, Hughes T, Goldman JM, Shah NP, Kantarjian H; the PACE Investigators. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013 Nov 7;369(19):1783-96. Epub 2013 Nov 1. [https://doi.org/10.1056/NEJMoa1306494 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3886799/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24180494 PubMed] NCT01207440
+
=Further notes=
−
## '''Update: Abstract:''' Dong-Wook Kim, Javier Pinilla-Ibarz, Philipp D le Coutre, Ronald Paquette, Charles Chuah, Franck E. Nicolini, Jane F Apperley, H. Jean Khoury, Moshe Talpaz, John F. DiPersio, Daniel J DeAngelo, Elisabetta Abruzzese, Delphine Rea, Michele Baccarani, Martin C. Müller, Carlo Gambacorti-Passerini, Stephanie Lustgarten, Victor M. Rivera, Tim Clackson, Christopher D Turner, Frank G Haluska, François Guilhot, Michael W. Deininger, Andreas Hochhaus, Timothy P. Hughes, John M Goldman, Neil P. Shah, Hagop M. Kantarjian. Ponatinib In Patients (pts) With Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) Resistant Or Intolerant To Dasatinib Or Nilotinib, Or With The T315I BCR-ABL Mutation: 2-Year Follow-Up Of The PACE Trial. Blood Nov 2013,122(21)650 [http://www.bloodjournal.org/content/122/21/650 link to original abstract]
+
''Pediatric ALL regimens tend to be very complex. [http://www.ped-onc.org/diseases/ALLtrials/ALLtrials.html This list on ped-onc.org] appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232.'' For now we will try to include a list of references here and potentially build these regimens here, over time.
 
[[Category:B-cell acute lymphoblastic leukemia regimens]]
 
[[Category:B-cell acute lymphoblastic leukemia regimens]]
−
[[Category:Biomarker-specific pages]]
+
[[Category:Disease-specific pages]]
 
[[Category:Acute lymphoblastic leukemias]]
 
[[Category:Acute lymphoblastic leukemias]]
 +
[[Category:Pediatric hematologic neoplasms]]

Revision as of 10:50, 21 October 2022

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Section editor transclusions This page contains studies that are specific to pediatric populations. For the more general B-cell acute lymphoblastic leukemia page, including regimens for adolescents and young adults, follow this link.

0 regimens on this page
0 variants on this page


Guidelines

"How I Treat"

NCCN

Upfront therapy

COG AALL0932 protocol

For Standard Risk B-ALL

Induction (Pegaspargase, Vincristine, Dexamethasone)

Study Years of enrollment Evidence
Maloney et al. 2019 (COG AALL0331) 2005-2010 Non-randomized portion of RCT
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Note: there are very minor differences in timing between protocols; see papers for details.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Initial Dose
1 - 1.99 years 30 mg
2 - 2.99 years 50 mg
≥ 3 years 70 mg 
CNS2 Patients will receive an additional dose of Cytarabine (Ara-C) IT on either day 4, 5, or 6, followed by Methotrexate (MTX) IT on day 8 and then another dose of Cytarabine (Ara-C) IT on either day 11 or 12 according to the following dosing.
Age Subsequent Doses
1 - 1.99 20 mg
2 - 2.99 30 mg
≥ 3 40 mg
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

DS Arm

35-day course

Subsequent treatment

  • COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
  • COG AALL0932: 6-MP & Vincristine consolidation

Protocol, Consolidation (Mercaptopurine & Vincristine)

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

For AR B-ALL patients, LR-C Arm, and B-LLy

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

DS Arm

28-day course

Subsequent treatment

Interim Maintenance I (Methotrexate & Vincristine)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 2000-2005 Phase 3 (E-de-esc) Mercaptopurine, MTX, Vincristine, Dexamethasone Superior EFS
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

For AR B-ALL patients, LR-C Arm, and B-LLy

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
    • Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted).
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

DS Arm

8-week course

Subsequent treatment

AALL0932 delayed intensification

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

For AR B-ALL patients, LR-C Arm, and B-LLy

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

DS Arm

8-week course

Subsequent treatment

Interim Maintenance II (Methotrexate & Vincristine)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 2000-2005 Phase 3 (E-de-esc) Mercaptopurine, MTX, Vincristine, Dexamethasone Superior EFS
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

For AR B-ALL patients, LR-C Arm, and B-LLy

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
    • Given over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted)
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

DS Arm

8-week course

Subsequent treatment

Maintenance Arm A and C (Vincristine/Dexamethasone Pulses)

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

For AR B-ALL patients, and LR-C Arm

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I

Maintenance Arm B and D (Vincristine/Dexamethasone Pulses)

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

Preceding treatment

Chemotherapy

  • Currently maintenance arm B and D are also treated with Methotrexate (MTX) PO at 20 mg/m2 (decreased from the starting dose of 40 mg/m2) on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I

Maintenance Arm DS (Vincristine/Dexamethasone)

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

For DS AR B-ALL patients and DS B-LLy

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I

Arm LR-M Consolidation

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

Chemotherapy

Given as a 200 mg/m2 bolus over 20 to 30 minutes followed by 800 mg/m2 over 23.5 hours (initial bolus of 30 minutes) or 23 hours and 40 minutes (if initial bolus was over 20 minutes)

Glucocorticoid therapy

Supportive therapy

  • Folinic acid (Leucovorin) 10 mg/m2 x 2 doses PO or IV (given 48 and 60 hours after the START of methotrexate infusion, continuing until methotrexate level < 0.2 μM) on days 9, 10, 30, 31, 51, 52, 72, 73, 93, 94, 114, 115

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once on days 8, 29, 50, 71, 92, 113 (To be delivered within 6 hours of the beginning of the IV methotrexate infusion, -6hr to + 6 hr)
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

19-week cycle

Arm LR-M Maintenance

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

Chemotherapy

Methotrexate (MTX) DATES CHANGE DEPENDING ON CYCLE NUMBER Cycles 1 and 4:

Cycles 2 and 5:

Cycles 3 and 6:

Cycle 7:

Glucocorticoid therapy

CNS therapy, prophylaxis

DATES CHANGE DEPENDING ON CYCLE NUMBER Cycles 1 and 4:

Cycles 2 and 5:

Cycles 3 and 6:

Cycle 7: NO MTX IT on Cycle 7

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

16-week cycles until a total duration of therapy of 2.5 years from the date of diagnosis is reached for both boys and girls.

Maintenance Arm LLy (Vincristine/Dexamethasone)

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Randomized portion of RCT

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-week cycles until total duration of therapy is 2 years for female and 3 years for male from the start of Interim I

References

  1. COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article PubMed NCT00005945
  2. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01190930

COG AALL1131 protocol

Induction (Daunorubicin, Pegaspargase, Vincristine, Dexamethasone)

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized portion of RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

Glucocorticoid therapy

Patients < 10 years ONLY:

Patients ≥ 10 years ONLY:

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following criteria:
    • Ages 1 to 1.99: 30 mg IT once on day 1
    • Ages 2 to 2.99: 50 mg IT once on day 1
    • Age 3 and older: 70 mg IT once on day 1
CNS2 Patients will receive an additional dose of Cytarabine (Ara-C) IT on either day 4, 5, or 6, and then another dose of Cytarabine (Ara-C) IT on either day 11 or 12 according to the following dosing.
  • Cytarabine (Ara-C) by the following criteria:
    • Ages 1 to 1.99: 20 mg IT once
    • Ages 2 to 2.99: 30 mg IT once
    • Age 3 and older: 40 mg IT once
  • Methotrexate (MTX) by the following criteria: (CNS3 also on Days 15 and 22)
    • Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
    • Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
    • Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
    • Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for HR B-ALL

Consolidation (Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine)

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Interim Maintenance with HD MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose Methotrexate (MTX)
  • Folinic acid (Leucovorin) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of high dose methotrexate infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT methotrexate within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-Day course

Delayed Intensification

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Maintenance HR B-ALL

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

Cycles 1-4
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 29, 57
  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: 20 mg/m2 PO once on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
    • Cycle 5 onwards: 20 mg/m2 PO once on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

  • Methotrexate (MTX) as follows:
    • Cycles 1 to 4: IT once per day on days 1, 29
    • Cycle 5 onwards: IT once per day on day 1
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-Week Cycles repeated until the total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for VHR B-ALL

Consolidation

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on days 1, 8, 15, 22 (Omit days 15 and 22 for CNS3 Patients)
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Interim Maintenance I with HD MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate.
  • Folinic acid (Leucovorin) 15 mg/m2 x a minimum of 3 doses PO or IV (given at 42, 48, and 54 hours after the START of HD MTX infusion) on days 3 to 4, 17 to 18, 31 to 32, 45 to 46

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

28-Day course

Protocol, Delayed Intensification

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Protocol, Interim Maintenance II with Capizzi MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
  • Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Protocol, VHR Arm Maintenance

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease
  • Total body irradiation (TBI) 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcomes for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for Ph-like B-ALL (Dasatinib Arm)

Consolidation

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Interim Maintenance with HD MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-Day course

Delayed Intensification

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Interim Maintenance II with Capizzi MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on day 1, 11, 21, 31, 41
  • Methotrexate (MTX) 100 mg/m2 IV over 2 to 5 minutes (undiluted) or over 10 to 15 minutes (diluted) on days 1, 150 mg/m2 on day 11, 200 mg/m2 on day 21, 250 mg/m2 on day 31, and 300 mg/m2 on day 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once on day 2, 22
  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, maximum dose of 140 mg/day) PO once daily on days 1 to 56

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

Maintenance

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease
  • Total body irradiation (TBI) 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5, 29 to 33, 57 to 61

Targeted therapy

  • Dasatinib (Sprycel) 60 mg/m2 (rounded to the nearest 5 mg, max of 140 mg/day) PO once daily on days 1 to 84

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

COG AALL1131 protocol for DS HR B-ALL

Protocol, Induction (Daunorubicin, Pegaspargase, Vincristine, Dexamethasone)

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

RER - M1 Marrow at Day 15

Glucocorticoid therapy

Patients < 10 years ONLY:

Patients ≥ 10 years ONLY:

Supportive therapy

  • Folinic acid (Leucovorin) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 10, 11, 31, 32 (CNS3 also on days 17, 18, 24, 25)

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • Ages 1 to 1.99: 30 mg IT once on day 1
    • Ages 2 to 2.99: 50 mg IT once on day 1
    • Age 3 and older: 70 mg IT once on day 1
  • Methotrexate (MTX) by the following age-based criteria:
    • Ages 1 to 1.99: 8 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • Ages 2 to 2.99: 10 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • Ages 3 to 8.99: 12 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)
    • Age 9 and older: 15 mg IT once per day on days 8 and 29 (CNS 3 also on days 15 and 22)

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

Consolidation

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg 
DS Arm
  • Folinic acid (Leucovorin) 5 mg/m2 x 2 doses PO (given at 48 and 60 hours after the lumbar puncture) on days 3, 4, 10, 11, 17, 18, 24, 25

56-Day course

Interim Maintenance with ID MTX

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

ANC must be ≥ 750/µL and platelets must be ≥ 75,000/µL prior to each dose of high dose methotrexate
  • Folinic acid (Leucovorin) 15 mg/m2 x a minimum of 5 doses PO or IV (given at 30, 36, 42, 48, and 54 hours after the START of intermediate dose methotrexate infusion) on days 2, 3, 17, 18, 31, 32, 45, 46

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg 
When IT methotrexate therapy and high dose methotrexate are scheduled for the same day, deliver the IT therapy within 6 hours of the beginning of the IV methotrexate infusion. (hour -6 or +6, with 0 being the start of the methotrexate bolus).

63-Day course

Delayed Intensification

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • Folinic acid (Leucovorin) 5 mg/m2 x 2 doses PO or IV (given at 48, and 60 hours after the lumbar puncture) on days 3, 4, 31, 32, 38, 39

CNS therapy, prophylaxis

Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

56-Day course

DS HR Arm Maintenance

Study Evidence
Burke et al. 2019 (COG AALL1131) Randomized portion of RCT

Radiotherapy

For Patients with CNS3 Disease
  • Total body irradiation (TBI) 1800 cGy in 10 fractions, during the first 4 weeks of Maintenance therapy and should be completed by day 29 of Maintenance

Chemotherapy

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2/dose PO or IV (methylprednisolone given at 80% of the oral dose) twice per day on days 1 to 5

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once per day on day 1 (also Day 29 of cycles 1 and 2, for patients who did NOT receive CNS Radiation)
Age Dose
1 - 1.99 8 mg
2 - 2.99 10 mg
3 - 8.99 12 mg
≥ 9 15 mg

12-Week Cycles repeated until total duration of therapy is 2 years for female patients and 3 years for male patients from the start of interim maintenance.

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

Prephase

Methylprednisolone monotherapy

Regimen

Study Years of enrollment Evidence
Place et al. 2015 (DFCI 05-001) 2005-2011 Non-randomized portion of RCT
Burns et al. 2020 (DFCI 11-001) 2012-2015 Non-randomized portion of RCT

Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001.

Glucocorticoid therapy

3-day course

Subsequent treatment

References

  1. DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article PubMed NCT00400946
    1. Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement PubMed
  2. DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement PubMed NCT01574274
    1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Prednisone monotherapy

Regimen

Study Years of enrollment Evidence
Möricke et al. 2016 (AIEOP-BFM ALL 2000) 2000-2006 Non-randomized portion of RCT

Glucocorticoid therapy

CNS therapy, prophylaxis

7-day course

Subsequent treatment

References

  1. AIEOP-BFM ALL 2000: Möricke A, Zimmermann M, Valsecchi MG, Stanulla M, Biondi A, Mann G, Locatelli F, Cazzaniga G, Niggli F, Aricò M, Bartram CR, Attarbaschi A, Silvestri D, Beier R, Basso G, Ratei R, Kulozik AE, Lo Nigro L, Kremens B, Greiner J, Parasole R, Harbott J, Caruso R, von Stackelberg A, Barisone E, Rössig C, Conter V, Schrappe M. Dexamethasone vs prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016 Apr 28;127(17):2101-12. Epub 2016 Feb 17. link to original article contains dosing details in supplement PubMed NCT00430118; NCT00613457

Vincristine & Prednisone

VP: Vincristine & Prednisone

Regimen

Study Years of enrollment Evidence
Sallan et al. 1978 1973-1977 Non-randomized

Note: this regimen is of historic interest as an induction regimen; it is still occasionally used as pre-phase in patients too ill to get cytotoxic chemotherapy at time of diagnosis.

Chemotherapy

Glucocorticoid therapy

21-day course

References

  1. Sallan SE, Cammita BM, Cassady JR, Nathan DG, Frei E 3rd. Intermittent combination chemotherapy with adriamycin for childhood acute lymphoblastic leukemia: clinical results. Blood. 1978 Mar;51(3):425-33. link to original article contains dosing details in manuscript PubMed

Upfront induction therapy

Calaspargase, Daunorubicin, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Angiolillo et al. 2014 (COG AALL07P4) 2008-2010 Randomized (E-RT-switch-ic) Daunorubicin, Pegaspargase, Vincristine, Prednisone Longer half-life

Chemotherapy

Glucocorticoid therapy

5-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. COG AALL07P4: Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Keilani T, Lane AR, Loh ML, Reaman GH, Adamson PC, Wood B, Wood C, Zheng HW, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol Escherichia coli L-asparaginase in the treatment of patients with acute lymphoblastic leukemia: results from Children's Oncology Group Study AALL07P4. J Clin Oncol. 2014 Dec 1;32(34):3874-82. Epub 2014 Oct 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00671034

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Evidence
Burke et al. 2019 (COG AALL1131) Non-randomized portion of RCT

Note: the referenced publication does not specifically focus on induction; the full regimen is available as a protocol. Per the protocol, it is intended only for patients less than 10 years old.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) by the following age-based criteria:
    • Ages 1 to 1.99: 30 mg IT once on day 1
    • Ages 2 to 2.99: 50 mg IT once on day 1
    • Age 3 and older: 70 mg IT once on day 1
  • Methotrexate (MTX) by the following age-based criteria:
    • Ages 1 to 1.99: 8 mg IT once per day on days 8 & 29
    • Ages 2 to 2.99: 10 mg IT once per day on days 8 & 29
    • Ages 3 to 8.99: 12 mg IT once per day on days 8 & 29
    • Age 9 and older: 15 mg IT once per day on days 8 & 29

4-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. COG AALL1131: Burke MJ, Salzer WL, Devidas M, Dai Y, Gore L, Hilden JM, Larsen E, Rabin KR, Zweidler-McKay PA, Borowitz MJ, Wood B, Heerema NA, Carroll AJ, Winick N, Carroll WL, Raetz EA, Loh ML, Hunger SP. Replacing cyclophosphamide/cytarabine/mercaptopurine with cyclophosphamide/etoposide during consolidation/delayed intensification does not improve outcome for pediatric B-cell acute lymphoblastic leukemia: a report from the COG. Haematologica. 2019 May;104(5):986-992. Epub 2018 Dec 13. link to original article link to PMC article PubMed NCT02883049

DOLP

DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone
DVPA: Daunorubicin, Vincristine, Prednisone, Asparaginase

Regimen variant #1, 25/1.5/6000/60

Study Years of enrollment Evidence
Seibel et al. 2008 (COG CCG-1961) 1996-2002 Non-randomized portion of phase 3 RCT
Termuhlen et al. 2012 (COG A5971) 2000-2005 Non-randomized portion of phase 3 RCT

Note: COG A5971 was intended for patients with localized lymphoblastic lymphoma, of which 75% had B-cell immunophenotype. Exact days were not specified for the L-asparaginase; suggested days are similar to those used in other protocols. COG CCG-1961 did not specify a tapering schedule for prednisone, and did not cap vincristine.

Chemotherapy

Glucocorticoid therapy

CNS therapy

  • Cytarabine (Ara-C) by the following age-based criteria:
    • Age 1-1.99 years: 30 mg IT once on day 0
    • Age 2-2.99 years: 50 mg IT once on day 0
    • Age 3 or greater: 70 mg IT once on day 0
  • Methotrexate (MTX) by the following age-based criteria:
    • Age 1-1.99 years: 8 mg IT once per day on days 7 & 28
    • Age 2-2.99 years: 10 mg IT once per day on days 7 & 28
    • Age 3 or greater: 12 mg IT once per day on days 7 & 28

5-week course

Subsequent treatment

  • COG CCG-1961: Standard versus increased intensity post-remission therapy (see paper for details)
  • COG A5971: Consolidation (see paper for details)

Regimen variant #2, 30/1.5/5000/60 ("Phase A" of ALL-BFM 95; "Phase 1" of ALL IC-BFM 2002)

Study Years of enrollment Evidence
Möricke et al. 2008 (ALL-BFM 95) 1995-2000 Non-randomized
Stary et al. 2013 (ALL IC-BFM 2002) 2002-2007 Non-randomized portion of phase 3 RCT

Note: see papers for details on dose adjustments based on risk. For example, in ALL IC-BFM 2002, days 22 & 29 of daunorubicin were omitted for standard risk B-cell precursor acute lymphoblastic leukemia.

Chemotherapy

Glucocorticoid therapy

CNS therapy

5-week course

Subsequent treatment

  • See papers for details

Regimen variant #3, 30/1.5/10,000/60 ("Protocol I")

Study Evidence
Schrappe et al. 2000 (ALL-BFM 90) Non-randomized
Kamps et al. 2002 (DCLSG ALL-8) Non-randomized

Note: see papers for details on dose adjustments based on risk.

Chemotherapy

Glucocorticoid therapy

CNS therapy

5-week course

Subsequent treatment

  • See papers for details

Regimen variant #4, 40/1.5/10,000/60 ("Induction Protocol I" of ALL-BFM 86)

Study Evidence
Reiter et al. 1994 (ALL-BFM 86) Non-randomized portion of RCT
Kamps et al. 1999 (DCLSG ALL-7) Non-randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

6-week course

Subsequent treatment

  • Induction phase II (see papers for details)

References

  1. ALL-BFM 86: Reiter A, Schrappe M, Ludwig WD, Hiddemann W, Sauter S, Henze G, Zimmermann M, Lampert F, Havers W, Niethammer D, Odenwald E, Ritter J, Mann G, Welte K, Gadner H, Riehm H. Chemotherapy in 998 unselected childhood acute lymphoblastic leukemia patients: results and conclusions of the multicenter trial ALL-BFM 86. Blood. 1994 Nov 1;84(9):3122-33. link to original article contains dosing details in manuscript PubMed
  2. DCLSG ALL-7: Kamps WA, Bökkerink JP, Hählen K, Hermans J, Riehm H, Gadner H, Schrappe M, Slater R, van den Berg-de Ruiter E, Smets LA, de Vaan GA, Weening RS, van Weerden JF, van Wering ER, den der Does-van den Berg A. Intensive treatment of children with acute lymphoblastic leukemia according to ALL-BFM-86 without cranial radiotherapy: results of Dutch Childhood Leukemia Study Group protocol ALL-7 (1988-1991). Blood. 1999 Aug 15;94(4):1226-36. link to original article PubMed
  3. ALL-BFM 90: Schrappe M, Reiter A, Ludwig WD, Harbott J, Zimmermann M, Hiddemann W, Niemeyer C, Henze G, Feldges A, Zintl F, Kornhuber B, Ritter J, Welte K, Gadner H, Riehm H; German-Austrian-Swiss ALL-BFM Study Group. Improved outcome in childhood acute lymphoblastic leukemia despite reduced use of anthracyclines and cranial radiotherapy: results of trial ALL-BFM 90. Blood. 2000 Jun 1;95(11):3310-22. link to original article contains dosing details in manuscript PubMed
    1. Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article PubMed
  4. DCLSG ALL-8: Kamps WA, Bökkerink JP, Hakvoort-Cammel FG, Veerman AJ, Weening RS, van Wering ER, van Weerden JF, Hermans J, Slater R, van den Berg E, Kroes WG, van der Does-van den Berg A. BFM-oriented treatment for children with acute lymphoblastic leukemia without cranial irradiation and treatment reduction for standard risk patients: results of DCLSG protocol ALL-8 (1991-1996). Leukemia. 2002 Jun;16(6):1099-111. link to original article refers to ALL-BFM 90 protocol PubMed
  5. COG CCG-1961: Seibel NL, Steinherz PG, Sather HN, Nachman JB, Delaat C, Ettinger LJ, Freyer DR, Mattano LA Jr, Hastings CA, Rubin CM, Bertolone K, Franklin JL, Heerema NA, Mitchell TL, Pyesmany AF, La MK, Edens C, Gaynon PS. Early postinduction intensification therapy improves survival for children and adolescents with high-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2008 Mar 1;111(5):2548-55. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00002812
  6. ALL-BFM 95: Möricke A, Reiter A, Zimmermann M, Gadner H, Stanulla M, Dördelmann M, Löning L, Beier R, Ludwig WD, Ratei R, Harbott J, Boos J, Mann G, Niggli F, Feldges A, Henze G, Welte K, Beck JD, Klingebiel T, Niemeyer C, Zintl F, Bode U, Urban C, Wehinger H, Niethammer D, Riehm H, Schrappe M; German-Austrian-Swiss ALL-BFM Study Group. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95. Blood. 2008 May 1;111(9):4477-89. Epub 2008 Feb 19. Erratum in: Blood. 2009 Apr 30;113(18):4478. Dosage error in article text. link to original article contains dosing details in manuscript PubMed
    1. Pooled subgroup analysis: Schrauder A, Reiter A, Gadner H, Niethammer D, Klingebiel T, Kremens B, Peters C, Ebell W, Zimmermann M, Niggli F, Ludwig WD, Riehm H, Welte K, Schrappe M. Superiority of allogeneic hematopoietic stem-cell transplantation compared with chemotherapy alone in high-risk childhood T-cell acute lymphoblastic leukemia: results from ALL-BFM 90 and 95. J Clin Oncol. 2006 Dec 20;24(36):5742-9. link to original article PubMed
  7. COG A5971: Termuhlen AM, Smith LM, Perkins SL, Lones M, Finlay JL, Weinstein H, Gross TG, Abromowitch M. Outcome of newly diagnosed children and adolescents with localized lymphoblastic lymphoma treated on Children's Oncology Group trial A5971: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2012 Dec 15;59(7):1229-33. Epub 2012 Apr 5. link to original article contains dosing details in supplement PubMed NCT00004228
  8. ALL IC-BFM 2002: Stary J, Zimmermann M, Campbell M, Castillo L, Dibar E, Donska S, Gonzalez A, Izraeli S, Janic D, Jazbec J, Konja J, Kaiserova E, Kowalczyk J, Kovacs G, Li CK, Magyarosy E, Popa A, Stark B, Jabali Y, Trka J, Hrusak O, Riehm H, Masera G, Schrappe M. Intensive chemotherapy for childhood acute lymphoblastic leukemia: results of the randomized intercontinental trial ALL IC-BFM 2002. J Clin Oncol. 2014 Jan 20;32(3):174-84. Epub 2013 Dec 16. link to original article contains dosing details in manuscript PubMed NCT00764907

DOLP (Prednisolone)

DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisolone

Regimen variant #1, 30/10,000/1.5/60

Study Years of enrollment Evidence Comparator Comparative Efficacy
de Moerloose et al. 2010 (EORTC CLG 58951) 1999-2002 Phase 3 (C) Daunorubicin, L-Asparaginase, Vincristine, Dexamethasone Did not meet primary endpoint of EFS

Note: see paper for details on CNS therapy and dose adjustments based on risk; these instructions include a 7-day pre-phase and are for AR1 patients.

Chemotherapy

Glucocorticoid therapy

5-week course

Subsequent treatment

  • See paper for details

Regimen variant #2, 45/6000/1.5/40

Study Evidence
Chessells et al. 1992 (UK MRC ALLX) Non-randomized portion of RCT

Note: exact days for L-asparaginase were not specified in the protocol.

Chemotherapy

Glucocorticoid therapy

29-day course

Subsequent treatment

References

  1. UK MRC ALLX: Chessells JM, Bailey C, Wheeler K, Richards SM. Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALL X. Lancet. 1992 Sep 5;340(8819):565-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Chessells JM, Bailey C, Richards SM; Medical Research Council Working Party on Childhood Leukaemia. Intensification of treatment and survival in all children with lymphoblastic leukaemia: results of UK Medical Research Council trial UKALL X. Lancet. 1995 Jan 21;345(8943):143-8. link to original article PubMed
  2. EORTC CLG 58951: De Moerloose B, Suciu S, Bertrand Y, Mazingue F, Robert A, Uyttebroeck A, Yakouben K, Ferster A, Margueritte G, Lutz P, Munzer M, Sirvent N, Norton L, Boutard P, Plantaz D, Millot F, Philippet P, Baila L, Benoit Y, Otten J; Children's Leukemia Group of the European Organisation for Research and Treatment of Cancer. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. 2010 Jul 8;116(1):36-44. Epub 2010 Apr 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003728
    1. Update: Domenech C, Suciu S, De Moerloose B, Mazingue F, Plat G, Ferster A, Uyttebroeck A, Sirvent N, Lutz P, Yakouben K, Munzer M, Röhrlich P, Plantaz D, Millot F, Philippet P, Dastugue N, Girard S, Cavé H, Benoit Y, Bertrand Y; Children's Leukemia Group (CLG) of European Organisation for Research and Treatment of Cancer. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. 2014 Jul;99(7):1220-7. Epub 2014 Apr 11. link to original article link to PMC article PubMed
    2. Update: Mondelaers V, Suciu S, De Moerloose B, Ferster A, Mazingue F, Plat G, Yakouben K, Uyttebroeck A, Lutz P, Costa V, Sirvent N, Plouvier E, Munzer M, Poirée M, Minckes O, Millot F, Plantaz D, Maes P, Hoyoux C, Cavé H, Rohrlich P, Bertrand Y, Benoit Y; Children's Leukemia Group (CLG) of the European Organisation for Research and Treatment of Cancer. Prolonged versus standard native E coli asparaginase therapy in childhood acute lymphoblastic leukemia and non-Hodgkin lymphoma: final results of the EORTC-CLG randomized phase III trial 58951. Haematologica. 2017 Oct;102(10):1727-1738. Epub 2017 Jul 27. link to original article link to PMC article PubMed

Doxorubicin, Mercaptopurine, Pegaspargase, Vincristine, Prednisolone

Regimen

Study Years of enrollment Evidence
Albertsen et al. 2019 (NOPHO ALL2008) 2008-2016 Non-randomized portion of RCT

See protocol for initiation dependencies of 6-MP and pegaspargase.

Chemotherapy

Glucocorticoid therapy

  • Prednisolone (Millipred) 20 mg/m2 PO three times per day on days 1 to 29, then 10 mg/m2 PO three times per day on days 30 to 32, then 5 mg/m2 PO three times per day on days 33 to 35, then 2.5 mg/m2 PO three times per day on days 36 to 38

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • Ages 1 to 1.9: 8 mg IT once per day on days 1, 8, 15, 29
    • Ages 2 to 2.9: 10 mg IT once per day on days 1, 8, 15, 29
    • Age 3 and older: 12 mg IT once per day on days 1, 8, 15, 29

5-week course

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. NOPHO ALL2008: Albertsen BK, Grell K, Abrahamsson J, Lund B, Vettenranta K, Jónsson ÓG, Frandsen TL, Wolthers BO, Heyman M, Schmiegelow K. Intermittent versus continuous PEG-asparaginase to reduce asparaginase-associated toxicities: a NOPHO ALL2008 randomized study. J Clin Oncol. 2019 Jul 1;37(19):1638-1646. Epub 2019 Apr 12. link to original article contains dosing details in supplement PubMed NCT00819351

Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Place et al. 2015 (DFCI 05-001) 2005-2011 Phase 3 (E-switch-ic) Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone Did not meet secondary endpoint of DFS Less anxiety
Burns et al. 2020 (DFCI 11-001) 2012-2015 Phase 3 (C) Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone Not reported

Note: Burns et al. 2020 is both an update of DFCI 05-001 and the primary publication of DFCI 11-001. Day numbering takes into account the pre-phase.

Preceding treatment

Chemotherapy

Glucocorticoid therapy

Supportive therapy

28-day course

CNS therapy, prophylaxis

Subsequent treatment

References

  1. DFCI 05-001: Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. link to original article PubMed NCT00400946
    1. Pooled update: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement PubMed
  2. DFCI 11-001: Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. link to original article contains dosing details in supplement PubMed NCT01574274
    1. Update: Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. link to original article PubMed

Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Years of enrollment Evidence
Maloney et al. 2019 (COG AALL0331) 2005-2010 Non-randomized portion of RCT
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Note: there are very minor differences in timing between protocols; see papers for details.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

35-day course

Subsequent treatment

  • COG AALL0331, M2 marrow or M1 marrow with MRD of at least 1% at day 29: Extended induction
  • COG AALL0932: 6-MP & Vincristine consolidation

References

  1. COG AALL0331: Maloney KW, Devidas M, Wang C, Mattano LA, Friedmann AM, Buckley P, Borowitz MJ, Carroll AJ, Gastier-Foster JM, Heerema NA, Kadan-Lottick N, Loh ML, Matloub YH, Marshall DT, Stork LC, Raetz EA, Wood B, Hunger SP, Carroll WL, Winick NJ. Outcome in Children With Standard-Risk B-Cell Acute Lymphoblastic Leukemia: Results of Children's Oncology Group Trial AALL0331. J Clin Oncol. 2020 Feb 20;38(6):602-612. Epub 2019 Dec 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00103285
  2. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript PubMed NCT01190930

Pegaspargase, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Avramis et al. 2002 (CCG 1962) 1997-1998 Randomized (E-RT-switch-ic) L-Asparaginase, Vincristine, Prednisone Did not meet secondary endpoint of EFS

Note: the primary endpoint of CCG 1962 was incidence of high-titer ASNase antibodies in the first dose intensification, which is neither an efficacy nor a toxicity endpoint.

Chemotherapy

Glucocorticoid therapy

Subsequent treatment

  • See protocol for details of treatment beyond induction

References

  1. CCG 1962: Avramis VI, Sencer S, Periclou AP, Sather H, Bostrom BC, Cohen LJ, Ettinger AG, Ettinger LJ, Franklin J, Gaynon PS, Hilden JM, Lange B, Majlessipour F, Mathew P, Needle M, Neglia J, Reaman G, Holcenberg JS, Stork L. A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study. Blood. 2002 Mar 15;99(6):1986-94. Erratum in: Blood 2002 Sep 1;100(5):1531. link to original article PubMed

Early intensification therapy

Cyclophosphamide, Etoposide, Methotrexate

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Dreyer et al. 2014 (COG P9407) 2001-2006 Non-randomized
Brown et al. 2021 (COG AALL0631) 2008-2014 Phase 3 (C) Cyclophosphamide, Etoposide, Lestaurtinib, Methotrexate Did not meet primary endpoint of EFS

Biomarker eligibility criteria

  • COG AALL0631: KMT2A rearrangement

Preceding treatment

  • Induction

Chemotherapy

  • Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 30 minutes once per day on days 15 to 19
  • Etoposide (Vepesid) 100 mg/m2 IV over 2 hours once per day on days 15 to 19
  • Methotrexate (MTX) 200 mg/m2 IV over 20 minutes, then 3800 mg/m2 IV continuous infusion over 23 hours and 40 minutes on days 1 & 8 (total dose: 8000 mg/m2)

Subsequent treatment

  • Reinduction

References

  1. COG P9407: Dreyer ZE, Hilden JM, Jones TL, Devidas M, Winick NJ, Willman CL, Harvey RC, Chen IM, Behm FG, Pullen J, Wood BL, Carroll AJ, Heerema NA, Felix CA, Robinson B, Reaman GH, Salzer WL, Hunger SP, Carroll WL, Camitta BM. Intensified chemotherapy without SCT in infant ALL: results from COG P9407 (Cohort 3). Pediatr Blood Cancer. 2015 Mar;62(3):419-26. Epub 2014 Nov 14. link to original article link to PMC article PubMed NCT00002756
  2. COG AALL0631: Brown PA, Kairalla JA, Hilden JM, Dreyer ZE, Carroll AJ, Heerema NA, Wang C, Devidas M, Gore L, Salzer WL, Winick NJ, Carroll WL, Raetz EA, Borowitz MJ, Small D, Loh ML, Hunger SP. FLT3 inhibitor lestaurtinib plus chemotherapy for newly diagnosed KMT2A-rearranged infant acute lymphoblastic leukemia: Children's Oncology Group trial AALL0631. Leukemia. 2021 May;35(5):1279-1290. Epub 2021 Feb 23. Erratum in: Leukemia. 2021 Apr 12. link to original article contains dosing details in supplement PubMed NCT00557193

Mercaptopurine & Methotrexate

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Mahoney et al. 1998 (POG 9005) 1991-1993 Phase 3 (E-switch-ic) 6-MP & MTX; LDMTX/IVMP Seems to have superior CCR
Lauer et al. 2001 (POG 9006) 1991-1994 Phase 3 (C) Intensive chemotherapy Might have inferior EFS

Preceding treatment

  • POG 9006: DOLP induction

Chemotherapy

Subsequent treatment

References

  1. POG 9005: Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B. Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol. 1998 Jan;16(1):246-54. link to original article PubMed
  2. POG 9006: Lauer SJ, Shuster JJ, Mahoney DH Jr, Winick N, Toledano S, Munoz L, Kiefer G, Pullen JD, Steuber CP, Camitta BM. A comparison of early intensive methotrexate/mercaptopurine with early intensive alternating combination chemotherapy for high-risk B-precursor acute lymphoblastic leukemia: a Pediatric Oncology Group phase III randomized trial. Leukemia. 2001 Jul;15(7):1038-45. link to original article PubMed

Consolidation after upfront therapy (including post-remission therapy)

Note that many of these regimens are complex and as such will be referred to by their study name, not by the individual drug names. This is also a phase of treatment often referred to as post-remission or postinduction therapy.

AALL0232 consolidation

Regimen

Study Evidence
Larsen et al. 2016 (COG AALL0232) Non-randomized portion of RCT

Chemotherapy

50-day course

Subsequent treatment

References

  1. COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00075725

Augmented BFM consolidation

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Nachman et al. 1998 1991-1995 Phase 3 (E-esc) Standard BFM consolidation Seems to have superior OS

Unlikely to be completed, but of historic interest.

Chemotherapy

References

  1. Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS. Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Engl J Med. 1998 Jun 4;338(23):1663-71. link to original article PubMed

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Years of enrollment Evidence
Thomas et al. 1979 1976-1977 Non-randomized

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

  • Total body irradiation by the following study-specific criteria:
    • Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
    • Other studies: 10 to 1200 cGy total

Immunotherapy

One course

Immunotherapy

Stem cells transfused on day 0

References

  1. Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL. Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood. 1979 Aug;54(2):468-76. link to original article contains dosing details in abstract PubMed

Etoposide & TBI, then allo HSCT

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Balduzzi et al. 2005 1995-2000 Quasi-randomized Chemotherapy Seems to have superior DFS
Peters et al. 2015 (ALL-SCT-BFM 2003) 2003-2011 Non-randomized

Chemotherapy

Radiotherapy

Immunotherapy

One course

Immunotherapy

Stem cells transfused on day 0

References

  1. Balduzzi A, Valsecchi MG, Uderzo C, De Lorenzo P, Klingebiel T, Peters C, Stary J, Felice MS, Magyarosy E, Conter V, Reiter A, Messina C, Gadner H, Schrappe M. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukaemia in first complete remission: comparison by genetic randomisation in an international prospective study. Lancet. 2005 Aug 20-26;366(9486):635-42. link to original article contains dosing details in manuscript PubMed
  2. ALL-SCT-BFM-2003: Peters C, Schrappe M, von Stackelberg A, Schrauder A, Bader P, Ebell W, Lang P, Sykora KW, Schrum J, Kremens B, Ehlert K, Albert MH, Meisel R, Matthes-Martin S, Gungor T, Holter W, Strahm B, Gruhn B, Schulz A, Woessmann W, Poetschger U, Zimmermann M, Klingebiel T. Stem-cell transplantation in children with acute lymphoblastic leukemia: a prospective international multicenter trial comparing sibling donors with matched unrelated donors-the ALL-SCT-BFM-2003 trial. J Clin Oncol. 2015 Apr 10;33(11):1265-74. Epub 2015 Mar 9. link to original article PubMed NCT01423747

Mercaptopurine & Vincristine

Regimen

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

28-day course

Subsequent treatment

References

  1. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript PubMed NCT01190930

Interim maintenance

Mercaptopurine, Methotrexate, Vincristine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Larsen et al. 2016 (COG AALL0232) 2004-2011 Phase 3 (E-switch-ic) 6-MP, Capizzi MTX, Pegaspargase, Vincristine Superior EFS

Chemotherapy

CNS therapy

References

  1. COG AALL0232: Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, Mattano LA Jr, Cole C, Eicher A, Haugan M, Sorenson M, Heerema NA, Carroll AA, Gastier-Foster JM, Borowitz MJ, Wood BL, Willman CL, Winick NJ, Hunger SP, Carroll WL. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children's Oncology Group study AALL0232. J Clin Oncol. 2016 Jul 10;34(20):2380-8. Epub 2016 Apr 25. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00075725

Methotrexate & Vincristine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Matloub et al. 2011 (COG CCG-1991) 2000-2005 Phase 3 (E-de-esc) 6-MP, MTX, Vincristine, Dexamethasone Superior EFS
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 100 mg/m2 IV once on day 1, then 150 mg/m2 IV once on day 11, then 200 mg/m2 IV once on day 21, then 250 mg/m2 IV once on day 31, then 300 mg/m2 IV once on day 41
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

8-week course

Subsequent treatment

References

  1. COG CCG-1991: Matloub Y, Bostrom BC, Hunger SP, Stork LC, Angiolillo A, Sather H, La M, Gastier-Foster JM, Heerema NA, Sailer S, Buckley PJ, Thomson B, Cole C, Nachman JB, Reaman G, Winick N, Carroll WL, Devidas M, Gaynon PS. Escalating intravenous methotrexate improves event-free survival in children with standard-risk acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood. 2011 Jul 14;118(2):243-51. Epub 2011 May 11. link to original article link to PMC article PubMed NCT00005945
  2. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript PubMed NCT01190930

Delayed intensification

AALL0932 delayed intensification

Regimen

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Preceding treatment

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

8-week course

Subsequent treatment

References

  1. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript PubMed NCT01190930

Interim maintenance II

Methotrexate & Vincristine

Regimen

Study Years of enrollment Evidence
Angiolillo et al. 2021 (COG AALL0932) 2010-2018 Non-randomized portion of RCT

Note: starting dose of the systemic MTX is 2/3 of the MTD from interim maintenance I; dosage below assumes that the final maximum dose was tolerated.

Preceding treatment

Chemotherapy

  • Methotrexate (MTX) 200 mg/m2 IV once on day 1, then 250 mg/m2 IV once on day 11, then 300 mg/m2 IV once on day 21, then 350 mg/m2 IV once on day 31, then 400 mg/m2 IV once on day 41
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41

CNS therapy, prophylaxis

8-week course

Subsequent treatment

  • Randomization to one of four maintenance arms; see paper for details.

References

  1. COG AALL0932: Angiolillo AL, Schore RJ, Kairalla JA, Devidas M, Rabin KR, Zweidler-McKay P, Borowitz MJ, Wood B, Carroll AJ, Heerema NA, Relling MV, Hitzler J, Lane AR, Maloney KW, Wang C, Bassal M, Carroll WL, Winick NJ, Raetz EA, Loh ML, Hunger SP. Excellent Outcomes With Reduced Frequency of Vincristine and Dexamethasone Pulses in Standard-Risk B-Lymphoblastic Leukemia: Results From Children's Oncology Group AALL0932. J Clin Oncol. 2021 May 1;39(13):1437-1447. Epub 2021 Jan 7. link to original article contains dosing details in manuscript PubMed NCT01190930

Maintenance after upfront therapy

Mercaptopurine & Methotrexate

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Millot et al. 2001 (EORTC 58881) 1990-1996 Phase 3 (C) 6-MP & MTX; IV 6-MP & PO MTX Superior DFS1
Conter et al. 2007 (I-BFM-SG IR ALL) 1995-2000 Phase 3 (C) D-OMP Did not meet primary endpoint of DFS

1Reported efficacy for EORTC 58881 is based on the 2005 update.

Preceding treatment

  • I-BFM-SG IR ALL: BFM re-induction

Chemotherapy

7-day cycle for 74 cycles or a total of 2 years from start of treatment

References

  1. EORTC 58881: Millot F, Suciu S, Philippe N, Benoit Y, Mazingue F, Uyttebroeck A, Lutz P, Mechinaud F, Robert A, Boutard P, Marguerite G, Ferster A, Plouvier E, Rialland X, Behard C, Plantaz D, Dresse MF, Philippet P, Norton L, Thyss A, Dastugue N, Waterkeyn C, Vilmer E, Otten J; Children's Leukemia Cooperative Group of the European Organiztaion for Research and Treatment of Cancer. Value of high-dose cytarabine during interval therapy of a Berlin-Frankfurt-Munster-based protocol in increased-risk children with acute lymphoblastic leukemia and lymphoblastic lymphoma: results of the European Organisation for Research and Treatment of Cancer 58881 randomized phase III trial. J Clin Oncol. 2001 Apr 1;19(7):1935-42. link to original article PubMed
    1. Update: Duval M, Suciu S, Ferster A, Rialland X, Nelken B, Lutz P, Benoit Y, Robert A, Manel AM, Vilmer E, Otten J, Philippe N. Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer-Children's Leukemia Group phase 3 trial. Blood. 2002 Apr 15;99(8):2734-9. link to original article PubMed
    2. Update: van der Werff Ten Bosch J, Suciu S, Thyss A, Bertrand Y, Norton L, Mazingue F, Uyttebroeck A, Lutz P, Robert A, Boutard P, Ferster A, Plouvier E, Maes P, Munzer M, Plantaz D, Dresse MF, Philippet P, Sirvent N, Waterkeyn C, Vilmer E, Philippe N, Otten J. Value of intravenous 6-mercaptopurine during continuation treatment in childhood acute lymphoblastic leukemia and non-Hodgkin's lymphoma: final results of a randomized phase III trial (58881) of the EORTC CLG. Leukemia. 2005 May;19(5):721-6. link to original article PubMed
  2. I-BFM-SG IR ALL: Conter V, Valsecchi MG, Silvestri D, Campbell M, Dibar E, Magyarosy E, Gadner H, Stary J, Benoit Y, Zimmermann M, Reiter A, Riehm H, Masera G, Schrappe M. Pulses of vincristine and dexamethasone in addition to intensive chemotherapy for children with intermediate-risk acute lymphoblastic leukaemia: a multicentre randomised trial. Lancet. 2007 Jan 13;369(9556):123-31. link to original article contains dosing details in manuscript PubMed NCT00411541

Observation

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Yang et al. 2021 (CCCG-ALL-2015) 2015-2020 Phase 3 (E-de-esc) Vincristine & Dexamethasone Non-inferior EFS60

No active maintenance treatment beyond 1 year. Patients in this study were required to be in continuous remission for 1 year after initial treatment.

References

  1. CCCG-ALL-2015: Yang W, Cai J, Shen S, Gao J, Yu J, Hu S, Jiang H, Fang Y, Liang C, Ju X, Wu X, Zhai X, Tian X, Wang N, Liu A, Jiang H, Jin R, Sun L, Yang M, Leung AWK, Pan K, Zhang Y, Chen J, Zhu Y, Zhang H, Li C, Yang JJ, Cheng C, Li CK, Tang J, Zhu X, Pui CH. Pulse therapy with vincristine and dexamethasone for childhood acute lymphoblastic leukaemia (CCCG-ALL-2015): an open-label, multicentre, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2021 Sep;22(9):1322-1332. Epub 2021 Jul 27. link to original article link to PMC article PubMed ChiCTR-IPR-14005706

Relapsed or refractory

Blinatumomab monotherapy

Regimen

Study Years of enrollment Evidence
von Stackelberg et al. 2016 (MT103-205) 2012-2014 Phase 1/2 (RT)

Note: this is the MTD of a phase I/II trial enrolling children under the age of 18.

Immunotherapy

  • Blinatumomab (Blincyto) as follows:
    • Cycle 1: 5 mcg/day IV continuous infusion over 7 days, started on day 1, then 15 mcg/day IV continuous infusion over 21 days, started on day 8 (total dose: 350 mcg)
    • Cycles 2 to 5: 28 mcg/day IV continuous infusion over 28 days, started on day 1 (total dose per cycle: 784 mcg)

42-day cycle for up to 5 cycles

References

  1. MT103-205: von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, Bader P, O'Brien MM, Brethon B, Bhojwani D, Schlegel PG, Borkhardt A, Rheingold SR, Cooper TM, Zwaan CM, Barnette P, Messina C, Michel G, DuBois SG, Hu K, Zhu M, Whitlock JA, Gore L. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. J Clin Oncol. 2016 Dec 20;34(36):4381-4389. link to original article contains dosing details in manuscript PubMed NCT01471782

CCE

CCE: Clofarabine, Cyclophosphamide, Etoposide

Regimen

Study Evidence
Locatelli et al. 2009 Non-randomized

Patients in this study were pediatric: ≤ 15 years old at diagnosis and ≤ 21 years old at time of treatment. No patients had CNS disease at time of treatment, and no patients received CNS prophylaxis.

Chemotherapy

Supportive therapy

  • Prophylactic steroids used for patients with greater than 30 x 109 blasts/L in the peripheral blood prior to treatment

5-day course 2 out of 25 patients received a second course of CCE as consolidation therapy. Responding patients were given allogeneic HSCT if a suitable donor was immediately available or were given consolidation courses of chemotherapy including multiple agents active against ALL cells, chosen according to the treating physician's preference."

References

  1. Locatelli F, Testi AM, Bernardo ME, Rizzari C, Bertaina A, Merli P, Pession A, Giraldi E, Parasole R, Barberi W, Zecca M. Clofarabine, cyclophosphamide and etoposide as single-course re-induction therapy for children with refractory/multiple relapsed acute lymphoblastic leukaemia. Br J Haematol. 2009 Nov;147(3):371-8. Epub 2009 Aug 29. link to original article contains dosing details in manuscript PubMed

Clofarabine monotherapy

Regimen

Study Years of enrollment Evidence
Jeha et al. 2003 2000-2002 Phase 1, <20 pts (RT)
Jeha et al. 2006 (CLO212) 2002-2004 Phase 2 (RT)

Note: this dose was the MTD in Jeha et al. 2003.

Chemotherapy

2- to 6-week cycles, depending on response count recovery

References

  1. Jeha S, Gandhi V, Chan KW, McDonald L, Ramirez I, Madden R, Rytting M, Brandt M, Keating M, Plunkett W, Kantarjian H. Clofarabine, a novel nucleoside analog, is active in pediatric patients with advanced leukemia. Blood. 2004 Feb 1;103(3):784-9. Epub 2003 Oct 9. link to original article PubMed
  2. CLO212: Jeha S, Gaynon PS, Razzouk BI, Franklin J, Kadota R, Shen V, Luchtman-Jones L, Rytting M, Bomgaars LR, Rheingold S, Ritchey K, Albano E, Arceci RJ, Goldman S, Griffin T, Altman A, Gordon B, Steinherz L, Weitman S, Steinherz P. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006 Apr 20;24(12):1917-23. link to original article contains dosing details in abstract PubMed NCT00042341

DOLP

DOLP: Daunorubicin, Oncovin (Vincristine), L-Asparaginase, Prednisone

Regimen

Study Evidence
Rivera et al. 1986 Non-randomized

Chemotherapy

Glucocorticoid therapy

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

References

  1. Rivera GK, Buchanan G, Boyett JM, Camitta B, Ochs J, Kalwinsky D, Amylon M, Vietti TJ, Crist WM; Pediatric Oncology Group. Intensive retreatment of childhood acute lymphoblastic leukemia in first bone marrow relapse: a Pediatric Oncology Group study. N Engl J Med. 1986 Jul 31;315(5):273-8. link to original article PubMed

Doxorubicin, Pegaspargase, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Abshire et al. 2000 (POG 9310) NR Non-randomized
Raetz et al. 2008 (COG AALL01P2) 2003-2005 Non-randomized portion of RCT
Lew et al. 2021 (COG AALL0433) 2007-2013 Phase 3 (C) Doxorubicin, Pegaspargase, Vincristine, Prednisone; high-dose vincristine Not reported

Note: This is "Block 1" of re-induction. Randomization in COG AALL0433 was discontinued early due to high rates of neuropathy in the experimental arm.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis (CNS-)

CNS therapy, treatment (CNS+)

5-week course

Subsequent treatment

  • See papers for details of treatment beyond induction block 1

References

  1. POG 9310: Abshire TC, Pollock BH, Billett AL, Bradley P, Buchanan GR. Weekly polyethylene glycol conjugated L-asparaginase compared with biweekly dosing produces superior induction remission rates in childhood relapsed acute lymphoblastic leukemia: a Pediatric Oncology Group Study. Blood. 2000 Sep 1;96(5):1709-15. link to original article PubMed
  2. COG AALL01P2: Raetz EA, Borowitz MJ, Devidas M, Linda SB, Hunger SP, Winick NJ, Camitta BM, Gaynon PS, Carroll WL. Reinduction platform for children with first marrow relapse of acute lymphoblastic Leukemia: A Children's Oncology Group Study[corrected]. J Clin Oncol. 2008 Aug 20;26(24):3971-8. Erratum in: J Clin Oncol. 2008 Oct 1;26(28): 4697. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00049569
  3. COG AALL0433: Lew G, Chen Y, Lu X, Rheingold SR, Whitlock JA, Devidas M, Hastings CA, Winick NJ, Carroll WL, Wood BL, Borowitz MJ, Pulsipher MA, Hunger SP. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433. Haematologica. 2021 Jan 1;106(1):46-55. link to original article link to PMC article does not contain dosing details PubMed NCT00381680

Inotuzumab ozogamicin monotherapy

Regimen

Study Years of enrollment Evidence
Kantarjian et al. 2012 (MDACC 2009-0872) 2010-2011 Phase 2

Antibody-drug conjugate therapy

  • Inotuzumab ozogamicin (Besponsa) 0.8 mg/m2 IV once on day 1, then 0.5 mg/m2 IV once per day on days 8 & 15
    • For patients achieving CR or CRi, day 1 dose was reduced to 0.5 mg/m2

21-day cycle for 1 cycle, then 28-day cycle for up to 5 cycles

References

  1. MDACC 2009-0872: Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O'Brien S. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-11. Epub 2012 Feb 21. link to original article contains dosing details in abstract PubMed NCT01134575

Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) 2003-2007 Phase 3 (E-switch-ic) Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone Superior OS

Note: per the protocol, this regimen is intended only for patients 18 and younger. This regimen is for patients allergic to pegaspargase.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • Age less than 2: 8 mg IT once per day on days 1 & 8
    • Age 2: 10 mg IT once per day on days 1 & 8
    • Age older than 2: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

References

  1. CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00967057

Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) 2003-2007 Phase 3 (E-switch-ic) Idarubicin, Pegaspargase, Vincristine, Dexamethasone Superior OS

Note: per the protocol, this regimen is intended only for patients 18 and younger.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria:
    • Age less than 2: 8 mg IT once per day on days 1 & 8
    • Age 2: 10 mg IT once per day on days 1 & 8
    • Age older than 2: 12 mg IT once per day on days 1 & 8

4-week course

Subsequent treatment

  • See paper for details of treatment beyond induction

References

  1. CCLG ALL R3: Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00967057

Tisagenlecleucel monotherapy

Regimen

Study Years of enrollment Evidence Efficacy
Grupp et al. 2013 (Pedi CART19) 2011-NR Pilot
Maude et al. 2014 (UPCC04409) 2012-2014 Phase 1/2a
Maude et al. 2018 (ELIANA) 2015-2017 Phase 2 (RT) ORR: 81%

Note: dosing instructions are based on ELIANA.

Preceding treatment

  • Lymphodepleting therapy with FC or CYVE

Immunotherapy

  • Tisagenlecleucel (Kymriah) by the following weight-based criteria:
    • Up to 50 kg: 2 to 5 x 106 CTL019 transduced viable T-cells per kg body weight IV once on day 0
    • Greater than 50 kg: 1.0 to 2.5 x 108 CTL019 transduced viable T-cells IV once on day 0

One course

References

  1. Pedi CART19: Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, Teachey DT, Chew A, Hauck B, Wright JF, Milone MC, Levine BL, June CH. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013 Apr 18;368(16):1509-1518. Epub 2013 Mar 25. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01626495
  2. UPCC04409: Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. Erratum in: N Engl J Med. 2016 Mar 10;374(10):998. link to original article link to PMC article PubMed NCT01029366
  3. ELIANA: Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. link to original article link to supplementary protocol contains dosing details in supplement link to PMC article PubMed NCT02435849

Consolidation after salvage therapy

Blinatumomab monotherapy

Regimen variant #1, 1 cycle

Study Years of enrollment Evidence Comparator Comparative Efficacy
Locatelli et al. 2021 (Amgen 20120215) 2015-2019 Phase 3 (E-switch-ooc) Standard salvage consolidation chemotherapy Superior EFS

Immunotherapy

  • Blinatumomab (Blincyto) 15 mcg/m2/day IV continuous infusion over 28 days, started on day 1 (total dose: 420 mcg/m2)

42-day course

Subsequent treatment


Regimen variant #2, 2 cycles

Study Years of enrollment Evidence Comparator Comparative Efficacy
Brown et al. 2021 (COG AALL1331) 2014-2019 Phase 3 (E-switch-ooc) Standard salvage consolidation chemotherapy Might have superior DFS

Note: insufficient dosing information was present in the abstract.

Immunotherapy

Subsequent treatment

References

  1. COG AALL1331: Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):833-842. link to original article PubMed NCT02101853
  2. Amgen 20120215: Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. link to original article contains dosing details in abstract PubMed NCT02393859

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Johnson et al. 1981 1976-1980 Non-randomized
Kersey et al. 1987 1982-1985 Quasi-randomized Auto HSCT Superior RFS

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

  • Total body irradiation by the following study-specific criteria:
    • Zhang et al. 2023: 450 cGy once per day on days -5 & -4 (900 cGy total)
    • Other studies: 10 to 1200 cGy total

Immunotherapy

One course

Immunotherapy

Stem cells transfused on day 0

References

  1. Johnson FL, Thomas ED, Clark BS, Chard RL, Hartmann JR, Storb R. A comparison of marrow transplantation with chemotherapy for children with acute lymphoblastic leukemia in second or subsequent remission. N Engl J Med. 1981 Oct 8;305(15):846-51. link to original article PubMed
  2. Kersey JH, Weisdorf D, Nesbit ME, LeBien TW, Woods WG, McGlave PB, Kim T, Vallera DA, Goldman AI, Bostrom B, Hurd D, Ramsay NKC. Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia. N Engl J Med. 1987 Aug 20;317(8):461-7. link to original article PubMed

Further notes

Pediatric ALL regimens tend to be very complex. This list on ped-onc.org appears to be fairly comprehensive and includes regimen details for some of the common regimens e.g. COG-AALL0232. For now we will try to include a list of references here and potentially build these regimens here, over time.

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