Difference between revisions of "Staging page"

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</div>
 
</div>
 
{{#lst:Section editor transclusions|peds}}
 
{{#lst:Section editor transclusions|peds}}
−
<big>''This page contains studies that were specific to pediatric populations. For the more general AML page, follow [[Acute myeloid leukemia|this link]].</big>
+
<big>''This page contains studies that were specific to pediatric populations. For the more general T-cell acute lymphoblastic leukemia page, follow [[T-cell acute lymphoblastic leukemia|this link]].</big>
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
Line 10: Line 10:
 
<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>
 
|}
 
|}
−
The following study protocols are included on this page:
+
{{TOC limit|limit=4}}
−
{| class="wikitable sortable" style="width: 50%; text-align:center;"  
+
=Guidelines=
−
! style="width: 50%" |Study
+
=="How I Treat"==
−
! style="width: 50%" |Years of enrollment
+
*'''2020:''' Teachey & O'Connor [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6966932/ How I treat newly diagnosed T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma in children]
 +
*'''2020:''' Hunger & Raetz. [https://doi.org/10.1182/blood.2019004043 How I treat relapsed acute lymphoblastic leukemia in the pediatric population]
 +
==[https://www.nccn.org/ NCCN]==
 +
*[https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia]
 +
=Upfront therapy=
 +
==COG AALL0434 protocol==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, Arms B (Nelarabine Arms) {{#subobject:1511c2|Variant=1}}===
 +
'''All Patients'''
 +
{| 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/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
|-
 
|-
−
|UK MRC AML10
+
|}
−
|1988-1995
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV once on day 4 (OR 5 OR 6)
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) 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
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28 (Total of 60 mg/m<sup>2</sup>/day, DO NOT TAPER)
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT once at time of diagnostic lumbar puncture or Day 1
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Initial Dose
 
|-
 
|-
−
|EORTC 58921
+
|1 to 1.99 years
−
|1992-2002
+
|30 mg
 
|-
 
|-
−
|I-BFM-SG 2001/01
+
|2 to 2.99 years
−
|2001-2009
+
|50 mg
 
|-
 
|-
−
|UK MRC AML15
+
|≥ 3 years
−
|2002-2006
+
|70 mg
 +
|}
 +
*[[Methotrexate (MTX)]] IT once per day on days 8, 29 (CNS3 patients on days 15, 22 ALSO)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 
|-
 
|-
−
|St. Jude AML02
+
|1 to 1.99
−
|2002-2008
+
|8 mg
 
|-
 
|-
−
|COG AAML0531
+
|2 to 2.99
−
|2006-2010
+
|10 mg
 
|-
 
|-
−
|St. Jude AML08
+
|3 to 8.99
−
|2008-2017
+
|12 mg
 
|-
 
|-
−
|COG AAML1031
+
|≥ 9
−
|2011-2016
+
|15 mg
 +
|}
 +
'''29-day course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine {{#subobject:ae17db|Regimen=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 
|-
 
|-
−
|COG AAML1421
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
−
|2016-2018
+
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (E-RT-esc)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 
|-
 
|-
 
|}
 
|}
−
{{TOC limit|limit=4}}
+
''Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.''
−
=Guidelines=
+
<div class="toccolours" style="background-color:#cbd5e8">
−
=="How I Treat"==
+
====Preceding treatment====
−
*'''2021:''' Rubnitz & Kaspers [https://doi.org/10.1182/blood.2021011694 How I treat pediatric acute myeloid leukemia]
+
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Daunorubicin, Pegaspargase, Vincristine, Prednisone]] induction
−
=Upfront induction therapy=
+
</div>
−
==COG AAML1031 arm A (low-risk)==
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day over 30 minutes on days 8, 50
 +
**Must reduce urine specific gravity to ≤ 1.015 prior to administration
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV over 1 to 30 minutes or SC once per day on days 8 to 11, 15 to 18, 50 to 53, 57 to 60
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21, 50 to 63
 +
**DO NOT escalate or modify dose based on blood counts during this course.  
 +
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV once per day over 60 minutes on days 1 to 5, 43 to 47
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IM or IV over 1 to 2 hours once per day on days 22 & 64
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 22, 29, 64, 71
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] IT on days 15, 22, 57, 64 (Omit Day 22 if CNS3 T-ALL)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|1 to 1.99
 +
|8 mg
 +
|-
 +
|2 to 2.99
 +
|10 mg
 +
|-
 +
|3 to 8.99
 +
|12 mg
 +
|-
 +
|≥ 9
 +
|15 mg
 +
|}
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]]
 +
**CNS3 T-ALL: 1,800cGy in 10 once daily fractions.
 +
**Intermediate/High Risk ARM B: 1,200 cGy in 8 once-daily fractions given during weeks 4 and 5 of consolidation
 +
'''71-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Interim maintenance
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part I===
+
===Interim Maintenance, with Capizzi MTX (Arms A and B) {{#subobject:9d711b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 +
|-
 +
|}
 +
''Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]] versus [[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Nelarabine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
**If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose.
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IM or IV over 1 to 2 hours once per day on days 2, 22
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1  
+
*[[Methotrexate (MTX)]] IT once on days 1, 31
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 
−
**
 
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''10-day course, followed by:'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part II===
+
===Delayed Intensification, Nelarabine Arms (Arms B and D) {{#subobject:9d711b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 +
|-
 +
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] by the following BSA-based criteria:
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 8, 15, 43, 50
−
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 8
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
−
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 8
+
*[[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
−
*[[Daunorubicin (Cerubidine)]] by the following BSA-based criteria:
+
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
−
**BSA 0.6 m<sup>2</sup> or more: 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IM or IV over 1 to 2 hours on day 4 (OR 5 OR 6), 43
−
**BSA < 0.6 m<sup>2</sup>: 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
−
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
+
**Should not be given to patients receiving CRT (Arm D and CNS3 T-ALL patients)
−
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV 60 minutes once per day on days 29 to 33
−
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID).
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
+
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
 
−
**
 
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''8-day course, followed by:'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Radiotherapy====
 +
*Arm D Only: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,200 cGy in 8 once daily fractions to start on day 50 of DI
 +
*CNS3 T-ALL: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy in 10 once daily fractions to start on day 50 of DI
 +
'''63-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part I===
+
===Maintenance, Arms B and D {{#subobject:9d711b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 +
|-
 +
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] by the following BSA-based criteria:
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 57
−
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 5
+
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 28, 36 to 84
−
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
−
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
+
**No dose escalation recommended for the first maintenance cycle
−
**BSA 0.6 m<sup>2</sup> or more: 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 through 5
+
**Thereafter, for ANC ≥ 1,500μL on 3 CBCs done over 6 weeks or 2 monthly CBCs, increase dose of methotrexate or mercaptopurine by 25%
−
**BSA < 0.6 m<sup>2</sup>: 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV over 60 minutes once per day on days 29 to 33
 +
**DO NOT Administer with other Chemotherapy agents
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> PO twice per day on days 1 to 5 and 57 to 61 (Total of 40 mg/m<sup>2</sup>/day, divided BID)
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II
+
*[[Methotrexate (MTX)]] IT once on day 1
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''5-day course, followed by:'''
+
Repeat above cycle for a total of 3 cycles.
 +
'''3 Cycles'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part II===
+
===Maintenance, continuation after cycle 3 (Arms B and D) {{#subobject:9d711b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 +
|-
 +
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] by the following BSA-based criteria:
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 29, 57
−
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
+
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
−
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
−
*[[Mitoxantrone (Novantrone)]] by the following BSA-based criteria:
+
**No dose escalation recommended for the first maintenance cycle
−
**BSA 0.6 m<sup>2</sup> or more: 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
+
**Thereafter, for ANC ≥ 1,500μL on 3 CBCs done over 6 weeks or 2 monthly CBCs, increase dose of methotrexate or mercaptopurine by 25%
−
**BSA < 0.6 m<sup>2</sup>: 0.4 mg/kg once per day on days 3 to 6
+
====Glucocorticoid therapy====
−
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
+
*[[Prednisone (Sterapred)]] 20 mg/m<sup>2</sup> PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (Total of 40 mg/m<sup>2</sup>/day, divided BID)  
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Intensification I
+
*[[Methotrexate (MTX)]] IT once on day 1
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''6-day course'''
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Duration====
 +
*Girls T-ALL: Continue repeating 12 week cycles of maintenance therapy II until the total duration of therapy is two years from the start of Interim Maintenance (~ Week 121)
 +
*Boys T-ALL: Continue to repeat 12 week cycles of Maintenance therapy II until the total duration of therapy is three years from the start of Interim Maintenance (~ Week 173).
 +
*T-NHL patients (regardless of gender): Continue to repeat 12 week cycles of maintenance therapy II until the total duration reaches two years from the start of Interim Maintenance (~ Week 121)
 +
'''84-day course'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
 
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
==COG AAML1031 arm A (high-risk)==
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
 +
==COG AALL1231 Protocol Arm A==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part I===
+
===Induction {{#subobject:61171f|Variant=1}}===
 +
All T-ALL and T-LLy patients
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ABFM_.26_Bortezomib_99|ABFM & Bortezomib]] induction
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4, 18
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
−
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
+
====Glucocorticoid therapy====
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1  
+
*[[Cytarabine (Ara-C)]] IT once on day 1 or at the time of diagnostic lumbar puncture (if within 72 hours of protocol initiation)
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
+
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Initial Dose
 +
|-
 +
|1 to 1.99 years
 +
|30 mg
 +
|-
 +
|2 to 2.99 years
 +
|50 mg
 +
|-
 +
|≥ 3 years
 +
|70 mg
 +
|}
 +
*[[Methotrexate (MTX)]] IT once per day on days 8, 29
 +
**CNS3 patients also receive [[Methotrexate (MTX)]] IT on days 15, 22
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''10-day course, followed by:'''
 
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part II===
+
===Consolidation {{#subobject:61171f|Variant=1}}===
 +
All T-ALL and T-LLy Patients
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day over 30 to 60 minutes on days 1, 29
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
+
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV over 1 to 30 minutes or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
−
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
−
**IF BSA < 0.6 m<sup>2</sup>, [[Mitoxantrone (Novantrone)]] 0.4 mg/kg once per day on days 3 to 6.
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 15, 43
−
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days on days 15, 22, 43, 50
−
====CNS therapy, prophylaxis====
+
====CNS prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction I
+
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
+
**CNS3 patients and CNS3 T-LLy: Omit days 15, 22
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''6-day course, followed by:'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part I===
+
===Interim Maintenance, SR patients, with CMTX {{#subobject:61171f|Variant=1}}===
 +
SR Patients Receive After Consolidation
 +
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours 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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
+
**If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 2, 22
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II
+
*[[Methotrexate (MTX)]] IT once on days 1, 31
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''5-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part II===
+
===Delayed Intensification {{#subobject:61171f|Variant=1}}===
−
<div class="toccolours" style="background-color:#b3e2cd">
+
All T-ALL and T-LLy Patients
−
====Chemotherapy====
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
*High Dose [[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 2, 8, 9
+
!style="width: 20%"|Study
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 100 mg/kg IV over 3 hours every 12 hours on days 1, 2, 8, 9
+
!style="width: 20%"|Years of enrollment
−
*[[E.Coli L-Asparaginase (LASP)]] 6000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
**IF BSA < 0.6 m<sup>2</sup>, [[E.Coli L-Asparaginase (LASP)]] 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
!style="width: 20%"|Comparator
−
may substitute with another asparaginase formulation
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 25,000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
|-
−
**IF BSA < 0.6 m<sup>2</sup>, [[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 830 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
−
If Erwinia asparaginase is not available, pegasparaginase should NOT be given, and asparaginase should be omitted
+
|2014-2017
−
'''28-day course'''
+
| style="background-color:#1a9851" |Phase 3 (C)
−
</div></div>
+
|[[#COG_AALL1231_delayed_intensification_.26_Bortezomib_99|Delayed intensification with bortezomib]]
−
===References===
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
−
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
+
|-
−
 
+
|}
−
==COG AAML1031 arm C (FLT3/ITD+)==
+
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Induction, part I===
 
−
<div class="toccolours" style="background-color:#fdcdac">
 
−
====Biomarker eligibility criteria====
 
−
*FLT3/ITD+
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 8, 15, 43, 50
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
−
====Targeted therapy====
+
====Glucocorticoid therapy====
−
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 11 to 28
+
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID)
−
**see [[Sorafenib Dosing Nomogram]] for more details.
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1  
+
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 
−
**
 
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''28-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part II===
+
===Delayed Intensification, IR patients {{#subobject:61171f|Variant=1}}===
 +
All T-ALL and T-LLy Patients
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 8  
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 8, 15, 43, 50
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 8
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
+
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
−
====Targeted therapy====
+
====Glucocorticoid therapy====
−
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 9 to 36
+
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID)
−
**see [[Sorafenib Dosing Nomogram]] for more details.
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
+
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
 
−
**
 
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''36-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part I===
+
===Interim Maintenance, #1 with HDMTX - ALL IR Patients {{#subobject:61171f|Variant=1}}===
 +
SR and VHR T-ALL and T-LLy DO NOT RECEIVE
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 5
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
+
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56.
−
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
+
*High Dose [[Methotrexate (MTX)]] 5,000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43.
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
+
**[[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
−
====Targeted therapy====
+
====Supportive therapy====
−
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 6 through 33
+
*[[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, 4, 17, 18, 31, 32, 45, 46
−
**see [[Sorafenib Dosing Nomogram]] for more details.
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II.
+
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''33-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part II===
+
===Interim Maintenance, #2 with CMTX - ALL IR Patients {{#subobject:61171f|Variant=1}}===
 +
IR T-ALL and T-LLy Patients receive this after DI as IM#2
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
+
**If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
−
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Mitoxantrone (Novantrone)]] 0.4 mg/kg once per day on days 3 to 6
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 2, 22
−
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
 
−
====Targeted therapy====
 
−
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 7 to 34
 
−
**see [[Sorafenib Dosing Nomogram]] for more details
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Intensification I
+
*[[Methotrexate (MTX)]] IT once on days 1 and 31
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''6-day course'''
+
'''56-day course'''
−
</div></div>
 
−
===References===
 
−
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
 
−
 
 
−
==COG AAML0531 arm B (Gemtuzumab)==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part I===
+
===Intensification, Block 1 (VHR patients) {{#subobject:61171f|Variant=1}}===
 +
VHR Patients receive immediately after consolidation
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] by the following weight-based criteria:
+
*High Dose [[Methotrexate (MTX)]] 5,000 mg/m<sup>2</sup> IV over 24 hours on day 1 ONLY.
−
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 15 minutes every 12 hours on days 1 to 10
+
**[[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
−
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 10
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 6
−
*[[Daunorubicin (Cerubidine)]] by the following weight-based criteria:
+
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup> every 12 hours IV over 1 to 6 hours x 5 doses on days 2 to 4
−
**BSA 0.6 m<sup>2</sup> or more: 50 mg/m<sup>2</sup> IV over 6 hours once per day on days 1, 3, 5
+
*High Dose [[Cytarabine (Ara-C)]] 2,000 mg/m<sup>2</sup> every 12 hours IV over 3 hours x 2 doses on day 5  
−
**BSA < 0.6 m<sup>2</sup>: 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 6
−
*[[Etoposide (Vepesid)]] by the following weight-based criteria:
+
** Administer 3 hours after completion of the second high dose [[Cytarabine (Ara-C)]] infusion
−
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5  
+
====Glucocorticoid therapy====
−
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 4 hours once per day on days 1 to 5
+
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 5 (20 mg/m<sup>2</sup>/day, divided BID)
−
====Antibody-drug conjugate therapy====
+
====Supportive therapy====
−
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following weight-based criteria:
+
*[[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, 4
−
**BSA 0.6 m<sup>2</sup> or more: 3 mg/m<sup>2</sup> IV over 2 hours once on day 6
+
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC or IV daily beginning on day 7 and until WBC > 3000μL
−
**BSA < 0.6 m<sup>2</sup>: 0.1 mg/kg IV once on day 6
+
**Alternative: [[Pegfilgrastim (Neulasta)]] 100 mcg/kg (Maximum dose of 6 mg) SC once during the 7 to 11th day
−
====CNS therapy, prophylaxis====
+
====CNS therapy, Triple Intrathecal Therapy====
−
*[[Cytarabine (Ara-C)]] IT on day 1
+
Given on day 1, 2 hours after the start of HD MTX infusion
−
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
+
*1 to < 2 yrs
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
**[[Methotrexate (MTX)]]: 8 mg
−
! style="width: 25%" |Age
+
**[[Hydrocortisone (Cortef)]]: 8 mg
−
! style="width: 25%" |Dose
+
**[[Cytarabine (Ara-C)]]: 16 mg
 +
*2 to < 3 yrs:
 +
**[[Methotrexate (MTX)]]: 10 mg
 +
**[[Hydrocortisone (Cortef)]]: 10 mg
 +
**[[Cytarabine (Ara-C)]]: 20 mg
 +
*3 to < 9 yrs:
 +
**[[Methotrexate (MTX)]]: 12 mg
 +
**[[Hydrocortisone (Cortef)]]: 12 mg
 +
**[[Cytarabine (Ara-C)]]: 24 mg
 +
*≥ 9 yrs:
 +
**[[Methotrexate (MTX)]]: 15 mg
 +
**[[Hydrocortisone (Cortef)]]: 15 mg
 +
**[[Cytarabine (Ara-C)]]: 30 mg
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, Block 2 {{#subobject:61171f|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]]
 
|-
 
|-
−
|0 - 0.99
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
−
|20
+
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
|-
 
|-
−
|1 - 1.99
+
|}
−
|30
+
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*High Dose [[Methotrexate (MTX)]] 5,000 mg/m<sup>2</sup> IV over 24 hours on day 1 ONLY
 +
**[[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
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 6
 +
*[[Ifosfamide (Ifex)]] 800 mg/m<sup>2</sup> every 12 hours IV infusion over 1 hour x 5 doses on days 2 to 4
 +
**Start Immediately after completion of high dose [[Methotrexate (MTX)]] infusion.
 +
*[[Daunorubicin (Cerubidine)]] 30 mg/m<sup>2</sup> IV over 1 to 15 minutes on day 5
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 6
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 5 (20 mg/m<sup>2</sup>/day, divided BID)
 +
====Supportive therapy====
 +
*[[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
 +
*[[Mesna (Mesnex)]] 300 mg/m<sup>2</sup> at hour 0, 4, and 8 from the start of each [[Ifosfamide (Ifex)]] infusion on days 2 to 4
 +
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC or IV daily beginning on day 7 and until WBC > 3000μL
 +
**Alternative: [[Pegfilgrastim (Neulasta)]] 100 mcg/kg (Max 6 mg/dose) SC once during the 7 to 11th day
 +
====CNS therapy, Triple Intrathecal Therapy====
 +
Given on day 1, 2 hours after the start of HD MTX infusion
 +
*1 to < 2 yrs
 +
**[[Methotrexate (MTX)]]: 8 mg
 +
**[[Hydrocortisone (Cortef)]]: 8 mg
 +
**[[Cytarabine (Ara-C)]]: 16 mg
 +
*2 to < 3 yrs:
 +
**[[Methotrexate (MTX)]]: 10 mg
 +
**[[Hydrocortisone (Cortef)]]: 10 mg
 +
**[[Cytarabine (Ara-C)]]: 20 mg
 +
*3 to < 9 yrs:
 +
**[[Methotrexate (MTX)]]: 12 mg
 +
**[[Hydrocortisone (Cortef)]]: 12 mg
 +
**[[Cytarabine (Ara-C)]]: 24 mg
 +
*≥ 9 yrs:
 +
**[[Methotrexate (MTX)]]: 15 mg
 +
**[[Hydrocortisone (Cortef)]]: 15 mg
 +
**[[Cytarabine (Ara-C)]]: 30 mg
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, Block 3 {{#subobject:61171f|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]]
 
|-
 
|-
−
|2 - 2.99
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
−
|50
+
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 
|-
 
|-
−
|≥ 3
 
−
|70
 
 
|}
 
|}
−
'''10-day course'''
+
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 2,000 mg/m<sup>2</sup> every 12 hours IV over 3 hours x 4 doses on days 1, 2
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> every 12 hours IV over 1 to 2 hours x 5 doses on days 3 to 5
 +
**First dose to be given 12 hours after the start of the 4th high dose [[Cytarabine (Ara-C)]] on day 2
 +
**Infusion rate should not exceed 300 mg/m<sup>2</sup>/hour (10 mg/kg/hour)
 +
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 6
 +
====Glucocorticoid therapy====
 +
*[[Dexamethasone (Decadron)]] 10 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 5 (20 mg/m<sup>2</sup>/day, divided BID)
 +
====Supportive therapy====
 +
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC or IV daily beginning on day 7 and until WBC > 3000μL
 +
**Alternative: [[Pegfilgrastim (Neulasta)]] 100 mcg/kg (Max 6 mg/dose) SC once during the 7 to 11th day
 +
====CNS therapy, Triple Intrathecal Therapy====
 +
Given on day 1, 2 hours after the start of HD MTX infusion
 +
*1 to < 2 yrs
 +
**[[Methotrexate (MTX)]]: 8 mg
 +
**[[Hydrocortisone (Cortef)]]: 8 mg
 +
**[[Cytarabine (Ara-C)]]: 16 mg
 +
*2 to < 3 yrs:
 +
**[[Methotrexate (MTX)]]: 10 mg
 +
**[[Hydrocortisone (Cortef)]]: 10 mg
 +
**[[Cytarabine (Ara-C)]]: 20 mg
 +
*3 to < 9 yrs:
 +
**[[Methotrexate (MTX)]]: 12 mg
 +
**[[Hydrocortisone (Cortef)]]: 12 mg
 +
**[[Cytarabine (Ara-C)]]: 24 mg
 +
*≥ 9 yrs:
 +
**[[Methotrexate (MTX)]]: 15 mg
 +
**[[Hydrocortisone (Cortef)]]: 15 mg
 +
**[[Cytarabine (Ara-C)]]: 30 mg
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Induction, part II===
+
===Delayed Intensification {{#subobject:61171f|Variant=1}}===
 +
All T-ALL and T-LLy Patients
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 15 minutes every 12 hours on days 1 to 8  
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 8, 15, 43, 50
−
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 8
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 6 hours once per day on days 1, 3, 5
+
*[[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
−
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
+
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
−
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 4 hours once per day on days 1 to 5
+
*[[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 and 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID)
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
+
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''28-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part I===
+
===Interim Maintenance, with CMTX {{#subobject:61171f|Variant=1}}===
 +
VHR Patients receive after DI
 +
{| 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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
+
*[[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
−
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 hour every 12 hours on days 1 to 5
+
**If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
−
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 5
+
*[[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
−
*[[Etoposide (Vepesid)]] by the following weight-based criteria:
+
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 2, 22
−
**BSA 0.6 m<sup>2</sup> or more: 150 mg/m<sup>2</sup> IV over 1 hour once per day on days 1 to 5
 
−
**BSA < 0.6 m<sup>2</sup>: 5 mg/kg IV over 4 hours once per day on days 1 to 5
 
−
**Each dose of [[Etoposide (Vepesid)]] should immediately follow the AM dose of [[Cytarabine (Ara-C)]]
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction II
+
*[[Methotrexate (MTX)]] IT once on days 1, 31
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''5-day course'''
+
'''56-day course'''
 
</div></div><br>
 
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Intensification, part II===
+
===Maintenance, all patients {{#subobject:61171f|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/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
 +
|2014-2017
 +
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
 +
|-
 +
|}
 +
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 29, 57
−
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 hour every 12 hours on days 1 to 4
+
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
−
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 4
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> once a day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
−
*[[Mitoxantrone (Novantrone)]] by the following weight-based criteria:
+
**Omit day 29 of the first FOUR cycles for SR T-ALL and T-LLy patients
−
**BSA 0.6 m<sup>2</sup> or more: 12 mg/m<sup>2</sup> IV over 1 hour once per day on days 3 to 6
+
**Omit day 29 of the first TWO cycles for IR T-ALL and T-LLy patients
−
**BSA < 0.6 m<sup>2</sup>: 0.4 mg/kg once per day on days 3 to 6
+
====Glucocorticoid therapy====
−
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
+
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (6 mg/m<sup>2</sup>/day, divided BID)
−
====Antibody-drug conjugate therapy====
 
−
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following weight-based criteria:
 
−
**BSA 0.6 m<sup>2</sup> or more: 3 mg/m<sup>2</sup> IV over 2 hours once on day 7
 
−
**BSA < 0.6 m<sup>2</sup>: 0.1 mg/kg once on day 7
 
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Intensification I
+
*[[Methotrexate (MTX)]] IT once on days 1
 +
**Also on day 29 of the first FOUR cycles for SR patients
 +
**Also on day 29 of the first TWO cycles for IR patients
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
! style="width: 25%" |Age
 
! style="width: 25%" |Age
 
! style="width: 25%" |Dose
 
! style="width: 25%" |Dose
 
|-
 
|-
−
|0 - 0.99
+
|1 to 1.99
−
|20
+
|8 mg
 
|-
 
|-
−
|1 - 1.99
+
|2 to 2.99
−
|30
+
|10 mg
 
|-
 
|-
−
|2 - 2.99
+
|3 to 8.99
−
|50
+
|12 mg
 
|-
 
|-
−
|≥ 3
+
|≥ 9
−
|70
+
|15 mg
 
|}
 
|}
−
'''7-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Intensification, part III===
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Radiotherapy====
−
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
+
ONLY the following groups receive CRT during the first cycle of maintenance.
−
**BSA 0.6 m<sup>2</sup> or more: 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 2, 8, 9
+
*T-ALL Patients
−
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1, 2, 8, 9
+
**CNS1 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,200 cGy
−
*[[E.Coli L-Asparaginase (LASP)]] by the following weight-based criteria:
+
**CNS2 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,200 cGy
−
**BSA 0.6 m<sup>2</sup> or more: 6000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
**CNS3 IR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
−
**BSA < 0.6 m<sup>2</sup>: 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
**CNS3 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
−
may substitute with another asparaginase formulation
+
*T-LLy Patients
−
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] by the following weight-based criteria:
+
**CNS3 IR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
−
**BSA 0.6 m<sup>2</sup> or more: 25,000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
**CNS3 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
−
**BSA < 0.6 m<sup>2</sup>: 830 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
+
'''Duration of therapy:'''
−
'''28-day course'''
+
*SR and IR T-ALL Girls: repeat 12 week cycles of maintenance for a total duration of 2 years from Interim Maintenance start.
 +
*VHR T-ALL Girls: Repeat 12 week cycles of maintenance for a total duration of 2 years from Intensification Block 1 start.
 +
*SR and IR T-ALL Boys: repeat 12 week cycles of maintenance for a total duration of 3 years from Interim Maintenance start.
 +
*VHR T-ALL Boys: Repeat 12 week cycles of maintenance for a total duration of 3 years from Intensification Block 1 start.
 +
*T-LLy regardless of gender: repeat 12 week cycles of maintenance for a total duration of 2 years from Interim Maintenance start.
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
 
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
==ADE (standard-dose Ara-C) {{#subobject:e221d7|Regimen=1}}==
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
−
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide
+
# '''COG AALL1231:''' Teachey DT, Devidas M, Wood BL, Chen Z, Hayashi RJ, Hermiston ML, Annett RD, Archer JH, Asselin BL, August KJ, Cho SY, Dunsmore KP, Fisher BT, Freedman JL, Galardy PJ, Harker-Murray P, Horton TM, Jaju AI, Lam A, Messinger YH, Miles RR, Okada M, Patel SI, Schafer ES, Schechter T, Singh N, Steele AC, Sulis ML, Vargas SL, Winter SS, Wood C, Zweidler-McKay P, Bollard CM, Loh ML, Hunger SP, Raetz EA. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022 Jul 1;40(19):2106-2118. Epub 2022 Mar 10. [https://doi.org/10.1200/jco.21.02678 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35271306/ PubMed] NCT02112916
−
<br>7-3-7: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide
+
=Pre-phase=
−
<br>8-3-5: '''<u>8</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
+
==Methylprednisolone monotherapy {{#subobject:5gh1bb|Regimen=1}}==
−
<br>10-3-5: '''<u>10</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 8-3-5, 1600/150/500, intermittent Ara-C {{#subobject:f7e0ca|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]]
 
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]
+
|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
−
|1988-1995
+
|2005-2011
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+8]]
 
−
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
+
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
−
|2002-2006
+
|2012-2015
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
 
−
|2006-2010
 
 
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
| style="background-color:#d3d3d3" |
 
−
| style="background-color:#d3d3d3" |
 
 
|-
 
|-
 
|}
 
|}
−
''Note: these trials have complicated treatment schemas; see papers for details. This is IND2 for COG AAML0531.''
+
''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:#cbd5e8">
 
−
====Preceding treatment====
 
−
*UK MRC AML10: [[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]] induction
 
−
*COG AAML0531: [[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]] induction versus [[#ADE_.26_GO|ADE & GO]]
 
−
</div>
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy====
+
====Glucocorticoid therapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 8
+
*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 1 to 3
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
'''3-day course'''
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 
−
'''8-day course'''
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*UK MRC AML10: [[#MACE_88|MACE]] consolidation
+
*DFCI 05-001: Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
−
*COG AAML0531: [[#CYVE|CYVE]] interim maintenance
+
*DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
−
*Other trials: Consolidation (see paper for details)
+
</div></div>
−
</div></div><br>
+
===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]
 +
=Upfront induction therapy=
 +
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:516f7b|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, 10-3-5, 2000/150/500, intermittent Ara-C {{#subobject:77fe46|Variant=1}}===
+
===Regimen, modified ABFM {{#subobject:88f520|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]]
 
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]
+
|[https://doi.org/10.1016/S1470-2045(12)70600-9 Vora et al. 2013 (UKALL 2003)]
−
|1988-1995
+
|2003-2011
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+10]]
 
−
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 
−
|-
 
−
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 
−
|2002-2006
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3171799/ Rubnitz et al. 2010 (AML02)]
 
−
|2002-2008
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#ADE_.28high-dose_Ara-C.29|ADE]]; high-dose Ara-C
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of MRD-positivity at day 22
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
 
−
|2006-2010
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#ADE_.26_GO|ADE & GO]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior EFS
 
 
|-
 
|-
 
|}
 
|}
−
''Note: these trials have complicated treatment schemas; see papers for details.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 or days 2, 4, 6
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 4 & 18
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5 or days 2 to 6
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
−
'''10-day course'''
+
====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)]] 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'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, cytarabine, mercaptopurine, pegaspargase, vincristine]] consolidation
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''UK MRC AML10:''' Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. [http://www.bloodjournal.org/content/89/7/2311.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9116274 PubMed]
+
# '''UKALL 2003:''' Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013 Mar;14(3):199-209. [https://doi.org/10.1016/S1470-2045(12)70600-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23395119 PubMed] ISRCTN07355119
−
##'''Update:''' Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. [https://doi.org/10.1016/S0140-6736(97)09214-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9504514 PubMed]
+
==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:a39331|Regimen=1}}==
−
#'''AML02:''' Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, Pounds S, Razzouk BI, Lacayo NJ, Cao X, Meshinchi S, Degar B, Airewele G, Raimondi SC, Onciu M, Coustan-Smith E, Downing JR, Leung W, Pui CH, Campana D. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010 Jun;11(6):543-52. Epub 2010 May 5. [https://doi.org/10.1016/s1470-2045(10)70090-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3171799/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20451454/ PubMed] NCT00136084
 
−
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
 
−
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
 
−
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 
−
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
 
−
==ADE (high-dose Ara-C) {{#subobject:c7eb71|Regimen=1}}==
 
−
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide
 
−
<br>HIDAC-3-5: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
 
−
<br>HIDAC-3-7: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:386dha|Variant=1}}===
+
===Regimen {{#subobject:1511c2|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://doi.org/10.1200/jco.19.00327 Rubnitz et al. 2019 (AML08)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
−
|2008-2017
+
|2007-2014
−
| style="background-color:#1a9851" |Phase 3 (C)
+
|style="background-color:#91cf61"|Non-randomized portion of RCT
−
|[[#Clofarabine_.26_Cytarabine_99|Clofarabine & Cytarabine]]
 
−
| style="background-color:#91cf60" |Seems to have superior MRD at day 22
 
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was intended for patients younger than 22 years.''
 
 
<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, 3, 5 (total dose per cycle: 18,000 mg/m<sup>2</sup>)
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 2, 4, 6
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 5 +/- 1 day
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 2 to 6
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
−
'''6-day course'''
+
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 +
'''4-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*Response- and risk-adapted therapy; see paper for details
+
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Nelarabine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine]] versus [[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''AML08:''' Rubnitz JE, Lacayo NJ, Inaba H, Heym K, Ribeiro RC, Taub J, McNeer J, Degar B, Schiff D, Yeoh AE, Coustan-Smith E, Wang L, Triplett B, Raimondi SC, Klco J, Choi J, Pounds S, Pui CH. Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. J Clin Oncol. 2019 Aug 10;37(23):2072-2081. Epub 2019 Jun 27. [https://doi.org/10.1200/jco.19.00327 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7001777/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31246522 PubMed] NCT00703820
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
==ADE & GO {{#subobject:e33id7|Regimen=1}}==
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
ADE & GO: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposidem, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
 +
==DOLP {{#subobject:3c9897|Regimen=1}}==
 +
DOLP: '''<u>D</u>'''aunorubicin, '''<u>O</u>'''ncovin (Vincristine), '''<u>L</u>'''-Asparaginase, '''<u>P</u>'''rednisone
 +
<br>DVPA: '''<u>D</u>'''aunorubicin, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone, '''<u>A</u>'''sparaginase
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:99ye46|Variant=1}}===
+
===Regimen (BFM 76/79 Phase I) {{#subobject:3fe1a2|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]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/S0140-6736(88)92596-2 Gaynon et al. 1988 (CCG-106)]
 +
|rowspan=2|1983-1984
 +
|rowspan=2 style="background-color:#1a9851"|Phase 3 (E-esc)
 +
|1. Control regimen
 +
| style="background-color:#91cf60" |Seems to have superior EFS36
 +
|-
 +
|2. New York regimen
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS36
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
+
|[https://doi.org/10.1002/(sici)1097-0142(19980201)82:3%3C600::aid-cncr24%3E3.0.co;2-4 Steinherz et al. 1998 (CCG-123)]
−
|2006-2010
+
|1983-1985
−
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
+
|style="background-color:#1a9851"|Phase 3 (C)
−
|[[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]]
+
|1. LSA2-L2 & WBRT<br>2. LSA-L2<br>3. New York regimen
−
| style="background-color:#91cf60" |Seems to have superior EFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 
|-
 
|-
 
|}
 
|}
 +
''Note: the specific days of L-asparaginase are not specified; the schedule here is similar to those of other similar protocols.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10
+
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
−
====Antibody-drug conjugate therapy====
+
====Glucocorticoid therapy====
−
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV over 2 hours once on day 6
+
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, then tapered over 2 weeks
−
'''10-day course'''
+
====CNS therapy====
 +
*[[Methotrexate (MTX)]] IT once per day on days 1, 15, 29 (dose not specified)
 +
'''6-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#ADE_.28standard-dose_Ara-C.29|ADE 8-3-5]] re-induction
+
*BFM 76/79 Phase II
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
+
# '''CCG-106:''' Gaynon PS, Steinherz PG, Bleyer WA, Ablin AR, Albo VC, Finklestein JZ, Grossman NJ, Littman PS, Novak LT, Pyesmany AF, Sather HN, Hammond GD. Intensive therapy for children with acute lymphoblastic leukaemia and unfavourable presenting features: early conclusions of study CCG-106 by the Childrens Cancer Study Group. Lancet. 1988 Oct 22;2(8617):921-4. [https://doi.org/10.1016/S0140-6736(88)92596-2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2902379 PubMed]
−
==AIE {{#subobject:948b49|Regimen=1}}==
+
# '''CCG-123:''' Steinherz PG, Gaynon PS, Breneman JC, Cherlow JM, Grossman NJ, Kersey JH, Johnstone HS, Sather HN, Trigg ME, Uckun FM, Bleyer WA. Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group. Cancer. 1998 Feb 1;82(3):600-12. [https://doi.org/10.1002/(sici)1097-0142(19980201)82:3%3C600::aid-cncr24%3E3.0.co;2-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9452280 PubMed]
−
AIE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>I</u>'''darubicin, '''<u>E</u>'''toposide
+
==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone {{#subobject:h1gtbb|Regimen=1}}==
−
<br>ICE: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:c7b35a|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://www.nature.com/articles/2403932 Entz-Werle et al. 2005 (EORTC 58921)]
+
|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
−
|1992-2002
+
|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
 +
|-
 +
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
 +
|2012-2015
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[#MEC_99|MEC]]
+
|[[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_99|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]]
−
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
+
| 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">
 +
====Preceding treatment====
 +
*[[#Methylprednisolone_monotherapy|Methylprednisolone]] pre-phase
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m<sup>2</sup>)
+
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 5
−
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
+
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 6
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 7
−
'''7-day course'''
+
*[[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====
 +
*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 4 to 32
 +
====Supportive therapy====
 +
*[[Dexrazoxane (Zinecard)]] 300 mg/m<sup>2</sup> IV once per day on days 4 & 5
 +
'''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_Vincristin|Doxorubicin, Mercaptopurine, Methotrexate, Vincristine]] consolidation (IA)
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''EORTC 58921:''' Entz-Werle N, Suciu S, van der Werff ten Bosch J, Vilmer E, Bertrand Y, Benoit Y, Margueritte G, Plouvier E, Boutard P, Vandecruys E, Ferster A, Lutz P, Uyttebroeck A, Hoyoux C, Thyss A, Rialland X, Norton L, Pages MP, Philippe N, Otten J, Behar C; [[Study_Groups#EORTC|EORTC]] Children Leukemia Group. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report. Leukemia. 2005 Dec;19(12):2072-81. [https://www.nature.com/articles/2403932 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16136166 PubMed] NCT00002517
+
# '''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
−
==DA 3 + 10 {{#subobject:5c0062|Regimen=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. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed]
−
DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine
+
# '''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]
 +
=Consolidation after upfront therapy=
 +
==Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine {{#subobject:ae17db|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 50 mg/m<sup>2</sup> dauno {{#subobject:99321e|Variant=1}}===
+
===Regimen {{#subobject:9d711b|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/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
−
|2002-2006
+
|2007-2014
−
| style="background-color:#1a9851" |Phase 3 (C)
+
|style="background-color:#1a9851"|Phase 3 (E-esc)
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
+
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]]
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
+
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen is very similar to [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.''
+
''Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Daunorubicin, Pegaspargase, Vincristine, Prednisone]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 8 & 50
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 8 to 11, 15 to 18, 50 to 53, 57 to 60
−
'''10-day course'''
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21, 50 to 63
 +
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV once per day on days 1 to 5, 43 to 47
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM once per day on days 22 & 64
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 22, 64, 71
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] (dose not specified) IT on days 15, 22, 57, 64
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] in some arms (see paper for details)
 +
'''71-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*See papers for details (to be completed).
+
*Interim maintenance; see paper for details
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
−
==DA 3 + 10, GO {{#subobject:e6f5bb|Regimen=1}}==
+
==Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine {{#subobject:9e619a|Regimen=1}}==
−
DA 3 + 10, GO: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:9d3523|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Years of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 +
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Nelarabine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine]]
 +
|style="background-color:#d3d3d3"|Not reported
 +
|style="background-color:#ffffbf"|Similar toxicity
 +
|-
 +
|}
 +
''Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Prednisone|Daunorubicin, Pegaspargase, Vincristine, Prednisone]] induction
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day on days 8 & 50
 +
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 8 to 11, 15 to 18, 50 to 53, 57 to 60
 +
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 8 to 21, 50 to 63
 +
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IM once per day on days 22 & 64
 +
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 22, 64, 71
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] (dose not specified) IT on days 15, 22, 57, 64
 +
*[[External_beam_radiotherapy|Whole-brain irradiation]] in some arms (see paper for details)
 +
'''71-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Interim maintenance; see paper for details
 +
</div></div><br>
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:6a938e|Variant=1}}===
+
===Regimen variant #2 {{#subobject:61171f|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://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ Teachey et al. 2022 (COG AALL1231)]
−
|2002-2006
+
|2014-2017
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
+
|style="background-color:#91cf61"|Non-randomized portion of phase 3 RCT
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
−
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 
 
|-
 
|-
 
|}
 
|}
−
''Note: This trial has complicated treatment schemas; see papers for details.''
+
''Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone|Daunorubicin, pegaspargase, vincristine, dexamethasone]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10
+
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 29
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
+
*[[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
−
====Antibody-drug conjugate therapy====
+
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
−
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 1
+
**Dose may be modified based on TPMT status
−
'''10-day course'''
+
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours 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
 +
====Supportive therapy====
 +
*[[Mesna (Mesnex)]] "is not required for this dose of cyclophosphamide, but may be administered at institutional discretion."
 +
====CNS therapy, prophylaxis====
 +
*[[Methotrexate (MTX)]] by the following age-based criteria, for CNS3:
 +
**Ages 1 to 1.99: 8 mg IT once per day on days 1 & 8
 +
**Ages 2 to 2.99: 10 mg IT once per day on days 1 & 8
 +
**Ages 3 to 8.99: 12 mg IT once per day on days 1 & 8
 +
**Age 9 and older: 15 mg IT once per day on days 1 & 8
 +
'''50-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*See paper for details (to be completed).
+
*See protocol for details of treatment beyond consolidation, which is guided by MRD status obtained at the end of induction.
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
−
 
+
# '''COG AALL1231:''' Teachey DT, Devidas M, Wood BL, Chen Z, Hayashi RJ, Hermiston ML, Annett RD, Archer JH, Asselin BL, August KJ, Cho SY, Dunsmore KP, Fisher BT, Freedman JL, Galardy PJ, Harker-Murray P, Horton TM, Jaju AI, Lam A, Messinger YH, Miles RR, Okada M, Patel SI, Schafer ES, Schechter T, Singh N, Steele AC, Sulis ML, Vargas SL, Winter SS, Wood C, Zweidler-McKay P, Bollard CM, Loh ML, Hunger SP, Raetz EA. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022 Jul 1;40(19):2106-2118. Epub 2022 Mar 10. [https://doi.org/10.1200/jco.21.02678 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9242409/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35271306/ PubMed] NCT02112916
−
==FLAG-Ida {{#subobject:7fc219|Regimen=1}}==
+
==Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone {{#subobject:03fb9e|Regimen=1}}==
−
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Lenograstim), '''<u>Ida</u>'''rubicin
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:44e85e|Variant=1}}===
+
===Regimen {{#subobject:9fedf6|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
Line 859: Line 1,293:
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ Asselin et al. 2011 (POG 9404)]
−
|2002-2006
+
|1996-2001
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|1. [[#ADE_.28standard-dose_Ara-C.29|ADE 10+3+5]]<br>2. [[#DA_3_.2B_10|DA 3+10]]<br> 3. [[#DA_3_.2B_10.2C_GO|DA 3+10 & GO]]<br> 4. [[#FLAG-Ida_.26_GO_99|FLAG-Ida & GO]]
+
|[[#Doxorubicin.2C_L-asparaginase.2C_Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Prednisone|Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
+
| style="background-color:#fc8d59" |Seems to have inferior EFS
 
|-
 
|-
 
|}
 
|}
−
''<sup>1</sup>While this was a negative trial, a predefined analysis by cytogenetics showed a significant survival benefit for GO in patients with favorable cytogenetics.''
 
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 to 6
+
*[[Doxorubicin (Adriamycin)]]
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 6, '''given 4 hours after fludarabine'''
+
*[[Asparaginase (Elspar)]]
−
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 4 to 6
+
*[[Mercaptopurine (6-MP)]]
−
====Growth factor therapy====
+
*[[Vincristine (Oncovin)]]
−
*[[Lenograstim (Granocyte)]] 263 mcg SC once per day on days 1 to 7
+
====Glucocorticoid therapy====
−
'''7-day course'''
+
*[[Prednisone (Sterapred)]]
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
+
# '''POG 9404:''' Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood. 2011 Jul 28;118(4):874-83. Epub 2011 Apr 7. [http://www.bloodjournal.org/content/118/4/874.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21474675 PubMed]
−
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
+
==Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone {{#subobject:03fb9e|Regimen=1}}==
−
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 
−
=Consolidation after upfront therapy=
 
−
==BuCy, then auto HSCT {{#subobject:9acbe9|Regimen=1}}==
 
−
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:5d4efb|Variant=1}}===
+
===Regimen {{#subobject:9fedf6|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://doi.org/10.1056/NEJM199605303342203 Ravindranath et al. 1996]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ Asselin et al. 2011 (POG 9404)]
−
|1988-1993
+
|1996-2001
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
|Intensive chemotherapy
+
|[[#Doxorubicin.2C_L-asparaginase.2C_Mercaptopurine.2C_Vincristine.2C_Prednisone|Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS24
+
| style="background-color:#91cf60" |Seems to have superior EFS
 
|-
 
|-
 
|}
 
|}
−
<div class="toccolours" style="background-color:#cbd5e8">
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Preceding treatment====
+
====Chemotherapy====
−
*[[#7.2B3d_.28standard-dose.29|7+3d]], then [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29|HiDAC]]
+
*[[Doxorubicin (Adriamycin)]]
−
{{#lst:Autologous HSCT|5d4efb}}
+
*[[Asparaginase (Elspar)]]
 +
*[[Mercaptopurine (6-MP)]]
 +
*[[Methotrexate (MTX)]]
 +
*[[Vincristine (Oncovin)]]
 +
====Glucocorticoid therapy====
 +
*[[Prednisone (Sterapred)]]
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. [https://doi.org/10.1056/NEJM199605303342203 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8618581 PubMed]
+
# '''POG 9404:''' Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood. 2011 Jul 28;118(4):874-83. Epub 2011 Apr 7. [http://www.bloodjournal.org/content/118/4/874.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21474675 PubMed]
−
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
+
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|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:45f841|Variant=1}}===
−
{| class="wikitable sortable" style="width: 40%; text-align:center;"
+
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
−
! style="width: 50%" |Study
+
!style="width: 33%"|Study
−
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 33%"|Years of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1056/NEJM198712243172602 Brochstein et al. 1987]
+
|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
 +
|2003-2011
 
| style="background-color:#91cf61" |Non-randomized
 
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
{{#lst:Allogeneic HSCT|6ca28d}}
+
{{#lst:Allogeneic HSCT|45f841}}
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Allogeneic stem cells]]
 
*[[Allogeneic stem cells]]
Line 930: Line 1,359:
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. [https://doi.org/10.1056/NEJM198712243172602 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3317056 PubMed]
+
# '''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]
−
=Relapsed or refractory, salvage therapy=
+
## '''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]
−
''Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.''
+
# '''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]
−
==COGAAML1421 protocol==
+
## '''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]
 +
# '''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
 +
==L-asparaginase monotherapy {{#subobject:d2a331|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Protocol===
+
===Regimen {{#subobject:65da55|Variant=1}}===
−
<div class="toccolours" style="background-color:#b3e2cd">
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
====Chemotherapy, cycle 1====
+
!style="width: 20%"|Study
−
*[[Cytarabine and daunorubicin liposomal (Vyxeos)]] 135 units/m<sup>2</sup> IV over 90 minutes on days 1, 3, 5
+
!style="width: 20%"|Years of enrollment
−
====CNS therapy====
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Cytarabine (Ara-C)]] IT 2 doses
+
!style="width: 20%"|Comparator
−
**At the time of diagnostic lumbar puncture or Day 0 of cycle 1
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
**At the time of the Day 28 to 30 bone marrow biopsy, or up to one week prior to Day 1 of cycle 2
 
−
*CNS2 Patients
 
−
**[[Cytarabine (Ara-C)]] IT twice weekly until the CSF is clear starting at least 48 hours following the 3rd dose of CPX-351
 
−
{| class="wikitable" style="width: 40%; text-align:center;"  
 
−
! style="width: 25%" |Age
 
−
! style="width: 25%" |Dose
 
−
|1 - 1.99
 
−
|30
 
 
|-
 
|-
−
|2 - 2.99
+
|[https://www.nature.com/articles/2401310 Amylon et al. 1999 (POG 8704)]
−
|50
+
|1987-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Observation_88|No L-asp]]
 +
| style="background-color:#1a9850" |Superior CRR
 
|-
 
|-
−
|≥ 3
 
−
|70
 
 
|}
 
|}
−
'''28-Day course'''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Chemotherapy, cycle 2====
+
====Chemotherapy====
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV or SQ once per day on days 1 to 5, one hour prior to each dose of [[Fludarabine (Fludara)]]
+
*[[Asparaginase (Elspar)]] 25,000 units/m<sup>2</sup> IM once per day on days 1, 8, 15, 22
−
**Restart on day 15 and continue until post-nadir ANC ≥ 500/μL
+
'''28-day cycle for 5 cycles'''
−
Pegfilgrastim cannot be utilized in the place of filgrastim or biosimilar
 
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 
−
*High Dose [[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 1 to 3 hours every once daily on days 1 to 5
 
−
**Begin [[Cytarabine (Ara-C)]] 4 hours after the start of [[Fludarabine (Fludara)]]
 
−
'''28-day course'''
 
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''COG AAML1421:'''Cooper TM, Absalon M, Alonzo TA, Gerbing RB, Leger KJ, Hirsch BA, Pollard JA, Razzouk BI, Aplenc R, Kolb EA. AAML1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A report from the Children's Oncology Group. Journal of Clinical Oncology. 2019 May;37(15). [https://doi.org/10.1200/JCO.2019.37.15_suppl.10003 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325367/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32401633/ PubMed]NCT02642965
+
# '''POG 8704:''' Amylon MD, Shuster J, Pullen J, Berard C, Link MP, Wharam M, Katz J, Yu A, Laver J, Ravindranath Y, Kurtzberg J, Desai S, Camitta B, Murphy SB. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999 Mar;13(3):335-42. [https://www.nature.com/articles/2401310 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10086723 PubMed]
−
 
+
=Interim maintenance=
−
==FLAG {{#subobject:551761|Regimen=1}}==
+
==Mercaptopurine, Methotrexate, Vincristine {{#subobject:ac9042|Regimen=1}}==
−
FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
+
BFM HDMTX: '''<u>B</u>'''erlin '''<u>F</u>'''rankfurt '''<u>M</u>'''uenster '''<u>H</u>'''igh-'''<u>D</u>'''ose '''<u>MTX</u>''' (Methotrexate) regimen
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:bdc7e4|Variant=1}}===
+
===Regimen {{#subobject:25de9f|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://doi.org/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
−
|2001-2009
+
|2007-2014
−
| style="background-color:#1a9851" |Phase 3 (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
−
|[[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
+
|[[#Methotrexate.2C_Pegaspargase.2C_Vincristine|COG C-MTX]]
−
| style="background-color:#fc8d59" |Seems to have inferior CR rate
+
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was studied in patients up to 21 years of age.''
+
''<sup>1</sup>Reported efficacy is based on the 2018 update.''<br>
 +
''Details to be completed''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]] versus [[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Nelarabine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine]] induction
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
+
*[[Mercaptopurine (6-MP)]]
−
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given third, 4 hours after the start of fludarabine'''
+
*[[Methotrexate (MTX)]]
−
====Growth factor therapy====
+
*[[Vincristine (Oncovin)]]
−
*[[Filgrastim (Neupogen)]] 200 mcg/m<sup>2</sup> (route not specified) once per day on days 0 to 5, '''given first'''
+
'''8-week course'''
−
'''2 cycles (length not specified)'''
 
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#CYVE_2|CYVE]] or [[#Cytarabine_.26_Thioguanine|Cytarabine & Thioguanine]] consolidation, as a bridge to [[Regimen_classes#Allogeneic_HSCT|allogeneic HSCT]]
+
*Delayed intensification
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
=Consolidation after salvage therapy=
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
==Cytarabine & Thioguanine {{#subobject:3c38bc|Regimen=1}}==
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
 +
==Methotrexate, Pegaspargase, Vincristine {{#subobject:dd9475|Regimen=1}}==
 +
COG C-MTX: '''<u>C</u>'''hildren's '''<u>O</u>'''ncology '''<u>G</u>'''roup '''<u>C</u>'''apizzi-style '''<u>MTX</u>''' (Methotrexate) regimen
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:f2728e|Variant=1}}===
+
===Regimen {{#subobject:1a0b22|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
! style="width: 50%" |Study
+
!style="width: 20%"|Study
−
! style="width: 50%" |[[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/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
|2007-2014
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#Mercaptopurine.2C_Methotrexate.2C_Vincristine|BFM HDMTX]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".''
+
''Details to be completed; reported efficacy is based on the 2018 update.''
 
<div class="toccolours" style="background-color:#cbd5e8">
 
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
+
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine]] versus [[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Nelarabine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine]] induction
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4
+
*[[Methotrexate (MTX)]]
−
*[[Thioguanine (Tabloid)]] as follows:
+
*[[Pegaspargase (Oncaspar)]]
−
**Cycles 1 & 2: 100 mg/m<sup>2</sup> PO once per day
+
*[[Vincristine (Oncovin)]]
−
'''14-day cycles'''
+
'''8-week course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic HSCT]]
+
*Delayed intensification
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
+
# '''COG AALL0434:''' Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. [https://doi.org/10.1002/pbc.25470 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25755211 PubMed] NCT00408005
−
==CYVE {{#subobject:4bd791|Regimen=1}}==
+
## '''Update:''' Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. [https://doi.org/10.1200/JCO.2018.77.7250 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6366301/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30138085 PubMed]
−
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)
+
## '''Update:''' Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. [https://doi.org/10.1200/jco.20.00256 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526719/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32813610/ PubMed]
 +
=Relapsed or refractory=
 +
==Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone {{#subobject:911679|Regimen=1}}==
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:a16529|Variant=1}}===
+
===Regimen {{#subobject:ech1e4|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
! style="width: 50%" |Study
+
!style="width: 20%"|Study
−
! style="width: 50%" |[[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/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
+
|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
|2003-NR
 +
|style="background-color:#91cf61"|Phase 3, <20 pts in this subgroup (E-switch-ic)
 +
|[[#Idarubicin.2C_Asparaginase_Erwinia_chrysanthemi.2C_Vincristine.2C_Dexamethasone_88|Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
 
|-
 
|-
 
|}
 
|}
−
''Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.''
+
''Note: per the protocol, this regimen is intended only for patients 18 and younger and for patients allergic to pegaspargase. This is the same regimen used in relapsed B-ALL, but this subgroup did not have a statistically significant difference between the regimens.''
−
<div class="toccolours" style="background-color:#cbd5e8">
+
<div class="toccolours" style="background-color:#b3e2cd">
−
====Preceding treatment====
+
====Chemotherapy====
−
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
+
*[[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>
 +
<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]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(10)62002-8 Parker et al. 2010 (CCLG ALL R3)]
 +
|2003-NR
 +
|style="background-color:#91cf61"|Phase 3, <20 pts in this subgroup (E-switch-ic)
 +
|[[#Idarubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone_88|Idarubicin, Pegaspargase, Vincristine, Dexamethasone]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
''Note: per the protocol, this regimen is intended only for patients 18 and younger. This is the same regimen used in relapsed B-ALL, but this subgroup did not have a statistically significant difference between the regimens.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 2000 mg/m<sup>2</sup>)
+
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV twice per day on days 1 to 4
+
*[[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>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic HSCT]]
+
*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
 +
==Nelarabine monotherapy {{#subobject:bb7a38|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:44a025|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 80%; text-align:center;"
 +
!style="width: 25%"|Study
 +
!style="width: 25%"|Years of enrollment
 +
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.03.426 Berg et al. 2005]
 +
|1997-2002
 +
|style="background-color:#91cf61"|Phase 2 (RT)
 +
|ORR: 14-55%
 +
|-
 +
|[https://doi.org/10.1111/bjh.14874 Zwaan et al. 2017 (GSK 111081)]
 +
|2009-2014
 +
|style="background-color:#91cf61"|Phase 4
 +
|style="background-color:#666666; color:white"|ORR: 39%
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 +
'''21-day cycles'''
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
+
# Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, Billett A, Kurtzberg J, Reaman G, Gaynon P, Whitlock J, Krailo M, Harris MB; Children's Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol. 2005 May 20;23(15):3376-82. [https://doi.org/10.1200/JCO.2005.03.426 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15908649 PubMed]
−
[[Category:Acute myeloid leukemia regimens]]
+
# '''GSK 111081:''' Zwaan CM, Kowalczyk J, Schmitt C, Bielorai B, Russo MW, Woessner M, Ranganathan S, Leverger G. Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol. 2017 Oct;179(2):284-293. Epub 2017 Aug 2. [https://doi.org/10.1111/bjh.14874 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28771663 PubMed] NCT00866671
 +
[[Category:T-cell acute lymphoblastic leukemia regimens]]
 
[[Category:Disease-specific pages]]
 
[[Category:Disease-specific pages]]
−
[[Category:Acute leukemias]]
+
[[Category:Acute lymphoblastic leukemias]]
 +
[[Category:T-cell leukemias]]
 
[[Category:Pediatric hematologic neoplasms]]
 
[[Category:Pediatric hematologic neoplasms]]

Revision as of 11:24, 23 October 2022

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Section editor transclusions This page contains studies that were specific to pediatric populations. For the more general T-cell acute lymphoblastic leukemia page, follow this link.

0 regimens on this page
0 variants on this page


Guidelines

"How I Treat"

NCCN

Upfront therapy

COG AALL0434 protocol

Induction, Arms B (Nelarabine Arms)

All Patients

Study Years of enrollment Evidence
Winter et al. 2015 (COG AALL0434) 2007-2014 Non-randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

Age Initial Dose
1 to 1.99 years 30 mg
2 to 2.99 years 50 mg
≥ 3 years 70 mg
Age Dose
1 to 1.99 8 mg
2 to 2.99 10 mg
3 to 8.99 12 mg
≥ 9 15 mg

29-day course


Consolidation, Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-RT-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.

Preceding treatment

Chemotherapy

  • Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once per day over 30 minutes on days 8, 50
    • Must reduce urine specific gravity to ≤ 1.015 prior to administration
  • Cytarabine (Ara-C) 75 mg/m2 IV over 1 to 30 minutes or SC once per day on days 8 to 11, 15 to 18, 50 to 53, 57 to 60
  • Mercaptopurine (6-MP) 60 mg/m2 PO once per day on days 8 to 21, 50 to 63
    • DO NOT escalate or modify dose based on blood counts during this course.
  • Nelarabine (Arranon) 650 mg/m2 IV once per day over 60 minutes on days 1 to 5, 43 to 47
  • Pegaspargase (Oncaspar) 2,500 units/m2 IM or IV over 1 to 2 hours once per day on days 22 & 64
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 22, 29, 64, 71

CNS therapy, prophylaxis

Age Dose
1 to 1.99 8 mg
2 to 2.99 10 mg
3 to 8.99 12 mg
≥ 9 15 mg
  • Whole-brain irradiation
    • CNS3 T-ALL: 1,800cGy in 10 once daily fractions.
    • Intermediate/High Risk ARM B: 1,200 cGy in 8 once-daily fractions given during weeks 4 and 5 of consolidation

71-day course

Subsequent treatment

  • Interim maintenance


Interim Maintenance, with Capizzi MTX (Arms A and B)

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.

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
    • If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose.
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IM or IV over 1 to 2 hours once per day on days 2, 22

CNS therapy, prophylaxis

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

56-day course


Delayed Intensification, Nelarabine Arms (Arms B and D)

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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

Radiotherapy

63-day course


Maintenance, Arms B and D

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) on days 1, 57
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 28, 36 to 84
  • Methotrexate (MTX) 20 mg/m2 PO on days 8, 15, 22, 36, 43, 50, 57, 64, 71, 78
    • No dose escalation recommended for the first maintenance cycle
    • Thereafter, for ANC ≥ 1,500μL on 3 CBCs done over 6 weeks or 2 monthly CBCs, increase dose of methotrexate or mercaptopurine by 25%
  • Nelarabine (Arranon) 650 mg/m2 IV over 60 minutes once per day on days 29 to 33
    • DO NOT Administer with other Chemotherapy agents

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO twice per day on days 1 to 5 and 57 to 61 (Total of 40 mg/m2/day, divided BID)

CNS therapy, prophylaxis

Age Dose
1 to 1.99 8 mg
2 to 2.99 10 mg
3 to 8.99 12 mg
≥ 9 15 mg 
Repeat above cycle for a total of 3 cycles.

3 Cycles


Maintenance, continuation after cycle 3 (Arms B and D)

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (max dose 2 mg) on days 1, 29, 57
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
  • Methotrexate (MTX) 20 mg/m2 PO on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
    • No dose escalation recommended for the first maintenance cycle
    • Thereafter, for ANC ≥ 1,500μL on 3 CBCs done over 6 weeks or 2 monthly CBCs, increase dose of methotrexate or mercaptopurine by 25%

Glucocorticoid therapy

  • Prednisone (Sterapred) 20 mg/m2 PO twice per day on days 1 to 5, 29 to 33, 57 to 61 (Total of 40 mg/m2/day, divided BID)

CNS therapy, prophylaxis

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

Duration

  • Girls T-ALL: Continue repeating 12 week cycles of maintenance therapy II until the total duration of therapy is two years from the start of Interim Maintenance (~ Week 121)
  • Boys T-ALL: Continue to repeat 12 week cycles of Maintenance therapy II until the total duration of therapy is three years from the start of Interim Maintenance (~ Week 173).
  • T-NHL patients (regardless of gender): Continue to repeat 12 week cycles of maintenance therapy II until the total duration reaches two years from the start of Interim Maintenance (~ Week 121)

84-day course

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed

COG AALL1231 Protocol Arm A

Induction

All T-ALL and T-LLy patients
Study Years of enrollment Evidence Comparator Comparative Efficacy
Teachey et al. 2022 (COG AALL1231) 2014-2017 Phase 3 (C) ABFM & Bortezomib induction Did not meet primary endpoint of EFS

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT once on day 1 or at the time of diagnostic lumbar puncture (if within 72 hours of protocol initiation)
Age Initial Dose
1 to 1.99 years 30 mg
2 to 2.99 years 50 mg
≥ 3 years 70 mg
Age Dose
1 to 1.99 8 mg
2 to 2.99 10 mg
3 to 8.99 12 mg
≥ 9 15 mg

Consolidation

All T-ALL and T-LLy Patients
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

CNS prophylaxis

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

56-day course


Interim Maintenance, SR patients, with CMTX

SR Patients Receive After Consolidation
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

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
    • If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once per day on days 2, 22

CNS therapy, prophylaxis

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

56-day course


Delayed Intensification

All T-ALL and T-LLy Patients
Study Years of enrollment Evidence Comparator Comparative Efficacy
Teachey et al. 2022 (COG AALL1231) 2014-2017 Phase 3 (C) Delayed intensification with bortezomib Did not meet primary endpoint of EFS

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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

56-day course


Delayed Intensification, IR patients

All T-ALL and T-LLy Patients
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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

56-day course


Interim Maintenance, #1 with HDMTX - ALL IR Patients

SR and VHR T-ALL and T-LLy DO NOT RECEIVE
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Supportive therapy

  • 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, 4, 17, 18, 31, 32, 45, 46

CNS therapy, prophylaxis

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

56-day course


Interim Maintenance, #2 with CMTX - ALL IR Patients

IR T-ALL and T-LLy Patients receive this after DI as IM#2
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

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
    • If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once per day on days 2, 22

CNS therapy, prophylaxis

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

56-day course

Intensification, Block 1 (VHR patients)

VHR Patients receive immediately after consolidation
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

  • 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, 4
  • Filgrastim (Neupogen) 5 mcg/kg SC or IV daily beginning on day 7 and until WBC > 3000μL

CNS therapy, Triple Intrathecal Therapy

Given on day 1, 2 hours after the start of HD MTX infusion

Intensification, Block 2

Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

Supportive therapy

CNS therapy, Triple Intrathecal Therapy

Given on day 1, 2 hours after the start of HD MTX infusion

Intensification, Block 3

Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

  • High Dose Cytarabine (Ara-C) 2,000 mg/m2 every 12 hours IV over 3 hours x 4 doses on days 1, 2
  • Etoposide (Vepesid) 100 mg/m2 every 12 hours IV over 1 to 2 hours x 5 doses on days 3 to 5
    • First dose to be given 12 hours after the start of the 4th high dose Cytarabine (Ara-C) on day 2
    • Infusion rate should not exceed 300 mg/m2/hour (10 mg/kg/hour)
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours on day 6

Glucocorticoid therapy

Supportive therapy

CNS therapy, Triple Intrathecal Therapy

Given on day 1, 2 hours after the start of HD MTX infusion

Delayed Intensification

All T-ALL and T-LLy Patients
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

Glucocorticoid therapy

CNS therapy, prophylaxis

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

56-day course


Interim Maintenance, with CMTX

VHR Patients receive after DI
Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

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
    • If delay is necessary for myelosuppression and/or Grade 3 mucositis, discontinue escalation and resume at 80% of last dose
  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
  • Pegaspargase (Oncaspar) 2,500 units/m2 IV over 1 to 2 hours once per day on days 2, 22

CNS therapy, prophylaxis

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

56-day course


Maintenance, all patients

Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Chemotherapy

  • Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) on days 1, 29, 57
  • Mercaptopurine (6-MP) 75 mg/m2 PO once per day on days 1 to 84
  • Methotrexate (MTX) 20 mg/m2 once a day on days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, 78
    • Omit day 29 of the first FOUR cycles for SR T-ALL and T-LLy patients
    • Omit day 29 of the first TWO cycles for IR T-ALL and T-LLy patients

Glucocorticoid therapy

CNS therapy, prophylaxis

  • Methotrexate (MTX) IT once on days 1
    • Also on day 29 of the first FOUR cycles for SR patients
    • Also on day 29 of the first TWO cycles for IR patients
Age Dose
1 to 1.99 8 mg
2 to 2.99 10 mg
3 to 8.99 12 mg
≥ 9 15 mg

Radiotherapy

ONLY the following groups receive CRT during the first cycle of maintenance.

Duration of therapy:

  • SR and IR T-ALL Girls: repeat 12 week cycles of maintenance for a total duration of 2 years from Interim Maintenance start.
  • VHR T-ALL Girls: Repeat 12 week cycles of maintenance for a total duration of 2 years from Intensification Block 1 start.
  • SR and IR T-ALL Boys: repeat 12 week cycles of maintenance for a total duration of 3 years from Interim Maintenance start.
  • VHR T-ALL Boys: Repeat 12 week cycles of maintenance for a total duration of 3 years from Intensification Block 1 start.
  • T-LLy regardless of gender: repeat 12 week cycles of maintenance for a total duration of 2 years from Interim Maintenance start.

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed
  2. COG AALL1231: Teachey DT, Devidas M, Wood BL, Chen Z, Hayashi RJ, Hermiston ML, Annett RD, Archer JH, Asselin BL, August KJ, Cho SY, Dunsmore KP, Fisher BT, Freedman JL, Galardy PJ, Harker-Murray P, Horton TM, Jaju AI, Lam A, Messinger YH, Miles RR, Okada M, Patel SI, Schafer ES, Schechter T, Singh N, Steele AC, Sulis ML, Vargas SL, Winter SS, Wood C, Zweidler-McKay P, Bollard CM, Loh ML, Hunger SP, Raetz EA. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022 Jul 1;40(19):2106-2118. Epub 2022 Mar 10. link to original article link to PMC article PubMed NCT02112916

Pre-phase

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

Upfront induction therapy

Daunorubicin, Pegaspargase, Vincristine, Dexamethasone

Regimen, modified ABFM

Study Years of enrollment Evidence
Vora et al. 2013 (UKALL 2003) 2003-2011 Non-randomized portion of RCT

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

References

  1. UKALL 2003: Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Hough R, Rowntree C, Richards S. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2013 Mar;14(3):199-209. link to original article PubMed ISRCTN07355119

Daunorubicin, Pegaspargase, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence
Winter et al. 2015 (COG AALL0434) 2007-2014 Non-randomized portion of RCT

Chemotherapy

Glucocorticoid therapy

4-week course

Subsequent treatment

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed

DOLP

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

Regimen (BFM 76/79 Phase I)

Study Years of enrollment Evidence Comparator Comparative Efficacy
Gaynon et al. 1988 (CCG-106) 1983-1984 Phase 3 (E-esc) 1. Control regimen Seems to have superior EFS36
2. New York regimen Did not meet primary endpoint of EFS36
Steinherz et al. 1998 (CCG-123) 1983-1985 Phase 3 (C) 1. LSA2-L2 & WBRT
2. LSA-L2
3. New York regimen 		Did not meet primary endpoint of EFS

Note: the specific days of L-asparaginase are not specified; the schedule here is similar to those of other similar protocols.

Chemotherapy

Glucocorticoid therapy

CNS therapy

6-week course

Subsequent treatment

  • BFM 76/79 Phase II

References

  1. CCG-106: Gaynon PS, Steinherz PG, Bleyer WA, Ablin AR, Albo VC, Finklestein JZ, Grossman NJ, Littman PS, Novak LT, Pyesmany AF, Sather HN, Hammond GD. Intensive therapy for children with acute lymphoblastic leukaemia and unfavourable presenting features: early conclusions of study CCG-106 by the Childrens Cancer Study Group. Lancet. 1988 Oct 22;2(8617):921-4. link to original article PubMed
  2. CCG-123: Steinherz PG, Gaynon PS, Breneman JC, Cherlow JM, Grossman NJ, Kersey JH, Johnstone HS, Sather HN, Trigg ME, Uckun FM, Bleyer WA. Treatment of patients with acute lymphoblastic leukemia with bulky extramedullary disease and T-cell phenotype or other poor prognostic features: randomized controlled trial from the Children's Cancer Group. Cancer. 1998 Feb 1;82(3):600-12. link to original article contains dosing details in manuscript PubMed

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

Consolidation after upfront therapy

Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (E-esc) Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine Not reported Similar toxicity

Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

71-day course

Subsequent treatment

  • Interim maintenance; see paper for details

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed

Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine

Regimen variant #1

Study Years of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (C) Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine Not reported Similar toxicity

Note: although the induction doses of vincristine are capped at 2 mg, capping is not mentioned in the subsequent phases of treatment.

Preceding treatment

Chemotherapy

CNS therapy, prophylaxis

71-day course

Subsequent treatment

  • Interim maintenance; see paper for details

Regimen variant #2

Study Years of enrollment Evidence
Teachey et al. 2022 (COG AALL1231) 2014-2017 Non-randomized portion of phase 3 RCT

Note: Per the protocol, it is intended only for patients greater than 1 and less than 31 years of age.

Preceding treatment

Chemotherapy

Supportive therapy

  • Mesna (Mesnex) "is not required for this dose of cyclophosphamide, but may be administered at institutional discretion."

CNS therapy, prophylaxis

  • Methotrexate (MTX) by the following age-based criteria, for CNS3:
    • Ages 1 to 1.99: 8 mg IT once per day on days 1 & 8
    • Ages 2 to 2.99: 10 mg IT once per day on days 1 & 8
    • Ages 3 to 8.99: 12 mg IT once per day on days 1 & 8
    • Age 9 and older: 15 mg IT once per day on days 1 & 8

50-day course

Subsequent treatment

  • See protocol for details of treatment beyond consolidation, which is guided by MRD status obtained at the end of induction.

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed
  2. COG AALL1231: Teachey DT, Devidas M, Wood BL, Chen Z, Hayashi RJ, Hermiston ML, Annett RD, Archer JH, Asselin BL, August KJ, Cho SY, Dunsmore KP, Fisher BT, Freedman JL, Galardy PJ, Harker-Murray P, Horton TM, Jaju AI, Lam A, Messinger YH, Miles RR, Okada M, Patel SI, Schafer ES, Schechter T, Singh N, Steele AC, Sulis ML, Vargas SL, Winter SS, Wood C, Zweidler-McKay P, Bollard CM, Loh ML, Hunger SP, Raetz EA. Children's Oncology Group Trial AALL1231: A Phase III Clinical Trial Testing Bortezomib in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia and Lymphoma. J Clin Oncol. 2022 Jul 1;40(19):2106-2118. Epub 2022 Mar 10. link to original article link to PMC article PubMed NCT02112916

Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Asselin et al. 2011 (POG 9404) 1996-2001 Phase 3 (C) Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone Seems to have inferior EFS

Chemotherapy

Glucocorticoid therapy

References

  1. POG 9404: Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood. 2011 Jul 28;118(4):874-83. Epub 2011 Apr 7. link to original article link to PMC article PubMed

Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Asselin et al. 2011 (POG 9404) 1996-2001 Phase 3 (E-esc) Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone Seems to have superior EFS

Chemotherapy

Glucocorticoid therapy

References

  1. POG 9404: Asselin BL, Devidas M, Wang C, Pullen J, Borowitz MJ, Hutchison R, Lipshultz SE, Camitta BM. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children's Oncology Group (POG 9404). Blood. 2011 Jul 28;118(4):874-83. Epub 2011 Apr 7. link to original article link to PMC article PubMed

Etoposide & TBI, then allo HSCT

Regimen

Study Years of enrollment Evidence
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. 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. 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
  2. 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. 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
  3. 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

L-asparaginase monotherapy

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Amylon et al. 1999 (POG 8704) 1987-1992 Phase 3 (E-esc) No L-asp Superior CRR

Chemotherapy

28-day cycle for 5 cycles

References

  1. POG 8704: Amylon MD, Shuster J, Pullen J, Berard C, Link MP, Wharam M, Katz J, Yu A, Laver J, Ravindranath Y, Kurtzberg J, Desai S, Camitta B, Murphy SB. Intensive high-dose asparaginase consolidation improves survival for pediatric patients with T cell acute lymphoblastic leukemia and advanced stage lymphoblastic lymphoma: a Pediatric Oncology Group study. Leukemia. 1999 Mar;13(3):335-42. link to original article contains dosing details in abstract PubMed

Interim maintenance

Mercaptopurine, Methotrexate, Vincristine

BFM HDMTX: Berlin Frankfurt Muenster High-Dose MTX (Methotrexate) regimen

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (C) COG C-MTX Seems to have inferior OS1

1Reported efficacy is based on the 2018 update.
Details to be completed

Preceding treatment

Chemotherapy

8-week course

Subsequent treatment

  • Delayed intensification

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed

Methotrexate, Pegaspargase, Vincristine

COG C-MTX: Children's Oncology Group Capizzi-style MTX (Methotrexate) regimen

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Winter et al. 2015 (COG AALL0434) 2007-2014 Phase 3 (C) BFM HDMTX Seems to have superior OS

Details to be completed; reported efficacy is based on the 2018 update.

Preceding treatment

Chemotherapy

8-week course

Subsequent treatment

  • Delayed intensification

References

  1. COG AALL0434: Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, Leonard Rn MS, Murphy J, Gastier-Foster JM, Carroll AJ, Heerema NA, Loh ML, Raetz EA, Winick NJ, Carroll WL, Hunger SP. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children's Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015 Jul;62(7):1176-83. Epub 2015 Mar 8. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408005
    1. Update: Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Gaynon PS, Borowitz MJ, Loh ML, Rabin KR, Raetz EA, Zweidler-Mckay PA, Winick NJ, Carroll WL, Hunger SP. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children's Oncology Group AALL0434 methotrexate randomization. J Clin Oncol. 2018 Oct 10;36(29):2926-2934. Epub 2018 Aug 23. link to original article link to PMC article PubMed
    2. Update: Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, Eisenberg N, Briegel N, Hayashi RJ, Gastier-Foster JM, Carroll AJ, Heerema NA, Asselin BL, Rabin KR, Zweidler-Mckay PA, Raetz EA, Loh ML, Schultz KR, Winick NJ, Carroll WL, Hunger SP. Children's Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020 Oct 1;38(28):3282-3293. Epub 2020 Aug 19. link to original article link to PMC article PubMed

Relapsed or refractory

Mitoxantrone, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Parker et al. 2010 (CCLG ALL R3) 2003-NR Phase 3, <20 pts in this subgroup (E-switch-ic) Idarubicin, Asparaginase Erwinia chrysanthemi, Vincristine, Dexamethasone Did not meet primary endpoint of PFS

Note: per the protocol, this regimen is intended only for patients 18 and younger and for patients allergic to pegaspargase. This is the same regimen used in relapsed B-ALL, but this subgroup did not have a statistically significant difference between the regimens.

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-NR Phase 3, <20 pts in this subgroup (E-switch-ic) Idarubicin, Pegaspargase, Vincristine, Dexamethasone Did not meet primary endpoint of PFS

Note: per the protocol, this regimen is intended only for patients 18 and younger. This is the same regimen used in relapsed B-ALL, but this subgroup did not have a statistically significant difference between the regimens.

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

Nelarabine monotherapy

Regimen

Study Years of enrollment Evidence Efficacy
Berg et al. 2005 1997-2002 Phase 2 (RT) ORR: 14-55%
Zwaan et al. 2017 (GSK 111081) 2009-2014 Phase 4 ORR: 39%

Chemotherapy

21-day cycles

References

  1. Berg SL, Blaney SM, Devidas M, Lampkin TA, Murgo A, Bernstein M, Billett A, Kurtzberg J, Reaman G, Gaynon P, Whitlock J, Krailo M, Harris MB; Children's Oncology Group. Phase II study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children's Oncology Group. J Clin Oncol. 2005 May 20;23(15):3376-82. link to original article contains dosing details in abstract PubMed
  2. GSK 111081: Zwaan CM, Kowalczyk J, Schmitt C, Bielorai B, Russo MW, Woessner M, Ranganathan S, Leverger G. Safety and efficacy of nelarabine in children and young adults with relapsed or refractory T-lineage acute lymphoblastic leukaemia or T-lineage lymphoblastic lymphoma: results of a phase 4 study. Br J Haematol. 2017 Oct;179(2):284-293. Epub 2017 Aug 2. link to original article contains dosing details in manuscript PubMed NCT00866671
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