Difference between revisions of "Staging page"

From HemOnc.org - A Hematology Oncology Wiki
Jump to navigation Jump to search
m (Blanked the page)
Tag: Blanking
 
(73 intermediate revisions by 2 users not shown)
Line 1: Line 1:
−
<span id="BackToTop"></span>
 
−
<div class="noprint" style="background-color:LightGray; position:fixed; bottom:2%; right:0.25%; padding-left:5px; padding-right:5px; margin: 15px; opacity:0.8; border-style: solid; border-color:DarkGray; border-width: 1px">
 
−
[[#top|Back to Top]]
 
−
</div>
 
−
{{#lst:Section editor transclusions|peds}}
 
−
<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;"
 
−
|-
 
−
|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
 
−
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
−
|}
 
−
{{TOC limit|limit=4}}
 
−
=Guidelines=
 
−
=="How I Treat"==
 
−
*'''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
 
−
|-
 
−
|}
 
−
<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
 
−
|-
 
−
|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 on days 15, 22 ALSO)
 
−
{| 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
 
−
|}
 
−
'''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]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 
−
|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
 
−
|-
 
−
|}
 
−
''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 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">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 
−
**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/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IM or IV over 1 to 2 hours once per day on days 2, 22
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 31
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 8, 15, 43, 50
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 
−
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push/infusion over 1 to 15 minutes once per day on days 1, 8, 15
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IM or IV over 1 to 2 hours on day 4 (OR 5 OR 6), 43
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
**Should not be given to patients receiving CRT (Arm D and CNS3 T-ALL patients)
 
−
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV 60 minutes once per day on days 29 to 33
 
−
====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====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
−
{| 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
 
−
|}
 
−
====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 class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 57
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 28, 36 to 84
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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/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====
 
−
*[[Methotrexate (MTX)]] IT once on day 1
 
−
{| 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
 
−
|}
 
−
Repeat above cycle for a total of 3 cycles.
 
−
'''3 Cycles'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 29, 57
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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/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====
 
−
*[[Methotrexate (MTX)]] IT once on day 1
 
−
{| 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
 
−
|}
 
−
====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>
 
  
−
===References===
 
−
# '''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]
 
−
## '''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">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours once on day 4, 18
 
−
*[[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====
 
−
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28 (DO NOT TAPER)
 
−
====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)
 
−
{| 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;"
 
−
! 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
 
−
|}
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV once per day over 30 to 60 minutes on days 1, 29
 
−
*[[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
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 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 on days 15, 22, 43, 50
 
−
====CNS prophylaxis====
 
−
*[[Methotrexate (MTX)]] IT once per day on days 1, 8, 15, 22
 
−
**CNS3 patients and CNS3 T-LLy: Omit days 15, 22
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 
−
**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/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 
−
*[[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====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 31
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Delayed Intensification {{#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)
 
−
|[[#COG_AALL1231_delayed_intensification_.26_Bortezomib_99|Delayed intensification with bortezomib]]
 
−
| 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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 8, 15, 43, 50
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 
−
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID)
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (max dose 2 mg) on days 1, 8, 15, 43, 50
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 
−
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
 
−
*[[Thioguanine (Tabloid)]] 60 mg/m<sup>2</sup> PO once per day on days 29 to 42
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 5 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 7, 15 to 21 (10 mg/m<sup>2</sup>/day, divided BID)
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 15, 29, 43
 
−
*[[Mercaptopurine (6-MP)]] 25 mg/m<sup>2</sup> PO once per day on days 1 to 56.
 
−
*High Dose [[Methotrexate (MTX)]] 5,000 mg/m<sup>2</sup> IV over 24 hours on days 1, 15, 29, 43.
 
−
**[[Methotrexate (MTX)]] 500 mg/m<sup>2</sup> IV infused over 30 minutes, then [[Methotrexate (MTX)]] 4,500 mg/m<sup>2</sup> given by continuous IV infusion over 23.5 hours
 
−
====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 infusion) on days 3, 4, 17, 18, 31, 32, 45, 46
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 
−
**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/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 
−
*[[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====
 
−
*[[Methotrexate (MTX)]] IT once on days 1 and 31
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
 
−
===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">
 
−
====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
 
−
*[[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
 
−
*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
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 6
 
−
** Administer 3 hours after completion of the second high dose [[Cytarabine (Ara-C)]] infusion
 
−
====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 infusion) on days 3, 4
 
−
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC or IV daily beginning on day 7 and until WBC > 3000μL
 
−
**Alternative: [[Pegfilgrastim (Neulasta)]] 100 mcg/kg (Maximum dose of 6 mg) 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 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]]
 
−
|-
 
−
|[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">
 
−
====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]]
 
−
|-
 
−
|[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">
 
−
====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 class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 8, 15, 43, 50
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once on day 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC or IV over 1 to 30 minutes on days 29 to 32, 36 to 39
 
−
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV push or infusion over 1 to 15 minutes once per day on days 1, 8, 15
 
−
*[[Pegaspargase (Oncaspar)]] 2,500 units/m<sup>2</sup> IV over 1 to 2 hours on day 4, 18, 43
 
−
*[[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====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 29, 36
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]] 100 mg/m<sup>2</sup> IV once on day 1, then 150 mg/m<sup>2</sup> IV once on day 11, then 200 mg/m<sup>2</sup> IV once on day 21, then 250 mg/m<sup>2</sup> IV once on day 31, then 300 mg/m<sup>2</sup> IV once on day 41
 
−
**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/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 11, 21, 31, 41
 
−
*[[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====
 
−
*[[Methotrexate (MTX)]] IT once on days 1, 31
 
−
{| 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
 
−
|}
 
−
'''56-day course'''
 
−
</div></div><br>
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===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">
 
−
====Chemotherapy====
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) on days 1, 29, 57
 
−
*[[Mercaptopurine (6-MP)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 84
 
−
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> 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====
 
−
*[[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)
 
−
====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
 
−
{| 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
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Radiotherapy====
 
−
ONLY the following groups receive CRT during the first cycle of maintenance.
 
−
*T-ALL Patients
 
−
**CNS1 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,200 cGy
 
−
**CNS2 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,200 cGy
 
−
**CNS3 IR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
 
−
**CNS3 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
 
−
*T-LLy Patients
 
−
**CNS3 IR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
 
−
**CNS3 VHR: [[External_beam_radiotherapy|Total body irradiation (TBI)]] 1,800 cGy
 
−
'''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.
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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
 
−
=Pre-phase=
 
−
==Methylprednisolone monotherapy {{#subobject:5gh1bb|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:88fgh7|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
 
−
|2005-2011
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
 
−
|2012-2015
 
−
| style="background-color:#91cf61" |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.''
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Glucocorticoid therapy====
 
−
*[[Methylprednisolone (Solumedrol)]] 8 mg/m<sup>2</sup> IV three times per day on days 1 to 3
 
−
'''3-day course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*DFCI 05-001: Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
 
−
*DFCI 11-001: Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone versus [[#Doxorubicin.2C_Methotrexate.2C_Pegaspargase.2C_Vincristine.2C_Methylprednisolone|Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone]] induction
 
−
</div></div>
 
−
===References===
 
−
# '''DFCI 05-001:''' Place AE, Stevenson KE, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Supko JG, Asselin BL, Athale UH, Clavell LA, Cole PD, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Welch JJ, Lipshultz SE, Kutok JL, Blonquist TM, Neuberg DS, Sallan SE, Silverman LB. Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial. Lancet Oncol. 2015 Dec;16(16):1677-90. Epub 2015 Nov 6. [https://doi.org/10.1016/s1470-2045(15)00363-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26549586/ PubMed] NCT00400946
 
−
## '''Pooled update:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed]
 
−
# '''DFCI 11-001:''' Burns MA, Place AE, Stevenson KE, Gutiérrez A, Forrest S, Pikman Y, Vrooman LM, Harris MH, Hunt SK, O'Brien JE, Asselin BL, Athale UH, Clavell LA, Cole PD, Gennarini LM, Kahn JM, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Schorin MA, Sulis ML, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Identification of prognostic factors in childhood T-cell acute lymphoblastic leukemia: Results from DFCI ALL Consortium Protocols 05-001 and 11-001. Pediatr Blood Cancer. 2021 Jan;68(1):e28719. Epub 2020 Oct 7. Erratum in: Pediatr Blood Cancer. 2021 Mar;68(3):e28885. [https://doi.org/10.1002/pbc.28719 link to original article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/33026184/ PubMed] NCT01574274
 
−
## '''Update:''' Vrooman LM, Blonquist TM, Stevenson KE, Supko JG, Hunt SK, Cronholm SM, Koch V, Kay-Green S, Athale UH, Clavell LA, Cole PD, Harris MH, Kelly KM, Laverdiere C, Leclerc JM, Michon B, Place AE, Schorin MA, Welch JJG, Neuberg DS, Sallan SE, Silverman LB. Efficacy and Toxicity of Pegaspargase and Calaspargase Pegol in Childhood Acute Lymphoblastic Leukemia: Results of DFCI 11-001. J Clin Oncol. 2021 Nov 1;39(31):3496-3505. Epub 2021 Jul 6. [https://doi.org/10.1200/jco.20.03692 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34228505/ PubMed]
 
−
=Upfront induction therapy=
 
−
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:516f7b|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen, modified ABFM {{#subobject:88f520|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1016/S1470-2045(12)70600-9 Vora et al. 2013 (UKALL 2003)]
 
−
|2003-2011
 
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 4 & 18
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
 
−
====CNS therapy, prophylaxis====
 
−
*[[Cytarabine (Ara-C)]] 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>
 
−
===References===
 
−
# '''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
 
−
==Daunorubicin, Pegaspargase, Vincristine, Prednisone {{#subobject:a39331|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:1511c2|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/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 
−
|2007-2014
 
−
|style="background-color:#91cf61"|Non-randomized portion of RCT
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 5 +/- 1 day
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 28
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*[[#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>
 
−
===References===
 
−
# '''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]
 
−
## '''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">
 
−
===Regimen (BFM 76/79 Phase I) {{#subobject:3fe1a2|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]]
 
−
|-
 
−
|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://doi.org/10.1002/(sici)1097-0142(19980201)82:3%3C600::aid-cncr24%3E3.0.co;2-4 Steinherz et al. 1998 (CCG-123)]
 
−
|1983-1985
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|1. LSA2-L2 & WBRT<br>2. LSA-L2<br>3. New York regimen
 
−
| 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">
 
−
====Chemotherapy====
 
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup> IM once per day on days 3, 5, 7, 10, 12, 14, 17, 19, 21
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 28, then tapered over 2 weeks
 
−
====CNS therapy====
 
−
*[[Methotrexate (MTX)]] IT once per day on days 1, 15, 29 (dose not specified)
 
−
'''6-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*BFM 76/79 Phase II
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
# '''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]
 
−
==Doxorubicin, Methotrexate, Pegaspargase, Vincristine, Methylprednisolone {{#subobject:h1gtbb|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:hgu1h7|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://doi.org/10.1016/s1470-2045(15)00363-0 Place et al. 2015 (DFCI 05-001)]
 
−
|2005-2011
 
−
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 
−
|[[#Doxorubicin.2C_L-asparaginase.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_88|Doxorubicin, L-Asparaginase, Methotrexate, Vincristine, Methylprednisolone]]
 
−
| style="background-color:#ffffbf" |Did not meet secondary endpoint of DFS
 
−
| style="background-color:#1a9850" |Less anxiety
 
−
|-
 
−
|[https://doi.org/10.1002/pbc.28719 Burns et al. 2020 (DFCI 11-001)]
 
−
|2012-2015
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Calaspargase.2C_Doxorubicin.2C_Methotrexate.2C_Vincristine.2C_Methylprednisolone_99|Calaspargase, Doxorubicin, Methotrexate, Vincristine, Methylprednisolone]]
 
−
| 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">
 
−
====Chemotherapy====
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 4 & 5
 
−
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 6
 
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV once on day 7
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 4, 11, 18, 25
 
−
====Glucocorticoid therapy====
 
−
*[[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>
 
−
===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]
 
−
=Consolidation after upfront therapy=
 
−
==Cyclophosphamide, Cytarabine, Mercaptopurine, Nelarabine, Pegaspargase, Vincristine {{#subobject:ae17db|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#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====
 
−
*[[#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
 
−
*[[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 class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Interim maintenance; see paper for details
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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]
 
−
==Cyclophosphamide, Cytarabine, Mercaptopurine, Pegaspargase, Vincristine {{#subobject:9e619a|Regimen=1}}==
 
−
<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">
 
−
===Regimen variant #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]]
 
−
|-
 
−
|[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:#cbd5e8">
 
−
====Preceding treatment====
 
−
*[[#Daunorubicin.2C_Pegaspargase.2C_Vincristine.2C_Dexamethasone|Daunorubicin, pegaspargase, vincristine, dexamethasone]] induction
 
−
</div>
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Cyclophosphamide (Cytoxan)]] 1000 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 29
 
−
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> IV or SC once per day on days 1 to 4, 8 to 11, 29 to 32, 36 to 39
 
−
*[[Mercaptopurine (6-MP)]] 60 mg/m<sup>2</sup> PO once per day on days 1 to 14, 29 to 42
 
−
**Dose may be modified based on TPMT status
 
−
*[[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 class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See protocol for details of treatment beyond consolidation, which is guided by MRD status obtained at the end of induction.
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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
 
−
==Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone {{#subobject:03fb9e|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:9fedf6|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ Asselin et al. 2011 (POG 9404)]
 
−
|1996-2001
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[#Doxorubicin.2C_L-asparaginase.2C_Mercaptopurine.2C_Methotrexate.2C_Vincristine.2C_Prednisone|Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior EFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Asparaginase (Elspar)]]
 
−
*[[Mercaptopurine (6-MP)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]]
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
==Doxorubicin, L-asparaginase, Mercaptopurine, Methotrexate, Vincristine, Prednisone {{#subobject:03fb9e|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:9fedf6|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292437/ Asselin et al. 2011 (POG 9404)]
 
−
|1996-2001
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Doxorubicin.2C_L-asparaginase.2C_Mercaptopurine.2C_Vincristine.2C_Prednisone|Doxorubicin, L-asparaginase, Mercaptopurine, Vincristine, Prednisone]]
 
−
| style="background-color:#91cf60" |Seems to have superior EFS
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Asparaginase (Elspar)]]
 
−
*[[Mercaptopurine (6-MP)]]
 
−
*[[Methotrexate (MTX)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
====Glucocorticoid therapy====
 
−
*[[Prednisone (Sterapred)]]
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:45f841|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 
−
!style="width: 33%"|Study
 
−
!style="width: 33%"|Years of enrollment
 
−
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2014.58.9747 Peters et al. 2015 (ALL-SCT-BFM 2003)]
 
−
|2003-2011
 
−
| style="background-color:#91cf61" |Non-randomized
 
−
|-
 
−
|}
 
−
{{#lst:Allogeneic HSCT|45f841}}
 
−
====Immunotherapy====
 
−
*[[Allogeneic stem cells]]
 
−
'''Stem cells transfused on day 0'''
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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-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]
 
−
## '''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">
 
−
===Regimen {{#subobject:65da55|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.nature.com/articles/2401310 Amylon et al. 1999 (POG 8704)]
 
−
|1987-1992
 
−
| style="background-color:#1a9851" |Phase 3 (E-esc)
 
−
|[[#Observation_88|No L-asp]]
 
−
| style="background-color:#1a9850" |Superior CRR
 
−
|-
 
−
|}
 
−
<div class="toccolours" style="background-color:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Asparaginase (Elspar)]] 25,000 units/m<sup>2</sup> IM once per day on days 1, 8, 15, 22
 
−
'''28-day cycle for 5 cycles'''
 
−
</div></div>
 
−
===References===
 
−
# '''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=
 
−
==Mercaptopurine, Methotrexate, Vincristine {{#subobject:ac9042|Regimen=1}}==
 
−
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">
 
−
===Regimen {{#subobject:25de9f|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 
−
|2007-2014
 
−
|style="background-color:#1a9851"|Phase 3 (C)
 
−
|[[#Methotrexate.2C_Pegaspargase.2C_Vincristine|COG C-MTX]]
 
−
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 
−
|-
 
−
|}
 
−
''<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">
 
−
====Chemotherapy====
 
−
*[[Mercaptopurine (6-MP)]]
 
−
*[[Methotrexate (MTX)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
'''8-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Delayed intensification
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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">
 
−
===Regimen {{#subobject:1a0b22|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433576/ Winter et al. 2015 (COG AALL0434)]
 
−
|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
 
−
|-
 
−
|}
 
−
''Details to be completed; reported efficacy is based on the 2018 update.''
 
−
<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">
 
−
====Chemotherapy====
 
−
*[[Methotrexate (MTX)]]
 
−
*[[Pegaspargase (Oncaspar)]]
 
−
*[[Vincristine (Oncovin)]]
 
−
'''8-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*Delayed intensification
 
−
</div></div>
 
−
===References===
 
−
# '''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]
 
−
## '''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">
 
−
===Regimen {{#subobject:ech1e4|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_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: 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:#b3e2cd">
 
−
====Chemotherapy====
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 20,000 units IM once per day on days 3, 5, 7, 9, 11, 13, 18, 20, 22, 24, 26, 28
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] by the following age-based criteria:
 
−
**Age less than 2: 8 mg IT once per day on days 1 & 8
 
−
**Age 2: 10 mg IT once per day on days 1 & 8
 
−
**Age older than 2: 12 mg IT once per day on days 1 & 8
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details of treatment beyond induction
 
−
</div></div>
 
−
===References===
 
−
# '''CCLG ALL R3:''' Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, Ancliff P, Morgan M, Masurekar A, Goulden N, Green N, Révész T, Darbyshire P, Love S, Saha V. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010 Dec 11;376(9757):2009-17. Epub 2010 Dec 3. [https://doi.org/10.1016/S0140-6736(10)62002-8 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3010035/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21131038 PubMed] NCT00967057
 
−
==Mitoxantrone, Pegaspargase, Vincristine, Dexamethasone {{#subobject:910a79|Regimen=1}}==
 
−
<div class="toccolours" style="background-color:#eeeeee">
 
−
===Regimen {{#subobject:e3cbe4|Variant=1}}===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[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">
 
−
====Chemotherapy====
 
−
*[[Mitoxantrone (Novantrone)]] 10 mg/m<sup>2</sup> IV once per day on days 1 & 8
 
−
*[[Pegaspargase (Oncaspar)]] 1000 units/m<sup>2</sup> IM once per day on days 3 & 18
 
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> IV once per day on days 3, 10, 17, 24
 
−
====Glucocorticoid therapy====
 
−
*[[Dexamethasone (Decadron)]] 20 mg/m<sup>2</sup> PO once per day on days 1 to 5, 15 to 19
 
−
====CNS therapy, prophylaxis====
 
−
*[[Methotrexate (MTX)]] by the following age-based criteria:
 
−
**Age less than 2: 8 mg IT once per day on days 1 & 8
 
−
**Age 2: 10 mg IT once per day on days 1 & 8
 
−
**Age older than 2: 12 mg IT once per day on days 1 & 8
 
−
'''4-week course'''
 
−
</div>
 
−
<div class="toccolours" style="background-color:#cbd5e7">
 
−
====Subsequent treatment====
 
−
*See paper for details of treatment beyond induction
 
−
</div></div>
 
−
===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>
 
−
===References===
 
−
# 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]
 
−
# '''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:Acute lymphoblastic leukemias]]
 
−
[[Category:T-cell leukemias]]
 
−
[[Category:Pediatric hematologic neoplasms]]
 

Latest revision as of 00:13, 18 June 2023

Retrieved from "https://hemonc.org/w/index.php?title=Staging_page&oldid=73776"