Difference between revisions of "Staging page"

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[[#top|Back to Top]]
 
[[#top|Back to Top]]
 
</div>
 
</div>
−
{| class="wikitable" style="text-align:center; width:100%;"
+
{{#lst:Section editor transclusions|peds}}
−
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''
+
<big>''This page contains studies that were specific to pediatric populations. For the more general AML page, follow [[Acute myeloid leukemia|this link]].</big>
−
! colspan="2" align="center" style="color:white; font-size:125%; background-color:#de2d26" |'''Section editor'''
 
−
|-
 
−
| style="background-color:#F0F0F0; width:15%" |[[File:MartinSchoen.jpg|frameless|upright=0.3|center]]
 
−
| style="width:35%" |<big>[[User:Marteens|Martin W. Schoen, MD, MPH]]<br>Saint Louis University<br>St. Louis, MO</big><br>[[File:Social-twitter-icon.png|frameless|upright=0.1]] [https://twitter.com/mwschoen mwschoen]
 
−
|style="background-color:#F0F0F0; width:15%"|[[File:Bdholaria.jpg|frameless|upright=0.3|center]]
 
−
| style="width:35%" |<big>[[User:Bdholaria|Bhagirathbhai Dholaria, MBBS]]<br>Vanderbilt University<br>Nashville, TN</big>
 
−
|-
 
−
|}
 
−
<big>Note that many of the regimens used to treat this disease are generic to '''[[B-cell acute lymphoblastic leukemia]]'''; this page contains regimens that are specific to T-cell acute lymphoblastic leukemia (a.k.a. T-cell lymphoblastic lymphoma when primarily nodal-based).</big>
 
−
<big>'''Note: certain regimens have been moved to dedicated pages:
 
−
*'''[[T-cell acute lymphoblastic leukemia, pediatric|Pediatric T-cell ALL]]
 
−
</big>
 
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
{| class="wikitable" style="float:right; margin-right: 5px;"
 
|-
 
|-
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
|}
 
|}
−
{{TOC limit|limit=3}}
+
The following study protocols are included on this page:
 +
{| class="wikitable sortable" style="width: 50%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |Years of enrollment
 +
|-
 +
|UK MRC AML10
 +
|1988-1995
 +
|-
 +
|EORTC 58921
 +
|1992-2002
 +
|-
 +
|I-BFM-SG 2001/01
 +
|2001-2009
 +
|-
 +
|UK MRC AML15
 +
|2002-2006
 +
|-
 +
|St. Jude AML02
 +
|2002-2008
 +
|-
 +
|COG AAML0531
 +
|2006-2010
 +
|-
 +
|St. Jude AML08
 +
|2008-2017
 +
|-
 +
|COG AAML1031
 +
|2011-2016
 +
|-
 +
|COG AAML1421
 +
|2016-2018
 +
|-
 +
|}
 +
{{TOC limit|limit=4}}
 
=Guidelines=
 
=Guidelines=
 
=="How I Treat"==
 
=="How I Treat"==
−
*'''2020:''' Aldoss I, Douer D. How I treat the toxicities of pegasparaginase in adults with acute lymphoblastic leukemia. Blood. 2020 Mar 26;135(13):987-995. [https://doi.org/10.1182/blood.2019002477 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31977001 PubMed]
+
*'''2021:''' Rubnitz & Kaspers [https://doi.org/10.1182/blood.2021011694 How I treat pediatric acute myeloid leukemia]
−
==[https://www.nccn.org/ NCCN]==
+
=Upfront induction therapy=
−
*[https://www.nccn.org/professionals/physician_gls/pdf/t-cell.pdf NCCN Guidelines - T-cell Lymphomas]
+
==COG AAML1031 arm A (low-risk)==
−
*[https://www.nccn.org/professionals/physician_gls/pdf/ped_all.pdf NCCN Guidelines - Pediatric Acute Lymphoblastic Leukemia]
+
<div class="toccolours" style="background-color:#eeeeee">
−
=Pre-phase=
+
===Induction, part I===
−
==Prednisone monotherapy {{#subobject:30c275|Regimen=1}}==
+
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 +
**
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''10-day course, followed by:'''
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:af8a3d|Variant=1}}===
+
===Induction, part II===
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 8
 +
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 8
 +
*[[Daunorubicin (Cerubidine)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
**BSA < 0.6 m<sup>2</sup>: 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
 +
**
 
{| class="wikitable" style="width: 40%; text-align:center;"  
 
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 25%" |Age
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2015.61.5385 Lepretre et al. 2015 (GRAALL-LYSA LL03)]
+
|2 - 2.99
−
|style="background-color:#91cf61"|Phase 2
+
|50
 
|-
 
|-
 +
|≥ 3
 +
|70
 
|}
 
|}
 +
'''8-day course, followed by:'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part I===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
*[[Etoposide (Vepesid)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 through 5
 +
**BSA < 0.6 m<sup>2</sup>: 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''5-day course, followed by:'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part II===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
*[[Mitoxantrone (Novantrone)]] by the following BSA-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
 +
**BSA < 0.6 m<sup>2</sup>: 0.4 mg/kg once per day on days 3 to 6
 +
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Intensification I
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''6-day course'''
 +
</div></div>
 +
===References===
 +
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
 +
==COG AAML1031 arm A (high-risk)==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part I===
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''10-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part II===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Mitoxantrone (Novantrone)]] 0.4 mg/kg once per day on days 3 to 6.
 +
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction I
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''6-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part I===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''5-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part II===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 2, 8, 9
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 100 mg/kg IV over 3 hours every 12 hours on days 1, 2, 8, 9
 +
*[[E.Coli L-Asparaginase (LASP)]] 6000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
**IF BSA < 0.6 m<sup>2</sup>, [[E.Coli L-Asparaginase (LASP)]] 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
may substitute with another asparaginase formulation
 +
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 25,000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Asparaginase Erwinia chrysanthemi (Erwinaze)]] 830 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
If Erwinia asparaginase is not available, pegasparaginase should NOT be given, and asparaginase should be omitted
 +
'''28-day course'''
 +
</div></div>
 +
===References===
 +
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
 +
==COG AAML1031 arm C (FLT3/ITD+)==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part I===
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*FLT3/ITD+
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
−
====Glucocorticoid therapy====
+
====Chemotherapy====
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days -7 to -1
+
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====Targeted therapy====
 +
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 11 to 28
 +
**see [[Sorafenib Dosing Nomogram]] for more details.
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 +
**
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''28-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part II===
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 1 to 30 minutes every 12 hours on days 1 to 8
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 8
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====Targeted therapy====
 +
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 9 to 36
 +
**see [[Sorafenib Dosing Nomogram]] for more details.
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
 +
**
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''36-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part I===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
 +
*[[Etoposide (Vepesid)]] 150 mg/m<sup>2</sup> IV over 60 to 120 minutes once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5
 +
====Targeted therapy====
 +
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 6 through 33
 +
**see [[Sorafenib Dosing Nomogram]] for more details.
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Induction II.
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''33-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part II===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] 1000 mg/m<sup>2</sup> IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
 +
*[[Mitoxantrone (Novantrone)]] 12 mg/m<sup>2</sup> IV over 15 to 30 minutes once per day on days 3 to 6
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Mitoxantrone (Novantrone)]] 0.4 mg/kg once per day on days 3 to 6
 +
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
 +
====Targeted therapy====
 +
*[[Sorafenib (Nexavar)]] 200 mg/m<sup>2</sup> (Maximum dose of 400 mg) PO once per day, rounded to accommodate tablet size on days 7 to 34
 +
**see [[Sorafenib Dosing Nomogram]] for more details
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with the bone marrow evaluation at the end of Intensification I
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''6-day course'''
 +
</div></div>
 +
===References===
 +
# '''COG AAML1031:''' Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. [https://doi.org/10.3324/haematol.2019.220962 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7327649/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32029509/ PubMed] NCT01371981
 +
==COG AAML0531 arm B (Gemtuzumab)==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part I===
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 15 minutes every 12 hours on days 1 to 10
 +
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 50 mg/m<sup>2</sup> IV over 6 hours once per day on days 1, 3, 5
 +
**BSA < 0.6 m<sup>2</sup>: 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 100 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5
 +
**BSA < 0.6 m<sup>2</sup>: 3.3 mg/kg IV over 4 hours once per day on days 1 to 5
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 3 mg/m<sup>2</sup> IV over 2 hours once on day 6
 +
**BSA < 0.6 m<sup>2</sup>: 0.1 mg/kg IV once on day 6
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1
 +
**For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''10-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Induction, part II===
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 15 minutes every 12 hours on days 1 to 8
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Cytarabine (Ara-C)]] 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 8
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV over 6 hours once per day on days 1, 3, 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Daunorubicin (Cerubidine)]] 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 4 hours once per day on days 1 to 5
 +
**IF BSA < 0.6 m<sup>2</sup>, [[Etoposide (Vepesid)]] 3.3 mg/kg IV over 4 hours once per day on days 1 to 5
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction I
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''28-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part I===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 hour every 12 hours on days 1 to 5
 +
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 5
 +
*[[Etoposide (Vepesid)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 150 mg/m<sup>2</sup> IV over 1 hour once per day on days 1 to 5
 +
**BSA < 0.6 m<sup>2</sup>: 5 mg/kg IV over 4 hours once per day on days 1 to 5
 +
**Each dose of [[Etoposide (Vepesid)]] should immediately follow the AM dose of [[Cytarabine (Ara-C)]]
 +
====CNS therapy, prophylaxis====
 +
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Induction II
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''5-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part II===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 1000 mg/m<sup>2</sup> IV over 1 hour every 12 hours on days 1 to 4
 +
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 4
 +
*[[Mitoxantrone (Novantrone)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 12 mg/m<sup>2</sup> IV over 1 hour once per day on days 3 to 6
 +
**BSA < 0.6 m<sup>2</sup>: 0.4 mg/kg once per day on days 3 to 6
 +
**On days where both are given, give [[Mitoxantrone (Novantrone)]] 8 hours AFTER the END of the high dose [[Cytarabine (Ara-C)]] infusions
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 3 mg/m<sup>2</sup> IV over 2 hours once on day 7
 +
**BSA < 0.6 m<sup>2</sup>: 0.1 mg/kg once on day 7
 
====CNS therapy, prophylaxis====
 
====CNS therapy, prophylaxis====
−
*[[Methotrexate (MTX)]] 15 mg IT once at some point between days -7 and -4
+
*[[Cytarabine (Ara-C)]] IT on day 1 or with bone marrow evaluation at the end of Intensification I
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|-
 +
|0 - 0.99
 +
|20
 +
|-
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 
'''7-day course'''
 
'''7-day course'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Intensification, part III===
 +
====Chemotherapy====
 +
*High Dose [[Cytarabine (Ara-C)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 3000 mg/m<sup>2</sup> IV over 3 hours every 12 hours on days 1, 2, 8, 9
 +
**BSA < 0.6 m<sup>2</sup>: 33 mg/kg IV over 1 hour every 12 hours on days 1, 2, 8, 9
 +
*[[E.Coli L-Asparaginase (LASP)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 6000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
**BSA < 0.6 m<sup>2</sup>: 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
may substitute with another asparaginase formulation
 +
*[[Asparaginase Erwinia chrysanthemi (Erwinaze)]] by the following weight-based criteria:
 +
**BSA 0.6 m<sup>2</sup> or more: 25,000 IU/m<sup>2</sup> IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
**BSA < 0.6 m<sup>2</sup>: 830 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
 +
'''28-day course'''
 +
</div></div>
 +
===References===
 +
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
 +
==ADE (standard-dose Ara-C) {{#subobject:e221d7|Regimen=1}}==
 +
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide
 +
<br>7-3-7: '''<u>7</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide
 +
<br>8-3-5: '''<u>8</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
 +
<br>10-3-5: '''<u>10</u>''' days of Cytarabine, '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 8-3-5, 1600/150/500, intermittent Ara-C {{#subobject:f7e0ca|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]
 +
|1988-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+8]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
 +
|2006-2010
 +
| style="background-color:#91cf61" |Non-randomized portion of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
''Note: these trials have complicated treatment schemas; see papers for details. This is IND2 for COG AAML0531.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*UK MRC AML10: [[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]] induction
 +
*COG AAML0531: [[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]] induction versus [[#ADE_.26_GO|ADE & GO]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 8
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
'''8-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Cyclophosphamide.2C_Daunorubicin.2C_L-Asparaginase.2C_Vincristine.2C_Prednisone|Cyclophosphamide, daunorubicin, L-asparaginase, vincristine, prednisone]] re-induction
+
*UK MRC AML10: [[#MACE_88|MACE]] consolidation
 +
*COG AAML0531: [[#CYVE|CYVE]] interim maintenance
 +
*Other trials: Consolidation (see paper for details)
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 10-3-5, 2000/150/500, intermittent Ara-C {{#subobject:77fe46|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
! style="width: 20%" |Study
 +
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://www.bloodjournal.org/content/89/7/2311.long Hann et al. 1997 (UK MRC AML10)]
 +
|1988-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[Acute_myeloid_leukemia_-_historical#DAT|DAT 3+10]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3171799/ Rubnitz et al. 2010 (AML02)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ADE_.28high-dose_Ara-C.29|ADE]]; high-dose Ara-C
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of MRD-positivity at day 22
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ADE_.26_GO|ADE & GO]]
 +
| style="background-color:#fc8d59" |Seems to have inferior EFS
 +
|-
 +
|}
 +
''Note: these trials have complicated treatment schemas; see papers for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5 or days 2, 4, 6
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5 or days 2 to 6
 +
'''10-day course'''
 +
</div></div>
 +
===References===
 +
#'''UK MRC AML10:''' Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. [http://www.bloodjournal.org/content/89/7/2311.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9116274 PubMed]
 +
##'''Update:''' Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. [https://doi.org/10.1016/S0140-6736(97)09214-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9504514 PubMed]
 +
#'''AML02:''' Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, Pounds S, Razzouk BI, Lacayo NJ, Cao X, Meshinchi S, Degar B, Airewele G, Raimondi SC, Onciu M, Coustan-Smith E, Downing JR, Leung W, Pui CH, Campana D. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010 Jun;11(6):543-52. Epub 2010 May 5. [https://doi.org/10.1016/s1470-2045(10)70090-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3171799/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20451454/ PubMed] NCT00136084
 +
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
 +
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
 +
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 +
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
 +
==ADE (high-dose Ara-C) {{#subobject:c7eb71|Regimen=1}}==
 +
ADE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposide
 +
<br>HIDAC-3-5: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>5</u>''' days of Etoposide
 +
<br>HIDAC-3-7: '''<u>HI</u>'''gh-'''<u>D</u>'''ose '''<u>A</u>'''ra-'''<u>C</u>''' (Cytarabine), '''<u>3</u>''' days of Daunorubicin, '''<u>7</u>''' days of Etoposide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:386dha|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/10.1200/jco.19.00327 Rubnitz et al. 2019 (AML08)]
 +
|2008-2017
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Clofarabine_.26_Cytarabine_99|Clofarabine & Cytarabine]]
 +
| style="background-color:#91cf60" |Seems to have superior MRD at day 22
 +
|-
 +
|}
 +
''Note: this regimen was intended for patients younger than 22 years.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 3000 mg/m<sup>2</sup> IV every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m<sup>2</sup>)
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 2, 4, 6
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV once per day on days 2 to 6
 +
'''6-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Response- and risk-adapted therapy; see paper for details
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!-- Presented at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. -->
+
#'''AML08:''' Rubnitz JE, Lacayo NJ, Inaba H, Heym K, Ribeiro RC, Taub J, McNeer J, Degar B, Schiff D, Yeoh AE, Coustan-Smith E, Wang L, Triplett B, Raimondi SC, Klco J, Choi J, Pounds S, Pui CH. Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. J Clin Oncol. 2019 Aug 10;37(23):2072-2081. Epub 2019 Jun 27. [https://doi.org/10.1200/jco.19.00327 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7001777/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31246522 PubMed] NCT00703820
−
#'''GRAALL-LYSA LL03:''' Lepretre S, Touzart A, Vermeulin T, Picquenot JM, Tanguy-Schmidt A, Salles G, Lamy T, Béné MC, Raffoux E, Huguet F, Chevallier P, Bologna S, Bouabdallah R, Benichou J, Brière J, Moreau A, Tallon-Simon V, Seris S, Graux C, Asnafi V, Ifrah N, Macintyre E, Dombret H. Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study. J Clin Oncol. 2016 Feb 20;34(6):572-80. Epub 2015 Dec 7. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.61.5385 link to data supplement] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26644537 PubMed] NCT00195871
+
==ADE & GO {{#subobject:e33id7|Regimen=1}}==
−
=Upfront induction therapy=
+
ADE & GO: '''<u>A</u>'''ra-C (Cytarabine), '''<u>D</u>'''aunorubicin, '''<u>E</u>'''toposidem, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin
−
==Cyclophosphamide, Daunorubicin, L-Asparaginase, Vincristine, Prednisone {{#subobject:b90dc3|Regimen=1}}==
 
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, "Pediatric-like GRAALL reinforced induction" {{#subobject:56ea06|Variant=1}}===
+
===Regimen {{#subobject:99ye46|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2015.61.5385 Lepretre et al. 2015 (GRAALL-LYSA LL03)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ Gamis et al. 2014 (COG AAML0531)]
−
|style="background-color:#91cf61"|Phase 2
+
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#ADE_.28standard-dose_Ara-C.29|ADE 10-3-5]]
 +
| style="background-color:#91cf60" |Seems to have superior EFS
 
|-
 
|-
 
|}
 
|}
−
''Note: This regimen was meant for patients less than 60 years old (up to age 59). Regimen is as per the [[Acute_lymphocytic_leukemia#Pediatric-like_GRAALL_induction|GRAALL-2003 Study]] with some minor differences. High-risk patients with an HLA sibling-matched donor or a fully matched (10/10) unrelated donor who achieved CR1 were offered allogeneic stem cell transplant.''
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<div class="toccolours" style="background-color:#cbd5e8">
+
====Chemotherapy====
−
====Preceding treatment====
+
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup>/day IV every 12 hours on days 1 to 10
−
*[[#Prednisone_monotherapy|Prednisone pre-phase]]
+
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 +
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV over 2 hours once on day 6
 +
'''10-day course'''
 
</div>
 
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#ADE_.28standard-dose_Ara-C.29|ADE 8-3-5]] re-induction
 +
</div></div>
 +
===References===
 +
#'''COG AAML0531:''' Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://doi.org/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25092781 PubMed] NCT00372593
 +
==AIE {{#subobject:948b49|Regimen=1}}==
 +
AIE: '''<u>A</u>'''ra-C (Cytarabine), '''<u>I</u>'''darubicin, '''<u>E</u>'''toposide
 +
<br>ICE: '''<u>I</u>'''darubicin, '''<u>C</u>'''ytarabine, '''<u>E</u>'''toposide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:c7b35a|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/2403932 Entz-Werle et al. 2005 (EORTC 58921)]
 +
|1992-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#MEC_99|MEC]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
|}
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV over 3 hours once on day 1, then 500 mg/m<sup>2</sup> IV every 12 hours on days 15 & 16
+
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m<sup>2</sup>)
−
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1 to 3, then 30 mg/m<sup>2</sup> IV once per day on days 15 & 16
+
*[[Idarubicin (Idamycin)]] 12 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 3
−
*[[Asparaginase (Elspar)]] 6000 units/m<sup>2</sup>/day (route not specified) on days 8, 10, 12, 20, 22, 24, 26, 28
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
−
*[[Vincristine (Oncovin)]] 2 mg IV once per day on days 1, 8, 15, 22
+
'''7-day course'''
−
====Glucocorticoid therapy====
+
</div></div>
−
*[[Prednisone (Sterapred)]] 60 mg/m<sup>2</sup>/day PO on days 1 to 14
+
===References===
−
====Supportive therapy====
+
#'''EORTC 58921:''' Entz-Werle N, Suciu S, van der Werff ten Bosch J, Vilmer E, Bertrand Y, Benoit Y, Margueritte G, Plouvier E, Boutard P, Vandecruys E, Ferster A, Lutz P, Uyttebroeck A, Hoyoux C, Thyss A, Rialland X, Norton L, Pages MP, Philippe N, Otten J, Behar C; [[Study_Groups#EORTC|EORTC]] Children Leukemia Group. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report. Leukemia. 2005 Dec;19(12):2072-81. [https://www.nature.com/articles/2403932 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16136166 PubMed] NCT00002517
−
*[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day from day 17 until myeloid recovery
+
==DA 3 + 10 {{#subobject:5c0062|Regimen=1}}==
−
====CNS therapy, prophylaxis====
+
DA 3 + 10: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine
−
*[[Methotrexate (MTX)]] 15 mg IT once per day on days 1 & 8
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Cytarabine (Ara-C)]] 40 mg IT once per day on days 1 & 8
+
===Regimen variant #1, 50 mg/m<sup>2</sup> dauno {{#subobject:99321e|Variant=1}}===
−
*[[Methylprednisolone (Solumedrol)|Methylprednisolone (Depo-Medrol)]] 40 mg IT once per day on days 1 & 8
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
'''28-day course'''
+
! 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/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|-
 +
|}
 +
''Note: this regimen is very similar to [[#7.2B3d_.28standard-dose.29|7+3d (standard-dose)]]; however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 +
'''10-day course'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*See papers for details (to be completed).
 +
</div></div>
 +
===References===
 +
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
 +
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
 +
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 +
==DA 3 + 10, GO {{#subobject:e6f5bb|Regimen=1}}==
 +
DA 3 + 10, GO: '''<u>D</u>'''aunorubicin & '''<u>A</u>'''ra-C (Cytarabine), '''<u>3</u>''' days of daunorubicin '''<u>+ 10</u>''' days of cytarabine, '''<u>G</u>'''emtuzumab '''<u>O</u>'''zogamicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6a938e|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/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|[[Complex_multipart_regimens#UK_MRC_AML15|See link]]
 +
|-
 +
|}
 +
''This trial has complicated treatment schemas; see papers for details.''
 +
====Chemotherapy====
 +
*[[Cytarabine (Ara-C)]] 100 mg/m<sup>2</sup> IV every 12 hours on days 1 to 10
 +
*[[Daunorubicin (Cerubidine)]] 50 mg/m<sup>2</sup> IV once per day on days 1, 3, 5
 +
====Antibody-drug conjugate therapy====
 +
*[[Gemtuzumab ozogamicin (Mylotarg)]] 3 mg/m<sup>2</sup> IV once on day 1
 +
'''10-day course'''
 
</div>
 
</div>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*See paper for details beyond induction
+
*See paper for details (to be completed).
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
<!-- Presented at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA, December 6-9, 2014. -->
+
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
−
#'''GRAALL-LYSA LL03:''' Lepretre S, Touzart A, Vermeulin T, Picquenot JM, Tanguy-Schmidt A, Salles G, Lamy T, Béné MC, Raffoux E, Huguet F, Chevallier P, Bologna S, Bouabdallah R, Benichou J, Brière J, Moreau A, Tallon-Simon V, Seris S, Graux C, Asnafi V, Ifrah N, Macintyre E, Dombret H. Pediatric-Like Acute Lymphoblastic Leukemia Therapy in Adults With Lymphoblastic Lymphoma: The GRAALL-LYSA LL03 Study. J Clin Oncol. 2016 Feb 20;34(6):572-80. Epub 2015 Dec 7. [https://doi.org/10.1200/JCO.2015.61.5385 link to original article] [https://ascopubs.org/doi/suppl/10.1200/JCO.2015.61.5385 link to data supplement] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/26644537 PubMed] NCT00195871
+
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
−
==Daunorubicin, Pegaspargase, Vincristine, Dexamethasone {{#subobject:516f7b|Regimen=1}}==
+
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 +
==FLAG-Ida {{#subobject:7fc219|Regimen=1}}==
 +
FLAG-Ida: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF (Lenograstim), '''<u>Ida</u>'''rubicin
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, modified ABFM {{#subobject:88f520|Variant=1}}===
+
===Regimen {{#subobject:44e85e|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
−
!style="width: 50%"|Study
+
!style="width: 20%"|Study
−
!style="width: 50%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
!style="width: 20%"|Years of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://doi.org/10.1016/S1470-2045(12)70600-9 Vora et al. 2013 (UKALL 2003)]
+
|[https://doi.org/10.1200/JCO.2010.31.4310 Burnett et al. 2010 (UK MRC AML15)]
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ADE_.28standard-dose_Ara-C.29|ADE 10+3+5]]<br>2. [[#DA_3_.2B_10|DA 3+10]]<br> 3. [[#DA_3_.2B_10.2C_GO|DA 3+10 & GO]]<br> 4. [[#FLAG-Ida_.26_GO_99|FLAG-Ida & GO]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 
|-
 
|-
 
|}
 
|}
 +
''<sup>1</sup>While this was a negative trial, a predefined analysis by cytogenetics showed a significant survival benefit for GO in patients with favorable cytogenetics.''
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Daunorubicin (Cerubidine)]] 25 mg/m<sup>2</sup> IV over 1 to 15 minutes once per day on days 1, 8, 15, 22
+
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 2 to 6
−
*[[Pegaspargase (Oncaspar)]] 2500 units/m<sup>2</sup> IV over 1 to 2 hours once per day on days 4 & 18
+
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 4 hours once per day on days 2 to 6, '''given 4 hours after fludarabine'''
−
*[[Vincristine (Oncovin)]] 1.5 mg/m<sup>2</sup> (maximum dose of 2 mg) IV once per day on days 1, 8, 15, 22
+
*[[Idarubicin (Idamycin)]] 8 mg/m<sup>2</sup> IV once per day on days 4 to 6
−
====Glucocorticoid therapy====
+
====Growth factor therapy====
−
*[[Dexamethasone (Decadron)]] 3 mg/m<sup>2</sup> IV or PO twice per day on days 1 to 28
+
*[[Lenograstim (Granocyte)]] 263 mcg SC once per day on days 1 to 7
−
====CNS therapy, prophylaxis====
+
'''7-day course'''
−
*[[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>
 
<div class="toccolours" style="background-color:#cbd5e7">
 
<div class="toccolours" style="background-color:#cbd5e7">
 
====Subsequent treatment====
 
====Subsequent treatment====
−
*[[#Cyclophosphamide.2C_Cytarabine.2C_Mercaptopurine.2C_Pegaspargase.2C_Vincristine|Cyclophosphamide, cytarabine, mercaptopurine, pegaspargase, vincristine]] consolidation
+
*See paper for details
 
</div></div>
 
</div></div>
 
===References===
 
===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
+
#'''UK MRC AML15:''' Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://doi.org/10.1200/JCO.2010.31.4310 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21172891 PubMed] ISRCTN17161961
 +
## '''Update:''' Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. [https://www.nature.com/articles/leu2012360 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23222369 PubMed]
 +
##'''Update:''' Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. [https://doi.org/10.1200/jco.2012.47.4874 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23940227 PubMed]
 
=Consolidation after upfront therapy=
 
=Consolidation after upfront therapy=
−
==Etoposide & TBI, then allo HSCT {{#subobject:b389e1|Regimen=1}}==
+
==BuCy, then auto HSCT {{#subobject:9acbe9|Regimen=1}}==
 +
BuCy: '''<u>Bu</u>'''sulfan & '''<u>Cy</u>'''clophosphamide
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen {{#subobject:e4216b|Variant=1}}===
+
===Regimen {{#subobject:5d4efb|Variant=1}}===
−
{| class="wikitable" style="width: 40%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |Years of enrollment
 +
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
 +
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199605303342203 Ravindranath et al. 1996]
 +
|1988-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|Intensive chemotherapy
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS24
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#7.2B3d_.28standard-dose.29|7+3d]], then [[#High-dose_Cytarabine_monotherapy_.28HiDAC.29|HiDAC]]
 +
{{#lst:Autologous HSCT|5d4efb}}
 +
</div></div>
 +
===References===
 +
#Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. [https://doi.org/10.1056/NEJM199605303342203 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8618581 PubMed]
 +
==Cyclophosphamide & TBI, then allo HSCT {{#subobject:a9f7e8|Regimen=1}}==
 +
Cy/TBI: '''<u>Cy</u>'''clophosphamide & '''<u>T</u>'''otal '''<u>B</u>'''ody '''<u>I</u>'''rradiation
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6ca28d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[http://www.bloodjournal.org/content/106/12/3760.long Rowe et al. 2005 (MRC UKALL XII/ECOG E2993)]
+
|[https://doi.org/10.1056/NEJM198712243172602 Brochstein et al. 1987]
−
| style="background-color:#91cf61" |Non-randomized portion of RCT
+
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
 
|}
 
|}
−
{{#lst:Allogeneic HSCT|e4216b}}
+
{{#lst:Allogeneic HSCT|6ca28d}}
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 
====Immunotherapy====
 
====Immunotherapy====
 
*[[Allogeneic stem cells]]
 
*[[Allogeneic stem cells]]
Line 149: Line 895:
 
</div></div>
 
</div></div>
 
===References===
 
===References===
−
# '''MRC UKALL XII/ECOG E2993:''' Rowe JM, Buck G, Burnett AK, Chopra R, Wiernik PH, Richards SM, Lazarus HM, Franklin IM, Litzow MR, Ciobanu N, Prentice HG, Durrant J, Tallman MS, Goldstone AH; ECOG; MRC/NCRI Adult Leukemia Working Party. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood. 2005 Dec 1;106(12):3760-7. Epub 2005 Aug 16. [http://www.bloodjournal.org/content/106/12/3760.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16105981 PubMed] NCT00002514
+
#Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. [https://doi.org/10.1056/NEJM198712243172602 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3317056 PubMed]
−
## '''Update:''' Goldstone AH, Richards SM, Lazarus HM, Tallman MS, Buck G, Fielding AK, Burnett AK, Chopra R, Wiernik PH, Foroni L, Paietta E, Litzow MR, Marks DI, Durrant J, McMillan A, Franklin IM, Luger S, Ciobanu N, Rowe JM. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood. 2008 Feb 15;111(4):1827-33. Epub 2007 Nov 29. [http://www.bloodjournal.org/content/111/4/1827.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/18048644 PubMed]
+
=Relapsed or refractory, salvage therapy=
−
## '''Update:''' Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, Marks DI, McMillan AK, Litzow MR, Lazarus HM, Foroni L, Dewald G, Franklin IM, Luger SM, Paietta E, Wiernik PH, Tallman MS, Goldstone AH. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009 May 7;113(19):4489-96. Epub 2009 Feb 24. [http://www.bloodjournal.org/content/113/19/4489.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188540/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19244158 PubMed]
+
''Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.''
−
## '''Update:''' Fielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. Epub 2013 Nov 25. [http://www.bloodjournal.org/content/123/6/843.full link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3916877/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24277073 PubMed]
+
==COGAAML1421 protocol==
−
=Relapsed or refractory=
+
<div class="toccolours" style="background-color:#eeeeee">
−
==Nelarabine monotherapy {{#subobject:bb7a38|Regimen=1}}==
+
===Protocol===
 +
====Chemotherapy, cycle 1====
 +
*[[Cytarabine and Daunorubicin Liposome (CPX-351)]] 135 units/m<sup>2</sup> IV over 90 minutes on days 1, 3, 5
 +
====CNS therapy====
 +
*[[Cytarabine (Ara-C)]] IT 2 doses
 +
**At the time of diagnostic lumbar puncture or Day 0 of cycle 1
 +
**At the time of the Day 28 to 30 bone marrow biopsy, or up to one week prior to Day 1 of cycle 2
 +
*CNS2 Patients
 +
**[[Cytarabine (Ara-C)]] IT twice weekly until the CSF is clear starting at least 48 hours following the 3rd dose of CPX-351
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 25%" |Age
 +
! style="width: 25%" |Dose
 +
|1 - 1.99
 +
|30
 +
|-
 +
|2 - 2.99
 +
|50
 +
|-
 +
|≥ 3
 +
|70
 +
|}
 +
'''28-Day course'''
 +
====Chemotherapy, cycle 2====
 +
*[[Filgrastim (Neupogen)]] 5 mcg/kg IV or SQ once per day on days 1 to 5, one hour prior to each dose of [[Fludarabine (Fludara)]]
 +
**Restart on day 15 and continue until post-nadir ANC ≥ 500/μL
 +
Pegfilgrastim cannot be utilized in the place of filgrastim or biosimilar
 +
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 to 5
 +
*High Dose [[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV over 1 to 3 hours every once daily on days 1 to 5
 +
**Begin [[Cytarabine (Ara-C)]] 4 hours after the start of [[Fludarabine (Fludara)]]
 +
'''28-day course'''
 +
</div></div>
 +
===References===
 +
# '''COG AAML1421:'''Cooper TM, Absalon M, Alonzo TA, Gerbing RB, Leger KJ, Hirsch BA, Pollard JA, Razzouk BI, Aplenc R, Kolb EA. AAML1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A report from the Children's Oncology Group. Journal of Clinical Oncology. 2019 May;37(15). [https://doi.org/10.1200/JCO.2019.37.15_suppl.10003 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325367/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32401633/ PubMed]NCT02642965
 +
==FLAG {{#subobject:551761|Regimen=1}}==
 +
FLAG: '''<u>FL</u>'''udarabine, '''<u>A</u>'''ra-C (Cytarabine), '''<u>G</u>'''-CSF
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #1, 5-day dosing {{#subobject:44a025|Variant=1}}===
+
===Regimen {{#subobject:bdc7e4|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
!style="width: 25%"|Study
+
! style="width: 20%" |Study
−
!style="width: 25%"|Years of enrollment
+
! style="width: 20%" |Years of enrollment
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+
! style="width: 20%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+
! style="width: 20%" |Comparator
 +
! style="width: 20%" |[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
 +
|2001-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
 +
| style="background-color:#fc8d59" |Seems to have inferior CR rate
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2005.03.426 Berg et al. 2005]
+
|}
−
|1997-2002
+
''Note: this regimen was studied in patients up to 21 years of age.''
−
|style="background-color:#91cf61"|Phase 2 (RT)
+
<div class="toccolours" style="background-color:#b3e2cd">
−
|ORR: 14-55%
+
====Chemotherapy====
 +
*[[Fludarabine (Fludara)]] 30 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given second'''
 +
*[[Cytarabine (Ara-C)]] 2000 mg/m<sup>2</sup> IV once per day on days 1 to 5, '''given third, 4 hours after the start of fludarabine'''
 +
====Growth factor therapy====
 +
*[[Filgrastim (Neupogen)]] 200 mcg/m<sup>2</sup> (route not specified) once per day on days 0 to 5, '''given first'''
 +
'''2 cycles (length not specified)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#CYVE_2|CYVE]] or [[#Cytarabine_.26_Thioguanine|Cytarabine & Thioguanine]] consolidation, as a bridge to [[Regimen_classes#Allogeneic_HSCT|allogeneic HSCT]]
 +
</div></div>
 +
===References===
 +
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
 +
=Consolidation after salvage therapy=
 +
==Cytarabine & Thioguanine {{#subobject:3c38bc|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f2728e|Variant=1}}===
 +
{| class="wikitable" style="width: 40%; text-align:center;"
 +
! style="width: 50%" |Study
 +
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
 
|-
 
|-
−
|[https://doi.org/10.1111/bjh.14874 Zwaan et al. 2017 (GSK 111081)]
+
|[https://doi.org/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
−
|2009-2014
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|style="background-color:#91cf61"|Phase 4
 
−
|style="background-color:#666666; color:white"|ORR: 39%
 
 
|-
 
|-
 
|}
 
|}
 +
''Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Nelarabine (Arranon)]] 650 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 to 5
+
*[[Cytarabine (Ara-C)]] 75 mg/m<sup>2</sup> SC once per day on days 1 to 4
−
'''21-day cycles'''
+
*[[Thioguanine (Tabloid)]] as follows:
−
</div></div><br>
+
**Cycles 1 & 2: 100 mg/m<sup>2</sup> PO once per day
 +
'''14-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic HSCT]]
 +
</div></div>
 +
===References===
 +
#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
 +
==CYVE {{#subobject:4bd791|Regimen=1}}==
 +
CYVE: '''<u>CY</u>'''tarabine & '''<u>VE</u>'''pesid (Etoposide)
 
<div class="toccolours" style="background-color:#eeeeee">
 
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen variant #2, intermittent dosing {{#subobject:b5ce00|Variant=1}}===
+
===Regimen {{#subobject:a16529|Variant=1}}===
−
{| class="wikitable sortable" style="width: 80%; text-align:center;"  
+
{| class="wikitable" style="width: 40%; text-align:center;"  
−
!style="width: 25%"|Study
+
! style="width: 50%" |Study
−
!style="width: 25%"|Years of enrollment
+
! style="width: 50%" |[[Levels_of_Evidence#Evidence|Evidence]]
−
!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 25%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 
 
|-
 
|-
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1941786/ DeAngelo et al. 2007 (CALGB 19801)]
+
|[https://doi.org/10.1200/JCO.2012.43.7384 Kaspers et al. 2013 (I-BFM-SG 2001/01)]
−
|1998-2001
+
| style="background-color:#91cf61" |Non-randomized portion of RCT
−
|style="background-color:#91cf61"|Phase 2 (RT)
 
−
|style="background-color:#666666; color:white"|ORR: 41% (95% CI, 15-43)
 
 
|-
 
|-
 
|}
 
|}
−
''Note: See paper for details about the schedule.''
+
''Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[#FLAG|FLAG]] versus [[Acute_myeloid_leukemia_-_historical#FLAG-DNX|FLAG-DNX]]
 +
</div>
 
<div class="toccolours" style="background-color:#b3e2cd">
 
<div class="toccolours" style="background-color:#b3e2cd">
 
====Chemotherapy====
 
====Chemotherapy====
−
*[[Nelarabine (Arranon)]] 1500 mg/m<sup>2</sup> IV over 2 hours once per day on days 1, 3, 5
+
*[[Cytarabine (Ara-C)]] 500 mg/m<sup>2</sup>/day IV continuous infusion over 96 hours, started on day 1 (total dose: 2000 mg/m<sup>2</sup>)
−
'''21-day cycle for 3 to 4 cycles (or delayed for count recovery)'''
+
*[[Etoposide (Vepesid)]] 100 mg/m<sup>2</sup> IV twice per day on days 1 to 4
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Regimen_classes#Allogeneic_HSCT|Allogeneic HSCT]]
 
</div></div>
 
</div></div>
 
===References===
 
===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]
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#'''I-BFM-SG 2001/01:''' Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. [https://doi.org/10.1200/JCO.2012.43.7384 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23319696 PubMed] NCT00186966
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# '''CALGB 19801:''' DeAngelo DJ, Yu D, Johnson JL, Coutre SE, Stone RM, Stopeck AT, Gockerman JP, Mitchell BS, Appelbaum FR, Larson RA. Nelarabine induces complete remissions in adults with relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: Cancer and Leukemia Group B study 19801. Blood. 2007 Jun 15;109(12):5136-42. Epub 2007 Mar 7. [http://www.bloodjournal.org/content/109/12/5136.long link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1941786/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17344466 PubMed]
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[[Category:Acute myeloid leukemia regimens]]
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# '''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
 
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[[Category:Pediatric hematologic neoplasms]]

Revision as of 01:21, 23 October 2022

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Section editor transclusions This page contains studies that were specific to pediatric populations. For the more general AML page, follow this link.

0 regimens on this page
0 variants on this page

The following study protocols are included on this page:

Study Years of enrollment
UK MRC AML10 1988-1995
EORTC 58921 1992-2002
I-BFM-SG 2001/01 2001-2009
UK MRC AML15 2002-2006
St. Jude AML02 2002-2008
COG AAML0531 2006-2010
St. Jude AML08 2008-2017
COG AAML1031 2011-2016
COG AAML1421 2016-2018


Guidelines

"How I Treat"

Upfront induction therapy

COG AAML1031 arm A (low-risk)

Induction, part I

Chemotherapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

10-day course, followed by:

Induction, part II

Chemotherapy

  • Cytarabine (Ara-C) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 100 mg/m2 IV over 1 to 30 minutes every 12 hours on days 1 to 8
    • BSA < 0.6 m2: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 8
  • Daunorubicin (Cerubidine) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 50 mg/m2 IV over 1 to 15 minutes once per day on days 1, 3, 5
    • BSA < 0.6 m2: 1.7 mg/kg IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Etoposide (Vepesid) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 100 mg/m2 IV over 60 to 120 minutes once per day on days 1 to 5
    • BSA < 0.6 m2: 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with bone marrow evaluation at the end of Induction I
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

8-day course, followed by:

Intensification, part I

Chemotherapy

  • High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 1000 mg/m2 IV over 1 to 3 hours every 12 hours on days 1 to 5
    • BSA < 0.6 m2: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 5
  • Etoposide (Vepesid) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 150 mg/m2 IV over 60 to 120 minutes once per day on days 1 through 5
    • BSA < 0.6 m2: 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Induction II
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

5-day course, followed by:

Intensification, part II

Chemotherapy

  • High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 1000 mg/m2 IV over 1 to 3 hours every 12 hours on days 1 to 4
    • BSA < 0.6 m2: 33 mg/kg IV over 1 to 3 hours every 12 hours on days 1 to 4
  • Mitoxantrone (Novantrone) by the following BSA-based criteria:
    • BSA 0.6 m2 or more: 12 mg/m2 IV over 15 to 30 minutes once per day on days 3 to 6
    • BSA < 0.6 m2: 0.4 mg/kg once per day on days 3 to 6
    • On days where both are given, give Mitoxantrone (Novantrone) 8 hours AFTER the END of the high dose Cytarabine (Ara-C) infusions

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Intensification I
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

6-day course

References

  1. COG AAML1031: Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01371981

COG AAML1031 arm A (high-risk)

Induction, part I

Chemotherapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

10-day course

Induction, part II

Chemotherapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Induction I
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

6-day course

Intensification, part I

Chemotherapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Induction II
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

5-day course

Intensification, part II

Chemotherapy

  • High Dose Cytarabine (Ara-C) 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 2, 8, 9
    • IF BSA < 0.6 m2, Cytarabine (Ara-C) 100 mg/kg IV over 3 hours every 12 hours on days 1, 2, 8, 9
  • E.Coli L-Asparaginase (LASP) 6000 IU/m2 IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
    • IF BSA < 0.6 m2, E.Coli L-Asparaginase (LASP) 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
may substitute with another asparaginase formulation

If Erwinia asparaginase is not available, pegasparaginase should NOT be given, and asparaginase should be omitted

28-day course

References

  1. COG AAML1031: Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01371981

COG AAML1031 arm C (FLT3/ITD+)

Induction, part I

Biomarker eligibility criteria

  • FLT3/ITD+

Chemotherapy

Targeted therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

28-day course

Induction, part II

Chemotherapy

Targeted therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with bone marrow evaluation at the end of Induction I
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments).
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

36-day course

Intensification, part I

Chemotherapy

Targeted therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Induction II.
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

33-day course

Intensification, part II

Chemotherapy

Targeted therapy

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Intensification I
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

6-day course

References

  1. COG AAML1031: Aplenc R, Meshinchi S, Sung L, Alonzo T, Choi J, Fisher B, Gerbing R, Hirsch B, Horton T, Kahwash S, Levine J, Loken M, Brodersen L, Pollard J, Raimondi S, Kolb EA, Gamis A. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children's Oncology Group. Haematologica. 2020 Jul;105(7):1879-1886. Epub 2020 Feb 6. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01371981

COG AAML0531 arm B (Gemtuzumab)

Induction, part I

Chemotherapy

  • Cytarabine (Ara-C) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 100 mg/m2 IV over 15 minutes every 12 hours on days 1 to 10
    • BSA < 0.6 m2: 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 10
  • Daunorubicin (Cerubidine) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 50 mg/m2 IV over 6 hours once per day on days 1, 3, 5
    • BSA < 0.6 m2: 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
  • Etoposide (Vepesid) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 100 mg/m2 IV over 4 hours once per day on days 1 to 5
    • BSA < 0.6 m2: 3.3 mg/kg IV over 4 hours once per day on days 1 to 5

Antibody-drug conjugate therapy

  • Gemtuzumab ozogamicin (Mylotarg) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 3 mg/m2 IV over 2 hours once on day 6
    • BSA < 0.6 m2: 0.1 mg/kg IV once on day 6

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1
    • For CNS positive patients: administer IT cytarabine twice weekly until CSF is clear (Minimum of 4 intrathecal treatments and maximum of 6 intrathecal treatments)
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

10-day course

Induction, part II

Chemotherapy

CNS therapy, prophylaxis

Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

28-day course

Intensification, part I

Chemotherapy

  • High Dose Cytarabine (Ara-C) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 1000 mg/m2 IV over 1 hour every 12 hours on days 1 to 5
    • BSA < 0.6 m2: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 5
  • Etoposide (Vepesid) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 150 mg/m2 IV over 1 hour once per day on days 1 to 5
    • BSA < 0.6 m2: 5 mg/kg IV over 4 hours once per day on days 1 to 5
    • Each dose of Etoposide (Vepesid) should immediately follow the AM dose of Cytarabine (Ara-C)

CNS therapy, prophylaxis

Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

5-day course

Intensification, part II

Chemotherapy

  • High Dose Cytarabine (Ara-C) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 1000 mg/m2 IV over 1 hour every 12 hours on days 1 to 4
    • BSA < 0.6 m2: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 4
  • Mitoxantrone (Novantrone) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 12 mg/m2 IV over 1 hour once per day on days 3 to 6
    • BSA < 0.6 m2: 0.4 mg/kg once per day on days 3 to 6
    • On days where both are given, give Mitoxantrone (Novantrone) 8 hours AFTER the END of the high dose Cytarabine (Ara-C) infusions

Antibody-drug conjugate therapy

  • Gemtuzumab ozogamicin (Mylotarg) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 3 mg/m2 IV over 2 hours once on day 7
    • BSA < 0.6 m2: 0.1 mg/kg once on day 7

CNS therapy, prophylaxis

  • Cytarabine (Ara-C) IT on day 1 or with bone marrow evaluation at the end of Intensification I
Age Dose
0 - 0.99 20
1 - 1.99 30
2 - 2.99 50
≥ 3 70

7-day course

Intensification, part III

Chemotherapy

  • High Dose Cytarabine (Ara-C) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 3000 mg/m2 IV over 3 hours every 12 hours on days 1, 2, 8, 9
    • BSA < 0.6 m2: 33 mg/kg IV over 1 hour every 12 hours on days 1, 2, 8, 9
  • E.Coli L-Asparaginase (LASP) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 6000 IU/m2 IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
    • BSA < 0.6 m2: 200 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
may substitute with another asparaginase formulation
  • Asparaginase Erwinia chrysanthemi (Erwinaze) by the following weight-based criteria:
    • BSA 0.6 m2 or more: 25,000 IU/m2 IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
    • BSA < 0.6 m2: 830 IU/kg IM on Day 2 (at hour 42), Day 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)

28-day course

References

  1. COG AAML0531: Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00372593

ADE (standard-dose Ara-C)

ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide
7-3-7: 7 days of Cytarabine, 3 days of Daunorubicin, 7 days of Etoposide
8-3-5: 8 days of Cytarabine, 3 days of Daunorubicin, 5 days of Etoposide
10-3-5: 10 days of Cytarabine, 3 days of Daunorubicin, 5 days of Etoposide

Regimen variant #1, 8-3-5, 1600/150/500, intermittent Ara-C

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hann et al. 1997 (UK MRC AML10) 1988-1995 Phase 3 (E-switch-ic) DAT 3+8 Did not meet efficacy endpoints
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link
Gamis et al. 2014 (COG AAML0531) 2006-2010 Non-randomized portion of RCT

Note: these trials have complicated treatment schemas; see papers for details. This is IND2 for COG AAML0531.

Preceding treatment

Chemotherapy

8-day course

Subsequent treatment

  • UK MRC AML10: MACE consolidation
  • COG AAML0531: CYVE interim maintenance
  • Other trials: Consolidation (see paper for details)

Regimen variant #2, 10-3-5, 2000/150/500, intermittent Ara-C

Study Years of enrollment Evidence Comparator Comparative Efficacy
Hann et al. 1997 (UK MRC AML10) 1988-1995 Phase 3 (E-switch-ic) DAT 3+10 Did not meet efficacy endpoints
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link
Rubnitz et al. 2010 (AML02) 2002-2008 Phase 3 (C) ADE; high-dose Ara-C Did not meet primary endpoint of MRD-positivity at day 22
Gamis et al. 2014 (COG AAML0531) 2006-2010 Phase 3 (C) ADE & GO Seems to have inferior EFS

Note: these trials have complicated treatment schemas; see papers for details.

Chemotherapy

10-day course

References

  1. UK MRC AML10: Hann IM, Stevens RF, Goldstone AH, Rees JK, Wheatley K, Gray RG, Burnett AK; Adult and Childhood Leukaemia Working Parties of the Medical Research Council. Randomized comparison of DAT versus ADE as induction chemotherapy in children and younger adults with acute myeloid leukemia: results of the Medical Research Council's 10th AML trial (MRC AML10). Blood. 1997 Apr 1;89(7):2311-8. link to original article contains dosing details in manuscript PubMed
    1. Update: Burnett AK, Goldstone AH, Stevens RM, Hann IM, Rees JK, Gray RG, Wheatley K; UK Medical Research Council Adult and Children's Leukaemia Working Parties. Randomised comparison of addition of autologous bone-marrow transplantation to intensive chemotherapy for acute myeloid leukaemia in first remission: results of MRC AML 10 trial. Lancet. 1998 Mar 7;351(9104):700-8. link to original article PubMed
  2. AML02: Rubnitz JE, Inaba H, Dahl G, Ribeiro RC, Bowman WP, Taub J, Pounds S, Razzouk BI, Lacayo NJ, Cao X, Meshinchi S, Degar B, Airewele G, Raimondi SC, Onciu M, Coustan-Smith E, Downing JR, Leung W, Pui CH, Campana D. Minimal residual disease-directed therapy for childhood acute myeloid leukaemia: results of the AML02 multicentre trial. Lancet Oncol. 2010 Jun;11(6):543-52. Epub 2010 May 5. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00136084
  3. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed
  4. COG AAML0531: Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00372593

ADE (high-dose Ara-C)

ADE: Ara-C (Cytarabine), Daunorubicin, Etoposide
HIDAC-3-5: HIgh-Dose Ara-C (Cytarabine), 3 days of Daunorubicin, 5 days of Etoposide
HIDAC-3-7: HIgh-Dose Ara-C (Cytarabine), 3 days of Daunorubicin, 7 days of Etoposide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Rubnitz et al. 2019 (AML08) 2008-2017 Phase 3 (C) Clofarabine & Cytarabine Seems to have superior MRD at day 22

Note: this regimen was intended for patients younger than 22 years.

Chemotherapy

6-day course

Subsequent treatment

  • Response- and risk-adapted therapy; see paper for details

References

  1. AML08: Rubnitz JE, Lacayo NJ, Inaba H, Heym K, Ribeiro RC, Taub J, McNeer J, Degar B, Schiff D, Yeoh AE, Coustan-Smith E, Wang L, Triplett B, Raimondi SC, Klco J, Choi J, Pounds S, Pui CH. Clofarabine Can Replace Anthracyclines and Etoposide in Remission Induction Therapy for Childhood Acute Myeloid Leukemia: The AML08 Multicenter, Randomized Phase III Trial. J Clin Oncol. 2019 Aug 10;37(23):2072-2081. Epub 2019 Jun 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00703820

ADE & GO

ADE & GO: Ara-C (Cytarabine), Daunorubicin, Etoposidem, Gemtuzumab Ozogamicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Gamis et al. 2014 (COG AAML0531) 2006-2010 Phase 3 (E-RT-esc) ADE 10-3-5 Seems to have superior EFS

Chemotherapy

Antibody-drug conjugate therapy

10-day course

Subsequent treatment

References

  1. COG AAML0531: Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00372593

AIE

AIE: Ara-C (Cytarabine), Idarubicin, Etoposide
ICE: Idarubicin, Cytarabine, Etoposide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Entz-Werle et al. 2005 (EORTC 58921) 1992-2002 Phase 3 (C) MEC Did not meet efficacy endpoints

Chemotherapy

7-day course

References

  1. EORTC 58921: Entz-Werle N, Suciu S, van der Werff ten Bosch J, Vilmer E, Bertrand Y, Benoit Y, Margueritte G, Plouvier E, Boutard P, Vandecruys E, Ferster A, Lutz P, Uyttebroeck A, Hoyoux C, Thyss A, Rialland X, Norton L, Pages MP, Philippe N, Otten J, Behar C; EORTC Children Leukemia Group. Results of 58872 and 58921 trials in acute myeloblastic leukemia and relative value of chemotherapy vs allogeneic bone marrow transplantation in first complete remission: the EORTC Children Leukemia Group report. Leukemia. 2005 Dec;19(12):2072-81. link to original article PubMed NCT00002517

DA 3 + 10

DA 3 + 10: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine

Regimen variant #1, 50 mg/m2 dauno

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) See link See link

Note: this regimen is very similar to 7+3d (standard-dose); however, 1) there is slightly more cytarabine given, in an intermittent schedule, and 2) the daunorubicin is given intermittently over 5 days, not 3. Both trials have complicated treatment schemas; see papers for details.

Chemotherapy

10-day course

Subsequent treatment

  • See papers for details (to be completed).

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

DA 3 + 10, GO

DA 3 + 10, GO: Daunorubicin & Ara-C (Cytarabine), 3 days of daunorubicin + 10 days of cytarabine, Gemtuzumab Ozogamicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (E-esc) See link See link

This trial has complicated treatment schemas; see papers for details.

Chemotherapy

Antibody-drug conjugate therapy

10-day course

Subsequent treatment

  • See paper for details (to be completed).

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

FLAG-Ida

FLAG-Ida: FLudarabine, Ara-C (Cytarabine), G-CSF (Lenograstim), Idarubicin

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15) 2002-2006 Phase 3 (C) 1. ADE 10+3+5
2. DA 3+10
3. DA 3+10 & GO
4. FLAG-Ida & GO 		Did not meet primary endpoint of OS1

1While this was a negative trial, a predefined analysis by cytogenetics showed a significant survival benefit for GO in patients with favorable cytogenetics.

Chemotherapy

Growth factor therapy

7-day course

Subsequent treatment

  • See paper for details

References

  1. UK MRC AML15: Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed ISRCTN17161961
    1. Update: Burnett AK, Hills RK, Grimwade D, Jovanovic JV, Craig J, McMullin MF, Kell J, Wheatley K, Yin JA, Hunter A, Milligan D, Russell NH; United Kingdom National Cancer Research Institute Acute Myeloid Leukaemia Subgroup. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia. 2013 Apr;27(4):843-51. Epub 2012 Dec 10. link to original article PubMed
    2. Update: Burnett AK, Russell NH, Hills RK, Hunter AE, Kjeldsen L, Yin J, Gibson BE, Wheatley K, Milligan D. Optimization of chemotherapy for younger patients with acute myeloid leukemia: results of the MRC AML15 trial. J Clin Oncol. 2013 Sep 20;31(27):3360-8. Epub 2013 Aug 12. link to original article PubMed

Consolidation after upfront therapy

BuCy, then auto HSCT

BuCy: Busulfan & Cyclophosphamide

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Ravindranath et al. 1996 1988-1993 Phase 3 (E-esc) Intensive chemotherapy Did not meet primary endpoint of EFS24

Preceding treatment

Chemotherapy

Supportive therapy

One course

References

  1. Ravindranath Y, Yeager AM, Chang MN, Steuber CP, Krischer J, Graham-Pole J, Carroll A, Inoue S, Camitta B, Weinstein HJ; Pediatric Oncology Group. Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. N Engl J Med. 1996 May 30;334(22):1428-34. link to original article contains dosing details in manuscript PubMed

Cyclophosphamide & TBI, then allo HSCT

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence
Brochstein et al. 1987 Non-randomized

Details in most of the manuscripts are limited.

Chemotherapy

Radiotherapy

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

Immunotherapy

One course

Immunotherapy

Stem cells transfused on day 0

References

  1. Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, O'Reilly RJ. Allogeneic bone marrow transplantation after hyperfractionated total-body irradiation and cyclophosphamide in children with acute leukemia. N Engl J Med. 1987 Dec 24;317(26):1618-24. link to original article PubMed

Relapsed or refractory, salvage therapy

Note: these are generally aggressive regimens intended to induce a second remission as part of a path towards pre-planned allogeneic HSCT.

COGAAML1421 protocol

Protocol

Chemotherapy, cycle 1

CNS therapy

  • Cytarabine (Ara-C) IT 2 doses
    • At the time of diagnostic lumbar puncture or Day 0 of cycle 1
    • At the time of the Day 28 to 30 bone marrow biopsy, or up to one week prior to Day 1 of cycle 2
  • CNS2 Patients
    • Cytarabine (Ara-C) IT twice weekly until the CSF is clear starting at least 48 hours following the 3rd dose of CPX-351
Age Dose 1 - 1.99 30
2 - 2.99 50
≥ 3 70

28-Day course

Chemotherapy, cycle 2

Pegfilgrastim cannot be utilized in the place of filgrastim or biosimilar

28-day course

References

  1. COG AAML1421:Cooper TM, Absalon M, Alonzo TA, Gerbing RB, Leger KJ, Hirsch BA, Pollard JA, Razzouk BI, Aplenc R, Kolb EA. AAML1421, a phase I/II study of CPX-351 followed by fludarabine, cytarabine, and G-CSF (FLAG) for children with relapsed acute myeloid leukemia (AML): A report from the Children's Oncology Group. Journal of Clinical Oncology. 2019 May;37(15). link to original article contains dosing details in manuscript link to PMC article PubMedNCT02642965

FLAG

FLAG: FLudarabine, Ara-C (Cytarabine), G-CSF

Regimen

Study Years of enrollment Evidence Comparator Comparative Efficacy
Kaspers et al. 2013 (I-BFM-SG 2001/01) 2001-2009 Phase 3 (C) FLAG-DNX Seems to have inferior CR rate

Note: this regimen was studied in patients up to 21 years of age.

Chemotherapy

Growth factor therapy

2 cycles (length not specified)

Subsequent treatment

References

  1. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains dosing details in manuscript PubMed NCT00186966

Consolidation after salvage therapy

Cytarabine & Thioguanine

Regimen

Study Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01) Non-randomized portion of RCT

Note: this regimen was studied in patients up to 21 years of age, and was intended for use when the time to transplant would be relatively short or for patients in "poor condition".

Preceding treatment

Chemotherapy

14-day cycles

Subsequent treatment

References

  1. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains dosing details in manuscript PubMed NCT00186966

CYVE

CYVE: CYtarabine & VEpesid (Etoposide)

Regimen

Study Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01) Non-randomized portion of RCT

Note: this regimen was studied in patients up to 21 years of age. It is unclear if the course is repeated more than once.

Preceding treatment

Chemotherapy

Subsequent treatment

References

  1. I-BFM-SG 2001/01: Kaspers GJ, Zimmermann M, Reinhardt D, Gibson BE, Tamminga RY, Aleinikova O, Armendariz H, Dworzak M, Ha SY, Hasle H, Hovi L, Maschan A, Bertrand Y, Leverger GG, Razzouk BI, Rizzari C, Smisek P, Smith O, Stark B, Creutzig U. Improved outcome in pediatric relapsed acute myeloid leukemia: results of a randomized trial on liposomal daunorubicin by the International BFM Study Group. J Clin Oncol. 2013 Feb 10;31(5):599-607. Epub 2013 Jan 14. link to original article contains dosing details in manuscript PubMed NCT00186966
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