Acute myeloid leukemia, pediatric

Section editor
	David Noyd, MD, MPH University of Washington Seattle, WA, USA LinkedIn

This page contains studies that were specific to pediatric populations. For the more general AML page, follow this link.
Are you looking for a regimen but can't find it here? It is possible that we've moved it to the historical regimens page.

14 regimens on this page 15 variants on this page

The following study protocols are included on this page:

Study	Dates 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

Upfront induction therapy

COG AAML1031 arm A (low-risk)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Aplenc et al. 2020 (COG AAML1031)	2011-2016	Phase 3 (C)	Standard chemotherapy with bortezomib	Did not meet primary endpoint of EFS

Induction, I

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 1 to 30 minutes every 12 hours on days 1 to 10
  • Less than 0.60 m²: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) by the following BSA-based criteria:
  • 0.60 m² or more: 50 mg/m² IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Less than 0.60 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:
  • 0.60 m² or more: 100 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 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
  • 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

10-day course, followed by:

Induction, II

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 1 to 30 minutes every 12 hours on days 1 to 8
  • Less than 0.60 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:
  • 0.60 m² or more: 50 mg/m² IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Less than 0.60 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:
  • 0.60 m² or more: 100 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

8-day course, followed by:

Intensification, I

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 5
  • Less than 0.60 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:
  • 0.60 m² or more: 150 mg/m² IV over 60 to 120 minutes once per day on days 1 through 5
  • Less than 0.60 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

5-day course, followed by:

Intensification, II

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 4
  • Less than 0.60 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, given 8 hours AFTER the END of cytarabine infusions on days 3 & 4:
  • 0.60 m² or more: 12 mg/m² IV over 15 to 30 minutes once per day on days 3 to 6
  • Less than 0.60 m²: 0.4 mg/kg once per day on days 3 to 6

CNS therapy, prophylaxis

• Cytarabine (Ara-C) IT on day 1 or with the bone marrow evaluation at the end of Intensification I

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	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)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Aplenc et al. 2020 (COG AAML1031)	2011-2016	Phase 3 (C)	Standard chemotherapy with bortezomib	Did not meet primary endpoint of EFS

Induction, part I

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 1 to 30 minutes every 12 hours on days 1 to 10
  • Less than 0.60 m²: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) by the following BSA-based criteria:
  • 0.60 m² or more: 50 mg/m² IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Less than 0.60 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:
  • 0.60 m² or more: 100 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 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
  • 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

10-day course, followed by:

Induction, part II

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 4
  • Less than 0.60 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, given 8 hours AFTER the END of cytarabine infusions on days 3 & 4:
  • 0.60 m² or more: 12 mg/m² IV over 15 to 30 minutes once per day on days 3 to 6
  • Less than 0.60 m²: 0.4 mg/kg once per day on days 3 to 6

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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

6-day course, followed by:

Intensification, part I

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 5
  • Less than 0.60 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:
  • 0.60 m² or more: 150 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

5-day course

Intensification, part II

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 3000 mg/m² IV over 3 hours every 12 hours on days 1, 2, 8, 9
  • Less than 0.60 m²: 100 mg/kg IV over 3 hours every 12 hours on days 1, 2, 8, 9
• Asparaginase (Elspar) by the following BSA-based criteria:
  • 0.60 m² or more: 6000 IU/m² IM once per day on days 2 (at hour 42) & 9 (at hour 42 after the start of the 1st dose of cytarabine on Day 8)
  • Less than 0.60 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 BSA-based criteria:
  • 0.60 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)
  • Less than 0.60 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)

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+)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Aplenc et al. 2020 (COG AAML1031)	2011-2016	Phase 3 (C)	Standard chemotherapy with bortezomib	Did not meet primary endpoint of EFS

Induction, part I

Biomarker eligibility criteria

• FLT3/ITD+

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 1 to 30 minutes every 12 hours on days 1 to 10
  • Less than 0.60 m²: 3.3 mg/kg IV over 1 to 30 minutes every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) by the following BSA-based criteria:
  • 0.60 m² or more: 50 mg/m² IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Less than 0.60 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:
  • 0.60 m² or more: 100 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 m²: 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5

Targeted therapy

• Sorafenib (Nexavar) 200 mg/m² (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)

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

28-day course

Induction, part II

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 1 to 30 minutes every 12 hours on days 1 to 8
  • Less than 0.60 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:
  • 0.60 m² or more: 50 mg/m² IV over 1 to 15 minutes once per day on days 1, 3, 5
  • Less than 0.60 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:
  • 0.60 m² or more: 100 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 m²: 3.3 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5

Targeted therapy

• Sorafenib (Nexavar) 200 mg/m² (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).

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

36-day course

Intensification, part I

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 5
  • Less than 0.60 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:
  • 0.60 m² or more: 150 mg/m² IV over 60 to 120 minutes once per day on days 1 to 5
  • Less than 0.60 m²: 5 mg/kg IV over 60 to 120 minutes once per day on days 1 to 5

Targeted therapy

• Sorafenib (Nexavar) 200 mg/m² (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.

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

33-day course

Intensification, part II

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 to 3 hours every 12 hours on days 1 to 4
  • Less than 0.60 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, given 8 hours AFTER the END of cytarabine infusions on days 3 & 4:
  • 0.60 m² or more: 12 mg/m² IV over 15 to 30 minutes once per day on days 3 to 6
  • Less than 0.60 m²: 0.4 mg/kg once per day on days 3 to 6

Targeted therapy

• Sorafenib (Nexavar) 200 mg/m² (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

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

34-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)

Study	Dates 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 (primary endpoint) EFS36: 53.1% vs 46.9% (HR 0.83, 95% CI 0.70-0.99) Did not meet secondary endpoint of OS OS36: 69.4% vs 65.4% (HR 0.91, 95% CI 0.71-1.13)

Induction, part I

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 15 minutes every 12 hours on days 1 to 10
  • Less than 0.60 m²: 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) by the following BSA-based criteria:
  • 0.60 m² or more: 50 mg/m² IV over 6 hours once per day on days 1, 3, 5
  • Less than 0.60 m²: 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
• Etoposide (Vepesid) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 4 hours once per day on days 1 to 5
  • Less than 0.60 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 BSA-based criteria:
  • 0.60 m² or more: 3 mg/m² IV over 2 hours once on day 6
  • Less than 0.60 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

10-day course

Induction, part II

Chemotherapy

• Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 15 minutes every 12 hours on days 1 to 8
  • Less than 0.60 m²: 3.3 mg/kg IV over 15 minutes every 12 hours on days 1 to 8
• Daunorubicin (Cerubidine) by the following BSA-based criteria:
  • 0.60 m² or more: 50 mg/m² IV over 6 hours once per day on days 1, 3, 5
  • Less than 0.60 m²: 1.67 mg/kg IV over 6 hours once per day on days 1, 3, 5
• Etoposide (Vepesid) by the following BSA-based criteria:
  • 0.60 m² or more: 100 mg/m² IV over 4 hours once per day on days 1 to 5
  • Less than 0.60 m²: 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

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

28-day course

Intensification, part I

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 hour every 12 hours on days 1 to 5
  • Less than 0.60 m²: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 5
• Etoposide (Vepesid) by the following BSA-based criteria:
  • 0.60 m² or more: 150 mg/m² IV over 1 hour once per day on days 1 to 5, immediately follow the AM dose of cytarabine
  • Less than 0.60 m²: 5 mg/kg IV over 4 hours once per day on days 1 to 5, immediately follow the AM dose of cytarabine

CNS therapy, prophylaxis

• Cytarabine (Ara-C) IT on day 1 or with bone marrow evaluation at the end of Induction II

Age (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

5-day course

Intensification, part II

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 1000 mg/m² IV over 1 hour every 12 hours on days 1 to 4
  • Less than 0.60 m²: 33 mg/kg IV over 1 hour every 12 hours on days 1 to 4
• Mitoxantrone (Novantrone) by the following BSA-based criteria, given 8 hours AFTER the END of cytarabine infusions on days 3 & 4:
  • 0.60 m² or more: 12 mg/m² IV over 1 hour once per day on days 3 to 6
  • Less than 0.60 m²: 0.4 mg/kg once per day on days 3 to 6

Antibody-drug conjugate therapy

• Gemtuzumab ozogamicin (Mylotarg) by the following BSA-based criteria:
  • 0.60 m² or more: 3 mg/m² IV over 2 hours once on day 7
  • Less than 0.60 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 (to the nearest hundredth)	Dose
0.00 to 0.99	20
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

7-day course

Intensification, part III

Chemotherapy

• High Dose Cytarabine (Ara-C) by the following BSA-based criteria:
  • 0.60 m² or more: 3000 mg/m² IV over 3 hours every 12 hours on days 1, 2, 8, 9
  • Less than 0.60 m²: 33 mg/kg IV over 1 hour every 12 hours on days 1, 2, 8, 9
• Asparaginase (Elspar) by the following BSA-based criteria:
  • 0.60 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)
  • Less than 0.60 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 BSA-based criteria:
  • 0.60 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)
  • Less than 0.60 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. Epub 2014 Aug 14. 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	Dates 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 part of phase 3 RCT

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

Preceding treatment

• UK MRC AML10: ADE; 10-3-5 induction
• COG AAML0531: ADE; 10-3-5 induction versus ADE & GO induction

Chemotherapy

• Cytarabine (Ara-C) 50 mg/m² IV every 12 hours on days 1 to 8
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1, 3, 5
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 1 to 5

8-day course

Subsequent treatment

• UK MRC AML10: MACE consolidation
• UK MRC AML15: MACE versus MACE & GO versus HiDAC versus HiDAC & GO versus MidAC versus MidAC & GO consolidation
• COG AAML0531: CYVE interim maintenance

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

Study	Dates 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

• Cytarabine (Ara-C) 50 mg/m² IV every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1, 3, 5 or days 2, 4, 6
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5 or days 2 to 6

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 contains dosing details in manuscript 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. Epub 2014 Aug 14. 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	Dates 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 (primary endpoint)

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

Chemotherapy

• Cytarabine (Ara-C) 3000 mg/m² IV every 12 hours on days 1, 3, 5 (total dose per cycle: 18,000 mg/m²)
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 2, 4, 6
• Etoposide (Vepesid) 100 mg/m² IV once per day on days 2 to 6

6-day course

Subsequent treatment

• AML08, low-risk patients and standard-risk patients: LD-ADE consolidation
• AML08, FLT3-ITD patients: LD-ADE & Sorafenib consolidation
• AML08, high-risk patients other than FLT3-ITD: LD-ADE & Vorinostat consolidation

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	Dates 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 (primary endpoint) EFS36: 53.1% vs 46.9% (HR 0.83, 95% CI 0.70-0.99) Did not meet secondary endpoint of OS OS36: 69.4% vs 65.4% (HR 0.91, 95% CI 0.71-1.13)

Chemotherapy

• Cytarabine (Ara-C) 100 mg/m²/day IV every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1, 3, 5
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5

Antibody-drug conjugate therapy

• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² IV over 2 hours once on day 6

10-day course

Subsequent treatment

• ADE; 8-3-5 re-induction

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. Epub 2014 Aug 14. 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	Dates 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

• Cytarabine (Ara-C) 100 mg/m² IV over 30 minutes twice per day on days 1 to 7 (total dose: 1400 mg/m²)
• Idarubicin (Idamycin) 12 mg/m² IV over 30 minutes once per day on days 1 to 3
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5

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	Dates 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

• Cytarabine (Ara-C) 100 mg/m² IV every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1, 3, 5

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 contains dosing details in manuscript 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	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Burnett et al. 2010 (UK MRC AML15)	2002-2006	Phase 3 (E-esc)	See link	See link

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

Chemotherapy

• Cytarabine (Ara-C) 100 mg/m² IV every 12 hours on days 1 to 10
• Daunorubicin (Cerubidine) 50 mg/m² IV once per day on days 1, 3, 5

Antibody-drug conjugate therapy

• Gemtuzumab ozogamicin (Mylotarg) 3 mg/m² IV once on day 1

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 contains dosing details in manuscript 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	Dates 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

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 2 to 6
• Cytarabine (Ara-C) 2000 mg/m² IV over 4 hours once per day on days 2 to 6, given 4 hours after fludarabine
• Idarubicin (Idamycin) 8 mg/m² IV once per day on days 4 to 6

Growth factor therapy

• Lenograstim (Granocyte) 263 mcg SC once per day on days 1 to 7

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 contains dosing details in manuscript 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

Busulfan & Cyclophosphamide, then auto HSCT

BuCy: Busulfan & Cyclophosphamide

Regimen

Study	Dates 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

• 7+3d induction, then HiDAC consolidation

Chemotherapy

• Busulfan (Myleran) 1 mg/kg PO every 6 hours on days -9 to -6
• Cyclophosphamide (Cytoxan) 50 mg/kg IV once per day on days -5 to -2

Supportive therapy

• Autologous stem cells re-infused on day 0

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

• Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

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

• Allogeneic stem cells transfused on day 0

One course

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

MACE

MACE: M-A-MSA (Amsacrine), Ara-C (Cytarabine), Etoposide

Regimen

Study	Dates of enrollment	Evidence
Hann et al. 1997 (UK MRC AML10)	1988-1995	Non-randomized part of phase 3 RCT

Preceding treatment

• UK MRC AML10: ADE; 8-3-5 induction

Chemotherapy

• Amsacrine (Amsidine) 100 mg/m² IV over 60 minutes once per day on days 1 to 5
• Cytarabine (Ara-C) 200 mg/m²/day IV continuous infusion over 120 hours, started on day 1 (total dose: 1000 mg/m²)
• Etoposide (Vepesid) 100 mg/m² IV over 60 minutes once per day on days 1 to 5

5-day course

Subsequent treatment

• MidAC consolidation

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. 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 contains dosing details in manuscript 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

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.

COG AAML1421 protocol

Regimen

Study	Dates of enrollment	Evidence
Cooper et al. 2019 (COG AAML1421)	2016-2018	Phase 1/2

Chemotherapy, CPX-351 portion (cycle 1)

• Cytarabine and daunorubicin liposomal (Vyxeos) 135 units/m² IV over 90 minutes once per day on days 1, 3, 5

Chemotherapy, FLAG portion (cycle 2)

• Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days 1 to 5
• High Dose Cytarabine (Ara-C) 2000 mg/m² IV over 1 to 3 hours once per day on days 1 to 5, given 4 hours after start of fludarabine

Growth factor therapy, FLAG portion (cycle 2)

• Filgrastim (Neupogen) 5 mcg/kg IV or SC once per day on days 1 to 5, given one hour prior to each dose of fludarabine, then restart on day 15 and continue until post-nadir ANC at least 500/μL
  • Pegfilgrastim cannot be utilized in the place of filgrastim or biosimilar

CNS therapy, both portions

• 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 (to the nearest hundredth)	Dose
1.00 to 1.99	30
2.00 to 2.99	50
3.00 or older	70

28-day cycle for 2 cycles

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. J Clin Oncol. 2019 May;37(15). Epub 2020 May 13.link to original article contains dosing details in manuscript link to PMC article PubMed NCT02642965

FLAG

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

Regimen

Study	Dates 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

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 1 to 5, given second
• Cytarabine (Ara-C) 2000 mg/m² 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/m² (route not specified) once per day on days 0 to 5, given first

2 cycles (length not specified)

Subsequent treatment

• CYVE consolidation or Cytarabine & Thioguanine, then allogeneic HSCT consolidation

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	Dates of enrollment	Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01)	2001-2009	Non-randomized part of phase 3 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

• Salvage FLAG versus FLAG-DNX

Chemotherapy

• Cytarabine (Ara-C) 75 mg/m² SC once per day on days 1 to 4
• Thioguanine (Tabloid) as follows:
  • Cycles 1 & 2: 100 mg/m² PO once per day

14-day cycles

Subsequent treatment

• Allogeneic HSCT consolidation

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

Cytarabine & Etoposide (CYVE)

CYVE: CYtarabine & VEpesid (Etoposide)

Regimen

Study	Dates of enrollment	Evidence
Kaspers et al. 2013 (I-BFM-SG 2001/01)	2001-2009	Non-randomized part of phase 3 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

• Salvage FLAG versus FLAG-DNX

Chemotherapy

• Cytarabine (Ara-C) 500 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 2000 mg/m²)
• Etoposide (Vepesid) 100 mg/m² IV twice per day on days 1 to 4

Subsequent treatment

• Allogeneic HSCT consolidation

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