Induction I
Drug
Dose for patients ≥10kg and
≥1 month, not born
significantly premature
Dose for patients <10kg and or
<3
month
and
born
significantly premature
Route
No.
doses
Schedule
Azacitidine AZA
75 mg/m2/day
2.5mg/kg/day
5
Day -4 to 0
100mg/m2/q12h
500mg/m2/day
3.3mg/kg/q12h
16.7mg/kg/day
IV over 10-40
mins
IV over 30m
IV over 15m
immediately
prior to
daunorubincin
IV over 6h
IV over 15m
IV over 4h
20
3
Day 1 -10
Day 1,3,5
3
3
5
Day 1,3,5
Day 3-5
Day 1-5
100mg/via/, $15233
Cytarabine
Dexrazoxane
Daunorubicin
50mg/m2/day
1.67mg/kg/day
2
Idarubicin
8mg/m /day
0.27 mg/kg/day
Etoposide
100mg/m2/day
3.3mg/kg/day
Emetogenicity of drugs used in Induction I.
Moderate
Azacitidine, Daunorubicin, Idarubicin
Cytarabine( ≤1000 mg/m2), Etoposide
Low
Induction II
Drug
Dose for patients ≥10kg and
≥1 month, not born
significantly premature
Dose for patients <10kg and or
<3
month
and
born
significantly premature
Route
No.
doses
Schedule
Azacitidine AZA
75 mg/m2/day
2.5mg/kg/day
5
Day -4 to 0
Fludarabine
Cytarabine
Dexrazoxane
30 mg/m2/day
2000mg/m2/day
400mg/m2/day
1 mg/kg/day
66.7mg/kg/day
13.5mg/kg/day
5
5
3
Day 1 -5
Day 1 -5
Day 3-5
Idarubicin
Filgrastim
8mg/m2/day
5mcg/kg/day
0.27 mg/kg/day
5mcg/kg/day
3
7
Day 3-5
Day 1-7
Sofarenib2
200mg/m2 QD
NA
IV over 10-40
mins
IV over 30m
IV over 4h1
IV over 15m
immediately
prior to ida
IV over 15m
SC or IV
15-30m
PO
21
For 21 days
1: Cytarabine should be given 4 hours after fludarabine
2: Sorafenid will be given for 21 days, as tolerated, for FLT3 ITD and NTP98-NSD1 or FLT3 and WT1 mutation
after completion of other agents.
Emetogenicity of drugs used in Induction II.
Moderate
Azacitidine, Cytarabine >1000 mg/m2, , Idarubicin
Minimal
Fludarabine
Intensification I
Drug
Dose for patients ≥10kg and
≥1 month, not born
significantly premature
Dose for patients <10kg and or
<3
month
and
born
significantly premature
Cytarabine
1000mg/m2/q12h
33.3mg/kg/q12h
Etoposide
150mg/m2/day
5mg/kg/day
Emetogenicity of drugs used in Intensification I.
Moderate
Cytarabine >1000 mg/m2
Low
Etoposide
Route
No.
doses
Schedule
IV over 2h
IV over 2h
10
5
Day 1 -5
Day 1-5
Intensification II
Drug
Dose for patients ≥10kg and
≥1 month, not born
significantly premature
Dose for patients <10kg and or
<3
month
and
born
significantly premature
Route
No.
doses
Schedule
Dexrazoxane
480mg/m2/day
16mg/kg/day
IV over 15m
immediately
prior to
mitoxantrone
3
Day 3-5
Mitoxantrone
12 mg/m2/day
0.4 mg/kg/day
2
Cytarabine
1000mg/m /q12h
33.3mg/kg/q12h
Emetogenicity of drugs used in Intensification II.
Moderate
Cytarabine >1000 mg/m2
Low
Mitoxantrone
IV over 1h
IV over 2h
3
8
Day 3-5
Day 1 -4
Intensification III
Drug
Dose for patients ≥10kg and
≥1 month, not born
significantly premature
Dose for patients <10kg and or
<3
month
and
born
significantly premature
Route
No.
doses
Schedule
Cytarabine
Erwinase1
Leunase
Sofarenib2
3000mg/m2/q12h
25000 U/m2/day
7500 U/m2/day*
200mg/m2 QD
100mg/kg/q12h
833 U/kg/day
250 U/kg/day*
NA
IV > 3h
IV >1h or IM
8
2
2
21
Day 1,2,8,9
Day 2, 9
Day 2, 9
For 21 days
PO
1: Erwinia asparaginase should be administered 3 hours after 4th and 8th dose of cytarabine.
2: Sorafenid will be given for 21 days, as tolerated, for FLT3 ITD and NTP98-NSD1 or FLT3 and WT1 mutation
after completion of other agents.
*: Leunase dose = Erwinase÷3.33 (from TPOG-ALL-2013, for patients hypersensitive to Leunase 6000 U/m2,
switch to the Erwinia 20000 U/m2). But in Dana-Farber Cancer InstituteALL Consortium Protocol 95-01, they
used 1:1 conversion (Blood. 2007;109:896-904).
Emetogenicity of drugs used in Intensification III.
Moderate
Cytarabine >1000 mg/m2
Supportive care requirements: prophylactic vancomycin, ciprofloxacin and voriconazole during times of
neutropenia.
Anthracycline cumulative dose after completing the treatment.
Drug
Daunorubicin
Epirubicin
Idarubicin – IV
Mitoxantrone
Maximum cumulative dose (mg/m2)
600
900
150
160
Received dose(mg/m2)
150 (25%)
225 (25%)
24 (16%)
36 (22.5%)
AML16 Principal Investigator: Tanja Andrea Gruber, MD PhD SJCRH
Confidential Document
Overview
Risk Stratification
Low-risk (LR) criteria (4 courses of chemo, not eligible for SCT)
．Inv16, t(8;21), NPM1 or CENPA and MRD < 0.1% after induction I
Intermediate-risk (IR) criteria ( 5 courses of chemo, not eligible for SCT)
．Absence of low or high risk features
High-risk (HR) criteria (candidates for SCT)
Presence of any of the following:
．DEK-NUP214[t(6;9)],KAT6A-CREBBP [t(8;16)], -7, -5, -5q, KMT2A-MLLT10 [t(6;11)],
KMT2A-MLLT4[t(10;11)], inv (3)(q21q26.2), CBFA2T3-GLIS2 [inv(16)(p13.3q24.3)], NUP98-KDM5A
[t(11;12)(p15;p13)],ETV6-HLXB [t(7;12)(q36;p13)], NUP98-HOXA9 [t(7;11)(p15.4;p15)], NUP98-NSD1
．Patients carrying FLT3-ITD in combination with either NUP98-NSD1 fusion or WT1 mutation.
．AML with minimal differentiation or acute erythroid leukemia
．Acute megakaryoblastic leukemia with KMT2A rearrangements, CBFA2T3-GLIS2 [inv(16)(p13.3q24.3)],
or NUP98-KDM5 [t(11;12)(p15;p13)]. All other acute megakaryoblasti leukemia subtypes will be
considered intermediate risk.
．Treatment-related (Secondary) AML.
．Refractory anemia with excessive blasts and >10% bone marrow blasts (RAEB-2) or AML arising from
prior MDS.
All other patients with poor response to therapy (must have one of the following features)
．MRD ≥ 1% after Induction I
．MRD ≥ 0.1% after Induction II.
Intrathecal Therapy
All patients should undergo lumbar puncture and receive an age-appropriate dose of intrathecal therapy
(IT) at the time of diagnosis.
Patient age
Methotrexate
Hydrocortisone
Cytarabine
Volume
< 1 year
6mg
12mg
18mg
6ml
1-2 years
8mg
16mg
24mg
8ml
2-3 years
10mg
20mg
30mg
10ml
>3 years
12mg
24mng
36mg
12ml
Leucovorin rescue (5mg/m2 per dose, 5mg maximum per dose) will be given orally or intravenously at
24 and 30 hours after each IT MHA treatment. Leucovorin dosing and intrathecal volume may be
adjusted according to local institutional guideline.
To reduce the risk of neurotoxicity, we recommend separating IT therapy from high-dose cytarabine
(HDAC)(1g/m2 or greater) by at least 24 hours for induction I and Intensification I/II. Metrotrexate may
be omitted from IT therapy for patients that have a history of MTX-induced leukoencephalopathy.
CNS1 (no evidence of CNS disease, no leukemic blast cells on CSF cytospin.)
．CNS1 participants will received 4 total doses of intrathecal therapy, given at approximately one
month intervals or at the beginning of each of the 4 courses of chemotherapy.
CNS2 (< 5 leukocytes per ul of CSF and the presence of leukemic blast cells on CSF cytospin.)
．CNS2 participants will receive weekly intrathecal therapy until the CSF is free of blast cells. These
patients will receive 3 additional doses of intrathecal therapy at approximately one month intervals
(generally given with each subsequent course of chemotherapy.) Patients who are unable to
undergo lumbar puncture and receive intrathecal therapy prior to starting Induction I should be
treated as CNS2 unless they have overt CNS leukemia CNS3)
CNS3 (overt CNS leukemia, ≥5 leukocytes per ul of CSF and the presence of leukemic blast cells on CSF
cytospin or traumatic tap)
．CNS3 participants will receive weekly intrathecal therapy until the CSF is free of blast cells (minimum
number of doses:4) These patients will then receive 3 additional doses of intrathecal therapy
(minimum number of doses: 7) at approximately 1-month intervals (generally given with each
subsequent course of chemotherapy).
AML16 Grade 4 non-hematologic events during induction I and II as of 12/11/2018 (N=31)
Description
Ind I Events Ind I patients Ind II Events Ind II patients
Alanine aminotransferase↑
1
1
2
2
Blood bilirubin↑
0
0
1
1
Hypernatremia
1
1
0
0
Hypocalcemia
1
1
0
0
Hypokalemia
0
0
2
2
Respiratory failure
0
0
1
1
Sepsis
2
2
4
4
J Clin Oncol 33:3774-3780.
Drug
Daunorubicin
Doxorubicin
Epirubicin
Idarubicin – IV
Idarubicin – PO
Mitoxantrone
Maximum recommended cumulative dose (mg/m2)
600
450
900
150
400
160