Acute myeloid leukemia, NPM1-mutated

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Note: these are regimens tested in biomarker-specific populations for patients with NPM1-mutated AML, please see the main AML page for other regimens.
Last updated on 2024-07-23:3 regimens on this page
4 variants on this page
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - Acute Myeloid Leukemia.
=Upfront induction therapy=
==ICE & ATRA==
ICE & ATRA: Idarubicin, Cytarabine, Etoposide, All-Trans Retinoic Acid
===Regimen variant #1, 60 or younger===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Schlenk et al. 2019 (AMLSG 09-09)	2010-2017 	Phase 3 (C)	ICE, ATRA, GO	Might have lower EFS61 (co-primary endpoint)EFS6: 53% vs 58%(HR 1.20, 95% CI 0.96-1.64)
1Reported efficacy is based on the 2023 update.
====Chemotherapy====
*Idarubicin (Idamycin) as follows:
**Cycle 1: 12 mg/m2 IV once per day on days 1, 3, 5
**Cycle 2: 12 mg/m2 IV once per day on days 1 & 3
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 700 mg/m2)
*Etoposide (Vepesid) as follows:
**Cycle 1: 100 mg/m2 IV once per day on days 1 to 3
**Cycle 2: 100 mg/m2 IV once per day on days 1 & 3
====Targeted therapy====
*All-trans retinoic acid (ATRA) 45 mg/m2/day PO on days 6 to 8, then 15 mg/m2/day PO on days 9 to 21
2 cycles
====Subsequent treatment====
*HiDAC & ATRA consolidation
===Regimen variant #2, older than 60===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Schlenk et al. 2019 (AMLSG 09-09)	2010-2017 	Phase 3 (C)	ICE, ATRA, GO	Might have lower EFS61 (co-primary endpoint)EFS6: 53% vs 58%(HR 1.20, 95% CI 0.96-1.64)
1Reported efficacy is based on the 2023 update.
====Chemotherapy====
*Idarubicin (Idamycin) 12 mg/m2 IV once per day on days 1 & 3
*Cytarabine (Ara-C) 100 mg/m2/day IV continuous infusion over 7 days, started on day 1 (total dose per cycle: 700 mg/m2)
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 & 3
====Targeted therapy====
*All-trans retinoic acid (ATRA) 45 mg/m2/day PO on days 6 to 8, then 15 mg/m2/day PO on days 9 to 21
2 cycles
====Subsequent treatment====
*HiDAC & ATRA consolidation
===References===
# AMLSG 09-09: Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, Leis C, Fiedler W, Kindler T, Schroeder T, Mayer K, Lübbert M, Wattad M, Götze K, Horst HA, Koller E, Wulf G, Schleicher J, Bentz M, Greil R, Hertenstein B, Krauter J, Martens U, Nachbaur D, Abu Samra M, Girschikofsky M, Basara N, Benner A, Thol F, Heuser M, Ganser A, Döhner K, Döhner H. Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study. J Clin Oncol. 2020 Feb 20;38(6):623-632. Epub 2019 Dec 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00893399
##Update: Döhner H, Weber D, Krzykalla J, Fiedler W, Kühn MWM, Schroeder T, Mayer K, Lübbert M, Wattad M, Götze K, Fransecky L, Koller E, Wulf G, Schleicher J, Ringhoffer M, Greil R, Hertenstein B, Krauter J, Martens UM, Nachbaur D, Samra MA, Machherndl-Spandl S, Basara N, Leis C, Schrade A, Kapp-Schwoerer S, Cocciardi S, Bullinger L, Thol F, Heuser M, Paschka P, Gaidzik VI, Saadati M, Benner A, Schlenk RF, Döhner K, Ganser A; German–Austrian AML Study Group. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2023 Jul;10(7):e495-e509. Epub 2023 May 12. link to original article EuroPMC
=First-line induction therapy, older or "unfit" patients=
Note: these regimens are generally considered to be part of a non-curative line of treatment.
==Cytarabine & Etoposide (CYVE)==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Schlenk et al. 2023 (AMLSG 15-10)	2011-05-11 to 2016-09-14	Phase 3 (C)	ATRA, Cytarabine, Etoposide	Might have longer OS (primary endpoint)Median OS: 9.2 vs 5 mo(aHR 0.70, 95% CI 0.49-1.01)
====Chemotherapy====
*Cytarabine (Ara-C) 20 mg SC twice per day on days 1 to 7
*Etoposide (Vepesid) as follows:
**Cycle 1: 50 mg/m2 PO or IV once per day on days 1 to 3
**Cycle 2 to 6: 100 mg/m2 PO or IV once per day on days 1 to 3
28-day cycle for 6 cycles
===References===
#AMLSG 15-10: Schlenk RF, Weber D, Krzykalla J, Kindler T, Wulf G, Hertenstein B, Salih HR, Südhoff T, Krauter J, Martens U, Wessendorf S, Runde V, Tischler HJ, Bentz M, Koller E, Heuser M, Thol F, Benner A, Ganser A, Döhner K, Döhner H. Randomized phase-III study of low-dose cytarabine and etoposide + /- all-trans retinoic acid in older unfit patients with NPM1-mutated acute myeloid leukemia. Sci Rep. 2023 Sep 8;13(1):14809. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01237808
=Consolidation after upfront therapy=
==HiDAC & ATRA==
HiDAC & ATRA: High Dose Ara-C (Cytarabine) & All-Trans Retinoic Acid
===Regimen===
Study 	Dates of enrollment	Evidence
Schlenk et al. 2019 (AMLSG 09-09)	2010-2017 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*ICE & ATRA induction
====Chemotherapy====
*Cytarabine (Ara-C) by the following age-based criteria:
**18 to 60 years old: 3000 mg/m2 IV every 12 hours on days 1 to 3 (6 doses total)
**Older than 60 years old: 1000 mg/m2 IV every 12 hours on days 1 to 3 (6 doses total)
====Targeted therapy====
*All-trans retinoic acid (ATRA) 15 mg/m2 PO once per day on days 4 to 21
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 8
3 cycles
===References===
# AMLSG 09-09: Schlenk RF, Paschka P, Krzykalla J, Weber D, Kapp-Schwoerer S, Gaidzik VI, Leis C, Fiedler W, Kindler T, Schroeder T, Mayer K, Lübbert M, Wattad M, Götze K, Horst HA, Koller E, Wulf G, Schleicher J, Bentz M, Greil R, Hertenstein B, Krauter J, Martens U, Nachbaur D, Abu Samra M, Girschikofsky M, Basara N, Benner A, Thol F, Heuser M, Ganser A, Döhner K, Döhner H. Gemtuzumab Ozogamicin in NPM1-Mutated Acute Myeloid Leukemia: Early Results From the Prospective Randomized AMLSG 09-09 Phase III Study. J Clin Oncol. 2020 Feb 20;38(6):623-632. Epub 2019 Dec 18. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00893399
##Update: Döhner H, Weber D, Krzykalla J, Fiedler W, Kühn MWM, Schroeder T, Mayer K, Lübbert M, Wattad M, Götze K, Fransecky L, Koller E, Wulf G, Schleicher J, Ringhoffer M, Greil R, Hertenstein B, Krauter J, Martens UM, Nachbaur D, Samra MA, Machherndl-Spandl S, Basara N, Leis C, Schrade A, Kapp-Schwoerer S, Cocciardi S, Bullinger L, Thol F, Heuser M, Paschka P, Gaidzik VI, Saadati M, Benner A, Schlenk RF, Döhner K, Ganser A; German–Austrian AML Study Group. Intensive chemotherapy with or without gemtuzumab ozogamicin in patients with NPM1-mutated acute myeloid leukaemia (AMLSG 09-09): a randomised, open-label, multicentre, phase 3 trial. Lancet Haematol. 2023 Jul;10(7):e495-e509. Epub 2023 May 12. link to original article EuroPMC
Category:Acute myeloid leukemia regimens
Category:Biomarker-specific pages
Category:Acute leukemias