Acute myeloid leukemia, NPM1-mutated

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 Ashwin Kishtagari, MD
Vanderbilt University
Nashville, TN, USA
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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.

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

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 inferior EFS61 (co-primary endpoint)

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

2 cycles

Subsequent treatment


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 inferior EFS61 (co-primary endpoint)

1Reported efficacy is based on the 2023 update.

Chemotherapy

Targeted therapy

2 cycles

Subsequent treatment

References

  1. 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 contains dosing details in manuscript PubMed NCT00893399
    1. 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 PubMed

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 Seems to have superior OS (primary endpoint)

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

  1. 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 contains dosing details in manuscript PubMed 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

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

Supportive therapy

3 cycles

References

  1. 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 contains dosing details in manuscript PubMed NCT00893399
    1. 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 PubMed
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