Venetoclax-based low intensity therapy in molecular failure of NPM1 mutated AML

Carlos Jimenez-Chillon, Jad Othman, David Taussig, Carlos Jiménez-Vicente, Alexandra Martínez-Roca, Ing Soo Tiong, Manish Jain, James Aries, Seda Cakmak, Steven Knapper, Daniel Tuyet Kristensen, Vidhya Murthy, Joy Zacharoula Galani, Charlotte Kallmeyer, Loretta Ngu, David Veale, Simon Bolam, Nina Orfali, Anne Parker, Cara MansonJane Parker, Thomas Erblich, Deborah Susan Richardson, Katya Mokretar, Nicola Potter, Ulrik Malthe Overgaard, Anne Stidsholt Roug, Andrew H. Wei, Jordi Esteve, Martin Jädersten, Nigel Russell, Richard Dilon*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Molecular failure in NPM1-mutated acute myeloid leukemia (AML) inevitably progresses to frank relapse if untreated. Recently published small case series show that venetoclax combined with low-dose cytarabine or azacitidine can reduce or eliminate measurable residual disease (MRD). Here, we report on an international multicenter cohort of 79 patients treated for molecular failure with venetoclax combinations and report an overall molecular response (≥1-log reduction in MRD) in 66 patients (84%) and MRD negativity in 56 (71%). Eighteen of 79 patients (23%) required hospitalization, and no deaths were reported during treatment. Forty-one patients were bridged to allogeneic transplant with no further therapy, and 25 of 41 were MRD negative assessed by reverse transcription quantitative polymerase chain reaction before transplant. Overall survival (OS) for the whole cohort at 2 years was 67%, event-free survival (EFS) was 45%, and in responding patients, there was no difference in survival in those who received a transplant using time-dependent analysis. Presence of FLT3-ITD mutation was associated with a lower response rate (64 vs 91%; P < .01), worse OS (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.06-5.86; P = .036), and EFS (HR, 1.87; 95% CI, 1.06-3.28; P = .03). Eighteen of 35 patients who did not undergo transplant became MRD negative and stopped treatment after a median of 10 months, with 2-year molecular relapse free survival of 62% from the end of treatment. Venetoclax-based low intensive chemotherapy is a potentially effective treatment for molecular relapse in NPM1-mutated AML, either as a bridge to transplant or as definitive therapy.

Original languageEnglish
JournalBlood advances
Volume8
Issue number2
Pages (from-to)343-352
Number of pages10
ISSN2473-9529
DOIs
Publication statusPublished - 23 Jan 2024

Bibliographical note

© 2024 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Keywords

  • Bridged Bicyclo Compounds, Heterocyclic
  • Humans
  • Leukemia, Myeloid, Acute/drug therapy
  • Mutation
  • Nuclear Proteins/genetics
  • Nucleophosmin
  • Recurrence
  • Sulfonamides

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