Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2024 Jan 23;8(2):343-352.
doi: 10.1182/bloodadvances.2023011106.

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

Carlos Jimenez-Chillon  1   2 , Jad Othman  2   3   4 , David Taussig  5 , Carlos Jimenez-Vicente  6 , Alexandra Martinez-Roca  6   7 , Ing Soo Tiong  8   9   10 , Manish Jain  11 , James Aries  12 , Seda Cakmak  12 , Steven Knapper  13 , Daniel Tuyet Kristensen  14 , Vidhya Murthy  15 , Joy Zacharoula Galani  16 , Charlotte Kallmeyer  17 , Loretta Ngu  18 , David Veale  18 , Simon Bolam  19 , Nina Orfali  20 , Anne Parker  21 , Cara Manson  21 , Jane Parker  22 , Thomas Erblich  23 , Deborah Richardson  24 , Katya Mokretar  25 , Nicola Potter  2 , Ulrik Malthe Overgaard  26   27 , Anne Stidsholt Roug  14   28 , Andrew H Wei  8 , Jordi Esteve  7 , Martin Jädersten  29   30 , Nigel Russell  3 , Richard Dillon  2   3
Affiliations
Multicenter Study

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

Carlos Jimenez-Chillon et al. Blood Adv. .

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.

PubMed Disclaimer

Conflict of interest statement

Conflict-of-interest disclosure: A.M.-R. reports consultancy or advisory role in Bristol Myers Squibb (BMS), AbbVie, and Kite Gilead; travel grants from Kite Gilead, Roche, Takeda, Janssen, and AbbVie; and speaker fees from AbbVie and Gilead. A.H.W. has served on advisory boards for Novartis, AstraZeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, and BeiGene; has consulted for AbbVie, Servier, Novartis, Shoreline, and Aculeus; receives research funding to the institution from Novartis, AbbVie, Servier, BMS, Syndax, Astex, AstraZeneca, and Amgen; serves on speaker’s bureaus for AbbVie, Novartis, BMS, Servier, and Astellas; is an employee of the Walter and Eliza Hall Institute (WEHI), and WEHI receives milestone and royalty payments related to the development of venetoclax; current and past employees of WEHI may be eligible for financial benefits related to these payments, and A.H.W. receives such a financial benefit. M. Jädersten has received institutional support from AbbVie for arranging educational webinars and has served on advisory boards for AbbVie. S.K. has served on advisory boards for Astellas, Jazz, AbbVie, Servier, and Novartis; speaker’s bureau of Astellas, Jazz, and Novartis; and research funding from Novartis. D.T.K. received consulting/advisory fees from AbbVie, Atheneum, and Astellas Pharma. V.M. has provided consultancy and received speaker honorarium from AbbVie, Jazz, Novartis, and Pfizer, and educational grants from Astellas and Takeda. N.O. has served on advisory boards for Takeda and Jazz; has consulted for AbbVie, Astellas, BMS, and Servier; and has received support for conference registration/accommodation/travel costs from AbbVie, Jazz, Pfizer, Servier, and Takeda. A.S.R. has provided consultancy to AbbVie and received travel grants from Jazz Pharmaceuticals. The remaining authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
MRD response. (A) MRD levels before treatment and after the first 3 courses of venetoclax combinations, expressed as NPM1 copies per 105ABL in bone marrow. (B) Response rates in the whole cohort and depending on type of molecular failure, FLT3-ITD status at diagnosis and type of low-intensity chemotherapy given with venetoclax.
Figure 2.
Figure 2.
Outcomes in the whole cohort and by FLT3-ITD status. (A) OS and (B) EFS in patients treated with venetoclax combinations. (C) OS and (D) EFS depending on FLT3-ITD status at diagnosis.
Figure 3.
Figure 3.
Time-dependent regression analysis using the Mantel-Byar test to evaluate the impact of allogeneic HSCT on OS (A) and EFS (B).
Figure 4.
Figure 4.
Comutations, follow-up, and outcomes after cessation of treatment. (A) Mutated genes at diagnosis and swimmer plot showing time of venetoclax treatment, response, and time off treatment. (B) OS and (C) molecular RFS in patients who ceased treatment after MRD negativity.
See this image and copyright information in PMC

References

    1. Grimwade D, Ivey A, Huntly BJP. Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood. 2016;127(1):29–41. - PMC - PubMed
    1. Balsat M, Renneville A, Thomas X, et al. Postinduction minimal residual disease predicts outcome and benefit from allogeneic stem cell transplantation in acute myeloid leukemia with NPM1 mutation: a study by the acute leukemia French association group. J Clin Oncol. 2017;35(2):185–193. - PubMed
    1. Krönke J, Schlenk RF, Jensen KO, et al. Monitoring of minimal residual disease in NPM1-mutated acute myeloid leukemia: a study from the German-Austrian acute myeloid leukemia study group. J Clin Oncol. 2011;29(19):2709–2716. - PubMed
    1. Kapp-Schwoerer S, Weber D, Corbacioglu A, et al. Impact of gemtuzumab ozogamicin on MRD and relapse risk in patients with NPM1-mutated AML: results from the AMLSG 09-09 trial. Blood. 2020;136(26):3041–3050. - PubMed
    1. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753–2767. - PMC - PubMed

Publication types

MeSH terms