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2024-05-15T11:38:55.000Z

Impact of molecular ontogeny on outcomes in patients with newly diagnosed AML treated with HMA + venetoclax

May 15, 2024
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Learning objective: After reading this article, learners will be able to cite a new development in the treatment of acute myeloid leukemia.

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Secondary ontogeny mutations in patients with acute myeloid leukemia (AML) are associated with adverse risk and poor survival outcomes.1 However, whether secondary mutations confer a poor prognosis with hypomethylating agents (HMA) + venetoclax (Ven) compared with HMA monotherapy is unknown.1

Here, we summarize results from a retrospective study by Shimony et al.1 published in Leukemia, evaluating whether secondary molecular ontogeny implies adverse risk in patients with AML treated with HMA + Ven. Also investigated was the benefit of adding Ven to HMA monotherapy by ontogeny group.

Study design1

  • A retrospective study in patients diagnosed with AML between August 2014 and July 2022 and treated with an HMA-based therapy.
  • Patients were classified into molecular ontogeny groups defined as de novo, secondary, and TP53 mutation.
  • The study endpoints were overall survival and composite complete remission (cCR), which was defined as CR plus CR with incomplete count recovery.

Key findings1

  • A total of 314 patients were analyzed
    • 53% were treated with HMA + Ven
    • 47% were treated with HMA
  • The median follow-up period was 29 months.
  • In the overall population, the median OS was higher in patients treated with HMA + Ven vs HMA monotherapy (9.9 months vs 7.4 months; p = 0.018).
  • Patients in the secondary ontogeny group treated with HMA + Ven showed improved OS compared to those treated with HMA monotherapy (Figure 1).

Figure 1. Median OS of patients with de novo, secondary, or TP53 mutated disease treated with HMA + Ven or HMA monotherapy* 

HMA, hypomethylating agent; OS, overall survival; Ven, venetoclax.

*Adapted from Shimony, et al.1
HMA + Ven (n = 38) and HMA monotherapy (n = 50).
HMA + Ven (n = 68) and HMA monotherapy (n = 47).

§HMA + Ven (n = 60) and HMA monotherapy (n = 51).

 

  • The cCR rate was higher in patients with de novo (54% vs 29%; p = 0.034) and secondary disease (61% vs 18%; p < 0.001) when treated with HMA + Ven vs HMA monotherapy.
  • There was no difference in cCR for patients with TP53 mutated disease when treated with HMA + Ven vs HMA monotherapy (33% vs 37%; p = 0.82).
  • A total of 41 patients proceeded to allogeneic hematopoietic stem cell transplantation
    • More patients treated with HMA + Ven proceeded to transplant vs HMA monotherapy (17% vs 8%; p = 0.018).
    • In the secondary ontogeny group, rates of transplant were higher in patients treated with HMA + Ven vs HMA (24% vs 6%; p = 0.02).

Key learnings

  • This study showed that survival rates were similar in patients with de novo or secondary disease treated with HMA + Ven.
  • In addition, patients in the secondary ontogeny group treated with HMA + Ven showed marked survival benefits.
  • The findings also highlight that patients with TP53-mutated AML may not benefit from adding Ven to HMA.

  1. Shimony S, Garcia JS, Keating J, et al. Molecular ontogeny underlies the benefit of adding venetoclax to hypomethylating agents in newly diagnosed AML patients. 2024. Online ahead of print. DOI: 10.1038/s41375-024-02230-w

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