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

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).

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.