HMA + venetoclax in adults with TP53-mutated AML

Hypomethylating agent (HMA)-based therapies are used in combination with venetoclax for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, it remains unclear whether the addition of venetoclax to HMA is beneficial in the treatment of older patients with TP53-mutated AML, where standard therapies do not yield an adequate response and therefore lead to a poor prognosis.

Here, we summarize results from the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND) study, published by Badar et al.¹ in Blood Cancer Journal, comparing HMA + venetoclax with HMA-based therapy alone in the treatment of newly diagnosed TP53-mutated AML.

Patient population¹

• This study used a multi-institutional real-world database of 381 adult patients diagnosed with TP53-mutated AML between 2012 and 2022 and included 154 patients treated with HMA + venetoclax (n = 104) and HMA-based therapies (n = 50).
• The median age was 71 years in the HMA + venetoclax group and 74 years in the HMA group, at the time of diagnosis.
• The majority of patients in both the HMA + venetoclax (90%) and HMA (86%) groups had complex cytogenetics.
• The rate of secondary AML was also similar between groups (HMA + venetoclax, 31%; HMA, 26%).

Key findings¹

• More patients treated with HMA + venetoclax achieved complete remission (CR) than those treated with HMA alone (35% vs 18%, respectively; p = 0.05).
  • Of these patients, 13% progressed to  allogeneic hematopoietic stem cell transplantation in the HMA + venetoclax group compared with 4% in the HMA group (p = 0.14).
• At a median follow-up of 6.5 months, survival outcomes were similar between treatment groups (Figure 1).

AML; acute myeloid leukemia; DOR, duration of response; EFS, event-free survival; HMA, hypomethylating agent; OS, overall survival.
*Data from Badar, et al.¹

• Multivariate analysis revealed an association between the achievement of CR/CR with incomplete recovery and overall survival (hazard ratio [HR], 0.36; 95% confidence interval [Cl], 0.22–0.59; p < 0.001) but not event-free survival (HR, 0.80; 95% CI, 0.18-3.52; p = 0.77).
• Progression to  allogeneic hematopoietic stem cell transplantation in patients who achieved CR/CR with incomplete recovery was associated with overall survival (HR, 0.10; 95% CI, 0.14–10.76; p = 0.02) and event-free survival (HR, 0.06; 95% CI, 0.09–0.50; p = 0.009).
• More deaths were observed in the first 30 days after induction in patients who received HMA + venetoclax compared with those who received HMA alone (25% vs 3%, respectively, p = 0.03).

Key learnings

In this study, the addition of venetoclax to HMA-based treatment did not improve survival in adult patients with TP53-mutated AML, despite improvements in CR rates, duration of response, and rates of progression to transplant. Therefore, the authors concluded that there is no benefit in adding venetoclax to HMA-based therapy for frail patients with TP53-mutated AML and sub-optimal performance status. This highlights the continued need for improved treatment options for TP53-mutated AML.