At the 65th American Society of Hematology (ASH) Annual Meeting in San Diego, California, Talha Badar, MD, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, Florida, speaks on a retrospective, multi-center, real world study conducted through the COMMAND consortium on the efficacy of venetoclax combined with hypomethylating agent (HMA) therapy for patients with TP53-mutated acute myeloid leukemia (AML). The combination demonstrated an improvement in complete remission (CR) rates, but did not correlate with an improvement in overall survival (OS) when compared with HMA monotherapy. 

Transcript:

Hi everyone. I'm Talha Badar. I'm a rheumatologist oncologist at [the] Mayo Clinic, and I would like to present my oral presentation [that was presented] at ASH 2023 [where] we compared the outcome of treatment-naive TP53-mutated AML patients treated with hypomethylating agent (HMA)-based therapy versus hypomethylating agent plus venetoclax-based combination.

TP53 is a frequently mirrored gene across all cancers, and it's all strongly associated with large structural and complex chromosomal aberrations. It's roughly found in 5 to 10% of patients with AML, [and] the incidence [is] higher among patients who are elderly or had a prior therapy-related AML. Historically, it's a bit poorer prognosis with anti-good response to conventional chemotherapies. [In our real world] data presented earlier [at the] ASH meeting, we evaluated the outcome of AML patients with evaluation of novel therapies. We observed that a higher portion of patients received event-based therapy in the most recent contemporary era. 

However, there wasn't any significant difference among outcomes and compared different lines of therapy [or] different modes of therapy. The only factor that came into play to improve [the] outcomes of this subgroup of patients was if we successfully bridge these patients to bone marrow transplant with improvement in 3-year survival rate among responding patients up to 45 to 50%. The benefit persists if the patient receives a transplant often in the first [complete remission] (CR) or receives salvage therapy for primary refractory or relapsed disease, or receives a bone marrow transplant. 

There [are] several studies in the past in which they have evaluated the gene signature in response to ven[etoclax]-based therapy. Among them, patients who had complex cytogenetics or TP53 mutation may achieve a response, but the response duration [is] long-lasting, and these are among the most unfit groups of patients when it comes to response to event-based therapy.

With this knowledge, with this background, we conducted this retro[spective] analysis utilizing our data from a command consortium in which we went over a case of around 383 patients and found 154 patients who were eligible for this analysis. Among [the] 154 patients, 32% of patients received hypomethylating agent-based therapy, versus 68% of patients received hypomethylating agent-based agent plus ven[etoclax]-based combination. The baseline characteristics among these 2 groups of patients were comparable, including advanced age, incidence of secondary AML, incidence of complex cytogenetics, or multi TP53 mutations. When it comes to completed remission rates, complete remission rates were higher---significantly higher. Among patients who receive HMA ven[etoclax]-based therapy compared to those who receive HMA-based therapy with response rate around 35% with combination versus 18% with HMA-based therapy, the bone marrow transplant was higher among patients who received HMA ven[etoclax]-based therapy compared to those who received HMA-based therapy. 

Also, the overall occurrence of bone marrow transplants is relatively low at the range of 15 to 20%. We didn't find any difference in TP53 mutation variant in terms of miss and variant versus truncating variants. Although, we did notice among patients who responded in both arms in HMA as well as HMA plus ven[etoclax]-based arm, [are] less likely to have concurrent somatic mutation. The median duration response was higher among patients [who] received HMA ven[etoclax]-based combination---around 15.6 months versus 7.93 months among patients [who] received HMA-based therapy. However, it wasn't significant. It wasn't powered enough to appreciate any significance. Statistically, similarly, the event-free survival from the time of diagnosis still progress, or relapse, or overall survival from the time of diagnosis to last follow-up or death was comparable among patients who received HMA versus HMA plus venetoclax-based therapy. 

We did [a] multi-variate analysis including significant variables in the univariate analysis for event-free survival and overall survival. When it comes to event-free survival, complex cytogenetics were associated with inferior event-free survival, [which was] significant in multivariate analysis. Similarly, no overall survival. The only factor that tends to have a favorable outcome are patients who achieve CR/ [complete remission with incomplete count recovery] (Cri) and are those patients who were bridged bone marrow transplant. 

In summary, in this real-world data, we observed a better CR rate with HMA plus ven[etoclax]-based combination [and] a better duration [of] response. However, the event-free survival and overall survival [were] insignificantly different among the 2 arms. Furthermore, we didn't find any significant difference among the high-risk variables such as secondary AML complex cytogenetics or multi TP53 mutation status. We observed significant benefits among patients who were bridged to bone marrow transplant, improving event-free survival on overall survival. 

We acknowledge the retrospective nature of this analysis and inherent biases with this, but this is real-world insight of a large cohort of patients. So, with the comprehensive genomic sequencing and patients were closely monitored longitudinally, this is some reference for future ongoing studies when we are utilizing HMA ven[etoclax]-based combination in patients with TP53-mutated AML. 

I would say, in summary, that if your patient is eligible for bone marrow transplant and fit enough, you may offer HMA ven[etoclax]-based therapy and bridge this patient to transplant to improve their long-term outcome. However, if you have an elderly frail patient with TP53 mutation, a ven[etoclax]-based combination may not improve their long-term outcome. As we know from prior studies [regarding] HMA, this combination among patients who are elderly [and] frail, the 60-day TRM, [or] treatment[-related] mortality, [is] around 19%. It'll give some insight [into] how to manage our patients with treat mutation and how to utilize ven[etoclax]-based combination with this. I would like to thank you all for listening.
 

Source: 

Badar T, Atallah EL, Shallis RM, et al. Comparable Survival of Treatment Naïve TP53 Mutated Acute Myeloid Leukemia Treated with Hypomethylating Agent Compared to Hypomethylating Agent Plus Venetoclax Based Therapy. Presented at the ASH 65th Annual Meeting & Exposition; December 9-12 2023; San Diego, California. Abstract 592