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Venetoclax Combination Therapy Works Better in Some AML Subtypes Than Others

June 14, 2022

Mid-July 2022

Patients with TP53-mutated acute myeloid leukemia (AML) had a comparably good overall survival (OS) time when treated with the BCL-2 inhibitor venetoclax in combination with hypomethylating agents (HMAs), according to a small study presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In a retrospective review of how patients with AML and various genetic mutations fared with the treatment combination, researchers from Massey Cancer Center at Virginia Commonwealth University found no significant differences between groups as a result of the small numbers in each genetic category. But the survival times and response rates varied considerably among the patients when they were divided by mutation type, which could offer some guidance, they found.

“Survival with venetoclax plus [HMAs] appears to numerically favor TP53-mutated AML when compared to more intensive strategies, consistent with prior literature reporting favorable responses to HMA monotherapy in this subset of disease,” the researchers reported.

Those with TP53-mutated disease had a composite response rate (CRR) – complete remission and complete remission with incomplete hematologic recovery – of 33.3%, with a median OS of 12.6 months.

Keri Maher, DO, who presented the findings at the ASCO meeting, said the results also revealed another finding: AML with NPM1 mutations, considered a favorable prognostic marker, had a CRR of 44.4%, but median OS of 8.2 months.

“This – in combination with data published by other authors, and as we have also presented at the 2021 [American Society of Hematology Annual Meeting], supports treatment with conventional chemotherapy for ‘good risk’ disease when patients are otherwise a candidate for such therapies,” such as having normal NPM1 cytogenetics, Dr. Maher said.

Researchers also reported additional results among patients with other mutation types:

  • DNMT3: CRR=28.6%, median OS = not reached after a median follow-up of 15.1 months
  • FLT3: CRR=45.6%, median OS = 6.3 months
  • NRAS or KRAS: CRR=16.7%, median OS = 8.9 months
  • ASLX1: CRR=28.5%, median OS = not reached after a median follow-up of 8.9 months
  • RUNX1: CRR=50.0%, median OS = not reached after 12.8 months of follow-up

Findings suggest venetoclax with HMAs could be a good candidate for patients with TP53 and DNMT mutations, Dr. Maher said.

“Use of this backbone may be more efficacious than conventional chemotherapy in TP53-mut,” she said. “DNMT-mutated disease is directly related to aberrant methylation and resultant alteration of gene expression, again leading to a strong preclinical rationale for the use of HMA and HMA combinatorial therapies in this group.”

Considering the small number of patients used in her research, Dr. Maher said caution is needed when interpreting the findings.

“When broken down by molecular sub-type, it is very difficult to see a statistically significant difference,” she said. “We have ongoing work to expand this [sample size] to detect statistical differences. One must be very careful about direct application to the clinical setting, and more research is warranted.”

She added that her team is building upon its work to gather more data points that could help guide treatment.

“We are currently expanding our data set to include a multi-institutional retrospective analysis, which will better allow us to detect differences in parameters such as relapse-free survival, OS, and measurable residual disease status with respect to extended mutational profiling in AML when treated on an HMA/venetoclax backbone,” Dr. Maher said. “We also plan to examine potential effects of cooperating mutations, variant allele frequencies, and clonal evolution of disease at relapse with regard to treatment strategy.”

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Maher KR. Molecular stratification of response and survival of venetoclax in combination with hypomethylating agents in AML. Abstract e19033. Presented at the American Society of Clinical Oncology Annual Meeting; Chicago, Illinois.

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