ASH 2025 | Choice of HMA for newly diagnosed TP53-mutant AML: a COMMAND registry study

In the community, among the treating leukemia physicians, based on the prior study, where it has shown that among patients who have previously mutated high-risk MDS in AML patients, if they were treated with a prolonged duration of azacitidine, which is one of the hypomethylating agents, it tends to clear the blasts more predominantly, whereas the later data from EDMAR studies suggest that either azacitidine or decitabine when given to high-risk myelodysplastic patients, it tends to have a comparable outcome. The criteria utilized for determining the complete response rate in the earlier study where they’ve shown that decitabine tends to do better in AML patients, they’ve utilized a blast clearance rather than true complete remission criteria. If you fall into that criteria among those 21 patients who had previously mutated MDS and AML, the complete remission rate was smaller than what has been reported. When, say, complete remission, clearance of blasts as well as improvement in blood count, neutrophil more than 1,000, hemoglobin more than 10, and platelets more than 100. So we did this study utilizing a common consortium, one of the largest databases of TP53 mutated AML. Among the 650 patients in our database, we queried patients who received hypomethylating agent-based therapy, either azacitidine or decitabine, in combination with or without venetoclax. Among those 321 patients, a relatively high proportion of patients received decitabine-based regimen based on the prior study that showed that these patients may respond better with decitabine compared to azacitidine. In terms of the predictors of outcome, the variables that have shown to predict outcomes such as multi-line disease, complex cytogenetics, bone marrow blasts, more than 30% were comparable. And when we did a matched control analysis, head-to-head, among 216 patients, one arm receiving decitabine, one arm receiving azacitidine, we didn’t see any difference in baseline characteristics, including the utilization of venetoclax-based therapy in this group of patients. Further on, when we evaluate the response rate, the complete remission, with or without count recovery, there was significance in achieving response rate among decitabine group, around 50% or so, compared to azacitidine group where it’s around 40% or so. However, the stringent CR were comparable. The proportion of patients receiving bone marrow transplant as a bridging therapy to potentially improve their long-term outcome was comparable. The event-free survival was comparable, although this was less than six months, as well as overall survival. Then we look at the outcome based on transplant. There’s all the concern about lead time bias when evaluating transplant outcome among these patients. So we look at those patients who remain event-free at day 60 from the time of diagnosis and look at their outcome. Although the proportion of patients receiving transplant were lower, however, the decitabine as well as azacitidine group have a two-year, event-free survival, overall survival, more than 60%. So, in conclusion, decitabine or azacitidine shown to have comparable outcome when it comes to TP53-mutated AML. However, having said that, decitabine oral formulation may have ease of administration, may improve patients’ quality of life getting these treatment at home; however, we didn’t see any significant different outcome having said that as per our earlier analysis where we looked at the outcome with or without venetoclax-based regimen in this scenario in multivariate analysis we saw the venetoclax has a tense hazard ratio not favoring the utilization of this among patients with TP53-mutated AML because these patients in this cohort are more elderly, more enriched with secondary AML, more enriched with thyroid disease, it tends to have frail, it tends to have more complications when it be utilized when you took like serious therapy.

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