Although hypomethylating agents remain the mainstay of therapy for patients with MDS, response rates are suboptimal, treatment effects are often short lived, and most patients cannot achieve durable responses. To address these limitations, multiple doublet regimens with azacitidine are under clinical investigation. Updated results from the phase 2 P-2001 trial showed that the complete remission (CR) rate with azacitidine plus pevonedistat was nearly double the rate with azacitidine alone (52% vs 27%). We are eagerly awaiting results from the phase 3 trial, which has a primary end point of event-free survival. While azacitidine plus venetoclax has been shown to be effective in AML, data from a phase 1b study in 57 treatment-naive high-risk patients who received the combination showed that only 42% achieved CR. However, myelosuppression associated with venetoclax may have had an impact on these preliminary response rates. In the above trials, responses have been observed in TP53 patients, but these cohorts have been relatively small.

In patients with TP53 mutations, restoring the function of p53 can promote malignant cell death. Eprenetapopt (APR-246) restores p53 function through stabilization and an overall shift toward a wild-type confirmation, allowing p53 to perform its proapoptotic tumor-suppressive function. In phase 2 studies, eprenetapopt demonstrated impressive CR and overall survival rates, which led to the only phase 3 trial in patients with high-risk MDS with TP53 mutations to date. Unfortunately, preliminary data showed that, while the CR rate was higher in the eprenetapopt-plus-azacitidine arm, this did not reach statistical significance. While this is a setback, we will have more information once the data mature from patients who received treatment with eprenetapopt in combination with azacitidine. Furthermore, there are ongoing trials with eprenetapopt in AML (in combination with azacitidine and venetoclax) as well as a maintenance trial with azacitidine post allogeneic stem cell transplantation.

Although there is evidence that doublet regimens with novel immunotherapies or targeted therapies improve response rates in select patients, triplet-based regimens may be necessary to achieve durable responses, particularly in patients with TP53 mutations. For example, planned and ongoing trials of triplet therapy with azacitidine, venetoclax, and novel therapies will evaluate whether synergy among these agents improves outcomes.

When evaluating novel combinations for high-risk MDS and AML in the frontline setting, a thorough understanding of resistance mechanisms and therapeutic synergy at the biological level can help to optimize treatment strategies. In my opinion, the goal of therapy is not only to achieve CR but also to eradicate the underlying clones that drive the disease. Importantly, we need to ensure safety with multidrug combinations in this elderly group of patients. As treatment strategies continue to evolve, the hope is that we can improve the depth of remission, quality of life, and, ultimately, survival in patients with MDS/AML.