Dr Daver on the Initial Safety of DSP-5336 in Relapsed/Refractory Acute Leukemia

Naval G. Daver, MD, professor, director, Leukemia Research Alliance Program, Department of Leukemia, Division of Cancer Medicine, The University of MD Anderson Cancer Center, discusses updated findings from a phase 1/2 study (NCT04988555) of the investigational menin-MLL inhibitor DSP-5336 in relapsed/refractory acute leukemias.

DSP-5336 is an oral small molecule designed to inhibit the interaction between menin and MLL. To identify a recommended the phase 2 dose and assess the clinical activity of this agent, a first-in-human trial was conducted in patients with relapsed/refractory acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML). This trial did not exclude patients based on prior therapies and focused on those with KMT2Ar and NPM1c mutations. The dose-escalation portion of the trial included 2 arms: Arm A without concomitant anti-fungal azoles and Arm B with azoles.

Results from the dose-escalation portion of the study were presented at the 2024 EHA Hybrid Congress and indicated that DSP-5336 was well tolerated with a favorable safety profile, Daver reports. There were no instances of treatment-related QT prolongation or cardiac effects, dose-limiting toxicities, treatment-related discontinuations, or deaths, he adds. Pharmacokinetic analyses revealed no significant drug-drug interactions with azoles.

The cardiac safety profile of DSP-5336 is notable, Daver says. Among the 58 patients in the current analysis, only 2 experienced grade 3 or higher QTcF on an EKG. In one case, the QTc prolongation was attributed to other arrhythmias and electrolyte changes, rather than DSP-5336, Daver recounts. In the other case, a possible relationship was considered, but the patient also had hypokalemia and was taking medications that could increase QTc, and the condition reverted to normal without clinical consequence, he explains. Overall, the cardiac profile of DSP-5336 appears very favorable, Daver summarizes.

Importantly, no differentiation syndrome was reported in patients with MLL rearrangements or NPM1 mutations, including those who achieved an objective response, Daver notes. This condition is often associated with other menin inhibitors, he explains. Unlike other menin inhibitors that often require ICU stays, drug discontinuation, or result in mortality due to severe differentiation syndrome, DSP-5336 has not shown significant clinical differentiation syndrome in the patients treated so far, Daver says. This absence of severe differentiation syndrome is observed despite the clinical responses and efficacy of DSP-5336, and without the use of prophylaxis, he adds.

However, it is important to note that these observations are based on a relatively small number of patients, Daver notes. As the trial continues and more patients are enrolled, the safety profile may evolve. Nonetheless, the preliminary results are promising and suggest that DSP-5336 has a very good safety profile, with minimal cardiac toxicity and an absence of severe differentiation syndrome, making it a potentially valuable treatment option for patients with relapsed/refractory ALL or AML, Daver concludes.