Steven Gore, MD

In discussions after these presentations, several points were made by several experts. To begin, Steven Gore, MD, Director of Hematologic Malignancies at Yale Medical School, called the study of venetoclax plus 10-day decitabine “very important,” but he raised the issue of appropriate dosing. He noted that researchers over the years (including himself) have tried different dosing schedules for hypomethylating agents, and the optimal schedule is still not fully established.

“We’ve often ignored data and pursued pharmaceutically convenient add-ons,” he said. Thus, the “conundrum” still exists over whether the best outcomes have yet been achieved in using hypomethylating agents plus other agents. “We sell our patients short because we often don’t take the time to do the pharmacokinetically and clinically important dose-finding that’s needed,” Dr. Gore commented.

Several listeners commented on the fact that patients with isocitrate dehydrogenase-1/2 (IDH1/2)-mutated acute myeloid leukemia (AML) achieved a complete remission or complete remission with incomplete hematologic recovery rate of 100% with venetoclax plus 10-day decitabine in the study by Abhishek Maiti, MD. Given the risk of differentiation syndrome with IDH inhibitors (there is now a U.S. Food and Drug Administration warning about this), perhaps a regimen such as this investigational regimen could be a safer way to initiate treatment in such patients, one listener suggested.

Identifying Patients Who May Benefit

Eyten Stein, MD, of Memorial Sloan Kettering Cancer Center, presented several studies at the 2018 American Society of Hematology (ASH) Meeting & Exposition on IDH inhibitors. “I think you have to think about what patient population you are treating. Azacitidine or decitabine plus venetoclax is myelosuppressive, which is why we have dose-holds built into protocols…. We need to think about how to combine all these agents together. The goal is to make progress, not on individual tracks but to have coalescence to attack multiple things at multiple times. I bet this would produce higher remission rates and longer survival.”

Eyten Stein, MD

Elihu H. Estey, MD

Several listeners questioned whether these venetoclax combinations might serve even “fit” patients well, perhaps better than chemotherapy. However, Elihu H. Estey, MD, Director of AML Clinical Research, University of Washington, Seattle, believes the opposite may be true. “Fitness is an important predictor of treatment-related mortality. A patient may look unfit but could, in fact, be fit enough for intensive chemotherapy. It’s fine to say that intensive chemotherapy is becoming passé, but my fear is [these current data] will seduce clinicians to give these regimens to patients who might benefit from intensive chemotherapy. In this vein, it’s important to point out that none of the people treated on the venetoclax trials had a performance status of 3 or 4 and only 16% had a performance status of 2, with poor performance status a principal predictor of treatment-related mortality. This raises the question of whether results with venetoclax combinations would be similar to those observed here had patients considered “unfit” using more objective criteria been treated. It’s easy to give these drugs—but it may not be best in the long run. The question is, how do we define patients who are not fit for intensive chemotherapy? ■

DISCLOSURE: Dr. Gore is a consultant for AbbVie and Celgene and has received research support from Celgene. Dr. Stein is an advisor for and has received consulting fees from AbbVie, Agios, and Celgene. Dr. Estey reported no conflicts of interest.