Alice Mims, MD, Associate Professor of Hematology at The Ohio State University Comprehensive Cancer Center–The James, shared her insights on the VIALE-A study. “The results of the VIALE-A study have been highly anticipated and are exciting, given the improvement seen in both overall survival and remission rates with the addition of venetoclax to azacitidine for older and less fit patients with acute myeloid leukemia (AML). We await the U.S. Food and Drug Administration review of the results but anticipate this combination will move on to full approval for these patient populations, based on meeting the study’s primary overall survival endpoint,” she predicted.
Cautious Optimism
Dr. Mims cautioned, however, that although the findings reflect significant progress in AML, there is still “room for improvement.” Although more effective than azacitidine alone, the combination is still not “curative,” and the majority of patients relapse. “There may be some patient populations who benefit with prolonged durations of response, but we will need more extended follow-up for this determination. There was improvement in complete remission/complete remission with incomplete hematologic recovery/complete remission with partial hematologic recovery for all four molecular subtypes mentioned but no difference in overall survival for patients with mutations in FLT3, NPM1, or TP53,” she pointed out.
Alice Mims, MD
Dr. Mims also mentioned the possibility of this regimen serving as a bridge to transplant; however, she considers that unlikely in an elderly, nonfit population. “Just three patients on this study were able to move forward with allogeneic transplantation.” However, this should “not detract” from the potential quality-of-life benefits conveyed to patients achieving complete responses.
“As with any clinical study, attempting to answer a question begets more questions,” Dr. Mims continued. For example, “We need larger outcome data for specific genomic subgroups of AML to help determine whether venetoclax plus azacitidine is the best upfront therapy for every older or less fit patient. Further knowledge about the depth of remission, with data pertaining to measurable residual disease in responders, would be of benefit.” Such information could help in the design of future trials that build upon the venetoclax/azacitidine backbone, noted Dr. Mims, such as those that add a targeted agent or immunotherapy in complete responders as a means of extending the duration of that response.
Other questions focus on whether venetoclax/azacitidine might play a role in a younger AML population and whether certain genomic subpopulations might benefit more from this doublet than intensive induction, the current standard, she added.
Clinical Considerations
“As this study included community centers along with academic institutions, we hope these results are a more realistic reflection of real-world outcomes,” Dr. Mims said. And, as this regimen is employed in the clinic, oncologists should be conscious of certain issues that can arise, especially compared with hypomethylating agents alone, she added.
One issue is the risk of tumor lysis, which still does occur, although it is seen less frequently than in the chronic lymphocytic leukemia population. Clinicians should be aware of this potential complication, monitor tumor-lysis labs appropriately, and cytoreduce hydroxyurea when patients have white blood cell counts higher than 25,000/mL prior to treatment initiation, advised Dr. Mims. They should also consider dose adjustments in patients concurrently on CYP3A inhibitors or inducers, which include most patients on antifungal prophylaxis.
“Also, the median time to complete remission/complete remission with incomplete hematologic recovery/complete remission with partial hematologic recovery is quicker than what we have grown to anticipate with hypomethylating agents alone, occurring typically after one or two cycles, as opposed to three or four,” Dr. Mims pointed out. “It’s important to check bone marrow biopsies earlier if no circulating peripheral blasts are present to determine remission. It is also necessary to follow the label in terms of holding therapy and/or making dose adjustments for grade ≥ 3 neutropenia and thrombocytopenia.”
DISCLOSURE: Dr. Mims has served as a consultant or advisor to Agios, PTC Therapeutics, Astellas Pharmaceuticals, Jazz Pharmaceuticals, Syndax Pharmaceuticals, Kura Oncology, and AbbVie.
