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Current and Future Steps for Venetoclax Combination Therapies in AML

By: Celeste L. Dixon
Posted: Wednesday, August 24, 2022

Initial results of combinations of the BCL2 inhibitor venetoclax with chemotherapy, immunotherapy, or targeted therapies to treat acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are encouraging, said Shai Shimony, MD, of Dana-Farber Cancer Institute, Boston, and colleagues. High remission rates with deep molecular responses can be achieved. However, concerns remain regarding the durability of remissions, the the effectiveness of combinations in high-risk populations (eg, those with p53-mutated disease), and—especially with venetoclax/chemotherapy combinations—the incomplete blood cell count recovery, prolonged cytopenia, and infection rates. The authors’ review in Current Opinion in Hematology of the most recent venetoclax-based combination therapies in patients with newly diagnosed or relapsed MDS and AML concluded that “much translational and clinical research will be required to maximally capitalize on the [therapies’] exciting initial results.”

One of the investigators’ major points is that long-term survival may not prove to be associated with remissions that lack blood cell count recovery, especially when consolidation with allogeneic stem cell transplantation is not possible. Yet outcomes in trials of the combination therapies frequently note so-called composite complete response rates: complete response plus additional remission definitions such as complete response with incomplete recovery, complete response without complete platelet recovery, complete response with partial hematologic recovery, and morphologic leukemia-free state. Any result other than “complete response with adequate bone marrow recovery may not reflect and [be] used as surrogate for survival outcomes…, [warranting] longer follow-up with true survival outcome,” they stressed.

More encouragingly, Dr. Shimony and co-investigators can foresee venetoclax being incorporated into pretransplant conditioning regimens to achieve faster and higher rates of negative measurable residual disease (MRD). This would be an important step forward, they noted, given that positive MRD prior to transplant is associated with higher relapse rates.

“We are now at the dawn of the age of proapoptosis in the management of patients with myeloid malignances,” concluded the investigators.

Disclosure: The study authors reported no conflicts of interest.


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