Acute Myeloid Leukemia: Evolving Perspectives on Testing, Targeted Therapies, and Transplantation - Episode 10

Role of Dual Targeted Therapy in AML

February 8, 2021
Harry P. Erba, MD, PhD, Duke University School of Medicine

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Alexander E. Perl, MD, University of Pennsylvania

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Eunice Wang, MD, Roswell Park Comprehensive Cancer Center

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Adam Bagg, MD, University of Pennsylvania

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Corey S. Cutler, MD, MPH, FRCPC, Dana-Farber Cancer Institute

Harry P. Erba, MD, PhD: I want to use that as a quick segue away from FLT3, and now talk about combinations. Eunice, I am going to turn to you for that. What do you think about the data presented from The University of Texas MD Anderson Cancer Center of gilteritinib with venetoclax, trying to combine both of these targeted approaches?

Eunice S. Wang, MD: This trial was also led by Sasha, and it was the dose-expansion cohort of a phase 1 study where they initially looked at the tolerability and safety, and they are now looking at the efficacy in patients with relapsed/refractory disease. A small proportion of those patients who had gone on study had failed either venetoclax alone or gilteritinib alone: about 20% of patients. The fact that you could have response rates well over 80% looking at CR [complete response], Cri [CR with incomplete count recovery], and CRh [complete response with partial hematologic recovery] in those individuals with the combination of venetoclax and gilteritinib was highly promising. This is something. Some of us are so impressed with these results that we are starting to consider using that combination in the off-label setting for patients with FLT3-mutant disease that has recurred or come back particularly after a venetoclax-azacitidine treatment. Even though Sasha says that would be his preferred regimen at the time of recurrence with FLT3-mutant disease, instead of just using the gilteritinib alone, we are continuing with the venetoclax as well.

That approach looks very promising for a few reasons. No. 1, it overcomes different mechanisms of resistance. As you know, you can get resistance developing to gilteritinib primarily through RAS mutations, and you can get resistance to venetoclax based on the development of FLT3 mutations. Combining the 2 seems to make a lot of sense from a biological point of view, and it overcomes cross-mechanisms of resistance. Patients also like it because it is a completely oral regimen. We have to say that the tolerability and dosing to minimize myelosuppression while preserving extremely high response rate is an attractive option, mostly because the patients who have gone on a bunch of therapy with either the VIALE-A trial or azacitidine-based therapy are usually unfit patients. These are not patients whom you would be asking to undergo a salvage treatment with MEC [mitoxantrone, etoposide, cytarabine] or FLAG [fludarabine, high-dose cytarabine, GCSF]. That combination is extremely promising. I know there is discussion about potentially moving that to the up-front setting and exploring that in a triplet regimen. That also suggests that it is feasible to give dual targeted therapy, which is also an important concept. Most of the combinatory studies at 2020 ASH [American Society of Hematology] Annual Meeting were combinations; for example, venetoclax with low-dose chemotherapy, venetoclax with high-dose chemotherapy, and venetoclax with a TKI [tyrosine kinase inhibitor]. The fact that we can combine venetoclax with a targeted TKI is valuable information, and it is very promising.

Transcript Edited for Clarity