This week’s highlighted AML article can be viewed below. Venetoclax plus an HMA has become a frontline treatment of choice in intensive chemotherapy–ineligible AML. Other HMA combinations, including triplet regimens, are actively being studied to try to improve responses in this setting.

Effective strategies for hypomethylating agent (HMA) resistance are needed in acute myeloid leukemia (AML), a disease that affects many older individuals who are ineligible for intensive chemotherapy. A number of targeted combination regimens are being studied to help meet this need.

We still do not fully understand HMA resistance as well as we should. Unfortunately, most patients who receive an HMA as monotherapy will experience resistance, even if these patients initially respond to treatment. There are a whole host of HMA combinations that are being studied to try to improve these outcomes. The combination with venetoclax has been very effective and has become a frontline HMA combination of choice, but there are other combinations that are under development as well.

For instance, there are combinations involving targeted therapies such as azacitidine with IDH1, IDH2, and FLT3 inhibitors. Data from the phase 3 AGILE study of azacitidine and the IDH1 inhibitor ivosidenib showed favorable results, and this is now also a combination that we can consider in our patients with newly diagnosed, IDH1-mutated AML who are not eligible for intensive induction chemotherapy.

When adding combinations, we have to be much more attuned to potential toxicity. With venetoclax-based therapy, we have to be aware of the potential for cytopenias; with other targeted agents, there are variable, unique toxicities that need to be considered.

Triplet therapies are also under evaluation. There are currently more and more clinical trials examining azacitidine plus venetoclax and a third agent such as an IDH inhibitor, an FLT3 inhibitor, or another targeted agent. There is more potential myelosuppression and toxicity with a triplet approach, but the hope is to achieve even deeper remissions and more durable survivals once we establish the optimal dosing strategies for triplet regimens.