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, both in the MDS and the AML space, 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.

When adding combinations, we have to be much more attuned to potential toxicity. We also must be especially careful when treating patients with MDS because their bone marrow already starts out a bit more disordered and dysfunctional. With venetoclax-based therapy, we have to be aware of the potential for cytopenias, and with immune checkpoint inhibitors (ICIs), we need to be more aware of some of the immune-related adverse events, such as pneumonitis, colitis, or rashes. Despite the varying toxicities, the rationale behind most of the combinations is similar and compelling when it comes to MDS, high-risk MDS, and AML (ie, the aim is to improve responses).

Some particularly exciting combinations in MDS and AML involve novel ICIs. Magrolimab is an antibody against CD47 that acts as a macrophage ICI to promote tumor cell phagocytosis. In both MDS and AML, combinations with azacitidine and magrolimab seem to be effective, even in patients with TP53 mutations. Individuals with TP53-mutated myeloid malignancies are among the most difficult to treat, so if this combination is truly effective in a TP53-agnostic way, that is going to be really important.

TIM-3 is a checkpoint that is particularly relevant for myeloid malignancies. Sabatolimab is the TIM-3 inhibitor that is furthest along in development, and there are several ongoing studies that are evaluating sabatolimab-based combinations. Agents targeting TIM-3 and CD47 are immunotherapy options that do not seem to be associated with as many immune-mediated adverse events as the standard PD-1, PD-L1, and CTLA-4 ICIs, which has been a positive development.

There are also combinations involving targeted therapies such as azacitidine with IDH1, IDH2, and FLT3 inhibitors. Data from the recently reported phase 3 AGILE study of azacitidine and the IDH1 inhibitor ivosidenib showed favorable results. I think that this may be another combination that we will be using in IDH1-mutated AML.

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 a novel ICI. 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.