Early data suggest that immune checkpoints are upregulated in patients with HR-MDS and AML, although not at the same level as in those with solid cancers. Additionally, hypomethylating agents such as azacitidine further upregulate checkpoints such as CTLA-4, PD-1, and PD-L1, contributing to the resistance associated with azacitidine therapy. While there are numerous ongoing trials with ICIs combined with a hypomethylating agent, preliminary data have been underwhelming. Early data with nivolumab or pembrolizumab combined with azacitidine report marginally higher response rates, but overall survival data are needed to determine whether these responses are durable. To further complicate matters, some trials have closed early due to toxicity concerns. Also, trials evaluating the efficacy of single agents have had a minimal response with increased toxicity. For immune-related adverse events, we need a better understanding of managing these reactions for our patients with myeloid malignancies.

Novel ICIs such as magrolimab and sabatolimab have shown promise in HR-MDS and AML. Magrolimab is an anti-CD47 innate immune activator that leads to macrophage-mediated phagocytosis and has demonstrated synergistic activity with azacitidine. We have recently presented the results from a phase 1b study that showed rapid and durable responses with magrolimab plus azacitidine. In this study, complete remission rates approached 50%, with encouraging results reported in patients with TP53 mutations. Sabatolimab, a TIM-3 inhibitor that has a dual mechanism of action via targeting leukemia stem cells (LSCs) while also activating adaptive immunity, also demonstrated high response rates and was well tolerated. The eradication of the founding LSC clone may help patients achieve durable responses, which is the ultimate goal of therapy. Therefore, these agents, in conjunction with stem cell transplantation, may improve the chances of a cure. However, it is important to realize that we cannot take a “one-size-fits-all” approach in immunotherapy. We need to think about the molecular subsets and other biomarkers that these therapies may best exploit.

Although there has been a paradigm shift with chimeric antigen receptor (CAR) T-cell therapy in hematologic malignancies, one of the challenges that we face in AML is the unavailability of a target on every myeloid, blast, or LSC. Another concern is that CD33 and CD123, which are the classic targets for CAR T-cell therapy, are also expressed on normal hematopoietic stem cells, placing patients at risk for aplasia. Therefore, all individuals who are enrolled in CAR T-cell therapy trials must have a donor available, limiting the patients who can receive these therapies.

I think that the horizon is bright, and I am hopeful that the availability of translational, preclinical, and initial clinical data will pave the path for immunotherapy in AML.