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PD-1/PD-L1 Pathway May Hold Promise in MDS/AML, Questions Remain


A new review article outlines the latest research and results into programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML).

Immune checkpoint inhibitors could play an important role in treating patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), but more research is needed to figure out how best to exploit a key pathway, according to a new review article in Experimental Hematology & Oncology.

MDS and AML originate in the bone marrow, and about 3 in 10 cases of MDS will eventually progress to AML. One of the key drivers of both conditions is believed to be dysregulated immune microenvironments, and immune checkpoint molecules like programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have been identified as playing key roles in oncogenesis by creating an immunosuppressive tumor microenvironment.

Recent investigation has shown these markers have aberrant expression in patients with MDS and AML, the authors noted. As a result, investigators are examining the potential for using PD-1/PD-L1 blockers to slow disease progression.

The investigators of the present study, from China, outlined some of the latest research related to the PD-1/PD-L1 pathway in patients with MDS/AML.

Most of the review article deals with preclinical investigation of PD-1/PD-L1 signaling. In that regard, the authors noted, most of the literature suggests that PD-1/PD-L1 blockers may produce a response in patients. Yet, the responses noted in current clinical trials have been mixed, they said.

For instance, a phase I study of pidilizumab in 9 patients with AML (8 patients) or MDS (1 patient) showed only a minimal response in a single patient with AML. “No trial employing pidilizumab has been conducted in MDS/AML subsequently,” the authors reported.

A phase II study that used the combination of Vidaza (azacitidine) and Opdivo (nivolumab) in 70 patients with relapsed/refractory AML had an overall response rate (ORR) of 33%, with a 58% response rate in patients who were hypomethylating agent (HMA) naive and 22% in patients who had experienced HMA failure.

A separate phase II study looked at combining azacitidine and Keytruda (pembrolizumab) for use in MDS. That study, which looked at patients with intermediate- to high-risk disease, found ORRs of 76% in HMA-naive patients and 25% in patients who had a history of HMA failure.

After outlining other results, the authors summarized that the existing literature “suggested PD-1/PD-L1 blockers combined with HMAs or chemotherapeutics could yield more promising results in treatment-naive patients, whereas they could also increase the frequency of [adverse events] compared with single agents.”

Looking forward, the investigators said there is a need for biomarkers to better predict which patients are more likely to respond favorably to treatment with PD-1/PD-L1 blockers. There is also a need for better methods to track treatment responses in these patients, they added.

The authors emphasized that PD-1/PD-L1 blockade may be most effective if it follows allogeneic hematopoietic stem cell transplantation, “which may achieve a competent immune system to fully eradicate the underlying malignancy.”

However, the authors also said that a PD-1/PD-L1 blocker may be more effective in some patients if it is paired with other immune checkpoint inhibitors. They said some trials have already investigated this strategy, with “promising” preliminary results.

In their conclusion, the authors said that immune checkpoint therapy broadly speaking represents a novel strategy, but they said a number of questions will need to be answered before the therapy can be leveraged in a reliably effective way.


Yang X, Ma L, Zhang X, Huang L, Wei J. Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia. Exp Hematol Oncol. Published online March 2, 2022. doi:10.1186/s40164-022-00263-4

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