Amer Zeidan, MBBS, MHS, Discusses Efficacy of Azacitdine Plus Durvalumab for AML, MDS


At the 2019 ASH Annual Meeting, Amer M. Zeidan, MBBS, MHS, Yale University and Yale Cancer Center, New Haven, Connecticut, discusses results from a large, international, randomized phase 2 study exploring azacitidine plus durvalumab for older patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) who are unfit for intensive chemotherapy.


Hi, my name is Amer Zeidan, I'm an Associate Professor of Medicine at Yale University. I'm here at the American Society of Hematology meeting in Orlando. One of my presentations that I'm giving is focusing on the use of immune checkpoint blockade in patients with myeloid malignancy.

As many of you know immune checkpoint blockade has been a major advancement in the therapeutic landscape of multiple solid tumors—in melanoma and lung cancer, for example—and has been approved in multiple areas. One of the areas of interest in myeloid malignancies has been to better understand how to use these immune checkpoint blockades to help improve the outcomes of our patients.

One of the standard treatments for patients who are older with acute myeloid leukemia and unfit for intensive chemo, and patients with higher risk myelodysplastic syndromes are hypomethylating agents. There is some pre‑clinical data that suggests that hypomethylating agents actually are not as good in terms of their outcomes as they appear in clinical trials, when we look at the real‑life outcomes.

One of the potential mechanisms of resistance for hypomethylating agents is the upregulation of PD‑1 and PD‑L1. There has been an interest to try to combine immune checkpoint blockade that targets PD‑1 and PD‑L1 expression with hypomethylating agents.

The study I'm presenting is actually the first randomized study of patients with acute myeloid leukemia and patients with high‑risk myelodysplastic syndrome, 2 cohorts. Specifically, 2 studies in one study to which patients were randomized either to receive azacytidine alone, or azacytidine with durvalumab, which is an anti‑PD‑L1 inhibitor.

Durvalumab was given on day 1 of each cycle, every 4 weeks. Azacytidine was given on the standard schedule which is 7 days each month. The study was done in an open‑label fashion, it wasn't blinded, and the patients were allowed to continue on treatment until unacceptable toxicity or disease progression.

The primary endpoints of the study were the overall response rate, and the secondary endpoints included overall survival, progression‑free survival, as well as safety parameters. We had a number of correlative laboratory assays to better understand predictors of response.

The results: 213 patients were randomized, again in this large international study that happened in 12 countries, in the US and Europe. I think it's important to know that most of the other studies have been so far only single‑center studies, and this is, I think, a major advantage of this study, so we're able to compare the combination among patients with high‑risk MDS and AML to the azacytidine monotherapy.

While the study clinical results basically were negative in the sense that there was no improvement in the overall response rate for high-risk MDS or for acute myeloid leukemia, the study allowed us to actually understand somewhat new insights about how does the immune system in patients with acute myeloid leukemia operate, and how can we move the field forward.

Beside the overall response rate, the progression‑free survival, and the overall survival, also did not seem to differ significantly between the 2 treatment arms. On the safety front, there were no specific new signals. We saw some immune checkpoint‑related toxicity, which we have seen in other settings. They were generally reversible with aggressive management.

I'm hoping that this study would lead to other studies in which we can optimize outcomes of patients and better understand the place of immune checkpoint blockade among patients with myeloid malignancies.

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