The following article features coverage from the European Hematology Association (EHA) 2021 Virtual Congress. Click here to read more of Hematology Advisor‘s conference coverage.

Results of a phase 2 study suggest that in patients treated with pevonedistat plus azacitidine, the combination may result in a lower residual mutation load than seen with azacitidine alone. The results were presented at the European Hematology Association (EHA) 2021 Virtual Congress by Mikkael Sekeres, MD, MS, of the Sylvester Comprehensive Cancer Center at the University of Miami in Miami, FL, and colleagues.

The phase 2 open-label P-2001 trial ( Identifier: NCT02610777) included patients with higher-risk myelodysplastic syndrome (MDS), higher-risk chronic myelomonocytic leukemia (CMML), or low-blast acute myeloid leukemia (LB-AML) who were randomized to receive pevonedistat with azacitidine or azacitidine alone.

In the P-2001 trial, the addition of pevonedistat to azacitidine improved overall response rate compared with azacitidine alone. In the current study, which was a prespecified comparative analysis, the researchers evaluated whether pevonedistat added to azacitidine also led to deeper, more persistent molecular responses.

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A total of 96 bone marrow aspiration samples had been collected at baseline, with DNA analyzed through next-generation sequencing. A total of 58 longitudinal were taken at time points throughout the treatment course from 33 patients with high-risk MDS, 7 patients with higher-risk CMML, and 18 patients with low-blast AML for ultra-sensitive duplex sequencing to measure the level of mutant allele burden in each arm of the study, compared with baseline.

The study investigators reported there was significantly less expansion of treatment-emergent mutations in patients from the pevonedistat plus azacitidine arm (29.3%) versus the azacitidine-only arm (49.6%; P =.002).

Clonal expansion was reportedly controlled with pevonedistat in patients regardless of complete response status. Additionally, the treatment effect was observed with genes related to lower-risk and higher-risk MDS, as well as genes associated with worse outcomes and AML transformation.

Dr Sekeres explained during his presentation that the reduced mutation burden with the combination gives potential clinical benefits including: “first, lesser likelihood of treatment-emergent resistance; second, controlled expansion of mutations associated with higher-risk MDS and AML transformation; and third, increased durability of treatment response, which is even more meaningful.”

Dr Sekeres also stated that pevonedistat with azacitidine will evaluated in the phase 3 PANTHER, PEVOLAM, and PEVENAZA trials ( Identifiers: NCT03268954, NCT04090736, and NCT04266795, respectively).

Disclosures: The author(s) have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

Read more of Cancer Therapy Advisor’s coverage of the EHA 2021 Virtual Congress by visiting the conference page.


Friedlander S, Krueger A, Galinsky K, et al. Lower residual mutation load following treatment with pevonedistat + azacitidine versus azacitidine alone: comparative analysis of study arms in P-2001, a randomized phase 2 trial. Paper presented at: European Hematology Association 2021 Virtual Congress; June 2021; Abstract S166.