Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML

Lionel Adès, Larisa Girshova, Vadim A Doronin, María Díez-Campelo, David Valcárcel, Suman Kambhampati, Nora-Athina Viniou, Dariusz Woszczyk, Raquel De Paz Arias, Argiris Symeonidis, Achilles Anagnostopoulos, Eduardo Ciliao Munhoz, Uwe Platzbecker, Valeria Santini, Robert J Fram, Ying Yuan, Sharon Friedlander, Douglas V Faller, Mikkael A Sekeres, Lionel Adès, Larisa Girshova, Vadim A Doronin, María Díez-Campelo, David Valcárcel, Suman Kambhampati, Nora-Athina Viniou, Dariusz Woszczyk, Raquel De Paz Arias, Argiris Symeonidis, Achilles Anagnostopoulos, Eduardo Ciliao Munhoz, Uwe Platzbecker, Valeria Santini, Robert J Fram, Ying Yuan, Sharon Friedlander, Douglas V Faller, Mikkael A Sekeres

Abstract

PANTHER is a global, randomized phase 3 trial of pevonedistat+azacitidine (n = 227) vs azacitidine monotherapy (n = 227) in patients with newly diagnosed higher-risk myelodysplastic syndromes (MDS; n = 324), higher-risk chronic myelomonocytic leukemia (n = 27), or acute myeloid leukemia (AML) with 20% to 30% blasts (n = 103). The primary end point was event-free survival (EFS). In the intent-to-treat population, the median EFS was 17.7 months with pevonedistat+azacitidine vs 15.7 months with azacitidine (hazard ratio [HR], 0.968; 95% confidence interval [CI], 0.757-1.238; P = .557) and in the higher-risk MDS cohort, median EFS was 19.2 vs 15.6 months (HR, 0.887; 95% CI, 0.659-1.193; P = .431). Median overall survival (OS) in the higher-risk MDS cohort was 21.6 vs 17.5 months (HR, 0.785; P = .092), and in patients with AML with 20% to 30% blasts was 14.5 vs 14.7 months (HR, 1.107; P = .664). In a post hoc analysis, median OS in the higher-risk MDS cohort for patients receiving >3 cycles was 23.8 vs 20.6 months (P = .021) and for >6 cycles was 27.1 vs 22.5 months (P = .008). No new safety signals were identified, and the azacitidine dose intensity was maintained. Common hematologic grade ≥3 treatment emergent adverse events were anemia (33% vs 34%), neutropenia (31% vs 33%), and thrombocytopenia (30% vs 30%). These results underscore the importance of large, randomized controlled trials in these heterogeneous myeloid diseases and the value of continuing therapy for >3 cycles. The trial was registered on clinicaltrials.gov as #NCT03268954.

© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Distribution of poor prognostic and frequently mutated genes in patients with higher-risk MDS by treatment arm. Mutational analysis was conducted on 270 bone marrow aspirate samples collected at screening (n = 135 samples from each treatment arm).
Figure 2.
Figure 2.
EFS and OS in the ITT population. Kaplan-Meier curve of EFS (A) and Kaplan-Meier curve of OS (B). ITT, intent-to-treat.
Figure 3.
Figure 3.
EFS in the higher-risk MDS cohort. Kaplan-Meier curve of EFS (A) and forest plot of subgroup analysis of EFS (B). *Lower confidence interval is truncated at 0.125. NE, not estimable.
Figure 4.
Figure 4.
OS in the higher-risk MDS cohort.
Figure 5.
Figure 5.
OS in patients with AML with 20% to 30% blasts. Kaplan-Meier curve of OS (A) and forest plot of subgroup analysis of OS (B). *Upper confidence interval is truncated at 8 and lower confidence interval is truncated at 0.125. ELN, European LeukemiaNet; NE, not estimable; WBC, white blood cell.
Figure 6.
Figure 6.
EFS and OS in patients with higher-risk CMML. Kaplan-Meier curve of EFS (A) and Kaplan-Meier curve of OS (B). NE, not estimable.
Figure 7.
Figure 7.
OS in patients with higher-risk MDS by number of cycles received. Patients who received greater than 3 cycles (A) and patients who received greater than 6 cycles (B).

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