Pevonedistat plus azacitidine vs azacitidine alone in higher-risk MDS/chronic myelomonocytic leukemia or low-blast-percentage AML
Open accessAbstract
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.
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AZA alone continues to represent standard of care in MDS because all recent studies have failed to improve median OS compared to monotherapy.
“AZA alone continues to represent the standard of care in MDS because all recent studies have failed to improve the median OS compared to monotherapy.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [37]
The Discussion describes azacitidine alone as standard care and says this phase 3 combination trial did not meet its primary endpoint. The Results (Efficacy) report no statistically significant OS benefit in higher-risk MDS, although median OS was numerically longer with the combination (21.6 versus 17.5 months). The paper does not establish that all recent studies failed to improve median OS across MDS generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredCombination therapies in MDS including HDAC inhibitors, lenalidomide, pevonedistat, and anthracyclines have not improved results.
“Combination therapies in this setting have included HDAC inhibitors, 33 , 34 , 35 lenalidomide, 36 pevonedistat, 37 and anthracyclines 38 all without improved results.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [37]
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“Combination therapies in this setting have included HDAC inhibitors, 33 – 35 lenalidomide, 36 pevonedistat, 37 and anthracyclines 38 all without improved results.”
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- Authors
- Adès, L., Girshova, L., Doronin, V. A., Díez-Campelo, M., Valcárcel, D., Kambhampati, S., Viniou, N.-A., Woszczyk, D., De Paz Arias, R., Symeonidis, A., Anagnostopoulos, A., Munhoz, E. C., Platzbecker, U., Santini, V., Fram, R. J., Yuan, Y., Friedlander, S., Faller, D. V., & Sekeres, M. A.
- Affiliations
- Inserm (FR)
- Federal Almazov North-West Medical Research Centre (RU)
- City Clinical Hospital (RU)
- 4Institute for Biomedical Research of Salamanca (IBSAL), University Hospital of Salamanca, Salamanca, Spain;
- Vall d'Hebron Hospital Universitari (ES)
- Research Medical Center (US)
- National and Kapodistrian University of Athens (GR)
- University of Opole (PL)
- 9Hematology, Hospital Universitario La Paz-IDIPaz, Madrid, Spain;
- General University Hospital of Patras (GR)
- 11Hematology Department, General Hospital “George Papanikolaou,” Thessaloniki, Greece;
- Hospital Erasto Gaertner (BR)
- University Hospital Leipzig (DE)
- Azienda Ospedaliero-Universitaria Careggi (IT)
- 15Takeda Development Center Americas, Inc (TDCA), Lexington, MA; and
- University of Miami (US)
- Corresponding author
- Adès, Lionel
- ORCID
- Venue
- Blood Advances
- Publisher
- American Society of Hematology
- Published
- 2022-09-02
- Volume
- 6
- Issue
- 17
- Pages
- 5132-5145
- ISSN
- 2473-9529 (ISSN-L)
- 2473-9537
- PMC
- PMC9631625
- OpenAlex
- W4283264931
- Cited by
- 130
- References
- 33
- Citations by year
- 2026: 25 · 2025: 32 · 2024: 32 · 2023: 34 · 2022: 6 · 2021: 1
- FWCI
- 18.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Blood Advances (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Takeda Pharmaceuticals U.S.A.
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- pevonedistat, azacitidine, myelodysplastic syndrome, chronic myelomonocytic leukemia, acute myeloid leukemia, event-free survival, overall survival, treatment-emergent adverse events, dose intensity, hematologic toxicity
- MeSH terms
- Antimetabolites, Antineoplastic, Azacitidine, Cyclopentanes, Drug Therapy, Combination, Humans, Pyrimidines, Leukemia, Myelomonocytic, Chronic
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