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Clinical Trial
. 2025 Aug;100(8):1365-1373.
doi: 10.1002/ajh.27723. Epub 2025 May 22.

A Phase 2 Trial of CPX-351 Combined With Venetoclax in Relapsed or Refractory Acute Myeloid Leukemia

Tapan M Kadia  1 , Wei-Ying Jen  1 , Alex Bataller  1 , Alexandre Bazinet  1 , Gautam Borthakur  1 , Elias Jabbour  1 , Wei Qiao  2 , Nicholas J Short  1 , Koichi Takahashi  1 , Ghayas C Issa  1 , Courtney D DiNardo  1 , Guillermo Montalban-Bravo  1 , Naveen Pemmaraju  1 , Andrew Tran  1 , Vanthana Bharathi  1 , Sanam Loghavi  3 , Amin M Alousi  4 , Uday Popat  4 , Naval G Daver  1 , Farhad Ravandi  1 , Hagop M Kantarjian  1
Affiliations
Clinical Trial

A Phase 2 Trial of CPX-351 Combined With Venetoclax in Relapsed or Refractory Acute Myeloid Leukemia

Tapan M Kadia et al. Am J Hematol. 2025 Aug.

Abstract

Outcomes in patients with relapsed/refractory (RR) AML are poor. We sought to investigate if CPX-531 in combination with venetoclax (CPX + VEN) was tolerable and effective in RR AML. This was a single institution phase 1b/2 trial of CPX + VEN. Patients aged ≥ 18 years with RR AML who were fit for intensive chemotherapy were eligible. Prior venetoclax exposure was allowed. The phase 1b portion followed a 3 + 3 design to identify the recommended phase 2 dose (RP2D) for the expansion cohort. At the starting dose level of -1, prolonged myelosuppression was observed, leading to dose level -2 (CPX-351 dosed at daunorubicin 44 mg/m2 on days 1,3, and 5 and venetoclax 300 mg days 2-8) being chosen as the RP2D. Thirty three patients with a median age of 58 years (range, 26-72) were treated. Patients were heavily pretreated, with 58% with prior venetoclax exposure, 44% in the second salvage or later, and 30% with prior stem cell transplant (SCT). Adverse cytogenetics were present in 51% of patients, with myelodysplasia-related mutations in 64%, and TP53mut in 21%. The overall response rate (ORR) was 46% (95% CI, 30-62), with a composite CR rate (CRc) of 39% (95% CI, 25-56). Patients in first salvage with wildtype TP53 had a CRc rate of 70% (95% CI, 40-89), with undetectable MRD in 71% (95% CI, 36-92) and a 2-year OS of 49% (95% CI, 23-100). Eleven (73%) responding patients underwent SCT. The 30-day mortality was 9%, with a 60-day mortality of 21%. The most common adverse events were related to myelosuppression. CPX + VEN has activity in RR AML, particularly when used in first salvage and in patients who do not harbor TP53 mutations. ClinicalTrials.gov Identifier: NCT03629171.

Keywords: AML; CPX‐VEN; clinical trial.

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Conflict of interest statement

TMK has been a consultant for AbbVie, Agios, BMS, Genentech, Jazz Pharmaceuticals, Novartis, Servier, and PinotBio; has received research funding from AbbVie, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage Pharma, GenFleet Therapeutics, Astellas Pharma, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion Therapeutics, GlycoMimetics, and Regeneron Pharmaceuticals; and has received honoraria from Astex Pharmaceuticals.

CDD reports research Support from: Abbvie, Astex, BeiGene, BMS, Cleave, Foghorn, Jazz, Loxo, Servier and Personal fees from: Abbvie, Astellas, BMS, GSK, GenMab, Genentech, Gilead, Jazz, Loxo, Notable Labs, Servier, Schrodinger.

NGD has received grants or contracts from Hanmi, Trovagene, Fate Therapeutics, Novimmune, and GlycoMimetics; consulting fees from Arog, Novartis, Jazz, Celgene, Syndax, Shattuck Labs, and Agios; and grants or contracts and consulting fees from Daiichi-Sankyo, Bristol-Meyers Squibb, Pfizer, Gilead Sciences, Inc., Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, and Trillium.

GCI received consultancy or advisory role fees from Novartis, Kura Oncology, Syndax Pharmaceuticals, Abbvie and NuProbe and received research funding from Celgene, Novartis, Kura Oncology, Syndax Pharmaceuticals, Merck, Cullinan Oncology, Astex and NuProbe.

NJS has received consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi; research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure; and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene.

SL has received honoraria, consulting or advisory role fees from AbbVie, Arima, Astellas, BMS, Daiichi-Sankyo, Immunogen, Jazz Pharmaceuticals, Kura Oncology, Qiagen, Recordati, Servier, Stemline, Syndax, Tempus AI, and research grants from Amgen and Astellas and hold stocks with Abbvie.

UP has received research funding from AbbVie.

FR has served as a consultant for AbbVie, reports receiving research grants from Astellas Pharma Inc. and Celgene/BMS, and has received honoraria from Astellas Pharma Inc. and Celgene/BMS.

HMK has received honoraria, consulting or advisory role fees from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline,Takeda and research grants from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis. TMK has received research funding from AbbVie, Amgen, Astex, BMS, Genentech, Jazz Pharmaceuticals, Pfizer, Cellenkos, Ascentage Pharma, GenFleet Therapeutics, Astellas Pharma, AstraZeneca, Amgen, Cyclacel Pharmaceuticals, Delta-Fly Pharma, Iterion Therapeutics, GlycoMimetics, Sellas, and Regeneron Pharmaceuticals; and has received personal fees from AbbVie, Agios, BMS, Genentech, Hikma, Jazz Pharmaceuticals, Novartis, Servier, Sellas, and PinotBio.

Figures

Figure 1:
Figure 1:
Disease Characteristics The heatmap shows the cytomolecular characteristics and prior treatments of RR AML patients enrolled on this trial. #, number; AML, acute myeloid leukemia; Other int., other cytogenetic abnormalities classified as intermediate risk by the European LeukemiaNet 2022 (ELN2022); RR, relapsed/refractory; VEN, venetoclax.
Figure 2:
Figure 2:
Swimmer Plot Swimmer plot showing patients treated with CPX-351, with attention to time on therapy and follow-up duration.
See this image and copyright information in PMC

References

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