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Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Anna B Halpern·Megan Othus·Mary-Elizabeth M Percival·Cristina Ghiuzeli·Jacob S Appelbaum·Paul C Hendrie·Ryan D Cassaday·Max Smith·Kathryn Russell·Bart L Scott·Jason P Cooper·Joshua R Veatch·Siobán B Keel·Vivian G Oehler·Erik L Kimble·Raya Mawad·Roland B Walter
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Abstract

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

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AdultAgedFemaleHumansMaleMiddle AgedYoung AdultAntineoplastic Combined Chemotherapy ProtocolsCladribineCytarabineGranulocyte Colony-Stimulating FactorLeukemia, Myeloid, AcuteMitoxantronePrognosisSurvival RateDaunorubicinJournal ArticleClinical Trial, Phase IIRandomized Controlled Trial

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Anna B Halpern, Megan Othus, Mary-Elizabeth M Percival, Cristina Ghiuzeli, Jacob S Appelbaum, Paul C Hendrie, Ryan D Cassaday, Max Smith, Kathryn Russell, Bart L Scott, Jason P Cooper, Joshua R Veatch, Siobán B Keel, Vivian G Oehler, Erik L Kimble, Raya Mawad, Roland B Walter. 2026-07-13. Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.. https://doi.org/10.1038/s41375-026-03044-8

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