Phase 1/2 study of CPX-351 for patients with Int-2 or high risk International Prognostic Scoring System myelodysplastic syndromes and chronic myelomonocytic leukaemia after failure to hypomethylating agents.

Failure after hypomethylating agents (HMAs) is associated with dismal outcomes in higher risk myelodysplastic syndromes (HR-MDS) or chronic myelomonocytic leukaemia (CMML). We aimed to evaluate the safety and preliminary activity of lower doses of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, in a single-centre, phase 1/2 study for patients with HR-MDS or CMML after HMA failure. Four doses of CPX-351 (10, 25, 50 and 75 units/m2 ) administered on Days 1, 3 and 5 of induction and Days 1 and 3 of consolidation were evaluated. Between June 2019 and June 2023, 25 patients were enrolled (phase 1: n = 15; phase 2: n = 10) including 19 (76%) with HR-MDS and 6 (24%) with CMML. Most common grade 3-4 non-haematological treatment-emergent adverse events were febrile neutropenia (n = 12, 48%) and lung infection (n = 5, 20%). Three patients (age >75) experienced cardiac toxicity at the 75 units/m2 dose. Further enrolment continued at 50 units/m2 . Four- and 8-week mortality were 0% and 8% respectively. The overall response rate was 56% with median relapse-free and overall survivals of 9.2 (95% CI 3.2-15.1 months) and 8.7 months (95% CI 1.8-15.6 months) respectively. These data suggest that lower doses of CPX-351 are safe. Further studies are needed to evaluate its activity.

Low-Dose Decitabine versus Low-Dose Azacitidine in Lower-Risk MDS.

BACKGROUND: The hypomethylating agents are part of the standard of care in the treatment of myelodysplastic syndromes (MDS), but their role in patients with lower-risk disease is unclear. METHODS: We randomly assigned patients with previously untreated MDS with low/intermediate-1 risk by the International Prognostic Scoring System with a Bayesian response-adaptive design to receive either 20 mg/m2 decitabine daily or 75 mg/m2 azacitidine daily on days 1 to 3 every 28-day cycle. RESULTS: A total of 113 patients were treated: 73 (65%) with decitabine and 40 (35%) with azacitidine. The overall response rate was 67% and 48% in the decitabine and azacitidine groups, respectively (P=0.042); among 59 patients with baseline transfusion dependency, 19 (32%) reached transfusion independence (decitabine, 16 of 39 [41%]; azacitidine, 3 of 20 [15%]; P=0.039). Of the 19 patients who reached transfusion independence, the median duration of transfusion independency was 22 months. Among 54 patients who were transfusion independent at baseline, 5 patients (9%) became transfusion dependent after therapy. No early death was observed. With a median follow-up of 68 months, the median overall event-free survival and overall survival were 17 months and 33 months, respectively. CONCLUSIONS: Attenuated dose treatment of hypomethylating agents in patients with lower-risk MDS can improve outcomes without dose-limiting side effects in a high-risk cohort as defined by the Lower-Risk Prognostic Scoring System. (Funded in part by The University of Texas MD Anderson Cancer Center and others; ClinicalTrials.gov number, NCT01720225.)