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

Abstract

SummaryFailure 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.

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“…From a practical point of view, new prognostic systems incorporating molecular data have moved a significant proportion of patients into higher risk categories of disease. Furthermore, the innovations introduced by the new classifications [1,2], as well as the availability of novel target drugs and more tolerable and safe formulations of intensive chemotherapy, such as CPX-351 [113], are progressively shifting haematological clinical practice, including treating HR-MDS similarly to AML [2,117]. Therefore, progress in molecular genomic knowledge and therapeutic advances are determining a progressive cultural transformation of haematological clinical practice.…”

“…Interestingly, blast percentage was not predictive of outcomes [112]. Other than venetoclax-based treatments, other measures, such as newer formulations of intensive chemotherapy, e.g., CPX-351, may be considered a valid option in selected patients after HMA failure [113], as was reported by a recently published paper reporting an ORR of 56% and a median relapse-free and OS of 9.2 and 8.7 months in HMA-failed patients with HR-MDS and chronic myelomonocytic leukaemia, respectively [113]. The clinical outcomes in patients with MDS-biTP53 [46][47][48] are poor and marked by HR clinical features, such as complex karyotype, prior exposure to leukaemogenic antineoplastic agents, low ORR to HMAs [46], and short survival after allogeneic SCT due to elevated risks of relapse [46].…”