Randomized Study of CPX-351 for Medically Less-Fit Adults with Newly Diagnosed Acute Myeloid Leukemia or Other High-Grade Myeloid Neoplasm

Background: Medically less-fit adults with AML are typically, but not invariably, older and thus best identified by examining several variable rather than age alone. Here we used a multi-component model (treatment-related mortality [TRM] score; J Clin Oncol 2011;29:4417) to select less-fit adults with newly diagnosed AML or MDS/MPN with ≥10% blasts in blood or bone marrow to receive attenuated doses of CPX-351 (32 or 64 units/m² per dose vs. the usual 101 units/m² per dose), a liposomal formulation of daunorubicin and cytarabine associated with longer survival in secondary AML. A wide therapeutic window seen in earlier trials suggested CPX-351 might retain efficacy at reduced doses. Our primary goal was to estimate whether any of the 2 CPX-351 doses were likely to improve TRM rates while keeping the complete remission (CR) rate comparable to historic controls.

Methods: Patients aged ≥18 years were eligible if they had a TRM score of ≥13.1, corresponding to a >13% expected rate of death within 28 days of beginning intensive induction chemotherapy. Patients were randomly assigned 1:1 to receive CPX-351 at either 32 or 64 units/m² per dose on days 1, 3, and 5 for up to 4 identical induction/re-induction courses. Patients achieving either CR or CR with incomplete platelet count recovery (CRp) could receive up to 4 courses of post-remission treatment with CPX-351 using the same dose on days 1 and 3 only. A Bayesian design was used to monitor both response (CR) and toxicity (TRM), with early stopping if, after entry of each cohort of 5 patients, the posterior probability was <0.10 that the true TRM rate was <15% (vs. the historical = 31%) or if the posterior probability was >0.90 that the true CR rate with CPX-351 was <30% (historical = 30%). If early stopping did not occur 45 patients were to be entered in each arm. Thus, parameterized there was a 94% probability of early termination (PET) if TRM and CR rates were truly the same as historical, a 52% PET if true TRM and CR rates were 15% and 30%, respectively, but an 88% PET if true TRM and CR rates were 10% and 40%, respectively. ClinicalTrials.gov: NCT01804101.

Results: 48 patients, median age 70.5 (range: 39.1-91.1) years, with a median TRM score of 25.7 (range: 13.2-90.0) and a median ECOG performance status of 2 (range: 1-4), were enrolled. Cytogenetic risk was favorable in 3, intermediate in 20, and adverse in 23, and unknown in 2; eighteen patients had a monosomal karyotype. 29 patients had secondary disease. Patients received a median of 2 (range, 1-6) cycles of induction therapy. The first 20 patients were randomized between the 2 CPX-351 doses. Among the 10 patients randomized to 64 unit/m², 1 CR and 1CRi were obtained. Median survival of these 10 patients was 6 months, with 20% 12-month survival. Four deaths (40%) by day 28 occurred, which were all infection-related in patients presenting with TRM scores of 14.7, 24.1, 33.4, and 58.1. Because of these 4 early deaths, accrual to the 64 units/m² arm stopped, and the remaining 28 patients were assigned to CPX-351 at 32 units/m² per dose. Among 38 patients given 32 units/m², there were 10 CRs (26%; 8 without measurable/"minimal" residual disease [MRD]), 1 CRi, 21 with resistant disease, and 6 deaths from indeterminate cause. Among the 6 patients who achieved an MRD-negative CR with the first cycle of therapy, median time to platelet count of 100,000/µL and ANC of 1,000/µL was 24.5 and 29.5 days. Eleven patients (29%) died before day 28, with 3 of these due to early disease progression and no evidence of drug toxicity. Disease progression was a major contributor to the early deaths of 2 additional patients. Median survival of these 38 patients was 3 months, with 17% 12-month survival. Among the 11 responders, relapse-free survival was 7 months.

Conclusion: Within the constraints of historical controls and the design which afforded more protection against a false-positive than a false-negative result, our data suggest that CPX-351 at either 32 or 64 units/m² is relatively unlikely to decrease TRM to 15% (from ~30% historically) while maintaining CR rate of 30% in patients at high risk of TRM. This study illustrates the challenge of balancing therapeutic resistance and disease/treatment-related complications in this challenging patient subset. Our findings suggest that further adjustments in eligibility and CPX-351 dosing to maximize efficacy and reduce early leukemia-related deaths are needed.