Randomized Study of Liposomal Cytarabine and Daunorubicin (CPX-351) for Adults with Untreated High-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) at High Risk of Treatment-Related Mortality
Authors: Walter Roland B. , Orlowski Kaysey F. , Powell Morgan A. , Becker Pamela S. , Hendrie Paul C. , Ostronoff Fabiana , Ranker Elizabeth M. , Othus Megan , Louie Arthur C. , Estey Elihu H. 
Published: October 2019

Abstract
Background: Because of the concern for therapeutic resistance and excessive toxicity or even treatment-related mortality (TRM), many medically unfit patients do not receive AML-directed therapy, although evidence suggests that outcomes are improved if essentially all of these patients are offered some form of chemotherapy rather than given supportive care only. Here, we evaluated the potential value of attenuated doses of CPX-351, a liposomal formulation of daunorubicin and cytarabine, in medically unfit patients with newly diagnosed AML or high-risk MDS (≥10% blasts). In earlier trials, CPX-351 appeared to afford superior outcomes in high-risk AML patients with a wide therapeutic window suggesting that reduced dose treatment may be helpful in this population.
Methods: Patients aged ≥18 years with untreated AML or high-risk MDS were eligible if they had a TRM score of ≥13.1, corresponding to an expected TRM (i.e. death within 28 days of treatment initiation) of 31% with standard induction chemotherapy. Bilirubin was to be <2.0 mg/ml because of hepatic excretion of CPX-351, and active infection was an exclusion criterion. Patients were randomly assigned 1:1 to receive CPX-351 at either 32 or 64 units/m2 per dose (previous phase 1 investigations established a maximum tolerated dose of 101 units/m2 per dose) on days 1, 3, and 5 for up to 4 identical induction/re-induction courses. Patients achieving either complete remission (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. The primary goal of the study was to estimate whether either the 32 or 64 units/m2 doses were likely to improve TRM rates while keeping the CR rate comparable to historic controls. Specifically, a Bayesian design was used to monitor both response (CR) and toxicity (TRM), with early stopping if 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%).
Results: 23 patients, median age 71.1 (range: 53.1-91.1) years, with a median TRM score of 25.7 (range: 13.7-90.0) and a median ECOG performance status of 2 (range: 1-3), were enrolled. Cytogenetic risk was favorable in 1, intermediate in 8, and adverse in 14 (including 3 with insufficient culture growth for analysis), with 9 patients having a monosomal karyotype. 13 patients had secondary disease. Overall, study patients received a median of 1 (range, 1-3) cycles of induction therapy. Among the first 9 patients randomized to 64 unit/m2, 1 CR, 1CRp, and 3 deaths by day 28 occurred. The deaths were due to overwhelming infection in patients presenting with TRM scores of 14.5, 44.4, and 57.9. Because of these 3 deaths, accrual to the 64 units/m2 arm stopped. The 9 patients given 64 units/m2 might have, by chance, been more unfavorable than the large number of historical pts. (n =2,238) used to derive the TRM score. We addressed this possibility by summing the TRM scores in these 9 patients, thus calculating the number of expected deaths by day 28 had these patients received historical treatments, principally 3+7 or higher doses of cytarabine. The number of expected deaths was 3.0, the same as the number observed. Because it met neither the early stopping bound for TRM or lack of CR, the 32 units/m2arm has continued accrual. 14 patients have been enrolled (including 3 who were enrolled without randomization after the higher-dose arm closed). 2 CRs (14.3%) were observed, and 4 patients died early; deaths were related to overwhelming infection in 1 (TRM score of 23.7), and early disease progression in 3 (TRM scores of 23.7, 33.3, and 90.0).
Conclusion: This study illustrates the challenge of balancing therapeutic resistance and disease/treatment-related complications in medically unfit adults with AML. Within the constraints of historical controls and an experience limited to 9 patients at the higher dose level, our data suggest that at 64 units/m2, CPX 351 is relatively unlikely to decrease TRM to 15% (from ~30% historically) and increase CR rate to 40% (from ~30% historically) in patients at high risk of TRM. These results present the first attempt at identifying and treating medically unfit patients with CPX-351 and suggest that further adjustments in eligibility and CPX-351 dosing to maximize efficacy and reduce early leukemia-related deaths are needed.

Disclosures
Off Label Use: CPX-351 currently has investigational drug status. Louie:Celator Pharmaceuticals, Inc: Employment.