Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML

Abstract

Background CPX-351 (United States: Vyxeos®; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality‐adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up. Methods Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses. Results The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology. Conclusions This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 (https://clinicaltrials.gov/ct2/show/NCT01696084) and is complete.

Pathogenesis and treatment of multiple myeloma

“…230 The results of clinical trials demonstrated clinical benefits and confirmed CPX-351 as a standard intensive therapy for high-risk or secondary acute myeloid leukemia in older patients. 231 Although nanomedicine has shown inspiring efficacy in preclinical studies, many limitations and difficulties remain in the path of clinical translation. The limited gain in OS has not satisfied clinicians and patients.…”

CPX-351: An Old Scheme with a New Formulation in the Treatment of High-Risk AML

“…In summary, CPX-351 requires optimal management and prophylaxis to mitigate the risk of infections probably related to the more prolonged neutropenia. Mucositis and alopecia are reduced, and this translates to improved quality of life for patients [ 42 ]. One fifth of patients presents skin toxicity that is self-resolving; however, severe cases have been reported [ 43 ].…”

“…Several studies indicated that the treatment with CPX-351 has the ability to produce quality-of-life benefits compared to conventional chemotherapy [ 42 , 44 , 45 , 46 ].…”

“…Cortes et al provided a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) exploratory analysis of the phase pivotal 3 trial with the aim to compare survival quality of life between patients receiving CPX-351 vs. conventional “3+7” after 5 years of follow-up [ 42 ]. After disease progression or relapse, the Q-TWiST is a weighted parameter that determines how much of a patient’s survival time is spent with toxicities or is “useful” time [ 47 ].…”

“…In this analysis, the relative Q-TWiST gain with CPX-351 versus “3+7” was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology [ 42 ].…”