The evidence supporting this protocol is provided by a phase III multi-centre randomised trial involving 309 patients (between December 2012 and November 2014), comparing liposomal daunorubicin and cytarabine (CPX-351) with conventional cytarabine plus daunorubicin (7-3 regimen) in older patients (aged 60-75 years) with newly diagnosed high-risk/secondary acute myeloid leukaemia (AML) (per the WHO 2008 criteria).rr
153 patients were randomised to receive CPX-351 (1-2 induction cycles and up to 2 consolidation cycles). Induction cycle consisted of liposomal daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 administered as a 90-minute infusion on days 1, 3 and 5. A second induction cycle (same dose) was administered on days 1 and 3 for patients who did not achieve hypoplastic marrow on a day 14 bone marrow assessment. If in complete remission (CR) or complete remission with incomplete neutrophil or platelet recovery (CRi), consolidation therapy was given, which consisted of up to 2 cycles of CPX-351 (liposomal daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) on days 1 and 3.r
156 patients were randomised to receive 7-3 induction with cytarabine 100 mg/m2/day administered by 7-day continuous infusion and daunorubicin 60 mg/m2 on days 1-3; second induction cycle and post-remission consolidation consisted of cytarabine 100 mg/m2/day by 5-day continuous infusion and daunorubicin 60 mg/m2 on days 1 and 2. Allogeneic stem cell transplant was performed at the discretion of the treating physician.r
The primary endpoint was overall survival (OS), and secondary endpoints were remission rates (CR, CR+CRi), remission duration, and event-free survival (EFS), which was measured as time since random assignment to the date of induction failure, relapse from CR+CRi, or death as a result of any cause.r
Efficacy
After a median follow-up of 20.7 months, the median OS was significantly longer in the CPX-351 cohort (9.56 months) compared to 7-3 (5.95 months; Hazard Ratio (HR)=0.69; Confidence Interval (CI) 0.52 to 0.90; p=0.003). In particular, improved OS with CPX-351 was seen in patients with therapy-related AML, FLT3 wild type and in AML with antecedent myelodysplastic syndrome (MDS) or chronic myelomonocytic leukaemia (CMML).r
Significantly higher remission rates (CR+CRi) were seen in the CPX-351 cohort compared to 7-3 (47.7% vs 33.3%; P=0.016). Median EFS was significantly longer in CPX-351 versus 7-3 (2.53 vs 1.31 months; HR 0.74; 95% CI, 0.58 to 0.96, p=0.021). There was no difference in the median remission duration between CPX-351 and 7-3 (6.93 vs 6.11 months, p=0.291).r
At 5 years, the OS benefit of CPX-351 was maintained (18% for CPX-351 and 8% for 7-3). Of the patients who achieved CR, OS at 5 years was 30% in the CPX-351 group and 19% in the 7-3 group.r
Figure 1. Median overall survival and event-free survivalr
© Journal of Clinical Oncology 2018
Figure 2. 3-year and 5-year Kaplan-Meier-estimated survival rates.r
© The Lancet Haematology, 2021
Toxicity
Overall, the type, severity and proportion of patients experiencing adverse events were comparable between CPX-351 and 7-3. The most frequently reported grade 3-5 adverse events were febrile neutropenia (68.0% CPX-351 vs 70.9% 7-3) and pneumonia (19.6% CPX-351 vs 14.6% 7-3).r
Three patients randomised to CPX-351 arm discontinued treatment (cardiac failure = 1, cardiomyopathy = 1, acute renal failure = 1) and two patients receiving 7-3 (decreased ejection fraction = 2).r
There was a longer time to neutrophil and platelet recovery (in patients who achieved CR+CRi after initial induction therapy) with CPX-351; 35.0 and 36.5 days, respectively, compared to 29.0 and 29.0 days with 7-3. Infection rates were similar across both arms (92.8% CPX-351 v 92.7% 7-3), but bleeding events were more common with CPX-351 than 7-3 (any grade: 74.5% vs 59.6%; grade 3-5: 11.8% vs 8.6%).r
Rates of grade 5 bleeding events were similar at 2.6% in both arms. 69.3% (n=106) of patients died in the CPX-351 arm and 84.5% (n=128) in the 7-3 cohort. Causes of death were similar.r
Figure 3. Most frequently reported adverse events.r
© Journal of Clinical Oncology 2018