Higher CPX-351 Induction Doses Lead to Delayed Hematologic Recovery in AML

Verena I. Gaidzik, MD

Treatment with higher doses of CPX-351 (Vyxeos) in younger patients with newly diagnosed high-risk or secondary acute myeloid leukemia (AML) was significantly associated with prolonged hematologic recovery times during induction cycles 1 and 2, according to findings from an interim safety analysis of the phase 3 AMLSG 30-18 study (NCT03897127) presented during the 2020 American Society of Hematology (ASH) Annual Meeting.¹

CPX-351, a liposomal formulation of daunorubicin and cytarabine in the fixed molar ratio (1:5), demonstrates selective uptake by leukemic cells compared with normal cells with increased concentration in the bone marrow. A prior pivotal phase 3 trial established the efficacy of this therapy as treatment of patients with newly diagnosed high-risk or secondary AML aged 60 to 75 years who are eligible for intensive therapy as compared with standard 7+3 induction chemotherapy. The open-label, parallel-arm, standard therapy–controlled study randomized patients, who had a median age of 68 years, 1:1 to receive either CPX-351 (n = 153) or 7+3 (n = 156).²

The study led to the approval of CPX-351 by both the FDA and the European Medicines Agency (EMA) for the treatment of adult patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC).

In this study, the overall remission rate was significantly higher with CPX-351 compared with 7+3 (P = .016), and the median overall survival was significantly improved with CPX-351 (P = .003).

The AMLSG 30-18 clinical trial explored the potential benefit of CPX-351 in a broader population of patients, enrolling patients over the age of 18 with newly diagnosed AML with intermediate or adverse genetics. To be included in this analysis of CPX-351, patients had to be eligible for intensive therapy.¹

In each arm, patients received 2 induction cycles consisting of 7+3 chemotherapy in the control arm for the first cycle followed by daunorubicin and intermediate-dose cytarabine for the second cycle and thereafter up to 3 consolidation cycles of intermediate-dose cytarabine alone. CPX-351 was administered on days 1, 3, and 5 of the first induction cycle and only on days 1 and 3 of subsequent cycles. Induction treatment with CPX-351 was administered at 44 mg/m2 of daunorubicin and 100 mg/m2 of cytarabine (100 U/m2) and at 29/65 mg/m2 (65 U/m2). Patients could be assigned to allogeneic hematopoietic cell transplantation after at least 1 induction cycle of therapy.

For the interim safety analysis presented at ASH by lead investigator Verena I. Gaidzik, MD, 66 patients had been enrolled as of November 6, 2020, and the median age was 60.5 years (range, 26-76). Overall, 52 patients had de novo AML, and 14 had secondary or therapy-associated AML. In terms of genetic risk, 26 patients each had intermediate and advanced risk, while genetic risk was not available in 14 patients.

Following 2 induction therapy cycles, 35 patients achieved a complete remission (CR) or CR with incomplete hematologic recovery (CRi). Sixteen patients had a CR, and 19 had a CRi. Three patients had refractory disease. According to an assessment of minimal residual disease (MRD) using leukemia-associated immunophenotypes, the majority of patients became MRD negative following treatment.

A continuous safety assessment explored 2 end points of 60-day mortality rate and hematologic recovery time. The 60-day mortality rate had a maximally tolerated rate (MTR) of 15%. The MTR was 25% for hematologic recovery times following adverse events of grade 4 neutropenia and grade 3/4 thrombocytopenia.

Thirty-six patients were included in the safety analysis as of July 20, 2020, including 19 who were allocated to the experimental arm and 17 to the control arm, and among patients who received CPX-351, 9 patients were aged 18 to 60 years and received a higher dose of CPX-351, and the standard dose was given for 10 patients. In the control arm, 9 patients were 60 years or younger while 8 were over the age of 60. The younger patients received a dose of 55 mg/m2 of daunorubicin and 125 mg/m2 of cytarabine (125 U/m2).

The 60-day mortality rate in both treatment arms was 0%. Serious adverse events (SAEs) occurred in 18 patients, and the most common SAE was fever in neutropenia/infections, occurring in 10 patients. Other SAEs observed, which occurred in 1 patient each, included non-cardiac chest pain, heart failure, dyspnea, gastrointestinal disorder, renal disorder, malignant neoplasms, and transfusion-related reaction.

"Overall, the median time to neutrophil recovery, [which] was absolute neutrophil count above 0.5 G/I, was longer in the CPX-351 arm compared to the 7+3 arm at 39 versus 28 days after induction [cycle] 1 and 26.5 versus 19 days after induction 2,” said Gaidzik, a senior physician in the Department of Internal Medicine at the University Hospital of Ulm in Ulm, Germany. “Time to platelet recovery above 50 G/I was significantly prolonged in the CXP-351 arm after induction [cycle] 1 at 40 versus 26 days. When comparing the higher dose to the standard dose of CPX-351, the median time to neutrophil recovery after induction [cycle] 1 was significantly longer with a higher dose [P = .002].”

The platelet recovery time was also significantly delayed after induction 1 with the higher dose of CPX-351 compared with the standard dose (P = .03). Among younger patients treated with the higher dose of the investigational therapy, the lower limit of the 95% confidence interval exceeded the MTR of 25% for thrombocytopenia but not for neutropenia.

In the investigational arm, 4 patients experienced grade 4 neutropenia for >42 days with the higher dose (95% CI, 0.31-0.86). Five patients who received the higher CPX-351 dose (95% CI, 0.31-0.86), 1 patient who received the standard dose (95% CI, 0.01-0.51), and 1 patient from both the younger (95% CI, 0.01-0.47) and older groups (95% CI, 0.01-0.56) in the control arm experienced grade 3/4 thrombocytopenia lasting >42 days.

Overall, no treatment-related deaths occurred in this study.

Based on these findings, the current package insert was amended with a CPX-351 dose reduction for induction treatment in patients who are 18 to 60 years of age to 44 mg/m2 of daunorubicin and 100 mg/m2 of cytarabine (100 U/m2).

_References

_{1. Gaidzik VI, Mayr-Benedikter V, Weber D, et al. Higher Dose of CPX-351 Is Associated with Prolonged Hematologic Recovery: Results from an Interim Safety Analysis of the Randomized, Phase III AMLSG 30-18 Trial. Presented at: 2020 ASH Annual Meeting; December 5-8, 2020; Virtual. Abstract 1043.}

_{2. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 (cytarabine and daunorubicin) Liposome for Injection Versus Conventional Cytarabine Plus Daunorubicin in Older Patients With Newly Diagnosed Secondary Acute Myeloid Leukemia. J Clin Oncol. 2018;36(26):2684-2692. doi:10.1200/JCO.2017.77.6112}