Real-world experience of CPX-351 as first-line treatment for patients with acute myeloid leukemia

Abstract

To investigate the efficacy and toxicities of CPX-351 outside a clinical trial, we analyzed 188 patients (median age 65 years, range 26-80) treated for therapy-related acute myeloid leukemia (t-AML, 29%) or AML with myelodysplasia-related changes (AML-MRC, 70%). Eighty-six percent received one, 14% two induction cycles, and 10% received consolidation (representing 22% of patients with CR/CRi) with CPX-351. Following induction, CR/CRi rate was 47% including 64% of patients with available information achieving measurable residual disease (MRD) negativity (<10^-3) as measured by flow cytometry. After a median follow-up of 9.3 months, median overall survival (OS) was 21 months and 1-year OS rate 64%. In multivariate analysis, complex karyotype predicted lower response (p = 0.0001), while pretreatment with hypomethylating agents (p = 0.02) and adverse European LeukemiaNet 2017 genetic risk (p < 0.0001) were associated with lower OS. Allogeneic hematopoietic cell transplantation (allo-HCT) was performed in 116 patients (62%) resulting in promising outcome (median survival not reached, 1-year OS 73%), especially in MRD-negative patients (p = 0.048). With 69% of patients developing grade III/IV non-hematologic toxicity following induction and a day 30-mortality of 8% the safety profile was consistent with previous findings. These real-world data confirm CPX-351 as efficient treatment for these high-risk AML patients facilitating allo-HCT in many patients with promising outcome after transplantation.

Fig. 1. Flow chart depicting treatment, response, and outcome of the study population.

Allo-HSCT allogeneic hematopoietic stem cell transplantation, BM bone marrow, CR complete remission, CRi complete remission with incomplete hematologic recovery, CTX chemotherapy, DRM disease-related mortality, d day, fav favorable, FU follow-up, HD-AraC high-dose cytarabine, ID-AraC intermediate dose cytarabin, MLFS morphologic leukemia-free state, NRM non-relapse mortality, pat patient, PD progressive disease, PS performance status, rel related, SD stable disease, Tx transplant.

Fig. 2. Overall (OS) of the entire cohort.

After a median follow-up of 9.3 months (range: 0.2–26.1 months) median OS of the entire cohort (n = 188) was 21 months and estimated 2-year OS was 35%. OS for the entire cohort was calculated as the time from the first day of treatment with CPX-351 to death from any cause or last follow-up in survivors.

Fig. 3. Overall (OS), relapse-free survival (RFS), cumulative incidences of relapse (CIR), and non-relapse mortality (NRM) of the transplant cohort.

With a median FU of 7.6 months (range: 0.1–24.1 months) estimated 2-year OS, RFS, CIR, and NRM probabilities of the entire cohort were 73%, 71%, 23%, and 12%, respectively. OS was estimated as time between allo-HSCT and death or date of last follow-up in surviving patients, while RFS was calculated as time from allo-HSCT until relapse or death without relapse censoring those patients, who had not relapsed until and were alive at date of last follow-up. CIR and NRM were considered as competing risks and calculated using cumulative incidence (CI) estimates employing Gray test for univariate comparisons.

Fig. 4. Posttransplant outcome of patients depending on pre-transplant MRD status assessed by flow cytometry (FC).

Among patients with CR/CRi (n = 85) after CPX-351-based induction data on MRD estimated by FC were available for 36 patients (42%) representing MRD negativity in 64% of the patients (n = 23). The figure represents outcome in terms of overall and relapse-free survival for patients with pre-transplant CR_MRD− (n = 23, green line) and CR_MRD+ (n = 13, orange line).