Late Hematologic Recovery after CPX-351 Induction Chemotherapy in AML: Predictive Disease and Patient’s Factors and Their Impact on Survival

In a randomized Phase III trial, CPX-351has shown to be more effective than conventional 3+7 chemotherapy as frontline treatment for secondary or therapy-related AML. However, longer time for haematologic recovery (HR) after induction cycle (IC) was observed among CPX-351 treated patients. Later real-world evidences confirmed this observation, noting in addition that the time to HR was quite variable among different patients, as some patients showed quick recovery whereas others showed very delayed HR. However, despite the high clinical relevance, no specific factors related to a longer time to HR have been identified in CPX-351 treated patients so far.The aim of this study was to identify patients-related factors related to delayed HR and the outcome of patients showing a late HR. Data from 130patientswith newly diagnosed AML who received 1 or 2 cycles of CPX-351 were retrospectively collected. All patients received the EMA–approved dosing and schedule of CPX-351. Median age was 66 years (32-78). MDS-related cytogenetic abnormalities(CA) were found in 68 patients (52%), whereas MDS-related genetic abnormalities in absence of CA were found in 30 patients (23%). 32 patients had t-AML (24%) and 61 (47%) had a previous diagnosis of MDS. The CR+CRi rate after induction cycle was 67%. 89/130 pts received a second course of CPX-351 after IC, with CR+CRi rate of 71% after the second induction course. Among 92 pts who achieved CR/Cri, 88 were evaluable for flow cytometry-based MRD and among them 62 (71%) had reached negativity. Forty-two patients underwent allogeneic stem cell transplantation (ASCT) in first CR (32%, 46% of responding patients), with a median time to transplant of 213 days (range 52-638). Nine more patients received ASCT in second CR. After a median follow-up of 23 months (IC 95% 14.4 – 36.7), the median OS was 21 months (95% CI 17.5-25.7). In responding patients, median time to neutrophils (PMN) >0.5×109/L and platelet (PLT)>20×109/L recovery was 32 (14-54) and 31 (10-94) days, respectively. Seven patients never achieved PMN or PLT recovery even if in CRi. A total of 23 patients (18%) showed a late HR, defined as a time to PMN >500 recovery > 35 days and/or PLT>20.000 > 40 days).

Only a low bone marrow cellularity at diagnosis correlated with late HR (p<0.05), whereas no correlation between late HR and baseline patient’s characteristics (sex, age), disease characteristics at diagnosis (cytogenetic risk, AML subtypes, diagnostic qualifiers, molecular profiles) or adverse events (bleeding, FUO, sepsis) was disclosed. Most patients with late HR showed no CA (68%), 26% of patients showed int risk CA, and only two patients (9%) had high risk CA. Interestingly, patients with late HR showed very high MRD negativity rate (19/22, 86%) and, while time to allo-HSCT was significantly longer, OS was not different from what observed in patients achieving CR without late HR.

In conclusions, CPX-treated patients who show a late HR are likely to be affected by AML progressing form MDS with low cellularity, having less adverse cytogenetic risk (hypoplastic/aplastic MDS). Those patients, despite the long time to HR, usually show a good response to CPX and an outcome superimposable with responding patients with normal time to HR time.