Preliminary Results from CPX-351 Italian Compassionate Use Program Show High Response Rate and Good Tolerability in Poor Prognosis AML Patients
Authors: Guolo Fabio , Minetto Paola , Fianchi Luana , Rondoni Michela , Daghia Giulia , D'Ardia Stefano , Morselli Monica , Pasciolla Crescenza , Pavesi Francesca , Scappini Barbara MD , Lanza Francesco , Gobbi Marco , Pagano Livio , Ferrara Felicetto , Lemoli Roberto Massimo 
Published: November 2019

Background: Therapy-related acute myeloid leukemia (t-AML) or AML evolving from a myelodisplastic syndrome are characterized by a low response rate to conventional chemotherapy and high relapse rate with poor overall survival (OS) despite intensive treatment and allogeneic stem cell transplantation consolidation (HSCT).
CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin, in a fixed synergistic 1:5 molar ratio. CPX-351 has been approved by FDA for the treatment of patients affected by t-AML or AML with myelodisplasia-related changes (MRC-AML) based on the results of a randomized phase III trial where the drug was compared with conventional 3+7 induction (Lancet et al, JCO 2018). Notably, CPX-351 proved to increase survival probabilities in comparison with standard chemotherapy even among patient achieving complete remission (CR) and proceeding to HSCT, suggesting that CPX-351 may allow deeper responses. However, few information is available on minimal residual disease (MRD) assessment after CPX-351 treatment, or on the impact of molecular alterations on response probability.
Aims: The aim of this study was to evaluate the clinical activity of CPX-351 in a real life setting, with particular focus on molecular characterization at diagnosis and MRD evaluation in responding patients.
Methods: Seventy five patients were enrolled in a compassionate use program (CUP) in 37 Italian Hematology Centers. CUP started on December 2018 and closed on June 2019. Data collection began on July 2019 and was completed, at the time of writing, for 25/75 patients, enrolled in 9 Centers.
Median age was 69 years (56-73), 10 patients were female. Molecular and MRD analysis were performed in each Center as per internal standard. MRD was assessed in most Centers with multicolor flow cytometry. NPM1 mutation was found in 2/22 assessed patients, FLT3-ITD in 3/22, with low allelic burden in 2/3 patients. TP53 mutations have been found in 4/12 patients.Four patients had complex Karyotype, one had isolated del(7q) whereas the remaining 19 had normal karyotype. Six patients had t-AML; 15 patients were previously diagnosed with MDS and 5 of them had already received hypomethilating agents for a median of 5 cycles (2-49). European Leukemia net risk score was low in 2 (8%), intermediate in 12 (48%) and high in 11 (44%) patients. Most patients (20/25) had relevant comorbidities upon enrollment, mostly COPD, diabetes and/or hypertension. As per CUP inclusion criteria, all patients had normal left ventricular function at the time of enrollment (defined by a normal ejection fraction).
Results: Induction-related mortality was 2/25 (8%). Fourteen patients experienced grade &gt;1 extra hematological adverse event during induction (mainly infections). Alopecia was observed in 4/25 patients (16%).Response was assessed in 20 patients:2 patients died during induction and 3 patients were not yet evaluated for response at the time of analysis. CR or CRi was observed in 19/22 (86.3%). MRD was performed in 11 patients, with 4 of them achieving flow MRD negativity after first cycle (defined as &lt;0.1%, Minetto et al. BJH 2019). Median time to neutrophil and platelets recovery in responding patients were 29 (18-60) and 24.5 (19-60) days, respectively. Among responding patients, 10 received further CPX-351 consolidation, which was very well tolerated. One patient proceeded directly to HSCT, one is currently waiting for HSCT to be performed and one patient received a conventional chemotherapy consolidation. The remaining patients are currently waiting for administration of consolidation therapy with CPX-351. Four patient had completed so far all planned consolidation therapy with CPX-351 and 2/4 of them were flow MRD negative at the end of therapy. Of note, 3/4 patients with mutated TP53 achieved MRD negative CR. After a median follow-up of 5 months, relapse was observed in 2/20 responding patients and 21 patients are alive at the time of analysis.
Conclusions: Our preliminary data confirm the high clinical activity and good tolerability of CPX-351 in a challenging AML cohort. The high median age and the high incidence of severe comorbidities did not result in unacceptable risk of death during induction. With the limitation of very small numbers, CPX-351 showed good antileukemic activity among TP53 mutated patients.

Disclosures
No relevant conflicts of interest to declare.