CPX-351 Induces Deep Response and Suppress the Impact of Poor Prognosis Mutations (TP53, ASXL1, RUNX1 and EVI1) Defined By ELN-2017 in t-AML and MRC AML: A Report from a Multicentric French Cohort
Authors: Chiche Edmond , Bertoli Sarah , Rahmé Ramy , Micol Jean Baptiste , Pasquier Florence , Peterlin Pierre , Chevallier Patrice , Thomas Xavier , Loschi Michael , Genthon Alexis , Legrand Olivier , Mohty Mohamad , Raffoux Emmanuel , Auberger Patrick , Caulier Alexis , Joris Magalie , Bonmati Caroline , Roth Guepin Gabrielle , Sauvezie Mathieu , Lejeune Caroline , Pigneux Arnaud , Recher Christian , Ades Lionel , Cluzeau Thomas 
Published: November 2019

Introduction

CPX-351 is a liposomal formulation of cytarabine and daunorubicin packaged at a 5:1 molar ratio. This drug has recently been approved by FDA and EMEA for patients with therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (MRC-AML).

The primary objective of this study was to analyze the efficacy of CPX-351 in a real-life setting, evaluating the impact of mutations on response and minimal residual disease (MRD) in responding patients.

Methods

We retrospectively collected data from patients treated by CPX-351 in eleven centers in France. Clinical, biological and treatment information were available for all patients. NGS (19 genes or more) was performed in 67 patients (84%) at diagnosis.

Overall response rate (ORR) was defined by complete remission (CR) and CR with incomplete haematological recovery (CRi). Among the patients in CR or CRi, 25 (56%) had MRD evaluation assessed by NGS or flow cytometry. Overall survival (OS) was calculated from the date of AML diagnosis to the date of death or last follow-up. All statistical analyses were performed using SPSS v.22 software (IBM SPSS Statistics).

Results

Between April 2018 and July 2019, 80 patients treated with CPX-351 were included in this study. Sex ratio M/F was 43/37 and median age was 66 years old (range 20-83). AML subtypes were MRC-AML (61%) including AML with prior myelodysplastic syndrome (MDS-AML) (33%), prior chronic myelomonocytic leukemia (CMML-AML) (7%), or t-AML (29%). Sixteen patients (20%) had received prior treatment by hypomethylating agents (HMA), at the time of MDS diagnosis, before AML evolution. According to ELN 2017 classification, genetic risk was favorable, intermediate and adverse in 1 (1%), 31 (38%) and 47 (58%), respectively. 36% and 28% patients had complex and monosomal karyotypes, respectively. Assessed by NGS the most frequent mutated gene were : RUNX1 (n=17, 25%), TP53 (n=15, 22%), ASXL1 (n=14, 21%), TET2 (n=13, 19%), DNMT3A (n=11, 16%), srsf2 (n=9, 13%), FLT3-ITD (n=8, 12%), CBL (n=7, 10%), WT1 (n=7, 10%), and EZH2 (n=7, 10%). According to a genetic ontogeny-based classifier (Lindsley et al., Blood 2015), 23 patients (34%), 29 (43%), 15 (22%) had de novo/pan-AML, secondary type mutations AML, and TP53 mutated AML, respectively.

Only 4 patients discontinuing treatment due to prolonged haematological toxicity. Early death rate was 5% and 8.75% through day 30 and day 60, respectively.

Median time to neutrophil recovery (&gt;0,5 G/L) and platelet recovery (&gt;20G/L) after induction was 29 days (range 19-78) and 28 days (range 12-77), respectively. Seventy-five patients (95%) had at least one grade 3 or more AEs, including 69 (86%) febrile neutropenia. We observed gastrointestinal toxicity 32 patients (40%) (nausea/vomiting (30%/11%), mucositis (15%)) including 4% with grade 3 or more and alopecia in only 12%.

ORR was 45/80 (56%) after induction 1 including 53% CR and 3% CRi. ORR increased to 58% after induction 2. Among the 45 CR/CRi patients, 25 were evaluable for MRD at the time of the 1st consolidation. 72% had MRD below 10-3 (64% below 10-4). Prior treatment by HMA and presence of monosomal karyotype were identified as factors predicting a lower rate of CR/CRi (P=0.001 and P=0.002, respectively). Lindsley's classifier predicted significantly a better chemosensitivity in de novo/pan-AML mutations (P= 0.037). Poor molecular prognosis subgroups defined by 2017 ELN risk stratification (n = 53) as TP53, ASXL1, RUNX1 and EVI1 mutations were not associated with a lower response rate with CPX-351 (Table 1).

Twenty-one (26%) patients underwent an allogeneic haematopoietic stem cell transplant (HSCT) with an improved median OS compared to non-transplanted patients (non reached vs 8 months, P= 0.004). With a median follow up of 8.5 months, median OS was not reached. Survival analysis in subgroups will be available for the ASH meeting.

Conclusion

These data confirmed the efficacy and safety of CPX-351 in poor risk AML (t-AML and MRC-AML). The high rate of CR with low MRD compares favorably with previous report using 7+3 in elderly unfavorable AML (Sylvie D. Freeman et al., JCO 2013) and may explain the favorable outcome observed in patients after HSCT. Moreover, CPX-351 erases the poor prognosis associated with unfavorable mutations defined in 2017 ELN risk stratification. Lindsley's classifier was the best prognostic scoring system in patients treated by CPX-351.

Disclosures

Bertoli: Daiichi Sankyo: Consultancy; Astellas: Consultancy, Honoraria; Sanofi: Honoraria; Jazz Pharmaceuticals: Honoraria. Peterlin:Jazz Pharma: Consultancy; AbbVie Inc: Consultancy; Astellas: Consultancy; Daiichi-Sankyo: Consultancy. Chevallier:Incyte: Consultancy, Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria. Thomas:INCYTE: Honoraria; DAICHI: Honoraria; PFIZER: Honoraria; ABBVIE: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding. Pigneux:Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Astellas: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Recher:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ades:Amgen: Research Funding; Helsinn Healthcare: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees. Cluzeau:Abbvie: Consultancy; Jazz Pharma: Consultancy; Menarini: Consultancy.