CPX-351 in Patients with Newly Diagnosed Post Myeloproliferative Neoplasms Acute Myeloid Leukemia
Authors: Garciaz Sylvain , Belhabri Amine , Guieze Romain , Goursaud Laure , Peterlin Pierre , Ledoux Marie-Pierre , Mathilde Hunault-Berger , Chebrek Safia , Robin Jean-Baptiste , Pigneux Arnaud , Bonnet Sarah , Bonmati Caroline , Bertoli Sarah , Braun Thorsten , Chantepie Sylvain , Meunier Mathieu , Heiblig Mael , Cluzeau Thomas , Jourdan Eric , Villate Alban , Recher Christian , Vey Norbert , Rey Jerome 
Published: December 2023

Background
Progression of myeloproliferative neoplasms (MPNs) including polycythemia Vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) to acute myeloid leukemia (post MPN AML) is associated with a poor prognosis. Studies evaluating intensive chemotherapy showed response rates ranging between 40% and 50% and a median event-free survival (EFS) of 3-4 months. CPX-351 (Vyxeos) is a new formulation of cytarabine and daunorubicin encapsulated at a fixed 5:1 molar-ratio in liposomes that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy. Induction therapy with CPX-351 is associated with a 47.7% response rate and significantly improved overall survival (OS) when compared to standard ICT (“7+3”) in older patients with newly diagnosed secondary AML (sAML) (Lancet, JCO 2018). However, patients with post MPN AML were not eligible in that trial. We report here the preliminary results of a prospective trial evaluating the effects of CPX351 in this difficult-to-treat patient population.
Methods
We designed an open label multicenter phase II non-randomized study to evaluate CPX-351 in post MPN AML. Patients received one to two induction cycles with CPX-351 100 U/m2 on days 1, 3, and 5. Patients in CR/CRi after induction cycle(s) received up to 2 courses of consolidation therapy with CPX-351 65 U/m2 on days 1 and 3 (or on day 1 only in case of unacceptable toxicity). The primary objective was to evaluate the complete remission rate (including CR and CR with incomplete hematological recovery, CRi) after one or two induction cycles with CPX-351.
Results
In this interim analysis, we present the results for the first 29 patients (14 males and 15 females). The median age was 67 (50-78). Prior MPN before leukemic transformation was ET in 13 (44.8%), PV in 1 (3.4%), PMF in 9 (31%), post ET myelofibrosis in 4 (13.8%) and post PV myelofibrosis in 2 (6.9%) patients. Median hemoglobin, platelet count and white blood cell count were 8.7g/dL (6.2-14.7), 9G/L (7-771) and 6 G/L (1.5-77.3), respectively. BM involvement showed a median of 40% blasts (8-96%). Cytogenetics was favorable, intermediate, unfavorable, or missing in 1 (3.4%), 9 (31%), 17 (58.6%), 2 (6.9%) of cases. Twelve patients (41.3%) achieved a complete response (CR) or a complete response with incomplete hematologic recovery (CRi) after 1 or 2 induction cycles; two patients (6.9%) had a partial response, and 15 patients (51.7%) failed. Minimal residual disease analysis for responding patients is on-going. At the time of analysis, 5 patients transitioned to an allogenic stem cell transplantation. Time for neutrophil count recovery (&gt;0.5G/L) was 26 days (0-41) after the first induction cycle. Mean time for platelet recovery (&gt;50G/L) was 27 days (14-54). Main severe adverse events (grade 3-4) consisted in infections (8, 27.6%), cardiac toxicities (2 tamponades, 6.9%), and expected hematological toxicities. We registered 7 deaths (6 associated with treatment failure and 1 occurring on day-56 of induction-1 related to a fungal infection). With a median follow up of 3.5 months, estimated OS and EFS were 7.1 months.
Conclusion
CPX-351 showed encouraging response rates and survival with a manageable safety profile. The study continues to accrue patients and results of the entire planned study group (42 patients) will be presented.