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2849 CPX-351 Induces High Rate of Complete Remission in the New ICC/ELN 2022 Adverse-Risk Entity ‘AML with MDS-Related Gene Mutations’: Evidence from a Large Real-World Italian Study

Program: Oral and Poster Abstracts
Session: 615. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Clinical Practice (Health Services and Quality), Treatment Considerations
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Gaetano Cimino1,2*, Matteo Caridi, MD1,2*, Valeria Cardinali, MD, PhD1*, Sofia Sciabolacci, MD, PhD1*, Luana Fianchi3*, Federico Lussana4*, Sara Mastaglio, MD5*, Monica Fumagalli, MD6*, Sara Galimberti7*, Luca Maurillo, MD8*, Federica Gigli, MD9*, Caterina Patti, MD10*, Erika Borlenghi, MD11*, Monia Lunghi12*, Samuele Gatani Jr.13*, Ivana Lotesoriere, MD13*, Marco Frigeni14*, Nicola Stefano Fracchiolla, MD15*, Patrizia Chiusolo, MD, PhD16*, Roberta La Starza, MD2*, Caterina Matteucci2*, Massimo Bernardi, MD17*, Antonio Pierini, MD, PhD1*, Alessandra Carotti, MD1*, Roberto Cairoli, MD18*, Livio Pagano16*, Roberto Massimo Lemoli, MD19*, Maria Teresa Voso, MD8, Adriano Venditti8, Fabio Guolo, MD, PhD19, Elisabetta Todisco13* and Maria Paola Martelli, MD, PhD1,2*

1Department of Medicine and Surgery, Division of Hematology and Clinical Immunology, S. Maria della Misericordia Hospital, Perugia, Italy
2Hematology, CREO, Centro Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy
3UOC Ematologia e TCSE, Fondazione Policlinico Universitario A. Gemelli, IRCCS, ROMA
4Department of Oncology and Hematology, University of Milan and ASST Papa Giovanni XXIII, Bergamo, Italy
5Hematology and Bone Marrow Transplant, Unit San Raffaele Scientific Institute, Milan, Italy
6Hematology Division and Bone Marrow Unit, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
7Ematologia di Pisa, Pisa, ITA
8Department of Onco-Hematology, Fondazione Policlinico Tor Vergata, Rome, Italy
9Onco-Hematology Division, IEO, European Institute of Oncology IRCCS, Milan, Italy
10U.O.C. di Oncoematologia, "Ospedali Riuniti Villa Sofia - Cervello (Presidio V. Cervello), Palermo, Italy
11ASST Spedali Civili, Brescia, Department of Hematology, Brescia, Italy
12Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
13Hematology, ASST Valle Olona, Ospedale di Busto Arsizio, Busto Arsizio, Italy
14Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
15Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
16Dipartimento di Scienze di Laboratorio ed Ematologiche, Fondazione Policlinico Universitario Agostino Gemelli, IRCCS, Sezione di Ematologia, Università Cattolica del Sacro Cuore, Rome, Italy
17Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy
18Department of Hematology and Oncology, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
19Clinic of Hematology, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Genoa, Italy

Introduction

CPX-351 is a liposomal formulation of daunorubicin and cytosine arabinoside approved for the treatment of therapy-related AML (t-AML) or AML with Myelodysplastic-related changes (AML-MRC). Despite the pivotal study showed significant improvements in OS compared to ‘7+3’ conventional chemotherapy, a recent study (UK NCRI AML19 trial) suggests that in patients <60 years of age CPX-351 does not improve results as compared to FLAG-IDA chemotherapy. Specifically, in this study, overall response rates (CR/CRi) were 64% and 76% with CPX-351 and FLAG-IDA, respectively, whilst there were no differences in terms of OS (13.3 vs 11.4 months). However, in an exploratory subgroup analysis, a significant improvement in OS was observed with CPX-351 in AML with MDS-related gene mutations (median, 38.4 vs 16.3 months). This is a new high-risk entity introduced in ICC/ELN 2022 characterized by the presence of at least one mutation among SRSF2, ASXL1, BCOR, EZH2, STAG2, SF3B1, U2AF1, ZRSR2 and RUNX1, in absence of TP53 mutations and with or without cytogenetics abnormalities. Actually, CPX-351 is not specifically indicated in this AML.

Methods

We conduct a multicenter retrospective study in 109 patients from a large cohort of AML patients who received commercially available CPX-351 treatment since the approval of the drug at 16 Italian Hematology centers focusing on the new ‘AML with MDS-related gene mutations’ entity as defined by ICC 2022. Primary endpoint was to evaluate the ORR (CR/CRi) to CPX-351 induction (1 or 2 cycles) and the rate of allo-HSCT. Secondary endpoint was to evaluate the impact of specific MDS-related gene mutations on ORR. Other secondary endpoints included OS between AML with MDS-related gene mutations and AML with MDS-related cytogenetic abnormalities. Moreover, to improve statistical power for specific subgroups analysis we generated synthetic data from our dataset using Synthpop package, expanding our cohort of 300% to obtain 327 pts.

Results

109 patients were selected from the database for available data on MDS-related gene mutations. Patients were treated between September 2019 and June 2024 (median age 65 yrs, range 19-80). Seventy-five patients (52%) satisfy the criteria to be classified as AML with MDS-related gene mutations, 30/70 (43%) with available karyotype showed MDS-related cytogenetic abnormalities. A group of 35 patients classified as AML with MDS-related cytogenetic abnormalities (i.e. without Tp53 mutations and without MDS-related gene mutations, according to ICC 2022) was used as comparison group.

In AML with MDS-related gene mutations we observed higher ORR as compared to AML with MDS-related cytogenetic abnormalities: 52/70 (74%) vs 18/32 (56%) respectively (p 0.0685). Strikingly, these results were also observed in our newly generated synthetic dataset (79% vs 54%)(p <0.0001). Median OS was 1031 dd and 349 dd between the two groups (p 0.0003). In AML with MDS-related gene mutations, subgroup analysis based on cytogenetics abnormalities showed no impact of the karyotype on the ORR (73% vs 75%)(p 0.83) neither on OS (median OS: 1014 vs 874 dd)(p 0.23). We then evaluated the rate of bridge to transplant in this adverse-risk categories; among patients who achieved CR/CRi, thirty-one out of 48 evaluable patients (65%) undergone to allo-HSCT as compared to 10/17 (59%) with AML with MDS-related cytogenetic abnormalities (p 0.51).

Interestingly, focusing on specific MDS-related gene mutations, we found ASXL1 mutation predictive of worst ORR (56% vs 84%, p 0,0091) and worst OS (p 0.0005).

Conclusions

Our results show that CPX-351 is highly effective in the new ICC/ELN 2022 adverse-risk entity ‘AML with MDS-related gene mutations’ in terms of ORR giving the opportunity to go to transplant in CR to the majority of patients. The presence of specific mutations such as ASXL1 have a strong prognostic impact opening new possibilities to further stratify this high-risk AML sub group. This study, based on one of the largest database available, also highlights the potential of synthetic augmentation analysis in facilitating advanced research.

Disclosures: Lussana: Amgen: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Borlenghi: Incyte: Other: Travel Grant; Abbvie: Consultancy; BMS: Consultancy; Amgen: Other: Travel Grant. Lemoli: Jazz Pharma: Speakers Bureau. Voso: Jazz: Other: Advisory Board, Speakers Bureau; Novartis: Other: Research support, Speakers Bureau; Astellas: Speakers Bureau; Abbvie: Speakers Bureau; Astra Zeneca: Speakers Bureau; Syros: Other: Advisory Board; Celgene/BMS: Other: Research support, Advisory Board, Speakers Bureau. Venditti: beigene: Consultancy; servier: Consultancy, Other: invited speaker; astellas: Consultancy, Other: invited speaker; jazz: Consultancy, Other: invited speaker, Research Funding; pfizer: Consultancy, Other: invited speaker; Abbvie: Consultancy, Other: invited speaker; Gilead: Consultancy, Other: invited speaker; menarini: Consultancy, Other: invited speaker; Janssen: Consultancy, Other: invited speaker; AstraZeneca: Consultancy; glycostem: Consultancy; BMs celgene: Consultancy, Other: invited speaker; laboratories Delbert: Consultancy; istituto gentili: Consultancy.

*signifies non-member of ASH