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3231 Chronic Myelomonocytic Leukemia (CMML) with AML Typical Mutations (NPM1, FLT3 or CEBPA) Identify a High-Risk CMML Group Independent of Molecular-Cpss

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes – Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, Clinical Practice (Health Services and Quality), Diseases
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Sandra Castaño-Díez, MD1,2*, Ines Zugasti3*, Xavier Calvo, MD, PhD2,4*, Felicitas Schulz5*, Alejandro Avendaño Pita2,6*, Elvira Mora, MD, PhD2,7*, Jose Francisco Falantes2,8*, Gemma Azaceta2,9*, Mariam Ibáñez2,10*, Tzu Chen2,11*, Cristina Notario2,12*, Neus Amer Salas, MD2,13*, Mònica López-Guerra14*, Carlos Jimenez-Vicente, MD15*, Daniel Esteban16*, Francesca Guijarro, MD17*, José Ramón Álamo Moreno, MD18*, Albert Cortés-Bullich, MD3*, Daniel Munárriz, MD16*, Víctor Torrecillas-Mayayo19*, Ana Triguero16*, Natalia Tovar, MD18*, Alexandra Martínez-Roca, MD3*, Beatriz Merchán Muñoz, MD15*, Esther Carcelero16*, Ulrich Germing20*, Beate Betz21*, María Rozman2,18*, Leonor Arenillas, MD, PhD2,4*, Lurdes Zamora, PhD2,22*, Maria Diez-Campelo, MD, PhD2,23*, Blanca Xicoy, MD2,24*, Jordi Esteve, MD, PhD15 and Marina Díaz-Beyá, MD, PhD1,2*

1Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain
2Grupo Español de Síndromes Mielodisplásicos (GESMD), Madrid, Spain
3Hematology Department, Hospital Clinic de Barcelona, ICMHO, Barcelona, Spain
4Laboratori de Citologia Hematològica, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM, Barcelona, Spain
5Dept of Hematology, Oncology and Clinical Immunology, University Clinic, Heinrich Heine University Düsseldorf, Düsseldorf, DEU
6Hospital Universitario de Salamanca, Salamanca, Spain
7Department of Hematology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
8Complejo Hospitalario Virgen del Rocío, Sevilla, ESP
9Hospital Clínico Universitario Lozano Blesa de Zaragoza, Zaragoza, ESP
10Hospital General Universitario de Valencia, VALENCIA, ESP
11Hospital General Universitario Morales Meseguer, Murcia, Spain
12Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
13Hospital Universitario Son Llàtzer, Palma de Mallorca, Spain
14Hematopathology Section, Pathology Department, Hospital Clínic Barcelona, Barcelona, Spain
15Hematopoietic Cell Transplantation Unit, Hospital Clínic de Barcelona, ICHMO, Barcelona, Spain
16Hospital Clínic de Barcelona, Barcelona, Spain
17Hematopathology Unit, Pathology Department, Hospital Clínic de Barcelona, Barcelona, Spain
18Hospital Clínic Barcelona, Barcelona, Spain
19University of Barcelona, Barcelona, Spain
20Department of Hematology, Oncology and Clinical Immunology, Universitatsklinik Dusseldorf, Dusseldorf, Germany
21Institute for Human Genetics, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
22Hematology Department, Institut Català d’Oncologia - Hospital Universitari Germans Trias i Pujol, Institut de Recerca Contra la Leucèmia Josep Carreras, Universitat Autònoma de Barcelona, Badalona, Spain
23Department of Hematology, Salamanca-IBSAL University Hospital, Salamanca, Spain
24Hematology Service, Hospital Germans Trias I Pujol, Institut Català Oncologia, Josep Carreras Leukemia Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain

CMML is rarely associated with AML typical mutations such as NPM1, FLT3, CEBPA, and IDH1/2 (mutAML-CMML). It is unknown what its clinical meaning is and if its presence should change our management into an AML-type treatment. The aim was to describe the characteristics, prognosis and treatment of mutAML-CMML patients.

We studied 83 CMML patients of Hospital Clinic diagnosed between 1998-2022, with Next Generation Sequencing (NGS). We included 53 patients with mutAML-CMML from other institutions.

We identified 31 patients with mutated IDH2 (all c.419G>A p.(Arg140Gln)), 13 with IDH1, 14 with NPM1,7 with CEBPA (4 bZIP) and 11 with FLT3 (3 FLT3-ITD and 7 FLT3-TKD: 6 TKD1 and 2 TKD2 variants, all different from p.(Asp835Tyr) except one).

Patient characteristics and outcome of the group with mutIDH1/2 was not significantly different from wtIDH.

Those patients with mutNPM1, FLT3 and/or CEBPA presented adverse characteristics and worse prognosis. Therefore, we grouped the patients with these mutations into a category named mutCFN (n=26) (Table 1). The mutCFN incidence in our series was 9%.

The mutCFN patients (n=26) vs wtCFN (n=96) were younger (63 vs 71 years, p=0.004), had more leucocytes (16 vs 7.7x109/L, p=0.015), monocytes (2.9 vs 1.7x109/L, p=0.006), anemia (9.1 vs 11.2 g/L, p<0.001) and bone marrow blasts (11.5 vs 4%, p<0.001). They belonged more frequently to myeloproliferative variant (57.7 vs 30.2%, p=0.012), CMML-2 (69.2 vs 14.7%, p<0.001), high risk CPSS and CPSS-Mol (72 vs 31%, p<0.001; 88.2 vs 44.9%, p=0.001). They showed more transfusion dependence (69.2 vs 22.9%, p<0.001). Co-mutational representation is shown in Figure 1. mutCFN patients have a different co-mutational pattern from wtCFN with more frequently mutated DNMT3A (42.9 vs 6.3%, p<0.001), SF3B1 (15.8 vs 2.3%, p=0.04), WT1 (10 vs 0%, p=0.03), and less TET2 (24 vs 58.3%, p=0.003).

mutCFN patients received treatment more frequently than wtCFN (84.6 vs 36.5%, p<0.001) and earlier (0.97 vs 4.6 months, p=0.005). They were more frequently treated with chemotherapy (53.8 vs 7.3%, p<0.001) and alloSCT (61.5 vs 11.5%, p<0.001). The median follow-up was 9.3 years (95% CI, 8-11). The 2-year cumulative incidence of AML (CIR-AML) transformation was higher in mutCFN patients (44% vs 13%, p<0.001) and overall survival (OS) was shorter (25 vs 38 months, p=0.057). Besides, when those who received and alloSCT were censored at time of alloSCT, mutCFN showed an inferior survival (9.6 vs 35.7 months, p<0.01). Multivariate analysis confirmed mutCFN as an adverse prognostic factor independent of age and CPSS-Mol (HR 2.42, IC 95% 1.23-4.76, p=0.011). Because CFN mutation showed independent prognostic value not captured by CPSS-Mol, we added to CPSS-Mol 1 point if patient had mutCFN. We derived a modified CPSS-Mol-CFN score and identified five groups with different median OS of 85 (95% CI, 54-117) vs 74 (95% CI, 53-94) vs 40 (95% CI, 17-63) vs 22 (95% CI, 11-33) vs 15 (95% CI, 5-25) months, p<0.001with a better predictive capacity than CPSS-Mol (C-index 0.66 vs 0.64).

Nowadays, there is no consensus between the two recent 2022 ICC and WHO classifications, but the identification of NPM1 or CEBPA mutations in cases of CMML could define AML. We analysed the group of patients who harboured bZIP-CEBPA or NPM1 mutations (“mutCN”) (n=17) and we found that these patients retained its chemosensitivity (90%CR) and those treated with chemotherapy had better OS (27 vs 9 months, p<0.001).

10 mutCFN patients received alloSCT with a median OS post-alloSCT of 21 months (95% CI, 16-26) and a 2year-CIR-AML of 37.5% (95% CI, 15-61). 5 patients received targeted therapy for a post-transplant relapse: 3 received sorafenib after a molecular relapse with prolonged responses and 2 received an IDH inhibitor, one of them persisting with a complete response after 4 years.

We analyzed 5 paired samples (diagnostic CMML-AML transformation). All of the AML related mutations were retained at AML transformation and emerged new mutations in genes of signaling (FLT3, NRAS), transcription (RUNX1, CEBPA) and splicing (STAG2) pathways.

Independently of CPSS-Mol, mutCFN CMML patients have a different profile, closer to AML and with worse prognosis. They could benefit from more aggressive AML-treatment based on chemotherapy and alloSCT when possible. Interestingly, some patients may benefit from approved targeted therapy for AML

FinancingISCIII PI19/01476 PI22/01660, co-financed EU, Emili-Letang HCPB

Disclosures: Jimenez-Vicente: Pfizer: Other: Travel Grants; Abbvie: Other: Speaker, Travel Grants. Martínez-Roca: Janssen: Other: travel grants; Takeda: Honoraria, Other: travel grants; Roche: Honoraria, Other: travel grants; Kite: Honoraria, Other: travel grants; Abbvie: Honoraria, Other: travel grants; BMS: Honoraria, Other: travel grants; Gilead: Other: Travel grants. Diez-Campelo: Gilead Sciences: Other: Travel expense reimbursement; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board fees. Esteve: Kronos Bio: Research Funding; Pfizer: Research Funding; Gilead: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas: Consultancy. Díaz-Beyá: Bristol Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Jazz Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria.

*signifies non-member of ASH