Real world outcomes in 355 patients with Acute Myeloid Leukemia arising from chronic myelomonocytic leukemia: A multinational retrospective study
Abstract
Abstract Background Secondary acute myeloid leukemia (sAML) designates AML arising from prior hematologic disorder or chemo/radiation. sAML cases evolving from myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) are often grouped under AML with myelodysplasia-related changes (AML-MR). Within this subset, CMML-derived sAML remains clinically and biologically poorly characterized and underreported in clinical trials and registry studies. Objectives In this multicenter study, we analyze the characteristics and outcomes of sAML arising from CMML treated with intensive chemotherapy (IC), hypomehtylating agents (HMAs), and modern strategies including CPX-351 and HMAs plus Venetoclax (HMA-VEN). Methods Overall, 355 patients diagnosed between 2005-2025 with AML (blast counts > 20%) evolving from previous CMML were included . This retrospective study combined patients from PETHEMA, UK, GROM-L, and 9 additional Italian centers. Genetic analyses were performed locally. The study was approved by institutional review board. Patients who did not receive therapy were excluded from the present analysis. Results Median age at diagnosis was 68.9 years (39-87), with prevalence of male gender (72%). All patients had previous documented diagnosis of CMML, and 67 (18.9%) received HMAs at their chronic phase. Median bone marrow blast infiltration was 35% (18-100) and median WBC 24.1 x106 (0.2-453). Normal karyotype was present in 39.2%, karyotype with trisomies in 16.5% (trisomy 8 in 7%), and complex in 15.0%. MRC cytogenetic adverse risk represented 14.0% ,intermediate 64.8%, and favorable 3%.Molecular biology by PCR , available in 300 patients, showed NPM1 (17%), FLT3-ITD in (13%), IDH1 (4%) and IDH2 (9.5%). NGS studies, available in 185 patients, disclosed median 3 mutations/pt (1-8); most frequently mutated genes were ASXL1 (n=64;42%), SRSF2 (n=61;40%), TET2 (n=56,;37%), RUNX1 (n=48;32%), KRAS/NRAS/CBL (n=51;44%), DNMT3A (n=17;11%), EZH2 (n=13, ;8.6%), and TP53 (n=5;3%). As per ELN2010 patients were classified in adverse (n=49,14%), favorable (n=37,10%), and intermediate risk (n=205,58%). For patients with available molecular data, ELN2022 stratified most patients in adverse risk (n=164,74%), intermediate (n=25,11%) and favorable (n=31,14%). Overall, 172(48%) patients received IC induction including 3+7 (n= 88), FLA-G-IDA (n=28), CPX-351 (n=36), other IC (n=20), while 183 (51%) received non intensive approaches including HMA-VEN (n=60), HMAs (n=54), less intensive chemo (FLUGA, n=36), LDAC-VEN (n=7), LDAC (n=6), or other non intensive (n=11). CR/CRi rate for the entire cohort was 35%, partial remission (PR) 14%, primary resistance 38%, early death (ED) 10%. Induction responses after IC were CR/CRi 42%, PR 14%, primary resistance 35%, and ED 7.2%. 3+7 showed higher rate of CR/CRi (53%) compared to CPX-351 (30.6%) and FLAG-IDA/FLA-IDA(32%) (p=0.01). 40/172 (23%) of IC patients underwent allo-SCT. Responses in the non-intensive group were CR/CRi 29%, PR 14%, primary resistance 43%, and ED 12%. HMA-VEN had highest CR/CRi (55%) vs HMAs (24%) and FLUGA (5.6%) (p=0.001). 4/58 patients treated with HMA-VEN proceeded to allo-SCT. OS for the entire cohort was 8.3 mos (0.95 CI, 6.9-9.5); 8.6 mos after IC (0.95CI, 7.5-11.9), and 8.3 mos after non intensive (0.95 CI, 6.3-12.8). For IC, 3+7 showed OS of 11.2 mos(0.95CI, 8.5-17.3), higher when compared to CPX-351 7.1 mos (0.95CI, 3.8-10.6) and FLA-IDA/FLAG-IDA 9.5 (0.95CI 5.12-na)( p=0.02). For the non intensive approaches, HMA-VEN OS was 14.1 mos(0.95CI, 7.4-21.8) and for HMAs 6.7(0.95CI, 5.3-16). OS for patients undergoing allo-SCT(n=44) was significantly superior to those not transplated (28.6 mos [0.95 CI, 17.7-nr] vs 6.55 [0.95 CI, 5.2-8; p<0.001]. Conclusions sAML following CMML presents distinct cytogenetic/molecular profile and dismal outcome. Cytogenetics is enriched in normal karyotype and trisomies with lower rates of complex. NGS showed frequent ASXL1, TET2, RUNX1 and SRSF2 mutations and NRAS/KRAS/CBL pathways, with low rate of TP53. Allo-SCT offers survival benefit, but only 23% of pts were successully bridged. 3+7 showed better outcomes in IC, compared to CPX-351 and fluda-based regimens while HMA-VEN yielded best CR/CRi and OS rates in the non-intensive setting. Multivariate and propensity score analyses will be performed in order to address impact of treatment and patient´s characteristics on outcomes.
Article Details
Authors (62)
Laura Cicconi
20Department of Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy
Jad Othman
3The University of Sydney, Sydney, Australia
Alessandra Spagnoli
3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
Enrico Attardi
1Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN
Eleonora De Bellis
7Azienda Sanitaria Universitaria Giuliano Isontina (ASUGI), SOC Ematologia, Trieste, Italy
Pilar Lloret Madrid
1Instituto de Investigación Sanitaria La Fe, Hematology, Valencia, Spain
Tamara Castaño
12Hospital Universitario Fundación Jiménez Díaz, Hematology, Madrid, Spain
Juan Miguel Bergua Burgues
Hospital San Pedro de Alcántara. Cáceres, Caceres, Spain
Arianna Savi
17Department of Clinical and Biological Sciences, University of Turin, Orbassano, Italy
Ida Carmosino
11Hematology, Department of Translational and Precision Medicine, Policlinico Umberto I-Sapienza University, ROME, Italy
Roberta Mazzarella
10Hematology, Department of Translational and Precision Medicine, Policlinico Umberto I-Sapienza University, Rome, Italy
Armando Mena Duran
25Hospital General de Valencia, Valencia, Spain
Mar Tormo
Hospital Clinico Universitary. INCLIVA Research Institute, Valencia 46010, Spain
Susana Vives
18Hospital U. Germans Trias i Pujol ICO Badalona, Badalona, Spain
Emília Cortesão
29Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
Fernanda Trigo
9Centro Hospitalar São João, Oporto, Portugal
Mercedes Colorado
Hospital Universitario Marqués de Valdecilla, Santander, Spain
Lorenzo Algarra
37Complejo Hospitalario Universitario de Albacete, Albacete, Spain., Hematology Department, Albacete, Spain
Olga Salamero
13Hospital U. Vall D'Hebron, Barcelona, Spain
José Antonio Pérez-Simón
Esther Perez
34Hospital Donostia, San Sebastián, Spain
ANA Yurena Oliva Hernandez
50Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain
Teresa Bernal del Castillo
Hospital Universitario Central de Asturias–Instituto Universitario del Principado de Asturias–Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain
Pilar Martinez Sanchez
Hematology Department. Hospital Universitario 12 de Octubre, Madrid, Spain
Claudia Lucia Scossa Melo
24FOSCAL, Colombia, Colombia
Cristina Gil
Hospital Alicante, alicante, Spain
Marta Valero Núñez
22Hospital Universitario Arnau de Vilanova, Valencia, Spain
Luis Felipe Casado Montero
4Hospital General Universitario de Toledo, Toledo, Spain
Teresa Olave
16Hospital Clínico U. Lozano Blesa, Hematology, Zaragoza, Spain
Maria Vidriales Vicente
24Hospital Universitario de Salamanca, Salamanca, Spain
Carla Amigo
30Hospital Morales Meseguer, Murcia, Spain
Irene Navarro Vicente
1Instituto de Investigación Sanitaria La Fe, Hematology, Valencia, Spain
Cristian Escolano Escobar
32Hospital Universitario de Getafe, Getafe, Spain
Pilar Herrera Puente
16Hospital Ramón y Cajal, Madrid, Madrid, Spain
Kenny Galvez
34Hospital Pablo Tobón Uribe, Medellín, Spain
Rosalia Riaza Grau
35ospital Universitario Severo Ochoa, Madrid, Spain
Annalina Piccioni
10San Giovanni Addolorata Hospital, Rome, Italy
Davide Facchinelli
37Hematology Unit, Ospedale San Bortolo, Vicenza, Italy
Enrico Santinelli
38Hematology and Stem Cell Transplantation Unit, Campus Bio-Medico University, Rome, Italy
Raffaele Palmieri
11Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Giovanni Luzi
39Haematology and Haematopoietic Stem Cells Transplant Unit, AO San Camillo-Forlanini, Rome, Italy
Monica Piedimonte
17Hematology, Department of Clinical and Molecular Medicine, University Hospital Sant'Andrea-Sapienza, Roma, Italy
Sabrina Mariani
40Hematology, Department of Clinical and Molecular Medicine, University Hospital Sant'Andrea-Sapienza, Rome, Italy
Luana Fianchi
8Dipartimento Di Diagnostica Per Immagini, Fondazione Policlinico Universitario A. Gemelli, IRCCS- Università Cattolica del Sacro Cuore, Radioterapia Oncologica Ed Ematologia, Roma, Italy
Carmela Gurrieri
11Azienda Ospedale-Università di Padova, UOC Ematologia, Padova, Italy
Ilaria Tanasi
43Hematology Unit, Department of Engineering for Innovation Medicine, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy
Davide Lanzarotto
44Clinica Ematologica - Centro Trapianti e Terapie Cellulari, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
Fabio Guolo
12Clinic of Hematology, Department of Internal Medicine, University of Genova, Genova, Italy
Salvatore Perrone
1Hematology and Transplant Unit, SM Goretti Hospital, University Polo Pontino, Latina, Italy., Latina, Italy
Elisabetta Todisco
15SC Ematologia, Ospedale “Busto Arsizio”, ASST Valle Olona, Varese, Italy
Anjum Khan
13Leeds Teaching Hospitals NHS Foundation Trust, Leeds, United Kingdom
Victoria Campbell
5Department of Haematology, Western General Hospital, Edinburgh, United Kingdom
Maria Teresa Voso
Daniela Cilloni
24Hematology Division, Mauriziano Hospital, Department of Clinical and Biological Sciences, University of Turin, Turin, Italy
Adriano Venditti
23Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Roberto Latagliata
1ASL Viterbo, Santa Rosa Hospital, Hematology Unit - Mieloma Unit, Viterbo, Italy
Richard Dillon
5King's College London, London, United Kingdom
Massimo Breccia
25Hematology, Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University, Rome, Italy
Luca Maurillo
23Department of Biomedicine and Prevention, University of Rome tor Vergata, Rome, Italy
Susanna Fenu
36Haematology Department, San Giovanni-Addolorata Hospital, Rome, Italy
Alessandro Pulsoni
Sapienza University of Rome, Rome
Pau Montesinos
Hospital Universitari i Politecnic La Fe, Valencia, Spain