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4765 Training and Validation Cohorts for Predicting the Impact of High Molecular Risk Mutations after Allogeneic Stem Cell Transplantation in Myelofibrosis

Program: Oral and Poster Abstracts
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Poster III
Hematology Disease Topics & Pathways:
Biological therapies, MPN, Chronic Myeloid Malignancies, Diseases, Therapies, Myeloid Malignancies, Transplantation
Monday, December 12, 2022, 6:00 PM-8:00 PM

Maria Chiara Finazzi1,2*, Alessia Civini, BioSc2*, Chiara Pavoni, MSc2*, Anna Grassi, MD2*, Maria Caterina Mico', MD2*, Alessandra Algarotti, MD2*, Marta Bellini, MD2*, Francesca Patriarca, MD, PhD3*, Paola Guglielmelli, MD, PhD4, Mario Luppi5*, Elisa Rumi, MD6,7*, Nicola Polverelli, MD, PhD8*, Giuseppe Messina, MD9*, Stefania Bregante, MD10*, Giuseppe Milone, MD11, Annalisa Imovilli, MD12*, Benedetto Bruno, MD, PhD13*, Maurizio Musso, MD14*, Stella Santarone, MD15, Massimo Pini, MD16, Martina Pennisi17*, Orietta Spinelli, PhD2*, Francesca Bonifazi, MD18*, Alessandro Rambaldi, MD1,2 and Silvia Salmoiraghi, BioSc2*

1Department of Oncology and Hematology, University of Milan, Milan, Italy
2Department of Oncology-Hematology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
3Hematologic Clinic and Transplant Center, University Hospital of Central Friuli, DAME, University of Udine, Udine, Italy
4CRIMM, Center of Research and Innovation of Myeloproliferative Neoplasms, University of Florence, AOU Careggi, Florence, Italy
5Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Modena, Italy
6Department of Molecular Medicine, University of Pavia, Pavia, Italy
7Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
8Unit of Blood Diseases and Stem Cell Transplantation, Dpt of Clinical and Experimental Sciences, University of Brescia, ASST-Spedali Civili di Brescia, Brescia, Italy
9Azienda Ospedaliera BMM, Reggio Calabria, Italy
10Division of Hematology and Bone Marrow Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
11Hematology and BMT Unit, Azienda Ospedaliero Universitaria Policlinico "G.Rodolico-San Marco", Catania, Italy
12Ematologia, Arcispedale S. Maria Nuova Reggio Emilia, Reggio Emilia, Italy
13Division of Hematology, Department of Molecular Biotechnology and Health Sciences, AOU Città della Salute e della Scienza di Torino, Turin, Italy
14U.O.C. OncoEmatologia e TMO, Dipartimento Oncologico, La Maddalena, Palermo, Palermo, Italy
15Ospedale Civile, Pescara, Italy
16Hematology Unit, Ospedale SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
17Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
18IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy

Introduction Myelofibrosis (MF) is the most aggressive form of Philadelphia negative myeloproliferative neoplasm and allogeneic hematopoietic stem cell transplantation (HSTC) is the only curative approach, but non relapse mortality limits the indication for HSTC to high-risk patients. The prognostic evaluation of MF patients is evolving during time together with a better understanding of the mutational landscape of this disease. The presence of high molecular risk (HMR) mutations, specifically ASXL1, SRSF2, EZH2, IDH1, IDH2 and U2AF1Q157, harbors a detrimental effect on survival and leukemic transformation and has been incorporated in different prognostic scoring systems. In this multicenter study we aimed to determine the impact of HMR mutations on transplant outcome.

Methods We studied two independent cohorts of patients: 44 patients (training, retrospective cohort) were part of a multicenter, randomized GITMO (Gruppo Italiano Trapianti di Midollo Osseo) clinical trial (Patriarca F, BBMT 2019) and 29 patients (validation, prospective cohort) were subsequently recruited at the Bergamo Bone Marrow Transplant Unit. Patients from the training cohort (median age 56, range 36-66) were conditioned with busulfan-fludarabine or thiotepa-fludarabin while patients in the validation cohort (median age 61, range 36-67) were conditioned with a reduced intensity thiotepa-busulfan-fludarabin regimen. The mutational profile obtained on the pre-transplant DNA was performed by sequencing 30 myeloid related genes by applying SOPHia GENETICS Myeloid Solution on Illumina MiniSeq platform.

Results In the training retrospective cohort, driver mutations were detected in 40 (29 JAK2/8 CALR/3 MPL) patients, with 4 patients having a triple negative MF. At least one HMR mutation was detected in 43% of patients and an unfavorable karyotype was present in 18% of patients. According to the Mutation-Enhanced International Prognostic Scoring System 70 plus (MIPPS70+) scoring system, 77% of patients were allocated in the high/very high groups. With a median follow up of 4.2 years (range 0.02-9), the 5-years Overall Survival (OS) and Progression Free Survival (PFS) were 61% and 45% respectively. The 5-years Non-Relapse Mortality (NRM) and Cumulative Incidence of Relapse (CIR) were 25% and 30%. In the prospective validation cohort, a driver mutation was detected in all patients (15 JAK2/7 CALR/7MPL). At least one HMR mutation was detected in 48% of patients and an unfavorable karyotype was present in 24% of patients. Patients allocated to the MIPPS70+ high/very group were 52%. After a median follow up of 10.7 months (range 0-44), the 2-years OS and PFS were 61% and 49% respectively. The 2-years NRM and CIR were 33% and 18%.

In the training cohort, a higher risk of death and progression was observed in patients with high/very high risk MIPPS70+ prognostic index [HR for OS 4.3 (95% CI 0.6-33.1), HR for PFS 4.1 (95% CI 0.9-16.9)]. Conversely, the presence of HMR mutations did not significantly affect OS, PFS (Figure 1), NRM or CIR. The prognostic significance of MIPSS70+ risk classification was confirmed in the validation cohort, with a higher risk of death and progression for high/very high MIPSS70+ group [OS HR 3.2 (95% CI 0.4-27.1), PFS HR 3.8 (95% CI 0.5-31.4)]. Similarly, in the validation cohort the presence of HMR mutations did not affect transplant outcome, with no impact on OS, PFS (Figure 2), NRM or CIR. In the whole group of 73 patients, the presence of JAK2V617F mutation showed an adverse prognostic impact on CIR [HR 3.4 (95% CI 1-11.8)], while MIPPS70+ confirmed its role on PFS.

Conclusions In this study we prospectively confirmed that the presence of HMR mutations did not impact on transplant outcome. Allogeneic stem cell transplantation can lead to a significant cure rate of MF patients, regardless the presence of HMR mutations. Patients in the high/very high MIPSS70+ risk group had a higher risk of death and progression after transplant. Appropriate timing and selection of patients is crucial for transplant outcome in MF.

Disclosures: Patriarca: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Guglielmelli: Novartis, Abbvie: Other: Other member of advisory board, speaker at meeting. Luppi: Gilead sci: Other: Travel grant; Abbvie, Jazz Pharma, Gilead sci, MSD, Novartis, Sanofi, Daiichi-Sankyo, Grifols: Membership on an entity's Board of Directors or advisory committees. Polverelli: Novartis Pharma: Consultancy. Bonifazi: JAZZ PHARMA: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rambaldi: Janssen: Honoraria; Roche: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Kite-Gilead: Honoraria; Jazz: Honoraria; ABBVIE: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Celgene-BMS: Honoraria; Omeros: Honoraria.

*signifies non-member of ASH