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4717 Impact of Fourth Methotrexate Dose in ATG-Cyclosporine GvHD Prophylaxis in HLA-Matched Unrelated HSCT: A GITMO Study

Program: Oral and Poster Abstracts
Session: 722. Allogeneic Transplantation: Acute and Chronic GVHD, Immune Reconstitution: Poster III
Hematology Disease Topics & Pathways:
adult, Combination therapy, Therapies, Study Population, Human
Monday, December 12, 2022, 6:00 PM-8:00 PM

Alessandra Picardi1,2*, Francesca Lorentino, PhD3*, Alessandro Rambaldi, MD4, Benedetto Bruno, MD, PhD5*, Fabio Benedetti, MD6,7*, Michela Cerno8*, Paolo Bernasconi, MD9, William Arcese10*, Pietro Pioltelli, MD11*, Domenico Russo, MD12, Andrea Bacigalupo, MD13, Massimo Martino14,15*, Emanuele Angelucci, MD16, Angelo Michele Carella, MD17*, Francesco Onida, MD18, Attilio Olivieri, MD19*, Anna Maria Raiola20*, Anna Paola Iori, MD21*, Francesca Patriarca, MD, PhD22*, Elena Oldani, MSc23,24*, Fabio Ciceri, MD25* and Francesca Bonifazi, MD26*

1Stem Cell Transplant Program of AORN Cardarelli, Naples, Italy
2Dipartimento di Biomedicina e Prevenzione, Università di Roma Tor Vergata, Rome, Italy
3PhD Program in Public Health, School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
4Hematology and Bone Marrow Transplant Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
5Division of Hematology, Department of Molecular Biotechnology and Health Sciences, AOU Città della Salute e della Scienza di Torino, Turin, Italy
6Hematology and Stem Cell Transplantation, Azienda Ospedaliera Universitaria di Verona, Verona, Italy
7Department of Medicine, Section of Hematology and Bone Marrow Transplant Unit, University of Verona, Verona, Italy
8Clinica Ematologica Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy
9HSCT Unit, UOC Ematologia, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
10Fondazione Policlinico Campus Biomedico, Rome Transplant Network, Rome, Italy
11Ospedale San Gerardo, Clinica Ematologica dell`Universita Milano-Biocca, Monza, MB, Italy
1214Bone Marrow Transplant Unit, ASST-Spedali Civili di Brescia, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
13Sezione di Ematologia, Dipartimento di Scienze Radiologiche ed Ematologiche, Universita’ Cattolica del Sacro Cuore, Rome, Italy
14Stem Cell Transplant and Cellular Therapies Unit, "BMM" Hospital, Reggio Calabria, Italy, Reggio Calabria, Italy
15Grande Ospedale Metropolitano BMM- Centro Unico Trapianti A. Neri, Alberto Neri, Bianchi-Melacrino-Morelli, Reggio Calabria, Italy
16Department of Hematology II, Ospedale San Martino, Genoa, Italy
17Ematologia e Centro Trapianto CSE, Fondazione Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
18BMT Center - Hematology Unit, IRCCS Ospedale Maggiore Policlinico Di Milano-University of Milan, Milano, Italy
19Università Politecnica Delle Marche, Ancona, Italy
20Divisione di Ematologia, Policlinico San Martino, IRCCS, Genova, Italy, Genova, Italy
21Dip. Biotecnologie Cellulari ed Ematologia, Univ. La Sapienza, Rome, Italy
22Haematological Clinic and Transplant Centre, University Hospital of Central Friuli, DAME, University of Udine, Udine, Italy
23Haematology Unit, “ASST Papa Giovanni XXIII”, Bergamo, Italy, Bergamo, Italy
24Department of Oncology-Hematology, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
25Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
26IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, NA, Italy

Background: Although, post-transplant Cyclophosfamide (PT-Cy) is currently spreading as GvHD prevention, the standard GvHD prophylaxis in unrelated haematopoietic stem cell allogeneic transplant (HSCT) series is still represented by Methotrexate (MTX), a CNI and Anti-thymoglobuline (ATG) combination. The dose of MTX (3 or 4 doses), in association with ATG and CNI remains a matter of debate.

Aim: The Gruppo Italiano Trapianto di Cellule Staminali e Terapie Cellulari (GITMO) analyzed 568 patients who received unrelated (UD) 10/10 HLA matched HSCT and GvHD prophylaxis based on a combination of cyclosporin (CSA), ATG and Methotrexate.

Methods: Patients were grafted in GITMO centers between 2012 to 2015 and GvHD prophylaxis was the same for all patients (ATG-MTX-CSA). The median dose for ATG Fresenius and Thymoglobulin was respectively 30 mg/kg (range 8-60) and 8 mg/Kg (range 4-18); 216 patients received 3 doses of MTX and 352 4 doses. Patient characteristics based on the two groups (MTX 4 and MTX 3 doses) are detailed in table 1. Main differences between the groups concerned conditioning intensity (myeloablative in 75% and 63% for MTX4 and MTX3 respectively, p 0.002), ATG dose (above the median in 59% of MTX4 and in 71% of MTX3 patients, p 0.005), and diagnosis (acute leukemias in 63% of MTX4 and 46% of MTX3, p<0.0001). Statystical analysis: The probabilities of DFS, OS and GRFS were estimated with the Kaplan-Meier method. Cumulative incidence (CI) was estimated for engraftment, GvHD, TRM and relapse to accommodate competing risks. Relapse or progression was a competing risk for TRM, and death from any cause was a competing risk for engraftment and relapse. Relapse or progression and death from any causes were competing risks for GvHD. Univariate comparisons of survival curves were made using the log-rank test and Gray’s test was used for univariate comparisons of CI functions. The type I error rate was fixed at 0.05. Statistical analyses were performed with the SPSS (SPSS 22 Inc. IBM, Armonk, NY, USA) and R (R Development Core Team, Vienna, Austria) software.

Results In the setting of 10/10 HLA matched unrelated allogeneic HSCT, whose median follow up was 42.5 months (range 3-75), univariate analysis showed that the administration of 3 versus 4 doses of MTX plays a significant favorable impact on the cumulative incidence of engraftment in terms of PMN (94% vs 90%, p=0.04) and PLTS (90% vs 86%, p= 0.04). Moreover, the 3 MTX doses group achieved significant better results in terms of 3-years CI of TRM (15% vs 23%, p=0.03), OS (66% vs 52%, p=0.001), PFS (54% vs 41%, p= 0.001) and GRFS (44% vs 27%, p=0.00001). We built a multivariate Cox model based on the following covariates: patient age (median value), Donor/host gender, Donor/host CMV status, Disease status, HCT-CI Sorror, Karnofsky PS, Conditioning intensity, Source of stem cells (PB vs BM), ATG dose (median value), MTX dose (4 doses vs 3), Center (≥10 transplants/year vs <10 transplants/year), host/donor Italian origin. Multivariate analysis confirmed the significant protective role of 3 MTX doses on grade 3-4 aGvHD (HR 0.41, p=0.03), TRM (HR 0.59, p=0.02), OS (HR 0.59, p=0.001), PFS (HR 0.6, p<0.0001) and GRFS (HR 0.58, p<0.0001). Interestingly, the relapse risk was significantly inferior in patients who received 3 doses of MTX instead of 4 (HR 0.60, p=0.003).

Conclusions: A fourth dose of MTX in patients receiving ATG+ CSA may negatively impact on engraftment, aGvHD, TRM, OS, PFS and GRFS. Our data support the need for a prospective investigation of MTX doses in the context of patients receiving unrelated matched HSCT and ATG+a CNI.

Disclosures: Picardi: Novartis: Honoraria; Jazz: Honoraria; MSD: Honoraria; Amgen: Honoraria; Gillead: Honoraria. Rambaldi: Astellas: Honoraria; Jazz: Honoraria; ABBVIE: Honoraria; Amgen: Honoraria; Kite-Gilead: Honoraria; Novartis: Honoraria; Incyte: Honoraria; Roche: Honoraria; Janssen: Honoraria; Celgene-BMS: Honoraria; Omeros: Honoraria; Pfizer: Honoraria. Angelucci: Novartis: Honoraria; Celgene: Honoraria, Other: Data monitoring committee; Bluebird Bio: Consultancy; Menarini/Stemline: Consultancy; Gilead: Consultancy; Roche: Consultancy; Vertex: Honoraria, Other: Data monitoring committee; Sanofi: Speakers Bureau; Vifopr: Honoraria, Other: Data monitoring committee; Glaxo: Consultancy. Patriarca: Roche: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: 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. Ciceri: Kite Pharma: Consultancy. Bonifazi: JAZZ PHARMA: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

*signifies non-member of ASH