OUTCOME of Unrelated DONOR BONE MARROW TRANSPLANTATION for THALASSEMIA MAJOR PATIENTS
Authors: Locatelli Franco , Littera Roberto , Pagliara Daria , Contoli Benedetta , Giorgiani Giovanna , Bernardo Maria Ester , Mastronuzzi Angela , Piras Eugenia , Orofino Maria Grazia , Giardini Claudio , Carcassi Carlo , La Nasa Giorgio 
Published: October 2019

Abstract
Abstract 149
At present, allogeneic bone marrow transplantation (BMT) is still recognized as the only treatment potentially able to cure a large proportion of patients with thalassemia major. For many years, the only donor employed was an HLA-identical sibling. Unfortunately, at least 70% of patients who might benefit from BMT lack a compatible sibling. With the establishment of bone marrow donor registries, including now more than 15 million volunteers world-wide, many patients are able to locate a suitable unrelated donor. Aim of this study was to evaluate the outcome of patients transplanted from an unrelated volunteer, selected using stringent criteria of compatibility after high-resolution molecular typing of HLA loci, and to identify factors with a prognostic relevance. We analyzed 122 thalassemia patients (96 children and 26 adults, age range at time of BMT 1–35 years, median 10,5) given the allograft in one of 4 Italian Centers participating to this study. Seventy-one patients were males and 51 females; 13 patients had positive Hepatitis C Virus (HCV) serology. Prior to transplantation, all patients underwent a complete check-up and children were assigned to one of 3 classes of risk according to the criteria proposed the Pesaro group. In detail, 39 pediatric patients belonged to the class I, 41 to the class II (23) and 16 to the class III of the Pesaro classification. In 105 donor/recipient pairs were matched for the HLA-A, -B, -C, -DRB1 loci; 17 donor/recipient pairs had a disparity at the HLA-C locus, but both HLA-C molecules pertained to the same HLA-C ligand group. The patients were prepared for the allograft using a myeloablative conditioning regimen based on the combination of busulfan/treosulfan (BU/TREO), thiotepa (TT) and either cyclophosphamide (CY, 54 patients), or fludarabine (FLU, 68 patients). All patients received fresh, unmanipulated bone marrow cells, the median dose of nucleated cells infused being 5×108/Kg recipient b.w. (range 1.4–15). Graft-versus-host disease (GvHD) prophylaxis was homogeneous in all patients and consisted of cyclosporine-A, short-term methotrexate (15 mg/m2 on day +1 and 10 mg/m2 on days +3, +6 and + 11) and anti-thymocyte globulin (ATG, 2.5 mg/Kg from day –4 to –2). Twenty patients died and 16 patients had either primary (11 patients) or secondary (5 patients) graft failure, the 5-year probability of overall survival (OS), and thalassemia-free survival (TFS) being 84% (95% Confidence Interval, CI, 76–90) and 75% (95% CI, 66–81) respectively. Acute and chronic GvHD were the main causes of death accounting for 6 and 4 fatal events respectively. Thirty-four patients at risk (28%) developed grade II-IV acute GvHD with 16 of them (13%) experiencing grade III-IV acute GvHD. Fourteen patients at risk (13%) had chronic GvHD, which was limited in 8 cases and extensive in 6. The probability of survival was not influenced by the occurrence of graft failure which was responsible of only 2 of the 20 fatal events. The chance of being alive for children belonging to class I, II and III of the Pesaro classification was 97% (95% CI, 83–100), 85% (95% CI, 70–93) and 78% (95% CI, 51–93), respectively, while that of adults was 65% (95% CI, 44–80) (p<0.01). Occurrence of both grade III-IV acute and chronic GvHD, older patient's age, positive HCV serology and adult/class III group of risk predicted a poor survival in univariate analysis; however, in multivariate analysis, only occurrence of grade III-IV acute GvHD was associated with a poor outcome (Hazard ratio, 10.4, 95% CI 3.19 – 34.06, P=0.001). Altogether, these data indicate that, provided that selection of the donor is based on stringent criteria of HLA-compatibility, transplantation from unrelated volunteers is able to cure a large proportion of patients with patients with thalassemia major, the results being comparable to those obtained when the donor is an HLA-compatible sibling. Prevention of severe acute GvHD is able to optimize the outcome of patients with thalassemia major transplanted from an unrelated volunteer.

Disclosures:
No relevant conflicts of interest to declare.