The need for a subsequent HCT is a late & continuous risk and with significant impact in overall survival in haemoaglobinopathies: Real-world data from 2000–2022. an analysis of the european society for blood and marrow transplantation (EBMT) hemoglobinopathy working party.

Abstract

Abstract INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) is the best established curative option for sickle cell disease (SCD) & transfusion dependent thalassemia (TDT). Primary and particularly secondary graft failure are important risks impacting on event free survival. However, real-world outcomes for second HCT are not known, even though this information is crucial in understanding long-term outcomes for patients. METHODS: Data on pediatric and adult patients with TDT and SCD receiving a HCT from January 2000 to December 2022 were extracted from the EBMT Hemoglobinopathy registry database. Only first transplants were included. Data are expressed as median with range unless otherwise specified. OS was evaluated using Kaplan-Meier analysis. RESULTS: 2,045 consecutive patients underwent transplanted in centers distributed accross 33 countries in Europe, Asia and Africa: 1,532 were for TDT and 513 for SCD. Median age at transplant was 9 years (IQR 5, 15; range 1-49) with 62% HCT up to the age of 10 years. The median year of HCT was 2012 (IQR 2006, 2017). A total of 1,425 patients received a matched related donor HCT (70%), 435 patients a matched unrelated donor HCT (21%) and 174 patients a haploidentical HCT (8.6%). Bone marrow as a stem cell sourse was used in 74% of HCT and 75% received a cell dose >3 x 108 TNC/kg. Half of HCT were donor-recipient gender mismatched: 512 female to male (26%) and 476 male to female (24%). 60% HCT (n=504) were ABO compatible whereas minor ABO incompatibility was present in 15% HCT (n=129), major ABO incompatibiolity in 19% HCT (n=163) and biderictional AOB incompatibioity in 4.8% HCT (n=40). CMV donor to patient was as follows: neg/neg 207 HCT (12%), neg/pos 242 HCT (14%), pos/neg 185 (11%), pos/pos 1,076 HCT (63%). 89% HCT received myeloablative conditioning. 134 patients (6.5%) received a second HCT: 111 with TDT (83%, 7.2% of first HCT) and 23 with SCD (17%, 4.4% of first HCT). The time to subsequent HCT was <3 months in 20% cases. A second HCT was undertaken for reasons other than graft failure in 9.4% of the cases, including clonal evolution. Only 18 patients had a third HCT. The age and year at HCT was no different from fisrt HCT. There were no differences in conditioning regimens (FluThioTreo, BuCy and BuFluThio predominate) and use of TBI (9% in both cohorts) and only small reduction in use of serotherapy (from 95% to 88%) between first and second HCT. The estimated incindence of subsequent HCT continues to increase over time with no apparent plateau. With median follow up of 5 years (IC95%, 4.6-5.1) the incidence at 1 year was 2.8% (2.1-3.6), at 2 years 3.9 (3.1-4.9), at 3 years 4.7 (3.7-5.7) and at 5.7 years (4.6-6.9). With median follow up of 4.8 years (IC95%, 3.3-6.7) from a second HCT, the overall survival at 1 years was 70.3% (62.7-76.6), at 2 years 66.7% (58.9-73.4), at 3 years 66.7% (58.9-73.4) and at 5 years 62.6% (54.1-69.9). CONCLUSIONS: Real-world data confirms a small but significant risk of the need for a subsequent HCT in haemoglobinopathies. This, unlike in malignancies, usually is a late event (after day +100) and the incidence does not achieve a plateau over time. The OS following a subsequent HCT is inferior to first HCT and continues to decline over time with no plateau unlike the outcomes of first HCT, highlighting the need for improvemenet to avoid graft failure in HCT for haemoglobinopathies.