Age Is a Crucial Determinant of GFRS with Incidence of Severe Chronic GVHD Reducing over Time in Haemopoietic Cell Transplantation for Transfusion Dependent Thalassaemia: Real World Data from 2010-2021. an Analysis of the European Society for Blood and Bone Marrow Transplantation Hemoglobinopathy Working Party

INTRODUCTION: Allogeneic hematopoietic cell transplantation (HCT) is the best established curative option for transfusion dependent thalassemia (TDT). This has been at least in part due to the real world outcomes identified by EBMT (Baronciani, BMT 2016; 51:536-41). However, these require updating as they were limited to the 2000-2010 period and no data exists on the incidence of severe GVHD, particularly important with advent of gene therapy.

METHODS: Data on pediatric and adult patients with TDT receiving a HCT from January 2010 to December 2021 were extracted by the EBMT Hemoglobinopathy registry database. Only first transplants were included. Data are expressed as median with range unless specifically indicated. Event free survial (EFS, defined as being alive and free of subsequent HCT, GVHD and event free survival), GRFS (defined as abence of second HCT, grade III-IV acute and extensive chronic GVHD) and overall survival (OS) were evaluated using Kaplan-Meier. GVHD outcomes and subsequent HCT were estimated using cumulative incidence function with death as competing risks. Differences between outcomes were tested by log-rank and Gray tests and multivariable Cox models were using for adjustement including age at HCT in class, year in periods and donor type.

RESULTS: 2,807 consecutive patients were transplanted in centers distributed accross 36 countries in Europe, Asia and Africa: 2,601 children (up to 18 years of age) and 206 adults. Median age at transplant of children was 6.7 years (range 0.5-18) and in adults 22.1 years (18-44.8). 55.1% children were male and 44.9% female, and 51.7% adults were male whereas 48.3% were female.

The numer of matched related, mismatched related and unrelated transplants were 1,879 (72.7%), 156 (6%) and 551 (21.3%) for children and 143 (69.4%), 14 (6.8%) and 49 (23.8%) for adults. 69.2% of children received bone marrow as the stem cell source whereas 59.3% adults received PBSC. The most common conditioning regimen for children was BuCy based (34.7%) for children whereas for adults it was FluBu (45.3%), a quarter of both groups using BuTreo based.

After a median follow up of 24 months, the 2 years OS and EFS were 92.1% (90.8 - 93.3) and 87.4% (85.7 - 88.9) for children and 84.4% (78.1 - 89) and 80.8% (73.9 - 86.1) for adults, respectively. Acute GVHD grade III/IV and chronic GVHD extensive occurred in 8.4% (7.2 - 9.6) and 4.4% (3.5 - 5.6) of children and 9.5% (5.8 - 14.3) and 7.2% (3.5 - 12.7) of adults, respectively. In multivariable analysis, impact of age of patient and donor type were statistically significant for age on overall survival and both on overall and severe GVHD; whereas year of HCT (before or after 2015) had a significant protective effect on severe chronic GVHD and overall survival. Compared to the class 0-4 years old, the impact on GRFS of age were HR 0.87 (0.65-1.16, p= 0.33) for the group 4-7 years, HR 0.96 (0.73-1.27, p = 0.8) for 7-12 years, HR 1.59 (1.2-2.1, p = <0.001) for 12-18 years and HR 1.63 (1.15-2.32, p = 0.006) for the group ≥18 years.

CONCLUSIONS: Real world data confirms allogeneic HCT as a curative therapy for TDT with high rate of cure. Age continues to be a crucial determinant of outcomes of HCT with best GFRS achieved in those transplanted up to 12 years of age. There has been a significant reduction in the risk of severe chronic GVHD over time despite almost a third of HCT being with alternative donors.