Allogeneic Transplantation for Sickle Cell Disease Offers High Rates of Cure with Low Incidence of Severe Chronic GVHD in Both Children and Adults: 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 most widely available curative option for sickle cell disease (SCD) but alternative approaches are no emergeing tieh licensing of gene therapy. Hence, in order to enable inform decision making up to date real world data is necessary and international registries are best place to enable this.

METHODS: Data on pediatric and adult patients with SCD 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 outcomes. 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: 1,484 consecutive patients were transplanted in centers distributed accross 36 countries in Europe, Asia and Africa: 1,331 children (up to 18 years of age) and 484 adults. Median age at transplant of children was 9.6 years (range 1.1-18) and in adults 26.5 years (18-49.2). 52% children were male and 48% female, and 51.5% adults were male whereas 48.5% were female, with 5 data was missing.

The numer of matched related, mismatche related and unrelated transplants were 1,066 (80.5%), 144 (10.6%) and 115 (8.7%) for children and 401 (83%), 72 (14.9%) and 10 (2.1%) for adults. 80.5% of children received bone marrow as the stem cell source whereas 64.9% adults received PBSC. The most common conditioning regimen for children was BuCy based (43.3%) for children whereas for adults it was TBI-based (68.7%), BuTreo based represented a quarter of all transpalnts in children. Only 171 children (13.1%) and 14 adults (2.9%) did not have serotherapy as part of conditioning regimen.

After a median follow up of 24 months, the 2 years OS and EFS were 95.7% (94.3 – 96.7) and 92.9% (91.3 - 94.3) for children and 93.7% (91 - 95.7) and 80.8% 90.5 (87.3 - 93) for adults, respectively. Acute GVHD grade III/IV and chronic GVHD extensive occurred in 3.9% (2.4 - 6) and 4.1% (2.5 - 6.3) of children and 8.4% (7.2 - 9.6) and 4.4% (3.5 - 5.6) of adults respectively. In multivariate analysis, age of patients had a significant effect on OS [ 12-18 years HR 2.01 (1.01-3.99, p = 0.047; >18 years HR 2.47 (1.23-4.94, p = 0.01)] but not on the incidence of acute or chronic GVHD resulting in no diffence in GFRS. The year of transplant has a significant effecton overall survival [HR 0.59 (0.37-0.93, p = 0.02) with lower risk of both acute GVHD [HR 1.87 (1.33-2.61, p = <0.001)] and chronic GVHD [HR 0.54 (0.34-0.86, p = 0.01] in those transplanted after 2015.

CONCLUSIONS: Real world data demonstrates allogeneic HCT offers excellent outcomes as a curative therapy for SCD across all ages with high rate of cure irrespective of age, likely due to the high proportion of adults using reduced intensity regimens with GVHD prevention strategies. The incidence of severe chronic GVHD is low irrespective of age.