Excellent long-term outcomes after alemtuzumab-based hematopoietic cell transplantation (HCT) for severe aplastic anemia (SAA) and inherited bone marrow failure syndromes (IBMF): A 25-year British society of blood and marrow transplantation and cellular therapy (BSBMTCT) retrospective analysis of 1754 patients from the United Kingdom (UK)

Abstract Background: Allogeneic stem cell transplantation (HCT) is a curative option for patients with acquired severe aplastic anemia (SAA) and inherited BMF syndromes (BMFs). The FCC regimen (fludarabine, cyclophosphamide and alemtuzumab) with cyclosporin (without irradiation and methotrexate) for Graft-versus-Host Disease (GvHD) prophylaxis is UK standard of care due to excellent survival and low GvHD/rejection incidence. FCC is uniformly used across ages, irrespective of BMF etiology. We report 10y outcomes following HCT for SAA and IBMFs reported to the BSBMTCT registry over the last 25 years. Methods: Retrospective data were collected from all SAA and IBMF patients transplanted using HLA 9-10/10 sibling/unrelated donors at 33 UK centres between 1999-2024. Overall survival (OS) and GvHD free, relapse free survival (GFRS) were calculated by Kaplan-Meier method. Comparison between groups was done by Cox regression. Results: 1718 patients (SAA 1374, 80% and IBMF 344, 20%), 888 (52%) pediatric (<18y) and 830 (48%) adult (>18y) patients were studied. SAA comprised 583 children (42%) and 791 adults (58%); median ages 10.5y (IQR 7-14y) and 36y (IQR 24-52y) respectively. 68% had ethnicity data: 83% self-reported white, 17% mixed, Asian or Black. 78% had HCT after 2010, with procedures rising over time ( e.g. 290 in 2019-2024 vs 84 in 2004-2008). Median time from diagnosis to HCT was 4m (IQR 1m-15y, pediatric) and 9m (IQR 1m-34y, adults). 38% of adults and 14% of paediatric SAA cases had HCT >12m after diagnosis. Comorbidity (HCT-CI) was 0-2 in 60% of <18 years and 50% of adults. Conditioning regimen included alemtuzumab in 74% or thymoglobulin in 12%. Alemtuzumab showed increased use in the last decade (87%); 8% incorporated total body irradiation due to HLA mismatch. Cell source was mainly bone marrow (BM) in children (80%) but largely peripheral blood (66%) in adults. 59% of donors were unrelated. IBMF group (Fanconi anemia (50%), Diamond Blackfan Anemia (19%) or telomeropathy (7%)) was mainly pediatric (n=305, 89%). Only 20% of adult cases were IBMFs. Median age at HCT was 7.5y (IQR 5-10y). Alemtuzumab was the commonly used serotherapy (60%) across all age groups; BM was the preferred source in 81% of <18 years compared to 33% of adults. Median follow-up was 5y (IQR 1.3-8.9y). Rates of primary and secondary graft failure were 3% and 2% (children) and 4% and 4% (adults). The rate of grade 2-4 acute GVHD and 1y cumulative incidence of any grade cGVHD was 9.2% and 9% in children and 5.5% and 13% in adults, with 5% moderate/severe/extensive cGVHD at 10 years. The 10y OS and GFRS for pediatric and adult patients in SAA was 93% (95% CI, 90-95%) & 83% (95%CI, 79-86%) and 78% (95%CI, 74-82%) & 68% (95%CI, 63-71%), whilst in IBMF 86 and 70% in children and 48 and 39% in adults, respectively. With FCC, 10y OS was 94% (95% CI, 89-97, children) and 79% (95% CI, 73-84, adults), whilst 10y GFRS was 83% and 70% respectively. FCC was statistically superior to other conditioning regimens for OS and GFRS, especially in adults (HR 0.67, p=0.029) vs pediatric (HR 0.52, p =0.070): Adults, HR 0.75, p=0.04 vs pediatric, HR 0.97, p=0.9). Age impacted OS in adults, HR 1.03, p<0.0005 (OS in18-39y, 85% vs 40-59y, 73% vs >60y 45%). Donor type did not influence OS; BM was superior only in children, both in SAA and IBMF: SAA (BM 95% vs PB 88%, P=0.01, HR 0.39) and IBMF (BM 90% vs PB 74%, P=0.009, HR 0.38). HCT-CI and Karnofsky performance score (KPS) impacted survival outcome in all age categories. FCC conditioning (OS: HR 0.35, p=0.034; GFRS, HR 0.49, p=0.01) and stem cell source (HR 0.41, p=0.033; HR 0.56, p=0.02) retained significance at multivariate analysis in children with SAA for both OS & GFRS, whilst advancing age (40-59 yrs, HR 1.96, p=0.002; >60 yrs, HR 3.25, p=0.0005) and KPS (<80, HR 1.99, P=0.005) impacted OS in adults. GFRS was impacted by FCC (>18y, HR 0.66, P=0.01) and by donor type (unrelated, <18y, HR 2.1, p=0.02 & >18y, HR 1.5, p=0.02) across the whole cohort of SAA.Conclusion: This is the largest report of BMF patients transplanted using a uniform alemtuzumab-based regimen, with excellent 10-year survival, low rates of graft failure and GVHD in both SAA and IBMF. The added benefit of BM as a stem cell source was evident in children; future efforts in the adult cohort should be directed toward improving outcomes in those >60yrs. Excellent OS and GFRS indicate alemtuzumab should be recommended in conditioning for all BMF syndromes.