Excellent overall and chronic graft‐versus‐host‐disease‐free event‐free survival in Fanconi anaemia patients undergoing matched related‐ and unrelated‐donor bone marrow transplantation using alemtuzumab–Flu–Cy: the UK experience

Abstract

Haematopoietic stem cell transplantation (HSCT) remains the only curative option in Fanconi anaemia (FA). We analysed the outcome of children transplanted for FA between 1999 and 2018 in the UK. A total of 94 transplants were performed in 82 patients. Among the donors, 51Á2% were matched related donors (MRD) while the remainder were alternative donors. Most patients received a fludarabine-cyclophosphamide (Flu-Cy)based conditioning regimen (86Á6%) and in vivo T-cell depletion with alemtuzumab (69Á5%). Five-year overall survival (OS) was 85Á4% [70Á4-93.2] with MRD, 95Á7% [72Á9-99.4] with matched unrelated donors (MUD), 44Á4% [6Á6-78.5] with mismatched unrelated donors (MMUD) and 44Á4% [13Á6-71.9] with mismatched related donors (MMRD) (P < 0Á001). Other factors significantly impacting OS were pre-transplant bone marrow status, source of stem cells, cytomegalovirus (CMV) serostatus, preparation with Flu-Cy, use of total body irradiation (TBI) and alemtuzumab as serotherapy. In multivariate analysis, absence of myelodysplastic syndrome (MDS) or leukaemia, bone marrow as source of stem cells, cytomegalovirus (CMV) other than +/À (Recipient/Donor) and Flu-Cy were protective factors for five-year OS. Five-year chronic graft-versus-host-disease (cGVHD)-free event-free survival was 75Á4% with the same risk factors except for CMV serostatus. Five-year non-relapse mortality was 13Á8% [7Á3-22.3]. Only five patients (6Á1%) developed grade II-IV acute GVHD and two patients chronic GVHD. These data confirm the excellent outcome of matched related or unrelated HSCT in children with FA.

Recent advances in hematopoietic cell transplantation for inherited bone marrow failure syndromes

“…Several studies have shown that chronic GVHD is highly associated with increased risk of secondary malignancies and late mortality in patients with FA, highlighting the need for the optimization of GVHD prophylaxis for HCT in these patients [9,13,16]. A recent study from the UK reported that fludarabine-based RIC with alemtuzumab provided excellent OS and chronic GVHD-free EFS in patients with FA undergoing HCT, suggesting the specific benefit of alemtuzumab for these patients [23]. Frequently observed malignancies after HCT in FA include head and neck squamous cell carcinoma (HNSCC) and gynecological cancers [13,16,24].…”

Unmanipulated haploidentical haematopoietic cell transplantation with radiation‐free conditioning in Fanconi anaemia: A retrospective analysis from the Chinese Blood and Marrow Transplantation Registry Group

“…Although the dose of irradiation is low (100-200 cGy), researchers have observed secondary tumour rates ranging from 3% to 7%, which leads to poor prognosis. [22][23][24][25] The reported results of conditioning patients with FA without radiation in haplo-settings are limited to case studies. [26][27][28] A single-centre pilot study reported 15 unmanipulated haplo-HCTs in FA, showing an engraftment rate of 100% and excellent survival of 93% after fludarabine (Flu), cyclophosphamide (Cy) and anti-thymocyte globulin (ATG) conditioning.…”

“…However, currently, most studies in haplo‐HCT for FA have included radiation in the conditioning regimens. Although the dose of irradiation is low (100–200 cGy), researchers have observed secondary tumour rates ranging from 3% to 7%, which leads to poor prognosis 22–25 …”