Hematopoietic stem cell transplantation for inherited bone marrow failure syndromes: alternative donor and disease-specific conditioning regimen with unmanipulated grafts

Abstract

Objective: The outcomes of alternative donor hematopoietic stem cell transplantation (HSCT) with unmanipulated grafts for Inherited bone marrow failure syndromes (IBMFS) are discouraging. Our study is to demonstrate that IBMFS with disease-specific characteristics requires a tailored conditioning regimens to enhance engraftment and reduce regimen related toxicities. Methods: We retrospectively analyzed 42 patients diagnosed with IBMFS and transplanted with an alternative donor graft at our center from November 2012 to August 2018. Twenty-seven patients had Fanconi anemia (FA), 7 had dyskeratosis congenita (DC), and 8 had severe congenital neutropenia (SCN). Patients received ex-vivo unmanipulated alternative donor grafts from a matched unrelated donor (MUD) (n = 22), haploidentical donor (HID) (n = 17) and unrelated cord blood donor (UCBD) (n = 3). FA and DC patient subgroups received reduce intensified conditioning (RIC), while SCN patients received a myeloablative conditioning (MAC) regimen. Results: The median follow-up time for the surviving patients was 38 months (range: 9-63 months). The failure-free survival (FFS) for entire cohort was 76.1%, and was 72.4%, 100% and 56.2% for patients with FA, DC and SCN, respectively. There were no primary graft failures. The cumulative incidence of aGVHD at day 100 was 48.1%. The cumulative incidence of cGVHD at 1 and 3 years was 35.0% and 69.3%, respectively. Conclusion: HSCT using alternative donors with unmanipulated grafts and disease-specific conditioning regimens for IBMFS patients shows promising survival.

Influence of cyclosporine A trough level on acute graft versus host disease prophylaxis in pediatric allo- hematopoietic stem cell transplantation

“…In addition, Handgretinger [22] estimates that more than half of all HLA haplotype-mismatched transplants will be performed worldwide following similar protocols. Previous studies at our center demonstrated that conditioning regimens based on GIAC achieved favorable engraftment, OS, and an acceptable morbidity of GVHD among allo-HSCT patients [23][24][25][26][27][28][29].…”

Fludarabine-based Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in a Pediatric Patient With Bone Marrow Failure Syndrome Type 3

“…In contrast, HSCT can cure the cytopenia, whereas, it has no effect on congenital malformations or the overall risk of developing malignancies which may increase with HSCT 2,10,11,13–15…”

“…10,11 In contrast, HSCT can cure the cytopenia, whereas, it has no effect on congenital malformations or the overall risk of developing malignancies which may increase with HSCT. 2,10,11,[13][14][15] Therefore, the tolerability of irradiation and high-dose chemotherapy in these disorders is limited and associated with significant tissue injury may causes co-existing organ defects as combination with the underlying genetic defect as well as consequences in the long term. 14,15 Subsequently, attenuated preparative regimens have been proposed in children with BMFS.…”

“…14,15 Subsequently, attenuated preparative regimens have been proposed in children with BMFS. [9][10][11][13][14][15] In the more recent years, many studies showed promising outcomes of successful stable donor chimerism rates with removing total body irradiation and using reduced intensity conditioning regimens in an attempt to minimizing regimen-related toxicity in nonmalignant diseases. [9][10][11]13,14,16,17 Although some patients had stable mixed chimerism, they had long-term cure with no symptoms of their underlying disease.…”

Cell and Gene Therapy for Anemia: Hematopoietic Stem Cells and Gene Editing

“…Stem cell transplantation (SCT) is the optimal choice for inducing normal hematopoiesis. Patients with severe pancytopenia (Hb ≤ 8 g/dL, absolute neutrophil count < 1000/µL, or platelet count ≤ 40-50,000/µL) who are otherwise healthy and have an available HLA-MSD are ideal candidates for HSCT [73,74].…”