Fludarabine–Cyclophosphamide-Based Conditioning with Antithymocyte Globulin Serotherapy Is Associated with Durable Engraftment and Manageable Infections in Children with Severe Aplastic Anemia

Abstract

Severe aplastic anemia (SAA) is a bone marrow failure syndrome that can be treated with hematopoietic cell transplantation (HCT) or immunosuppressive (IS) therapy. A retrospective cohort of 56 children with SAA undergoing transplantation with fludarabine–cyclophosphamide–ATG-based conditioning (FluCyATG) was analyzed. The endpoints were overall survival (OS), event-free survival (EFS), cumulative incidence (CI) of graft versus host disease (GVHD) and CI of viral replication. Engraftment was achieved in 53/56 patients, and four patients died (two due to fungal infection, and two of neuroinfection). The median time to neutrophil engraftment was 14 days and to platelet engraftment was 16 days, and median donor chimerism was above 98%. The overall incidence of acute GVHD was 41.5%, and that of grade III-IV acute GVHD was 14.3%. Chronic GVHD was diagnosed in 14.2% of children. The probability of 2-year GVHD-free survival was 76.1%. In the univariate analysis, a higher dose of cyclophosphamide and previous IS therapy were significant risk factors for worse overall survival. Episodes of viral replication occurred in 33/56 (58.9%) patients, but did not influence OS. The main advantages of FluCyATG include early engraftment with a very high level of donor chimerism, high overall survival and a low risk of viral replication after HCT.

Human leucocyte antigen‐matched related haematopoietic stem cell transplantation using low‐dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia

“…There have been limited studies that utilized a lower dosage of Cy in combination with fludarabine for children with SAA who are undergoing MRD HSCT. Cy dose ranging from 100 to 120 mg/kg was used successfully in combination with Flu and ATG or alemtuzumab in children with SAA with disease‐free survival ranging from 94% to 100% 25–27 . In a small pilot study, Flu and ATG‐based conditioning with low (60 mg/kg) dose Cy was used in 7 children with acquired SAA who underwent HSCT.…”

“…with Flu and ATG or alemtuzumab in children with SAA with disease-free survival ranging from 94% to 100%. [25][26][27] In a small pilot study, Flu and ATG-based conditioning with low (60 mg/kg) dose Cy was used in 7 children with acquired SAA who underwent HSCT. No rejection occurred in three patients who underwent BM 6/6 MRD HSCT as compared to high secondary rejection with the use of 5/6 MMRD BM and unrelated cord blood transplant.…”

Shifting Paradigms: The Case of Autologous Reconstitution after an Upfront Matched Unrelated Hematopoietic Cell Transplantation for Severe Acquired Aplastic Anemia in a Child

“…In a retrospective series of 56 children receiving sibling or MUD allografts, after a conditioning regimen with fludarabine, cyclophosphamide and ATG, including 32 in the first line, none developed graft rejection [17]. In another study, including 50 patients (children and adults) who received HCT between 1999 and 2009 conditioned with FCC regimen, rejection occurred in six patients, of whom four transplanted from an MUD.…”

Short- and long-term outcome of allogeneic stem cell transplantation in infants: A single-center experience over 20 years

“…Changes in the diagnostic criteria for SOS/VOD and the wider availability of defibrotide for the treatment of this complication were other factors limiting the adverse effect in post-transplant outcomes. Viral infections constitute a significant cause of morbidity and mortality after HSCT, but the incidence of viral replication in the literature varies and has a wide range; depending, for example, on the type of disease ( 14 , 21 ). We observed a statistically significant association between post-transplantation ADV, and EBV, replication and type of the donor, but this was a consequence of underdiagnosing in patients transplanted between 1999 and 2009, when the number of haploidentical donors was higher than in the second period.…”

“…In two patients minimal, non-myeloablative (NMA) conditioning was administered. Patients undergoing transplantation were screened weekly for the replication of viruses [adenovirus (ADV), polyoma BK virus (BKV), human cytomegalovirus (CMV), Epstein-Barr virus (EBV)], blood cultures and multidrug resistant bacteria colonization as a part of routine monitoring [as summarized by Salamonowicz-Bodzioch et al ( 14 )]. However, until 2007 the diagnostics of ADV, BKV and EBV was limited in comparison to the later period.…”