Fludarabine-Based HLA-Identical Sibling HSCT for Patients with Severe Aplastic Anemia (SAA) Older Than 30 Years: A Study from the French (SFGM-TC) and Italian (GITMO) Registries.
Authors: Maury S. , Bruno B. , Chir Z. , Garban F. , Blaise D. , Contentin N. , Esperou H. , Cordonnier C. , Bacigalupo A. 
Published: October 2019

Survival after HSCT from HLA-identical siblings is inferior in SAA patients 30 years or older as compared with younger patients, with long-term overall survival of 58% and 80%, respectively (Bacigalupo et al, Semin in Hematol 2000). In order to improve survival in patients >30 years, the use of a less toxic regimen including low dose cyclophosphamide (<200 mg/kg) in combination with ATG, while adding fludarabine, might be an option to explore with the aim to reduce transplant-related mortality (Marsh et al, Br J Haematol, 2003). In order to evaluate the toxicity profile, engraftment potential, and efficacy of HLA-identical HSCT using such fludarabine-based conditioning regimen, we conducted this study from the SFGM-TC and GITMO databases, focussing on patients older than 30 years or those younger than 30 years but with co-morbidities at HSCT. From December 1998 to June 2004, 15 HSCT were performed in 14 patients (median age 39 years, range 16–60 years), for idiopathic SAA (n=13), or paroxysmal nocturnal hemoglobinuria (PNH) (n=1). HSCT was performed either as first-line treatment (n=8), or after failure of immune suppression with ATG/ciclosporine (CsA) (n=4), or failure of a first allogeneic HSCT (n=3). In addition to fludarabine (120 mg/m2) and ATG (3.75 mg/kg x 2 to 4 days), the patients received two different reduced doses of cyclophosphamide of 120 mg/kg (n=4) or 20 mg/kg (n=9). Two patients received only ATG and fludarabine (175 mg/m2) without cyclophosphamide. Marrow (n=12, median dose of nucleated cells 5.108/kg, range 2–15.108/kg) or PBSC (n=3) grafts were unmanipulated. GVHD prophylaxis consisted of CsA/methotrexate (n=11), CsA alone (n=1), methotrexate alone (n=1), or nothing (n=2 second grafts). Graft rejection occurred in one patient, who received a second graft from the same donor with the same conditioning regimen (fluda/ATG/cyclophosphamide 20 mg/kg) successfully. All other patients engrafted with a neutrophil (ANC >500 cells/μL) and platelet (PLT >50 000/μL) recovery occurring at a median of 18 days (range 12–28 days), and 26 days (range 11–272 days) after transplant, respectively. Acute GVHD occurred in 3 patients with a maximum grade II in 2 patients and grade III in one. Among 11 evaluable patients, six developed chronic GVHD (limited in 3 cases). Four patients died of infection (n=3) or multi-organ failure (n=1), within the 3 months post-HSCT for 3 of them. With a median follow-up of 28 months (range 11–48 months), 10/14 patients survived with long-term engraftment and full (n=8) or mixed (n=2) donor chimerism (KM probability of long-term survival 71%-see figure). In conclusion, reduced intensity fludarabine-based conditioning regimen is feasible in SAA patients over the age of 30 and produces encouraging survival: a prospective trial is being conducted within the European Group for Blood and Marrow Transplantation (EBMT).

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