Long-term event-free survival, chimerism and fertility outcomes in 234 patients with sickle-cell anemia younger than 30 years after myeloablative conditioning and matched-sibling transplantation in France

Abstract

A llogeneic stem cell transplantation remains the only curative treatment for sickle cell anemia (SCA), but the place of myeloablative conditioning in the procedure remains to be defined. The aim of the present study was to analyze long-term outcomes, including chimerism, SCA-related events and biological data (hemoglobin, reticulocytes, HbS%), and fertility in a French series of 234 SCA patients under 30 years of age who, from 1988 to 2012, received a matched-sibling-donor stem cell transplantation following standardized myeloablative conditioning [busulfan, cyclophosphamide and rabbit anti-thymocyte globulin (ATG)]. Since the first report of the series (1988)(1989)(1990)(1991)(1992)(1993)(1994)(1995)(1996)(1997)(1998)(1999)(2000)(2001)(2002)(2003)(2004), 151 new consecutive patients with SCA have been similarly transplanted. Considering death, nonengraftment or rejection (donor cells <5%) as events, the 5-year event-free survival was 97.9% (95% confidence interval: 95.5-100%), confirming, since the year 2000, an at least 95% chance of cure. In the overall cohort (n=234, median follow up 7.9 years), event-free survival was not associated with age, but chronic-graft-versus-host disease (cGvHD) was independently associated with recipient's age >15 years (hazard ratio=4.37; P=0.002) and lower (5-15 vs. 20 mg/kg) ATG dose (hazard ratio=4.55; P=0.001). At one year, 44% of patients had mixed chimerism (5-95% donor cells), but those prepared with ATG had no graft rejection. No events related to SCA occurred in patients with mixed chimerism, even those with 15-20% donor cells, but hemolytic anemia stigmata were observed with donor cells <50%. Myeloablative transplantation with matched-sibling donor currently has a higher event-free survival (98%) in patients under 30 years of age than that reported for non-myeloablative conditioning (88%). Nevertheless, the risk of cGvHD in older patients and the need to preserve fertility might be indications for a non-myeloablative conditioning.

Early viral reactivation despite excellent immune reconstitution following haploidentical Bone marrow transplant with post‐transplant cytoxan for sickle cell disease

“…We also have shown favorable outcomes following this reduced intensity conditioning approach, a platform that offers curative potential for most eligible patients, even those with chronic organ dysfunction . As hypothesized, transplant‐related outcomes in terms of engraftment and incidence of acute and chronic GvHD were comparable to trials involving matched sibling donor grafts . The drug‐induced immunologic tolerance with PTCy has greatly reduced historic life‐limiting severe acute and chronic GvHD .…”

“…A novel finding in our study was the early immune reconstitution of T‐, B‐, and NK‐cell subsets despite intense immunodepletion . Multiple reasons exist for favorable immune reconstitution in the setting of haplo‐BMT, which historically has required intense immunosuppression either pre‐transplant with T‐cell depletion strategies or post transplant with drug‐induced immunologic tolerance, most commonly with PTCy .…”

“…In addition, graft rejection was found to be 3.1% (95% CI 0.7%‐5.5%). The incidence of acute GvHD grade ≥ II was 20.1% (95% CI 14.9%‐25.3%) and of chronic GvHD 10.5% (95% CI 6.5%‐14.5%) . The main infection complications were CMV reactivation, seen in 23.9% of patients, and asymptomatic EBV viral replication was observed in 6% of patients .…”

“…Myeloablative conditioning followed by infusion of bone marrow allografts from matched siblings donors remains the gold standard for achieving optimal transplant‐related outcomes for children and adults with sickle cell disease. In the longest follow‐up study to date, Bernaudin et al detail the outcomes of 234 patients with sickle cell anemia younger than 30 years who underwent transplant . The 5‐year cumulative incidence of transplant‐related mortality was 3% (95% CI 0.8%‐5.2%) .…”

“…In the longest follow‐up study to date, Bernaudin et al detail the outcomes of 234 patients with sickle cell anemia younger than 30 years who underwent transplant . The 5‐year cumulative incidence of transplant‐related mortality was 3% (95% CI 0.8%‐5.2%) . In addition, graft rejection was found to be 3.1% (95% CI 0.7%‐5.5%).…”