Related Myeloablative Stem Cell Transplantation (SCT) to Cure Sickle Cell Anemia (SCA): Update of French Results

Abstract 3518 Background: Despite progress made in sickle cell anemia (SCA) management, such as the prevention of pneumococcal infections, introduction of hydroxyurea therapy and early cerebral vasculopathy detection with transcranial Doppler, SCA remains a disease with high risk of morbidity and early death. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for SCA; nevertheless, its use has been limited by the risk of transplant-related mortality (TRM). Our first experience, reported in Blood 2007, included 87 consecutive severe SCA- patients transplanted in France between 1988 and Dec-2004. We showed that the introduction of rabbit anti-thymocyte globulin (ATG) in the conditioning regimen in 2000 allowed a significant reduction of the rejection rate from 22.6% to 3% and that the outcome improved significantly with time as the DFS rate among the 44 patients transplanted after January 2000 was 95.3%. These data have justified continuing to transplant symptomatic young sickle cell patients having a geno-identical donor with the same conditioning regimen (CR) consisting of intravenous Busulfan (BU), Cyclophosphamide (CY) and rabbit ATG. Patients and Methods: In France, from 1992 to 2010, 144 SCA-patients (84M, 60F) have now been transplanted with a geno-identical donor using BU-CY-ATG as CR at the median age of 9.0 years (range:3.2-27.5). Transplants were performed in 16 different centers but 60 were performed in Hopital St-Louis and 21 in Hopital Debré in Paris. All recipients were SS or Sb0 and 76% of them were CMV+. All had been transfused and 47% had received more than 20 units. The source of cells was the bone marrow (BM) (n=121), cord blood (CB) alone (n=21), CSP (n=1) or BM+CB (n=1). GvHD prophylaxis consisted of the association of cyclosporine (CSA)-short MTX for BMT and CSA alone for CBT. Results: Engraftment was successful in 141/144; the time to absolute neutrophil count > 500/mm3 was significantly shorter after BMT compared to CBT (mean ± SD; 21.3 ± 6.7 vs 32.1 ± 9.8, respectively; p<0.001) and platelets reached 50,000/mm3 sooner after BMT (day 28.3 ± 16.6) than after CBT (day 48.5 ± 20.3; p<0.001). No engraftment occurred in 3 cases (1 BMT, 2 CBT) with gradual autologous reconstitution, and one rejection was observed 3 years post-transplant. GvHA grade ≥ II occurred in 23% of patients, GvHA ≥ III in 4.4%, chronic GvH in 9.6% (extensive in 3 cases). No GvHD ≥ II or chGvHD were observed after CBT. Death occurred in 6 cases (4 were GvHD-related, 1 hemorrhagic stroke in a patient with severe cerebral vasculopathy with Moya and 1 sepsis in aplasia). No veno-occlusive disease was observed, but hemorrhagic cystitis (n=4), EBV proliferative disease requiring anti-CD20 therapy (n=1), nephrotic syndrome (n=1), and cerebral vasculopathy not SCA-related (n=1) were. Despite preventive measures such as anticonvulsant prophylaxis, strict control of hypertension, swift magnesium replacement, and an increase in the red blood cell and platelet transfusion thresholds to 9 g/dL and 50,000/mm3, respectively, seizures and posterior leukoencephalopathy, albeit reversible, remained a particularly frequent adverse effect of CSA and steroid therapy. Replacing CSA in 2002 by mycophenolate mofetil in case of GvHD requiring steroid therapy resulted in a significant reduction of the rate of these complications. With a median follow-up of 3.1 years (range 0.2–15.5), the overall survival at 3 yr was 95% (95%CI:91-99%). Considering as events the non-engraftments, rejections and deaths, the event-free survival (EFS) was 92.9% (95%CI:88.3-97.5). However, comparing the results before (n=23) and after 2000 (n=121) showed significant improvement of EFS at 3 yr: 73.9% (95%CI: 55.5–92.3) for transplants performed before 2000 vs 96.8% (95%CI:93.2-100) after 2000. Conclusion: These results with 121 patients transplanted since 2000 confirm that it is possible to offer more than 95% chances of cure to SCA-children, indicating that HLA-geno-identical HSCT after myeloablative conditioning with ATG should be considered as standard of care for SCA children, not only for those at high risk of stroke but also for children experiencing crises or other complications requiring intensive therapy such as transfusion program or hydroxyurea. Sibling cord-blood cryopreservation should be systematically offered and pre-implantation genetic diagnosis coupled with HLA selection discussed with the parents. Disclosures: No relevant conflicts of interest to declare.