Allogeneic Stem Cell Transplantation in Congenital Hemoglobinopathies Using a Tailored Busulfan-Based Conditioning Regimen: Single-Center Experience

Abstract

Hematopoietic stem cell transplantation (HSCT) is the only proven curative option for patients with hemoglobinopathies, both thalassemia and sickle cell anemia (SCA). A busulfan-based myeloablative conditioning regimen is the standard of care for HSCT in these patients, although increased treatment-related morbidity, including veno-occlusive disease (VOD), has been demonstrated. Thirty-eight pediatric patients, median age 8 years (range, 6 months to 22 years), suffering from hemoglobinopathy were treated at Rambam Medical Center in Haifa, Israel, between 1998 and 2011. Thirty-four patients had thalassemia major and 4 had SCA. The 38 patients underwent 40 HSCTs, 34 of which were first transplants and 6 second transplants. Most transplants (32/40) were from matched sibling donors. Sources of stem cells were peripheral blood in 30 transplants, bone marrow in 7 transplants, and cord blood in 3 transplants. All received different customized busulfan-based conditioning regimens tailored by pharmacokinetic analysis of busulfan levels. Primary engraftment occurred in 37 of 40 transplants. Neutrophil engraftment (>.5 × 10(9)/L) occurred at a median of 15.3 days post-transplantation (range, 10 to 45). Platelet transfusion independence (>20 × 10(9)/L) occurred at a median of 22.3 days (range, 11 to 60). The rate of 5-year overall survival for thalassemia patients after first transplantation was 90.5% ± 5.3%. The rate of 5-year thalassemia-free survival was 81.7% ± 6.8%. Cumulative incidence of acute graft-versus-host disease (GVHD) was 17.6%. Rate of grades III to IV GVHD was 8.8%. Cumulative incidence of chronic GVHD was 23.5%, with 11.8% incidence of extensive chronic GVHD. One patient developed VOD. Full donor chimerism occurred in 36.4% of patients with class 1 + 2 thalassemia, compared with 78.6% in class 3 thalassemia (P = .049). Overall survival above 90% in patients undergoing their first transplant was demonstrated using busulfan-based conditioning regimens. The low incidence of VOD was probably due to busulfan area under the curve measurements and dose adjustment.

A Multicenter Retrospective Analysis Stressing the Importance of Long-Term Follow-Up after Hematopoietic Cell Transplantation for β-Thalassemia

“…Mixed chimerism in nonmalignant disorders is often associated with reduced-intensity transplants [9,[40][41][42]. This pattern of mixed chimerism is prevalent in thalassemia and may be due to engraftment barriers posed by transfusion exposure, alloreactive antibodies, and recipient immunocompetence [17,43,44].…”

Conditioning Regimens in Patients with β-Thalassemia Who Underwent Hematopoietic Stem Cell Transplantation: A Scoping Review

“…A high graft failure rate requires a more active protocol for pretransplant immunosuppression (PTI) and myelosuppression. Class 3 patients experienced reduced TMR and graft failure, as well as increased OS and TFS, upon being treated with protocol 26 (P26), a pretransplant treatment involving 30 mg/kg/day of hydroxyurea (HU), 3 mg/kg/day of azathioprine (Azat), 20 mg/m 2 /day of Flu, and anti-thymocyte globulin (ATG) in addition to Bu-Cy [24,58]. The use of PTI was also extended in HR class 3 patients.…”

How I manage children with Diamond‐Blackfan anaemia

“…Chronically transfused DBA patients, in addition to iron overload, often have HLA‐antibodies following numerous RBC transfusions. Therefore, similar to patients with homozygous beta‐thalassaemia or other transfusion‐dependent haematological disorders, a modified preconditioning regimen can be considered as an additional pre‐treatment in order to decrease the risk of graft‐rejection (Shenoy & Thompson, ; Zaidman et al , ).…”