Safety and efficacy of targeted busulfan therapy in children undergoing myeloablative matched sibling donor BMT for sickle cell disease

Abstract

Busulfan influences engraftment and toxicities during hematopoietic stem cell transplantation (HSCT). We report our single-institution experience of targeted busulfan therapy for myeloablative, matched sibling donor (MSD) HSCT for sickle cell disease (SCD) and assess the relationships of busulfan levels to engraftment and toxicities. Twenty-seven patients with SCD underwent MSD HSCT from 1993 to 2007, 25 with busulfan measurements. The conditioning regimen was busulfan (initial dose 0.875 mg/kg for 16 doses), CY and antithymocyte globulin. Busulfan area under curve (AUC) was determined with the first dose, and dose adjustments were made to target the desired AUC range. Median AUC was 963 lmol min/L (range 780-1305 lmol min/L). Engraftment occurred in all cases: 21 (84%) full donor chimerism (495% donor cells), 4 (16%) partial donor chimerism. Hepatic veno-occlusive disease (VOD) occurred in 8 (32%) patients. Lower AUC was seen with partial donor chimerism (862±73 lmol min/L) versus full donor chimerism (AUC 1018 ± 122 lmol min/L) (P ¼ 0.022). VOD was not associated with busulfan AUC (P ¼ 0.153). Of 25 patients, 24 survived with median follow-up of 4.9 years. Our experience shows that targeting busulfan AUC above the range used in previous multicenter trials appears safe and may contribute to sustained engraftment in SCD.

Hematopoietic SCT for the Black African and non-Black African variants of sickle cell anemia

“…[15][16][17][18][19][20][21][22][23] The results of several major studies summarized in Table 5 show an OS of 490% and an EFS of 480%.…”

Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel

“…34,[73][74][75] Growth does not seem to be impaired following myeloablative conditioning as long as it is not performed near or during the adolescent growth spurt. However, the risks of infertility and secondary neoplasm are a major concern.…”

“…OS was found to be around 95%. [72][73][74][75] Bernaudin et al reported 121 patients transplanted in France after 2000 with a DFS of 95% at three years. 76 Taking into account that: 1) overall survival has become equal or even better in patients who undergo HSCT compared to those on supportive treatment, and disease-free survival is over 95%; 2) diseaserelated morbidity and mortality are increasing with age, and event-free survival following HSCT is significantly better in patients transplanted before developing SCDrelated organ damage; and 3) in children, TRM increases with age, the use of early HSCT is justified in children with any SCD-associated symptoms or event.…”

“…As demonstrated, persistent MC does not impact DFS and OS either in TM or in SCD; however, chimerism should be regularly checked in both diseases after HSCT. 34,75,78,90 …”

Targeted Busulfan therapy with a steady-state concentration of 600–700 ng/mL in patients with sickle cell disease receiving HLA-identical sibling bone marrow transplant

“…There were five (10%) patients who experienced graft rejection and two (4%) patients who died of transplant-related complications. McPherson et al 18 reported on the effect of BU PK on the outcome of 25 patients with SCD receiving allogeneic BMT in a single center. In that study, the target BU level changed over time.…”