Confirming a Reasonable Next Step for HSCT in Children with Hemoglobinopathies

For children and adults with sickle cell disease (SCD) and beta thalassemia major who have available matched sibling donors, hematopoietic stem cell transplantation (HSCT) is becoming a more common therapeutic option. The decision to perform HSCT is based on the historical context that both hemoglobinopathies are life threatening diseases, coupled with the lack of options for alternative medical therapies that will attenuate the progression of the disease. Traditionally, myeloablative conditioning and matched sibling donor HSCT has been the primary curative option for children with hemoglobinopathies; however, successful donor engraftment has been linked to long-term toxicities for survivors, including but not limited to, severe chronic graft-versus-host disease and sterility. The multicenter, reduced-intensity, matched sibling HSCT trial conducted by Dr. Allison A. King and colleagues has provided critical data which advances our knowledge about HSCT and its role for selected children with hemoglobinopathies.

Dr. King and colleagues from 18 pediatric hematology-oncology programs created a consortium to test the hypothesis that adequate and stable donor cell engraftment could be successfully achieved following immunoablative reduced intensity conditioning and matched sibling donor HSCT in children with SCD or thalassemia major. Over 12 years, a total of 43 children with SCD and nine with thalassemia received matched sibling donor HSCT with reduced-intensity conditioning that included alemtuzumab, fludarabine, and melphalan. The overall and event-free survival rates were 94.2 percent and 92.3 percent, respectively, with a median follow-up of 3.42 years. Subgroup analysis for SCD and thalassemia revealed overall and event-free survival rates of 93 percent and 90.7 percent, respectively, for SCD, and 100 percent for thalassemia. One year after the HSCT, no participant was on immunosuppression and no GVHD or rejection was noted. Furthermore, for SCD, no disease progression events (strokes, vaso-occlusive pain episodes, or pulmonary complications) were noted, Regarding thalassemia, all patients eventually became transfusion-independent.

The recently completed trial offers promise for children with SCD receiving immunoablative reduced-intensity conditioning regimens for matched sibling donor HSCT, but falls short of becoming standard care for this population due to several unanswered questions. The median follow-up of 3.4 years prevents direct assessment of long-term sequelae, such as infertility, and the absence of a central adjudication committee to evaluate end-organ function dampens confidence about absence of end-organ disease progression after HSCT. However, the biggest limitation is the lack of a contemporaneous comparison group of children with SCD and beta thalassemia receiving optimal medical therapy. For both children with SCD and thalassemia, advances in supportive therapy provide reasonable options to delay the HSCT until a clinical trial is completed comparing the short- and long-term sequelae of the HSCT conditioning regimen to a comparable group of children receiving maximum medical therapy; alternatively, the burden and progression of end organ disease may justify HSCT in the context of a clinical trial. When the trial by Dr. King and colleagues started in 2003, hydroxyurea had not been recommended as standard care for children with SCD, but it is now recommended to at least offer therapy at nine months.¹  In 2003, many hematologists elected to offer hydroxyurea therapy to those children with severe disease, with criteria similar to entry criteria for the HSCT trial.

Two large pediatric SCD cohorts have been completed. In a prospective cohort study, 185 children receiving hydroxyurea, with median duration of treatment of 10.3 years, had a 15 year Kaplan-Meier (KM) survival estimate of more than 98 percent.²  In the second recent retrospective cohort study, 1,033 children with SCD, followed for approximately 6.7 years, had a five-year KM survival estimate of more than 98 percent.³  Collectively, these two large pediatric SCD cohort studies provide inconvertible evidence that SCD in children is no longer a life threatening disease, but a chronic disease that may have life threatening episodes. Similarly for thalassemia, in 2003 the major chelation therapy (deferoxamine) was provided subcutaneously, typically eight to 10 hours a night for five nights a week, and resulted in poor adherence with concomitant excessive iron load and end organ damage. Now several oral chelators are available, significantly improving adherence and subsequently decreasing the prevalence of associated comorbidities.