pre-HSCT (top) and post-HSCT
Credit: NIH Molecular and
Clinical Hematology Branch
In a small study, a nonmyeloablative hematopoietic stem cell transplant (HSCT) regimen reversed sickle cell disease (SCD) phenotype in a majority of adult patients, some of whom also had thalassemia.
Half of the patients were able to stop taking immunosuppressants and did not develop graft-vs-host disease (GVHD).
There were adverse events associated with the regimen, but the researchers believe it shows promise and could be “transformative” for patients with severe SCD.
The team described the regimen and its effects in JAMA.
Matthew M. Hsieh, MD, of the National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, and his colleagues first explored a nonmyeloablative HSCT approach in a pilot group of 10 adults with severe SCD.
The regimen had few toxic effects, but all patients continued taking immunosuppression medication. The researchers have since revised the protocol to include an option to stop immunosuppression after 1 year in patients with donor CD3 engraftment of greater than 50% and normalization of hemoglobin.
In JAMA, the team described the outcomes for 20 additional patients with severe SCD, with or without thalassemia, along with updated results from the first 10 patients.
All 30 patients (ages 16-65 years) were enrolled in the study from July 2004 to October 2013. Two patients had heterozygous hemoglobin S and C, 1 patient had HbSβ+-thalassemia, 1 patient had HbSβ0- thalassemia, and 1 had transfusion-dependent β-thalassemia intermedia. The remaining patients had homozygous hemoglobin S.
Patients received alemtuzumab (1mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and an infusion of unmanipulated, filgrastim-mobilized peripheral blood stem cells (5.5-31.7 × 106 cells/kg) from HLA-matched siblings.
There were 38 serious adverse events. The most common were pain-related (n=15), transplant-related infections (n=6), abdominal events (n=6), and toxic effects associated with sirolimus (n=5).
As of October 25, 2013, 29 patients were still alive, with a median follow-up of 3.4 years. Twenty-six patients (87%) had long-term stable donor engraftment without acute or chronic GVHD.
Hemoglobin levels improved after HSCT. At 1 year, 25 patients (83%) had full donor-type hemoglobin. Fifteen engrafted patients discontinued immunosuppression medication and did not develop GVHD.
“Typically, stem cell recipients must take immunosuppressants all their lives,” Dr Hsieh noted. “That the patients who discontinued this medication were able to do so safely points to the stability of the partial transplant regimen.”
Hospitalization rates also decreased following HSCT. The average annual hospitalization rate was 3.2 the year before HSCT, 0.63 the first year after, 0.19 the second year after, and 0.11 the third year after transplant.
“One of the most debilitating effects of sickle cell disease is the often relentless pain,” Dr Hsieh pointed out. “Following the transplant, we saw a significant decrease in hospitalizations and narcotics to control that pain.”
Eleven patients were taking narcotics long-term at the time of transplant. During the week they were hospitalized and received their HSCT, the average narcotics use per week was 639 mg of intravenous morphine-equivalent dose. The dosage decreased to 140 mg at 6 months after the transplant.
“The devastating complications associated with sickle cell disease can deeply affect quality of life, ability to work, and long-term well-being,” said study author Griffin P. Rodgers, MD, director of the National Institute of Diabetes and Digestive and Kidney Diseases.
“This study represents an important advance in our efforts to make a potentially transformative treatment available to a wider range of people, especially those who could not tolerate a standard stem cell transplant or long-term use of immunosuppressants.”
