‘Half-Matched’ Donors Successfully Increase Availability of HSCT for Sickle Cell Disease

The use of “half-matched” donors and a less taxing chemotherapy regimen appears to be successful in curing sickle cell disease and expanding the donor pool for adults with the condition, according to results presented at the annual meeting of the American Society of Hematology meeting in December.

The study involved related but not highly genetically matched donors and a lower intensity chemotherapy conditioning regimen for hematopoietic stem cell transplant (HSCT) patients with severe sickle cell disease (SCD). Of the 42 patients who underwent the modified procedure, the overall rate of survival at 2 years post-transplant was 95% and the estimated rate of event-free survival (defined as survival without graft failure or a second infusion of stem cells) was 88%.

The modified approach “actually beat our expectations. This study has clearly shown that you can take selected adult patients with significant comorbidities to transplant, and hopefully change the trajectory of their disease,” lead author Adetola A. Kassim, MBBS, said in a press release. Kassim is a professor of medicine at Vanderbilt University Medical Center in Nashville.

The standard approach to HSCT for adults with SCD has relied on the use of matched sibling donors. However, it’s estimated that fewer than a quarter of people with SCD have a matched sibling who could potentially serve as a donor. In contrast, about 90% have a relative who could serve as a half-matched donor.

The standard chemotherapy conditioning regimen is taxing, and many patients with severe disease do not tolerate it well. The lower intensity conditioning regimen used in this study is more easily tolerated by people with health issues such as organ damage, a complication of SCD that often becomes more common with age.

The single-arm, phase-II, prospective clinical trial enrolled 54 individuals with SCD between the ages of 15 to 46 years who also had a history of stroke, reduced heart functioning (acute chest syndrome, tricuspid valve regurgitant jet velocity greater than or equal to 2.7 m/sec) or pain episodes, or chronic blood transfusions — common consequences of SCD. In the end, 42 participants underwent the modified stem cell transplantation procedure with an average age of 22.8 years — 92.6% were Black and 3.7% were Hispanic.

The preconditioning regimen included hydroxyurea, and the conditioning regimen included thymoglobulin, thiotepa, fludarabine and cyclophosphamide. Notably, cyclophosphamide was given post-transplant as graft-vs-host disease (GVHD), along with sirolimus and mycophenolate mofetil.

At 100 days post-transplant, 4.8% of patients experienced a primary graft failure and 4.8% experienced adverse events of grade three or higher. Of these, infections were the most common. In addition, more than three-quarters (78.6%) of patients experienced at least one hospital admission following their transplant.

At day 100, the cumulative incidence of grades II-IV acute GVHD was 26.2%, while more serious acute GVHD (grades III-IV) was 4.8%. Two participants died within the first year post-transplant: one from organ failure and one from fluid buildup in the lungs associated with COVID-19 infection.

“Some of these patients are really thriving and now getting back into the community,” said Kassim. “Our hope is that long-term follow-up will be able to quantify the added value of curing patients of SCD.”