Researchers are leading several studies designed to improve hematopoietic stem cell transplantation (HSCT) for patients with sickle cell disease (SCD), experts at the National Heart, Lung, and Blood Institute reported during a recent webinar.
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“HSCT offers a potential cure [for SCD], which may improve quantity and quality of life [for patients],” said Courtney D. Fitzhugh, MD, a Lasker Clinical Research Scholar in the Laboratory of Early Sickle Mortality Prevention at NHLBI.
Currently, HLA-matched sibling and matched unrelated donor sources provide the best outcomes for sickle cell patients undergoing allogeneic HSCT, she explained. Alternative stem cell sources include umbilical cord blood and haploidentical donors.
Over the past 2 years, the majority of novel transplant techniques have been primarily aimed at improving conditioning regimens and lowering rates of graft-versus-host disease (GVHD).
Recent evidence
A recent international survey found high survival rates in patients with SCD who underwent HLA-matched sibling HSCT during 1986-2013. At 5-years, overall- and event-free survival rates were 92.9% and 91.4%, respectively, with even higher rates (95% and 93%) seen in children aged younger than 16 years.
With respect to safety, the cumulative incidence rates of acute and chronic GVHD were 14.8% and 14.3%, Dr. Fitzhugh reported.
Much of the success seen with HLA-matched sibling donors is attributable to recent data demonstrating that complete transformation of patient’s bone marrow is unnecessary to illicit a curative effect.
With donor myeloid chimerism levels of at least 20%, the sickle disease phenotype can be reversed, and there’s a reduced risk of GVHD, she said.
In mouse models, researchers have found that inclusion of sirolimus in HLA-matched pretransplant conditioning regimens leads to higher levels of donor cell engraftment. As a result, some conditioning regimens now administer sirolimus (target 10-15 ng/dL) one-day prior to transplantation.
In 55 patients transplanted using this technique, overall- and event-free survival rates of 93% and 87% have been reported, with no transplant-related mortality or evidence of GVHD. Other institutions have also begun to adopt this technique, and have reported similar findings, Dr. Fitzhugh reported.
“When you [administer high-dose] chemotherapy, you don’t expect that patients are able to have children, but we are excited to report that 8 of our patients have had 13 healthy babies post transplant,” Dr. Fitzhugh said.
As a whole, several recent studies have emphasized the importance of the conditioning regimen in successful transplantation for patients with SCD.
With HLA-matched sibling donors, myeloablative regimens that include antithymocyte globulin have demonstrated greater efficacy, she said.
In patients receiving a transplant from a matched unrelated donor, early use of alemtuzumab is linked to higher rates of GVHD, while ongoing studies are exploring whether abatacept reduces the risk of GVHD, she further explained.
With respect to haploidentical and unrelated umbilical cord donors, T-cell depletion and higher-intensity conditioning have been shown to reduce graft rejection rates, she said.
Dr. Fitzhugh acknowledged that long-term efficacy and safety of these novel conditioning regimens is largely unknown. Thus, ongoing follow-up is essential to monitor for potential late effects.
NHLBI-funded trials
Nancy L. DiFronzo, PhD, program director at NHLBI, explained that the agency has funded specific clinical studies evaluating allogeneic HSCT in patients with severe SCD.