“If there is an indication for intervention, for a curative therapy, in the absence of a matched sibling donor, gene therapy is the first choice,” Jaap-Jan Boelens, MD, PhD, of Memorial Sloan Kettering Cancer Center, New York City, argued in a presentation at the annual meeting of the Society of Hematologic Oncology (SOHO) in Houston.
“In the registries, alternative transplant outcomes are pretty poor, although there is some encouraging data coming up. The time is not there yet when this is the [best] choice.”
But Adetola Kassim, MBBS, of Vanderbilt University Medical Center in Nashville, Tennessee, said patients with sickle cell disease (SCD) who don’t qualify for a matched sibling donor transplant can still have good transplant options. And the results can be impressive.
“Once you’re engrafted, and you don’t lose your graft, the effect in transplant is lifelong,” he said. When it comes to long-lasting effects, he added, “we’re not sure yet about gene therapy.”
As Dr. Kassim noted, SCD continues to take a huge toll.
“Median survival for patients with sickle cell anemia remains stuck in the fifth decade of life with no change in 25 years,” he said. Heart, lung, and kidney complications account for 50% of identifiable causes of death, followed by about 26% attributed to cardiovascular disease, he said. “The question here is about which therapy can impact the most debilitating complication in children, which is stroke, and improve survival in adults with progressive organ dysfunction.”
Dr. Boelens said there are “huge barriers” to stem cell transplant in SCD because only 15% of patients eligible for the treatment have a matched related donor, and only 10% have a matched related or unrelated donor.
“There’s also a lack of financial and psychosocial support in many of the families. There is also parental refusal because of the mortality risk, and there’s also physician refusal because hematologists aren’t always in the same hospitals as the transplant programs.”
Dr. Boelens highlighted a 2019 study of data from 2008-2017 that found outcomes in unmatched donor transplantations are “not great,” with higher risk for mortality and graft failure.
As an alternative, he said, two gene therapies, both gene “additions,” are now approved by the US Food and Drug Administration (FDA). They are exagamglogene autotemcel (exa-cel, Casgevy) and betibeglogene autotemcel (LentiGlobin, Zynteglo). There’s also a gene “correction” option in the works, but it’s not yet ready for prime time, he said.
In the two approved gene therapy treatments, stem cells are removed from the patient, modified/manufactured in an outside facility, and then engrafted.
The advantages of gene therapy include no need to find a donor or worry about graft resistance, and there’s no need for immunosuppression, he said. However, the process takes a long time, there’s limited long-term data, and there’s a risk for loss of fertility and other chemotherapy-related adverse effects.
For his part, Dr. Kassim noted how several groups are excluded from the strong outcomes in matched sibling donor stem-cell transplants: Children with strokes and no eligible donors, others without eligible donors, and adults with severe disease and organ dysfunction who are typically excluded.
“We need transplants with less toxicity and alternative donors,” he said. Another challenge: “How do we decrease graft failure without increasing transplant-related mortality?”
Researchers are exploring several strategies to adjust drug therapy during conditioning, Dr. Kassim said, and he led a promising phase II study that explored one approach. The results of that study were recently published in the journal Blood. Graft failures were very low in both adults and children, he said, and 2-year survival among 70 patients was 94.8%. The five deaths were related to infection.
The evidence about the various strategies shows that “virtually all SCD patients, except those with severe heart, lung, or kidney disease” can benefit from a curative transplant, Dr. Kassim said.
Dr. Boelens had no disclosures. Disclosures for Dr. Kassim were not provided, but he recently reported no disclosures in a report about transplants in SCD.
A version of this article appeared on Medscape.com.