Stem Cell Transplantation Still the Main Treatment Option for Beta-Thalassemia

While gene therapy has emerged as a promising alternative for treating beta-thalassemia, hematopoietic stem cell transplantation (HSCT) remains the only widely accessible curative option for this inherited blood disorder.

“The best candidates for transplant are ideally children less than 8 years of age, but they actually do quite well up to 15 years,” said Lawrence Faulkner, MD, a specialist in pediatric hematology-oncology and stem cell transplantation at the Cure2Children Foundation in Florence, Italy, noting that children are particularly good candidates if they received optimal transfusions and regular iron chelation treatments before a transplant.

A 2016 study of patients under 18 undergoing HSCT showed that the 2-year overall survival (OS) and event-free survival (EFS) rates were 88% and 81%, respectively. Transplantation from a human leukocyte antigen (HLA)-matched sibling offered the best results, with OS and EFS rates of 91% and 83%, respectively. In addition, the study showed that the threshold age for optimal transplant outcomes was around 14 years, with OS rates ranging from 90% to 96% and EFS rates from 83% to 93% when transplants were performed before this age.

While the highest success rates historically have been seen in patients receiving transplants from matched sibling donors, advances in conditioning regimens and T-cell depletion strategies have contributed to higher OS and EFS rates in other scenarios, such as with matched unrelated or haploidentical donors.

“It used to be true that you needed a perfectly matched brother or sister, or possibly unrelated donors, but the field has changed,” said Robert Brodsky, MD, of Johns Hopkins School of Medicine in Baltimore.

There are multiple reasons for this sea change, Brodsky told MedPage Today, pointing out that better HLA typing is a major reason. However, a “big quantum leap” was the marked improvement in engraftment and the reduction of graft-versus-host disease (GVHD), he added, “mainly due to the use of post-transplant cyclophosphamide.”

Outcomes With Alternative Donors

In a 2020 study, researchers used a program consisting of a pharmacologic pretransplant immune suppression phase and two courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine plus busulfan and post-transplant GVHD prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil for patients with severe thalassemia (median age 12 years) who were undergoing transplant from haploidentical donors.

The 3-year projected OS and EFS rates were both 96%, and 7% of patients developed severe GVHD.

The study “demonstrated that outcomes after [haploidentical stem cell transplant] in patients with severe thalassemia are acceptable and now very similar to what is expected with [allogeneic HSCT] using matched donors,” the authors wrote.

In a Chinese study of patients with transfusion-dependent thalassemia presented at this year’s American Society of Hematology annual meeting, the 2-year OS and EFS rates in the full cohort were 95%. For patients who received transplants with matched sibling donors, these rates were 97% compared with 93% for patients with matched unrelated donors and 95% for patients with haploidentical donors.

The transplant-related mortality rate was 4.4% overall, and again was lower in the matched sibling cohort (2.5%) compared with the matched unrelated cohort (6.5%) and the haploidentical cohort (4.6%). The incidence of GVHD was significantly lower in the matched sibling cohort compared with the other groups.

The researchers suggested that the GVHD prophylaxis regimen of cyclosporine A, methotrexate, mycophenolate mofetil, and anti-thymocyte globulin “effectively prevented GVHD in patients with matched sibling donors,” and patients who underwent transplant with alternative donors “would benefit from an improved GVHD prophylaxis strategy.”

Transplanting Adults?

As Faulkner pointed out to MedPage Today, ideally a patient with beta-thalassemia should be young — 16 or younger — when undergoing a transplant.

The main reason, he said, is that hemochromatosis from chronic transfusions reduces a patient’s chances of a successful transplant because it can cause irreversible organ damage.

“Thalassemia is usually diagnosed quite early — most likely in the first 2 years of life — and if a patient is getting regular transfusions, iron is accumulated in the body and it can take 7 or 8 years before it can cause irreversible organ damage to the endocrine system, or heart or liver,” Faulkner explained. “So we want to perform the transplant before there is any irreversible organ damage, so that a patient will better tolerate the transplant.”

Also, “it is well known that for biological reasons that are not completely clear, children in general do better with transplant, and have less GVHD,” he added.

However, there are indications that improvements in treatment may make adult transplantation more viable. Last year, the U.K.’s National Health System (NHS) began offering stem cell transplants to adults with transfusion-dependent thalassemia for the first time.

An evidence review from the NHS suggested that six or seven of 10 adults with transfusion-dependent thalassemia who undergo HSCT can live for up to 23 years without thalassemia.

The authors of the review said the findings were “important for adults with TDT [transfusion-dependent thalassemia] who are receiving standard treatment with blood transfusions and chelation therapy because allogenic HSCT treats the underlying cause of TDT and is potentially curative (assuming there are no complications such as graft rejection or failure), whereas standard treatment controls the disease.”

“Without HSCT, people with TDT need blood transfusions and iron chelation for life, together with regular monitoring for treatment efficacy and screening for complications,” they added.

Transplant or Gene Therapy?

Two gene therapies — betibeglogene autotemcel (Zynteglo) and exagamglogene autotemcel (Casgevy) — have been approved for treating beta-thalassemia.

While this is “very exciting,” Brodsky pointed out that treatment with gene therapy still requires a toxic myeloablative conditioning regimen, and “the cost is prohibitive” (with bluebird bio setting a price tag of $2.8 million for betibeglogene autotemcel).

Gene therapy “needs to continue to evolve,” he said. “It’s really in its infancy. If you had asked me these questions about bone marrow transplant 25 years ago, I would have been telling you there is a 20% to 30% chance of dying from the procedure, 30% to 40% are going to get graft-versus-host disease and some of it will be chronic, and there will be all sorts of late infections.”

In the meantime, gene therapy does provide another option for a complicated disease, Brodsky suggested, adding that there are patients with beta-thalassemia whose options are limited because they don’t have a suitable donor or have anti-HLA antibodies.

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