Doubling the dose of total-body irradiation (TBI) led to a near-doubling of the engraftment rate for patients with severe hemoglobinopathies undergoing haploidentical transplants, a small clinical trial showed.
All but one of 17 patients had successful engraftment after receiving 400 cGy TBI as part of a nonmyeloablative conditioning regimen. Following successful engraftment, 15 of 16 patients remained transfusion independent, and 14 of 16 discontinued immunosuppression.
Four patients developed grade 2 acute graft-versus-host disease (GVHD) and one developed grade 3, but GVHD had resolved in all cases at the most recent follow-up, Javier Bolaños-Meade, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, and co-authors reported online in The Lancet Haematology.
"These results suggest that engraftment after haploidentical bone marrow transplantation for hemoglobinopathies is possible, and primary graft failure -- the main problem previously reported -- might be addressed by this strategy," the authors concluded. "Therefore, this curative approach should no longer be restricted to patients with HLA-matched donors."
The author of an accompanying commentary said the findings represent a "substantial advance" in making potentially curative therapies more broadly available to patients with sickle cell disease and β-thalassemia.
"The relatively simple condition regimen, without the need for donor graft engineering, should allow further validation of this approach in a larger cohort of patients who are ineligible for standard myeloablative transplantation, either because of the absence of an HLA-matched sibling donor or the presence of end-organ complications that exclude them from these traditional approaches," wrote John Tisdale, MD, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.
"Additionally, haploidentical transplantation now takes its place as another broadly available curative approach for sickle cell disease and β-thalassemia, alongside approaches such as gene addition and gene editing, which are under development."
Two decades ago, hematologists learned that bone marrow transplants offered potentially curative therapy for sickle cell disease and β-thalassemia. However, use of the procedure remained limited by the need for HLA-matched donors, either related or unrelated. Additionally, allogeneic blood or marrow transplantation required myeloablative conditioning to facilitate engraftment, which carried a high risk of severe morbidity and mortality, the authors noted.
In 2012, Bolaños-Meade and colleagues reported successful engraftment of haploidentical (half-matched) bone marrow transplants, facilitated by the use of a nonmyeloablative conditioning regimen, followed by posttransplant treatment with cyclophosphamide. Still, engraftment was unsuccessful in about half of cases.
In an effort to improve engraftment without increasing risk, investigators modified the nonmyeloablative conditioning regimen by increasing the low dose of TBI used to date (200 cGy). The researchers evaluated the modified regimen in 12 patients with sickle cell disease and five with β-thalassemia. None of the patients had a prior transplant, and the study population had a median age of 16 (range 6 to 31).
All patients received conditioning that consisted of rabbit-derived anti-thymocyte globulin, fludarabine, cyclophosphamide, and 400 cGy administered in a single fraction. Following infusion of unmanipulated bone marrow, patients received GVHD prophylaxis with cyclophosphamide. The trial had a primary objective of engraftment, as assessed by chimerism.
The authors reported that the one patient who did not achieve successful engraftment had recovery of host hematopoiesis. All but three of the patients who had successful engraftment achieved full donor chimerism, and the remaining three had mixed donor-host chimerism.
In addition to the five cases of grade 2-4 acute GVHD, three patients developed chronic GVHD. At last follow-up visit, no patient was receiving systemic therapy for GVHD. After a median follow-up of 705 days, all patients remained alive.
"These results are really exciting as we're approaching a 90% cure rate for sickle cell and beta-thalassemia," senior author Robert Brodsky, MD, also of Johns Hopkins, said in a statement. "Bone marrow transplants are not just for patients with a perfectly matched donor. A half-match is definitely good enough."
The study was supported by the Maryland Stem Cell Research Fund and the National Institutes of Health.
Bolaños-Meade disclosed a relationship with Incyte. Several co-authors disclosed relationships with pharmaceutical companies and other commercial interests.
Tisdale reported having no relevant relationships.
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