In the Journals

Higher radiation dose safely reduces graft failure after haploidentical bone marrow transplantation

Robert Brodsky, MD
Robert Brodsky

Increasing the dose of total body irradiation to 400 cGy from 200 cGy greatly reduced graft failure among patients with sickle cell disease or beta-thalassemia who received a haploidentical bone marrow transplant with post-transplantation cyclophosphamide, according to results of a phase 2 prospective study published in The Lancet Haematology.

The approach, which did not increase toxicity, could represent a curative option for patients with severe haemoglobinopathies who have only half-matched donors, according to researchers.

“These results are really exciting as we’re approaching a 90% cure rate for sickle cell disease and beta-thalassemia,” Robert Brodsky, MD, professor of medicine and oncology research at Johns Hopkins University School of Medicine and director of the division of hematology and member of Johns Hopkins Kimmel Cancer Center, said in a press release. “Bone marrow transplants are not just for patients with a perfectly matched donor. A half-match is definitely good enough.”

Previous studies demonstrated that nonmyeloablative haploidentical related bone marrow transplants with posttransplant cyclophosphamide increased the number of potential donors while limiting graft-versus-host disease.

Graft failure, however, occurred in half of the patients.

Brodsky and colleagues hypothesized that increasing total body radiation from 200 cGy to 400 cGy before bone marrow transplantation would safely increase the rate of successful engraftments.

The researchers analyzed 12 patients with sickle cell disease and five patients with beta-thalassemia major (median age, 16 years; range, 6-31) receiving their first bone marrow transplant. Each patient had a relative to serve as a haploidentical donor, including seven siblings, five mothers, four fathers and one aunt.

Researchers modified the planned primary objectives of PFS and transplant-related mortality after a coverage decision by the CMS prompted the trial to close to accrual.

Engraftment, assessed by chimerism, served as the new primary endpoint, with toxic effects of transplantation as a secondary endpoint .

All patients received antithymocyte globulin, fludarabine, cyclophosphamide and 400 cGy total body irradiation prior to transplantation, and IV cyclophosphamide, oral mycophenolate mofetil and oral sirolimus after transplantation as GVHD prophylaxis.

Researchers assessed chimerism in peripheral blood at days 30, 60, 180 and 360, followed by yearly assessments.

At median follow-up of 705 days (range, 355-1,294), all patients remained alive.

Results showed only one patient (6%) had primary graft failure with recovery of host hemopoiesis, whereas 13 (76%) achieved full donor chimerism and three (18%) had mixed donor-host chimerism. One patient remained transfusion dependent, and 14 (88%) discontinued immunosuppression.

Five patients (29%) developed grade 2 to grade 4 acute GVHD, and three (18%) developed chronic GVHD. However, the condition had resolved in all patients as of the last follow-up visit.

The funding issue served as a limitation to the study.

“These latest findings add to an extensive and growing body of evidence supporting the safety and effectiveness of half-matched bone marrow transplants,” Richard Jones, MD, director of the Johns Hopkins Kimmel Cancer Center bone marrow transplantation program, said in the release. “We have performed more than 1,000 half-matched bone marrow transplants, and our clinical studies have proved so successful, with safety and toxicity comparable to matched transplants, that half-identical transplants must be made available to more patients as a curative option.”

The results represent a big step toward the goal of broadly curable therapies for sickle cell disease and beta-thalassemia; however, more research is needed in larger cohorts with patients who have comorbidities, John F. Tisdale, MD, senior investigator in the molecular therapeutics branch at NIH, wrote in an accompanying editorial.

“The relatively simple conditioning 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,” he wrote. – by John DeRosier

Disclosures: Brodsky reports grants from Maryland Stem Cell Research Fund and advisory board roles with and research funding from Achillion Pharmaceuticals and Alexion Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures. Tisdale reports no relevant financial disclosures.

Robert Brodsky, MD
Robert Brodsky

Increasing the dose of total body irradiation to 400 cGy from 200 cGy greatly reduced graft failure among patients with sickle cell disease or beta-thalassemia who received a haploidentical bone marrow transplant with post-transplantation cyclophosphamide, according to results of a phase 2 prospective study published in The Lancet Haematology.

The approach, which did not increase toxicity, could represent a curative option for patients with severe haemoglobinopathies who have only half-matched donors, according to researchers.

“These results are really exciting as we’re approaching a 90% cure rate for sickle cell disease and beta-thalassemia,” Robert Brodsky, MD, professor of medicine and oncology research at Johns Hopkins University School of Medicine and director of the division of hematology and member of Johns Hopkins Kimmel Cancer Center, said in a press release. “Bone marrow transplants are not just for patients with a perfectly matched donor. A half-match is definitely good enough.”

Previous studies demonstrated that nonmyeloablative haploidentical related bone marrow transplants with posttransplant cyclophosphamide increased the number of potential donors while limiting graft-versus-host disease.

Graft failure, however, occurred in half of the patients.

Brodsky and colleagues hypothesized that increasing total body radiation from 200 cGy to 400 cGy before bone marrow transplantation would safely increase the rate of successful engraftments.

The researchers analyzed 12 patients with sickle cell disease and five patients with beta-thalassemia major (median age, 16 years; range, 6-31) receiving their first bone marrow transplant. Each patient had a relative to serve as a haploidentical donor, including seven siblings, five mothers, four fathers and one aunt.

Researchers modified the planned primary objectives of PFS and transplant-related mortality after a coverage decision by the CMS prompted the trial to close to accrual.

Engraftment, assessed by chimerism, served as the new primary endpoint, with toxic effects of transplantation as a secondary endpoint .

All patients received antithymocyte globulin, fludarabine, cyclophosphamide and 400 cGy total body irradiation prior to transplantation, and IV cyclophosphamide, oral mycophenolate mofetil and oral sirolimus after transplantation as GVHD prophylaxis.

Researchers assessed chimerism in peripheral blood at days 30, 60, 180 and 360, followed by yearly assessments.

At median follow-up of 705 days (range, 355-1,294), all patients remained alive.

Results showed only one patient (6%) had primary graft failure with recovery of host hemopoiesis, whereas 13 (76%) achieved full donor chimerism and three (18%) had mixed donor-host chimerism. One patient remained transfusion dependent, and 14 (88%) discontinued immunosuppression.

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Five patients (29%) developed grade 2 to grade 4 acute GVHD, and three (18%) developed chronic GVHD. However, the condition had resolved in all patients as of the last follow-up visit.

The funding issue served as a limitation to the study.

“These latest findings add to an extensive and growing body of evidence supporting the safety and effectiveness of half-matched bone marrow transplants,” Richard Jones, MD, director of the Johns Hopkins Kimmel Cancer Center bone marrow transplantation program, said in the release. “We have performed more than 1,000 half-matched bone marrow transplants, and our clinical studies have proved so successful, with safety and toxicity comparable to matched transplants, that half-identical transplants must be made available to more patients as a curative option.”

The results represent a big step toward the goal of broadly curable therapies for sickle cell disease and beta-thalassemia; however, more research is needed in larger cohorts with patients who have comorbidities, John F. Tisdale, MD, senior investigator in the molecular therapeutics branch at NIH, wrote in an accompanying editorial.

“The relatively simple conditioning 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,” he wrote. – by John DeRosier

Disclosures: Brodsky reports grants from Maryland Stem Cell Research Fund and advisory board roles with and research funding from Achillion Pharmaceuticals and Alexion Pharmaceuticals. Please see the study for all other authors’ relevant financial disclosures. Tisdale reports no relevant financial disclosures.