High-dose cyclophosphamide is safe and effective when given as prophylaxis for chronic graft-versus-host disease (GVHD) to patients who have undergone transplantation of mobilized blood cells, finds a phase 2 trial reported in Blood.
Investigators led by Dr. Marco Mielcarek, medical director of the Adult Blood and Marrow Transplant Program and an oncologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington, enrolled in the trial 43 patients with high-risk hematologic malignancies.
Dr. Marco Mielcarek
The patients underwent myeloablative conditioning followed by transplantation with growth factor–mobilized blood cells from related or unrelated donors, and were given high-dose cyclophosphamide on two early posttransplantation days.
Main results showed that the cumulative 1-year incidence of chronic GVHD was 16%, less than half of the roughly 35% seen historically with conventional immunosuppression.
Moreover, cyclophosphamide did not appear to compromise engraftment or control of the underlying malignancy. Only a single patient, one with an HLA-mismatched donor, had failure of primary engraftment; after amendment of the protocol to require HLA matching, there were no additional cases. Just 17% of patients experienced a recurrence of their malignancy by 2 years.
Taken together, the findings suggest that high-dose cyclophosphamide—as combined with two myeloablative conditioning options (to accommodate different malignancies) and with posttransplantation cyclosporine (to reduce the risk of acute GVHD)—may eliminate most of the drawbacks to using mobilized blood cells for transplantation, according to the investigators.
“If these findings are confirmed in future studies, HLA-matched mobilized blood cell transplantation may gain even greater acceptance and further replace marrow as a source of stem cells for most indications,” they maintain.
The patients studied had a median age of 43 years, and slightly more than half were in remission without minimal residual disease.
Blood cells were mobilized with granulocyte colony-stimulating factor (G-CSF). Overall, 28% of patients received grafts from related donors, while 72% received grafts from unrelated donors.
For pretransplant conditioning, patients received fludarabine and targeted busulfan, or total body irradiation with use of a minimum dose of 12 Gy.
The patients were given cyclophosphamide at 50 mg/kg per day on days 3 and 4 after transplantation. This was followed by cyclosporine starting on day 5.
The cumulative 1-year incidence of chronic GVHD as defined by National Institutes of Health criteria (i.e., that requiring systemic immunosuppressive therapy)—the trial’s primary endpoint—was 16%, which fell just short of the goal of 15% the investigators were aiming for (Blood. 2016;127:1502-8). Analyses failed to identify any predictors of this outcome.
Although the estimated cumulative incidence of grade 2 acute GVHD was high, at 77%, none of the patients developed grade 3 or 4 acute GVHD, according to the investigators, who disclosed that they had no competing financial interests.
The single patient who experienced failure of primary engraftment had familial myelodysplastic syndrome and had received a graft from an HLA A-antigen–mismatched unrelated donor.
The 2-year cumulative incidence of nonrelapse mortality was 14%, and the 2-year cumulative incidence of recurrent malignancy was 17%. Projected overall survival was 70%.
Among the 42 patients having at least a year of follow-up, 50% were alive and free of relapse without any systemic immunosuppression at 1 year after transplantation.