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GVHD prophylaxis with single-agent cyclophosphamide effective after allogeneic transplant
Post-transplant graft-versus-host disease prophylaxis with single-agent cyclophosphamide appeared safe and effective in patients who underwent conditioning with busulfan and fludarabine prior to allogeneic bone marrow transplantation, according to results of a multi-institutional study.
Several single-institution studies have demonstrated the safety and efficacy of conditioning with IV busulfan (Busulfex, Otsuka Pharmaceutical) and fludarabine, as well as the benefits of graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide.
In the current study, Christopher G. Kanakry, MD, of Johns Hopkins Kimmel Cancer Center, and colleagues assessed whether the clinical efficacy of the two techniques would be maintained when they were combined.
The analysis included 92 patients with high-risk leukemias or myeloid malignancies; of them, 45 received related allografts and 47 received unrelated allografts.
All patients received IV busulfan and fludarabine 2 to 5 days prior to bone marrow transplantation. Patients also received cyclophosphamide 50 mg/kg daily on days 3 and 4 after transplantation.
Median follow-up was 2.2 years.
Researchers observed grade 2 to grade 4 GVHD in 51% of patients, grade 3 to grade 4 in 15% of patients, and chronic GVHD in 14% of patients.
Nonrelapse mortality rates were 9% at 100 days post-transplant and 16% at 1 year post-transplant. The researchers reported 2-year DFS of 62% and 2-year OS of 67%.
Donor relatedness did not affect nonrelapse mortality, DFS or OS, Kanakry and colleagues wrote.
Patients in complete remission without evidence of minimal residual disease exhibited noticeably superior DFS and OS than patients in complete remission with minimal residual disease or those with active disease at the time of transplantation (P=.0005 for DFS; P=.019 for OS).
The results are even more compelling based on the fact GVHD prophylaxis with cyclophosphamide lasts only 2 days. Traditionally, most transplant patients undergo 6 months of immunosuppression to reduce risk for GVHD.
“The lack of a requirement for immunosuppression in a significant subset of patients can facilitate the early integration of adjunct therapies to prevent relapse,” Kanakry and colleagues wrote. “As [post-transplantation cyclophosphamide] is a promising strategy for GVHD prophylaxis in both HLA-matched and HLA-mismatched [allogeneic bone marrow transplantation], its efficacy relative to other approaches requires further study through randomized clinical trials.”
Disclosure: The researchers report research funding and consultant/advisory roles with Otsuka Pharmaceuticals and Sanofi-Aventis.
Perspective
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In contrast to other approaches of GVHD prevention, active GVHD prophylaxis is done with 2 days of post-transplant cyclophosphamide only, ending on day 4, and without the administration of anti-thymocyte globulins. The results are very promising with respect to toxicity, safety, severe acute GVHD and chronic GVHD, and do not appear inferior to current standard of care.
In this study, from day 5 post-transplant, patients were not on active immunosuppressive therapy for GVHD prophylaxis. Using standard approaches, patients are required to compliantly take medication for several months. The latter means the risk for drug-related side effects, which can significantly affect life quality, and the need for repeated drug level measurements to ensure efficacy and avoid toxicity. Moreover, there is always concern that being on active immunosuppression weakens the so-called graft-versus-leukemia effect, which is mediated by donor immune cells after transplant and contributes to improved long-term disease control, and can interfere with post-transplant strategies to prevent or treat disease relapse.
Therefore, discontinuation of GVHD prophylaxis as early as in this study makes post-transplant care and medication compliance easier for the patient and possibly allows for a better utilization of allogeneic hematopoietic cell transplantation as a platform for immune-modulatory approaches and novel concepts of post-transplant disease control.
Open questions remain how this approach compares with other approaches in a direct randomized fashion, how the use of peripheral blood stem cells instead of bone marrow affects outcome, and whether the results observed for post-transplant cyclophosphamide as single-agent GVHD prophylaxis in patients with myeloid hematologic malignancies and receiving myeloablative conditioning can be safely and efficaciously expanded to other diseases and/or reduced-intensity conditioning regimens. In addition, in times of rising health care costs and patient-reported outcomes, the idea of omitting expensive post-transplant immunosuppressive drugs and related drug tests plus life-quality assessments are of general interest and warrant further investigation.