Following allogeneic hematopoietic stem cell transplantation, cyclophosphamide significantly reduced grades II to IV acute and chronic extensive graft-vs-host disease compared with conventional immunosuppression, investigators reported during the Plenary Session at the 2019 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Annoek E.C. Broers, MD, PhD
“The application of high-dose posttransplant cyclophosphamide, combined with a short course of cyclosporine, resulted in a significant reduction in grades II to IV acute and chronic graft-vs-host disease. The composite endpoint, graft-vs-host disease–free/relapse-free survival, was 22% with conventional prophylaxis vs 45% with posttransplant cyclophosphamide—a 50% reduction in risk that was highly significant (P = .001),” said Annoek E.C. Broers, MD, PhD, of Erasmus MC Cancer Institute, Rotterdam, The Netherlands. “It’s important to note, this difference was seen irrespective of donor type—it was true for sibling and matched unrelated donors and with a median follow-up of 3.2 years, so there is no difference in relapse, progression-free survival, or overall survival.”
“A more intensified immunosuppression regimen with posttransplant cyclophosphamide might be preferred as graft-vs-host disease prophylaxis in the setting of allogeneic transplant,” Dr. Broers concluded.
Current Success of Graft-vs-Host Disease Prophylaxis
As noted by Dr. Broers, graft-vs-host disease is the major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT) and is the main obstacle for a broader application of transplantation. To reduce the incidence of graft-vs-host disease, prophylactic strategies have been developed, both for myeloablative and reduced-conditioning regimens. These strategies have resulted in an incidence of 30% to 50% for grades II to IV graft-vs-host disease and 40% to 60% for chronic graft-vs-host disease.
Among the prophylactic strategies are conventional immunosuppression with posttransplantation cyclosporine and mycophenolic acid, and posttransplantation cyclophosphamide, with or without conventional immunosuppression. Studies in haplo- and HLA-matched donor transplantation have shown that posttransplantation cyclophosphamide is well tolerated and associated with low rates of severe graft-vs-host disease and transplant-related mortality. However, randomized clinical trials comparing this approach with conventional immunosuppression have been lacking.
“The application of high-dose posttransplantation cyclophosphamide, combined with a short course of cyclosporine, resulted in a significant reduction in grades II to IV acute and chronic graft-vs-host disease.”— Annoek E.C. Broers, MD, PhD
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Background on Posttransplantation Cyclophosphamide
“Cyclophosphamide is an alkylating agent with a strong immunosuppressive capacity. Administration of a properly timed high-dose cyclophosphamide has been shown to inhibit both graft rejection and graft-vs-host disease by selective action on rapidly proliferating T cells. This occurs without hampering engraftment, as pluripotent stem cells are relatively resistant to the action of posttransplantation cyclophosphamide,” Dr. Broers explained.
The first clinical studies of this approach were done in the setting of haplo-identical bone marrow transplantation, resulting in acceptable rates of graft failure and graft-vs-host disease. Subsequently, it was used in HLA-matched related and unrelated bone marrow transplantation, showing “a strikingly low” incidence of acute and chronic graft-vs-host disease. HOVON-96 investigators, therefore, developed a multicenter randomized prospective trial to compare posttransplantation cyclophosphamide with conventional immunosuppression in patients qualifying for allogeneic HSCT using grafts from HLA-matched siblings and unrelated donors.
HOVON-96 Trial Details
The phase III HOVON-96 trial randomly assigned 160 patients 1:2 to one of two treatments: conventional immunosuppression with cyclosporine on days –3 to +180 plus mycophenolic acid on days 0 to +84 or posttransplantation cyclophosphamide with cyclosporine on days +5 to +70 plus cyclophosphamide at 50 mg/kg on days +3 and +4.
Endpoints were the cumulative incidence of acute and chronic graft-vs-host disease; relapse and nonrelapse mortality; progression-free survival; overall survival; graft-vs-host disease–free/relapse-free survival; and adverse events. The composite of graft-vs-host disease–free/relapse-free survival was defined as the absence of acute graft-vs-host disease grade III to IV and chronic graft-vs-host disease requiring systemic immunosuppression, plus disease relapse and death). The median follow-up was 38.7 months.
Fit patients (aged 18 to 70) had high-risk hematologic malignancies and a related or unrelated donor with a 10 of 10 HLA match. Transplantation was completed by 151 patients. Myeloablative conditioning was performed in two patients. The donor type was matched related in 31% and matched unrelated in 69% of patients. Transplants were derived from peripheral blood in 97% of patients and consisted of a median 6.14 x 106/kg CD34-positive cells/kg and a median 230 x 106/kg CD3-positive T cells. Baseline patient and transplantation characteristics were comparable between the arms.
Outcomes Improved With Cyclophosphamide After Transplantation
Multiple outcomes were improved with posttransplantation cyclophosphamide vs conventional immunotherapy, as shown here:
- Reduced incidence of acute grades II to IV graft-vs-host disease: 32% vs 48% (P = .014)
- Reduced incidence of chronic extensive graft-vs-host disease: 19% vs 50% (P = .001)
- Reduced incidence of 12-month graft-vs-host disease–free, relapse-free survival: 45% vs 22% (P = .001).
These benefits in prevention were achieved without compromising nonrelapse mortality, which was observed in 11% of the experimental arm and 14% of the conventional arm (P = .54). Similarly, no differences were seen in progression-free survival (P = .67) and overall survival (P = .63).
“The use of high-dose posttransplantation cyclophosphamide results in a significant reduction in severe acute and chronic graft-vs-host disease without affecting relapse, thereby resulting in improved graft-vs-host disease–free/relapse-free survival,” said Dr. Broers.
Adverse Events Within 6 Months
Grade 3 or 4 adverse events were observed in 60% of the experimental arm and 42% of the conventional arm. They included more infections with cyclophosphamide (41% vs 21%) and neutropenic fever (25% vs 15%). Cardiac toxicity was rare, seen in just one patient (1%) on the cyclophosphamide arm and two patients (4%) on the conventional arm. There were two graft failures, one in each arm.
DISCLOSURE: Dr. Broers reported no conflicts of interest.
REFERENCE
1. De Jong CN, Meijer E, Bakunina K, et al: Post-transplantation cyclophosphamide after allogeneic hematopoietic stem cell transplantation: Results of the prospective randomized HOVON-96 trial in recipients of matched related and unrelated donors. 2019 ASH Annual Meeting & Exposition. Abstract 1. Presented December 8, 2019.
