HOVON-96: Better outcomes with cyclophosphamide after transplantation

Following allogeneic haematopoietic stem cell transplantation, cyclophosphamide significantly reduced grades 2 to 4 acute and extensive chronic extensive graft-versus-host disease (GVHD) compared with conventional immunosuppression.

Dr Annoek Broers (Erasmus MC Cancer Institute, the Netherlands) presented the study [1]. She noted that GVHD is the major cause of morbidity and mortality after allogeneic haematopoietic stem cell transplantation. Thus, HOVON-96 investigators developed a multicentre, randomised, prospective trial to compare post-transplantation cyclophosphamide with conventional immunosuppression in patients qualifying for allogeneic haematopoietic stem cell transplantation using grafts from HLA-matched siblings and unrelated donors.

HOVON-96 randomly assigned 160 patients 1:2 to either conventional immunosuppression with cyclosporine from days -3 to +180 plus mycophenolic acid from days 0 to +84 or post-transplantation cyclophosphamide with cyclosporine from days +5 to +70 plus cyclophosphamide at 50 mg/kg on days +3 and +4. The composite of GVHD-free/relapse-free survival was defined as the absence of acute GVHD grade 3-4 and chronic GVHD requiring systemic immunosuppression, plus disease relapse and death. The median follow-up was 38.7 months.

Transplantation was completed by 151 patients with high-risk haematologic malignancies and a related or unrelated donor with a 10 of 10 HLA match. Myeloablative conditioning was performed in 2 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 characteristics were comparable between the arms.

The composite endpoint, GVHD-free/relapse-free survival, was 22% with conventional prophylaxis compared with 45% with post-transplant cyclophosphamide—a 50% reduction in risk (P=0.001). Furthermore, post-transplantation cyclophosphamide versus conventional immunosuppression reduced the incidence of acute grades 2-4 GVHD: 32% versus 48% (P=0.014), respectively. Similarly, researchers reported reduced incidence of chronic GVHD: 19% versus 50% (P=0.001), respectively. However, no differences were observed in non-relapse mortality (P=0.54), progression-free survival (P=0.67) or overall survival (P=0.63).

Grade 3 or 4 adverse events were observed in 60% of the experimental arm and 42% of the conventional arm. There were more infections with cyclophosphamide (41% vs 21%, respectively) and neutropenic fever (25% vs 15%, respectively). Cardiac toxicity was rare, seen in just 1 patient (1%) in the cyclophosphamide arm and 2 patients (4%) in the conventional arm. There were also 2 graft failures, 1 in each arm.

1. De Jong CN, et al. Abstract 1, ASH 2019, 7-10 December, Oralando, USA.

Posted on 5 March 202025 March 2024