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Significant reduction in severe graft-versus-host disease with post-transplantation cyclophosphamide after allogeneic hematopoietic stem cell transplantation

Results of the prospective randomized phase III HOVON-96 trial demonstrated that, compared to conventional immunosuppression, the use of high-dose post-transplantation cyclophosphamide results in a significant reduction in the risk for severe acute and chronic graft-versus host disease. Moreover, high dose post-transplantation cyclophosphamide was also associated with a significantly longer graft-versus host disease free/relapse-free survival.

Background

Although allogeneic hematopoietic stem cell transplantation (alloHSCT) is a powerful treatment modality for patients with hematological malignancies, it is often associated with the occurrence of graft-versus-host disease (GVHD), which represents a major cause of morbidity and mortality. Common strategies to prevent GVHD following T cell replete alloHSCT include conventional immunosuppression (CIS) with post-transplant administration of cyclosporine A (CyA) and mycophenolic acid (MA), or post-transplant cyclophosphamide (PT-Cy) either or not combined with CIS. Studies in haplo- and HLA matched donor transplantation have shown that PT-Cy is well tolerated and associated with low rates of severe GVHD and transplant related mortality (TRM). However, randomized evidence on the efficacy of PT-Cy as compared to CIS in the setting of HLA matched alloHSCT is scarce.

In the prospective, randomized HOVON-96 study, CIS was compared to PT-Cy in 160 patients qualifying for an allogeneic peripheral blood stem cell transplantation using grafts from HLA matched siblings and matched unrelated donors (8 out of 8 match). Patients were randomly assigned (1:2) to CIS (CyA twice daily until day +120 followed by tapering until day +180 and mycophenolic acid 16 mg/kg twice daily with a maximum dose of 2160 mg a day until day 84 post-transplant) or PT-Cy (50 mg/kg of cyclophosphamide on day +3 and +4 combined with CyA from day +5 until day +70). Of the 160 patients enrolled in the study, 94% of the patients proceeded to transplant. The endpoints of the study included the cumulative incidence of acute and chronic GVHD, the cumulative incidence of relapse and the cumulative incidence of non-relapse mortality. In addition to this, the study also looked into the progression-free (PFS), overall (OS) and GVHD free/relapse-free survival of patients in both treatment arms.

Results

All patients included in the HOVON-96 trial had a high-risk hematological malignancy and good WHO performance status (0-2). The median age of the patients in the study was 58 years (range 20-70 years) and approximately two thirds were male. In both treatment arms, most patients (67% and 70% for the CIS and PT-Cy arm respectively) received stem cells from a matched unrelated donor. Stem cells were retrieved from peripheral blood for all patients in the CIS arm and in 96% of patients in the PT-Cy arm. Almost all patients in the study received a reduced intensity conditioning regimen prior to transplantation. Transplants included a median of 6.14 x106/kg CD34+ cells (range: 1.36-19.4) and a median of 230 x106/kg CD3+ T cells (range: 0-519).

The cumulative incidence (CI) of grade II-IV acute GVHD at 6 months was 48% in patients who received CIS as compared to 32% following PT-Cy (SHR 0.52 [95% CI: 0.31-0.87], p=0.014). The two-year CI of chronic extensive GVHD was 50% in recipients of CIS versus only 19% following PT-Cy (SHR 0.38[95% CI: 0.21-0.67], p=0.001). No significant difference was seen between both arms in terms of relapse/progression (3-year rates of 32% versus 26% with PT-Cy and CIS, respectively, p=0.36) or non-relapse mortality (3 year rates: 11% versus 14% respectively, p=0.53). After a median follow-up of 38.7 months, no difference between CIS and PT-Cy with respect to PFS (p=0.67) and OS (p=0.63) was detected. The three-year estimates for PFS were 60% and 58% for CIS- and PT-Cy respectively, with 3-year OS rates of 69% and 63%.

Interestingly, the investigators did report a significant benefit in the GVHD free/relapse-free survival with PT-Cy compared to CIS. This composite endpoint looked at the survival of patients without acute grade 3/4 GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse or death. The one-year estimate of GVHD free/relapse-free survival was 22% with CIS, which was significantly lower than the 45% seen with PT-Cy (p=0.001). Of note, this improvement in GVHD free/relapse-free survival was seen irrespective of the donor type (sibling or matched unrelated).

In recipients of PT-Cy, acute GVHD was generally limited to stage 1 skin involvement, whereas more severe skin involvement and bowel involvement were observed following CIS. Severe adverse events within six months post-transplantation were higher in the PT-Cy arm (60%) as compared to the CIS arm (42%). This higher incidence of adverse events is mainly attributable to the higher level of infections seen with PR-Cy (41% versus 21%). Cardiac toxicity was low and similar in the two treatment arms (1% in the PT-Cy group versus 4% in the CIS group). In total, two patients experienced a graft failure (one in each arm).

Conclusions

Application of a high-dose post-transplantation cyclophosphamide combined with a short course of cyclosporine A results in a significant reduction in the incidence of grade II-IV acute, or chronic GVHD compared to CIS. No difference was seen between CIS and PT-Cy with respect to the cumulative incidence of progression/relapse, PFS or OS. In contrast, high dose PT-Cy did significantly improve the GVHD free/relapse-free survival compared to CIS. The latter reflects the long-term benefit and positive impact on the quality of life of patients after an alloHSCT.

Reference

Broers AEC, 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. Presented at ASH 2019; Abstract 1.

Speaker Annoek Broers

Broers

Annoek EC Broers, MD, PhD, Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

 

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