High-dose post-transplant cyclophosphamide reduces severe GVHD without affecting relapse
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ORLANDO — The use of high-dose post-transplant cyclophosphamide reduced the incidence of severe acute and chronic graft-versus-host disease without affecting risk for relapse among patients undergoing allogeneic hematopoietic stem cell transplant with matched related or unrelated donors, according to results of the randomized phase 3 HOVON-96 study presented during the plenary session of ASH Annual Meeting and Exposition.
“GVHD is a major cause of morbidity and mortality after an allogeneic stem cell transplantation, making it the main obstacle for broader application,” Annoek E.C. Broers, MD, PhD, hematologist at Erasmus MC Cancer Institute in The Netherlands, said during the presentation. “To reduce the incidence of GVHD, conventional prophylactic strategies have been developed for both myeloablative conditioning regimens and reduced-intensity conditioning. To further diminish the incidence of GVHD, pharmacological strategies have been developed.”
Allogeneic HSCTs are an effective treatment for patients with hematological malignancies. Graft-versus-leukemia effect, however, is strongly associated with the incidence of GVHD and subsequent transplant-related mortality.
Treatments to prevent GVHD following allogeneic HSCT include conventional immunosuppression with post-transplant administration of cyclosporine A and mycophenolic acid or post-transplant cyclophosphamide sometimes combined with conventional immunosuppression.
Previous studies have shown that post-transplant cyclophosphamide is well-tolerated and associated with low rates of severe GVHD and transplant-related mortality; however, randomized data are lacking on the comparison of transplant cyclophosphamide vs. conventional immunosuppression for HLA-matched allogeneic HSCT.
Thus, Broers and colleagues evaluated whether post-transplant cyclophosphamide is associated with improved GVHD-free survival or RFS compared with conventional immunosuppression.
Researchers randomly assigned 151 patients (median age, 58 years; range, 20-70; 66% men) to conventional immunosuppression, which consisted of cyclosporine A twice daily until day 120 followed by tapering until day 180 and mycophenolic acid at 16 mg/kg twice daily with a maximum dose of 2,160 mg until 84 days after post-transplant (n = 52; median age, 58 years; range, 26-70), or to post-transplant cyclophosphamide at 50 mg/kg on day 3 and 4 in combination with cyclosporine A from day 5 to 70 (n = 99; median age, 57 years; range, 20-70).
Thirty-one percent of patients had matched donor relatives and 69% had matched nonrelated donors.
Most transplants (97%) were derived from peripheral blood and consisted of a median 6.14 x 106/kg CD34-positive cells/kg (range, 1.36-19.4) and median 230 x 106/kg CD3-positive T cells (range, 0-519).
Results showed that the cumulative incidence of grade 2 to grade 4 acute GVHD at 6 months was 48% among patients who received conventional immunosuppression compared with 31% who received post-transplant cyclophosphamide (subdistribution HR [SHR] = 0.52; 95% CI, 0.31-0.87).
Twelve percent of patients who received conventional immunosuppression experienced grade 3 to grade 4 acute GVHD compared with 6% of patients who received post-transplant cyclophosphamide.
Researchers noted that most cases of GVHD among patients who received post-transplant cyclophosphamide were limited to stage 1 skin involvement. More severe skin and bowel involvement were observed after administration of conventional immunosuppression.
Further, 50% of patients who received conventional immunosuppression experienced chronic extensive GVHD at 2 years compared with 19% of patients who received post-transplant cyclophosphamide (SHR = 0.38; 95% CI, 0.21-0.67).
Researchers noted that post-transplant cyclophosphamide did not impact the risk for progression or relapse, with a similar proportion of patients achieving 3-year PFS in the conventional immunosuppression and post-transplant cyclophosphamide groups (60% vs. 58%) and demonstrating progression or relapse at 3 years (26% vs. 32%).
Estimates of 3-year OS rates included 69% (95% CI, 53-80) in the conventional immunosuppression group and 63% (95% CI, 52-73) in the post-transplant cyclophosphamide group.
One-year estimates of GVHD RFS included 22% (range, 12-34) in the conventional immunosuppression group and 45% (range, 35-55) in the post-transplant cyclophosphamide group.
“With median follow-up of 3.2 years, there has been no difference in progression or relapse or in PFS or OS,” Broers said. “However, high-dose post-transplant cyclophosphamide does significantly improve GVHD relapse-free survival compared with conventional immunosuppression, thereby reflecting its long-term benefit and positive impact on the quality of life after an allogeneic stem cell transplant.” – by John DeRosier
Reference:
DeJong CN, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosures: Broers reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.
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Zachariah DeFilipp, MD
This abstract is of high interest to those in the field of bone marrow transplantation.
GVHD is one of the major complications of allogeneic transplants and, in its severe forms, contributes to morbidity and mortality after transplant.
The conventional approach to GVHD prevention is through the administration of immunosuppressant agents, typically beginning in the days prior to stem cell infusion. An alternative strategy of post-transplant cyclophosphamide has led to great improvements in transplant performed from a haploidentical, or “half-matched” donor.
In the HOVON-96 trial, researchers randomly assigned 160 patients who underwent allogeneic transplants from fully matched donors to receive post-transplant cyclophosphamide or conventional immunosuppression as a GVHD prevention strategy.
The use of high-dose post-transplant cyclophosphamide resulted in a significant reduction in severe acute and chronic GVHD without affecting relapse, resulting in improved GVHD RFS.
This trial provides compelling data that post-transplant cyclophosphamide may eventually be considered the standard-of-care approach to GVHD prevention in all patients receiving allogeneic HSCT.
A limitation of the study, which was conducted in Europe, is that the conventional immunosuppression arm consisted of cyclosporine and mycophenolate. Many centers in the U.S. instead use tacrolimus and methotrexate.
An upcoming study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN; study 1703) will randomly assign 428 patients undergoing reduced-intensity allogeneic transplant from HLA-matched donors to receive either post-transplant cyclophosphamide or tacrolimus/methotrexate for GVHD prevention. There will be much anticipation to see if similar outcomes are seen in this BMT CTN study.
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