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Epstein–Barr virus status affects GVHD risk after HSCT
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Donor Epstein–Barr virus donor and recipient status significantly influenced risk for acute and chronic graft-versus-host disease among patients with leukemia undergoing allogeneic hematopoietic stem cell transplantation, according to study results from the European Society for Blood and Marrow Transplantation.
“Epstein–Barr virus [EBV] is very common virus that belongs to the herpesviruses family, which also includes cytomegalovirus,” Jan Styczynski, MD, PhD, professor of pediatric hematology and oncology at Nicolaus Copernicus University College of Medicine in Bydgoszcz, Poland, and chairman of the European Society for Blood and Marrow Transplantation’s infectious disease working party, told HemOnc Today. “We know from several large studies that donor and/or recipient cytomegalovirus seropositivity is associated with an adverse prognosis in patients with acute leukemia after allogeneic HSCT, which caused us to ask the question: What is the impact of EBV serology on transplant outcomes, and especially OS?”
Jan Styczynski
Styczynski and colleagues evaluated 11,364 patients (median age, 38.9 years; range, 0.4-74.8; 18.8% 18 years) undergoing peripheral-blood (n = 6,593) or bone marrow transplantation (n = 4,771) for acute leukemia between 1997 and 2012.
The majority of patients (63%; n = 6,556) had acute myeloid leukemia; the remainder (37%; n = 3,857) had acute lymphoblastic leukemia.
Most donors (81.8%) were EBV–seropositive and 18.2% were EBV–seronegative. In 75.3% (n = 8,559), of cases, donors and recipients were both seropositive. Donors and recipients were both seronegative in 8.7% (n = 987) of cases.
The impact of donor and recipient EBV serologic status on OS served as the primary endpoint. Secondary endpoints included the impact of serologic status on RFS, relapse incidence, nonrelapse mortality and GVHD incidence after allogeneic HSCT.
Median follow-up was 4.9 years (range, 4.76-5).
At follow-up, 45.2% (n = 5,134) of patients had died, the majority due to relapse or progression (n = 2,792). Other causes of death included infections (n = 790), GVHD (n = 751), organ damage or failure (n = 202), second malignancy (n = 47) and other causes (n = 552).
Patients who received grafts from EBV–seropositive donors had similar OS to patients who received grafts from EBV–seronegative donors (HR = 1.05; 95% CI, 0.97-1.12). Serologic status also did not influence RFS outcomes (HR = 1.04; 95% CI, 0.97-1.11), relapse incidence (HR = 1.03; 95% CI, 0.94-1.12) or nonrelapse mortality (HR = 1.05; 95% CI, 0.94-1.17).
Acute GVHD occurred in 29% of EBV–seronegative patients with a seronegative donor, 31.9% of seropositive patients with a seropositive donor, and 35.1% of seronegative patients with a seropositive donor (P = .037).
The increased risk for acute GVHD was considered by the researchers to be relatively low. Seropositive patients with seropositive donors (HR = 1.24; 95% CI, 1.07-1.45) demonstrated slightly increased risks for acute GVHD.
The 2-year cumulative incidence of chronic GVHD was significantly higher with EBV–seropositive vs. –seronegative donors (40.82% vs. 31.03%). If both donor and recipient were EBV seropositive, the incidence of chronic GVHD was 41.44%.
A univariate analysis showed patients who received grafts from seropositive donors experienced a higher risk for chronic GVHD than those who received grafts from seronegative donors (HR = 1.42; 95% CI, 1.3-1.56).
With seropositive donors, the HR for chronic GVHD was 1.3 (95% CI, 1.06-1.59) for seronegative patients and 1.43 (95% CI, 1.23-1.67) for seropositive patients.
Seropositive patients with seronegative donors did not have an increased risk for GVHD.
Confounding factors associated with an increased risk for acute GVHD included patient age, donor age, diagnosis of ALL, disease remission at HSCT, female donor for male recipient, unrelated donor, no T-cell depletion and earlier year of transplantation.
Factors associated with increased chronic GVHD risk included patient age, donor age, female donor for male recipient, peripheral-blood source, donor type other than sibling, no T-cell depletion and earlier year of transplantation.
“As we know how to inhibit replication of EBV, it is possible that we can prevent development of GVHD in a large group of patients,” Styczynski said. “Rituximab [Rituxan; Genentech, Biogen Idec] is used to treat patients with developing EBV–DNAemia, and another prophylactic option is the use of EBV–specific cytotoxic T cells for destroying transient B lymphocytes. This study shows that we still don’t know how deeply EBV can influence health conditions. In this meaning, the next step should be to assess if prevention of EBV–DNAemia will decrease the incidence of acute and chronic GVHD.”
Richard E. Champlin
Many questions remain as to best practices for controlling EBV status among donors and recipients, Katayoun Rezvani, MD, PhD, and Richard E. Champlin, MD, both of The University of Texas MD Anderson Cancer Center, wrote in an accompanying editorial.
“If donor EBV seropositivity is an important mediator of GVHD in the recipient, one may hypothesize that it may be possible to prevent or possibly treat GVHD by controlling EBV infection,” Rezvani and Champlin wrote. “One possible strategy is preferential selection of EBV–seronegative donors, although this may not be practical in view of the high seroprevalence of the virus in the general population. Another strategy is B-cell depletion with monoclonal antibodies; memory B cells are the reservoir of EBV infection, and thus, depletion of memory B cells by rituximab may have therapeutic antiviral effects in addition to effects on B-lymphocyte antigen presentation.” – by Cameron Kelsall
For more information:
Jan Styczynski , MD, PhD, can be reached at jstyczynski@cm.umk.pl.
Disclosure: Styczynski reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Rezvani reports research funding from Pharmacyclics and a leadership role with Kiadis Pharma. Champlin reports research funding from Sanofi and consultant roles with Actinium Pharmaceuticals, Pfizer and Pharmacyclics.
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