Preemptive Management of Epstein-Barr Virus Reactivation after Hematopoietic Stem Cell Transplantation.
Authors: Ahmad Imran , Kwan John , Meuleman Nathalie , Lewalle Philippe , Crokaert Francoise , Bron Dominique 
Published: October 2019

Introduction - Epstein-Barr virus (EBV) reactivation after hematopoietic stem cell transplantation can lead to posttransplant lymphoproliferative disease (PTLD), which carries a high mortality rate. Transplants using T-cell-depleted graft or antithymocyte globulin are considered as high-risk. Among therapeutic and prophylactic options being developed, B-cell depletion with monoclonal antibodies is encouraging. Since viral load after transplantation is correlated to PTLD occurrence, we have developed a preemptive attitude based on PCR-guided rituximab administration.

Methods - We monitored 115 transplant patients with a quantitative PCR for EBV DNA performed on whole-blood samples. Criteria for treatment initiation were a single PCR above 40,000 DNA genome copies per litre (gCop/L) or two rising values above 10,000 gCop/L. Weekly rituximab infusion at the dose of 375 mg/m2 was administered until negative PCR results were available. We evaluated incidence of EBV reactivation and PTLD development.

Results - 19 patients (16.5%) met the criteria for treatment. Incidence of reactivation was the same in high-risk and standard-risk patients (12 vs 7, p=0.38). One patient developed PTLD after discontinuation of therapy due to a serious adverse event. No other serious adverse events were noticed. Viral load disappeared after a median of 3 cycles of therapy and weekly monitoring allowed prompt intervention. No PTLD-related death was observed, all-cause mortality in the treated population was 68%.

Conclusions - Our PCR-guided and rituximab-based preemptive approach to avoid PTLD after allogeneic hematopoietic stem cell transplantation is safe and feasible but probably overtreated patients. Prospective trials should concentrate on high-risk patients, use uniform PCR techniques, and consider higher threshold values for treatment initiation.

Characteristics of transplant population (n=115) Age (median and range) 39 (15–69) Diagnosis AML : acute myeloid leukemia - ALL : acute lymphoblastic leukemia - NHL : non Hodgkin’s lymphoma - CML : chronic myelogenous leukemia - MM : multiple myeloma - MDS : myelodysplastic syndrome - CLL : chronic lymphocytic leukemia - AA : aplastic anemia - Sib donor : HLA-matched sibling donor - MUD : HLA-matched unrelated donor     AML 31     ALL 17     NHL 15     CML 12     MM 11     MDS 10     CLL 6     AA 4     Others 9 Type of transplant     Myeloablative Sib donor 29     Myeloablative MUD 12     Nonmyeloablative Sib donor 32     Nonmyeloablative MUD 9     Haploidentical 33 Alive 32 (28%) Characteristics of treated patients (n=19) Age (median) 30 (18–62) AML : acute myeloid leukemia - ALL : acute lymphoblastic leukemia - NHL : non Hodgkin’s lymphoma - CML : chronic myelogenous leukemia - MM : multiple myeloma - MDS : myelodysplastic syndrome - CLL : chronic lymphocytic leukemia - AA : aplastic anemia - Sib donor : HLA-matched sibling donor - MUD : HLA-matched unrelated donor - TCD : ex vivo T cell depletion - ATG : antithymocyte globulin administration - D/R : donor / recipient serology - Cnl : calcineurin inhibitor (cyclosporin, tacrolimus) - MMF : mycophenolate mofetil Diagnosis AML 4 ALL 6 NHL 0 CML 4 MM 0 MDS 1 CLL 1 AA 1 Others 2 Type of transplant Myeloablative Sib donor 6 Myeloablative MUD 3 Nonmyeloablative Sib donor 4 Nonmyeloablative MUD 0 Haploidentical 6 TCD/ATG 12 EBV serology D+/R+ 17 D−/R− 0 D+/R− 1 D−/R+ 1 Immunosuppressive drugs Cnl alone 2 steroids alone 1 Cnl-steroids 5 Cnl-MMF-steroids 4 Others 1 None 0 GVHD Acute 9 Chronic 2 Alive 6 (32%) Cause of death relapse of malignancy 4 GVHD 4 Infection 4 Others 1