Low Incidence of CMV Reactivation and Infection after Allogeneic Bone Marrow Transplantation (BMT) Incorporating Post-Transplantation Cyclophosphamide (Cy).
Authors: Symons Heather J. , Luznik Leo , Phelps Michele , Crawford Angelita , McIntyre Katherine , Levy M. Yair , Jones Richard J. , Fuchs Ephraim J. 
Published: October 2019

Abstract
Cytomegalovirus (CMV) disease remains an important complication of allogeneic stem cell transplantation (SCT). A major goal has been to develop bone marrow transplant (BMT) preparative regimens that minimize the duration of post-transplantation immunosuppression, and thus the risk of severe infectious complications. Previously, we reported a low rate of CMV reactivation (17.6%, 6/34 eligible patient-donor pairs) among hematologic malignancies patients receiving partially HLA-mismatched (haploidentical) BMT after non-myeloablative conditioning including high dose, post-transplantation Cy (50 mg/kg IV on days 3 and 4). Here, we have retrospectively analyzed an additional 99 recipients of post-transplantation Cy after fludarabine/200 cGy TBI-based nonmyeloablative conditioning and haploidentical BMT (n=44) or busulfan/Cy-based myeloablative conditioning and HLA-matched BMT (n=55). After high-dose Cy, patients undergoing haploidentical BMT received mycophenolate mofetil and tacrolimus, while recipients of HLA-matched grafts received no further graft-versus-host disease (GVHD) prophylaxis. Patients did not receive CMV prophylaxis. CMV reactivation, measured weekly by quantitative PCR, occurred in 38.7% (12/31 eligible donor-patient pairs) in the mini-haploBMT trial and 31% (13/42 eligible patient donor pairs) in the myeloablative trial. CMV reactivation occurred twice in two patients in each trial. CMV disease occurred in two patients in the haploidentical BMT trial (1 retinitis, 1 pneumonia) but in no recipients of HLA-matched grafts. No deaths have been attributed to CMV infection on either trial. In the mini-haplo BMT patients, 58.3% (7/12) of those with CMV reactivation were considered high-risk (recipient CMV IgG positive, donor CMV IgG positive or negative) and 25% (3/12) were considered to be at intermediate risk (recipient CMV IgG negative and donor CMV IgG positive). Of the myeloablative BMT patients, 100% (13/13) of patients with CMV reactivation were part of the high-risk group. In addition to recipient CMV positivity, the presence of graft-versus-host disease (GVHD) was a risk factor for CMV reactivation on the myeloablative trial as 77% (10/13) of patients who reactivated their CMV had GVHD, but not on the “mini-haploBMT” trial where only 41.7% (5/12) had GVHD. The median number of days post-transplant to CMV reactivation was 49 (range 19–197) in the “mini-haploBMT” patients and 56 (range 19–140) in the myeloablative group. The median number of weeks to clear detectable CMV was 1 (range 1–11 in the mini-haploBMT group and 1–4 in the myeloablative group). These rates of CMV reactivation and infection compare favorably to the rates seen in patients receiving haploidentical and HLA-matched grafts following myeloablative conditioning without post-transplantation Cy. The low rates of CMV reactivation may be secondary to low rates of Grade 3–4 GVHD (9.1%, 4/44 “mini-haploBMT patients”; 7.3%, 4/55 myeloablative patients) and rapid immunologic recovery facilitated by the absence of prolonged pharmacologic immunosuppression, especially among recipients of HLA-matched grafts.