Successful treatment of refractory CMV colitis after haploidentical HSCT with post-transplant cyclophosphamide using CD45RA+ depleted donor lymphocyte infusion

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for high-risk acute leukemia; however, there is an associated risk of severe infections and graft-versus-host disease (GvHD). T-cell depletion has been used to reduce the chance of GvHD, but it causes delay of T-cell recovery, which may lead to more infections. Selective T-cell depletion, such as CD45RA naïve T cell, is on the rise to resolve the problem. Recently, HSCT with CD45RA+ naïve T-cell depleted graft has been reported to reduce the incidence of chronic GvHD, while preserving rapid T-cell recovery and transfer of protective virusspecific immunity [1]. Moreover, CD45RA+ depleted donor lymphocyte infusion (DLI) has shown a promising result of an effective antiviral boost after haploidentical HSCT (hHSCT) [2]. Herein, we report the successful treatment of refractory cytomegalovirus (CMV) colitis after post-transplant cyclophosphamide-based hHSCT using CD45RA depleted DLI. A 21-year-old woman was diagnosed with Philadelphiapositive acute lymphoblastic leukemia 5 years ago. After achieving first complete remission, she received allogeneic peripheral blood stem cell transplantation (PBSCT) from unrelated matched donor. Five years later, extramedullary relapse was confirmed. She received reinduction chemotherapy (hyper-CVAD plus MA regimen [3]) with imatinib and achieved second complete remission. Due to the non-availability of matched donor, the patient received hPBSCT from her mother. Busulfan was administered at 120 mg/m as a starter dose, and using the therapeutic drug monitoring, a subsequent targeted dose was administered for 3 days. The total target area under the curve of busulfan was set at 74,000 to 76,000 μg × h/L. Fludarabine (40 mg/m for 5 days) and cyclophosphamide (14.5 mg/kg for 2 days) were used as conditioning regimen. Cyclophosphamide (50 mg/kg at day 3 and day 4) was used for GvHD prophylaxis, along with prograf (target drug level 5–15 ng/mL from day 5 to day 90) and mycophenolate mofetil (15–20 mg/kg per dose q12h from day 5 to day 35) [4]. Maculopapular rash appeared on day 15 at 89% of the body surface area, and diarrhea occurred, which amounted more than that of stage 1 gutGvHD. Intravenous methylprednisolone was administered at the dose of 2 mg/kg/day for the treatment of overall grade II acute GvHD. Skin rash and diarrhea improved after 6 days of methylprednisolone administration. Watery diarrhea recurred on day 55. Methylprednisolone administration was restarted under the impression of recurrent GvHD. However, the diarrhea did not improve, so colonoscopic biopsy was performed on day 68, which revealed CMV colitis. Induction of ganciclovir and foscarnet was started from day 70 and day 74, respectively, but her colitis did not improve. Neutropenia occurred due to drug-induced bone marrow suppression, and vancomycinresistant enterococci sepsis (Fig. 1a). We planned granulocyte-colony stimulating factor primed, CD45RA depleted DLI to treat the refractory CMV colitis and augment immune recovery on day 87. CMV immunoglobulin G of donor was positive. Granulocyte-colony stimulating factor was administered for 4 days before leukapheresis. Whole blood from the donor was separated by density centrifugation using a closed bag system to obtain a leukocyte enriched cell fraction for These authors contributed equally: Hyun Jin Park, Kyung Taek Hong