Transmission of Human T-Lymphotropic Virus Type I to Donor-Origin T Cells During Allogeneic Hematopoietic Stem Cell Transplantation

Human T-lymphotropic virus type I (HTLV-I) is a retrovirus that causes adult T-cell leukemia/lymphoma (ATLL), an aggressive CD4-positive mature T-cell malignancy with a dismal prognosis [1, 2]. In addition, the virus is associated with chronic inflammatory diseases such as HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP), arthritis, uveitis, dermatitis, and bronchioloalveolar disorders. It is estimated that HTLV-I infects 5 20 million individuals worldwide [3, 4]. HTLV-I is transmitted via breast feeding, sexual intercourse, needle sharing, and blood products containing cells. Organ transplantation has also been considered a rare route of HTLV-I transmission [5]. Here, we describe a case of HTLV-I transmission to T cells of an HTLV-I-negative donor through allogeneic hematopoietic stem cell transplantation (allo-HSCT). A 56-year-old man with a history of ATLL was referred to our hospital for dyspnea. Two years before the presentation, he underwent allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an HTLV-I-negative female donor with a reduced intensity conditioning (RIC) regimen consisting of fludarabine, melphalan, and total body irradiation (4 Gy). T-cell depletion was carried out using thymoglobulin. At the time of transplantation, the patient had systemic lymphadenopathy due to refractory ATLL. After transplantation, the patient achieved a complete remission. The HTLV-I-negative donor had neither atypical lymphocytes in the peripheral blood (PB) nor lymphadenopathy. The seronegativity of anti-HTLV-I antibody was confirmed by chemiluminescence enzyme immunoassay. Serum immunoglobulin levels of the donor were within normal limits. When the patient was referred to our hospital with dyspnea, he was receiving tacrolimus therapy for chronic graft-vshost disease (GVHD). He immediately underwent a complete blood count, which revealed 11 × 109/L white blood cells with 17% of atypical lymphocytes. The morphologic feature of the atypical lymphocytes was pleomorphic with condensed chromatin and convoluted or lobulated nucleus (Fig. 1a). Flow cytometric analysis (FCM) revealed that the atypical lymphocytes were positive for CD3 (Fig. 1b), CD25 (Fig. 1b) and CD4, and negative for CD8. Furthermore, the atypical lymphocytes, unlike his pretransplant ATLL cells, expressed CD7 (Fig. 1c). An increased HTLV-I proviral load (PVL) of 397.2 copies/1,000 PB mononuclear cells (PBMCs) was detected. Although no hypercalcemia was observed, serum lactate dehydrogenase and soluble interleukin (IL)-2 receptor levels were elevated to 290 U/L (normal: 124 222 U/L) and 30,573 U/ mL (normal: 145 519 U/mL), respectively. Epstein-Barr virus (EBV) and cytomegalovirus were negative in real-time quantitative polymerase chain reaction. Computed tomography of the chest revealed a mediastinal tumor and pleural effusion (arrows: Fig. 1d). Tumor biopsy showed diffuse infiltration of medium to large, atypical cells with irregular nuclear contour (Fig. 1e). The infiltrating tumor cells showed strong immunohistochemical staining for CD3 (Fig. 1f), CD4 (Fig. 1g), CD7 (Fig. 1h), and CD25 (Fig. 1i), but they were negative for CD8 (Fig. 1j) and EBV-encoded small RNA. FCM of the infiltrating tumor cells showed the same results as those of PB. Southern blot analysis (SBA) of the atypical lymphocytes using HTLV-I DNA as a probe (Fig. 2a) revealed internal bands following Pst1 digestion (lane 6; arrowheads). However, no monoclonal band pattern was observed in EcoR1 digestion (lane 5; arrow). In contrast, SBA results obtained from his pretransplant ATLL cells (Fig. 2b) revealed monoclonal integration of a defective HTLV-I provirus (lane 5; arrow). Moreover, XY-fluorescence in situ hybridization (XY-FISH) of the atypical lymphocytes was performed to determine the origin of the atypical lymphocytes. All tested cells revealed a typical XX pattern of a female donor (Fig. 2c). The G-band karyotype of the lymphocytes was also 46, XX. Bone marrow examination confirmed complete donor chimerism. Thus, our results demonstrated acquired HTLV-I infection of donor-origin T cells in the recipient. Two months after the discontinuation of tacrolimus, white blood cell counts in PB returned to normal, and no atypical lymManuscript submitted January 10, 2022, accepted February 15, 2022 Published online March 12, 2022