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Background We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. Patients and Methods Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert’s formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. Results In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed Conclusion The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) spreads through cell contact. Therefore, this virus persists and propagates within the host by two routes: clonal proliferation of infected cells and de novo infection. The proliferation is influenced by the host immune responses and expression of viral genes. However, the detailed mechanisms that control clonal expansion of infected cells remain to be elucidated. In this study, we show that newly infected clones were strongly suppressed, and then stable clones were selected, in a patient who was infected by live liver transplantation from a seropositive donor. Conversely, most HTLV-1+ clones persisted in patients who received hematopoietic stem cell transplantation from seropositive donors. To clarify the role of cell-mediated immunity in this clonal selection, we suppressed CD8+ or CD16+ cells in simian T-cell leukemia virus type 1 (STLV-1)-infected Japanese macaques. Decreasing CD8+ T cells had marginal effects on proviral load (PVL). However, the clonality of infected cells changed after depletion of CD8+ T cells. Consistent with this, PVL at 24 hours in vitro culture increased, suggesting that infected cells with higher proliferative ability increased. Analyses of provirus in a patient who received Tax-peptide pulsed dendritic cells indicate that enhanced anti-Tax immunity did not result in a decreased PVL although it inhibited recurrence of ATL. We postulate that in vivo selection, due to the immune response, cytopathic effects of HTLV-1 and intrinsic attributes of infected cells, results in the emergence of clones of HTLV-1-infected T cells that proliferate with minimized HTLV-1 antigen expression., Author summary HTLV-1 spreads in vivo through two routes: de novo infection and clonal proliferation of infected cells. Reverse transcriptase inhibitors and integrase inhibitors do not influence the PVL in HTLV-1-infected individuals, indicating that clonal proliferation is dominant to maintain and increase PVL in vivo in the chronic phase. It is assumed that the host immune responses are critical factors for clonal proliferation. We found that HTLV-1-infected clones dramatically changed during de novo infection whereas the clones in the chronic phase survived long-term after transplantation, indicating that HTLV-1-infected clones are selected for survival in vivo. Surprisingly, depletion of CD8+ cells had a small impact on PVL in a STLV-1 infected Japanese macaque, but modified the clonality of infected cells. The cells after depletion of CD8+ cells showed a higher proliferative activity during short-term in vitro culture. This study reveals that intrinsic attributes of selected clones contribute to clonal proliferation of infected cells.

Background: Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive peripheral T-cell neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1). Although most patients respond to initial therapy, relapse is inevitable and the overall prognosis is dismal. Therefore, we developed a novel immune therapy consisting of autologous dendritic cells (DC) pulsed with Tax peptides (ATL-DC-101) to prevent relapse. The used peptides are corresponding to the major epitopes of HTLV-1 Tax-specific cytotoxic T lymphocytes (CTLs) that potentially act as anti-ATL effectors. Mogamulizumab is an anti-CCR4 antibody, which binds to ATL cells and regulatory T cells. A preceding pilot study suggested the safety of ATL-DC-101 monotherapy, and then we conducted a phase Ia/Ib study to investigate safety and efficacy of ATL-DC-101 combined with mogamulizumab. Methods: ATL patients pretreated and stable for at least 4 weeks were enrolled. Peripheral blood mononuclear cells were obtained by apheresis and differentiated into DC, which was pulsed with Tax-peptides. The study consisted of 2 cohorts, i.e., Ia and Ib phase, in which patients were assigned ATL-DC-101 monotherapy and ATL-DC-101 combined with mogamulizumab, respectively. The protocol consisted of three subcutaneous injections of ATL-DC-101 at 2-week intervals. Mogamulizumab was administered once before ATL-DC-101 in Ib phase. The primary endpoint of the study was to evaluate safety and feasibility of ATL-DC-101. The secondary endpoints were anti-tumor effects, progression-free survival (PFS), overall survival (OS), and time to next treatment, estimated by Kaplan-Meier method. The safety and disease status were accessed at day 56 and followed until 2 years. Results: Six aggressive ATL patients who were in stable condition by previous therapies were enrolled in this study from 2015 to 2016. Frequent DC- related toxicities were mild injection site reaction (n=5, 83.3%), decreased WBC count (n=3, 50%), and liver damage (n=2, 33.3%), all of which were grade 1 or 2. Notably, 2 patients (1 in each cohort) with partial response (PR) after chemotherapy were converted into complete response (CR) after ATL-DC-101. The 2-year PFS and OS were both 83.3%. All three patients who received ATL-DC-101 monotherapy (Ia) maintained CR for more than two years. Although one patient in phase Ib developed progressive disease after one year, the other two patients remained in CR. Interestingly ATL cells in a relapsed case harbored deletion of Tax gene, which resulted in the loss of the target peptide presentation. After a median follow-up of 29 months, 5/6 patients are alive without any additional chemotherapy after ATL-DC-101. Conclusions: ATL-DC-101 was well tolerated and successfully maintained CR more than 2 years in 5/6 patients irrespective of additional mogamulizumab, indicating that this therapy could be a safe and effective long-lasting maintenance therapy even for elderly ATL patients. Currently, we are preparing Phase II trial to confirm anti-tumor effects of ATL-DC-101 monotherapy. Disclosures Shiratsuchi: Kyowa Hakko Kirin Co.Ltd: Research Funding; Chugai Pharmaceutical Co.Ltd: Research Funding; Daiichi Sankyo Co.Ltd: Research Funding. Fukuda:Chugai Pharmaceutical: Speakers Bureau. Ishida:Kyowa Hakko Kirin Co.Ltd: Honoraria, Research Funding; Celgene K.K: Honoraria, Research Funding; Bayer AG: Research Funding; Mundiparma K: Honoraria. Akashi:Ono Pharmaceutical: Research Funding; MSD: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Celgene: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Novartis pharma: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Research Funding; Eisai: Research Funding; Pfizer: Research Funding; Astellas Pharma: Research Funding; Asahi-kasei: Research Funding; Chugai Pharma: Research Funding. Matsuoka:Bristol Myers Squibb: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding.