Cytotoxic T-Lymphocyte Analysis of Aggressive Types of Adult T-Cell Leukemia/Lymphoma Patients with Complete Remission after Intensive Combination Chemotherapy
Authors: Jo Tatsuro , Horio Kensuke , Shigematsu Kazuto 
Published: October 2019

Abstract
Introduction: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell malignancy caused by human T-lymphotropic virus type I (HTLV-I). Most ATLL cells are CD4 and CCR4 positive, and CD8 negative. ATLL is classified into 4 clinical subtypes: smoldering, chronic, acute, and lymphoma. Acute and lymphoma type ATLLs, which are aggressive types, have a very poor prognosis. In Japan, aggressive ATLLs are commonly treated by intensive chemotherapies, such as VCAP-AMP-VECP, modified LSG15 therapy, and biweekly CHOP therapy. Recently, an anti-CCR4 monoclonal antibody (mogamulizumab) was approved for relapse and refractory ATLL in Japan. Mogamulizumab induces a highly potent antibody dependent cellular cytotoxicity, suggesting the importance of immuno-cell therapy for treatment of ATLL. We report here the extremely interesting results of aggressive ATLL patients with long-term survival and complete remission (CR) after activation of cellular immunity against ATLL cells following intensive chemotherapies.
Patients and Methods: We retrospectively evaluated 46 cases of aggressive ATLLs diagnosed at the Nagasaki Genbaku Hospital between January 2001 and August 2011. Of these, 7 patients had long-term survival greater than 3 years with CR after intensive chemotherapies. Four of these 7 patients had human leukocyte antigen (HLA)-A02:01 or HLA-A24:02, and were investigated using anti-HTLV-I specific cytotoxic T-lymphocyte (CTL) analysis. The HTLV-I provirus load in peripheral blood was also analyzed.
Results: Table 1 summarizes the characteristics of 7 aggressive type ATLL patients with long-term survival. Four patients were male and 3 were female. Six patients were classified as lymphoma type and 1 as acute type ATLL. The median age was 68 (range, 60–78) years. The median survival period from the onset of the disease was 111 (range, 36–165) months. In all 7 patients, the CD4/CD8 ratio reversed during, or shortly after, chemotherapy and CD8 predominance continued for more than 1 year (range, 13–165 months, median 24 months). Three patients had herpes virus infection during chemotherapy and reversal of the CD4/CD8 ratio appeared just after herpes virus infection in 2 of these patients. These observations suggested that HTLV-I specific CTLs were induced and contributed to the treatment of ATLL in these patients. An HTLV-I specific CTL analysis currently is available in patients with HLA-A02:01 and HLA-A24:02. Three of 7 aggressive ATLL patients with long-term survival and CR had HLA-A02:01 and 1 had HLA-A24:02. Therefore, HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood were performed in all 4 patients. Each patient was examined twice, once in 2012 and once in 2014. HTLV-I specific CTLs were detected in all patients (Table 2 and Figure 1). Although all patients maintained CR for, HTLV-I proviruses were detected in the peripheral blood in all patients (Table 2). This phenomenon was observed both in 2012 and in 2014 (Table 2 and Figure 1).
Conclusions: The findings from this study suggest that HTLV-I specific CTLs can be induced in patients with aggressive types of ATLL. In patients having long survival with CR, these CTLs can contribute to treatment and may play a roll inhibiting the relapse of ATLL. The development of efficacious methods to induce HTLV-I specific CTLs in individual ATLL patients may lead to improved outcomes for aggressive types of ATLL.
Table 1. Summary of aggressive type ATLL patients with long-term survival and complete remission PatientNo. Gender Age(year) Survival fromthe onset of ATLL (months) Duration ofCD4/CD8 reversal(months) Herpes virus infection 1 Male 69 165 165 + 2 Male 68 140 96 + 3 Female 71 71 65 - 4 Male 60 124 13 + 5 Female 61 111 18 - 6 Male 78 36 13 - 7 Female 65 56 24 -
Table 2. A Summary of HTLV-I specific CTL analysis and HTLV-I provirus load in the peripheral blood Patient No. HLA 2012 2014 CTL HTLV-I provirus CTL HTLV-I provirus (%) (copies/1000 cells) (%) (copies/1000 cells) 1 A02:01 0.11 35.4 0.13 61.9 2 A02:01 0.78 24.4 1.56 14.7 5 A02:01 1.06 7.1 1.31 13.3 7 A24:02 2.07 26.4 3.64 27.9
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.