Takuya Fukushima

VCAP-AMP-VECP Compared With Biweekly CHOP for Adult T-Cell Leukemia-Lymphoma: Japan Clinical Oncology Group Study JCOG9801

PURPOSEnOur previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL.nnnPATIENTS AND METHODSnPreviously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis.nnnRESULTSnA total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm.nnnCONCLUSIONnThe longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.

Poor outcome of autologous stem cell transplantation for adult T cell leukemia/lymphoma: a case report and review of the literature

A limited number of patients with adult T cell leukemia/lymphoma (ATL) who received autologous stem cell transplantation (ASCT) have been reported. We report here a case of fatal systemic Candida krusei infection in a female patient with ATL undergoing ASCT. All of the eight patients (including seven patients in the literature) with ATL who received ASCT developed relapse of ATL or death due to ASCT complication, irrespective of subtype or remission state of ATL, source or selection of SCT or conditioning regimen. At present, ASCT appears to provide little benefit for ATL in contrast to that for other types of aggressive non-Hodgkin’s lymphoma.

Treatment of relapsed adult T-cell leukemia/lymphoma after allogeneic hematopoietic stem cell transplantation: the Nagasaki Transplant Group experience

Adult T-cell leukemia/lymphoma (ATL) relapse is a serious therapeutic challenge after allogeneic hematopoietic stem cell transplantation (allo-SCT). In the present study, we retrospectively analyzed 35 patients who experienced progression of or relapsed persistent ATL after a first allo-SCT at 3 institutions in Nagasaki prefecture (Japan) between 1997 and 2010. Twenty-nine patients were treated by the withdrawal of immune suppressants as the initial intervention, which resulted in complete remission (CR) in 2 patients. As the second intervention, 9 patients went on to receive a combination of donor lymphocyte infusion and cytoreductive therapy and CR was achieved in 4 patients. Of 6 patients who had already had their immune suppressants discontinued before the relapse, 3 patients with local recurrence received local cytoreductive therapy as the initial treatment, which resulted in CR for more than 19 months. Donor lymphocyte infusion-induced remissions of ATL were durable, with 3 cases of long-term remission of more than 3 years and, interestingly, the emergence or progression of chronic GVHD was observed in all of these cases. For all 35 patients, overall survival after relapse was 19.3% at 3 years. The results of the present study suggest that induction of a graft-versus-ATL effect may be crucial to obtaining durable remission for ATL patients with relapse or progression after allo-SCT.

Japan Clinical Oncology Group (JCOG) prognostic index and characterization of long-term survivors of aggressive adult T-cell leukaemia-lymphoma (JCOG0902A)

This study evaluated the clinical features of 276 patients with aggressive adult T‐cell leukaemia‐lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long‐term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG‐PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease‐related deaths in 10 patients with lymphoma‐type were observed in contrast to the 10 ATL‐related deaths in other types. In multivariate analysis of 193 patients, the JCOG‐PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG‐PI was reproducible in an external validation. Patients with lymphoma‐type who survived >5 years might have been cured. The JCOG‐PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies.

Diversity of leukaemic cell morphology in ATL correlates with prognostic factors, aberrant immunophenotype and defective HTLV-1 genotype

To investigate the diversity of morphology in adult T‐cell leukaemia/lymphoma (ATL) and its possible association with the pathophysiology of ATL, we selected 36 acute cases and 14 chronic cases phenotypically confirmed to have >90% ATL cells in peripheral blood mononuclear cells. Prototype ATL cells were observed in all cases, although the percentage of all lymphoid cells varied considerably (48.9u2003±u200323.8 in acute type, 29.6u2003±u200318.9 in chronic type; Pu2003=u20030.015). Chronic lymphocytic leukaemia (CLL)‐like morphology with round nuclei was more frequent in chronic type than in acute type (52.0u2003±u200324.9% v 16.6u2003±u200313.1%; Pu2003<u20030.0001). Unusual morphology (UM; lymphoblastic, vacuolated, granular pleomorphic or large cells) was more frequent in acute type than in chronic type (20.1u2003±u200318.7% v 2.7u2003±u20033.2%; Pu2003<u20030.0001). Furthermore, there were significant negative and positive correlations of % CLL‐like cells and % UM cells respectively, with serum LDH level, hypercalcaemia, performance status, and total number of involved lesions. Cases with aberrant immunophenotype (nu2003=u20036) or defective HTLV‐1 integration (nu2003=u200322) showed lower % CLL‐like cells and higher % UM cells than other cases, respectively. Cases with >50% CLL‐like cells (nu2003=u20037; all chronic type) were younger (53.1u2003±u200312.2 v 66.9u2003±u200310.6 years; Pu2003=u20030.038) and showed longer acute‐crisis free survival (mean: 16.7 v 3.0 years; Pu2003=u20030.012) than chronic cases with <50% CLL‐like cells. These results suggest that diversity in genotype, phenotype, morphology and behaviour of ATL are closely associated, and that CLL‐like morphology is a good prognostic factor for chronic type.

Feasibility of cord blood transplantation in chemosensitive adult T-cell leukemia/lymphoma: a retrospective analysis of the Nagasaki Transplantation Network

It has been reported that cord blood transplantation (CBT) for patients with aggressive adult T-cell leukemia/lymphoma (ATL) results in poorer outcomes than transplantation using other stem cell sources. To identify a subset of ATL in which CBT is feasible, we retrospectively analyzed 27 patients treated with CBT at three institutions in Nagasaki Prefecture, Japan. The estimated overall survival (OS) rate at 3xa0years was 27.4xa0%. Of 16 patients who received CBT during remission (complete, CR, or partial, PR), the OS rate at 3xa0years was 50xa0%, while during refractory periods (non-CR or non-PR), the OS rate was 9.1xa0%. Reduced intensity conditioning (RIC) was given to 18 patients, and myeloablative conditioning (MAC) was used in nine, with 3-year OS of 50.0 and 0xa0%, respectively. Of the 19 deaths, nine were due to progressive disease, eight (five MAC and three RIC) to infection, and two to multiple organ failure. These results suggest that CBT provides similar results with those in other transplantation procedures for selected ATL patients, such as those in CR or PR. Further studies are needed to evaluate the use of CBT in aggressive ATL.

Distinct Clinical Features of Infectious Complications in Adult T Cell Leukemia/Lymphoma Patients after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis in the Nagasaki Transplant Group

Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is performed as a curative option in adult T cell leukemia-lymphoma (ATL) patients, its high transplantation-related mortality raises a serious issue. The clinical features of infectious complications after transplantation are not well known. To analyze the impact of infections after allo-SCT for ATL, we retrospectively compared infectious complications in 210 patients at 3 institutions in Nagasaki prefecture between 1997 and 2009. There were 91 patients with acute myeloid leukemia (AML), 51 with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), and 68 with ATL. No patient received ganciclovir or foscarvir as prophylaxis, and most patients received antifungal prophylaxis with fluconazole or itraconazole. The cumulative incidence of cytomegalovirus (CMV) infection at 3 years was 69.2% in ATL patients versus 54.4% in AML patients (Pxa0= .0255). Cumulative infection-related mortality was significantly higher in ATL patients than in the 2 other groups (ATL versus AML, Pxa0= .0496; ATL versus ALL/LBL, Pxa0= .0075), and most death-causing pathogens were bacteria and fungus. The appearance of CMV infection was negatively associated with infectious mortality in ATL patients, but the P value for this association was near the borderline of significance (Pxa0= .0569). In multivariate analysis, transplantation using unrelated bone marrow and episodes of CMV infection were associated with worse overall survival in ATL patients, but were not in either AML or ALL/LBL patients. Collectively, the impact of infectious complications after transplantation in ATL patients was different from that in AML and ALL/LBL patients, suggesting that a more intensive strategy for infection control in ATL patients is required to reduce infectious mortality.

Absolute quantification of HTLV-1 basic leucine zipper factor (HBZ) protein and its plasma antibody in HTLV-1 infected individuals with different clinical status

BackgroundHuman T cell leukemia virus type 1 (HTLV-1) basic leucine zipper factor (HBZ), which is encoded by a minus strand mRNA, is thought to play important roles in the development of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). However, a comprehensive analysis of HBZ, including mRNA and protein expression, humoral immunoreactivity against HBZ, and HTLV-1 proviral load (PVL), in HTLV-1-infected individuals with different clinical status has not been reported previously.ResultsIn this study, using novel monoclonal antibody-based in-house enzyme-linked immunosorbent assay systems, we report the absolute quantification of HBZ protein and its plasma antibody in clinical samples from HTLV-1-infected individuals with different clinical status. The data were compared to both HBZ mRNA levels and PVL. The results showed that plasma anti-HBZ antibody was detectable only in 10.4xa0% (5/48) of asymptomatic carriers (ACs), 10.8xa0% (13/120) of HAM/TSP patients, and 16.7xa0% (7/42) of ATL patients. HBZ protein was detected in three out of five patients with acute ATL, but was not detected in patients with HAM/TSP (0/10) or ACs (0/4). Thus, an antibody response to HBZ was not associated with the PVL or the expression of HBZ (both at the mRNA and protein levels) or the clinical status of the infection.ConclusionsThe present results emphasize the extremely low expression and immunogenicity of HBZ in natural HTLV-1 infection. However, there is a possibility that the low but distinct expression of HBZ protein in PBMCs is associated with the survival of HTLV-1-infected cells and the development of ATL.

Human T-cell leukemia virus type-I Tax induces the expression of CD83 on T cells

BackgroundCD83, a cell surface glycoprotein that is stably expressed on mature dendritic cells, can be transiently induced on other hematopoietic cell lineages upon cell activation. In contrast to the membrane form of CD83, soluble CD83 appears to be immunosuppressive. In an analysis of the phenotype of leukemic CD4+ T cells from patients with adult T-cell leukemia (ATL), we found that a number of primary CD4+ T cells became positive for cell surface CD83 after short-term culture, and that most of these CD83+ CD4+ T cells were positive for human T-cell leukemia virus type-I (HTLV-I) Tax (Tax1). We hypothesized that Tax1 is involved in the induction of CD83.ResultWe found that CD83 was expressed selectively on Tax1-expressing human CD4+ T cells in short-term cultured peripheral blood mononuclear cells (PBMCs) isolated from HTLV-I+ donors, including ATL patients and HTLV-I carriers. HTLV-I-infected T cell lines expressing Tax1 also expressed cell surface CD83 and released soluble CD83. CD83 can be expressed in the JPX-9 cell line by cadmium-mediated Tax1 induction and in Jurkat cells or PBMCs by Tax1 introduction via infection with a recombinant adenovirus carrying the Tax1 gene. The CD83 promoter was activated by Tax1 in an NF-κB-dependent manner. Based on a previous report showing soluble CD83-mediated prostaglandin E2 (PGE2) production from human monocytes in vitro, we tested if PGE2 affected HTLV-I propagation, and found that PGE2 strongly stimulated expression of Tax1 and viral structural molecules.ConclusionsOur results suggest that HTLV-I induces CD83 expression on T cells via Tax1 -mediated NF-κB activation, which may promote HTLV-I infection in vivo.

Recurrence of Psoriasis Vulgaris Accompanied by Treatment with C-C Chemokine Receptor Type 4 (CCR4) Antibody (Mogamulizumab) Therapies in a Patient with Adult T cell Leukemia/ Lymphoma: Insight into Autoinflammatory Diseases

Adult T cell leukemia / lymphoma (ATL) is one of the most aggressive hematological malignancies caused by human T-lymphotropic virus type-I (HTLV-1). Mogamulizumab is a new defucosylated humanized monoclonal antibody agent which targets C-C chemokine receptor type 4 (CCR4) expressed occasionally on the surface of ATL cells. However, adverse events such as drug eruptions have also been highlighted, at least in part, via the dysfunction of regulatory T cells (Tregs). We herein report a pronounced recurrence of systemic psoriasis vulgaris accompanied by the treatment of mogamulizumab in a patient with ATL. Pathological examinations may suggest a mechanistic link between the recurrence of autoinflammatory diseases and anti-CCR4 antibody therapies.