Clinical significance of soluble CADM1 as a novel marker for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/leukemia (ATLL) is an aggressive peripheral T-cell malignancy, caused by infection with the human T-cell leukemia virus type 1 (HTLV-1). We have recently shown that cell adhesion molecule 1 (CADM1), a member of the immunoglobulin superfamily, is specifically and consistently overexpressed in ATLL cells, and functions as a novel cell surface marker. In this study, we first show that a soluble form of CADM1 (sCADM1) is secreted from ATLL cells by mainly alternative splicing. After developing the Alpha linked immunosorbent assay (AlphaLISA) for sCADM1, we showed that plasma sCADM1 concentrations gradually increased during disease progression from indolent to aggressive ATLL. Although other known biomarkers of tumor burden such as soluble interleukin-2 receptor α (sIL-2Rα) also increased with sCADM1 during ATLL progression, multivariate statistical analysis of biomarkers revealed that only plasma sCADM1 was selected as a specific biomarker for aggressive ATLL, suggesting that plasma sCADM1 may be a potential risk factor for aggressive ATLL. In addition, plasma sCADM1 is a useful marker for monitoring response to chemotherapy as well as for predicting relapse of ATLL. Furthermore, the change in sCADM1 concentration between indolent and aggressive type ATLL was more prominent than the change in the percentage of CD4+CADM1+ ATLL cells. As plasma sCADM1 values fell within normal ranges in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients with higher levels of serum sIL-2Rα, a measurement of sCADM1 may become a useful tool to discriminate between ATLL and other inflammatory diseases, including HAM/TSP.

Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.

The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab.

The relation between clinical features of adult T-cell leukemia/lymphoma and the serum levels of soluble CD25 and CD30.

Adult T-cell leukemia (ATL) is an aggressive neoplasm of mature T cells. We aimed to ascertain the relationships between soluble CD25 (sIL-2R) and CD30 (sCD30) levels and nodal or extra-nodal involvement of ATL. Our study subjects were ATL patients whose sIL-2R and sCD30 levels were measured before initial therapy (n=32). Their sCD30 levels correlated significantly with the number of ATL cells in peripheral blood (PB) (ρ=0.456; P=0.009), while sIL-2R levels correlated significantly with the number of nodal lesions (ρ=0.660; P=0.001). We then also assessed the relationships of pulmonary lesions with the number of ATL cells in PB, lactate dehydrogenase levels, sIL-2R levels, and sCD30 levels in 24 patients whose pleural effusions and hilar lymphadenopathy were investigated before initial therapy. The results suggested that a high number of ATL cells in PB may be associated with pulmonary lesions. It is known that metalloproteinases shed and cleave cytokine receptors such as CD25 and CD30 from the cell surface as well as E-cadherin and extracellular matrix. It seems that serum levels of sIL-2R and sCD30 indicate the activation of metalloproteinases associated with ATL involvement in vivo.

Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study.

This multicentre, randomized, phase II study was conducted to examine whether the addition of mogamulizumab, a humanized anti-CC chemokine receptor 4 antibody, to mLSG15, a dose-intensified chemotherapy, further increases efficacy without compromising safety of patients with newly diagnosed aggressive adult T-cell leukaemia-lymphoma (ATL). Patients were assigned 1:1 to receive mLSG15 plus mogamulizumab or mLSG15 alone. The primary endpoint was the complete response rate (%CR); secondary endpoints included the overall response rate (ORR) and safety. The %CR and ORR in the mLSG15-plus-mogamulizumab arm (n = 29) were 52% [95% confidence interval (CI), 33-71%] and 86%, respectively; the corresponding values in the mLSG15 arm (n = 24) were 33% (95% CI, 16-55%) and 75%, respectively. Grade ≥ 3 treatment-emergent adverse events, including anaemia, thrombocytopenia, lymphopenia, leucopenia and decreased appetite, were observed more frequently (≥10% difference) in the mLSG15-plus-mogamulizumab arm. Several adverse events, including skin disorders, cytomegalovirus infection, pyrexia, hyperglycaemia and interstitial lung disease, were observed only in the mLSG15-plus-mogamulizumab arm. Although the combination strategy showed a potentially less favourable safety profile, a higher %CR was achieved, providing the basis for further investigation of this novel treatment for newly diagnosed aggressive ATL. This study was registered at ClinicalTrials.gov, identifier: NCT01173887.

Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

[Serum sickness induced by rituximab infusion; report of two cases with hematological malignancies].

We report 2 cases of serum sickness after rituximab infusion. Case 1 is a patient with Waldenström's macroglobulinemia, and case 2 is a patient with marginal-zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type and Sjögren's syndrome. Both patients had polyclonal hypergammaglobulinemia, were treated with rituximab monotherapy, developed serum sickness between 9 and 17 days after the first rituximab infusion, developed fever and arthralgia, and improved soon after corticosteroid treatment. Serum sickness after rituximab treatment for hematological malignancies is very rare as far as we know. We identified three risk factors of serum sickness after rituximab infusion from previous reports and our cases; administration of rituximab alone, the existence of Sjögren's syndrome, and polyclonal hypergammaglobulinemia.

A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions.

The human T-cell lymphotropic virus type 1 (HTLV-1) infects and transforms CD4+ lymphocytes and causes adult T-cell leukemia/lymphoma (ATLL), an aggressive lymphoproliferative disease that is often fatal. Here, we demonstrate that the HTLV-1 pX splice-variant p30II markedly enhances the transforming potential of Myc and transcriptionally activates the human cyclin D2 promoter, dependent upon its conserved Myc-responsive E-box enhancer elements, which are associated with increased S-phase entry and multinucleation. Enhancement of c-Myc transforming activity by HTLV-1 p30II is dependent upon the transcriptional coactivators, transforming transcriptional activator protein/p434 and TIP60, and it requires TIP60 histone acetyltransferase (HAT) activity and correlates with the stabilization of HTLV-1 p30II/Myc-TIP60 chromatin-remodeling complexes. The p30II oncoprotein colocalizes and coimmunoprecipitates with Myc-TIP60 complexes in cultured HTLV-1-infected ATLL patient lymphocytes. Amino acid residues 99 to 154 within HTLV-1 p30II interact with the TIP60 HAT, and p30II transcriptionally activates numerous cellular genes in a TIP60-dependent or TIP60-independent manner, as determined by microarray gene expression analyses. Importantly, these results suggest that p30II functions as a novel retroviral modulator of Myc-TIP60-transforming interactions that may contribute to adult T-cell leukemogenesis.

Oridonin, a diterpenoid purified from Rabdosia rubescens, inhibits the proliferation of cells from lymphoid malignancies in association with blockade of the NF-kappa B signal pathways.

This study found that oridonin, a natural diterpenoid purified from Rabdosia rubescens, inhibited growth of multiple myeloma (MM; U266, RPMI8226), acute lymphoblastic T-cell leukemia (Jurkat), and adult T-cell leukemia (MT-1) cells with an effective dose that inhibited 50% of target cells (ED50) ranging from 0.75 to 2.7 microg/mL. Terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining showed that oridonin caused apoptosis of MT-1 cells in a time-dependent manner. We explored effects of oridonin on antiapoptotic Bcl-2 family members and found that it down-regulated levels of Mcl-1 and BCL-x(L), but not Bcl-2 protein, in both MT-1 and RPMI8226 cells. Further studies found that oridonin inhibited nuclear factor-kappa B (NF-kappa B) DNA-binding activity in these cells as measured by luciferase reporter gene, ELISA-based, and electrophoretic mobility shift assays. Oridonin also blocked tumor necrosis factor-alpha- and lipopolysaccharide-stimulated NF-kappa B activity in Jurkat cells as well as RAW264.7 murine macrophages. Of note, oridonin decreased survival of freshly isolated adult T-cell leukemia (three samples), acute lymphoblastic leukemia (one sample), chronic lymphocytic leukemia (one sample), non-Hodgkin's lymphoma (three samples), and MM (four samples) cells from patients in association with inhibition of NF-kappa B DNA-binding activity. On the other hand, oridonin did not affect survival of normal lymphoid cells from healthy volunteers. Taken together, oridonin might be useful as adjunctive therapy for individuals with lymphoid malignancies, including the lethal disease adult T-cell leukemia.

Immune thrombocytopenic purpura associated with rheumatoid arthritis: case report.

A 54-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) in 1995 on the basis of symmetric effusive polyarthritis, morning stiffness, and strongly positive rheumatoid factor. She had received low-dose prednisolone, indomethacin, methotrexate (MTX), and cyclophosphamide (CPA), at least, over 4 years before the current admission and showed partial improvement of polyarthralgia. In November 2002, she suddenly developed thrombocytopenia (platelet count was 0.3 x 10(4) mm(-3)) with purpura and was diagnosed with immune thrombocytopenic purpura (ITP). As she had refractory ITP, the administration of pulsed high-dose dexamethasone (DEX) therapy was started, resulting in the complete remission of ITP. The present paper reports that pulsed high-dose DEX therapy was useful for the treatment of refractory ITP associated with RA.

Plasma Soluble CD30 as a Possible Marker of Adult T-cell Leukemia in HTLV-1 Carriers: a Nested Case-Control Study.

Elevated levels of soluble CD30 (sCD30) are linked with various T-cell neoplasms. However, the relationship between sCD30 levels and the development of adult T-cell leukemia (ATL) in human T-cell leukemia virus type 1 (HTLV-1) carriers remains to be clarified. We here investigated whether plasma sCD30 is associated with risk of ATL in a nested case-control study within a cohort of HTLV-1 carriers. We compared sCD30 levels between 11 cases (i.e., HTLV-1 carriers who later progressed to ATL) and 22 age-, sex- and institution-matched control HTLV-1 carriers (i.e., those with no progression). The sCD30 concentration at baseline was significantly higher in cases than in controls (median 65.8, range 27.2-134.5 U/mL vs. median 22.2, range 8.4-63.1 U/mL, P=0.001). In the univariate logistic regression analysis, a higher sCD30 (≥30.2 U/mL) was significantly associated with ATL development (odds ratio 7.88 and the 95% confidence intervals 1.35-45.8, P = 0.02). Among cases, sCD30 concentration tended to increase at the time of diagnosis of aggressive-type ATL, but the concentration was stable in those developing the smoldering-type. This suggests that sCD30 may serve as a predictive marker for the onset of aggressive-type ATL in HTLV-1 carriers.

Genetic mutation and early onset of T-cell leukemia in pediatric patients infected at birth with HTLV-I.

T-cell leukemia/lymphoma (T-c LL) associated with prior infection with HTLV-I is rarely described in children. We present herein, the clinical, morphological, and virologic features of T-c LL, which occurred in eight pediatric cases with similar features of ATLL described in adults. There were three girls and five boys with age ranging from 2 to 18 years. Lymphoadenopathy, hepatosplenomegaly and marked skin lesions were presented in all cases. Five patients had hypercalcemia. The diagnostic criteria of T-c LL were based on both morphological and immunophenotypical analyses characterized by T-cell markers positively. Seven cases were cCD3+, CD4/CD25+, whereas CD1a and TdT were negative in all cases tested. HTLV-I antibodies were detected in all cases. HTLV-I provirus integration of at least one provirus was seen in all cases tested by molecular analysis. Mother-to-child transmission of HTLV-I was demonstrated in six cases. Interestingly, a homozygous deletion in p16 gene locus was observed in all four cases studied, while exons 7 and 8 of p53 were deleted in one child. The deletion of the p16(INK4A)/p14(ARF) or mutation of p53, key regulatory protein of cell cycle checkpoint in G1/S progression, found in five of the eight pediatric patients suggests that in these cases genetic lesions associated with HTLV-I infection may predispose for an early onset of leukemia.

Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study.

PURPOSE: Adult T-cell leukemia-lymphoma (ATL) is usually resistant to conventional chemotherapies, and there are few other treatment options. Because CC chemokine receptor 4 (CCR4) is expressed on tumor cells from most patients with ATL, KW-0761, a humanized anti-CCR4 monoclonal antibody, which markedly enhances antibody-dependent cellular cytotoxicity, was evaluated in the treatment of patients with relapsed ATL. PATIENTS AND METHODS: A multicenter phase II study of KW-0761 for patients with relapsed, aggressive CCR4-positive ATL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary end point was overall response rate, and secondary end points included progression-free and overall survival from the first dose of KW-0761. Patients received intravenous infusions of KW-0761 once per week for 8 weeks at a dose of 1.0 mg/kg. RESULTS: Of 28 patients enrolled onto the study, 27 received at least one infusion of KW-0761. Objective responses were noted in 13 of 26 evaluable patients, including eight complete responses, with an overall response rate of 50% (95% CI, 30% to 70%). Median progression-free and overall survival were 5.2 and 13.7 months, respectively. The mean half-life period after the eighth infusion was 422 ± 147 hours (± standard deviation). The most common adverse events were infusion reactions (89%) and skin rashes (63%), which were manageable and reversible in all cases. CONCLUSION: KW-0761 demonstrated clinically meaningful antitumor activity in patients with relapsed ATL, with an acceptable toxicity profile. Further investigation of KW-0761 for treatment of ATL and other T-cell neoplasms is warranted.

Serum level of soluble CD30 correlates with the aggressiveness of adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a highly aggressive disease with poor prognosis. CD30(+) cells are frequently observed in lymph node cells and peripheral blood mononuclear cells of ATL patients. In order to elicit the role of CD30(+) cells in ATL development, we investigated expression of the membrane type of CD30 (mCD30) and the soluble form of CD30 (sCD30) on ATL cells. Both mCD30 and sCD30 are expressed on various numbers of ATL cells in vivo as well as cell lines such as MT-2, L540 and Karpas 299. The level of serum sCD30 in each clinical stage showed an elevated level in patients with acute type (mean +/- standard error; 545.2 +/- 18.6 U/mL) rather than with lymphoma type ATL (327.62 +/- 94.85 U/mL). In four patients whose sera were stored and examined longitudinally, the levels decreased following the response to chemotherapy but not in patients with chemotherapy resistance. Thus, our results imply that sCD30 levels may be another useful marker for the activity and aggressiveness of ATL.

Treatment for HTLV-I associated arthropathy: a case study and synovial tissue culture analysis.

OBJECTIVE: There are few reports regarding the treatment of HTLV-I associated arthropathy (HAAP). This is a case study describing the treatment of a patient diagnosed with HAAP. We also analyzed the effects of various agents on cultured synovial tissue explants from the patient. METHODS: Arthroscopic synovectomy of the left knee was performed. We investigated the effects of pirarubicin (THP), bestatin, betamethasone, and hyaluronic acid (HA) in synovial tissue culture to evaluate the efficacy of these medications. RESULTS: Swelling and pain of the left knee was transiently diminished after synovectomy. However, bilateral swelling of the knees and C reactive protein (CRP) concentrations were increased. In the explant culture experiments, CD8+ cells decreased with the addition of bestatin, betamethasone, and HA. The structure of synovial cells was preserved by the addition of HA. However, the addition of THP induced fibrosis of synovial tissues, increased cells without nuclei, and diminished fascin-expressing cells. CONCLUSION: THP inhibited, but HA preserved the structure of hypertrophic synovial cells. Scopic synovectomy effectively improved joint effusion and pain; however, the effect was transient, and additional treatment with predonisolone was required. Therefore, it is important to develop a more effective treatment for HAAP.