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.
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.
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.
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.
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.
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.
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.
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 (ED 50 ) ranging from 0.75 to 2.7 μg/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-κB
(NF-κB) 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-α– and lipopolysaccharide-stimulated NF-κB 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-κB 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.
Purpose
Skin disorders demonstrate highly variable phenotypical and histopathological features. Mogamulizumab, a humanized anti‐CC chemokine receptor 4 monoclonal antibody indicated for the treatment ...of adult T‐cell leukemia‐lymphoma, has been shown to induce skin‐related adverse events in some patients, including rare cases of Stevens‐Johnson syndrome. Hence, we aimed to elucidate immunological primary reactions in skins of mogamulizumab by quantitatively comparing any patterns of other skin disorders.
Methods
We quantitatively analyzed Foxp3+, CD8+, CD4+, granzyme B+, CD56+, and macrophage‐derived chemokine‐positive cells, and compared the results with trends observed in other inflammatory skin disorders such as psoriasis vulgaris, atopic dermatitis, and lichen planus. The analysis was separately performed in dermis, basement membrane, or epidermis of skins.
Results
Foxp3+/CD8+ cell ratio in dermis and basement membrane of mogamulizumab‐emergent skin disorders was significantly lower compared with those of the other skin disorders. In inflammatory skins, the more the number of CD8+ cells were infiltrated, the more the number of Foxp3+ cells were prone to be infiltrated, but not in mogamulizumab‐emergent skin disorders. No significant difference between all of the other skin disorders was observed in other immunological markers.
Conclusion
The low Foxp3+/CD8+ cell ratio of skins is the underlying reason for mogamulizumab‐emergent skin disorders.
Skin disorders demonstrate highly variable phenotypical and histopathological features. Mogamulizumab, a humanized anti-CC chemokine receptor 4 monoclonal antibody indicated for the treatment of adult T-cell leukemia-lymphoma, has been shown to induce skin-related adverse events in some patients, including rare cases of Stevens-Johnson syndrome. Hence, we aimed to elucidate immunological primary reactions in skins of mogamulizumab by quantitatively comparing any patterns of other skin disorders, and the low Foxp3+/CD8+ cell ratio of skins is the underlying reason for mogamulizumab-emergent skin disorders.
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. (Cancer Sci 2005; 96: 810–815)
Human T cell leukemia/lymphotropic virus type I (HTLV-I) induces adult T cell leukemia/lymphoma (ATLL). The mechanism of HTLV-I oncogenesis in T cells remains partly elusive. In vitro, HTLV-I induces ...ligand-independent transformation of human CD4+T cells, an event that correlates with acquisition of constitutive phosphorylation of Janus kinases (JAK) and signal transducers and activators of transcription (STAT) proteins. However, it is unclear whether the in vitro model of HTLV-I transformation has relevance to viral leukemogenesis in vivo. Here we tested the status of JAK/STAT phosphorylation and DNA-binding activity of STAT proteins in cell extracts of uncultured leukemic cells from 12 patients with ATLL by either DNA-binding assays, using DNA oligonucleotides specific for STAT-1 and STAT-3, STAT-5 and STAT-6 or, more directly, by immunoprecipitation and immunoblotting with anti-phosphotyrosine antibody for JAK and STAT proteins. Leukemic cells from 8 of 12 patients studied displayed constitutive DNA-binding activity of one or more STAT proteins, and the constitutive activation of the JAK/STAT pathway was found to persist over time in the 2 patients followed longitudinally. Furthermore, an association between JAK3 and STAT-1, STAT-3, and STAT-5 activation and cell-cycle progression was demonstrated by both propidium iodide staining and bromodeoxyuridine incorporation in cells of four patients tested. These results imply that JAK/STAT activation is associated with replication of leukemic cells and that therapeutic approaches aimed at JAK/STAT inhibition may be considered to halt neoplastic growth.
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