[Show abstract][Hide abstract] ABSTRACT: CC chemokine receptor 4 (CCR4) is expressed by peripheral T-cell lymphomas (PTCLs) and is associated with poor outcomes. Mogamulizumab (KW-0761) is a defucosylated humanized anti-CCR4 antibody engineered to exert potent antibody-dependent cellular cytotoxicity. This multicenter phase II study evaluated the efficacy and safety of mogamulizumab in patients with relapsed PTCL and cutaneous T-cell lymphoma (CTCL).
Mogamulizumab (1.0 mg/kg) was administered intravenously once per week for 8 weeks to patients with relapsed CCR4-positive PTCL or CTCL. The primary end point was the overall response rate, and the secondary end points included safety, progression-free survival (PFS), and overall survival (OS).
A total of 38 patients were enrolled, and 37 patients received mogamulizumab. Objective responses were noted for 13 of 37 patients (35%; 95% CI, 20% to 53%), including five patients (14%) with complete response. The median PFS was 3.0 months (95% CI, 1.6 to 4.9 months), and the median OS was not calculated. The mean maximum and trough mogamulizumab concentrations (± standard deviation) after the eighth infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μ g/mL, respectively. The most common adverse events were hematologic events, pyrexia, and skin disorders, all of which were reversible and manageable.
Mogamulizumab exhibited clinically meaningful antitumor activity in patients with relapsed PTCL and CTCL, with an acceptable toxicity profile. Further investigation of mogamulizumab for treatment of T-cell lymphoma is warranted.
Journal of Clinical Oncology 03/2014; · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The number of elderly patients with diffuse large B-cell lymphoma (DLBCL) continues to increase but the data of autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients aged 60 years or over diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range: 60-78). To evaluate the impact of age at ASCT, patients were classified into three groups those aged 60 to 64, 65 to 69, and 70 years or over. Overall non-relapse mortality (NRM) at day 100, one year and two years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (p = 0.60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients aged 60-64, however, survival rate was acceptable even in those aged 70 or over with a two-year OS of 46%. ASCT is feasible in selected elderly patients and age alone would not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2014; · 3.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gastrointestinal (GI) tract is one of the most common extranasal sites in extranodal NK/T-cell lymphoma (ENKTL). However, data regarding ENKTL involving the GI tract are relatively scarce. Thus, we performed a multicenter, multinational retrospective study to analyze clinical features and treatment outcomes of ENKTL involving the GI tract.Patients and methods: Patients with ENKTL involving the GI tract diagnosed in twelve participating centers between 1991 and 2012 were retrospectively analyzed from five Asian countries.
The analysis of 81 patients with ENKTL involving the GI tract revealed that more than 60% of patients presented as advanced disease with B symptoms. 55 patients (68%) had GI manifestations including abdominal pain (n = 26, 32%), GI tract bleeding (n = 17, 21%) and bowel perforation (n = 12, 15%). The most common GI site was the small intestine, including the jejunum and ileum (n = 57, 70.3%). There were 34 patients (42%) who received systemic chemotherapy while 33 patients (41%) underwent surgery plus chemotherapy. However, 35 patients (43%) died due to disease progression, and treatment-related mortality including sepsis occurred in 17 patients (21%). Thus, the median overall survival was 7.8 months (95% Confidence interval: 3.9 -- 11.7 months). Patients who could undergo surgery plus chemotherapy showed a trend of better survival than those treated with chemotherapy alone.
Overall, the data indicated that ENKTL involving the GI tract has a dismal prognosis despite active treatment including chemotherapy and surgery. Thus, more effective treatment strategies are required for this disease entity.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive and associated with poor prognosis. Basic research to develop new treatment regimens is critically needed. METHODS: The effects of imatinib mesylate on MPNSTs were examined in six human MPNST cell lines and in a xenograft mouse model. RESULTS: The results showed expression of platelet-derived growth factor receptor-beta and suppression of its phosphorylation by imatinib mesylate in all six cell lines. Imatinib mesylate effectively suppressed MPNST cell growth in vitro at concentrations similar to those used clinically (1.46 - 4.6 muM) in three of six cell lines. Knockdown of PDGFR-beta by transfection with a specific siRNA also caused significant reduction in cell proliferation in the sensitive cell lines, but not in the resistant cell lines. Furthermore, imatinib mesylate also significantly suppressed colony formation within soft agar and tumor growth in xenograft models using two of the three sensitive MPNST cell lines. There was excellent agreement between in vitro and in vivo sensitivity to imatinib mesylate, suggesting possible selection of imatinib-sensitive tumors by in vitro analysis. CONCLUSIONS: The results suggest that imatinib mesylate may be useful in the treatment of MPNST patients and in vitro studies may help select cells that are sensitive to imatinib mesylate in vivo.
BMC Cancer 05/2013; 13(1):224. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Reports of non-anaplastic peripheral T-cell lymphoma (PTCL) in paediatric patients, especially results of stem cell transplantation (SCT), are relatively rare. We herein report the results of SCT using the Transplant Registry Unified Management Program system of the Japanese Society of Stem Cell Transplantation in paediatric patients with non-anaplastic PTCL. We analysed 26 patients (13 females and 13 males) aged ≤18 years with non-anaplastic PTCL who underwent a total of 28 SCT. Median age at transplantation was 13·5 years (range: 0-18 years). PTCL not otherwise specified was diagnosed in 17 patients; extranodal Natural Killer (NK)/T cell lymphoma, nasal type in nine; and subcutaneous panniculitis-like T-cell lymphoma in two. Transplantation was with syngeneic donor in one, related donor in 10; unrelated donor in 10; and auto transplantation in 7. Five-year overall survival rate and event-free survival rate was 62·96% and 55·56%, respectively. Male gender, chronic graft-versus-host disease (GVHD), and reduced intensity conditioning were good prognostic factors in all patients. In 20 patients with refractory or relapsed disease, male gender and chronic GVHD were also good prognostic factors. This study is the first report concerning transplantation in children with non-anaplastic PTCL, although the number of patients was small. Larger studies are needed to confirm these findings.
British Journal of Haematology 08/2012; 159(1):88-93. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is an Epstein-Barr virus (EBV)-associated lymphoma for which a new chemotherapeutic regimen called SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide) recently showed promising results.
The amount of EBV-DNA was prospectively measured in whole-blood and plasma samples by real-time quantitative PCR from 26 patients registered in the SMILE phase II study.
Before treatment, the EBV-DNA was detected in 22 samples of whole blood with a median number of 3,691 copies/mL (range: 0-1.14 × 10(7)), but 15 samples of plasma with a median of 867 copies/mL (range: 0-1.27 × 10(7)). Results of these 2 measurements of EBV-DNA well correlated (R(2) = 0.994, P < 0.001). The overall response rate to SMILE was significantly higher in patients with less than 10(5) copies/mL of EBV-DNA in whole blood at enrollment (90% vs. 20%, P = 0.007) and in patients with less than 10(4) copies/mL of EBV-DNA in plasma (95% vs. 29%, P = 0.002). The incidence of grade 4 toxicity of SMILE other than leukopenia/neutropenia was significantly higher in patients with 10(5) copies/mL of EBV-DNA or more in whole blood (100% vs. 29%, P = 0.007) than that of others and in patients with 10(4) copies/mL or more in plasma (86% vs. 26%, P = 0.002).
These findings suggest that whole blood is more sensitive for clinical use than plasma. The EBV-DNA amount in whole blood was useful for predicting tumor response, toxicity, and prognosis after SMILE chemotherapy for ENKL.
Clinical Cancer Research 06/2012; 18(15):4183-90. · 7.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Clinical features and outcomes of extranodal natural killer/T-cell lymphoma (ENKL) arising from extranasal sites are not fully understood. The purpose of this study was to study the prognosis and treatment outcome of skin/soft tissue primary ENKL. Patients and methods This multicenter retrospective study included 48 patients with skin/soft tissue primary ENKL diagnosed from 1993 to 2010. Results Patients with Ann Arbor stage I, T1-2N0M0 by International Society for Cutaneous Lymphomas-European Organization of Research and Treatment of Cancer TNM (tumour-node-metastasis) stage, International prognostic index score of 0-1, and a Korean prognostic index (KPI) score of 0-1 were associated with better survival. Four of five patients with T1-2N0M0 disease achieved complete response with radiation alone. In disseminated disease, only 6 of 13 patients responded to anthracycline-containing chemotherapy, and all the two patients receiving SMILE showed response. Conclusion In conclusion, we identified the prognostic value of KPI, and we suggest a treatment recommendation according to the TNM (tumour-node-metastasis) stage. Radiotherapy with/without chemotherapy seemed to be optimal in localized disease. In advanced stages, a more aggressive treatment regimen with newer agents should be sought.
Annals of Oncology 04/2012; 23(10):2703-7. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prognosis of acute- and lymphoma-type adult T-cell leukemia/lymphoma (ATL) is poor, but there is marked diversity in survival outcomes. The aim of this study was to develop a prognostic index (PI) for acute- and lymphoma-type ATL (ATL-PI).
In a retrospective review, data from 807 patients newly diagnosed with acute- and lymphoma-type ATL between January 2000 and May 2009 were evaluated. We randomly divided subjects into training (n = 404) and validation (n = 403) samples, and developed a PI using a multivariable fractional polynomial model.
Median overall survival time (MST) for the 807 patients was 7.7 months. The Ann Arbor stage (I and II v III and IV), performance status (0 to 1 v 2 to 4), and three continuous variables (age, serum albumin, and soluble interleukin-2 receptor [sIL-2R]) were identified as independent prognostic factors in the training sample. Using these variables, a prognostic model was devised to identify different levels of risk. In the validation sample, MSTs were 3.6, 7.3, and 16.2 months for patients at high, intermediate, and low risk, respectively (P < .001; χ(2) = 89.7, 2 df; log-rank test). We also simplified the original ATL-PI according to dichotomizing age at 70 years, serum albumin at 3.5 g/dL, and sIL-2R at 20,000 U/mL and developed an easily calculable PI with prognostic discrimination power (P < .001; χ(2) = 74.2, 2 df; log-rank test).
The ATL-PI is a promising new tool for identifying patients with acute- and lymphoma-type ATL at different risks.
Journal of Clinical Oncology 04/2012; 30(14):1635-40. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Lymphopenia is a marker of inferior survival in patients with various malignancies. However, the prognostic significance of lymphopenia in peripheral T-cell lymphoma (PTCL) is unclear. We analyzed the prognostic significance of lymphopenia in 826 patients with different types of PTCL and natural killer/T-cell lymphoma (NKTCL) from the International Peripheral T-cell Lymphoma Project. Lymphopenia was defined as an absolute lymphocyte count of less than 1,000 cells per microliter. The overall frequency of lymphopenia was 35.3%, ranging from 21.1% in ALK(+) anaplastic large cell lymphoma (ALCL) to 47.5% in angioimmunoblastic T-cell lymphoma (AITL). Lymphopenia was independently associated with an inferior overall survival (OS) in patients with the lymphoma type of adult T-cell leukemia/lymphoma (ATLL), with a 2-year OS of 15% versus 40% for those without lymphopenia (P < 0.001). Lymphopenia was also an adverse predictor of survival in PTCL, not otherwise specified, but was associated with other unfavorable prognostic factors. A trend toward inferior survival for lymphopenic patients was also observed in AITL, ALK(-) ALCL and extranasal NKTCL lymphoma, whereas no difference in survival was found in nasal NKTCL, ALK(+) ALCL, or enteropathy-associated T-cell lymphoma. In this study, lymphopenia was identified as a new adverse prognostic factor in the lymphoma type of ATLL.
American Journal of Hematology 03/2012; 87(8):790-4. · 4.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We conducted a retrospective Japan-Korea multicenter study to better elucidate the clinicopathologic features and therapeutic modalities for aggressive natural killer cell leukemia (ANKL). A total of 34 patients were analyzed. The median age of the patients was 40 years. Among the patients in the study, four had a history of Epstein-Barr virus-related disorders. Three types of ANKL cells were categorized according to their morphological features. Leukemic cells were below 20% in both peripheral blood and bone marrow of 11 patients. The clinical characteristics and prognoses of these 11 patients did not differ significantly from those of the others. As an initial therapy, l-asparaginase chemotherapy resulted in a better response. A total of six patients received allogeneic hematopoietic stem cell transplantation (HSCT) and two received autologous HSCT, with all in non-complete remission (CR). After HSCT, four with allogeneic and one with autologous HSCT reached CR. Median survival of all patients was 51 days. Median survival for the patients with and without HSCT were 266 and 36 days, respectively. A total of two patients with allogeneic HSCT were alive and in CR. All patients without HSCT died of ANKL. The use of L-asparaginase was indicated as a factor for longer survival (HR 0.33, 95% confidence interval; 0.13-0.83, P = 0.02). Early diagnosis of ANKL, l-asparaginase-based chemotherapy and allogeneic HSCT might lead to improved patient outcomes.
Cancer Science 02/2012; 103(6):1079-83. · 3.48 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Resistance to gemtuzumab ozogamicin (GO) hampers the effective treatment of refractory acute myeloid leukemia (AML). To clarify the mechanism of resistance to GO, HL-60 cells were persistently exposed to GO in order to establish GO-resistant HL-60 (HL-60/GOR) cells. Multidrug resistance 1 (MDR-1) was strongly expressed in HL-60/GOR cells, but not in HL-60 cells. Although withdrawal of GO after the chronic exposure of HL-60/GOR cells to this compound gradually decreased MDR-1 expression to trace levels, reintroducing GO restored high MDR-1 expression in HL-60/GOR cells, but not in HL-60 cells. These results indicate that HL-60/GOR cells acquired the ability to induce MDR-1 expression in response to GO. U0126, a MEK1/2 inhibitor, prevented GO-inducible MDR-1 expression and abrogated GO resistance in HL-60/GOR cells. These results suggest that in the clinical use of GO, inducible MDR-1 expression in tumor cells should be investigated before treatment with GO. If the cells are positive then MEK1/2 inhibitors may be effective in overcoming resistance to GO.
[Show abstract][Hide abstract] ABSTRACT: Epstein-Barr virus (EBV)-DNA was prospectively analyzed in plasma and mononuclear cells (MNCs) from peripheral blood in patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, to evaluate the clinical significance for diagnosis, monitoring the tumor burden, and prognostication. Thirty-three patients were enrolled, and 32 were evaluable. Pretreatment plasma and MNC EBV-DNA was detectable in 14 (range, 50-71 000 copies/mL) and 6 patients (range, 20-780 copies/μg DNA), respectively, and both were well correlated (r = 0.8741, P < .0001). Detectable plasma EBV-DNA was associated with higher clinical stage (P = .02), presence of B symptoms (P = .02), worse performance status (P = .02), and higher serum soluble IL-2 receptor level (P < .0001). Twenty-two patients attained complete response. Plasma EBV-DNA level was significantly higher in nonresponders than in responders (mean, 16,472 vs 2,645 copies/mL; P = .02). Multivariate analysis showed clinical stage (hazard ratio, 9.0; 95% confidence interval, 1.8%-45.0%) and pretreatment plasma EBV-DNA (hazard ratio, 10.6; 95% confidence interval, 1.3%-87.0%) were significant prognostic factors. Three-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (P = .0009). Plasma was a preferable sample for this purpose in NK/T-cell lymphoma, nasal type, and EBV-DNA level was a good indicator for response and overall survival.
[Show abstract][Hide abstract] ABSTRACT: To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen.
Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment.
A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%).
SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.
Journal of Clinical Oncology 11/2011; 29(33):4410-6. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Stromal cells are the main source of matrix metalloproteinases (MMPs) in human carcinoma tissues. Emmprin is a glycosylated transmembrane protein containing two immunoglobulin (Ig) domains that is expressed in carcinoma cells and stimulates MMP production by adjacent stromal cells. The first Ig domain (ECI) of emmprin contains the biologically active site. We investigated whether synthetic peptides carrying a partial ECI sequence could inhibit emmprin activity. Only the second peptide (emp#2), which contains a putative N-glycosylation site sequence, inhibited emmprin-stimulated production of MMP-2 in co-cultures of fibroblasts and several different human tumor cells types, including carcinoma, sarcoma, melanoma, leukemia and glioma cells. Moreover, emp#2 significantly inhibited the invasive activity of glioblastoma cells promoted by interaction with fibroblasts. Perturbation of emmprin activity by this peptide may have potential therapeutic uses in the prevention of MMP-2-dependent cancer invasion.
International Journal of Oncology 05/2011; 39(3):657-64. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Congenital macrothrombocytopenia is a genetically heterogeneous group of rare disorders. αIIbβ3 has not been implicated in these conditions. We identified a novel, conserved heterozygous ITGA2B R995W mutation in 4 unrelated families. The surface expression of platelet αIIbβ3 was decreased to 50% to 70% of control. There was spontaneous PAC-1 and fibrinogen binding to resting platelets without CD62p expression. The activation state of αIIbβ3 in 293T cells was higher for αIIb-W995 than for β3-H723 but was weaker than for β3-N562. FAK was spontaneously phosphorylated in αIIb-W995/β3-transfected 293T cells. These results indicate that αIIb-W995/β3 has a constitutive, activated conformation but does not induce platelet activation. αIIb-W995/β3-transfected CHO cells developed membrane ruffling and abnormal cytoplasmic protrusions. The increased size and decreased number of proplatelet tips in αIIb-W995/β3-transduced mouse fetal liver-derived megakaryocytes indicate defective pro-platelet formation. We propose that activating mutations in ITGA2B and ITGB3 represent the etiology of a subset of congenital macrothrombocytopenias.