To evaluate the efficacy and feasibility of upfront high-dose chemotherapy (HDCT) and rituximab (R) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) in patients with ...newly diagnosed high-intermediate(HI)-, and high(H)-risk diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter prospective phase II trial. In 15–60-year-old patients with H- or HI-risk DLBCL, after three courses of (R-)CHOP14, high-dose etoposide was given prior to peripheral blood stem cell harvesting. After an additional three courses of (R-)CHOP14, auto-PBSCT was performed following HDCT. The primary endpoint of the study is progression-free survival (PFS) at 2 years after registration in eligible patients. The expected PFS and the threshold PFS were estimated to be 70 and 50 %, respectively. Among 40 eligible patients registered, 30 patients completed treatment. With a median observation period in surviving eligible patients of 63 months, the 2- and 4-year PFS after registration were 79.9 and 72.0 %, respectively. The 2- and 4-year overall survival (OS) were 92.5 and 84.6 %, respectively. In 30 patients who completed treatment, the 4-year PFS and OS after auto-PBSCT were 79.2 and 85.9 %, respectively. In conclusion, the results of our study suggest that upfront HDCT and auto-PBSCT combined with rituximab is highly effective as an initial treatment for HI-, and H-risk DLBCL.
The management of myelodysplastic syndrome (MDS) remains challenging. We performed a phase I/II study to evaluate the safety and efficacy of decitabine in patients with MDS in Japan. Patients with ...MDS with red cell transfusion dependence or 5–30% blasts in marrow and with an International Prognostic Scoring System score of intermediate‐1 or higher were eligible. Patients received intravenous decitabine at 15 or 20 mg/m2 daily for 5 days every 4 weeks. A total of 37 patients were enrolled. Three patients received 15 mg/m2 and experienced no dose limiting toxicity during the first cycle. Thirty‐four patients received 20 mg/m2. Grade 3 or greater non‐hematologic toxicities included cerebral infarction (n = 1), subdural hematoma (n = 1), elevated blood glucose (n = 1), and pulmonary hypertension (n = 1). At 20 mg/m2, complete response, partial response, and hematologic improvement were observed in 7 (20.6%), 2 (5.9%), and 7 (20.6%) patients, respectively. Complete cytogenetic response was observed in 30% of evaluable 20 patients. The median number of cycles to clinical response was 4 (range 4–8), and duration of remission was 474+ days (range 294–598+). The 2‐year rate of acute myeloid leukemia‐free survival was 52%. Correlative studies revealed hypomethylation in multiple genes in peripheral blood cells after treatment. Hypomethylation was generally more profound in CD15 + peripheral blood cells, which reflects myeloid cells, than in peripheral blood mononuclear cells. In summary, decitabine was safe and demonstrated efficacy in Japanese patients with high‐risk MDS. This trial was registered at ClinicalTrials.gov (NCT00796003).
Sixty-four cases of malignant lymphoma involving the liver were examined. Of these, 20 cases were histologically confirmed to be primary hepatic B-cell lymphoma. Twelve of these 20 cases were diffuse ...large B-cell lymphoma (DLBCL) and eight cases were mucosa-associated lymphoid tissue (MALT) lymphoma. Of the 12 cases of DLBCL, six were immunohistologically positive for CD10 and/or Bcl6 (indicating a germinal center phenotype), six were positive for Bcl2, and five were positive for CD25. Eight of the 12 DLBCL cases (66.7%) and two of the eight MALT lymphoma cases (25%) had serum anti-hepatitis C virus (HCV) antibodies and HCV RNA. The incidence of HCV infection was significantly higher in the hepatic DLBCL cases than in systemic intravascular large B-cell cases with liver involvement (one of 11 cases, 9.1%) and T/NK-cell lymphoma cases (one of 19 cases, 5.3%) (
p
< 0.01 for both). Two hepatic DLBCL cases (16.7%) had rheumatoid arthritis treated with methotrexate, and four MALT lymphoma cases (50%) had Sjögren’s syndrome, primary biliary cirrhosis, or autoimmune hepatitis; one case in each of these two groups was complicated by chronic HCV-seropositive hepatitis. Although primary hepatic lymphoma is rare, persistent inflammatory processes associated with HCV infection or autoimmune disease may play independent roles in the lymphomagenesis of hepatic B cells.
Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non‐Hodgkin lymphoma (B‐NHL), in particular for patients pretreated with rituximab, ...is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B‐NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1–7). At the median follow‐up of 12.2 months, the overall response rate (ORR), complete response rate (%CR), and median progression‐free survival (PFS) were 69% (95% confidence interval CI 53%–82%), 47% (95% CI 32%–62%), and 15.6 months (95% CI 10.6– months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5 months for median PFS, respectively). All mild‐to‐moderate infusion‐related toxicities were reversible. Grade 3/4 non‐hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late‐onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B‐NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late‐onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.) (Cancer Sci 2011; 102: 1698–1705)
A Phase II, multicenter clinical trial of bendamustine plus rituximab (BR) regimen was conducted in previously untreated patients with high-tumor-burden indolent B-cell non-Hodgkin lymphoma (B-NHL) ...and previously untreated elderly patients with mantle cell lymphoma (MCL) in Japan. Bendamustine 90 mg/m
2
/day on days 1 and 2, as well as rituximab 375 mg/m
2
on day 1 were administered intravenously up to six cycles. The primary endpoint was the complete response (CR) rate as assessed by the International Workshop Response Criteria (1999). Sixty-nine patients (59 with indolent B-NHL and 10 with MCL) were treated. The median number of delivered cycles was six (range 1–6). The CR rates were 67.8% 95% confidence interval (CI) 54.4–79.4% and 70.0% (95% CI 34.8–93.3%) for indolent B-NHL and MCL, respectively. Estimated progression-free survival at 30 months was 72.1% (95% CI 58.5–82.0%) in indolent B-NHL and was 67.5% (95% CI 29.1–88.2%) in MCL. Major grade 3/4 toxicities were hematologic and included lymphopenia (97%), CD4 lymphopenia (91%), neutropenia (86%), and leukopenia (83%). No treatment-related death was found. The BR regimen showed high efficacy as evidenced by the expected CR rate and durable response, as well as an acceptable safety profile for the study populations.
Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of ...lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas.
In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298.
We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia cohort 2, one grade 3 QT prolongation on electrocardiogram cohort 3, and one grade 3 fatigue and grade 4 thrombocytopenia cohort 3). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight 62% patients), lymphopenia (seven 54% patients), and thrombocytopenia (four 31% patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient.
We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study.
Celgene Corporation.
Recent large-scale randomized clinical trials in Europe and the US demonstrated that maintenance therapy with rituximab significantly improved the progression-free survival (PFS) in indolent B-cell ...non-Hodgkin lymphoma (B-NHL) patients, especially those with follicular lymphoma (FL). However, rituximab maintenance has not been approved in Japan, because there are no clinical data supporting the benefit of rituximab maintenance in Japanese patients. Therefore, we conducted a single-arm, multicenter bridging study in previously untreated indolent B-NHL patients with high tumor burden. The primary endpoint was 4-year PFS and was expected to be 70 % based on previous studies. Sixty-two patients, including 55 FL patients, were enrolled and received induction therapy with CHOP combined with rituximab (R-CHOP). Fifty-eight patients responding to R-CHOP induction received rituximab at 375 mg/m
2
every 8 weeks for 2 years as for the rituximab maintenance arm in the PRIMA study. A 4-year PFS of 69.8 % was obtained (95 % confidence interval 55.9–80.0 %). Rituximab maintenance was well tolerated and common adverse events were infections, neutropenia, and/or leukopenia that were manageable with conventional supportive care. No patients died. These data were compatible with the PRIMA data. R-CHOP induction followed by rituximab is useful in Japanese patients with untreated indolent B-NHL having high tumor burden.
Clinical trial number
UMIN000001191
Phase I study was conducted to evaluate the safety, pharmacokinetics (PK) and efficacy of the oral mammalian target of rapamycin inhibitor, everolimus (RAD001), in patients with relapsed or ...refractory non-Hodgkin lymphoma (NHL). Patients received everolimus 5 or 10 mg orally once daily. Dose escalation was based on the safety assessment and the probability of dose-limiting toxicities (DLTs) using a Bayesian logistic model. DLTs were evaluated in six patients at each dose level during the initial 28 days of study treatment. A total of 13 patients were enrolled; 5 mg (seven) and 10 mg (six). No DLTs were observed at either dose level. Frequently observed potentially drug-related adverse events included leukopenia (8/13), thrombocytopenia (8/13), elevated hepatic transaminase (9/13), stomatitis (7/13), anemia (6/13), and nasopharyngitis (6/13). All adverse events were reversible. Non-infectious pneumonitis (grade 1) in one patient resolved following discontinuation of everolimus. Two patients with diffuse large B cell lymphoma and two patients with follicular lymphomas achieved objective responses with an overall response rate of 31% (4/13). The pharmacokinetic profiles were not different from those in non-Japanese patients. Everolimus was well tolerated at doses up to 10 mg/day and showed potential efficacy in relapsed or refractory NHL, warranting further investigation.
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a small percentage of infected individuals. ...ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC) already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8+ T-cells in various clinical status of HTLV-1 infection.
By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8+ T-cells in the peripheral blood from 87.0% of ACs (n = 20/23) and 100% of HAM/TSP patients (n = 18/18) tested. We also detected Tax-specific CD8+ T-cells in 38.1% of chronic type ATL (cATL) patients (n = 8/21), although its frequencies in peripheral blood CD8+ T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8+ T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8+ T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8+ T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8+ T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69) and degranulation (CD107a) markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV) pp65-specific CD8+ T-cells that possessed functions upon CMV pp65 peptide stimulation. We further examined additional samples of two smoldering type ATL patients and found that they also showed dysfunctions of Tax-specific but not CMV-specific CD8+ T-cells.
These findings indicated that Tax-specific CD8+ T-cells were scarce and dysfunctional not only in ATL patients but also in a limited AC population, and that the dysfunction was selective for HTLV-1-specifc CD8+ T-cells in early stages.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: Steroid-refractory acute graft vs. host disease (SR-aGVHD) remains a significant complication of allogenic hematopoietic stem cell transplantation (allo-HSCT). In this phase II-III ...multicenter clinical study we evaluated the efficacy and safety of MSCs(JR-031; JCR Pharmaceuticals Co., Ltd., Japan) for SR-aGVHD.
Method: 25 patients (age: 5-66 years, median 33years; male 15, female 10) who developed SR-aGVHD (grade III 22, grade IV 3) after allo-HSCT (Nov. 2011-Sept. 2012) were enrolled and given 8 biweekly infusions of 2x106 cells/kg of JR-031 for 4 weeks, with an additional 4 infusions weekly after 28 days in patients with partial response (PR). They were followed up to 24 weeks.
Results: At 4 weeks after the first dose, 6 (24%) patients showed complete response (CR), 9 (36%) patients showed PR, 4 (16%) patients showed mixed response (MR) and 1(4%)patient showed no change (NC). During 24 weeks of observation period, 12 (48%) patients achieved durable CR (CR >=28days). As for response by organ, 80% (16/20) of GI, 66.7% (8/12) of skin and 66.7%(4/6) of liver GVHD completely responded (stage 0). 15 (60%) patients survived up to 24 weeks after the first dose.All patients experienced at least one adverse event(AE). Common AEs were leukopenia (12 patients), thrombopenia (9 patients), sepsis, anemia, TMA and hepatic dysfunction (6 patients). Among 10 death, causal relationship with JR-031 were not completely ruled out in 4 cases (TTP, pneumonia, sepsis and relapse of underlying malignancy), however there was no case in which the causality was strongly suggested.
Conclusion: It was suggested that JR-031 is a safe and effective therapy in the treatment of patients with SR-aGVHD.
Miyamura:Novartis: Honoraria, Speakers Bureau.
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