Masanobu Nakata

Histology According to the Revised European-American Lymphoma Classification Significantly Predicts the Prognosis of Ocular Adnexal Lymphoma

Lymphoid infiltrates in the ocular adnexa are mostly low-grade B-cell lymphoma, but their clinicopathologic characteristics and prognostic factors have not been extensively analyzed according to the Revised European-American Lymphoma (REAL) Classification. We reviewed histopathologic sections from 77 patients with primary ocular adnexal lymphoid infiltrates, and conducted univariate and multivariate analyses of possible prognostic factors. Fifty-seven of the 77 patients were confirmed to have malignant lymphoma. Histopathologic sections from 44 of the 57 patients were reclassified into the following categories; marginal zone lymphoma (MZL) in 35, mantle cell lymphoma (MCL) in two, diffuse large cell lymphoma (DLCL) in six, and lymphoplasmacytoid lymphoma (LPL) in one. In the remaining 13 patients, biopsied specimens were inadequate for further subclassification. The cause-specific survival rates of the 57 patients with primary ocular adnexal lymphoma at 5, 10, and 15 years were 90.1%, 84.8% and 84.8%, respectively. The univariate analysis showed that the clinical stage, serum lactate dehydrogenase (LDH) value and histopathologic subtype were significant. The 5-year cause-specific survival rate of the 35 patients with MZL was 100%, whereas that of the eight patients with non-MZL (DLCL and MCL) was 25% (p<0.0001). The multivariate analysis revealed that the histologic subtype (p=0.010) and serum LDH value (p=0.015) were independent significant predictors of survival. We conclude that malignant lymphomas occurring in the ocular adnexa histologically consist mostly of MZL. The histologic subtype according to the REAL Classification significantly predicts the prognosis of ocular adnexal lymphoma.

Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma

The purpose of this phase I and II study was to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of bortezomib in Japanese patients with relapsed or refractory multiple myeloma. This was a dose‐escalation study designed to determine the recommended dose for Japanese patients (phase I) and to investigate the antitumor activity and safety (phase II) of bortezomib administered on days 1, 4, 8, and 11 every 21 days. Thirty‐four patients were enrolled. A dose‐limiting toxicity was febrile neutropenia, which occurred in one of six patients in the highest‐dose cohort in phase I and led to the selection of 1.3 mg/m2 as the recommended dose. Adverse events ≥ grade 3 were rare except for hematological toxicities, although there was one fatal case of interstitial lung disease. The overall response rate was 30% (95% confidence interval, 16–49%). Pharmacokinetic evaluation showed a biexponential decline, characterized by a rapid distribution followed by a longer elimination, after dose administration, whereas the area under the concentration–time curve increased proportionately with the dose. Bortezomib was effective in Japanese patients with relapsed or refractory multiple myeloma. A favorable tolerability profile was also seen, although the potential for pulmonary toxicity should be monitored closely. The pharmacokinetic and pharmacodynamic profiles of bortezomib in the present study warrant further investigations, including more relevant administration schedules. (Cancer Sci 2008; 99: 140–144)

Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study

BACKGROUND There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).

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.

Phase III trial of CHOP-21 versus CHOP-14 for aggressive non-Hodgkin’s lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG 9809

BACKGROUND CHOP-21 has remained the standard chemotherapy for aggressive non-Hodgkins lymphoma (NHL), and dose intensification is a potential strategy for improving therapeutic results. We conducted a phase III trial to determine whether dose-dense strategy involving interval shortening of CHOP (CHOP-14) is superior to CHOP-21. PATIENTS AND METHODS A total of 323 previously untreated patients (aged 15-69 years) with stages II-IV aggressive NHL were randomized. The primary end point was progression-free survival (PFS). RESULTS Treatment compliance was comparable in both study arms. At 7-year follow-up, no substantial differences were observed in PFS and overall survival (OS) between CHOP-21 (n = 161) and CHOP-14 (n = 162) arms. Median PFS was 2.8 and 2.6 years with CHOP-21 and CHOP-14, respectively (one-sided log-rank P = 0.79). Eight-year OS and PFS rates were 56% and 42% [95% confidence interval (CI) 47% to 64% and 34% to 49%], respectively, with CHOP-21 and 55% and 38% (95% CI 47% to 63% and 31% to 46%), respectively, with CHOP-14. Subgroup analyses showed no remarkable differences in PFS or OS for patients stratified as per the International Prognostic Index or by age. CONCLUSION Dose-intensification strategy involving interval shortening of CHOP did not prolong PFS in advanced, aggressive NHL.

Phase I study of radioimmunotherapy with an anti‐CD20 murine radioimmunoconjugate (90Y‐ibritumomab tiuxetan) in relapsed or refractory indolent B‐cell lymphoma

We conducted a phase I study to evaluate the safety and efficacy of radioimmunotherapy with yttrium‐90‐ibritumomab tiuxetan (Y2B8) in Japanese patients with relapsed or refractory indolent B‐cell lymphoma. Indium‐111‐labeled ibritumomab tiuxetan (In2B8; 3.5 or 5 mCi [129.5 or 185 MBq]) was administered on day 1, followed by serial gamma‐camera imaging to investigate the distribution of In2B8 in the whole body of patients and to judge the feasibility of Y2B8 administration. Y2B8 with a dose of 0.3 mCi/kg (11.1 MBq/kg) or 0.4 mCi/kg (14.8 MBq/kg) was administered on day 8. Grade 4 neutropenia and grade 3 thrombocytopenia were observed in three of nine of the patients evaluated for safety. Critical toxicities (prolonged thrombocytopenia or severe non‐hematological toxicities) were observed in two of six patients in the 0.4 mCi/kg (14.8 MBq/kg) dose group but were not seen in any of the three patients in the 0.3 mCi/kg (11.1 MBq/kg) dose group. The non‐hematological toxicities of the nine patients were of grade 2 or less, except in two patients who had been heavily treated previously. They experienced critical toxicities such as infection, diarrhea, hyponatremia and prolonged thrombocytopenia, as well as other frequent grade 2 non‐hematological toxicities. Although the pharmacokinetic profiles were similar to those in the US study, one of the two patients was clarified retrospectively as showing abnormal biodistribution of In2B8 in the bone marrow, as judged by an independent third party panel of radiologists. Five of the 10 participants achieved complete responses or unconfirmed complete responses and two partial responses. In conclusion, the recommended dose of Y2B8 for the subsequent phase II study for Japanese patients is 0.4 mCi/kg (14.8 MBq/kg). This dose of radioimmunotherapy was feasible when patients with altered biodistribution of In2B8 were excluded, and it was highly effective. (Cancer Sci 2005; 96: 903–910)

Detection of t(11;18) in MALT-Type Lymphoma With Dual-Color Fluorescence In Situ Hybridization and Reverse Transcriptase–Polymerase Chain Reaction Analysis

t(11:8) is a recurrent chromosomal abnormality observed in mucosa-associated lymphoid tissue (MALT)-type lymphoma. API2 and MLT genes have been implicated. The authors devised a dual-color interphase fluorescence in situ hybridization (FISH) system to detect splitting of 11q22 and its fusion with 18q21. Subjects were 44 cases of extranodal lymphoma and cases of primary macroglobulinemia. Whenever RNA was available, reverse transcriptase-polymerase chain reaction followed by sequence analysis was performed. Positive cases by dual-color FISH analysis were restricted to MALT-type lymphoma and one case of primary macroglobulinemia. Among 24 cases of MALT-type lymphoma, 14 (58%) (4 gastric, 5 pulmonary, 3 orbital, 1 salivary, and 1 thyroid lymphomas) had splitting of the 11q22 region probes and fusion of signals suggesting the translocation of chromosome 11 and 18. Reverse transcriptase-polymerase chain reaction analysis showed the API2/MLT gene fusion in 9 of 10 cases. Sequence analyses showed three different modes of involvement of the MLT gene, whereas the breakpoint at API2 was the same. Monoclonal component of serum immunoglobulin M was observed in 3 of 14 positive cases for the translocation. Direct visualization using dual-color FISH on samples serves as a molecular tool for management of MALT-type lymphoma with API2/MLT gene fusion.

Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma

Oral fludarabine is more convenient than intravenous fludarabine in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine in combination with rituximab in patients with relapsed indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), we conducted a multicenter phase II study. Patients with relapsed indolent B‐NHL with two or fewer prior regimens and up to 16 doses of rituximab were eligible. Patients received 375 mg/m2 rituximab on day 1, and 40 mg/m2 oral fludarabine once daily on days 1 through 5 every 28 days for up to six cycles. The primary endpoint was the overall response rate. Forty‐one patients were enrolled, including 38 (93%) with follicular lymphoma. Thirty‐four patients (83%) had received rituximab as prior therapy. Twenty‐seven patients (66%) completed the planned six cycles. Dose reduction of oral fludarabine was required in 17 patients (41%). The overall response rate was 76% (31 of 41 patients; 95% confidence interval, 60–88%) with a complete response rate of 68% (28 of 41 patients; 95% confidence interval, 52–82%). Median progression‐free survival for the 41 patients was 19.7 months (95% confidence interval, 12.3–26.5 months). Hematological toxicities, including grade 4 neutropenia (68%), were the most frequent toxicities. Non‐hematological toxicities were mild, except for one patient who died of Pneumocystis jiroveci pneumonia 4 months after the protocol treatment. In conclusion, oral fludarabine in combination with rituximab is a highly effective and convenient therapy for patients with relapsed indolent B‐NHL who have mostly been pretreated with rituximab. (ClinicalTrials.gov number, NCT00311129.) (Cancer Sci 2009; 100: 1951–1956)

Phase I/II and pharmacokinetic study of cladribine with 2‐h infusion in Japanese patients with relapsed indolent B‐cell lymphoma mostly pretreated with rituximab

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2‐h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B‐cell lymphoma. This was a dose‐escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose‐limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35–65%), with 11% (2/18) complete response. With a median follow‐up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non‐hematologic toxicities were mild. In conclusion, cladribine with 2‐h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B‐cell lymphoma, including those pretreated with rituximab. (Cancer Sci 2009; 100: 1344–1350)

Chemotherapy in the treatment of advanced or recurrent olfactory neuroblastoma

Background:  Olfactory neuroblastoma is a rare sino‐nasal tumor arising from the olfactory epithelium and is often characterized by local invasion or metastasis. The role of chemotherapy in the treatment of this tumor is unclear. The purpose of this study was to review our institution’s experience of chemotherapy for advanced or recurrent olfactory neuroblastoma.