Dai Maruyama

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).

Phase I / II study of brentuximab vedotin in Japanese patients with relapsed or refractory CD30-positive Hodgkin's lymphoma or systemic anaplastic large-cell lymphoma

Brentuximab vedotin is an antibody–drug conjugate that selectively delivers the antimicrotubule agent monomethyl auristatin E into CD30‐expressing cells. To assess its safety, pharmacokinetics, and efficacy in Japanese patients with refractory or relapsed CD30‐positive Hodgkins lymphoma or systemic anaplastic large‐cell lymphoma, we carried out a phase I/II study. Brentuximab vedotin was given i.v. on day 1 of each 21‐day cycle up to 16 cycles. In the phase I part of a dose‐escalation design, three patients per cohort were treated at doses of 1.2 and 1.8 mg/kg. In the phase II part, a dose of 1.8 mg/kg was given to 14 patients (nine with Hodgkins lymphoma and five with systemic anaplastic large‐cell lymphoma). The median number of treatment cycles was 16 (range, 4–16). In the phase I part, no dose‐limiting toxicity event was observed. In the total population, common adverse events included lymphopenia (80%), neutropenia (65%), leukopenia (65%), and peripheral sensory neuropathy (60%). Grade 3/4 adverse events in more than two patients were lymphopenia (50%) and neutropenia (15%). The pharmacokinetic profile was similar to that observed in the previous studies in the USA. In the phase II part, six patients (67%) with Hodgkins lymphoma achieved an objective response with 56% of complete response rate, and five patients (100%) with systemic anaplastic large‐cell lymphoma achieved an objective response with 80% of complete response rate. These results show that brentuximab vedotin has an acceptable safety profile and promising antitumor activity in the Japanese population. This trial was registered in JAPIC Clinical Trials Information (JapicCTI‐111650).

Histological and immunophenotypic changes in 59 cases of B-cell non-Hodgkin's lymphoma after rituximab therapy.

Rituximab is a chimeric monoclonal antibody that recognizes the CD20 antigen. It has been used to treat B‐cell non‐Hodgkin lymphoma (B‐NHL), but recently rituximab resistance has been a cause for concern. We examined histological and immunohistochemical changes in 59 patients with B‐NHL after rituximab therapy. The patients comprised 32 men and 27 women with a median age of 59 years. Pre‐rituximab specimens comprised 34 follicular lymphomas (FL), 11 diffuse large B‐cell lymphomas (DLBCL), 10 mantle cell lymphomas, two marginal zone B‐cell lymphomas (MZBCL), and two chronic lymphocytic leukemias (CLL). CD20 expression in lymphoma cells was evaluated by immunohistochemistry or flow cytometry. Post‐rituximab materials were taken a median of 6 months (4 days to 59 months) after rituximab therapy. Sixteen cases (27%) showed loss of CD20 expression with four histological patterns: pattern 1, no remarkable histological change (FL, 5; DLBCL, 3; and CLL, 2); pattern 2, proliferation of plasmacytoid cells (FL, 2; DLBCL, 1; and MZBCL, 1); pattern 3, transformation to classical Hodgkins lymphoma (FL, 1); and pattern 4, transformation to anaplastic large cell lymphoma‐like undifferentiated lymphoma (FL, 1). Loss of CD20 was unrelated to the interval of biopsies, treatment regimen, clinical response, and frequency of rituximab administration. Loss of CD20 within 1 month of rituximab therapy (3/14, 21%) and regain of CD20 (2/7, 29%) were not frequent. CD20‐positive relapse with transformation occurred most frequently in cases of early relapse. In conclusion, B‐NHL showed various histological and immunophenotypic changes after rituximab therapy, including not only CD20 loss but also proliferation of plasmacytoid cells or transformation to special subtypes of lymphoma. (Cancer Sci 2009; 100: 54–61)

Diffuse large B‐cell lymphoma after transformation from low‐grade follicular lymphoma: morphological, immunohistochemical, and FISH analyses

Follicular lymphoma (FL) is one of the most common subtypes of non‐Hodgkin lymphoma and frequently transforms to diffuse large B‐cell lymphoma (DLBCL). To clarify some aspects of the natural history of FL, we retrospectively examined 43 consecutive patients who had DLBCL with pre‐ or coexisting FL grade 1 or 2. The patients comprised 22 men and 21 women with a median age of 53 years. Most of the patients (34/43) showed advanced‐stage (III or IV) disease initially. We examined both FL and DLBCL components morphologically, immunohistochemically, and by interface fluorescence in situ hybridization (FISH: IGH/BCL2 fusion, BCL6 translocation) analysis. Most of the DLBCLs were classified as the centroblastic subtype, with two exceptions of the anaplastic subtype. Immunohistochemical analysis of both the FL and DLBCL components revealed the following respective positivity rates: CD20 100%/100%, CD10 86%/66%, Bcl‐2 96%/91%, Bcl‐6 84%/88%, MUM1 16%/34%, CD30 0%/20%, CD138 0%/0%, and CD5 0%/3%. Loss of CD10 (6/36, 17%) and gain of MUM1 (7/28, 25%) and CD30 (5/21, 24%) through transformation were not infrequent. High positivity rates for Bcl‐2 and Bcl‐6 were maintained throughout transformation. Among the DLBCLs, 84% were classified as the germinal center B‐cell phenotype (GCB) and 16% as non‐GCB in accordance with the criteria of Hans et al. IGH/BCL2 fusion was detected by FISH in 89% of FLs and 82% of DLBCLs. BCL6 translocation was detected in 1/6 (17%) DLBCLs without IGH/BCL2 fusion. Thus, although the morphological features and FISH results for DLBCL were consistent with transformed FL, the immunophenotype showed wide heterogeneity. (Cancer Sci 2008; 99: 1760–1768)

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma

Patients with follicular lymphoma (FL), where position 158 of FcγR‐IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F‐carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F‐carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody‐dependent cell‐mediated cytotoxicity. This dose‐escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20‐positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m2 weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F‐carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose‐limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F‐carriers. Further investigation of FL is warranted. (Cancer Sci 2011; 102: 432–438)

Pneumocystis jiroveci pneumonia in relation to CD4+ lymphocyte count in patients with B-cell non-Hodgkin lymphoma treated with chemotherapy.

An increasing incidence of Pneumocystis jiroveci pneumonia (PCP) in patients with B-cell non-Hodgkin lymphoma (B-NHL) receiving rituximab treatment has been reported. We reviewed patients with B-NHL who underwent chemotherapy from 2004 to 2008 at our institution to identify risk factors for PCP development during and after chemotherapy. Among 297 patients with B-NHL, six developed PCP. Of 121 patients (41%) who received PCP prophylaxis with sulfamethoxazole–trimethoprim during chemotherapy, none developed PCP (0%), while among 176 patients (59%) who had no prophylaxis, six (3.4%) developed PCP at a median of 2 months (range: 1–3 months) after starting chemotherapy. Patients with CD4+ lymphocyte counts ≤200/mm3 before chemotherapy had a higher risk of developing PCP (p = 0.045), while a history of rituximab treatment was not related to PCP. CD4+ lymphocyte counts ≤200/mm3 during and after chemotherapy were observed in 18.9% of patients.

Deletion of the TNFAIP3/A20 gene detected by FICTION analysis in classical Hodgkin lymphoma

BackgroundThe TNFAIP3 gene, which encodes a ubiquitin-modifying enzyme (A20) involved in the negative regulation of NF-κB signaling, is frequently inactivated by gene deletions/mutations in a variety of B-cell malignancies. However, the detection of this in primary Hodgkin lymphoma (HL) specimens is hampered by the scarcity of Hodgkin Reed-Sternberg (HR-S) cells even after enrichment by micro-dissection.MethodsWe used anti-CD30 immunofluorescence with fluorescence in-situ hybridization (FISH) to evaluate the relative number of TNFAIP3/CEP6 double-positive signals in CD30-positive cells.ResultsFrom a total of 47 primary classical Hodgkin lymphoma (cHL) specimens, 44 were evaluable. We found that the relative numbers of TNFAIP3/CD30 cells were distributed among three groups, corresponding to those having homozygous (11%), heterozygous (32%), and no (57%) deletions in TNFAIP3. This shows that TNFAIP3 deletions could be sensitively detected using our chosen methods.ConclusionsComparing the results with mutation analysis, TNFAIP3 inactivation was shown to have escaped detection in many samples with homozygous deletions. This suggests that TNFAIP3 inactivation in primary cHL specimens might be more frequent than previously reported.

Follicular Lymphoma of the Duodenum: A Clinicopathologic Analysis of 26 Cases

OBJECTIVE Follicular lymphomas (FLs) occur commonly in the lymph nodes, and duodenal FL (DFL) is reported to be rare. METHODS We analysed the clinical, morphological, immunohistochemical and genetic features of 26 cases of DFL. Primary DFLs and systemic FLs that involved the duodenum at any point during the clinical course were included in the analysis. RESULTS Typically, primary DFLs (14 cases) were found incidentally at routine medical check-ups, whereas involvement of the duodenum by systemic FLs (12 cases) was found through staging procedures. All cases involved the second portion of the duodenum. Helicobacter pylori infection was common (71%). In all cases, the histologic grade was low (either grade 1 or 2), and CD20, CD10 and Bcl-2 were positive by immunohistochemistry. Immunoglobulin heavy chain gene (IGH) and bcl-2 gene (BCL2) fusion was frequently shown by fluorescence in situ hybridization (FISH) analysis: nine of 12 cases (75%) of primary DFL and 10 of 12 cases (83%) of systemic DFL were positive. Treatment regimens employed were rituximab (R) plus chemotherapy (10), R (6), chemotherapy (3), irradiation (3) and the other three patients were subjected to observation. After a median follow-up duration of 40 months (ranging 11-96 months), 17 patients were alive without disease, seven were alive with disease and one had died of lymphoma. CONCLUSIONS Primary DFLs resemble systemic and nodal FLs, except that the former has high incidence of early stage and low-grade histology. The duodenum appears to be a frequently involved extranodal site of FL with IGH/BCL2.

Bulky disease has an impact on outcomes in primary diffuse large B-cell lymphoma of the breast: A retrospective analysis at a single institution

Objectives: Primary breast lymphoma (PBL) is rare, and its clinical behavior and standard initial treatment are not yet established. Methods: We retrospectively analyzed the clinicopathological features and treatment outcomes of 14 patients with primary breast diffuse large B‐cell lymphoma. Results: There were nine patients with stage IE and five with stage IIE disease. The median largest tumor diameter was 4.5 cm, and five patients had bulky disease >5 cm. The complete response rate was 94%. However, the 5‐year progression‐free survival rate was 52% with a median follow‐up of 5.2 years. Patients with bulky disease had an unfavorable prognosis. All five patients with bulky disease progressed or relapsed. Of the four patients that recurred in the central nervous system (CNS), three had bulky disease although some received rituximab. There were no CNS recurrences in the three patients who received CNS prophylaxis. All eight patients who responded to radiotherapy (RT) did not have recurrences in the ipsilateral breast, although one patient with bulky disease relapsed in the adjacent regional lymph nodes within the RT field despite immunochemotherapy. Conclusions: Patients with bulky disease had a poorer prognosis and recurred frequently in the CNS. CNS prophylaxis might yield better outcomes, but a larger, prospective trial is needed to elucidate the optimal initial treatment of PBL in the rituximab era.