Chizuko Hashimoto

Phase II Study of SMILE Chemotherapy for Newly Diagnosed Stage IV, Relapsed, or Refractory Extranodal Natural Killer (NK)/T-Cell Lymphoma, Nasal Type: The NK-Cell Tumor Study Group Study

PURPOSE 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 AND METHODS 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. RESULTS 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%). CONCLUSION 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.

Apollon ubiquitinates SMAC and caspase-9, and has an essential cytoprotection function

Apollon (also known as BRUCE or BIRC6) is a large protein containing baculoviral-IAP-repeat (BIR) and ubiquitin-conjugating enzyme (UBC) domains at the amino- and carboxy termini, respectively. Apollon inhibits apoptosis, but its molecular and physiological function remains unclear. Here we report that Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, which both contain IAP-binding motifs. Targeted disruption of Apollon in mice caused embryonic and neonatal lethality. Notably, SMAC induced apoptosis in Apollon-deficient cells, but not in Apollon-expressing cells. Furthermore, the IAP-binding motif of SMAC was required to induce apoptosis in Apollon-deficient cells. These results suggest that Apollon has an essential function in preventing SMAC-induced apoptosis.

Central nervous system involvement in diffuse large B‐cell lymphoma

Background: Malignant lymphoma with central nervous system (CNS) involvement has an extremely poor prognosis. We retrospectively studied the risk factors for CNS involvement in patients with diffuse large B‐cell lymphoma (DLBCL) treated by cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or rituximab (R) ‐CHOP chemotherapy.

Central nervous system event in patients with diffuse large B-cell lymphoma in the rituximab era

Central nervous system (CNS) events, including CNS relapse and progression to CNS, are known to be serious complications in the clinical course of patients with lymphoma. This study aimed to evaluate the risk of CNS events in patients with diffuse large B‐cell lymphoma in the rituximab era. We performed a retrospective survey of Japanese patients diagnosed with diffuse large B‐cell lymphoma who underwent primary therapy with R‐CHOP chemoimmunotherapy between September 2003 and December 2006. Patients who had received any prophylactic CNS treatment were excluded. Clinical data from 1221 patients were collected from 47 institutions. The median age of patients was 64 years (range, 15–91 years). We noted 82 CNS events (6.7%) and the cumulative 5‐year probability of CNS events was 8.4%. Patients with a CNS event demonstrated significantly worse overall survival (P < 0.001). The 2‐year overall survival rate after a CNS event was 27.1%. In a multivariate analysis, involvement of breast (relative risk [RR] 10.5), adrenal gland (RR 4.6) and bone (RR 2.0) were identified as independent risk factors for CNS events. We conclude that patients with these risk factors, in addition to patients with testicular involvement in whom CNS prophylaxis has been already justified, are at high risk for CNS events in the rituximab era. The efficacy and manner of CNS prophylaxis in patients for each involvement site should be evaluated further. (Cancer Sci 2012; 103: 245–251)

Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type

Purpose: 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. Experimental Design: 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. Results: 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 × 107), but 15 samples of plasma with a median of 867 copies/mL (range: 0–1.27 × 107). Results of these 2 measurements of EBV-DNA well correlated (R2 = 0.994, P < 0.001). The overall response rate to SMILE was significantly higher in patients with less than 105 copies/mL of EBV-DNA in whole blood at enrollment (90% vs. 20%, P = 0.007) and in patients with less than 104 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 105 copies/mL of EBV-DNA or more in whole blood (100% vs. 29%, P = 0.007) than that of others and in patients with 104 copies/mL or more in plasma (86% vs. 26%, P = 0.002). Conclusions: 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. Clin Cancer Res; 18(15); 4183–90. ©2012 AACR.

Prognostic impact of extranodal involvement in diffuse large B‐cell lymphoma in the rituximab era

Extranodal involvement is considered a poor prognostic factor for patients with diffuse large B‐cell lymphoma (DLBCL); however, the prognostic impact of specific sites of involvement has not been fully elucidated.

Cellular FLIP Inhibits β-Catenin Ubiquitylation and Enhances Wnt Signaling

ABSTRACT Cellular FLIP (cFLIP) is a close homologue of caspase 8 without caspase activity that inhibits Fas signaling. The cFLIP protein is often expressed in human tumors and is believed to suppress antitumor immune responses involving the Fas system. Here, we report that a long form of cFLIP (cFLIP-L) inhibits β-catenin ubiquitylation and increases endogenous cytosolic β-catenin, which results in translocation of β-catenin into nuclei and induction of β-catenin-dependent gene expression in cFLIP-L-expressing cells. When cells stably expressing cFLIP-L were stimulated with Wnt3a, enhanced Wnt signaling was observed compared with the control cells. Conversely, depletion of endogenous cFLIP results in reduced Wnt signaling. Furthermore, cFLIP-L increases secondary-body axis formation when coinjected with suboptimal doses of β-catenin into early Xenopus embryos. Down-regulation of FADD by RNA-mediated interference abolishes the β-catenin-dependent gene expression induced by cFLIP-L. These results indicate that cFLIP-L, in cooperation with FADD, enhances canonical Wnt signaling by inhibiting proteasomal degradation of β-catenin, thus suggesting an additional mechanism involved with tumorgenesis, in addition to inhibiting Fas signaling.

Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B-cell lymphoma in the rituximab era

The tumor microenvironment, including tumor‐infiltrating lymphocytes and myeloid‐derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear.

The therapeutic effect of rituximab on CD5-positive and CD5-negative diffuse large B-cell lymphoma

The prognosis of diffuse large B‐cell lymphoma (DLBCL) has improved markedly in recent years of rituximab era. The prognosis of de novo CD5‐positive DLBCL is reported to be poor, but the effect of rituximab on this type of lymphoma remains unclear. To investigate the effect of rituximab on CD5‐positive DLBCL, we collected DLBCL patients and analysed prognostic factors. A total of 157 patients with DLBCL who were immunophenotyped with flow‐cytometry (FCM) and treated with chemotherapy were subjected to analysis. Those treated with radiotherapy alone or with supportive therapy only were not included. Patients diagnosed in 2003 or later were treated with rituximab combined chemotherapy. There were 95 males and 62 females. Their age ranged from 20 to 91 years old, and the median was 65 years. Nineteen patients were diagnosed as having de novo CD5‐positive DLBCL. Rituximab was given alongside chemotherapy in 85 patients. Of these, 11 were positive for CD5 and 74 were negative. The addition of rituximab improved the overall survival (OS) of DLBCL patients (2‐year OS: 82% vs. 70%, p = 0.01). For CD5‐negative DLBCL, patients treated with rituximab showed 2‐year OS of 84%, which was significantly better than those treated without rituximab (70%, p = 0.008). However, for CD5‐positive DLBCL, the prognosis was not statistically different between the patients treated with and without rituximab (59% vs. 50%, p = 0.72). Although rituximab improved the prognosis of DLBCL, such improvement was restricted to the CD5‐negative group. Further investigation is required to improve the prognosis of patients with CD5‐positive DLBCL. Copyright

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma

Long‐term observation has identified a pattern of continuing relapse in limited stage diffuse large B‐cell lymphoma (DLBCL) treated by three cycles of R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved‐field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R‐CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full‐dose R‐CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R‐CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5‐year progression‐free survival and 5‐year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the ‘standard’ strategy of three cycles of R‐CHOP followed by involved‐field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R‐CHOP alone.