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Background Patients with diffuse large B-cell lymphoma (DLBCL) with an International Prognostic Index (IPI) ≥3 are at higher risk for relapse after a complete response (CR) to first-line rituximab-based chemotherapy (R-chemo). Everolimus has single-agent activity in lymphoma. PILLAR-2 aimed to improve disease-free survival (DFS) with 1 year of adjuvant everolimus. Patients and methods Patients with high-risk (IPI ≥3) DLBCL and a positron emission tomography/computed tomography-confirmed CR to first-line R-chemo were randomized to 1 year of everolimus 10 mg/day or placebo. The primary end point was DFS; secondary end points were overall survival, lymphoma-specific survival, and safety. Results Between August 2009 and December 2013, 742 patients were randomized to everolimus (n = 372) or placebo (n = 370). Median follow-up was 50.4 months (range 24.0–76.9). Overall, 47% of patients were ≥65 years, 50% were male, and 42% had an IPI of 4 or 5. 48% and 67% completed everolimus and placebo, respectively. Primary reasons for everolimus discontinuation versus placebo were adverse events (AEs; 30% versus 12%) and relapsed disease (6% versus 13%). Everolimus did not significantly improve DFS compared with placebo (hazard ratio 0.92; 95% CI 0.69–1.22; P = 0.276). Two-year DFS rate was 77.8% (95% CI 72.7–82.1) with everolimus and 77.0% (95% CI 72.1–81.1) with placebo. Common grade 3/4 AEs with everolimus were neutropenia, stomatitis, and decreased CD4 lymphocytes. Conclusions Adjuvant everolimus did not improve DFS in patients already in PET/CT-confirmed CR. Future approaches should incorporate targeted agents such as everolimus with R-CHOP rather than as adjuvant therapy after CR has been obtained. ClinicalTrials.gov NCT00790036

Background Information on the clinical behavior of the recently proposed primary duodenal follicular lymphoma (DFL) is limited. Patients and methods Demographic data, signs, symptoms, disease stage, and treatment of the patients diagnosed in National Cancer Center Hospital from 1999 to 2007 were collected and analyzed. Results Twenty-seven patients were studied. Nineteen patients were asymptomatic at the time of diagnosis. Twenty patients had stage I disease. The histological grade was 1 or 2 in 26 patients. IgH/BCL2 fusion was shown in 20 of the examined 24 cases (83%). Fourteen patients received therapy upon diagnosis (local radiotherapy in 2 patients and chemotherapy in 12 including rituximab therapy), their response rate was 85%, and the estimated progression-free survival (PFS) rate at 3 years was 70%. One patient developed histological transformation. The other 13 patients were followed up; their estimated PFS rate at 3 years was 74%. Five among six cases responded to treatment even after progressive disease. All 27 patients have survived with a median follow-up time of 47.9 months. Conclusions The majority of primary DFL patients have a localized tumor of low-grade histology and are positive for t(14;18). Watchful waiting might be an alternative approach for its indolent course; however, further studies are warranted.

Background: The primary objective of this study was to investigate the tolerability, efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). Patients and methods: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. Results: Twelve patients were enrolled. One patient at 40 mg/m2/day developed grade 4 hyperuricemia. At 50 mg/m2/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC0–24h values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). Conclusions: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m2/day is recommended for a following pivotal phase II study.

Background: The majority of lymphomas in the ocular adnexa are low-grade B-cell lymphomas of mucosa-associated lymphoid tissue (MALT lymphoma). Although radiotherapy is the most frequently applied management, cataract and dry eye are problematic complications. Patients and methods: Between 1973 and 2003, the clinical features of 36 patients with ocular adnexal MALT lymphoma with no symptoms who were managed with no initial therapy after biopsy or surgical resection were retrospectively analyzed. Results: The median patient age was 63 years (range 22–84) and all patients had stage I disease, consisting of 31 unilateral cases and five bilateral cases. With a median follow-up of 7.1 years, 25 (69%) did not require treatment. The median time until the initiation of treatment in the remaining 11 patients (31%) was 4.8 years. Six patients (17%) died, and among them only two (6%) died due to progressive lymphoma. Seventeen patients (47%) progressed, but histologic transformation was recognized in only one (3%). The estimated overall survival rates of the 36 patients after 5, 10 and 15 years were 94%, 94% and 71%, respectively. Conclusions: In selected patients with ocular adnexal MALT lymphoma, no initial therapy might be an acceptable approach, because 70% of patients remained untreated at a median of 8.6 years, and their survival was comparable to that of reports on immediate therapy.

Background The majority of T-cell neoplasms express T-cell antigen receptor (TCR) alpha beta on their cell surface, and a few cases show the TCR gamma delta phenotype. Recently, a variety of gamma delta T-cell neoplasm was recognized; however, its clinicopathological features have not been extensively analyzed. Here we report the results of a clinicopathological study of 11 cases of gamma delta T-cell neoplasm. Patients and methods During the 11-year period from 1989 to 1999, 104 patients with T-cell neoplasms were examined by flow cytometric analysis and/or immunohistochemical analysis. Tumor cells from all 104 patients expressed one or more of the T-cell antigens-CD2, CD3, CD5 and CD7. Forty-nine of the 104 cases of T-cell neoplasms were examined immunophenotypically for TCR alpha beta/gamma delta subsets. Results Expression of TCR gamma delta on tumor cells was found in five (33%) of 15 patients with precursor T-cell lymphoblastic leukemia/lymphoma, one (25%) of four with T-cell granular lymphocytic leukemia and five (26%) of 19 with peripheral T-cell lymphoma (PTCL), whereas no expression was found in 11 patients with adult T-cell leukemia-lymphoma. Primary sites of the five patients with gamma delta PTCL were as follows: lymph node, three; skin, one and liver, tonsil and skin, one. The courses of the three patients with gamma delta PTCL of nodal onset were very short (3, 5 and 9 months, respectively), and they were all resistant to combination chemotherapies. Conclusions Although gamma delta T-cell neoplasm constitutes a heterogeneous population, it is important to examine the expression of TCR with the view to identifying possible poor prognostic subgroups, such as primary nodal gamma delta T-cell lymphoma.

Background CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) is accepted as the best available standard treatment for first-line chemotherapy in aggressive non-Hodgkin’s lymphoma (NHL). However, the therapeutic efficacy of CHOP remains unsatisfactory, particularly in high-intermediate risk and high risk patients, and a new strategy is warranted in this patient population. The aim of the present study was to explore a suitable therapeutic-intensified regimen for the treatment of aggressive NHL. Patients and methods Between May 1995 and July 1998, a total of 70 patients with high-intermediate risk or high risk aggressive NHL, according to the International Prognostic Index, were enrolled and randomly assigned to receive either eight cycles of standard CHOP (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 and prednisolone 100 mg for 5 days) every 2 weeks, or six cycles of dose-escalated CHOP (cyclophosphamide 1,500 mg/m2, doxorubicin 70 mg/m2, vincristine 1.4 mg/m2 and prednisolone 100 mg for 5 days) every 3 weeks. Lenograstim (glycosylated rHuG-CSF), at a dose of 2 µg/kg/day s.c., was administered daily from day 3 until day 13 with biweekly CHOP and until day 20 with the dose-escalated CHOP. The primary endpoint was complete response rate. Results The complete response rate was 60% [21 of 35; 95% confidence interval (CI) 42% to 76%] with biweekly CHOP and 51% (18 of 35; 95% CI 34% to 69%) with dose-escalated CHOP. The major toxicity was grade 4 neutropenia and was more frequent in the dose-escalated CHOP arm (86%) than in the biweekly CHOP arm (50%). Grade 4 thrombocytopenia was also more frequent in the dose-escalated CHOP arm (20%) than the biweekly CHOP arm (3%). Non-hematological toxicities were acceptable in both arms. One treatment-related death (due to cardiac arrhythmia) was observed in a dose-escalated CHOP patient. Progression-free survival at 3 years was 43% (95% CI 27% to 59%) in the biweekly CHOP arm and 31% (95% CI 16% to 47%) in the dose-escalated CHOP arm. Although seven patients were deemed ineligible by central review of the pathological diagnosis, the results for both eligible and all enrolled patients were similar. Conclusions Similar complete response rates and progression-free survival rates, but lower toxicity, indicated that biweekly CHOP was superior to dose-escalated CHOP in the treatment of aggressive NHL. Based on these results, the Lymphoma Study Group of the Japan Clinical Oncology Group is conducting a randomized phase III study comparing biweekly CHOP with standard CHOP in newly diagnosed patients with advanced-stage aggressive NHL.

Background: The aim of the study was to determine factors affecting the toxicity and efficacy of rituximab monotherapy in relapsed patients with indolent B-cell lymphoma and mantle cell lymphoma (MCL). Patients and methods: A total of 90 patients were enrolled and treated with rituximab infusions at 375 mg/m 2 once weekly for 4 weeks. Central pathology review revealed that histologically, 81 patients had indolent B-cell lymphoma or MCL: 59 with follicular lymphoma, 17 with MCL, four with marginal zone lymphoma and one with lymphoplasmacytoid lymphoma. Of these, four were ineligible due to violation of other eligibility criteria. Pre-treatment variables affecting toxicities were analyzed for all 90 patients, and those affecting response and progression-free survival (PFS) were analyzed for 77 eligible patients with confirmed indolent B-cell lymphoma or MCL. The relationship between serum rituximab levels and efficacy was also analyzed for 66 eligible patients. Results: Hematological toxicities (grade ≥3) occurred more frequently in females (P

Summary Background In clinical trials in the USA, IDEC-C2B8 (a mouse-human chimeric anti-CD20 monoclonal antibody) has demonstrated high response rates with only mild toxic effects in relapsed B-cell lymphoma at a dose of four weekly 375 mg/m2 infusions. The aim of the present trial was to determine whether or not this dose is practically applicable to Japanese patients with relapsed B-cell lymphoma with respect to safety, pharmacokinetics and efficacy. Patients and methods Patients with relapsed CD20 + B-cell lymphoma received intravenous infusions of IDEC-C2B8 once a week for four weeks. A total of 12 patients (four at 250 mg/m2 and eight at 375 mg/m2) were enrolled. Results All 11 eligible patients treated with either dose level tolerated IDEC-C2B8 well. Commonly observed adverse drug reactions were grades 1 or 2 non-hematologic toxicities during the infusion, consisting mostly of flu-like symptoms and skin reactions. All of the observed hematologic toxicities were of grade 3 or less, and transient. A rapid and sustained B-cell decrease in peripheral blood was observed, but no infectious episodes were encountered. Human anti-mouse and anti-chimeric antibodies were not detected. Of the 11 eligible patients (eight with follicular, two with diffuse large-cell and one with mantle cell lymphoma), two showed a complete response and five showed a partial response, and all of the seven responders had lymphoma with follicular histology. A pharmacokinetic analysis showed that the elimination half-life (T1/2) of IDEC-C2B8 was 445 ± 361 hours, and that the serum antibody levels increased in parallel with the course of infusions, and in most patients was still measurable at three months. Conclusions The dose of four weekly 375 mg/m2 infusions of IDEC-C2B8 is safe and effective in Japanese patients with relapsed B-cell lymphoma. Further studies evaluating IDEC-C2B8 are warranted.

Introduction: Disseminated varicella zoster virus (VZV) disease is seen in highly immunocompromised hosts, most incidents occurring after allogeneic hematopoietic stem cell transplantation (HSCT). Only few cases have been reported of disease onset during conventional chemotherapy in non-Hodgkin lymphoma patients. Visceral dissemination has a high mortality rate, thus, a prompt diagnosis and therapy is essential. Case: A 61-year-old female with heavily treated recurrent follicular lymphoma, undergoing COP therapy, presented with epigastralgia, peritoneal irritation, and intestinal pseudo-obstruction. Upper gastrointestinal endoscopy revealed no abnormalities and CT scan showed a localized bowel wall thickening but otherwise normal findings. She was restricted oral intake and opioid therapy was initiated. On the fourth day of admission, she was diagnosed with syndrome of inappropriate antidiuretic hormone secretion (SIADH), and on the sixth day, with febrile neutropenia. In spite of initiation of a broad spectrum beta lactamase, her fever persisted and serum total bilirubin levels increased to 5.5 U/L. On the ninth day, a widespread rash on the trunk and extremities appeared. Her serum IgG level was 308 mg/dl, and CD4 count was 117/µl at that point. Intravenous systemic aciclovir therapy was immediately initiated at a dose of 1500 mg per day and immunoglobulin replacement therapy. Polymerase chain reaction of the serum showed an increase of 8.0 x 102 VZV DNA copies. After the initiation of aciclovir therapy, her abdominal symptoms, SIADH, and bilirubin levels immediately improved. On the 16th day, she was able to start oral intake again. Conclusion: Disseminated VZV infection is not limited to patients undergoing stem cell transplantation, and may present with abdominal pain. Visceral infection may take a poor clinical course, therefore, attention should be paid to this particular complication, and a prompt diagnosis and therapy is essential.

Background Inotuzumab ozogamicin (INO) is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on the majority of B-cell non-Hodgkin's lymphomas (B-NHL). This phase II study evaluated the safety and efficacy of INO in patients (patients) with CD22+ indolent B-NHL refractory to rituximab (R), R plus chemotherapy, or radioimmunotherapy (RIT). Methods Patients that had progressed after ≥2 systemic therapies with no response/progression within 6 mo of R-containing therapy or 12 mo of RIT were enrolled. Patients received INO 1.8 mg/m2 every 28 days for 4 to 8 cycles, with dose/frequency adjusted based on toxicity. Results 81 patients (72 follicular lymphoma [FL], 4 marginal zone, 5 small lymphocytic lymphoma) have been enrolled: the median age was 63 years (29–84 years), 54% were male, and 65% had >2 prior anticancer regimens. Based on the Follicular Lymphoma International Prognostic Index, 24%, 28%, and 48% of FL patients, respectively, were low, intermediate, and high risk. Treatment-emergent adverse events (AEs; >30% all grades/ ≥ 5% grade ≥3) were thrombocytopenia (69%/57%), neutropenia (51%/26%), nausea (48%/5%), fatigue (47%/3%), AST increased (43%/4%), lymphopenia (36%/12%), leukopenia (32%/9%), and GGT increased (20%/6%). Seventeen patients reported 35 serious AEs. Twenty-six patients reported 35 AEs that led to discontinuation (thrombocytopenia [19], neutropenia [5], GGT increased [3], hyperbilirubinemia [2], leukopenia, Budd-Chiari syndrome, hepatic cirrhosis, abnormal hepatic function, pneumonia, and blood alkaline phosphatase [1 each]). In 74 evaluable patients, overall response rate (ORR) was 58% (in 65 FL patients, ORR was 63%, including 32% with complete response). The progression-free survival rate at 12 months was 52%. Thirteen deaths (disease progression [9], other [4]) were reported, all >30 days after the last dose of INO. Conclusions In patients with indolent B-NHL refractory to R-containing therapy or RIT, INO showed definitive clinical activity and had a safety profile similar to that previously reported.