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Background: Lenalidomide is an immunomodulatory drug with effects on the immune system that may enhance antibody-dependent cell-mediated cytotoxicity and reverse tumor-induced immune suppression. Furthermore, single-agent lenalidomide has therapeutic activity in relapsed/refractory B-cell lymphomas. These immunologic effects potentially may enhance the action of rituximab., Methods: To test the efficacy of lenalidomide combined with rituximab, the authors conducted a phase 2 trial of lenalidomide, low-dose dexamethasone, and rituximab in patients who had rituximab-resistant, relapsed/refractory, indolent B-cell or mantle cell lymphomas. Patients received two 28-day treatment cycles of lenalidomide 10 mg daily and dexamethasone 8 mg once weekly (part I). During cycle 3, 4 weekly doses of rituximab 375 mg/m2 were administered with lenalidomide-dexamethasone (part II). After the part II response assessment, stable or responding patients continued to receive lenalidomide-dexamethasone., Results: Twenty-seven patients with follicular (n=18), mantle cell (n=5), small lymphocytic (n=3), and marginal zone (n=1) lymphomas started therapy; 3 of 27 patients discontinued therapy because of adverse events and were not evaluable for response. For 24 patients, the overall response rate after part I was 29% (4 patients had a complete response [CR] or CR unconfirmed, and 3 patients had a partial response), and the overall response rate after part II was 58% (8 patients had a CR, and 6 patients had a partial response). For 27 patients, at a median follow-up of 12.2 months, the median progression-free survival was 23.7 months., Conclusions: The combination of lenalidomide, low-dose dexamethasone, and rituximab achieved high response rates with durable responses in patients with rituximab-resistant, indolent B-cell and mantle cell lymphomas. Overall response rate increased from 29% after two 28-day cycles of lenalidomide and low-dose dexamethasone to 58% after the addition of rituximab, suggesting that lenalidomide can overcome resistance to rituximab., (© 2013 American Cancer Society.)

Background: Indolent B cell lymphoid malignancies include follicular lymphoma, small lymphocytic lymphoma, mantle cell lymphoma, lymphoplasmacytic lymphoma and marginal zone lymphomas. Chronic lymphocytic leukaemia (CLL) is a lymphoid malignancy similar to small lymphocytic lymphoma (SLL) in its leukaemic phase.Indolent lymphoid malignancies including CLL are characterised by slow growth, a high initial response rate and a relapsing and progressive disease course. Advanced-stage indolent B cell lymphoid malignancies are often incurable. If symptoms or progressive disease occur, chemotherapy plus rituximab is indicated. No chemotherapy regimen has been shown to improve overall survival compared to a different regimen.Bendamustine is efficacious in the treatment of patients with indolent B cell lymphoid malignancies. A number of randomised controlled trials have examined the effect of bendamustine compared to other chemotherapy regimens in these patients. Improved disease control with no survival benefit is shown., Objectives: To evaluate the efficacy of bendamustine therapy for patients with indolent B cell lymphoid malignancies including CLL., Search Methods: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2), MEDLINE (1966 to May 2012), EMBASE (1974 to November 2011), LILACS (1982 to May 2012), databases of ongoing trials (accessed 30 April 2012) and relevant conference proceedings. We searched references of identified trials and contacted the first author of each included trial., Selection Criteria: Randomised controlled trials that compared a bendamustine-containing regimen to other chemotherapy with or without immunotherapy., Data Collection and Analysis: Two authors independently appraised the quality of each trial and extracted data from included trials. We estimated and pooled hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI)., Main Results: We included five trials randomising 1343 adult patients in the systematic review. Allocation and blinding were unclear in three trials and adequate in two. Incomplete outcome data and selective reporting were adequate in all trials. Trials varied in the type of lymphoid malignancy, bendamustine regimen and the comparator regimen. In the three trials that included patients with follicular lymphoma, mantle cell lymphoma and other indolent lymphomas the comparator treatment was cyclophosphamide, a combination of cyclophosphamide, vincristine, doxorubicin and prednisone, and fludarabine. Two trials included only patients with CLL and compared bendamustine to chlorambucil, and to fludarabine. We did not conduct a meta-analysis due to the clinical heterogeneity among trials. Bendamustine had no statistically significant effect on the overall survival of patients with indolent B cell lymphoid malignancies in any of the included trials (trials of moderate quality). Progression-free survival was statistically significantly improved with bendamustine treatment compared to other chemotherapy in three of the four trials that reported on it. One trial demonstrated a non statistically significant improvement of PFS. The risk of grade 3 or 4 adverse events was similar when bendamustine was compared to CHOP and fludarabine, and higher when compared to chlorambucil. Compared to chlorambucil quality of life was unaffected by bendamustine treatment (one trial, no meta-analysis)., Authors' Conclusions: As none of the currently available chemotherapeutic protocols for induction therapy in indolent B cell lymphoid malignancies confer a survival benefit and due to the improved progression-free survival in each of the included trials, and a similar rate of grade 3 or 4 adverse events, bendamustine may be considered for the treatment of patients with indolent B cell lymphoid malignancies. However, the unclear effect on survival and the higher rate of adverse events compared to chlorambucil in patients with CLL/SLL does not support the use of bendamustine for these patients.The effect of bendamustine combined with rituximab should be evaluated in randomised clinical trials with more homogenous populations and outcomes for specific subgroups of patients by type of lymphoma should be reported. Any future trial should evaluate the effect of bendamustine on quality of life.

Background: Indolent nonfollicular non-Hodgkin B-cell lymphomas (INFLs) are clonal mature B-cell proliferations for which treatment has not been defined to date., Methods: In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first-line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m(2) intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m(2) intravenously on days 2-4, cyclophosphamide 250 mg/m(2) intravenously on Days 2-4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m(2) intravenously on day 1) every 2 months for responders., Results: Forty-seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow-up of 40.9 months, the failure-free survival and progression-free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients., Conclusions: FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity., (Copyright © 2011 American Cancer Society.)

Background: Patients affected by relapsed or primary refractory lymphomas currently have a poor prognosis and no standard salvage treatment options. This study was carried out to assess the efficacy and safety of a dexamethasone, high-dose cytarabine, and oxaliplatin as salvage therapy in those patients, replacing cisplatin with oxaliplatin in the standard dexamethasone, cytarabine, and cisplatin scheme., Methods: Seventy patients with relapsed or refractory aggressive non-Hodgkin or Hodgkin lymphoma were treated from September 2001 to September 2007. The median age of patients was 51 years (range, 19-75 years). Histological subtypes were: diffuse large B-cell lymphoma (n=47) and Hodgkin lymphoma (n=23). The overall response rate was 73% (51 of 70), with 30 (43%) complete remissions and 21 (30%) partial remissions. Fifty-two patients were treated with dexamethasone, high-dose cytarabine, and oxaliplatin as second-line chemotherapy. Forty-eight patients were enrolled in an autologous stem cell transplantation program; forty (83%) finally proceeded to high-dose consolidation and autografting., Results: No grade 3 or 4 nonhematological toxicity was demonstrated; in particular, no renal or neurotoxicity was reported. After a median follow-up period of 21 months (range, 2-87 months), 22 (31%) patients had died. Probabilities of 2-year progression-free survival (PFS) and overall survival (OS) were 44% and 71%, respectively. In the chemosensitive patients, the PFS and OS were 52% and 83%, respectively. The only factor that significantly correlated with better OS was the response to therapy., Conclusions: This study confirms that dexamethasone, high-dose cytarabine, and oxaliplatin ± rituximab is an effective and feasible outpatient regimen for salvage therapy in patients affected by relapsed or refractory lymphoma. Moreover, the feasibility and efficacy of this scheme as an in vivo chemosensitive test in patients in autotransplantation programs was confirmed., (Copyright © 2010 American Cancer Society.)

Background: Radioimmunotherapy with radiolabeled monoclonal antibodies to CD20 produces a high response rate in patients with recurring non-Hodgkin lymphoma (NHL), but the durability of those remissions is not well defined., Methods: Data on patients with recurring NHL treated with yttrium Y 90 ibritumomab tiuxetan in 4 clinical trials were reviewed to identify patients with a long-term response, defined as a time to progression of 12 months or longer., Results: Long-term responses were seen in 37% (78/211) of patients. At a median follow-up of 53.5 months (range, 12.7-88.9) the median duration of response was 28.1 months and the median time to progression was 29.3 months. A third of these patients had been treated with at least 3 previous therapies, and 37% of them had not responded to their last therapy. The findings in patients with follicular lymphoma (n=59) were similar to those in the overall population of long-term responders. The estimated overall survival at 5 years was 53% for all patients treated with 90Y ibritumomab tiuxetan and 81% for long-term responders., Conclusions: A single dose of 90Y ibritumomab tiuxetan can produce durable responses and prolonged overall survival in a substantial number of patients in whom previous therapies have failed., (Copyright (c) 2007 American Cancer Society)

Background: The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL)., Methods: The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted., Results: Twenty patients were enrolled in this trial. The median patient age was 59 years. Ten patients had been treated previously (median, 2 regimens; range, 1 to 7). Eighteen (90%) patients had stage III or IV disease. Autologous vaccines were successfully prepared for 17 (85%) patients and all received at least 1 dose. The treatment was very well tolerated. One patient experienced a response with biopsy-proven clearance of the lymphoma cells in 2 of the skin nodules at 3.0 months that lasted for 7.0 months. Eight patients had stable disease for 6.0 to 19.8 months. The median failure-free survival duration in patients who received vaccine therapy was 5.2 months., Conclusions: HSPPC-96 can be prepared from tumor specimens for the majority of lymphoma patients, but it had limited efficacy in inducing responses in patients with active diseases. Further studies of HSPPCs, therefore, should be considered in adjuvant settings or in combination with other immunomodulatory agents to assess survival benefit., ((c) 2006 American Cancer Society.)

Background: High-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) remain controversial for indolent lymphoma patients., Methods: The study was designed to evaluate the benefit of this strategy by retrospectively comparing for each patient the event-free survival (EFS) after ASCT with the duration of the disease phase just before the phase including ASCT (ie, the last qualifying phase, LQP)., Results: A total of 109 indolent lymphoma (mostly follicular lymphoma) patients were treated with HDT and ASCT. Before ASCT, patients experienced a median of 2 disease phases (range, 1-4). After a median 5-year follow-up from ASCT, overall survival was 67% and EFS was 43%. When each of the 92 patients experiencing recurrence was taken as her/his own control, EFS was longer after ASCT than the duration of LQP (62%, P < .01). During LQP, 86 patients (93%) experienced recurrence in less than 5 years, compared with only 58 (63%) who experienced recurrence in the 5 years after ASCT (P < .01)., Conclusion: HDT and ASCT can significantly increase EFS in comparison with the duration of the LQP for indolent lymphoma patients and can change disease course. This methodology has been found useful for evaluating new strategies, especially with monoclonal antibodies., ((c) 2006 American Cancer Society.)

Background: Posttransplant lymphoproliferative disorders (PTLD) remain an uncommon complication of solid organ transplantation with a high mortality rate reported after conventional therapies. Alternative treatments such as rituximab have been explored., Methods: Eleven patients with PTLD, who were CD20 positive, received an intravenous dose of rituximab, 375 mg/m2, weekly x 4 weeks, repeated every 6 months for 2 years in responding patients. The median age of the patients was 56 years (range, 43-68 yrs), and 9 patients were male. The type of solid organ transplantation that these patients received included lung (five patients), kidney (four patients), heart (one patient), and kidney/pancreas (one patient). The median time from transplantation to a PTLD diagnosis was 9 months (range, 1-122 mos). Diagnostic B-cell histology was diffuse large cell lymphoma or polymorphous process. No patient had bone marrow or central nervous system involvement. Primary extranodal disease was noted in 82% of patients. Immunosuppressive therapy was decreased at the time of diagnosis., Results: Rituximab was well tolerated, with mild infusional blood pressure alterations noted in two patients. The median follow-up period was 10 months (range, 1-32 mos). The overall response rate was 64%, with 6 complete responses (CR), 1 partial response, 2 cases of progressive disease, and 2 deaths. The median duration of CR was 8 months (range, 2-19+ mos). The median time to treatment failure was 10 months (range, 5-25+ mos). The median survival was 14 months (range, < 1-32+ mos). Four patients were alive at the time of last follow-up., Conclusions: Single-agent rituximab may offer a response and survival advantage in patients with PTLD. Further evaluation of rituximab in these disorders, potentially in combination with other therapies, is warranted., (Copyright 2005 American Cancer Society)

Background: Systemic B-cell lymphomas have been studied using microarrays, which has led to a better understanding of their molecular characteristics. Initial microarray studies of these lymphomas have implicated several genes as important predictors of outcome. In this study, we used a tissue microarray (TMA) to characterize primary cutaneous large B-cell lymphomas (PCLBCL)., Methods: We studied 14 patients for whom clinical follow up was available, including four patients whose lesions were limited to the leg on presentation. Immunohistochemical staining with CD20, CD44, CD21, CD5, CD10, bcl-2, bcl-6, Ki67, p53, and multiple myeloma 1 (MUM1) was examined., Results: Our results identify two subgroups of lymphomas. The first group showed staining with bcl-6 and had an overall survival of 176 months (p = 0.003). The majority of this group was negative for MUM1. The second group lacked staining with bcl-6 and had an overall survival of 26 months, with a majority of these cases staining with MUM1. Three of four patients with PCLBCL of the leg showed no staining with bcl-6., Conclusions: Our study demonstrates the utility of TMAs in the analysis of PCLBCL and that expression of bcl-6 and MUM1 correlates with survival.

Background: To assess the impact of T-cell/B-cell phenotype on clinical outcome, the authors retrospectively compared patients who had peripheral T-cell lymphoma, unspecified (PTCL-U), with patients who had diffuse large B-cell lymphoma (DLBCL)., Methods: Two hundred ninety-seven cases of PTCL-U and 496 cases of DLBCL that had been transferred from the files of the Intergruppo Italiano Linfomi or the Gruppo Italiano Linfomi were integrated into a unique working file and reviewed by the authors., Results: The PTCL-U group and the DLBCL group had significantly different distribution patterns with respect to patient age, gender, disease stage, performance status (PS), the presence or absence of systemic "B" symptoms, the presence or absence of bulky disease, lactic acid dehydrogenase (LDH) levels, and number of extranodal sites (ENS). A significantly greater number of patients in the DLBCL group experienced complete remission (P < 0.0001). Multinomial logistic regression analysis confirmed that immunophenotype, PS, LDH concentration, and number of ENS were independent predictors of response. At a median follow-up duration of 43 months, there was no observable difference in disease-free survival (DFS) between patients with DLBCL and patients with PTCL-U; however, multivariate analysis did reveal that poorer PS and bone marrow involvement were significantly associated with shorter DFS. Furthermore, although the overall survival (OS) curves associated with the T-cell and B-cell immunophenotypes were significantly different from each other at a median follow-up duration of 37 months (P = 0.0012), Cox multivariate analysis excluded immunophenotype from the final OS model., Conclusions: The findings made in the current study indicate that the natural history of PTCL-U may differ from that of DLBCL. Patients with PTCL-U tended to have less favorable clinical outcomes, although the observed difference in outcome was only partially attributable to immunophenotype, which was independently associated with response, but not with survival. Differences in prognostic factor distributions between patients with PTCL-U and patients with DLBCL may account for some portion of the expected phenotype-associated risk., ((c) 2004 American Cancer Society.)

Background: We present the results of doxorubicin-based chemotherapy with or without involved-field radiotherapy for patients with diffuse large B-cell lymphoma (DLBCL) according to the international prognostic index (IPI)., Methods: From September 1988 through December 1996, 294 patients with Stage I-IV Working Formulation large B-cell or T-cell lymphomas were treated prospectively on two protocols at our center. Diagnoses were reclassified subsequently according to the new World Health Organization classification. Two-hundred and twenty-four patients had DLBCL, including 24 patients with primary mediastinal large B-cell lymphoma. Treatment consisted of a median of six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy with or without involved-field radiotherapy (median dose, 39.6 Gy)., Results/conclusions: The median length of follow-up among surviving patients was 5.0 years. Patient subgroups differed from each other in terms of progression-free (P = 0.003), cause-specific (P = 0.003), and overall (P = 0.001) survival rates when analyzed by IPI. Five-year progression-free, cause-specific, and overall survival rates for 212 patients with an IPI of 0-2 were 73%, 84%, and 82%, respectively, versus only 37%, 33%, and 32% for 12 patients with an IPI of 3-4. To improve our results, we are conducting clinical trials with young DLBCL patients and with patients who are older than 60 years. The young DLBCL patients, who have more than two adverse prognostic features, are receiving high-dose chemotherapy and autologous stem cell rescue. The patients who are older than 60 years, regardless of IPI, are receiving rituximab immunotherapy and liposomal CHOP chemotherapy with or without involved-field radiotherapy., (Copyright 2002 American Cancer Society.)

Background: Cryoglobulinemia has been reported in several chronic infectious and autoimmune diseases, and in patients with HIV-1 infection. Cryoglobulinemia associated with hepatitis C virus infection is considered a risk factor for the development of neoplasia, especially B-cell non-Hodgkin lymphoma. This study was undertaken to investigate whether the presence of circulating cryoglobulins is associated with survival or development of neoplastic disease in HIV-1 infection., Design: We evaluated 87 unselected consecutive HIV-1 infected patients for the presence of cryoglobulinemia and they were prospectively followed up for a median of 34 months, with clinic visits at 4-month intervals. None of the patients had neoplasia at study entry. Time-to-event analysis for death, neoplasm and B-cell lymphoproliferative disorder were performed with Cox proportional hazards models., Results: Mixed cryoglobulinemia (types II and III) was detected in 24 (28%) of the 87 patients. During the follow up, 12 patients died and 8 developed neoplastic disease. Multivariate analysis showed that circulating cryoglobulins were an independent predictor of death [relative risk (RR), 4.97; 95% confidence intervals (CI), 1.26-19.63] and development of neoplasia (RR, 5.18; 95% CI, 1.23-21.83). In addition, cryoglobulinemia reached borderline significance as a predictor of lymphoproliferative disorder of B-cell origin (P = 0.08; RR, 4.53; 95% CI, 0.83-24.75)., Conclusions: Our results suggest that cryoglobulinemia is associated with an increased risk for death, neoplasia or development of lymphoproliferative disorder of B-cell origin, in HIV-1 infected patients.

Background: Primary cutaneous B-cell lymphoma (CBCL) constitutes approximately 20% of all primary cutaneous lymphomas. Apart from primary cutaneous large B-cell lymphoma presenting on the legs (PCLBCL-leg), primary CBCLs run an indolent clinical course, rarely disseminate to extracutaneous sites, and have an excellent prognosis. Because of recent observations in two patients who developed central nervous system (CNS) involvement, follow-up data of all primary CBCL patients registered at the Dutch Cutaneous Lymphoma Group between 1985 and 1998 were investigated for evidence of CNS involvement., Methods: Follow-up data from 160 primary CBCLs were evaluated. This group included 122 primary cutaneous follicle center cell lymphomas (PCFCCLs), 16 primary cutaneous immunocytomas or marginal zone B-cell lymphomas, and 22 PCLBCL-leg., Results: Of all 160 patients with primary CBCLs, 11 died of lymphoma, including 4 of 122 patients (3%) with PCFCCL and 7 of 22 patients (32%) with PCLBCL-leg. Four of these 11 patients, including 3 with PCFCCL and 1 with PCLBCL-leg, had developed CNS involvement 3-93 months (median, 30 months) after diagnosis. All patients died 1-9 months (median, 7 months) after the development of CNS involvement. In the group of 122 patients with PCFCCL, CNS involvement occurred in 3 of 7 patients (43%) who developed extracutaneous disease and accounted for 3 of 4 lymphoma-related deaths (75%)., Conclusions: The results of this study indicate that approximately 2% of all primary CBCLs may develop CNS involvement. Whereas, in rare PCFCCL patients, developing extracutaneous disease CNS involvement was an important cause of death, patients with PCLBCL-leg and secondary CBCL died more frequently due to involvement of non-CNS organ systems., (Copyright 2000 American Cancer Society.)

Background: Primary cutaneous large B-cell lymphoma of the leg (LBCLL) is a recently defined type of non-Hodgkin's lymphoma. It forms a separate category in the new classification of primary cutaneous lymphomas elaborated by the European Organization for Research and Treatment of Cancer. It is associated with a less favorable prognosis than the most frequently occurring types of primary cutaneous B-cell lymphoma., Methods: The authors present four patients with the typical clinicopathologic constellation of LBCLL. Three of them died during the years 1993-1996. The authors reviewed their courses. The fourth patient was staged by sentinel lymph nodectomy (SLNE), i.e., the selective surgical removal and histologic examination of the first draining lymph node associated with the cutaneous tumor., Results: The courses of the three previous patients were characterized by secondary involvement of regional lymph nodes followed by systemic dissemination of the lymphoma in a third step. Although the conventional staging of the fourth patient had been negative for any extracutaneous lymphoma manifestation, the SLNE revealed initial regional lymph node involvement, which had decisive implications for the choice of therapy., Conclusions: SLNE may gain a prominent role in the staging of circumscribed cutaneous lymphomas, in addition to its already established position in melanoma management. Further positive effects of SLNE are 1) better distinction of primary cutaneous lymphomas with secondary lymph node involvement from primary lymph node lymphomas with skin manifestation, and 2) better insight into the biology of different primary cutaneous lymphoma types.

Background: Lymphoblastic lymphoma is typically of thymic T-cell phenotype. Lymphoblastic lymphoma of B-cell origin (B-lymphoblastic lymphoma) has been relatively poorly described. Whether B-lymphoblastic lymphoma should be managed like its T-cell counterpart remains to be clarified., Methods: From 1983 to 1991, 10 adult patients were diagnosed as having B-lymphoblastic lymphoma at National Taiwan University Hospital by using the histomorphologic criteria of international working formulation. B-cell phenotype was determined by the immunohistochemistry method. Clinicopathologic features of these 10 patients were reviewed., Results: Seven patients were grouped as typical type and were characterized by an aggressive clinical course with lymph node (7 of 7), bone marrow (6 of 7), liver (3 of 7), spleen (3 of 7), and central nervous system (2 of 7) involvement. The median survival time was 8 months. In contrast, three patients had an atypical clinical picture. They were older patients (64-73 years) and were characterized by a relatively less aggressive course with predominantly bulky nodal involvement. Two of these three patients are alive (31 and 49 months, respectively) and well at this report, with one of them being repeatedly experiencing disease remission with the use of simple salvage chemotherapeutic regimens. Further studies revealed that tumor tissues of these three atypical cases had strong expression of CD5 (Leu-1) marker., Conclusion: B-lymphoblastic lymphoma diagnosed by histomorphologic criteria should be further distinguished from a relatively favorable subtype, which probably represents a variant of blastic lymphocytic lymphoma of intermediate differentiation as described by Lardelli et al. Clinical features of typical B-lymphoblastic lymphoma, except for the lack of mediastinal involvement, is similar to its T-cell counterpart.

Interest in equivalence trials has been increasing for many years, though the methodology which has been developed for such trials is mainly for uncensored data. In cancer research we are more often concerned with survival. In an efficacy trial, the null hypothesis specifies equality of the two survival distributions, but in an equivalence trial, a null hypothesis of inequivalence H0 has to be tested. The usual logrank test has to be modified to test whether the true value r of the ratio of hazard rates in two treatment groups is at least equal to a limit value r0. If prognostic factors have to be taken into account, the Cox model provides tests of Ho, and a useful confidence interval for the adjusted relative derived from the regression parameter for the treatment indicator. An equivalence trial of maintenance therapy was carried out in children with B non-Hodgkin lymphoma, and serves as an illustration.

Background: The frequency and clinical significance of bcl-2 rearrangement in de novo B-cell diffuse large cell lymphoma is largely unknown., Methods: Using Southern blot hybridization and multiple DNA probes, the status of the protooncogene bcl-2 was investigated in frozen tissue samples from 45 carefully selected cases of de novo diffuse large cell lymphoma of B-cell origin. Results were correlated with the presenting clinical and immunophenotypic features and with the subsequent clinical course., Results: Rearrangements of bcl-2 were identified in nine tumor specimens (20%). The bcl-2-positive cases more often presented as early-stage, nonmucosal associated extranodal tumors (P = 0.06) and were more often HLA-DR negative (P = 0.07). Five-year failure-free survival was poor among the bcl-2-positive cases (11% versus 48%). Overall survival was no different, however, because relapses in bcl-2-positive cases tended to be responsive to further therapy., Conclusions: Analysis of bcl-2 rearrangements in de novo diffuse large cell lymphoma may identify a subset of patients with unusual clinical features.