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The anti-CD20 monoclonal antibody, rituximab, and interferon alpha (IFN) are active agents in advanced stage, indolent lymphoma. Some data obtained in vitro suggest upregulation of CD20 by IFN, and clinical trials have reported additive or synergistic activity of IFN with rituximab. A prospective phase II study in advanced stage, follicular and non-follicular indolent lymphoma was performed. Peginterferon alpha 2b (pegIFN) 0.5 microg/kg s.c. weekly x 6 and rituximab 375 mg/m2 i.v. weekly x 4 (beginning on week 3 of pegIFN) was administered. Quantitative CD20 antigen was measured pre-treatment and pre-rituximab in lymph node aspirates. Nine patients were treated: one complete response and three partial responses; however, all relapsed within 12 months and two were withdrawn for grade 3 toxicity (both with serum sickness). No up-regulation of CD20 was documented in seven patients studied (median change in CD20: decrease by 11.9%). PegIFN plus rituximab as delivered in this study is not recommended. PegIFN does not appear to upregulate CD20 expression in peripheral lymph node tumor cells.

The role of high dose therapy, including autologous stem cell transplantation (ASCT) in indolent non-Hodgkin's lymphomas remains controversial. We evaluated a dose intense regimen of CHOP induction followed by high dose cyclophosphamide consolidation (CHOP-HC) versus CHOP alone in a prospective comparison to assess intensified therapy without ASCT. Twenty-five patients with previously untreated advanced stage indolent NHL were enrolled: follicular lymphoma, grade 1 (11 patients) and grade 2 (8 patients); small lymphocytic lymphoma (5 patients); and lymphoplasmacytic lymphoma (1 patient). All patients were treated as clinically indicated. The median age was 47 years (21-70). There were 15 males, and 10 females. Three patients had intra-abdominal stage II, 2 patients with stage III, and 20 patients with stage IV disease. All patients received induction with CHOP for 4 cycles (weeks 1, 4, 7, 10): cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., vincristine 1.4 mg/m2 i.v. (2 mg capped dose) and prednisone 100 mg p.o. x 5 days. Following induction, responding patients were given consolidation with either high dose cyclophosphamide @ 3 gm/m2 i.v. for 3 doses with G-CSF (weeks 13, 15, 17) or 2 additional cycles of CHOP (weeks 13, 16), stratified by stage and bulk of disease. The overall response rate to CHOP was 92% (3 CR, 8 PR) and to CHOP-HC was 93% (4 CR, 8 PR). The overall response, complete response and partial response rates were comparable in both arms. Median progression free survival for CHOP was 15.9 and 23.0 months for CHOP-HC. At 74.3 months median follow-up, all patients in the CHOP arm have recurred; 3 patients in the CHOP-HC arm (3 CR) have not recurred. The median overall survival has not been reached (at 5 years, 77% OS for CHOP-HC versus 83% OS for CHOP alone]. Greater hematologic toxicity was observed with CHOP-HC resulting in an increased number of hospitalizations for sepsis. There were no treatment-related deaths. No myelodysplasia or acute leukemia has been seen to date. With no obvious improvement in CR and with greater hematologic toxicity than CHOP, CHOP-HC is not recommended for treatment of indolent non-Hodgkin's lymphomas.

T-cell rich B-cell lymphoma (TCR-BCL) is a recently described pathologic diagnosis without a place among traditional lymphoma classification systems. In the past, TCR-BCL has been included among other diagnoses, in particular lymphocyte predominant Hodgkin's disease (LPHD). The study of TCR-BCL cohorts may elucidate clinical distinctiveness, response to therapy, and the effect of treatment regimen on outcome. Between 1992 and 1997, a hematopathologist at Memorial Sloan-Kettering Cancer Center (MSKCC) diagnosed 45 patients with TCR-BCL according to published criteria. Clinical data was collected through retrospective chart review and communication with other patient providers. Our patients presented most commonly as males in their fourth decade with advanced stage disease. Three-year overall survival (OS) and failure-free survival (FFS) were 73 and 37%, respectively. Conventional combination chemotherapy regimens were utilized for an aggressive non-Hodgkin's lymphoma (NHL) diagnosis in 26 and for a Hodgkin's disease (HD) diagnosis in 10. Disease-free survival (DFS) was significantly better for NHL (36%) vs. HD (10%) directed chemotherapy at 3 years (p = 0.003). Overall survival at 3 years was not statistically different (62 vs. 79%) due to successful salvage therapy in both groups. It is important to distinguish TCR-BCL from LPHD and classical HD. Advanced stage, extranodal disease, involvement of the mediastinum, mesentery and/or spleen are clinical clues to a TCR-BCL diagnosis. Chemotherapy directed to a NHL diagnosis rather than HD results in a significant improvement in disease-free survival. Initial Hodgkin's disease-directed (HD-directed) chemotherapy should be avoided, although salvage transplantation may result in prolonged survival.

Cytogenetic abnormalities at chromosome 1q21 are among the most common second genetic events observed in Non-Hodgkin's Lymphomas and have prognostic significance. Recently, BCL9 has been cloned from a pre-B-cell lymphoblastic leukemia cell line, which carried a t(1:14)(q21;q32). However, among a panel of 39 B-cell malignancies with 1q21 translocation, only two cases showed rearrangement for the BCL9 gene. We report the establishment of a new lymphoma cell line from a patient with relapsed diffuse large cell lymphoma. This cell line SKI-DLCL-1 showed cell surface antigens identical to the original tumor and demonstrated the profile of a mature B-cell phenotype: CD19 and CD20 positive, CD5 and C10 negative. It carried a t(1;14)(q21;q32) translocation identical to the original tumor. Although the clinical presentation was an isolated effusion lymphoma, studies for HIV-1, HHV8 and EBV were all negative. Southern blot analysis demonstrated that BCL9 was not rearranged in the SKI-DLCL-1 cell line. In addition, the BCL9 gene was not over-expressed in SKI-DLCL-1 cell line. The identification of a new locus at 1q21 will help clarify the pathogenesis of B-cell malignancies with a translocation involving this locus.

Advanced age is an adverse prognostic factor in patients with DLCL. CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has frequent dose-limiting toxicities, including myelosuppression. We retrospectively reviewed 50 consecutive patients > 60 years of age (median age 72) with B-cell DLCL who received CHOP with G-CSF. Patients received CHOP (median 6 cycles) at three-week intervals. G-CSF was given following all cycles of chemotherapy ("prophylactic G-CSF") in 28 of 50 patients, and following an episode of febrile neutropenia and thereafter in 19 patients, according to ASCO guidelines. Dose intensity, treatment delays, episodes of febrile neutropenia, complete response (CR) rate, disease-free survival, time-to-treatment failure, and overall survival were all analyzed according to the age-adjusted International Prognostic Index (aaIPI). The actual dose intensity for cyclophosphamide was 225.9 mg/m2/week and 0.90, respectively and for doxorubicin was 14.9 mg/m2/week (90% of ideal CHOP dosing for both drugs). Median followup was 4 years for the patients still living. Treatment delays and episodes of febrile neutropenia were less frequent among patients receiving G-CSF with all cycles of CHOP. The CR rates were 100%, 81%, 85%, and 36% for the low, low-intermediate, high-intermediate, and high aalPI risk groups, respectively. The 5-year actuarial relapse-free and overall survival for our patients were comparable to that of the cohort < or = 60 years of age and superior to the > 60 years of age cohort used to establish the aaIPI. With optimization of CHOP dosing, advanced age may not be an adverse prognostic factor for patients with DLCL. The routine use of G-CSF in elderly patients with DLCL should be further investigated.

Although high-dose chemotherapy and a blood cell or bone marrow autotransplant are commonly used to treat people with diffuse large-cell lymphoma, there is controversy whether this is better than conventional-dose chemotherapy. Subject-selection and time-to-treatment biases preclude comparison of data from uncontrolled trials and there are few date from randomized trials. We used a Delphi-panel group judgment process to determine appropriateness of high-dose chemotherapy and a blood cell or bone marrow transplant. Results were compared to those of randomized trials. Nine lymphoma experts from diverse geographic sites and practice settings were panelists. Boolean MEDLINE searches of lymphoma and chemotherapy and an autotransplant formed the dataset. Panelists were asked to rate appropriateness of high-dose chemotherapy and an autotransplant compared to conventional-dose chemotherapy. Clinical variables were permuted to define 80 clinical settings rated by the panelists on a 9-point ordinal scale. Results were used to determine an appropriateness index reflecting the mean and distribution of ratings. The relationship of appropriateness indices to permuted clinical variables was considered by analysis of variance and recursive partitioning. In people with initial diffuse large-cell lymphoma, autotransplants were never rated appropriate. They were rated uncertain in all settings except in people never receiving chemotherapy and in those with a complete response to chemotherapy and an international prognostic index < 3, where they were rated inappropriate. In people with recurrent lymphoma, autotransplants were rated appropriate in those with a complete or partial response to chemotherapy, uncertain in those with a less than partial response and in those not receiving re-induction chemotherapy and inappropriate in people with CNS lymphoma. These conclusions agree with results of randomized trials.

This multicenter study reports on 49 patients with hairy cell leukemia (HCL) who were treated subcutaneously with alfa-2b interferon (Intron A, Schering Corporation, Kenilworth, N.J.), three times a week at a reduced dosage of 200,000 units/m(2), one-tenth the dose of the standard 2 million units/m(2). The response rate (normalized blood counts) was 22% (11 of 49); an additional 12 patients had a minor response for an overall response rate of 47% (23 of 49). When response was assessed by prior IFN therapy, no significant difference was noted. Five of 21 (24%) with no prior IFN and 6 of 28 (21%) with prior IFN therapy achieved at least a normalization of blood counts (p = 0.07). The response rate with low-dose interferon is inferior to that with standard dose interferon and should not be used for remission induction, but should be evaluated for its role in long-term maintenance of response.