BioOncology Watch Timely Information for Practicing Physicians
june 2001 Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL) New rituximab dosing regimens. John Byrd and colleagues conducted a phase I/II trial to investigate if the lack of rituximab efficacy observed in CLL/SLL patients was due to a suboptimal dosing schedule. All CLL/SLL patients (n=33; 27 patients had received prior therapy) were given an initial 100 mg dose of rituximab infused intravenously over 4 hours. Escalating doses of rituximab (250 mg/m^2 to 3 patients and 375 mg/m^2 to 30 patients) were then infused on Day 3 and thereafter 3 times weekly for 4 weeks. An overall response rate of 45% (1 CR and 14 PRs) was achieved with median response duration of 10 months (range, 3 to 17+ months). One patient discontinued therapy due to first infusion-related toxicity and developed progressive pulmonary symptoms resulting in death. In addition, transient episodes of hypoxemia, hypotension, or dyspnea associated with increased plasma levels of inflammatory cytokines were observed in 13 patients. This trial showed that rituximab administered thrice weekly for 4 weeks had moderate toxicity and was active in patients with CLL/SLL. Susan O'Brien and coworkers performed a dose escalation trial of rituximab administered as 4 weekly intravenous infusions in patients with CLL (n=40) or other mature B-cell leukemias (mantle-cell leukemia, marginal zone leukemia, and prolymphocytic leukemia; n=10). All 50 patients were given rituximab 375 mg/m^2 as the first weekly dose. For weeks 2 through 4, patients received a fixed higher dose of rituximab (doses were escalated from 500 to 2250 mg/m^2). Grade 3 or 4 toxicities were seen in 6 (12%) patients following the first weekly dose of rituximab. Rituximab administered on weeks 2 to 4 was well tolerated and no grade 3 or 4 toxicity was observed during dose escalation. At the 2250 mg/m^2 dose level, 8 of 12 patients experienced grade 2 toxicity and dose escalation was halted. Overall, responses were seen in 18 of 45 evaluable patients (40%); all CLL responses were partial remissions. Response rate correlated with dose: 22% with 500 to 825 mg/m^2; 43% with 1000 to 1500 mg/m^2; and 75% with 2250 mg/m^2 (P=0.007). These findings show that high-dose rituximab has activity in CLL and is well tolerated. However, these dosing regimens are costly and not yet considered a standard of care. (Byrd JC, et al. J Clin Oncol 2001;19:2153-2164; O'Brien SM, et al. J Clin Oncol 2001;19:2165-2170) Non-Hodgkin's Lymphoma (NHL) Down-regulation of Bcl-2 by rituximab. The anti-lymphoma effects of rituximab are thought to be mediated by antibody-dependent cell cytotoxicity, complement-dependent cytotoxicity, inhibition of cell proliferation, and/or anti-CD20-mediated apoptosis. However, the mechanisms by which rituximab induces these anti-tumor effects are not fully understood. Steve Alas and associates investigated the effects of rituximab on NHL 2F7 tumor cells and found interleukin-10 (IL-10) to be inhibited by exposure of 2F7 cells to rituximab. In addition, the expression of Bcl-2, a known tumor cell protective factor, in 2F7 cells was shown to be dependent on IL-10 levels and was down-regulated by rituximab. These effects were confirmed by experiments with a second NHL cell line (10C9). Other gene products (i.e., Bax, Bcl-x, p53, Bad, c-myc, and latent membrane protein-I) were not affected by rituximab. These observations suggest that the inhibition of the anti-apoptotic IL-10 autocrine/paracrine loop results in down-regulation of Bcl-2 and sensitization of NHL cells to chemotherapeutic agents. (Alas S, et al. Clin Cancer Res 2001;7:709-723)    Breast Cancer Reactivated memory T cells. Peripheral blood and bone marrow samples from 84 patients with primary breast carcinomas were studied by Markus Feuerer et al to investigate the functional T-cell activity of cancer patients. Patients' T cells were expanded in vitro and co-cultured with autologous dendritic cells pulsed with tumor-cell lysate or defined tumor-associated antigens and peptides derived from cancer cells. They found that memory T cells from bone marrow, but not peripheral blood, could be specifically reactivated to become cytotoxic effector cells. These T cells showed anti-tumor activity in vitro and exerted a strong graft-versus-tumor response in a NOD/SCID mouse model in which regression of implanted autologous human breast cancer was associated with tumor infiltration by human T cells. These studies show that T cells from the bone marrow of patients with breast cancer maintain a specific recognition for breast cancer antigens and may represent a novel approach to anti-tumor immunotherapy. (Feuerer M, et al. Nat Med 2001;7:452-458) Multiple Myeloma (MM) Idiotype (Id)-specific cytotoxic T lymphocytes (CTLs). The monoclonal immunoglobulin secreted by myeloma plasma cells carries Id-specific antigenic determinants. Yue-Jin Wen and associates used dendritic cells as antigen-presenting cells and myeloma cells obtained from patients with MM to generate autologous Id-specific CTL lines containing both CD4+ and CD8+ T cells. The CTLs were found to lyse autologous primary myeloma cells. The cytotoxicity was major histocompatibility complex (MHC) I and II restricted which indicated that myeloma cells can process and present Id peptides in the context of their surface MHC molecules. Concanamycin A experiments showed that cytotoxicity occurred through the perforin-mediated pathway. This investigation is the first study to demonstrate that Id-specific CTLs are able to lyse autologous myeloma cells, indicating that Id-based immunotherapy may have a role in the treatment of MM. (Wen Y-J, et al. Blood 2001;97:1750-1755)
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