BioOncology Watch Timely Information for Practicing Physicians
april 2003 MULTIPLE MYELOMA (MM) PS-341 potentiates sensitivity to chemotherapy. PS-341 (Millenium Pharmaceuticals) is a proteasome inhibitor that inhibits the activation of NF-kB and has been previously shown to have clinical activity against MM. In the current study, Nicholas Mitsiades and colleagues at the Dana Farber Cancer Institute investigated the effect of PS-341 when combined with doxorubicin or melphalan on MM cell lines and MM cells freshly isolated from the bone marrow of MM patients. Subtoxic concentrations of PS-341 enhanced the sensitivity to subtoxic concentrations of doxorubicin and melphalan while it did not increase the effect of dexamethasone. PS-341 lowered the apoptotic threshold to doxorubicin and melphalan and was also found to reverse drug resistance. Further experiments showed that PS-341 abolished cell adhesion-mediated drug resistance (CAM-DR) and that it down-regulated effectors involved in the cellular response to genotoxic stress. These studies suggest that PS-341 inhibits genotoxic stress response pathways and increases sensitivity of MM cells to doxorubicin and melphalan. (Mitsiades N, et al. Blood 2003;101:2377-2380) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Cytogenetic findings predict response to rituximab. John Byrd et al correlated interphase cytogenetic abnormalities with response to rituximab in 28 patients with CLL. Response to rituximab was found to be lower in patients with del(17)(p13.1) compared to those with other cytogenetic abnormalities (p = 0.05): del(17)(p13.1) [n = 5], 0%; del(11)(q22.3) [n = 9], 66%; del(13)(q14.3) [n = 7], 86%; trisomy 12 [n = 4], 25%; and normal [n = 3], 0%. These preliminary data suggest that interphase cytogenetic findings may be predictive for response to rituximab in CLL patients. (Byrd JC, et al. Cancer Res 2003;63:36-38) CHRONIC MYELOID LEUKEMIA (CML) Imatinib versus interferon alfa plus low-dose cytarabine. Stephen O'Brien et al from the International Randomized Study of Interferon and STI571 randomized 1,106 newly diagnosed chronic-phase CML patients to oral imatinib 400 mg daily or interferon alfa (target dose of 5 million U/m^2/day) plus subcutaneous cytarabine 20 mg/m^2/day for 10 days every month. After a median follow-up of 19 months, the complete cytogenetic response rate was 76.2% for imatinib-treated patients compared to 14.5% for patients given interferon plus cytarabine (p <0.001). The 18-month freedom-from-progression (to accelerated phase or blast crisis) rates were 96.7% and 91.5% for the imatinib and combination-therapy groups, respectively (p <0.001). This trial demonstrates that imatinib therapy is associated with improved outcomes in patients with newly diagnosed chronic-phase CML compared to conventional combination therapy with interferon alfa and cytarabine. (O'Brien SG, et al. N Engl J Med 2003;348:994-1004) ACUTE MYELOID LEUKEMIA (AML) Interleukin (IL)-2 therapy after autologous stem-cell transplantation (ASCT). Preclinical data indicate IL-2 may induce a graft versus malignancy effect when administered post-ASCT. Anthony Stein et al at the City of Hope National Medical Center treated AML patients in first remission with high-dose cytarabine and idarubicin consolidation therapy supported by ASCT. At hematologic recovery, 39 patients were given 9 x 10^6 U/m^2/24 hours of IL-2 by continuous i.v. infusion for 4 days, followed by 1.6 million U/m^2/24 hours of IL-2 for 10 days. The 2-year cumulative probability of disease-free survival (DFS) was 74% for these IL-2-treated patients. These encouraging early results suggest that the addition of IL-2 to consolidation ASCT may improve DFS for patients with AML in first remission. Further study is warranted. (Stein AS, et al. J Clin Oncol 2003;21:615-623) PROSTATE CANCER Atrasentan therapy. Atrasentan (Abbot Laboratories) is a novel oral endothelin-A receptor antagonist. Michael Carducci et al studied 288 asymptomatic patients with hormone-refractory prostate cancer who were randomized to receive daily placebo, 5 mg atrasentan, or 10 mg atrasentan. Compared to the placebo group, patients given 10 mg atrasentan had longer median times to PSA progression (71 vs. 155 days; p = 0.002) and to clinical progression (for evaluable patients, 129 vs. 196 days [p = 0.021]; for intent-to-treat patients, 137 vs. 183 days [p = 0.13]). Atrasentan was well tolerated; mild to moderate headaches, peripheral edema, and rhinitis were the most commonly reported adverse events. Atrasentan 10 mg daily is active against hormone-refractory prostate cancer and further studies are warranted. (Carducci MA, et al. J Clin Oncol 2003;21:679-689) RENAL CELL CANCER (RCC) Autologous tumor vaccination. Alfred Chang et al at the University of Michigan vaccinated stage IV RCC patients with irradiated autologous tumor cells admixed with Calmette-Guerin bacillus. Seven to 10 days later, the enlarged vaccine-primed tumor-draining lymph nodes were removed for culture. In culture, lymphoid cells were activated secondarily and expanded with anti-CD3 monoclonal antibody and IL-2 and then infused intravenously over 30 minutes followed by i.v. administration of 15 doses of 360,000 U/kg of IL-2 given over 5 days. Of the 34 patients who were infused, 9 responses were achieved (4 CRs, 5 PRs). The median cytokine release ratio of interferon gamma to IL-10 was 992 and 5 for responders and nonresponders, respectively (p = 0.047). Response durations for CR and PR patients ranged from 12 to >48 months and 4 to >63 months, respectively. Durable responses can be obtained with autologous vaccination of patients with stage IV RCC. (Chang AE, et al. J Clin Oncol 2003;21:884-890)
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