BioOncology Watch Timely Information for Practicing Physicians
january 2003 Highlights of the 44^th Annual Meeting of the American Society of Hematology December 6-10, 2002 RITUXIMAB In combination with CHOP (R-CHOP). Nicolas Mounier and colleagues retrospectively analyzed bcl-2 protein expression and clinical outcome from the GELA LNH-985 trial in which patients aged 60 to 80 years with untreated diffuse large B-cell lymphoma (DLBCL) were randomized to receive 8 cycles of standard CHOP or R-CHOP. Among 292 patients with evaluable biopsy material, 193 (66%) cases were found to be positive for bcl-2 protein (92 treated with CHOP; 101 treated with R-CHOP). R-CHOP therapy was associated with an improved response (CR and CRu) rate (78% vs. 61%; p=0.009), 2-year event-free survival (EFS) rate (58 ± 10% vs. 32 ± 10%; p<0.0001), and 2-year overall survival rate (67 ± 9% vs. 48 ± 11%; p=0.004) in the bcl-2-positive group, but not in bcl-2-negative patients. These data suggest that rituximab overcomes bcl-2-associated chemotherapy resistance in DLBCL patients. (Abstract 603) Prolonged rituximab treatment. Michele Ghielmini and associates of the Lymphoma Working Group (Swiss Group for Clinical Cancer Research) conducted a study in which 151 patients with newly diagnosed or resistant/relapsed follicular lymphoma (FL) who had achieved at least stable disease with induction rituximab treatment (375 mg/m^2 weekly for 4 weeks) were randomized to observation or maintenance rituximab therapy (375 mg/m^2 at months 3, 5, 7, and 9). The patient groups were balanced for prognostic factors. At a median follow-up of 35 months, the median EFS for the maintenance group was greater than that for the observation group (23 vs.12 months; p=0.02). The effect of maintenance therapy was greatest in the chemotherapy naive subgroup (36 vs. 9 months; p=0.009). These data indicate that maintenance rituximab treatments prolong EFS for patients with FL. (Abstract 604) RADIOIMMUNOTHERAPY (RIT) Y^90-Zevalin treatment of relapsed low grade and follicular non-Hodgkin's lymphoma (NHL). Gregory Wiseman and colleagues at the Mayo Clinic (Rochester, MN) conducted a phase I study of Y^90-Zevalin (an anti-CD20 monoclonal antibody) therapy in patients with relapsed low grade and follicular NHL. All patients (n=14) received a standard initial dose of Y^90-Zevalin of 0.4 mCi/kg. Eight patients also received a second dose 12 to 24 weeks later. The clearance of Zevalin from blood was found to be up to twice as long after the second dose compared to the initial dose. None of 3 patients receiving a second dose of 0.2 mCi/kg Y^90-Zevalin had a dose-limiting toxicity (DLT). However, 1 of 5 patients has experienced DLT (neutropenia) at the 0.3 mCi/kg dose level. These preliminary results demonstrate that a second dose of Y^90-Zevalin can be safely administered to patients with relapsed/refractory low grade follicular NHL. Lower tumor volume, resulting in less tumor binding of radiolabeled antibody, may cause slower clearance of Zevalin. (Abstract 1387) Iodine-^131-tagged anti-CD30 antibody treatment of refractory Hodgkin's lymphoma (HL). Roland Schnell and associates at the University of Cologne (Germany) treated 21 patients with relapsed/refractory CD30-positive HL with a novel radioimmunoconstruct consisting of the murine anti-CD30 monoclonal antibody Ki-4 labeled with iodine-131. An initial intravenous infusion of 5 mg of Ki-4 was found to be sufficient to bind soluble CD30. Six patients achieved a response (1 CRu, 5 PRs), 3 patients had a minor or mixed response, and 2 had stable disease. Acute toxicity (fatigue, nausea) was mild and transient and 7 patients experienced grade 4 hematologic toxicity (particularly thrombocytopenia). These findings suggest that I^131-Ki-4 therapy is active and feasible in patients with relapsed/refractory CD30-positive HL. (Abstract 762) I^131-tositumomab treatment of previously untreated advanced FL. Mark Kaminski and coworkers at The Johns Hopkins Oncology Center performed a phase II trial in which 76 patients with previously untreated, advanced-stage FL were given I^131-tositumomab (Bexxar^Ò). Ninety-five percent (72) of patients achieved a response and 56 patients (74%) had a confirmed CR (45 patients remained in CR for 30 to 66 months and the 5-year progression-free survival rate was 62%). Ninety-four percent of patients who were PCR-positive for t[14;18] at baseline became PCR-negative following therapy. Human anti-murine antibody developed in 63% of patients. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 34% and 17% of patients, respectively. Hypothyroidism was found in 12% of patients following study treatment. These results suggest that I^131-tositumomab therapy produces a high durable CR rate in previously untreated advanced-stage FL patients with acceptable toxicity. (Abstract 1381) CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) Fludarabine followed by alemtuzumab (Campath-1H). Kanti Rai et al. (Cancer and Leukemia Group B [CALGB] Study 19901) administered alemtuzumab (30 mg intravenously 3 times weekly for 6 weeks) to previously untreated CLL patients with active disease who had achieved at least stable disease after 4 months of an initial course of fludarabine treatments (25 mg/m^2/day intravenously for 5 days monthly) in an effort to improve the CR rate. Fifty-six patients received fludarabine. Two patients (4%) had a CR and 29 (52%) had a PR after the 4-month fludarabine course of therapy. Thirty-six patients went on to receive alemtuzumab. After the alemtuzumab phase of therapy, the CR rate increased to 27%. Alemtuzumab-related infusion reactions occurred in all patients and were grade 1 or 2 in most cases. Grade 3 or 4 infections developed in 12 patients (33%) and CMV infections occurred in 8 patients (22%; 1 case was fatal). Although toxicity was substantial, the early response rate results associated with the sequential administration of fludarabine and alemtuzumab in these previously untreated CLL patients is encouraging. However, the CR rate reported for fludarabine in this study was lower than previously reported in an earlier study by the authors, suggesting that the number patients enrolled in this study was suboptimal. Further follow-up is needed to determine if the natural history of CLL is altered by this regimen. (Abstract 772) MULTIPLE MYELOMA (MM) Novel agents. Preliminary results from multicenter phase II studies of 2 novel agents undergoing clinical development for the treatment of patients with relapsed/refractory MM were reported. Paul Richardson and colleagues showed that 68% of an initial 78 patients enrolled in a single-arm trial evaluating intravenously administered (Days 1, 4, 8, and 11 every 21 days) bortezomib (Velcade^TM; Millenium Pharmaceuticals), a proteasome inhibitor, had either decreased or stable paraprotein levels. Twenty-seven percent of patients achieved a ³ 50% reduction of paraprotein levels (4% CR, 23% PR [9% of the PRs were immunofixation-positive near CRs]). In a second study, Richardson et al. randomized relapsed/refractory MM patients to receive either of 2 dosing regimens (15 mg bid or 30 mg daily for 3 weeks every 4 weeks) of CDC-5013 (REVIMID^TM; Celgene Corp.), a potent oral immunomodulatory analog of thalidomide. Of the first 19 patients evaluable for paraprotein response with a follow-up of at least 1 month (range, 1-3 months), 32% of patients had a ³ 25% reduction in paraprotein level and 53% of patients had stable disease. Grade 3 thrombocytopenia or neutropenia have occurred in 4 patients (13%) while there have been no reports of somnolence, constipation, or neuropathy. These early results demonstrate promising clinical activity for these novel agents in an advanced myeloma patient population. (Abstracts 385 and 386)
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