BioOncology Watch Timely Information for Practicing Physicians
june 2003 LYMPHOID MALIGNANCIES Alemtuzumab plus rituximab. Stefan Faderl and colleagues at the M.D. Anderson Cancer Center treated 48 patients with relapsed and refractory lymphoid malignancies with alemtuzumab plus rituximab therapy to investigate the effects of combination anti-CD52 and anti-CD20 monoclonal antibody treatments. Diagnoses: 32 with chronic lymphocytic leukemia (CLL), 9 with CLL/prolymphocytic leukemia (PLL), 1 with PLL, 4 with mantle cell leukemia/lymphoma, and 2 with Richter transformation. Prior exposure to rituximab or alemtuzumab did not exclude patients from study participation. Intravenous rituximab was administered at a dose of 375 mg/m^2 weekly for 4 weeks. Alemtuzumab was given intravenously in doses of 3, 10, and 30 mg on 3 consecutive days, respectively, during the first week and 30 mg on days 3 and 5 of weeks 2, 3, and 4. Patients received prophylactic antibiotics during the 4 weeks of monoclonal antibody treatments and for at least 2 months following completion of therapy. Responses were achieved in 52% of patients (40% partial responses [PRs], 8% complete responses [CRs], and 4% nodular PRs). The median follow-up time was 6.5 months and the median time-to-progression was 6 months. The median survival times for responders and nonresponders were 11+ months and 6 months, respectively (overall survival time of 11 months). Cytomegalovirus (CMV) antigenemia assays were positive in 27% of patients and 15% of patients required therapy for CMV infection. Pneumonia developed in 10% of patients. Most other toxicities were grade 1 or 2 infusion-related events. These findings demonstrate that combination alemtuzumab and rituximab therapy is feasible and active in poor prognostic relapsed and refractory lymphoid malignancies. However, the risk of CMV infection must be balanced against the modest survival benefits of this combination regimen. (Faderl S, et al. Blood 2003;101:3413-3415) First-line and maintenance rituximab treatment. John Hainsworth et al. from the Minnie Pearl Cancer Research Network conducted a phase II study in which 44 previously untreated patients with CLL or small lymphocytic lymphoma (SLL) received single-agent rituximab 375 mg/m^2 weekly for 4 weeks. Patients who had a response or stable disease were eligible to receive up to 4 additional 4-week courses of rituximab therapy at 6-month intervals. After the first course of rituximab, 22 of 43 evaluable patients achieved a response (2 CRs). Fourteen patients developed disease progression prior to the second scheduled rituximab course and 1 responder refused further treatment. Thus, 28 patients received at least 1 additional course of rituximab. At the time of the report, the overall response rate was 58% with 9% CRs. With a median follow-up time of 20 months, the median progression-free survival (PFS) time was 18.6 months. The 1- and 2-year PFS rates were 62% and 49%, respectively. Treatment was well tolerated with only 2 episodes of ³ grade 3 infusion-related toxicities. These data show that rituximab was effective first-line therapy for patients with CLL or SLL, producing higher response rates than previously reported in relapsed or refractory CLL/SLL patients. These findings must be tempered by the observation that over 30% of CLL and SLL patients in this study were unresponsive to single-agent first-line rituximab therapy. (Hainsworth JD, et al. J Clin Oncol 2003;21:1746-1751) Mechanisms of rituximab resistance. Recent data has shown that caspases-dependent apoptosis contributes to the clearance of CLL cells following rituximab treatment. However, little is known about the biologic features that predict response to rituximab or promote resistance to this monoclonal antibody. Rajat Bannerji and coworkers obtained pretreatment CLL cells from 21 patients treated in a single-agent rituximab study. Ten of these patients achieved a PR to rituximab therapy. The mean pretreatment expression of Bcl-2, Mcl-1, XIAP, CD55, CD59, and the ratio of Bcl/Bax were not different in nonresponding versus responding patients. However, the pretreatment Mcl-1/Bax ratio was higher in nonresponding patients compared to patients responding to rituximab (0.82 ± 0.28 vs. 0.39 ± 0.29). When compared to baseline CLL cell observations, higher levels of CD59 were found in cells that were not cleared from the blood by rituximab treatment at the completion of therapy. These preliminary studies indicate that the baseline Mcl-1/Bax ratio may predict for clinical response to rituximab therapy. (Bannerji R, et al. J Clin Oncol 2003;21:1466-1471) ACUTE MYELOID LEUKEMIA (AML) Gemtuzumab ozogamicin treatment in children. Phase I and II studies of gemtuzumab ozogamicin have demonstrated response rates in approximately 30% of adult AML patients. Christian Zwaan and others reported the first clinical experience of gemtuzumab ozogamicin therapy in children with relapsed/refractory CD33+ AML. Fifteen children were treated with gemtuzumab ozogamicin (4-9 mg/m^2 for up to 3 courses) on a compassionate use basis. Eight of these patients had a reduction in bone marrow blasts to £ 5%. Six of the 8 responding patients subsequently underwent stem cell transplantation (SCT) and 2 patients remained alive 6 and 9 months after SCT. Hematologic toxicity was difficult to assess due to the subsequent use of SCT or the progression of leukemia. Side effects that were reported in 1 patient each included veno-occlusive disease, transient grade 3 hyperbilirubinemia, transient grade 3 transaminase elevation, and grade 3 hypotension during gemtuzumab ozogamicin administration. These findings suggest that gemtuzumab ozogamicin has activity against CD33+ AML in children and further studies are warranted. (Zwaan CM, et al. Blood 2003;101:3868-3871)
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