BioOncology Watch Timely Information for Practicing Physicians
january 2001 highlights of the 42ND annual meeting of the american society of Hematology December 1 - December 5, 2000 Hodgkin’s Disease (HD) Rituximab (chimeric anti-CD20 monoclonal antibody) therapy. Jennifer Lucas and colleagues are conducting a phase II study of rituximab therapy (IDEC Pharmaceuticals) in patients with lymphocyte predominance Hodgkin’s disease (LPHD), a subtype of HD that expresses the CD20 antigen. Thirteen patients have been enrolled (3 patients had been previously treated with chemotherapy) and have received intravenous rituximab 375 mg/m^2 weekly for 4 weeks. All patients have tolerated the treatments well without grade 3 or 4 toxicities. Of 9 evaluable patients, 6 patients have achieved complete responses and 3 patients had partial responses (PR). One patient has relapsed and retreatment with rituximab has resulted in a PR at 3 months of follow-up. These initial data provide evidence that rituximab may be effective therapy for patients with LPHD and further study is warranted. (abstract 3592) Chronic Lymphocytic Leukemia (CLL) Combination rituximab-chemotherapy. Single-agent rituximab has been shown to be effective therapy in CLL and to sensitize lymphoid cells to chemotherapy. These findings led Michael Keating et al to investigate the activity of rituximab treatments combined with fludarabine (F) and cyclophosphamide (C) for patients with advanced CLL. Their combination regimen comprises intravenous (IV) F 25 mg/m2 and C 250 mg/m2 on Days 1, 2, and 3 and IV rituximab (375 mg/m^2 for cycle 1 and 500 mg/m^2 for subsequent cycles) on Day 1 every 4 weeks. Sixty-eight previously untreated patients have been enrolled and adverse reactions to rituximab have been uncommon. Thirty-five patients are evaluable after 6 cycles of therapy and the objective response rate is 94% (57% complete response rate). All but 2 responders had <5% CD5 and CD19 co-expressing lymphocytes in their marrow and 4 of 10 complete responders became PCR negative for Ig heavy chain rearrangement. In a second study of this rituximab/FC regimen, (Guillermo Garcia-Manero et al) a response rate of 69.9% has been achieved in 43 previously treated patients who received at least 3 cycles of therapy. These preliminary results indicate that rituximab combined with FC may be a very active regimen for patients with advanced CLL. (abstracts 2214, 3275) Graft Versus Host Disease (GVHD) Anti-CD3 monoclonal antibody (mAb) therapy. Murine anti-CD3 mAbs have been shown to be immunosuppressive. P.A. Carpenter and coworkers have begun a phase I study of HuM291, a humanized anti-CD3 mAb that is a more potent immunosuppressor than murine anti-CD3 mAb, in posttransplant patients with grade III-IV acute GVHD refractory to glucocorticoids. Six patients have been treated with an every other day schedule of HuM291 (3 at 0.25 mg/m^2 for 7 doses and 3 at 1.0 mg/m^2 for 7 doses) and 6 patients have received a single 3.0 mg/m^2 dose of HuM291 following pharmacokinetic analyses showing a serum half-life as long as 177 hours. All patients also received methotrexate plus cyclosporine for GVHD prophylaxis. GVHD improved in all patients: the first 6 patients had partial remissions (PRs) and of the 6 single-dose patients at 3.0 mg/m^2,4 had complete remissions and 2 had PRs. HuM291 was tolerated well, however in 8 patients a reactivation of latent EBV occurred, and 2 patients developed posttransplant lymphoproliferative disease (PTLD). A single dose of rituximab resulted in undetectable EBV titers in 2 other patients and PTLD did not occur. These early results are encouraging and further phase II investigation of HuM291 treatment with rituximab prophylaxis is warranted. (abstract 3048) Non-Hodgkin’s lymphoma (NHL) Rituximab plus CHOP. B. Coiffier and associates report results from a planned interim analysis (n=328) of a randomized study comparing standard CHOP chemotherapy to CHOP plus rituximab 375 mg/m^2 on Day 1 of each cycle (R-CHOP) in patients with stage II-IV diffuse large B-cell lymphoma (DLBCL). Toxicities were similar in both treatment groups. A greater percentage of patients in the R-CHOP treatment group compared to the CHOP alone group had complete remissions (76% vs 60%; p=0.004), 12-month event-free survival (69% vs 49%; p<0.0005), and 12-month overall survival (83% vs 68%; p<0.01). This early analysis suggests that the addition of rituximab to CHOP chemotherapy adds clinical benefit for patients with DLBCL. Confirmatory trials are nearing completion. However, these data do not necessarily extrapolate to younger patients, or those with other histologies (e.g. low-grade NHL). (abstract 950) Rituximab plus fludarabine (F) therapy. A 92% response rate (22 of 24 patients) with 67% complete responders has been observed in the interim results of a Phase II study by M. S. Czuczman et al of a rituximab/F combination therapy in both naïve and previously treated patients with advanced stage indolent B-cell NHL. Patients received 7 doses of rituximab (375 mg/m^2/dose in combination with 6 cycles of fludarabine (25mg/m^2/d x 5 days q 28 days). The most common adverse event attributed to rituximab/F combination was neutropenia, which was observed in the first 10 patients treated and resulted in discontinuation of prophylactic Bactrim, limited use of growth factors and, if needed, a 40% reduction of F in patients with prolonged cytopenia. Of the next 14 patients treated, only 2 required transient growth factor support, and no serious or opportunistic infections have been seen to date. These data indicate that the combination therapy of rituximab/F demonstrates excellent anti-tumor activity and is a novel approach for the treatment of indolent NHL. (abstract 3154) Radioimmunotherapy. Studies investigating the role of radioimmunotherapy (RIT) included 2 trials in which RIT was administered to patients with follicular NHL refractory to rituximab therapy. Therapy with Zevalin™ (IDEC Pharmaceuticals), a murine anti-CD20 monoclonal antibody (ibritumomab) bound to tiuxetan which chelates ^90Yttrium (^90Y), resulted in a response rate of 54%, a complete response rate of 15%, and a median time to progression (TPP) of 7.5+ months in a study performed by T.E. Witzig and colleagues. Susan Horning et al also found iodine-131 tositumomab (Bexxar^TM; Coulter Pharmaceuticals, Inc.) treatments to result in a high overall response rate (58%) and complete response rate (21%) with a median TTP of 182 days in rituximab-refractory patients (n=38). Additionally, T.E. Witzig et al compared a Zevalin regimen (Day 0 rituximab 250 mg/m^2 plus a dosimetric dose of 5 mCi ^111Indium-labeled Zevalin and Day 7 rituximab 250 mg/m^2 followed by 0.4 mCi/kg ^90Y Zevalin) to a standard regimen of rituximab alone in patients with relapsed or refractory low-grade, follicular, or CD20+ transformed B-cell NHL (n=143). The Zevalin regimen resulted in a greater overall response rate (p=0.002) and complete response rate (p=0.04) than rituximab alone. These studies show that RIT is effective salvage therapy for patients with rituximab-refractory follicular NHL and may be superior to rituximab alone for the treatment of B-cell NHL. (abstracts 2183, 2184, 3591) Mechanism of action. Several investigations of the mechanism of action of mAb therapies were undertaken. Jennifer Green and coworkers found that humanized 1D10 mAb (Protein Design Labs, Inc.) induces apoptosis in malignant B-cells through the formation of crosslinks with HLA-DR which activates a variety of plasma membrane-associated signaling molecules including the src-family kinase, lyn, and the non-receptor tyrosine kinase, syk. Another study by J. Golay et al utilizing a human B-NHL cell line resistant to rituximab showed fludarabine to be synergistic with rituximab. It is postulated that a demonstrated down modulation of the membrane expression of CD55, a complement inhibitory protein, by fludarabine is responsible for its synergistic activity. A second study performed by J. Golay and colleagues provides additional data suggesting that the levels of CD20 expression and complement inhibitory molecules (eg. CD55 and CD59) are predictive of response of freshly isolated lymphoma cells to rituximab in vitro. In an analysis of the effect of rituximab on cells obtained from patients with B-cell lymphoproliferative disorders, B. Bellosillo et al observed rituximab-induced complement-dependent cell death (CDC) to occur only when CD20 density exceeded 50,000 molecules/cell. In addition, rituximab-induced CDC was enhanced by anti-CD59 and was not prevented by caspase inhibitors. These investigations indicate that mAbs may exert their effect through several different mechanisms. (abstracts 573, 1463, 1460, 1315) From the 23^rd Annual San Antonio Breast Cancer Symposium December 6-9, 2000 HER2 expression. The identification of HER2 expression in tumor is essential because of the importance of Herceptin™ (trastuzumab) therapy in breast cancer. Previous trials have shown that, in general, patients that have tumors that stain only 2+ by immunohistochemistry techniques for HER2 do not derive benefit from Herceptin treatment. H. Buehler et al have shown in an analysis of 142 breast cancer patients that the subgroup of 2+ HER2 patients who demonstrate gene amplification (>10 gene copies) by fluorescence in situ hybridization (FISH) are more likely to respond to Herceptin. In addition, SM Edgerton and colleagues evaluated the HER2/neu/ErbB-2 status of primary breast cancers and their recurrent and metastatic lesions by immunohistochemistry and FISH techniques (n=193). They found that up to 25% of recurrent and metastatic tumors had discordant HER2 data compared to the corresponding primary tumor. These data emphasize the importance of HER2 diagnosis for guiding Herceptin therapy. (abstracts 202 and 180)
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