Some of the clinically relevant mAbs are discussed here. Targeting CD20 CD20 is an important antigen expressed by B cell lymphoproliferative disorders including CLL. Rituximab is a chimeric anti CD20 mAb, which has shown efficacy in patients with CLL. The activity of single agent rituximab in CLL is modest at standard doses with ORR from 15 to 25 .39 O,Brien et al reported a dose response association with an ORR of 40 , 22 in 500 825 mg m2, 43 in 1000 1500 mg m2, and 75 in 2250 mg m2.40 The major impact of targeting the CD20 has been shown in combination Lapatinib 388082-77-7 with conventional chemotherapy. This has resulted in improved ORR, CR rate, and survival advantage.41 In this context the most effective combination strategy is the FCR regimen, as reported by Keating et al, Wierda et al, and Tam et al.5,42,43 This combination resulted in ORR and CR rates of 95 and 72 , respectively. Hallek et al recently reported a follow up study comparing this chemoimmunotherapy regimen with chemotherapy only combination.44 This phase III clinical study confirmed the benefit of adding anti CD20 mAb and thus the importance of target specific therapy in patients with CLL.
The impressive results of incorporating target directed anti CD20 mAb into anti CLL treatment regimens has fueled the development of several new mAbs including new anti CD20 molecules with improved target binding.45 Ofatumumab is a fully humanized mAb, also designed to target the CD20 molecule on CLL cells.
In comparison with rituximab, ofatumumab recognizes a novel epitope on the CD20 molecule that is localized in the second extracellular loop, distinct Topotecan structure from the site recognized by rituximab. Ofatumumab has demonstrated superior antitumor effects in vitro with the ability to induce CDC in rituximab resistant cells.45,46 Fludarabine refractory disease remains a challenging group among CLL patients with limited treatment options. In an international multicenter study clinical activity of ofatumumab was evaluated in patients with fludarabine and alemtuzumab refractory disease.47 The patient population evaluated in this trial included a group with refractory disease to both fludarabine and alemtuzumab therapy and another group with bulky disease refractory to fludarabine therapy. Other important clinical characteristics include median of five and four prior therapies, advanced Rai stage III and IV among 54 and 69 of patients, high risk cytogenetics del and del were noted among 28 and 17 , and 40 and 27 , in the FA ref and BF ref groups, respectively. Ofatumumab was administered intravenously weekly for 8 weeks followed by monthly infusions for 4 months for a total of 24 weeks. The study demonstrated activity of ofatumumab in FA ref as well as BF ref patients with ORRs of 58 and 47 , respectively. CR was also reported in one patient.