Novel Agents for Lymphomas: The Hopeful Puzzle

Abstract

11 ISSN 2045-1393 10.2217/IJH.12.5 © 2012 Future Medicine Ltd Int. J. Hematol. Oncol. (2012) 1(1), 11–14 The development of targeted therapies for lymphomas is more challenging than for any other type of cancer. This is mostly owing to the fact that lymphomas are more than 40 distinctive entities with different pathogenetic mechanisms, clinical behavior, molecular profiles and prognosis, requiring varied treatments, with constant knowledge improvements. The era of the targeted therapies for lym‐ phomas started more than 15 years ago with the identification of a small surface molecule called CD20, the perfect target for rituxi‐ mab, the first unconjugated monoclonal antibody (mAb) developed with therapeutic purposes. This is a chimeric mAb, with a human constant region and variable regions derived from murine sequences, approved by the US FDA in 1997 for the treatment of a wide variety of CD20 B‐cell non‐Hodg‐ kin’s lymphomas (NHLs). Rituximab has efficiently contributed to change the his‐ tory of some types of lymphomas, such as follicular (FL) and diffuse large B‐cell lymphomas (DLBCLs), especially in com‐ bination with CHOP (cyclophosphamide, adriamicine, vincristine and prednisone) or CHOP‐like chemotherapy regimens [1]. Since the introduction of rituximab, anti‐ body technology has moved forward with the introduction of more active mAbs. The first clinical trials on ofatumumab, a second‐generation fully human anti‐CD20 mAb, started in 2006. Ofatumumab binds to a different small‐loop epitope of CD20 and elicits rapid in vitro cell lysis via comple‐ ment‐dependent cytotoxicity [2,3]. In mono‐ therapy, it demonstrated a 58% overall response rate (ORR) in relapsed/refractory (r/r) chronic lymphocytic leukemia (CLL). The results obtained were not compara‐ ble with other rituximab‐refractory B‐cell lymphomas [4]. Recently, a new humanized anti‐CD20 mAb, with high affinity for FcRgIII, named GA101, was developed. GA101 demonstrated antibody‐dependent com‐ plement‐mediated cytotoxicity and strong caspase‐independent apoptosis activity upon CD20 binding [5]. As a single agent, GA101 showed an ORR of up to 50% in rituximab‐refractory NHL [6,7]. A European randomized Phase III trial finalized to com‐ pare rituximab versus GA101 in association with standard chemotherapy CHOP in DLBCL is ongoing.