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Novel Immune-Based Treatment Strategies for Chronic Lymphocytic Leukemia Williamg.Wierda,Thomasj.Kipps,Andmichaelj.Keating

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Novel Immune-Based Treatment Strategies for Chronic Lymphocytic Leukemia Williamg.Wierda,Thomasj.Kipps,Andmichaelj.Keating VOLUME 23 d NUMBER 26 d SEPTEMBER 10 2005 JOURNAL OF CLINICAL ONCOLOGY REVIEW ARTICLE Novel Immune-Based Treatment Strategies for Chronic Lymphocytic Leukemia WilliamG.Wierda,ThomasJ.Kipps,andMichaelJ.Keating From the Department of Leukemia, Division of Cancer Medicine, The ABSTRACT University of Texas M.D. Anderson Cancer Center, Houston, TX; Immune-based treatments represent a new group of therapeutic strategies for patients with Department of Medicine, Division of cancer, including chronic lymphocytic leukemia (CLL), that employ immune effector mecha- Hematology and Oncology, University nisms. Among these strategies is passive immunotherapy with monoclonal antibody, alone or of California, San Diego, San Diego, in combination with chemotherapy. Active immunotherapy strategies currently under devel- CA; and the Chronic Lymphocytic Leukemia Research Consortium, opment include vaccines, administration of expanded and activated T cells, and allogeneic San Diego, CA. stem cell transplantation. These immune-based strategies represent new treatments with potentially complementary mechanisms of action to standard therapies and signify major ad- Submitted May 5, 2005; accepted May 17, 2005. vances in treatments for patients with CLL. Authors’ disclosures of potential J Clin Oncol 23:6325-6332. 2005 by American Society of Clinical Oncology conflicts of interest are found at the end of this article. INTRODUCTION This review will discuss these immuno- Address reprint requests to William G. logic treatment strategies and review out- Wierda, MD, PhD, The University of Immune-based treatment strategies offer Texas M.D. Anderson Cancer Center, comes of clinical trials using immune-based Department of Leukemia, 1515 exciting new treatment options for patients treatment strategies in patients with CLL. Holcombe Blvd, Unit 428, Houston, with chronic lymphocytic leukemia (CLL). TX 77030; e-mail: wwierda@ Certainly, harnessing and utilizing the mdanderson.org. mAb THERAPY immune system’s great potential as a thera- 2005 by American Society of Clinical The binding of an mAb to its respective an- peutic modality against malignancy offers Oncology tigen on the surface of the CLL B cells can a unique and powerful spectrum of tools 0732-183X/05/2326-6325/$20.00 target the neoplastic cell for destruction distinct from traditional chemotherapy. DOI: 10.1200/JCO.2005.05.008 through a variety of mechanisms. One Passive immune therapy involves trans- such mechanism is antibody-dependent cel- fer of antigen-specific antibodies to an indi- lular cytotoxicity. In addition, leukemia cells vidual and is effective in patients with CLL coated with bound mAb may be targeted for (Table 1). Molecular biology has enabled clearance by the reticuloendothelial system. production of large amounts of monoclonal Another mechanism may be through com- antibody (mAb) directed against surface pliment activation leading to lysis of the antigens found on CLL B cells. Such mAbs antibody-bound target cell. Finally, the can be used alone or in combination with binding of mAb to certain surface proteins chemotherapeutic agents in the treatment on leukemia cells may directly kill leukemia of patients with CLL. Already, mAbs such cells by activating an apoptotic cascade or by as alemtuzumab and rituximab have signif- blocking the binding of signaling factors icantly advanced the treatment of CLL. responsible for maintaining leukemia-cell Active immune therapy invokes adap- viability, both independent of extrinsic tive immunity and is induced by exposure effector mechanisms. to antigen, thereby inducing specific lym- phocyte responses (Table 1). Specifically, Alemtuzumab vaccine strategies are being developed Alemtuzumab (anti-CD52 mAb; that induce or enhance T-cell responses Campath-1H) is a humanized mAb specific against autologous leukemia cells. for CD52, a surface proteins present on 6325 Information downloaded from jco.ascopubs.org and provided by at Christian Medical College-Vellore on August 9, 2011 from Copyright © 2005 American Society220.225.126.138 of Clinical Oncology. All rights reserved. Wierda, Kipps, and Keating Table 1. Immune-Based Treatment Strategies for CLL Immunotherapy Target Clinical Trial Passive Monoclonal antibodies Alemtuzumab CD52 Phase II Rituximab CD20 Phase II Lumiliximab CD23 Phase I LYM-1 HLA-DR Phase II Apolizumab HLA-DR-␤ Phase I CHIR-12.12 CD40 Phase I Active Modified autologous leukemia-cell vaccine Ad-CD154–modified autologous CLL B cells Unselected leukemia antigens Phase I Oxidized autologous CLL B cells Unselected leukemia antigens Phase I Autologous dendritic-cell vaccine Antigen-pulsed autologous dendritic cells Selected antigen v unselected leukemia antigens Phase I/II Activated autologous T cells Xcellerate T cells Unidentified leukemia antigen Phase I/II Adoptive Allogeneic stem cell transplantation Donor hematopoietic cells (myeloablative v Unidentified leukemia antigen Phase II nonmyeloablative conditioning) Abbreviation: CLL, chronic lymphocytic leukemia. CLL B cells as well as normal B and T cells.1 Alemtuzumab with alemtuzumab provided benefit for patients was approved by the US Food and Drug Administration as with very poor prognosis. Subsequent studies confirmed a single agent for patients with fludarabine-refractory CLL. the activity of alemtuzumab in previously treated patients In the pivotal trial, alemtuzumab was administered to with CLL and when administered via subcutaneous (SQ) fludarabine-refractory patients at a standard dose of 30 administration.3-7 Higher response rates were observed in mg intravenous (IV) three times weekly for a total of 12 chemotherapy-naı¨ve patients who receive alemtuzumab as weeks (Table 2).2 The overall objective response in 93 pa- front-line therapy.8 Alemtuzumab 30 mg SQ three times tients was 33%, with 2% complete remission (CR) and weekly for up to 18 weeks produced 19% CR and 68% 31% partial remission (PR). The median time to progres- PR in 38 previously untreated patients with CLL. A sion for responders was 9.5 months; clinical benefit was number of these studies found that alemtuzumab was noted in both responders and those with stable disease. highly effective in clearing leukemia cells from the blood The overall median survival was 16 months, 32 months and marrow, but less active in clearing bulky lymph for responders. Notable infections occurred in a little nodes. Also, alemtuzumab may be effective in clearing more than a quarter of the patients. Overall, treatment leukemia cells that lack p53 function.9,10 Such leukemia Table 2. Passive Immunotherapy of CLL With Single-Agent Monoclonal Antibody Prior No. of Patients Complete Overall Median TTP Monoclonal Antibody Study Treatment Assessable Remission (%) Response (%) (months) Alemtuzumab 30 mg IV TIW ϫ 12 Keating2 Yes* 93 2 33 9.5 30 mg IV TIW ϫ 12 Osterborg3 Yes 29 4 42 12 30 mg IV TIW ϫ 16 Rai5 Yes 24 0 33 19.6 30 mg IV TIW ϫ 12 Ferrajoli6 Yes 42 5 31 NA 30 mg SQ TIW ϫ 18 Lundin8 No 41 19 87 NA Rituximab 375 mg/m2 weekly ϫ 4 McLaughlin15 Yes 30 0 13 NA 375 mg/m2 weekly ϫ 4 Winkler16 Yes 9 0 11 NA 375 mg/m2 weekly ϫ 4 Nguyen17 Yes 12 0 0 NA 375 mg/m2 weekly ϫ 4 Huhn18 Yes 28 0 25 5 500-825 mg/m2 weekly ϫ 4 O’Brien20 Yes 24 0 21 1,000-1,500 mg/m2 weekly ϫ 4 Yes 7 0 43 8 2,250 mg/m2 weekly ϫ 4 Yes 8 0 75 375 mg/m2 TIW ϫ 4 weeks† Byrd19 No/Yes 29 4 52 11 375 mg/m2 weekly ϫ 4, then every Hainsworth21,22 No 43 9 58 19 6 months for 2 years Abbreviations: CLL, chronic lymphocytic leukemia; TTP, time-to-progression for responders; TIW, three times weekly; IV, intravenous; SQ, subcutaneous; NA, not available. *Fludarabine refractory. †Three patients received 250 mg/m2 TIW for 4 weeks. 6326 JOURNAL OF CLINICAL ONCOLOGY Information downloaded from jco.ascopubs.org and provided by at Christian Medical College-Vellore on August 9, 2011 from Copyright © 2005 American Society220.225.126.138 of Clinical Oncology. All rights reserved. Immunotherapies for CLL cells may be resistant to standard antileukemia drugs such Rituximab was administered concurrently at 375 mg/m2 as chlorambucil or purine analogs. Finally, in CLL the weekly for all 4 weeks. Responses were reported for 48 efficacy of alemtuzumab does not appear to be affected patients: 32 with CLL, nine with CLL/prolymphocytic by Fc receptor polymorphisms.11 leukemia (PLL), one with PLL, four with mantle-cell lym- phoma, and two with Richter’s transformation. The over- Rituximab all response rate was 52%; CR was noted in 8%, nodular Rituximab (anti-CD20 mAb) is a humanized mAb PR (nPR) in 4%, and PR in 40% of treated patients. The that binds to human CD20.12 Relatively low levels of median time to progression and overall survival were 6 CD20 typically are expressed on CLL B cells compared and 11 months, respectively. Toxicities included infusion- with that expressed by normal or neoplastic B cells of other related reactions. Infections occurred in 52% of patients lymphomas.13 Also, the plasma of patients with CLL may with cytomegalovirus reactivation occurring in 27% of pa- contain soluble CD20 that can inhibit the capacity of tients. Overall, this was a well-tolerated combination for rituximab to bind to CLL B cells in vivo.14 This likely relapsed patients with CLL. influences the pharmacokinetics and clinical activity of rituximab in patients with CLL. At the standard dose of Lumiliximab 375 mg/m2 weekly for 4 weeks, single-agent rituximab Lumiliximab (anti-CD23 mAb) is a macaque-human had only modest anti–leukemia cell activity in CLL (Table chimeric antihuman CD23 mAb that has been evaluated in 2).15-18 Studies demonstrated that dose-intense or dose- a phase I clinical trial for previously treated patients with dense administration of rituximab significantly improved CLL.25 Increasing doses of lumiliximab up to 500 mg/m2 response rates.19,20 O’Brien et al20 evaluated higher doses three times weekly for 4 weeks were studied.
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