Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study

Chanan‐Khan, Asher; Miller, Kena C.; Musial, Laurie; Lawrence, David; Padmanabhan, Swaminathan; Takeshita, Kenichi; Porter, Carl W.; Goodrich, David W.; Bernstein, Zale P.; Wallace, Paul K.; Spaner, David; Mohr, Alice; Byrne, Catriona; Hernandez‐Ilizaliturri, Francisco J.; Chrystal, Cynthia; Starostik, Petr; Czuczman, Myron S.

doi:10.1200/jco.2005.05.0401

Cited by 377 publications

(314 citation statements)

References 31 publications

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“…This synapse defect in CLL can be repaired in part by treatment with the immunomodulatory drug lenalidomide. Lenalidomide has clinical activity in CLL (17,18) and also improves CLL B-cell APC function (19). The demonstration that treatment of E -TCL1 transgenic leukemic and T cells with this agent improves the defective immune synapse formation in CLL lends further support that this mouse model can be used to examine unique agents in CLL (20).…”

Section: Discussionmentioning

confidence: 91%

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Görgün¹,

Ramsay

Holderried³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

115

102

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Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) E -TCL1 transgenic mouse model. With development of leukemia, E -TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young E -TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.C ancer cells induce changes in the tumor microenvironment.The mechanisms whereby this occurs are poorly understood, but include direct cancer cell-T cell interactions, production of immune-suppressive factors by cancer cells, and induction of regulatory T-cell subsets (1, 2). Understanding the elusive mechanisms of tumor-driven immune evasion will aid the refinement of existing cancer immunotherapy strategies and identify novel treatments. To date, preclinical animal models that closely model human cancer and, in particular, include examination of the immune-suppressive mechanisms used by cancer cells have been under-characterized. The identification and use of such models should allow better predictions of successful human responses to immunotherapy.Chronic lymphocytic leukemia (CLL) is an ideal model cancer to study immune T cells that have been exposed to circulating tumor B cells and is associated with immune dysfunction. CLL is the most common adult leukemia in North America and Europe and is currently incurable. Immunotherapeutic strategies are believed to represent a promising treatment modality for this disease if immune suppression can be controlled (3). Extensive research has been carried out using CLL human patient cells, including the characterization of altered gene and proteinexpression profiles (4) and suppressed functional responses in patient T cells compared to healthy-donor T cells (1, 5).We sought to determine whether development of leukemia in the well-established E -TCL1 transgenic murine model of CLL (6) would induce changes in nonmalignant T cells. To examine this, we examined changes in gene-expression profile, protein expression, and function in T cells from E -TCL1 transgenic mice as they developed CLL. We demonstrate that development of CLL in these transgenic mi...

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Section: Discussionmentioning

confidence: 91%

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Görgün¹,

Ramsay

Holderried³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

115

102

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“…6 New agents such as bortezomib, flavopiridol, thalidomide and lenalidomide are also promising, but are still under investigation in clinical trials. [7][8][9][10] Despite the introduction of these new treatments, CLL is still considered to be incurable. Furthermore, the continuous use of chemotherapeutic agents actually leads to development of resistance.…”

Section: Introductionmentioning

confidence: 99%

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

et al. 2009

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“…6 out of 23 fludarabine refractory patients achieved a PR, one patient a CR. Hematological toxicity seems to be a major problem: in 78 % of the cases occurred neutropenia and thrombocytopenia [33]. In the second trial 44 patients were treated continuously with 10 mg daily.…”

Section: Lenalidomidementioning

confidence: 99%

Refractory chronic lymphocytic leukemia - new therapeutic strategies

Schnaiter

Stilgenbauer

2010

Oncotarget

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AbstrAct:Treatment outcome of chronic lymphocytic leukemia (CLL) has considerably improved since the introduction of fludarabine (F) as part of the standard therapy. Nevertheless, refractoriness to fludarabine occurs in a significant number of patients and is associated with an unfavorable prognosis. Important risk factors are 17p deletion and/or mutation of TP53. For this subgroup the CD52 antibody alemtuzumab (A) presents a new treatment approach and has already been approved. Meanwhile we have to face also refractoriness to alemtuzumab. Importantly, the monoclonal CD20 antibody ofatumumab has now shown efficacy in F and A double-refractory CLL. The next generation CD20 antibody GA-101 is currently compared to rituximab (R) and will possibly be its more potent successor. Further B-cell antigens are targeted by lumiliximab (CD23), TRU-016 (CD37) and blinatumomab (CD19). Apart from monoclonal antibody therapies, a great number of small molecules are examined for the treatment of refractory and relapsed CLL. Most of these agents aim to overcome apoptosis resistance in CLL cells or influence the microenvironment. Typical targets are regulators of the cell cycle and antiapoptotic molecules like the members of the Bcl-2 family. Up to now the most promising agents appear to be flavopiridol and lenalidomide among others.

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Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study

Abstract: Lenalidomide is clinically active in patients with relapsed or refractory B-CLL. These findings are encouraging and warrant further investigation of this agent in the treatment of this disorder.

Cited by 377 publications

References 31 publications

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction

Antileukemic activity of valproic acid in chronic lymphocytic leukemia B cells defined by microarray analysis

Refractory chronic lymphocytic leukemia - new therapeutic strategies

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