Chronic Lymphocytic Leukemia News Headlines

Bilateral infiltrative disease of the extraocular muscles: a rare clinical presentation of early stage chronic lymphocytic leukemia.

Orbit. 2008;27(4):293-5

Authors: Ramkissoon YD, Lee RW, Malik R, Hsuan JD, Potts MJ

Orbital involvement in chronic lymphocytic leukemia (CLL) is highly unusual and most commonly involves hemorrhage or soft tissue infiltration in advanced disease. We report a case of rapid onset bilateral orbital muscle infiltration as the presenting feature of early stage CLL. In addition, we demonstrate clinico-pathological correlation with an identical chronic B-cell lymphocytic infiltrate in both orbit and bone marrow, with good response of the orbital disease to local radiotherapy.

PMID: 18716967 [PubMed - in process]

Chronic lymphocytic leukemia cells bind and present the erythrocyte protein band 3: possible role as initiators of autoimmune hemolytic anemia.

J Immunol. 2008 Sep 1;181(5):3674-83

Authors: Galletti J, Cañones C, Morande P, Borge M, Oppezzo P, Geffner J, Bezares R, Gamberale R, Giordano M

The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4(+) T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.

PMID: 18714043 [PubMed - in process]

Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.

Curr Pharm Des. 2008;14(21):2051-60

Authors: Bernard MP, Bancos S, Sime PJ, Phipps RP

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastasis. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

PMID: 18691115 [PubMed - in process]

An update on the xenograft and mouse models suitable for investigating new therapeutic compounds for the treatment of B-cell malignancies.

Curr Pharm Des. 2008;14(21):2023-39

Authors: Macor P, Secco E, Zorzet S, Tripodo C, Celeghini C, Tedesco F

B-cell malignancies account for over the 90% of all lymphoid neoplasms. The clonal proliferations of B-cells show a high degree of variation in terms of clinical and presenting features, histopathology, immunophenotype, and genetics. Primary tumor samples are useful for examining the characteristics of a patient's own tumor, although both primary leukemic cells and cell lines provide an initial step for screening novel compounds for their activity in some hematological malignancies, they should be followed by models in intact animals. In this review, we try to summarize the animal models generated to study B-cell malignancies, in particular, B-cell lymphoma, B-cell CLL and MM that represent the major part of B-cell malignancies. Animals that spontaneously develop cancer are flawed to predict human disease. The development of human tumor xenograft models represented a big step towards more clinically relevant models. The major problems of these models are the requirement of immuno-compromised animals and the inability of these models to recapitulate the complex relationship between the tumor and the microenvironment. A number of strategies have been also applied to develop genetically engineered models of malignancies, in which the tumor arises "naturally" in the host. The disadvantages of these models include the differences between rodent and human stroma and that they can not be used to characterise anti-tumor activity of many immunotherapeutic drugs. These models can be used to study the molecular processes critical for the development, proliferation and survival of hematological malignancies and to characterise potential therapeutic targets.

PMID: 18691113 [PubMed - in process]

Within Peripheral Blood Mononuclear Cells, Antibody-Dependent Cellular Cytotoxicity of Rituximab-Opsonized Daudi cells Is Promoted by NK Cells and Inhibited by Monocytes due to Shaving.

J Immunol. 2008 Aug 15;181(4):2916-24

Authors: Beum PV, Lindorfer MA, Taylor RP

Treatment of chronic lymphocytic leukemia patients with anti-CD20 mAb rituximab (RTX) leads to substantial CD20 loss on circulating malignant B cells soon after completion of the RTX infusion. This CD20 loss, which we term shaving, can compromise the therapeutic efficacy of RTX, and in vitro models reveal that shaving is mediated by effector cells which express FcgammaRI. THP-1 monocytes and PBMC promote shaving, but PBMC also kill antibody-opsonized cells by antibody-dependent cellular cytotoxicity (ADCC), a reaction generally considered to be due to NK cells. We hypothesized that within PBMC, monocytes and NK cells would have substantially different and competing activities with respect ADCC or shaving, thereby either enhancing or inhibiting the therapeutic action of RTX. We measured ADCC and RTX removal from RTX-opsonized Daudi cells promoted by PBMC, or mediated by NK cells and monocytes. NK cells take up RTX and CD20 from RTX-opsonized B cells, and mediate ADCC. PBMC depleted of NK cells show little ADCC activity, whereas PBMC depleted of monocytes have greater ADCC than the PBMC. Pre-treatment of RTX-opsonized B cells with THP-1 cells or monocytes suppresses NK cell-mediated ADCC, and blockade of FcgammaRI on monocytes or THP-1 cells abrogates their ability to suppress ADCC. Our results indicate NK cells are the principal cells in PBMC that kill RTX-opsonized B cells, and that monocytes can suppress ADCC by promoting shaving. These results suggest that RTX-based immunotherapy of cancer may be enhanced based on paradigms which include infusion of compatible NK cells and inhibition of monocyte shaving activity.

PMID: 18684983 [PubMed - in process]