Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal malignancy that results from expansion of the mature lymphocyte compartment. This expansion is a consequence of prolonged cell survival, despite a low proliferative index. The affected lymphocytes are of B-cell lineage in 95% of cases, and the remaining cases involve T lymphocytes, likely representing a distinct disorder.

[1]  D. Mukhopadhyay,et al.  The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy. , 2011, Blood.

[2]  Valeria Grieco,et al.  Complement Activation Determines the Therapeutic Activity of Rituximab In Vivo 1 , 2003, The Journal of Immunology.

[3]  Xiao-Jie Yan,et al.  B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. , 2002, Blood.

[4]  R. Hendriks,et al.  The B Cell Antigen Receptor Controls Integrin Activity through Btk and PLCγ2 , 2003, The Journal of experimental medicine.

[5]  G. Packham,et al.  B-cell receptor signaling in chronic lymphocytic leukemia. , 2011, Blood.

[6]  M. Cragg,et al.  CD20 as a target for therapeutic type I and II monoclonal antibodies. , 2010, Seminars in hematology.

[7]  K. Haas,et al.  The Innate Mononuclear Phagocyte Network Depletes B Lymphocytes through Fc Receptor–dependent Mechanisms during Anti-CD20 Antibody Immunotherapy , 2004, The Journal of experimental medicine.

[8]  Annelieke Jaspers,et al.  Differential Noxa/Mcl-1 balance in peripheral versus lymph node chronic lymphocytic leukemia cells correlates with survival capacity. , 2007, Blood.

[9]  Gabriel Pons,et al.  Bcl-2 inhibitors induce apoptosis in chronic lymphocytic leukemia cells. , 2006, Experimental hematology.

[10]  Ronald Levy,et al.  Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. , 2010, Blood.

[11]  A. Kohlmann,et al.  Protein Kinase C-β-Dependent Activation of NF-κB in Stromal Cells Is Indispensable for the Survival of Chronic Lymphocytic Leukemia B Cells In Vivo , 2013, Cancer cell.

[12]  H. Urlaub,et al.  The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85 , 2011, The EMBO journal.

[13]  B. Vanhaesebroeck,et al.  Oncogenic transformation induced by the p110β, -γ, and -δ isoforms of class I phosphoinositide 3-kinase , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[14]  A. Kretz-Rommel,et al.  Rationale for anti-CD200 immunotherapy in B-CLL and other hematologic malignancies: new concepts in blocking immune suppression , 2008, Expert opinion on biological therapy.

[15]  Francisco Cervantes,et al.  Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. , 2003, The New England journal of medicine.

[16]  Michael Hallek,et al.  Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. , 2008, Blood.

[17]  Juliane C. Dohm,et al.  Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia , 2011, Nature.

[18]  J. Byrd,et al.  Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  J. Drachman,et al.  A phase I study of dacetuzumab (SGN-40, a humanized anti-CD40 monoclonal antibody) in patients with chronic lymphocytic leukemia , 2010, Leukemia & lymphoma.

[20]  Jeffrey A Jones,et al.  Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. , 2011, Blood.

[21]  E. Vigorito,et al.  A Crucial Role for the p110δ Subunit of Phosphatidylinositol 3-Kinase in B Cell Development and Activation , 2002, The Journal of experimental medicine.

[22]  R. Rickert,et al.  Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases , 2008, The Journal of experimental medicine.

[23]  H. Pelicano,et al.  Antibody-induced nonapoptotic cell death in human lymphoma and leukemia cells is mediated through a novel reactive oxygen species-dependent pathway. , 2012, Blood.

[24]  J. Byrd,et al.  Phase I study of the anti-CD40 humanized monoclonal antibody lucatumumab (HCD122) in relapsed chronic lymphocytic leukemia , 2012, Leukemia & lymphoma.

[25]  Z. Estrov,et al.  Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. , 2009, Blood.

[26]  Jan Delabie,et al.  Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma , 2010, Nature.

[27]  Kostas Stamatopoulos,et al.  Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies. , 2012, Blood.

[28]  N. Chiorazzi,et al.  Many chronic lymphocytic leukemia antibodies recognize apoptotic cells with exposed nonmuscle myosin heavy chain IIA: implications for patient outcome and cell of origin. , 2010, Blood.

[29]  W. Wierda,et al.  Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. , 2011, Blood.

[30]  R. Rosenquist,et al.  A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies. , 2008, Blood.

[31]  K. Stamatopoulos,et al.  Targeting the LYN/HS1 signaling axis in chronic lymphocytic leukemia. , 2012, Blood.

[32]  Steven L. Allen,et al.  Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia , 2004, The Journal of experimental medicine.

[33]  Brian J. Smith,et al.  Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab. , 2005, Blood.

[34]  G. Juliusson,et al.  Chronic lymphocytic leukemias utilizing the VH3-21 gene display highly restricted Vlambda2-14 gene use and homologous CDR3s: implicating recognition of a common antigen epitope. , 2003, Blood.

[35]  D. Green,et al.  Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. , 2006, Molecular cell.

[36]  R. DePinho,et al.  PI3 Kinase Signals BCR-Dependent Mature B Cell Survival , 2009, Cell.

[37]  S. Stilgenbauer,et al.  Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. , 2009, Blood.

[38]  T. Kurosaki,et al.  Phospholipase C-γ2 and Vav cooperate within signaling microclusters to propagate B cell spreading in response to membrane-bound antigen , 2008, The Journal of Experimental Medicine.

[39]  Hirokazu Tamamura,et al.  Small peptide inhibitors of the CXCR4 chemokine receptor (CD184) antagonize the activation, migration, and antiapoptotic responses of CXCL12 in chronic lymphocytic leukemia B cells. , 2005, Blood.

[40]  N. Chiorazzi.  Implications of new prognostic markers in chronic lymphocytic leukemia. , 2012, Hematology. American Society of Hematology. Education Program.

[41]  W. Khan,et al.  Bruton's Tyrosine Kinase Is Required for Activation of Iκb Kinase and Nuclear Factor κb in Response to B Cell Receptor Engagement , 2000, The Journal of experimental medicine.

[42]  Jeffrey A Jones,et al.  Phosphatidylinositol 3-kinase- inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals , 2010 .

[43]  Lisa S. Chen,et al.  Pim kinase inhibitor, SGI-1776, induces apoptosis in chronic lymphocytic leukemia cells. , 2008, Blood.

[44]  A. Rosenwald,et al.  IgVH Mutational Status and Clonality Analysis of Richter's Transformation: Diffuse Large B-cell Lymphoma and Hodgkin Lymphoma in Association With B-cell Chronic Lymphocytic Leukemia (B-CLL) Represent 2 Different Pathways of Disease Evolution , 2007, The American journal of surgical pathology.

[45]  C. Klein,et al.  Preclinical Studies on the Mechanism of Action and the Anti-Lymphoma Activity of the Novel Anti-CD20 Antibody GA101 , 2011, Molecular Cancer Therapeutics.

[46]  A. Osterborg,et al.  Variability in B-cell antigen expression: implications for the treatment of B-cell lymphomas and leukemias with monoclonal antibodies. , 2001, The hematology journal : the official journal of the European Haematology Association.

[47]  Y. Refaeli,et al.  Mouse models of non-Hodgkin lymphoma reveal Syk as an important therapeutic target. , 2009, Blood.

[48]  J. Byrd,et al.  A Phase I Dose-Finding Trial of Recombinant Interleukin-21 and Rituximab in Relapsed and Refractory Low Grade B-cell Lymphoproliferative Disorders , 2012, Clinical Cancer Research.

[49]  A Benner,et al.  Genomic aberrations and survival in chronic lymphocytic leukemia. , 2000, The New England journal of medicine.

[50]  R. Dalla‐Favera,et al.  Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. , 2013, Blood.

[51]  M. Minden,et al.  Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling , 2012, Nature.

[52]  S. Rhee,et al.  Mechanism of B-Cell Receptor-Induced Phosphorylation and Activation of Phospholipase C-γ2 , 2004, Molecular and Cellular Biology.

[53]  L. Rassenti,et al.  Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors. , 1998, The Journal of clinical investigation.

[54]  C. Klein,et al.  Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity. , 2010, Blood.

[55]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[56]  R. Foà,et al.  Molecular pathogenesis of chronic lymphocytic leukemia. , 2012, The Journal of clinical investigation.

[57]  J. Leonard,et al.  Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin's lymphoma: phase I/II results. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[58]  M. Hallek,et al.  Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. , 1996, Leukemia & lymphoma.

[59]  F. Martín-Saavedra,et al.  A sustained activation of PI3K/NF-κB pathway is critical for the survival of chronic lymphocytic leukemia B cells , 2004, Leukemia.

[60]  M. Czuczman,et al.  Ofatumumab demonstrates activity against rituximab‐sensitive and ‐resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B‐cell lymphoma , 2012, British journal of haematology.

[61]  A. Berrebi,et al.  Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial , 2010, The Lancet.

[62]  W. Khan,et al.  Phospholipase C-γ2 Couples Bruton's Tyrosine Kinase to the NF-κB Signaling Pathway in B Lymphocytes* , 2001, The Journal of Biological Chemistry.

[63]  V. Quesada,et al.  Chronic lymphocytic leukemia with SF3B1 mutation. , 2012, The New England journal of medicine.

[64]  A. LaCasce,et al.  Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia , 2011, Clinical Cancer Research.

[65]  T. Illidge,et al.  Radiation Therapy with Tositumomab (B1) Anti-CD20 Monoclonal Antibody Initiates Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase–Dependent Cell Death that Overcomes Resistance to Apoptosis , 2008, Clinical Cancer Research.

[66]  Ya-jun Guo,et al.  Characterization of a rituximab variant with potent antitumor activity against rituximab-resistant B-cell lymphoma. , 2009, Blood.

[67]  M. Dyer,et al.  Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia , 2010 .

[68]  B. Cubelos,et al.  Essential function for the GTPase TC21 in homeostatic antigen receptor signaling , 2009, Nature Immunology.

[69]  L. Pleyer,et al.  Molecular and cellular mechanisms of CLL: novel therapeutic approaches , 2009, Nature Reviews Clinical Oncology.

[70]  M. Cragg,et al.  Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. , 2003, Blood.

[71]  D. Oscier,et al.  Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia. , 2003, Blood.

[72]  C. Geest,et al.  The clinically active BTK inhibitor PCI-32765 targets B-cell receptor- and chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. , 2012, Blood.

[73]  Göran Roos,et al.  Subsets with restricted immunoglobulin gene rearrangement features indicate a role for antigen selection in the development of chronic lymphocytic leukemia. , 2004, Blood.

[74]  I Royston,et al.  IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. , 1997, Blood.

[75]  Richard Sherry,et al.  The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. , 2011, Blood.

[76]  M. Hallek,et al.  Prognostic factors in chronic lymphocytic leukemia—what do we need to know? , 2011, Nature Reviews Clinical Oncology.

[77]  Lisa L. Smith,et al.  Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. , 2004, Blood.

[78]  P. Parren,et al.  The Biological Activity of Human CD20 Monoclonal Antibodies Is Linked to Unique Epitopes on CD201 , 2006, The Journal of Immunology.

[79]  Jeffrey A Jones,et al.  Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[80]  R. Rickert,et al.  Emergence of the PI3-kinase pathway as a central modulator of normal and aberrant B cell differentiation. , 2011, Current opinion in immunology.

[81]  R. Gascoyne,et al.  A phase 1 study of obinutuzumab induction followed by 2 years of maintenance in patients with relapsed CD20-positive B-cell malignancies. , 2012, Blood.

[82]  C. I. Smith,et al.  Redistribution of Bruton's tyrosine kinase by activation of phosphatidylinositol 3‐kinase and Rho‐family GTPases , 2000, European journal of immunology.

[83]  M. Jeddi-Tehrani,et al.  Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells , 2012, Leukemia.

[84]  A. Sepulveda,et al.  Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ. , 2010, Gastroenterology.

[85]  J. Gribben,et al.  5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[86]  F. Ravandi,et al.  Selective, novel spleen tyrosine kinase (Syk) inhibitors suppress chronic lymphocytic leukemia B-cell activation and migration , 2012, Leukemia.

[87]  Tony Pawson,et al.  Syk tyrosine kinase required for mouse viability and B-cell development , 1995, Nature.

[88]  N. Chiorazzi,et al.  The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. , 2012, Blood.

[89]  M. Czuczman,et al.  Properties and structure-function relationships of veltuzumab (hA20), a humanized anti-CD20 monoclonal antibody. , 2009, Blood.

[90]  T. Robak,et al.  Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[91]  T. Kipps,et al.  Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. , 2011, Blood.

[92]  S. Akira,et al.  Augmented TLR9-induced Btk activation in PIR-B–deficient B-1 cells provokes excessive autoantibody production and autoimmunity , 2009, The Journal of experimental medicine.

[93]  B. Coiffier,et al.  Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study. , 2008, Blood.

[94]  Emili Montserrat,et al.  ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. , 2003, The New England journal of medicine.

[95]  Nikolaos Laoutaris,et al.  Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: Pathogenetic implications and clinical correlations. , 2006, Blood.

[96]  Victor L. J. Tybulewicz,et al.  The SYK tyrosine kinase: a crucial player in diverse biological functions , 2010, Nature Reviews Immunology.

[97]  L. Ginaldi,et al.  Levels of expression of CD52 in normal and leukemic B and T cells: correlation with in vivo therapeutic responses to Campath-1H. , 1998, Leukemia research.

[98]  Douglas H. Thamm,et al.  The Bruton tyrosine kinase inhibitor PCI-32765 blocks B-cell activation and is efficacious in models of autoimmune disease and B-cell malignancy , 2010, Proceedings of the National Academy of Sciences.

[99]  J. Gribben,et al.  T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. , 2013, Blood.

[100]  B. Cheson,et al.  Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia. , 2009, Blood.

[101]  K. Okkenhaug,et al.  The PI3K Isoforms p110α and p110δ Are Essential for Pre–B Cell Receptor Signaling and B Cell Development , 2010, Science Signaling.

[102]  D. Rossi,et al.  CD38/CD31, the CCL3 and CCL4 chemokines, and CD49d/vascular cell adhesion molecule-1 are interchained by sequential events sustaining chronic lymphocytic leukemia cell survival. , 2009, Cancer research.

[103]  M. Caligiuri,et al.  IL-21 mediates apoptosis through up-regulation of the BH3 family member BIM and enhances both direct and antibody-dependent cellular cytotoxicity in primary chronic lymphocytic leukemia cells in vitro. , 2008, Blood.

[104]  C. Le Roy,et al.  AMD3100 disrupts the cross-talk between chronic lymphocytic leukemia cells and a mesenchymal stromal or nurse-like cell-based microenvironment: pre-clinical evidence for its association with chronic lymphocytic leukemia treatments , 2012, Haematologica.

[105]  M. Keating,et al.  The phosphoinositide 3'-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. , 2011, Blood.

[106]  G. Leone,et al.  Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B cells , 2009, Leukemia.

[107]  C. Peschel,et al.  Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL , 2006, Leukemia.

[108]  B. Coiffier,et al.  Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[109]  M. Andreeff,et al.  Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[110]  Thomas M. Schmitt,et al.  The B-cell tumor-associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor. , 2010, Blood.

[111]  M. Dyer,et al.  Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[112]  W. Fridman,et al.  Long-lasting antitumor protection by anti-CD20 antibody through cellular immune response. , 2010, Blood.

[113]  K. Rajewsky,et al.  In Vivo Ablation of Surface Immunoglobulin on Mature B Cells by Inducible Gene Targeting Results in Rapid Cell Death , 1997, Cell.

[114]  R. Ulrich,et al.  CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. , 2011, Blood.