Abstract
There have been remarkable advances in our understanding of the biology and therapeutics of chronic lymphocytic leukemia. B cell receptor signaling and micro-environment in CLL biology have been the most modern areas of research. In CLL therapeutics, we have come a long way from alkylating agents to chemo-immunotherapy. Despite this there remain significant lacunae in the disease biology that has hindered our quest to achieve the ultimate in CLL: Cure. This review aims to summarize the past, present and future in the biology and treatment of CLL.
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References
Caligaris Cappio F (2009) Chronic lymphocytic leukemia: cinderella is becoming a star. Mol Med 15:67–69
Klein U, Dalla Favera R (2010) New insights into the pathogenesis of chronic lymphocytic leukemia. Semin Cancer Biol 20:377–383
Scarfò L, Dagklis A, Scielzo C, Fazi C, Ghia P (2010) CLL like monoclonal B-cell lymphocytosis: are we all bound to have it? Cancer Biol 20:384–390
Kem W, Bacher U, Haferlach C, Dicker F et al (2012) Monoclonal B-cell lymphocytosis is closely related to chronic lymphocytic leukemia and may be better classified as early stage CLL. Br J Haematol 157:86–96
Chiorazzi N, Rai KR, Ferrarini M (2005) Chronic lymphocytic leukemia. N Engl J Med 352:804–815
Burger JA, Ghia P, Rosenwald A, Caligaris-Cappio F (2009) The microenvironment in mature B-cell malignancies: a target for new treatment strategies. Blood 114:3367–3375
Packham G, Stevenson S (2010) The role of B-cell receptor in the pathogenesis of chronic lymphocytic leukemia. Semin Cancer Biol 20:391–399
Pederson IM, Reed JC (2004) Microenvironmental interactions and survival of CLL B-cells. Leuk Lymphoma 45:2365–2372
Herishanu Y, Perez-Galan P, Liu D et al (2011) The lymph-node microenvironment promotes B-cell receptor signaling, NF-kB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood 117:563–574
Furman RR (2010) Prognostic markers and stratification of chronic lymphocytic leukemia. Hematology 2010:77–81
Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS (1975) Clinical staging of chronic lymphocytic leukemia. Blood 46:219–234
Binet JL, Auquier A, Dighiero G et al (1981) A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48:198–206
Hodgson K, Ferrer G, Montserrat E, Moreno C (2011) Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica 96:752–761
Molica S, Alberti A (1987) Prognostic value of lymphocyte doubling time in CLL. Cancer 60:2712–2716
Gentile M, Cutrona G, Neri A, Molica S, Ferrarini M, Morabito F (2009) Predictive value of beta2-microglobulin (beta2-m) levels in chronic lymphocytic leukemia since Binet A stages. Haematologica 94:887–888
Döhner H, Stilgenbauer S, Benner A et al (2000) Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343:1910–1916
Oscier DG, Gardiner AC, Mould SJ et al (2002) Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 100:1177–1184
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK (1999) Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848–1854
Orchard JA, Ibbotson RE, Davis Z et al (2004) ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363:105–111
Crespo M, Bosch F, Villamor N et al (2003) ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348:1764–1775
Varma S, Lad D, Varma N, Sachdeva MUS, Bose P, Malhotra P (2011) Do regulatory T cells have a role in disease progression and autoimmune cytopenias of chronic lymphocytic leukemia? (Abstract). Blood 118:3864
Hallek M, Cheson BD, Catovsky D et al (2008) Guidelines for the diagnosis of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute Working Group 1996 guidelines. Blood 111:5446–5456
Altman SJ, Haut A, Cartwright GE, Wintrobe MM (1956) Early experience with p-(N,N-D1-2-chloroethyl) aminophenylbutyric acid (CB1348), a new chemotherapeutic agent effective in the treatment of chronic lymphocytic leukemia. Cancer 9:512–517
No authors cited (1999) Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists’ Collaborative Group. J Natl Cancer Inst 91:861–868
Knauf WU, Lissichkov T, Aldaoud A et al (2009) Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:4378–4384
Rai KR, Peterson BL, Appelbaum FR et al (2000) Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750–1757
Rai KR, Hollweg A (2011) Fludarabine versus chlorambucil: is the debate over? Clin Lymphoma Myeloma Leuk 11:S7–S9
Eichhorst BF, Busch R, Stilgenbauer S et al (2009) First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114:3382–3391
Eichhorst BF, Busch R, Hopfinger G et al (2006) German CLL Study Group. Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107:885–891
Richards S, Steurer M, for the (CLLTCG) CLL Trialists Collaborative Group, UK (2012) Systematic review of purine analogue treatment for chronic lymphocytic leukemia: lessons for future trials. Haematologica 97:428–3696
McLaughlin P, Grillo-López AJ, Link BK et al (1998) Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825–2833
Itälä M, Geisler CH, Kimby E et al (2002) Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study. Eur J Haematol 69:129–134
Hainsworth JD, Litchy S, Barton JH et al (2003) Minnie Pearl Cancer Research Network. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21:1746–1751
Osterborg A, Dyer MJ, Bunjes D et al (1997) Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia. J Clin Oncol 15:1567–1574
Rai KR, Freter CE, Mercier RJ et al (2002) Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine. J Clin Oncol 20:3891–3897
Osterborg A, Mellstedt H, Keating M (2002) Clinical effects of alemtuzumab (Campath-1H) in B-cell chronic lymphocytic leukemia. Med Oncol 19:S21–S26
Lundin J, Kimby E, Björkholm M et al (2002) Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100:768–773
Skoetz N, Bauer K, Elter T et al (2012) Alemtuzumab for patients with chronic lymphocytic leukaemia. Cochrane Database Syst Rev 2:CD008078
Byrd JC, Peterson BL, Morrison VA et al (2003) Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6–14
Hallek M, Fischer K, Fingerle-Rowson G et al (2010) International Group of Investigators; German Chronic Lymphocytic Leukaemia Study Group. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomized, open-label, phase 3 trial. Lancet 376:1164–1174
Fischer K, Cramer P, Busch R et al (2011) Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 29:3559–3566
Tam CS, Keating MJ (2010) Chemoimmunotherapy of chronic lymphocytic leukemia. Nat Rev Clin Oncol 7:521–532
Schetelig J, Thiede C, Bornhauser M et al (2003) Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 21:2747–2753
Malhotra P, Hogan WJ, Litzow MR et al (2008) Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years. Leuk Lymphoma 49:1724–1730
Sorror ML, Storer BE, Sandmaier BM et al (2008) Five-year follow- up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 26:4912–4920
Brown JR, Stevenson K, Kim HT et al (2008) Comparative outcome of myeloablative and reduced intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia. Blood 112:972
Dreger P, Corradini P, Kimby E et al (2007) Chronic leukemia working party of the EBMT. Indications for Allogeneic stem cell transplantation in CLL: the EBMT transplant consensus. Leukemia 21:12–17
Sutton L, Chevret S, Tournilhac O et al (2011) Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and Groupe Français d’étude de la Leucémie Lymphoïde Chronique (GFLLC). Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 117:6109–6119
Del Giudice I, Mauro FR, Foà R (2011) Chronic lymphocytic leukemia in less fit patients “slow-go’’. Leuk Lymphoma 52:2207–2216
Zent CS, Kay NE (2011) Management of patients with chronic lymphocytic leukemia with a high risk of adverse outcome: the Mayo Clinic approach. Leuk Lymphoma 52:1425–1434
Hallek M, Fischer K, Fingerle-Rowson G et al (2010) Addition of Rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia: a randomized, open label, phase 3 trial. Lancet 376:1164–1174
Fischer K, Cramer P, Stilgenbauer S et al (2009) Bendamustine combined with rituximab (BR) in first line therapy of advanced CLL: a multicenter phase II trial of the German CLL Study group (GCLLSG) (Abstract). Blood 114:89
Woyach JA, Ruppert AS, Heerema NA et al (2011) Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 29:1349–1355
Knauf WU, Lissichkov T, Aldaoud A et al (2009) Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. Blood 114:3382–3391
Foon KA, Boyiadzis M, Land SR et al (2009) Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:498–503
Hillmen P, Gribben JG, Follows GA et al (2010) Rituximab plus chlorambucil in patients with CD20-positive B-cell chronic lymphocytic leukemia (CLL): final response analysis of an open-label phase II study (Abstract). Blood 116:697
Pitini V, Arrigo C, Naro C et al (2008) Subcutaneous low-dose alemtuzumab as first linetherapy for elderly CLL patients with deletion of 17p. J Clin Oncol 26:384s
Riches JC, Ramsay AG, Gribben JG (2010) T-cell function in chronic lymphocytic leukaemia. Semin Cancer Biol 20:431–438
Wendtner C, Hillmen P, Mahadevan D et al (2012) Final results of the phase I study of lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia (CLL-001 Study). Leuk Lymphoma 53:417–423
Wierda WG, Kipps TJ, Dürig J et al (2011) Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 117:6450–6458
Morschhauser F, Cartron G, Lamy T et al (2009) Phase I study of RO5072759 (GA101) in relapsed/refractory CLL (Abstract). Blood 114:364
Furmann RR, Byrd JC, Brown JR et al (2010) CAL-101, an isoform selective inhibitor of phosphatidylinositol 3-kinase P110δ, demonstrates clinical activity and pharmacodynamic effects in patients with relapsed or refractory CLL (Abstract). Blood 116:31
Burger JA, O-Brien S, Fowler N et al (2010) The Brutons tyrosine kinase inhibitor, PCI-32765, is well tolerated and demonstrates promising clinical activity in CLL and SLL: an update on ongoing phase 1 studies (Abstract). Blood 116:32
Lanasa MC, Andritsos L, Brown JR et al (2010) Interim analysis of EFC6663, a multicenter phase 2 study of Alvocidib (Flavopiridol), demonstrates clinical responses among patients with Fludarabine refractory CLL (Abstract). Blood 116:32
Badoux XC, Keating MJ, Wang X et al (2011) Fludarabine, cyclophosphamide and rituximab chemoimmunotherapy is highly effective for relapsed patients with CLL. Blood 117:3016–3024
Stigenbauer S, Zenz T, Winkler D et al (2009) Subcutaneous alemtuzumab in fludarabine refractory chronic lymphocytic leukemia: clinical results and prognostic marker analysis from the CLL2H study of the German CLL study group. J Clin Oncol 27:3994–4001
Ferrajoli A, Lee BN, Sclette EJ et al (2008) Lenalidomide induces complete and partial remissions in with relapsed and refractory CLL. Blood 111:5291–5297
Stilgenbauer S, Cymbalista F, Leblond V et al (2010) Subcutaneous Alemtuzumab combined with oral Dexamethasone, followed by Alemtuzumab maintenance or Allo-SCT in CLL with 17p or refractory to fludarabine: interim analysis of the CLL 20 trial of the GCLLSG and FCCLL/MW (Abstract). Blood 116:920
Castro JE, Sandoal-Sus JD, Bole J, Rassenti L, Kipps TJ (2008) Rituximab in combination with high dose methylprednisolone for the treatment of fludarabine refractory high risk chronic lymphocytic leukemia. Leukemia 22:2048–2053
Moreton P, Kennedy B, Lucas G et al (2005) Eradication of minimal residual disease in B-cell CLL after Alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23:2971–2979
Wendtner CM, Ritgen M, Schweighofer CD et al (2004) Consolidation with alemtuzumab in patients with CLL in first remission: experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL study group (GCLLSG). Leukemia 18:1093–1101
Porter DL, Levine BL, Kalos M, Bagg A, June CH (2011) Chimeric antigen receptor: modified T-cells in chronic lymphocytic leukemia. N Engl J Med 365:725–733
Sadelain M, Brentjens R, Riviere (2009) The promise and pitfalls of chimeric antigen receptors. Curr Opin Immunol 21:215–223
June Ch, Blazar BR, Riley JL (2009) Engineering lymphocyte subsets: tools, trials and tribulations. Nat Rev Immunol 9:704–716
Lesterhuis WJ, Haanen JB, Punt CJ (2011) Cancer immunotherapy: revisited. Nat Rev Drug Dis 10:591–600
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Lad, D.P., Malhotra, P. & Varma, S. Chronic Lymphocytic Leukemia: Inception to Cure: Are We There?. Indian J Hematol Blood Transfus 29, 1–10 (2013). https://doi.org/10.1007/s12288-012-0192-5
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DOI: https://doi.org/10.1007/s12288-012-0192-5