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Chronic Lymphocytic Leukemia: An Update on Biology and Treatment

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Abstract

Combination chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has emerged as the current standard of care in the treatment of chronic lymphocytic leukemia (CLL). Despite very high response rates, this treatment is too toxic for many patients, and it remains unclear as how to manage patients who do not respond to these agents or who relapse early after treatment. An increase in our understanding of the biology of CLL has led to the development of a wide range of therapies aimed at specific defects in this disease. B-cell receptor signaling is aberrantly increased in CLL, and so many of these drugs target key steps in these pathways. Antitumor immunity is also impaired, and a number of strategies are being developed to repair this acquired immune dysfunction. This review highlights some of the emerging agents and describes the biological rationale for their use in CLL.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. •• Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164–74. This phase 3 trial demonstrates the survival advantage of the addition of rituximab to fludarabine and cyclophosphamide, and underpins the current standard of care in CLL.

    Article  PubMed  CAS  Google Scholar 

  2. Eichhorst BF, Busch R, Stilgenbauer S, et al. First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood. 2009;114:3382–91.

    Article  PubMed  CAS  Google Scholar 

  3. National Cancer Institute: Surveillance Epidemiology and End Results, SEER Stat Fact Sheets: Chronic Lymphocytic Leukemia. Available at http://seer.cancer.gov/statfacts/html/clyl.html. Accessed March 2011.

  4. Hamblin TJ, Davis Z, Gardiner A, et al. Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94:1848–54.

    PubMed  CAS  Google Scholar 

  5. Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101:4944–51.

    Article  PubMed  CAS  Google Scholar 

  6. Niiro H, Clark EA. Regulation of B-cell fate by antigen-receptor signals. Nat Rev Immunol. 2002;2:945–56.

    Article  PubMed  CAS  Google Scholar 

  7. Rosen A, Murray F, Evaldsson C, et al. Antigens in chronic lymphocytic leukemia–implications for cell origin and leukemogenesis. Semin Cancer Biol. 2010;20:400–9.

    Article  PubMed  CAS  Google Scholar 

  8. Efremov DG, Gobessi S, Longo PG. Signaling pathways activated by antigen-receptor engagement in chronic lymphocytic leukemia B-cells. Autoimmun Rev. 2007;7:102–8.

    Article  PubMed  CAS  Google Scholar 

  9. Pepper C, Lin TT, Pratt G, et al. Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood. 2008;112:3807–17.

    Article  PubMed  CAS  Google Scholar 

  10. Contri A, Brunati AM, Trentin L, et al. Chronic lymphocytic leukemia B-cells contain anomalous Lyn tyrosine kinase, a putative contribution to defective apoptosis. J Clin Invest. 2005;115:369–78.

    PubMed  CAS  Google Scholar 

  11. Amrein L, Hernandez TA, Ferrario C, et al. Dasatinib sensitizes primary chronic lymphocytic leukaemia lymphocytes to chlorambucil and fludarabine in vitro. Br J Haematol. 2008;143:698–706.

    Article  PubMed  CAS  Google Scholar 

  12. Amrein PC, Attar EC, Takvorian RW, et al. Phase II Study of Dasatinib in Relapsed or Refractory Chronic Lymphocytic Leukemia. Clin Cancer Res. 2011.

  13. Gobessi S, Laurenti L, Longo PG, et al. Inhibition of constitutive and BCR-induced Syk activation downregulates Mcl-1 and induces apoptosis in chronic lymphocytic leukemia B-cells. Leukemia. 2009;23:686–97.

    Article  PubMed  CAS  Google Scholar 

  14. Suljagic M, Longo PG, Bennardo S, et al. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Emu- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood. 2010;116:4894–905.

    Article  PubMed  CAS  Google Scholar 

  15. Friedberg JW, Sharman J, Sweetenham J, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578–85.

    Article  PubMed  CAS  Google Scholar 

  16. Herman SEM, Gordon AL, Mahoney E, et al. The Kinase Inhibitor, PCI-32765, Demonstrates Activity in Chronic Lymphcytic Leukemia Cells Independent of Microenvironmental Survival Signals. Blood. 2010; 116:Abstract 1385.

  17. Burger J, O’Brien S, Fowler N, et al. The Bruton’s Tyrosine Kinase Inhibitor, PCI-32765, Is Well Tolerated and Demonstrates Promising Clinical Activity In Chronic Lymphocytic Leukemia (CLL) and Small Lymphcytic Lymphoma (SLL): An Update on Ongoing Phase 1 Studies. Blood 2010; 116:Abstract 57.

  18. Cuni S, Perez-Aciego P, Perez-Chacon G, et al. A sustained activation of PI3K/NF-kappaB pathway is critical for the survival of chronic lymphocytic leukemia B-cells. Leukemia. 2004;18:1391–400.

    Article  PubMed  CAS  Google Scholar 

  19. Herman SE, Gordon AL, Wagner AJ, et al.: Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood, 116:2078–88

  20. Furman RR, Byrd JC, Brown JR, et al. CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110δ, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. Blood. 2010; 116:Abstract 55.

  21. Flinn IW, Schreeder MT, Wagner-Johnson ND, et al. A Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110d, In Combination with Rituximab and/or Bendamustine In Patients with Relapsed or Refractory B-cell Malignancies. Blood. 2010; 116:Abstract 2832.

  22. Aleskog A, Norberg M, Nygren P, et al. Rapamycin shows anticancer activity in primary chronic lymphocytic leukemia cells in vitro, as single agent and in drug combination. Leuk Lymphoma. 2008;49:2333–43.

    Article  PubMed  CAS  Google Scholar 

  23. Decker T, Sandherr M, Goetze K, et al. A pilot trial of the mTOR (mammalian target of rapamycin) inhibitor RAD001 in patients with advanced B-CLL. Ann Hematol. 2009;88:221–7.

    Article  PubMed  CAS  Google Scholar 

  24. • Zent CS, LaPlant BR, Johnston PB, et al. The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation. Cancer. 2010;116:2201–7. This trial illustrates the potential benefit of agents that mobilize CLL cells into the peripheral blood.

    PubMed  Google Scholar 

  25. Gottardi D, Alfarano A, De Leo AM, et al. In leukaemic CD5+ B-cells the expression of BCL-2 gene family is shifted toward protection from apoptosis. Br J Haematol. 1996;94:612–8.

    Article  PubMed  CAS  Google Scholar 

  26. Longo PG, Laurenti L, Gobessi S, et al. The Akt/Mcl-1 pathway plays a prominent role in mediating antiapoptotic signals downstream of the B-cell receptor in chronic lymphocytic leukemia B-cells. Blood. 2008;111:846–55.

    Article  PubMed  CAS  Google Scholar 

  27. O’Brien S, Moore JO, Boyd TE, et al. Randomized phase III trial of fludarabine plus cyclophosphamide with or without oblimersen sodium (Bcl-2 antisense) in patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2007;25:1114–20.

    Article  PubMed  Google Scholar 

  28. •• O’Brien S, Moore JO, Boyd TE, 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. J Clin Oncol. 2009;27:5208–12. This study demonstrates the additional benefit of the bcl-2 inhibitor, oblimersen, when combined with fludarabine and cyclophosphamide.

    Article  PubMed  Google Scholar 

  29. Roberts AW, Seymour JF, Brown JR, et al. An Ongoing Phase1/2a Study of ABT-263; Pharmokinetics (PK), Safety and Anti-Tumor Activity in Patients (pts) with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). Blood. 2009; 114:Abstract 883.

  30. Kipps TJ, Wierda W, Jones J, et al. Navitoclax (ABT-263) Plus Fludarabine/Cyclophosphamide/Rituximab (FCR) or Bendamustine/Rituximab (BR): A Phase 1 Study In Patients with Relapsed/Refractory Chronic Lymphocytic Leukaemia. Blood. 2010; 116:Abstract 2455.

  31. Allen JC, Talab F, Zuzel M, et al. c-Abl regulates Mcl-1 gene expression in chronic lymphocytic leukemia cells. Blood. 2011;117:2414–22.

    Article  PubMed  CAS  Google Scholar 

  32. Dazzi F, D'Andrea E, Biasi G, et al. Failure of B-cells of chronic lymphocytic leukemia in presenting soluble and alloantigens. Clin Immunol Immunopathol. 1995;75:26–32.

    Article  PubMed  CAS  Google Scholar 

  33. Gorgun G, Holderried TA, Zahrieh D, et al. Chronic lymphocytic leukemia cells induce changes in gene expression of CD4 and CD8 T-cells. J Clin Invest. 2005;115:1797–805.

    Article  PubMed  Google Scholar 

  34. Cantwell M, Hua T, Pappas J, et al. Acquired CD40-ligand deficiency in chronic lymphocytic leukemia. Nat Med. 1997;3:984–9.

    Article  PubMed  CAS  Google Scholar 

  35. Ranheim EA, Kipps TJ. Activated T-cells induce expression of B7/BB1 on normal or leukemic B-cells through a CD40-dependent signal. J Exp Med. 1993;177:925–35.

    Article  PubMed  CAS  Google Scholar 

  36. Wierda WG, Cantwell MJ, Woods SJ, et al. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood. 2000;96:2917–24.

    PubMed  CAS  Google Scholar 

  37. Wierda WG, Castro JE, Aguillon R, et al. A phase I study of immune gene therapy for patients with CLL using a membrane-stable, humanized CD154. Leukemia. 2010;24:1893–900.

    Article  PubMed  CAS  Google Scholar 

  38. Chu P, Wierda WG, Kipps TJ. CD40 activation does not protect chronic lymphocytic leukemia B-cells from apoptosis induced by cytotoxic T lymphocytes. Blood. 2000;95:3853–8.

    PubMed  CAS  Google Scholar 

  39. Jak M, van Bochove GG, van Lier RA, et al. CD40 stimulation sensitizes CLL cells to rituximab-induced cell death. Leukemia. 2011.

  40. Ramsay AG, Johnson AJ, Lee AM, et al. Chronic lymphocytic leukemia T-cells show impaired immunological synapse formation that can be reversed with an immunomodulating drug. J Clin Invest. 2008;118:2427–37.

    PubMed  CAS  Google Scholar 

  41. Xu Y, Li J, Ferguson GD, et al. Immunomodulatory drugs reorganize cytoskeleton by modulating Rho GTPases. Blood. 2009;114:338–45.

    Article  PubMed  CAS  Google Scholar 

  42. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T-cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol. 1999;163:380–6.

    PubMed  CAS  Google Scholar 

  43. LeBlanc R, Hideshima T, Catley LP, et al. Immunomodulatory drug costimulates T-cells via the B7-CD28 pathway. Blood. 2004;103:1787–90.

    Article  PubMed  CAS  Google Scholar 

  44. Lapalombella R, Andritsos L, Liu Q, et al. Lenalidomide treatment promotes CD154 expression on CLL cells and enhances production of antibodies by normal B-cells through a PI3-kinase dependent pathway. Blood. 2009;115:2619–29.

    Article  PubMed  Google Scholar 

  45. •• Chen CI, Bergsagel PL, Paul H, et al. Single-Agent Lenalidomide in the Treatment of Previously Untreated Chronic Lymphocytic Leukemia. J Clin Oncol. 2010. This study shows that single-agent lenalidomide has comparable efficacy to cytotoxic agents in the treatment of previously untreated CLL.

  46. Andritsos LA, Johnson AJ, Lozanski G, et al. Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol. 2008;26:2519–25.

    Article  PubMed  CAS  Google Scholar 

  47. Chanan-Khan A, Miller KC, Lawrence D, et al. Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer. 2010.

  48. Kochenderfer JN, Dudley ME, Stetler-Stevenson M, et al. A Phase I Clinical Trial of Treatment of B-cell Malignancies with Autologous Anti-CD19-CAR-Transduced T-cells. Blood. 2010; 116:Abstract 2865.

  49. Hudecek M, Schmitt TM, Baskar S, et al. The B-cell tumor associated antigen ROR1 can be targeted with T-cells modified to express a ROR1-specific chimeric antigen receptor. Blood. 2010; [Epub ahead of print].

  50. Giordano Attianese GM, Marin V, Hoyos V, et al. In vitro and in vivo model of a novel immunotherapy approach for chronic lymphocytic leukemia by anti-CD23 chimeric antigen receptor. Blood. 2011.

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Disclosure

J. C. Riches: none; A. G. Ramsay: none; J. G. Gribben: consultant to Celgene and honoraria from Roche, GlaxoSmithKline, and Mundipharma.

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  1. Barts Cancer Institute—A CR-UK Centre of Excellence, Queen Mary University of London, 3rd Floor John Vane Science Centre Charterhouse Square, London, UK, EC1M 6BQ

    John C. Riches, Alan G. Ramsay & John G. Gribben

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  1. John C. Riches
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Correspondence to John C. Riches.

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Riches, J.C., Ramsay, A.G. & Gribben, J.G. Chronic Lymphocytic Leukemia: An Update on Biology and Treatment. Curr Oncol Rep 13, 379–385 (2011). https://doi.org/10.1007/s11912-011-0188-6

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  • DOI: https://doi.org/10.1007/s11912-011-0188-6

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