Current Hematologic Malignancy Reports

, Volume 9, Issue 1, pp 33–43

PI3-Kinase Inhibitors in Chronic Lymphocytic Leukemia

Chronic Leukemias (S O'Brien, Section Editor)

Abstract

The phosphatidylinositol 3-kinase (PI3K) pathway is being explored as a target of inhibition for B-cell lymphoproliferative disorders, with agents specific for inhibition of the PI3K-δ subunit showing significant clinical activity in chronic lymphocytic leukemia (CLL). Idelalisib (CAL-101, GS-1101) and IPI-145 (INK-1147) are novel oral PI3K-δ inhibitors in development, with rates of objective response of 40-60 % and nodal responses exceeding 70 % in relapsed and refractory CLL. High rates of response have been seen in high-risk CLL (i.e., 17p and 11q deletions), and may allow for more effective therapy in inherently chemotherapy-resistant disease. Combination chemotherapy regimens with idelalisib have similarly demonstrated favorable tolerability and activity. Like other agents that target the B-cell receptor pathway, peripheral lymphocytosis, due to drug-induced changes in lymphocyte trafficking, is common. Noteworthy toxicities include transaminitis and pneumonia/pneumonitis. Multiple studies are evaluating PI3K-δ inhibitor combination regimens, and the rationale for these ongoing and planned studies is reviewed.

Keywords

New targets PI3K PI3K delta PI3K-δ PI3K Gamma PI3K-γ CAL-101 GS-1101 Idelalisib INK-1197 IPI-145 Chronic lymphocytic leukemia Small lymphocytic lymphoma 

Abbreviations

CLL

Chronic lymphocytic leukemia

CR

Complete response

DLT

Dose limiting toxicity

DOR

Duration of response

IB

Idelalisib + bendamustine

IBR

Idelalisib + bendamustine + rituximab

IR

Idelalisib + rituximab

IWG

International Working Group

NHL

Non-Hodgkin lymphoma

ORR

Overall response rate

OS

Overall survival

PFS

Progression-free survival

PI3K

Phosphatidylinositol 3-kinase

PR

Partial response

R/R

Relapsed and refractory

SLL

Small lymphocytic lymphoma

References

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

  1. 1.
    Tam CS, O’Brien S, Wierda W, Kantarjian H, Wen S, Do KA, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112(4):975–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Hallek M, Fischer K, Fingerle-Rowson G, Fink AM, Busch R, Mayer J, 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(9747):1164–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Keating MJ, O’Brien S, Kontoyiannis D, Plunkett W, Koller C, Beran M, et al. Results of first salvage therapy for patients refractory to a fludarabine regimen in chronic lymphocytic leukemia. Leuk Lymphoma. 2002;43(9):1755–62.PubMedCrossRefGoogle Scholar
  4. 4.
    Fischer K, Cramer P, Stilgenbauer S, Busch R, Balleisen L, Kilp J, et al. Bendamustine Combined with Rituximab (BR) in First-Line Therapy of Advanced CLL: A Multicenter Phase II Trial of the German CLL Study Group (GCLLSG). ASH Annual Meeting Abstracts. 2009;114(22):205.Google Scholar
  5. 5.
    Fischer K, Cramer P, Busch R, Stilgenbauer S, Bahlo J, Schweighofer CD, et al. 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. 2011;29(26):3559–66.PubMedCrossRefGoogle Scholar
  6. 6.
    Dennie TW, Kolesar JM. Bendamustine for the treatment of chronic lymphocytic leukemia and rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Clin Ther. 2009;31(Pt 2):2290–311.PubMedCrossRefGoogle Scholar
  7. 7.
    Kahl BS, Bartlett NL, Leonard JP, Chen L, Ganjoo K, Williams ME, et al. Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a multicenter study. Cancer. 2010;116(1):106–14.PubMedCentralPubMedGoogle Scholar
  8. 8.
    Knauf WU, Lissichkov T, Aldaoud A, Liberati A, Loscertales J, Herbrecht R, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol. 2009;27(26):4378–84.PubMedCrossRefGoogle Scholar
  9. 9.
    Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, et al. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25(35):5616–23.PubMedCrossRefGoogle Scholar
  10. 10.
    Cheson BD. Ofatumumab, a novel anti-CD20 monoclonal antibody for the treatment of B-cell malignancies. J Clin Oncol. 2010;28(21):3525–30.PubMedCrossRefGoogle Scholar
  11. 11.
    Coiffier B, Lepretre S, Pedersen LM, Gadeberg O, Fredriksen H, van Oers MH, 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. Blood. 2008;111(3):1094–100.PubMedCrossRefGoogle Scholar
  12. 12.
    Stilgenbauer S, Zenz T, Winkler D, Buhler A, Schlenk RF, Groner S, et al. Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol. 2009;27(24):3994–4001.PubMedCrossRefGoogle Scholar
  13. 13.
    Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105(11):1684–92.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Perkins JG, Flynn JM, Howard RS, Byrd JC. Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer. 2002;94(7):2033–9.PubMedCrossRefGoogle Scholar
  15. 15.
    Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJ, Bezares RF, et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet. 2007;370(9583):230–9.PubMedCrossRefGoogle Scholar
  16. 16.
    Grever MR, Lucas DM, Dewald GW, Neuberg DS, Reed JC, Kitada S, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25(7):799–804.PubMedCrossRefGoogle Scholar
  17. 17.
    Jain N, O’Brien S. Chronic lymphocytic leukemia with deletion 17p: emerging treatment options. Oncology (Williston Park). 2012;26(11):1067–70.PubMedGoogle Scholar
  18. 18.
    Stilgenbauer S, Krober A, Busch R, Eichhorst B, Kienle D, Winkler D, et al. 17p Deletion Predicts for Inferior Overall Survival after Fludarabine - Based First Line Therapy in Chronic Lymphocytic Leukemia: First Analysis of Genetics in the CLL4 Trial of the GCLLSG. ASH Annual Meeting Abstracts. 2005;106(11):715.Google Scholar
  19. 19.
    Macias-Perez IM, Flinn IW. GS-1101: a delta-specific PI3K inhibitor in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2013;8(1):22–7.PubMedCrossRefGoogle Scholar
  20. 20.
    Bunney TD, Katan M. Phosphoinositide signalling in cancer: beyond PI3K and PTEN. Nature reviews Cancer. 2010;10(5):342–52.PubMedCrossRefGoogle Scholar
  21. 21.
    Cantrell DA. Phosphoinositide 3-kinase signalling pathways. J Cell Sci. 2001;114(Pt 8):1439–45.PubMedGoogle Scholar
  22. 22.
    Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329–41.PubMedCrossRefGoogle Scholar
  23. 23.
    Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci U S A. 1997;94(9):4330–5.PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Furman RR, Byrd JC, Brown JR, Coutre SE, Benson Jr DM, Wagner-Johnston ND, et al. CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, Demonstrates Clinical Activity and Pharmacodynamic Effects In Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia. ASH Annual Meeting Abstracts. 2010;116(21):55.Google Scholar
  25. 25.
    Porter JR, editor. Development of the potent PI3K-δ,γ inhibitor IPI-145 in hematologic malignancies and inflammatory disease indications. Infinity Pharmaceuticals presentation at the 2013 American Society of Clinical Oncology Annual Meeting. Chicago, IL. 2013. http://infi.com/pdfs/IPI145_ACS2013.pdf.
  26. 26.
    Ali K, Camps M, Pearce WP, Ji H, Ruckle T, Kuehn N, et al. Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol. 2008;180(4):2538–44.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annual review of immunology. 2013;31:675–704.PubMedCrossRefGoogle Scholar
  28. 28.
    Schmid MC, Avraamides CJ, Dippold HC, Franco I, Foubert P, Ellies LG, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kgamma, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19(6):715–27.PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Webb HK, Chen H, Yu AS, Peterman S, Holes L, Lannutti B, et al. Clinical Pharmacokinetics of CAL-101, a p110{delta} Isoform-Selective PI3K Inhibitor, Following Single- and Multiple-Dose Administration In Healthy Volunteers and Patients with Hematological Malignancies. ASH Annual Meeting Abstracts. 2010;116(21):1774.Google Scholar
  30. 30.•
    Benson DM, Kahl BS, Furman RR, Brown JR, Wagner-Johnston ND, Coutre SE, et al. Final results of a phase I study of idelalisib, a selective inhibitor of PI3K{delta}, in patients with relapsed or refractory indolent non-Hodgkin lymphoma (iNHL). ASCO Meeting Abstracts. 2013;31(15 Suppl):8526. Final results of the phase I dose-escalation study of idelalisib in R/R indolent NHL, including SLL.Google Scholar
  31. 31.•
    Kahl BS, Furman RR, Flinn IW, Brown JR, Wagner-Johnston ND, Coutre SE, et al. Final report of a phase I study of idelalisib, a selective inhibitor of PI3K-delta, in patients wtih relapsed or refractory indolent non-Hodgkin lymphoma (Poster presentation: 12th International Conference on Malignant Lymphoma, Lugano, Switzerland). Hematological Oncology. 2013;31(S1):296. Final results of the phase I dose-escalation study of idelalisib in R/R indolent NHL, including SLL.Google Scholar
  32. 32.••
    Brown JR, Furman RR, Flinn I, Coutre SE, Wagner-Johnston ND, Kahl BS, et al. Final results of a phase I study of idelalisib (GSE1101) a selective inhibitor of PI3K{delta}, in patients with relapsed or refractory CLL. ASCO Meeting Abstracts. 2013;31(15 Suppl):7003. Final results of the phase I dose-escalation study of idelalisib in R/R CLL.Google Scholar
  33. 33.••
    Flinn IW, Brown JR, Byrd JC, Coutre SE, Wagner-Johnston ND, Kahl BS, et al. Final report of a phase I study of idelalisib (GS-1101), a selective inhibitor of PI3K-delta, in patients with relapsed or refractory CLL (Poster presentation: 12th International Conference on Malignant Lymphoma, Lugano, Switzerland). Hematological Oncology. 2013;31(S1):297. Final results of the phase I dose-escalation study of idelalisib in R/R CLL.Google Scholar
  34. 34.
    Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Coutre SE, Leonard JP, Furman RR, Barrientos JC, de Vos S, Flinn IW, et al. Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study. ASH Annual Meeting Abstracts. 2012;120(21):191.Google Scholar
  36. 36.
    Barrientos JC, Furman RR, Leonard J, Flinn I, Rai KR, De Vos S, et al. Update on a phase I study of the selective PI3K{delta} inhibitor idelalisib (GS-1101) in combination with rituximab and/or bendamustine in patients with relapsed or refractory CLL. ASCO Meeting Abstracts. 2013;31(15 Suppl):7017.Google Scholar
  37. 37.••
    Furman RR, Coutre SE, Flinn IW, Barrientos JC, Rai K, de Vos S, et al. Update on a phase I study of the selective PI3K-delta inhibitor idelalisib (GS-1101) in combination with rituximab, bendamustine, or bendamustine/rituximab in patients wtih relapsed or refractory chronic lymphocytic leukaemia (Poster presentation: 12th International Conference on Malignant Lymphoma, Lugano, Switzerland). Hematological Oncology. 2013;31(S1):298. Most updated results of response and PFS with idelalisib and rituximab with or without bendamustine in R/R CLL.Google Scholar
  38. 38.
    Fowler NH, de Vos S, Schreeder MT, Leonard JP, Flinn IW, Coutre S, et al. Combinations of the Phosphatidylinositol 3-Kinase-Delta (PI3K{delta}) Inhibitor Gs-1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Previously Treated, Indolent Non-Hodgkin Lymphoma: Results From a Phase I Study. ASH Annual Meeting Abstracts. 2012;120(21):3645.Google Scholar
  39. 39.
    Leonard J, Wagner-Johnston ND, Coutre SE, Flinn I, Schreeder MT, Fowler NH, et al. Tolerability and activity of combinations of the PI3K{delta} inhibitor idelalisib (GS-1101) with rituximab and/or bendamustine in patients with previously treated, indolent non-Hodgkin lymphoma (iNHL): Updated results from a phase I study. ASCO Meeting Abstracts. 2013;31(15 Suppl):8500.Google Scholar
  40. 40.••
    O’Brien SM, Lamanna N, Kipps TJ, Flinn I, Zelenetz AD, Burger JA, et al. A phase II study of the selective phosphatidylinositol 3-kinase delta (PI3K{delta}) inhibitor idelalisib (GS-1101) in combination with rituximab (R) in treatment-naive patients (pts) > =65 years with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). ASCO Meeting Abstracts. 2013;31(15 Suppl):7005. Promising activity of idelalisib in 6/6 patients with previously untreated high-risk 17p deletion CLL/SLL..Google Scholar
  41. 41.
    Furman RR, Barrientos JC, Sharman JP, De Vos S, Leonard J, Coutre SE, et al. A phase I/II study of the selective phosphatidylinositol 3-kinase-delta (PI3K{delta}) inhibitor, GS-1101 (CAL-101), with ofatumumab in patients with previously treated chronic lymphocytic leukemia (CLL). ASCO Meeting Abstracts. 2012;30(15 Suppl):6518.Google Scholar
  42. 42.
    Flinn I, Kimby E, Cotter FE, Giles FJ, Janssens A, Pulczynski EJ, et al. A phase III, randomized, controlled study evaluating the efficacy and safety of idelalisib (GS-1101) in combination with ofatumumab for previously treated chronic lymphocytic leukemia (CLL). ASCO Meeting Abstracts. 2013;31(15 Suppl), TPS7131.Google Scholar
  43. 43.
    Flinn IW, Horwitz SM, Patel M, Younes A, Porter JR, Sweeney J, et al. Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-{delta},{gamma}, in Patients with Advanced Hematologic Malignancies. ASH Annual Meeting Abstracts. 2012;120(21):3663.Google Scholar
  44. 44.
    Patel MR, Kahl BS, Horwitz SM, Younes A, Foss FM, Oki Y, et al. Preliminary safety and efficacy of IPI-145, a potent inhibitor of phosphoinositide-3-kinase-{delta},{gamma}, in patients with relapsed/refractory CLL. ASCO Meeting Abstracts. 2013;31(15 Suppl):7070.Google Scholar
  45. 45.••
    Flinn IW, Patel M, Horwitz S, Younes A, Foss FM, Oki Y, et al. Preliminary safety and efficacy of IPI-145: a potent inhibitor of phosphoinositide-3-kinase-delta-gamma, in patients wtih relapsed/refractory CLL/SLL (Oral presentation: 12th International Conference on Malignant Lymphoma, Lugano, Switzerland). Hematological Oncology. 2013;31(S1):145. Most updated data on responses with single-agent idelalisib in R/R CLL/SLL.Google Scholar
  46. 46.•
    Flinn IW, Byrd JC, Furman RR, Brown JR, Benson DM, Coutre SE, et al. Evidence of Clinical Activity in a Phase 1 Study of CAL-101, An Oral P110{Delta} Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase, in Patients with Relapsed or Refractory B-Cell Malignancies. ASH Annual Meeting Abstracts. 2009;114(22):922. Initial report with idelalisib to report observation of lymphocyte redistribution.Google Scholar
  47. 47.
    Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, et al. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115(13):2578–85.PubMedCrossRefGoogle Scholar
  48. 48.
    Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32–42.PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Sharman J, de Vos S, Leonard JP, Furman RR, Coutre SE, Flinn IW, et al. A Phase 1 Study of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3K{delta}) Inhibitor, CAL-101 (GS-1101), in Combination with Rituximab and/or Bendamustine in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL). ASH Annual Meeting Abstracts. 2011;118(21):1787.Google Scholar
  50. 50.
    Kahl B, Byrd JC, Flinn IW, Wagner-Johnston N, Spurgeon S, Benson Jr DM, et al. Clinical Safety and Activity In a Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, In Patients with Relapsed or Refractory Non-Hodgkin Lymphoma. ASH Annual Meeting Abstracts. 2010;116(21):1777.Google Scholar
  51. 51.
    Flinn IW, Schreeder MT, Wagner-Johnston N, Boccia RV, Leonard JP, Coutre SE, et al. A Phase 1 Study of CAL-101, An Isoform-Selective Inhibitor of Phosphatidylinositol 3-Kinase P110{delta}, In Combination with Rituximab and/or Bendamustine In Patients with Relapsed or Refractory B-Cell Malignancies. ASH Annual Meeting Abstracts. 2010;116(21):2832.Google Scholar
  52. 52.
    Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero G, Dohner H, 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. Blood. 2008;111(12):5446–56.PubMedCrossRefGoogle Scholar
  53. 53.
    Cheson BD, Byrd JC, Rai KR, Kay NE, O’Brien SM, Flinn IW, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol. 2012;30(23):2820–2.PubMedCrossRefGoogle Scholar
  54. 54.
    Choi MY, Kipps TJ. Inhibitors of B-cell receptor signaling for patients with B-cell malignancies. Cancer Journal. 2012;18(5):404–10.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.University of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.University of Wisconsin School of Medicine and Public HealthMadisonUSA

Personalised recommendations