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Molecular Targeting in Follicular Lymphoma

  • Loretta J. NastoupilEmail author
Chapter
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Abstract

Follicular lymphoma is one of the most common subtypes of lymphoma and is characterized by an indolent course with high response rates coupled with recurrent relapse. Emphasis has been placed on understanding the biology of this lymphoma to improve therapeutic strategies and inform rational clinical trial development as all patients will likely relapse following chemotherapy-based approaches. The B-cell receptor signaling pathway has been implicated as vital to the survival and proliferation of malignant B cells and provides numerous therapeutic targets. However, the addiction on the B-cell receptor signaling is highly variable across lymphoma subtypes which may explain heterogeneity in responses observed with B-cell receptor targeting agents in follicular lymphoma. Additional therapeutic targets that appear promising include BCL2 inhibitors and EZH2 inhibitors that target genetic alterations in follicular lymphoma. Here we review the recent advances in targeted therapy in follicular lymphoma. The future of targeted therapy will focus on identifying optimal combinations that result in enhanced efficacy with improved depth and durability of responses without compromising tolerability.

Keywords

Follicular lymphoma Bruton tyrosine kinase (BTK) inhibitor Phosphatidylinositol 3-kinase (PI3K) inhibitor Enhancer of zeste homolog 2 (EZH2) inhibitor Idelalisib Copanlisib Ibrutinib Tazemetostat 
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References

  1. 1.
    Nastoupil LJ, Sinha R, Byrtek M, Ziemiecki R, Taylor M, Friedberg JW, et al. Comparison of the effectiveness of frontline chemoimmunotherapy regimens for follicular lymphoma used in the United States. Leuk Lymphoma. 2015;56(5):1295–302.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Chen Q, Ayer T, Nastoupil LJ, Seward M, Zhang H, Sinha R, Flowers CR. Initial management strategies for follicular lymphoma. Int J Hematol Oncol. 2012;1(1):35–45.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Tan D, Horning SJ, Hoppe RT, Levy R, Rosenberg SA, Sigal BM, et al. Improvements in observed and relative survival in follicular grade 1-2 lymphoma during 4 decades: the Stanford University experience. Blood. 2013;122(6):981–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Nastoupil LJ, Sinha R, Byrtek M, Zhou X, Taylor MD, Friedberg JW, et al. The use and effectiveness of rituximab maintenance in patients with follicular lymphoma diagnosed between 2004 and 2007 in the United States. Cancer. 2014;120(12):1830–7.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Friedberg JW, Taylor MD, Cerhan JR, Flowers CR, Dillon H, Farber CM, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol. 2009;27(8):1202–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, et al. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017;377(14):1331–44.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203–10.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014;123(19):2944–52.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88–92.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Dühren-von Minden M, Übelhart R, Schneider D, Wossning T, Bach MP, Buchner M, et al. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling. Nature. 2012;489(7415):309–12.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Gopal AK, Kahl BS, de Vos S, Wagner-Johnston ND, Schuster SJ, Jurczak WJ, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008–18.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002;196(6):753–63.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. Inactivation of PI(3)K p110 delta breaks regulatory T-cell-mediated immune tolerance to cancer. Nature. 2014;510(7505):407–11.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Okkenhaug K, Patton DT, Bilancio A, Garçon F, Rowan WC, Vanhaesebroeck B. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol. 2006;177(8):5122–8.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, et al. Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4+CD25+Foxp3+ regulatory T cells. J Immunol. 2006;177(10):6598–602.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583):1031–4.PubMedGoogle Scholar
  18. 18.
    Steinbach EC, et al. Innate PI3K p110 delta regulates Th1/Th17 development and microbiota-dependent colitis. J Immunol. 2014;192(8):3958–68.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Paul J, Soujon M, Wengner AM, Zitzmann-Kolbe S, Sturz A, Haike K, et al. Simultaneous inhibition of PI3K delta and PI3K alpha induces ABC-DLBCL regression by blocking BCR-dependent and -independent activation of NF- kappaB and AKT. Cancer Cell. 2017;31(1):64–78.PubMedCrossRefGoogle Scholar
  20. 20.
    Wang X, Huang H, Young KH. The PTEN tumor suppressor gene and its role in lymphoma pathogenesis. Aging (Albany NY). 2015;7(12):1032–49.CrossRefGoogle Scholar
  21. 21.
    Psyrri A, Papageorgiou S, Liakata E, Scorilas A, Rontogianni D, Kontos CK, et al. Phosphatidylinositol 3′-kinase catalytic subunit alpha gene amplification contributes to the pathogenesis of mantle cell lymphoma. Clin Cancer Res. 2009;15(18):5724–32.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Cui W, Cai Y, Wang W, Liu Z, Wei P, Bi R, et al. Frequent copy number variations of PI3K/AKT pathway and aberrant protein expressions of PI3K subunits are associated with inferior survival in diffuse large B cell lymphoma. J Transl Med. 2014;12:10.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma (CHRONOS-1). 14th international conference on malignant lymphoma 2017. 14–17 Jun 2017. Abstract 108.Google Scholar
  24. 24.
    Mato A, Burris HA, Flinn I, et al. Long-term follow-up of the next generation PI3K-delta inhibitor TGR1202 demonstrates safety and high response rates in NHL: integrated analysis of TG1202 monotherapy and combined with ublituximab. Haematologica. 2016;101:50–1.Google Scholar
  25. 25.
    Zinzani PL, Wagner-Johnston N, Miller C, et al. DYNAMO: a phase 2 study demonstrating the clinical activity of duvelisib in patients with double-refractory indolent non-Hodgkin lymphoma. Hematol Oncol. 2017;35:69–70.CrossRefGoogle Scholar
  26. 26.
    Fowler N, Davis E. Targeting B-cell receptor signaling: changing the paradigm. Hematology Am Soc Hematol Educ Program. 2013;2013:553–60.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Advani RH, Buggy JJ, Sharman JP, Smith SM, Boyd TE, Grant B, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88–94.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Bartlett NL, Costello BA, LaPlant BR, Ansell SM, Kuruvilla JG, Reeder CB, et al. Single-agent ibrutinib in relapsed or refractory follicular lymphoma: a phase 2 consortium trial. Blood. 2018;131:182–90.  https://doi.org/10.1182/blood-2017-09-804641.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Niemann CU, Herman SE, Maric I, Gomez-Rodriguez J, Biancotto A, Chang BY, et al. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by Ibrutinib—findings from an investigator-initiated phase II study. Clin Cancer Res. 2016;22(7):1572–82.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Fowler NH, Nastoupil L, De Vos S, et al. Ibrutinib plus rituximab in treatment-naïve patients with follicular lymphoma: results from a multicentre, phase II study. ASH annual meeting abstracts 2015;126:470.CrossRefGoogle Scholar
  31. 31.
    Fowler NH, Nastoupil L, De Vos S, et al. Ibrutinib combined with rituximab in treatment-naïve patients with follicular lymphoma: arm 1 + arm 2 results from a multicenter, open-label phase 2 study. 58th American Society of Hematology (ASH) annual meeting; San Diego, 3–6 Dec 2016. Abstract 1804.Google Scholar
  32. 32.
    Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–32.CrossRefGoogle Scholar
  33. 33.
    Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, et al. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2017;391:659–67.  https://doi.org/10.1016/S0140-6736(17)33108-2.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wu J, Liu C, Tsui ST, Liu D. Second-generation inhibitors of Bruton tyrosine kinase. J Hematol Oncol. 2016;9(1):80.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Tam C, Simpson D, Opat S, et al. Safety and activity of the highly specific BTK inhibitor BGB-3111 in patients with indolent and aggressive non-Hodgkin’s lymphoma. Oral abstract #152: ASH 59th annual meeting and exposition, Atlanta, Dec 2017.Google Scholar
  36. 36.
    Yang Y, Shaffer AL 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, et al. Exploiting synthetic lethality for the therapy of ABC diffuse large B cell lymphoma. Cancer Cell. 2012;21(6):723–37.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Ujjani CS, Jung SH, Pitcher B, Martin P, Park SI, Blum KA, et al. Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103. Blood. 2016;128(21):2510–6.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Kridel R, Sehn LH, Gascoyne RD. Pathogenesis of follicular lymphoma. J Clin Invest. 2012;122(10):3424–31.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Davids MS, Roberts AW, Seymour JF, Pagel JM, Kahl BS, Wierda WG, et al. Phase I first-in-human study of venetoclax in patients with relapsed or refractory non-Hodgkin lymphoma. J Clin Oncol. 2017;35(8):826–33.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, et al. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010;42(2):181–5.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Pastore A, Jurinovic V, Kridel R, Hoster E, Staiger AM, Szczepanowski M, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16(9):1111–22.CrossRefGoogle Scholar
  43. 43.
    Okosun J, Bödör C, Wang J, Araf S, Yang CY, Pan C, et al. Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma. Nat Genet. 2014;46(2):176–81.CrossRefGoogle Scholar
  44. 44.
    Bödör C, Grossmann V, Popov N, Okosun J, O'Riain C, Tan K, et al. EZH2 mutations are frequent and represent an early event in follicular lymphoma. Blood. 2013;122(18):3165–8.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Caganova M, Carrisi C, Varano G, Mainoldi F, Zanardi F, Germain PL, et al. Germinal center dysregulation by histone methyltransferase EZH2 promotes lymphomagenesis. J Clin Invest. 2013;123(12):5009–22.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Huet S, Zerri L, Tesson B, Mareschal S, Taxi S, Mescam-Mancini L, et al. EZH2 alterations in follicular lymphoma: biological and clinical correlations. Blood Cancer J. 2017;7(4):e555.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Ribrag V, Soria JC, Michot JM, et al. Phase 1 study of tazemetostat (EPZ-6438), an inhibitor of enhancer of zeste-homolog 2 (EZH2): preliminary safety and activity in relapsed or refractory non-Hodgkin lymphoma (NHL) patients. Blood. 2015;126:473.CrossRefGoogle Scholar
  48. 48.
    Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of Tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas. Hematol Oncol. 2017;35(Suppl S2):24–5.CrossRefGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.UT MD Anderson Cancer Center, Department of Lymphoma/MyelomaHoustonUSA

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