Skip to main content

Advertisement

SpringerLink
Log in

Pitfalls of Combining Novel Agents in Lymphoma

  • Lymphoma (DO Persky, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

As our knowledge of lymphoma and its intricate signaling pathways has grown, so has the development of novel agents. While their mechanisms of action vary considerably, these therapies supplement and in some cases offer alternatives to standard chemotherapy. Initial studies have highlighted tolerable side effects though in the majority of instances limited efficacy when used as monotherapy. Research has focused on combining these novel agents to improve outcomes and perhaps offer refined treatment options. Novel combinations represent new territory, inherently dissimilar to combination chemotherapy with new pitfalls and challenges given their unique mechanisms of action. Though promising, it is crucial to consider the complex interplay that can occur. While there is potential for improved outcomes, there is also the possibility of unexpected toxicities. For this reason, it is critical that novel combinations be carefully considered and tested in clinical trials before widespread use. Thus far, research has shown that combination therapies are successful when not only avoiding overlapping toxicity but also capitalizing on synergy. We believe that more specific targets and an improved understanding of their off-/on-target effects will further successful novel combinations.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

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

  1. Dameshek W, Weisfuse L, Stein T. Nitrogen mustard therapy in Hodgkin’s disease. Analysis of fifty consecutive cases. Blood. 1949;4(4):338–79.

    PubMed  CAS  Google Scholar 

  2. McKelvey EM, Gottlieb JA, Wilson HE, Haut A, Talley RW, Stephens R, et al. Hydroxyldaunomycin (adriamycin) combination chemotherapy in malignant lymphoma. Cancer. 1976;38(4):1484–93.

    Article  PubMed  CAS  Google Scholar 

  3. Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP Chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(4):235–42.

    Article  PubMed  CAS  Google Scholar 

  4. Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343(26):1910–6.

    Article  PubMed  Google Scholar 

  5. O’Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910–19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, et al. Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994;152(2):557–65.

    PubMed  CAS  Google Scholar 

  7. Mohammad DK, Nore BF, Hussain A, Gustafsson MO, Mohamed AJ, Smith CI. Dual phosphorylation of Btk by Akt/protein kinase b provides docking for 14-3-3zeta, regulates shuttling, and attenuates both tonic and induced signaling in B cells. Mol Cell Biol. 2013;33(16):3214–26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993;361(6409):226–33.

    Article  PubMed  CAS  Google Scholar 

  9. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286–94.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29(4):895–900.

    Article  PubMed  CAS  Google Scholar 

  11. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922.

    Article  PubMed  CAS  Google Scholar 

  13. Dubovsky JA, Beckwith KA, Natarajan G, Woyach JA, Jaglowski S, Zhong Y, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Honigberg LA, Smith AM, Sirisawad M, Verner E, Loury D, Chang B, 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. Proc Natl Acad Sci U S A. 2010;107(29):13075–80.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tillman BF, Pauff JM, Satyanarayana G, Talbott M, Warner JL. Systematic review of infectious events with the BTK inhibitor ibrutinib in the treatment of haematologic malignancies. Eur J Haematol. 2017;100(4):325–34.

    Article  CAS  Google Scholar 

  16. Caron F, Leong DP, Hillis C, Fraser G, Siegal D. Current understanding of bleeding with ibrutinib use: a systematic review and meta-analysis. Blood Advances. 2017;1(12):772–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Senis YA, Mazharian A, Mori J. Src family kinases: at the forefront of platelet activation. Blood. 2014;124(13):2013–24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Herman SE, Niemann CU, Farooqui M, Jones J, Mustafa RZ, Lipsky A, et al. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia. 2014;28(11):2188–96.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Keating MJ, Wierda WG, Hoellenriegel J, Jeyakumar G, Ferrajoli A, Faderl SH, et al. Ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients. Blood. 2013;122(21):675.

    Google Scholar 

  20. Wang M, Hagemeister F, Westin JR, Fayad L, Samaniego F, Turturro F, et al. Ibrutinib and rituximab are an efficacious and safe combination in relapsed mantle cell lymphoma: preliminary results from a phase II clinical trial. Blood. 2014;124(21):627.

    Google Scholar 

  21. • Burger JA, Sivina M, Ferrajoli A, Jain N, Kim E, Kadia T, et al. Randomized trial of ibrutinib versus ibrutinib plus rituximab (Ib + R) in patients with chronic lymphocytic leukemia (CLL). Blood. 2017;130(Suppl 1):427. Rapid response of ibrutinib+rituximab however did not demonstrate improved PFS. Highlights challenges with multi-kinase inhibitors.

    Google Scholar 

  22. Khurana D, Arneson LN, Schoon RA, Dick CJ, Leibson PJ. Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk. J Immunol. 2007;178(6):3575–82.

    Article  PubMed  CAS  Google Scholar 

  23. Kohrt HE, Sagiv-Barfi I, Rafiq S, Herman SEM, Butchar JP, Cheney C, et al. Ibrutinib antagonizes rituximab-dependent NK cell–mediated cytotoxicity. Blood. 2014;123(12):1957–60.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. • Jerkeman M, Ek S, Freiburghaus C, Lindblad AA. Ibrutinib in combination with anti-CD20-antibody negatively affects antibody dependent cellular cytotoxic (ADCC) on mantle cell lymphoma cell lines, not reversed by the addition of lenalidomide. Blood. 2017;130(Suppl 1):1266. Provides rationale for difficulty of ibrutinib in combination with anti-CD20 antibody.

    Google Scholar 

  25. • 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. 2015;374(4):323–32. Demonstrates reduced side effects with more specific BTK inhibitors.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Bye AP, Unsworth AJ, Desborough MJ, Hildyard CAT, Appleby N, Bruce D, et al. Severe platelet dysfunction in NHL patients receiving ibrutinib is absent in patients receiving acalabrutinib. Blood Advances. 2017;1(26):2610–23.

    PubMed  PubMed Central  Google Scholar 

  27. Golay J, Ubiali G, Introna M. The specific Bruton tyrosine kinase inhibitor acalabrutinib (ACP-196) shows favorable in vitro activity against chronic lymphocytic leukemia B cells with CD20 antibodies. Haematologica. 2017;102(10):e400–e3.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Lampson BL, Kasar SN, Matos TR, Morgan EA, Rassenti L, Davids MS, et al. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity. Blood. 2016;128(2):195–203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. 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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 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.

    Article  PubMed  CAS  Google Scholar 

  31. Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, et al. Inactivation of PI3Kγ and PI3Kδ distorts T-cell development and causes multiple organ inflammation. Blood. 2007;110(8):2940–7.

    Article  PubMed  CAS  Google Scholar 

  32. •• Robak T, Coiffier B, Delgado J, Marlton P, Adewoye AH, Kim Y, et al. Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study. Blood. 2015;126(23):LBA-5-LBA. Demonstrates challenges of combination chemoimmunotherapy with PI3K inhibitors.

    Google Scholar 

  33. •• Barr PM, Saylors GB, Spurgeon SE, Cheson BD, Greenwald DR, O’Brien SM, et al. Phase 2 study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127(20):2411–5. Study demonstrating combination of BCR inhibitors with unexpected side effects.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Forero-Torres A, Barr PM, Magid Diefenbach CS, Sher T, Schaub R, Zhou L, et al. A phase 1 study of INCB040093, a PI3Kδ inhibitor, alone or in combination with INCB039110, a selective JAK1 inhibitor: Interim results from patients (pts) with relapsed or refractory (r/r) classical Hodgkin lymphoma (cHL). J Clin Oncol. 2015;33(15_suppl):8558.

    Google Scholar 

  35. Flinn IW, O’Brien S, Kahl B, Patel M, Oki Y, Foss FF, et al. Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies. Blood. 2017.

  36. O’Connor OA, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, et al. TGR-1202, a novel once daily PI3K-delta inhibitor, demonstrates clinical activity with a favorable safety profile in patients with CLL and B-cell lymphoma. Blood. 2015;126(23):4154.

    Google Scholar 

  37. Burris HA, III, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, et al. Umbralisib, a novel PI3Kδ and casein kinase-1 ε inhibitor, in relapsed or refractory chronic lymphocytic leukemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486–96.

  38. • Davids MS, Kim HT, Nicotra A, Savell A, Francoeur K, Hellman J, et al. TGR-1202 in Combination with ibrutinib in patients with relapsed or refractory CLL or MCL: preliminary results of a multicenter phase I/Ib study. Blood. 2016;128(22):641. Demonstrating alternative PI3K inhibitor with less toxicity in combination with ibrutinib.

    Google Scholar 

  39. Fowler NH, Nastoupil LJ, Lunning MA, Vose J, Siddiqi T, Flowers C, et al. Safety and activity of the chemotherapy-free triplet of ublituximab, TGR-1202, and ibrutinib in relapsed B-cell malignancies. J Clin Oncol. 2015;33(15_suppl):8501.

    Google Scholar 

  40. Mahadevan D, Pauli EK, Cutter K, Dietz LA, Sportelli P, Miskin HP, et al. A phase I trial of TGR-1202, a next generation once daily PI3K-delta inhibitor in combination with obinutuzumab plus chlorambucil, in patients with chronic lymphocytic leukemia. Blood. 2015;126(23):2942.

    Google Scholar 

  41. Lunning MA, Vose J, Fowler NH, Nastoupil LJ, Schreeder MT, Siddiqi T, et al. Ublituximab plus TGR-1202 activity and safety profile in relapsed/refractory B-cell NHL and high-risk CLL. J Clin Oncol. 2015;33(15_suppl):8548.

    Google Scholar 

  42. Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4.

    Article  PubMed  CAS  Google Scholar 

  43. Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–9.

    Article  PubMed  CAS  Google Scholar 

  44. Lesokhin AM, Ansell SM, Armand P, Scott EC, Halwani A, Gutierrez M, et al. Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34(23):2698–704.

    Article  CAS  Google Scholar 

  45. Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in patients with chronic lymphocytic leukemia with Richter’s transformation and relapsed CLL. Blood. 2017;129(26):3419–27.

  46. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Kondo K, Shaim H, Thompson PA, Burger JA, Keating M, Estrov Z, et al. Ibrutinib modulates the immunosuppressive CLL microenvironment through STAT3-mediated suppression of regulatory B-cell function and inhibition of the PD-1/PD-L1 pathway. Leukemia. 2017;32(4):960–70.

  48. •• Younes A, Brody J, Carpio C, Lopez-Guillermo A, Ben-Yehuda D, Ferhanoglu AB, et al. Safety and efficacy of the combination of ibrutinib and nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia. Blood. 2017;130(Suppl 1):833. Demonstration of efficacy between checkpoint inhibition and ibrutinib.

    Google Scholar 

  49. Jain N, Basu S, Thompson PA, Ohanian M, Ferrajoli A, Pemmaraju N, et al. Nivolumab combined with ibrutinib for CLL and Richter transformation: a phase II trial. Blood. 2016;128(22):59.

    Google Scholar 

  50. Pachter JA, Weaver DT. The dual PI3K-δ,γ inhibitor duvelisib stimulates anti-tumor immunity and enhances efficacy of immune checkpoint and co-stimulatory antibodies in a B cell lymphoma model. Blood. 2017;130(Suppl 1):1541.

    Google Scholar 

  51. Palumbo A, Mateos M-V, San Miguel J, Shah J, Thompson S, Marinello PM, et al. KEYNOTE-185: a randomized, open-label phase 3 study of pembrolizumab in combination with lenalidomide and low-dose dexamethasone in newly diagnosed and treatment-naive multiple myeloma (MM). J Clin Oncol. 2016;34(15_suppl):TPS8069-TPS.

    Article  Google Scholar 

  52. Roberts ZJ, Better M, Bot A, Roberts MR, Ribas A. Axicabtagene ciloleucel, a first-in-class CAR-T cell therapy for aggressive NHL. Leuk Lymphoma. 2017;1–12.

  53. Fraietta JA, Beckwith KA, Patel PR, Ruella M, Zheng Z, Barrett DM, et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood. 2016;127(9):1117–27.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. •• Gill S, Frey NV, Hexner EO, Lacey SF, Melenhorst JJ, Byrd JC, et al. CD19 CAR-T cells combined with ibrutinib to induce complete remission in CLL. J Clin Oncol. 2017;35(15_suppl):7509. Rationale and efficacy of ibrutinib combination with CAR-T therapy.

    Article  Google Scholar 

  55. Chong EA, Melenhorst JJ, Lacey SF, Ambrose DE, Gonzalez V, Levine BL, et al. PD-1 blockade modulates chimeric antigen receptor (CAR)–modified T cells: refueling the CAR. Blood. 2017;129(8):1039–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. McDonnell TJ, Deane N, Platt FM, Nunez G, Jaeger U, McKearn JP, et al. bcl-2-immunoglobulin transgenic mice demonstrate extended B cell survival and follicular lymphoproliferation. Cell. 1989;57(1):79–88.

    Article  PubMed  CAS  Google Scholar 

  57. Huang JZ, Sanger WG, Greiner TC, Staudt LM, Weisenburger DD, Pickering DL, et al. The t(14;18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood. 2002;99(7):2285–90.

    Article  PubMed  CAS  Google Scholar 

  58. Bentz M, Plesch A, Bullinger L, Stilgenbauer S, Ott G, Muller-Hermelink HK, et al. t(11;14)-positive mantle cell lymphomas exhibit complex karyotypes and share similarities with B-cell chronic lymphocytic leukemia. Genes Chromosom Cancer. 2000;27(3):285–94.

    Article  PubMed  CAS  Google Scholar 

  59. Hermine O, Haioun C, Lepage E, d’Agay MF, Briere J, Lavignac C, et al. Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin’s lymphoma. Groupe d’Etude des Lymphomes de l’Adulte (GELA). Blood. 1996;87(1):265–72.

    PubMed  CAS  Google Scholar 

  60. Kipps TJ, Eradat H, Grosicki S, Catalano J, Cosolo W, Dyagil IS, et al. A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia. Leuk Lymphoma. 2015;56(10):2826–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Roberts AW, Davids MS, Pagel JM, Kahl BS, Puvvada SD, Gerecitano JF, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311–22.

    Article  PubMed  CAS  Google Scholar 

  62. Leverson JD, Phillips DC, Mitten MJ, Boghaert ER, Diaz D, Tahir SK, et al. Exploiting selective BCL-2 family inhibitors to dissect cell survival dependencies and define improved strategies for cancer therapy. Sci Transl Med. 2015;7(279):279ra40.

    Article  PubMed  CAS  Google Scholar 

  63. Zinzani PL, Topp MS, Yuen SL, Rusconi C, Fleury I, Pro B, et al. Phase 2 Study of venetoclax plus rituximab or randomized ven plus bendamustine+rituximab (BR) versus BR in patients with relapsed/refractory follicular lymphoma: interim data. Blood. 2016;128(22):617.

    Google Scholar 

  64. •• Jain N, Thompson PA, Ferrajoli A, Burger JA, Borthakur G, Takahashi K, et al. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial. Blood. 2017;130(Suppl 1):429. Combination therapy with ibrutinib and venetoclax demonstrating efficacy and tolerable side effects.

    Google Scholar 

  65. Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211–23.

    Article  PubMed  CAS  Google Scholar 

  66. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Ibrutinib therapy increases BCL-2 dependence and enhances sensitivity to venetoclax in CLL. Blood. 2015;126(23):490.

    Google Scholar 

  67. Kumar S, Witzig TE, Rajkumar SV. Thalidomide as an anti-cancer agent. J Cell Mol Med. 2002;6(2):160–74.

    Article  PubMed  CAS  Google Scholar 

  68. Chaudhry V, Cornblath DR, Corse A, Freimer M, Simmons-O’Brien E, Vogelsang G. Thalidomide-induced neuropathy. Neurology. 2002;59(12):1872–5.

    Article  PubMed  CAS  Google Scholar 

  69. Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol Off J Am Soc Clin Oncol. 2011;29(8):986–93.

    Article  CAS  Google Scholar 

  70. Kritharis A, Coyle M, Sharma J, Evens AM. Lenalidomide in non-Hodgkin lymphoma: biological perspectives and therapeutic opportunities. Blood. 2015;125(16):2471–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Richardson PG, Blood E, Mitsiades CS, Jagannath S, Zeldenrust SR, Alsina M, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108(10):3458–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau J-L, Dmoszynska A, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357(21):2123–32.

    Article  PubMed  CAS  Google Scholar 

  73. Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, et al. Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomized, multicentre trial. Lancet Oncol. 2016;17(3):319–31.

  74. Moros A, Bustany S, Cahu J, Saborit-Villarroya I, Martinez A, Colomer D, et al. Antitumoral activity of lenalidomide in in vitro and in vivo models of mantle cell lymphoma involves the destabilization of cyclin D1/p27KIP1 complexes. Clin Cancer Res. 2014;20(2):393–403.

    Article  PubMed  CAS  Google Scholar 

  75. Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, et al. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012;13(7):716–23.

    Article  PubMed  CAS  Google Scholar 

  76. •• Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, et al. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015;373(19):1835–44. Demonstration of synergy between lenalidomide and anti-CD20 rituximab leading to improved efficacy.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Morschhauser F, Salles G, Le Gouill S, Tilly H, Thieblemont C, Bouabdallah K, et al. A phase Ib study of obinutuzumab combined with lenalidomide for relapsed/refractory follicular B-cell lymphoma. Blood. 2014;124(21):4458.

    Google Scholar 

  78. Zhang L, Qian Z, Cai Z, Sun L, Wang H, Bartlett JB, et al. Synergistic antitumor effects of lenalidomide and rituximab on mantle cell lymphoma in vitro and in vivo. Am J Hematol. 2009;84(9):553–9.

    Article  PubMed  CAS  Google Scholar 

  79. Ruan J, Martin P, Christos PJ, Cerchietti L, Shah BD, Schuster SJ, et al. Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma: 5-year follow-up and correlative analysis from a multi-center phase II study. Blood. 2017;130(Suppl 1):154.

    Google Scholar 

  80. Fowler NH, Davis RE, Rawal S, Nastoupil L, Hagemeister FB, McLaughlin P, et al. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial. Lancet Oncol. 2014;15(12):1311–8.

  81. Cheah CY, Nastoupil LJ, Neelapu SS, Forbes SG, Oki Y, Fowler NH. Lenalidomide, idelalisib, and rituximab are unacceptably toxic in patients with relapsed/refractory indolent lymphoma. Blood. 2015;125(21):3357–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. • Jerkeman M, Hutchings M, Räty R, Wader KF, Laurell A, Kuitunen H, et al. Ibrutinib-lenalidomide-rituximab in patients with relapsed/refractory mantle cell lymphoma: first results from the nordic lymphoma group MCL6 (PHILEMON) phase II trial. Blood. 2016;128(22):148. Significant toxicity from triplet therapy with multiple mechanisms of action.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. James P. Wilmot Cancer Institute, University of Rochester Medical Center, 601 Elmwood Avenue, Box 704, Rochester, NY, 14642, USA

    Thomas D. Rodgers MD & Paul M. Barr MD

Authors
  1. Thomas D. Rodgers MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paul M. Barr MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Thomas D. Rodgers MD.

Ethics declarations

Conflict of Interest

Thomas D. Rodgers declares that he has no conflict of interest. Paul M. Barr has received compensation from AbbVie, Seattle Genetics, Gilead, Novartis, Genentech, Celgene, and Merck for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Lymphoma

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rodgers, T.D., Barr, P.M. Pitfalls of Combining Novel Agents in Lymphoma. Curr. Treat. Options in Oncol. 19, 35 (2018). https://doi.org/10.1007/s11864-018-0548-7

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11864-018-0548-7

Keywords

Search

Navigation