International Journal of Hematology

, Volume 92, Issue 1, pp 5–11

Targeted treatment and new agents in follicular lymphoma

Progress in Hematology Targeted treatment and new agents in malignant lymphoma

Abstract

Follicular lymphomas are indolent diseases, which, while highly responsive to chemotherapy, remain incurable. Various combinations of standard chemotherapy drugs have not improved the outcome. The availability of effective and well-tolerated monoclonal antibodies (MoAbs), such as rituximab, provided the first evidence that new agents could prolong the survival of these patients. An increasing number of effective drugs are now being evaluated either as single agents or in combinations. These include chemotherapy drugs, bendamustine and bortezomib, MoAbs, other agents that inhibit various cellular pathways including spleen tyrosine kinase, mammalian target of rapamycin, PI3-kinase and apoptosis, and drugs that target the tumor microenvironment, such as the immunomodulatory agent lenalidomide. Rational development of combination strategies, including correlative studies to enhance our understanding of the mechanisms of action and resistance of the drugs, and the biology of the tumor, will continue to improve the outcome of patients with follicular lymphoma.

Keywords

New drugs Follicular lymphoma 

References

  1. 1.
    Fisher RI, LeBlanc M, Press OW, Maloney DG, Unger JM, Miller TP. New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol. 2005;23:8447–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Ozegowski W, Krebs D. IMET 3393, (-[1-Methyl-5-bis-(β-chloräthyl)-aminobenzimidazolyl-(2)]-butter säurehydrochlorid, ein neues Zytostatikum aus der Reihi der Benzimidazol-Loste. Zbl Pharm. 1971;110:1013–9.Google Scholar
  3. 3.
    Strumberg D, Harstrick A, Doll K, Horffmann B, Seeber S. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anticancer Drugs. 1996;7:415–21.CrossRefPubMedGoogle Scholar
  4. 4.
    Schwaenen C, Karakas T, Schrader M. Bendamustine in induction of apoptosis in B-cell chronic lymphocytic leukemia. Ann Oncol. 1999;10:132 (Abstract).Google Scholar
  5. 5.
    Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008;14:309–17.CrossRefPubMedGoogle Scholar
  6. 6.
    Leoni LM, Bailey B, Reifert J. SDX-105 (bendamustine), a clinically active antineoplastic agent possesses a unique mechanism of action. Blood. 2003;102:640a (Abstract 2363).Google Scholar
  7. 7.
    Leoni LM, Bailey B, Niemeyer CC, Kerfoot C, et al. In vivo and ex vivo activity of SDX-105 (bendamustine) in drug-resistant lymphoma cells. Proc Am Assoc Cancer Res. 2004;45 (Abstract 1214).Google Scholar
  8. 8.
    Chow KU, Sommerlad WD, Boehrer S, et al. Anti-CD20 antibody (IDEC-C2B8, rituximab) enhances efficacy of cytotoxic drugs on neoplastic lymphocytes in vitro: role of cytokines, complement, and caspases. Haematologica. 2002;87:33–43.PubMedGoogle Scholar
  9. 9.
    Heider A, Niederle N. Efficacy and toxicity of bendamustine in patients with relapsed low-grade non-Hodgkin’s lymphomas. Anticancer Drugs. 2001;12:725–9.CrossRefPubMedGoogle Scholar
  10. 10.
    Bremer K. High rates of long-lasting remissions after 5-day bendamustine chemotherapy cycles in pre-treated low-grade non-Hodgkin’s lymphomas. J Cancer Res Clin Oncol. 2002;128:603–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Herold M, Schulze A, Niederwieser D, et al. Bendamustine, vincristine and prednisone (BOP) versus cyclophosphamide, vincristine and prednisone (COP) in advanced indolent non-Hodgkin’s lymphoma and mantle cell lymphoma: results of a randomised phase III trial (OSHO#19). J Cancer Res Clin Oncol. 2006;132:105–12.CrossRefPubMedGoogle Scholar
  12. 12.
    Friedberg JW, Cohen P, Chen L, et al. Bendamustine in patients with rituximab refractory and alkylator-refractory, indolent and transformed non-Hodgkin’s lymphoma: results from a phase II multicenter single-agent study. J Clin Oncol. 2008;28:204–10.CrossRefGoogle Scholar
  13. 13.
    Kahl BS, Bartlett NL, Leonard JP, et al. Bendamustine is effective therapy in patients with rituximab-refractory indolent B-cell non-Hodgkin’s lymphoma: results from a large multicenter study. Cancer. 2010;116:106–114.Google Scholar
  14. 14.
    Cheson BD, Friedberg JW, Kahl BS, van der Jagt RH, Tremmel L, Zaks T. Bendamustine produces durable responses with an acceptable long-term safety profile in patients with rituximab-refractory non-Hodgkin’s lymphoma: a pooled analysis. Blood. 2009;114:1049 (Abstract #2681).Google Scholar
  15. 15.
    Rummel MJ, Al-Batran S, Kim SZ, et al. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:3383–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Robinson KS, Williams ME, van der Jagt RH, et al. Bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin’s lymphoma: a phase II multicenter study. J Clin Oncol. 2008;26:4473–9.CrossRefPubMedGoogle Scholar
  17. 17.
    Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab is superior in respect of progression free survival and CR rate when compared to CHOP plus rituximab as first-line treatment of patients with advanced follicular, indolent, and mantle cell lymphomas: final results of a randomized phase III study of the StiL (Study Group Indolent Lymphomas, Germany). Blood. 2009;114:168–9 (Abstract #405).Google Scholar
  18. 18.
    Fisher RI, Bernstein SH, Kahl BS, et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006;24:4867–74.CrossRefPubMedGoogle Scholar
  19. 19.
    O’Connor OA, Wright J, Moskowitz C, et al. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin’s lymphoma and mantle cell lymphoma. J Clin Oncol. 2005;23:676–84.CrossRefPubMedGoogle Scholar
  20. 20.
    Goy A, Younes A, McLaughlin P, et al. Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:667–75.CrossRefPubMedGoogle Scholar
  21. 21.
    Di Bella N, Taetle R, Kolibaba K, et al. Results of a phase II study of bortezomib in patients with relapsed or refractory indolent lymphoma. Blood. 2009 (e-pub ahead of print).Google Scholar
  22. 22.
    de Vos S, Goy A, Dakhil SR, et al. Multicenter randomized phase II study of weekly or twice-weekly bortezomib plus rituximab in patients with relapsed or refractory follicular or marginal zone B-cell lymphoma. J Clin Oncol. 2009;27:5023–30.CrossRefPubMedGoogle Scholar
  23. 23.
    Matous J, Letzer J, Rosen P, et al. Bortezomib, bendamustine, and rituximab in patients (pts) with relapsed (rel) or refractory (ref) follicular lymphoma (FL): dose-finding results of the VERTICAL study. J Clin Oncol. 2009;27:446s (Abstract 8550).Google Scholar
  24. 24.
    Fowler N, Kahl BS, Rosen P, et al. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory folicular lymphoma: encouraging activity in the phase 2 VERTICAL study. Blood. 2009;114:384–5 (Abstract #933).CrossRefGoogle Scholar
  25. 25.
    Friedberg JW, Vose JM, Kelly JL, et al. Bendamustine, bortezomib and rituximab in patients (pts) relapsed/refractory indolent and mantle cell non-Hodgkin’s lymphoma (NHL): a multicenter phase II clinical trial. Blood. 2009;114:381 (Abstract #924).Google Scholar
  26. 26.
    Feugier P, Van Hoof A, Sebban C, et al. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Eetude des Lymphomes de l’Adulte. J Clin Oncol. 2005;23:4117–26.CrossRefPubMedGoogle Scholar
  27. 27.
    Hagenbeek A, Gadeberg O, Johnson P, et al. First clinical use of ofatumumab, a novel fully human anti-CD20 monoclonal antibody in relapsed or refractory follicular lymphoma: results of a phase 1/2 trial. Blood. 2008;111:5486–95.CrossRefPubMedGoogle Scholar
  28. 28.
    Friedberg JW, Vose JM, Kahl BS, et al. A phase I study of PRO131921, a novel anti-CD20 monoclonal antibody in patients with relapsed/refractory CD20+ indolent NHL: correlation between clinical responses and AUC pharmacokinetics. Blood. 2009;114:1440–1 (Abstract #3742).Google Scholar
  29. 29.
    Salles G, Morschhauser F, Lamy T, et al. Phase I study of RO5072759 (GA101) in patients with relapsed/refractory CD20+ non-Hodgkin’s lymphoma (NHL). Blood. 2009;114:679 (Abstract #1704).CrossRefGoogle Scholar
  30. 30.
    Morschhauser F, Leonard JP, Fayad L, et al. Humanized anti-CD20 antibody, veltuzumab, in refractory/recurrent non-Hodgkin’s lymphoma: phase I/II results. J Clin Oncol. 2009;27:3346–53.CrossRefPubMedGoogle Scholar
  31. 31.
    Hagenbeek A, Fayad L, Delwail V, et al. Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in rituximab-refractory follicular lymphoma. Blood. 2009;114 (Abstract 935).Google Scholar
  32. 32.
    Leonard JP, Coleman M, Ketas JC, et al. Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-Hodgkin’s lymphoma. J Clin Oncol. 2003;21:3051–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Leonard JP, Coleman M, Ketas J, et al. Combination antibody therapy with epratuzumab and rituximab in relapsed/refractory non-Hodgkin’s lymphoma. J Clin Oncol. 2005;23:5044–51.CrossRefPubMedGoogle Scholar
  34. 34.
    Strauss SJ, Morschhauser F, Rech J, et al. Multicenter phase II trial of immunotherapy with the humanized anti-CD22 antibody, epratuzumab, in combination with rituximab, in refractory or recurrent non-Hodgkin’s lymphoma. J Clin Oncol. 2006;24:3880–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Leonard JP, Friedberg JW, Younes A, et al. A phase I/II study of galiximab (anti-CD80) monoclonal antibody in combination with rituximab for relapsed or refractory follicular lymphoma. Ann Oncol. 2007;18:1216–23.CrossRefPubMedGoogle Scholar
  36. 36.
    Czuczman MS, Leonard JP, Johnson JL, et al. FLIPI score is applicable and predictive of response to upfront immunotherapy in CALGB 50402: phase II trial of extended induction galiximab ([G] anti-CD80 monoclonal antibody) plus rituximab [R]. Blood. 2008;112:93 (Abstract #233).Google Scholar
  37. 37.
    Zhao X, Lapalombella R, Joshi T, et al. Targeting CD37-positive lymphoid malignancies with a novel engineered small modular immunopharmaceutical. Blood. 2007;110:2569–77.CrossRefPubMedGoogle Scholar
  38. 38.
    Baum PR, Cerveny C, Gordon B, et al. Evaluation of the effect of TRU-16, an anti-CD37 directed SMIP in combination with other therapeutic drugs in models of non-Hodgkin’s lymphoma. J Clin Oncol. 2009;27:451s (Abstract 8571).Google Scholar
  39. 39.
    Andritsos A, Furman RR, Flinn IW, et al. A phase 1 trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SMIPTM) protein in relapsed and refractory CLL: early promising clinical activity. Blood. 2009 (in press).Google Scholar
  40. 40.
    Bargou R, Leo E, Zugmaier G, et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science. 2008;321:974–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Fayad L, Patel H, Verhoef G, et al. Clinical activity of the immunoconjugate CMC_544 on B-cell malignancies: preliminary report of the expanded maximum tolerated dose (MTD) cohort of a phase I study. Blood. 2006;108:766a (Abstract 2711).Google Scholar
  42. 42.
    Dang N, Smith MR, Offner F, et al. Anti-CD22 immunoconjugate inotuzumab ozogamicin (CMC-544) + rituximab: clinical activity including survival in patients with recurrent/refractory follicular or “aggressive” lymphoma. Blood. 2009;114:242–3.Google Scholar
  43. 43.
    Chanan-Khan AA, Cheson BD. Lenalidomide for the treatment of B-cell malignancies. J Clin Oncol. 2008;26:1544–52.CrossRefPubMedGoogle Scholar
  44. 44.
    Witzig TE, Wiernik PH, Moore T, et al. Efficacy of lenalidomide oral monotherapy in relapsed or refractory indolent non-Hodgkin’s lymphoma: final results of NHL-001. J Clin Oncol. 2009;27:448s (Abstract 8560).CrossRefGoogle Scholar
  45. 45.
    Fowler N, McLaughlin P, Hagemeister FB, et al. A biologic combination of lenalidomide and rituximab for front-line therapy of indolent B-cell non-Hodgkin’s lymphoma. Blood. 2009;114:683 (Abstract #1714).CrossRefGoogle Scholar
  46. 46.
    Chen L, Monti S, Juszczynski P, et al. SYK-dependent tonic B-cell receptor signalling is a rational treatment target in diffuse large B-cell lymphoma. Blood. 2008;111:2230–7.CrossRefPubMedGoogle Scholar
  47. 47.
    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.CrossRefPubMedGoogle Scholar
  48. 48.
    Ogura M, Uchida T, Maruyama D, et al. Phase I and pharmacokinetic (PK) study of everolimus (RAD-001) in patients with relapsed or refractory non-Hodgkin’s lymphoma (NHL). Blood. 2009;114:682–3 (Abstract #1712).Google Scholar
  49. 49.
    Flinn IW, Byrd JC, Furman RR, et al. Evidence of clinical activity in a phase 1 study of CAL-101, an oral P110∆ isoform-selective inhibitor of phosphatidylinositol 3-kinase, in patients with relapsed or refractory B-cell malignancies. Blood. 2009;114:380 (Abstract #922).CrossRefGoogle Scholar
  50. 50.
    Cheson BD, Vose JM, Bartlett NL, et al. Safety and efficacy of YM155 in diffuse large B-cell lymphoma (DLBCL). J Clin Oncol. 2009;27:434s (Abstract 8502).Google Scholar
  51. 51.
    Wilson WH, O’Connor OA, Czuczman MS, et al. Phase 1/2a study of ABT-263 in relapsed or refractory lymphoid malignancies. Blood. 2009;114:682 (Abstract #1711).Google Scholar
  52. 52.
    Younes A, Vose JM, Zelenetz AD, et al. A phase 2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin’s lymphoma. J Clin Oncol. 2010 (in press).Google Scholar

Copyright information

© The Japanese Society of Hematology 2010

Authors and Affiliations

  1. 1.Lombardi Comprehensive Cancer CenterGeorgetown University HospitalWashingtonUSA

Personalised recommendations