Reassessing the Standard of Care in Indolent Lymphoma: A Clinical Update to Improve Clinical Practice

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Non-Hodgkin's lymphoma (NHL) represents a diverse group of hematologic malignancies originating in B or T lymphocytes. Approximately 85% of NHLs are of B-cell origin, with the remainder mostly of T-cell origin. The most common NHL types are diffuse large B-cell lymphoma (31%) and follicular lymphoma (22%). More than 65,000 new cases of NHL develop each year, and approximately 20,000 people with NHL died of the disease 2009. NHL is the seventh most common cancer in the United States, contributes to approximately 4% to 5% of all cancer cases in the United States, and causes approximately 3% of all cancer-related deaths. Currently, nearly 500,000 people are living with the disease or are in remission. Several new and encouraging advances have been made in the treatment of indolent NHL. Although the watch and wait approach still has a role, combined immunochemotherapy remains the standard of care for both first-line and relapsed/refractory disease. As front-line treatment, bendamustine plus rituximab may become a new standard of care, especially for older patients. In contrast, rituximab in combination with chemotherapy followed by rituximab maintenance seems to be the optimal option in patients with relapsed disease.

  • 1

    Zelenetz AD, Abramson JS, Advani RH. NCCN clinical practice guidelines in oncology: non-Hodgkin’s lymphomas. Version 1, 2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nhl.pdf. Accessed June 30,2010.

    • Search Google Scholar
    • Export Citation
  • 2

    A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:39093918.

    • Search Google Scholar
    • Export Citation
  • 3

    Jemal A, Siegel R, Ward E. Cancer statistics, 2009. CA Cancer J Clin 2009;59:225249.

  • 4

    Leukemia & Lymphoma Society. Facts 2009–2010. Available at: http://www.leukemia-lymphoma.org/attachments/National/br_1247234696.pdf. Accessed May 3, 2010.

    • Search Google Scholar
    • Export Citation
  • 5

    Armitage JO. Is lymphoma occurring in the elderly the same disease? Leuk Lymphoma 2008;49:1416.

  • 6

    Anderson KC, Alsina M, Bensinger W. NCCN clinical practice guidelines in oncology: multiple myeloma. Version 3, 2010. Available at: http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Accessed June 30, 2010.

    • Search Google Scholar
    • Export Citation
  • 7

    Bende RJ, Smit LA, van Noesel CJ. Molecular pathways in follicular lymphoma. Leukemia 2007;21:1829.

  • 8

    Jaffe ES, Harris NL, Stein H, Isaacson PG. Classification of lymphoid neoplasms: the microscope as a tool for disease discovery. Blood 2008;112:43844399.

    • Search Google Scholar
    • Export Citation
  • 9

    Jaffe ES. The 2008 WHO classification of lymphomas: implications for clinical practice and translational research. Hematology Am Soc Hematol Educ Program 2009;113:523531.

    • Search Google Scholar
    • Export Citation
  • 10

    Thieblemont C. Non-MALT marginal zone lymphomas. Ann Oncol 2008;19(Suppl 4):7073.

  • 11

    Vijay A, Gertz MA. Current treatment options for Waldenström macroglobulinemia. Clin Lymphoma Myeloma 2008;8:219229.

  • 12

    Friedberg JW, Taylor MD, Cerhan JR. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol 2009;27:12021208.

    • Search Google Scholar
    • Export Citation
  • 13

    Gribben JG. How I treat indolent lymphoma. Blood 2007;109:46174626.

  • 14

    Marcus RE, Imrie K, Solal-Celigny P. A phase III study of rituximab plus CVP versus CVP alone in patients with previously untreated advanced follicular lymphoma: updated results with 53 months” median follow-up and analysis of outcomes according to baseline prognostic factors. J Clin Oncol, In press.

    • Search Google Scholar
    • Export Citation
  • 15

    Hiddemann W, Kneba M, Dreyling M. Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 2005;106:37253732.

    • Search Google Scholar
    • Export Citation
  • 16

    Schulz H, Bohlius JF, Trelle S. Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta-analysis. J Natl Cancer Inst 2007;99:706714.

    • Search Google Scholar
    • Export Citation
  • 17

    Foran JM, Rohatiner AZ, Cunningham D. European phase II study of rituximab (chimeric anti-CD20 monoclonal antibody) for patients with newly diagnosed mantle-cell lymphoma and previously treated mantle-cell lymphoma, immunocytoma, and small B-cell lymphocytic lymphoma. J Clin Oncol 2000;18:317324.

    • Search Google Scholar
    • Export Citation
  • 18

    Treon SP, Agus DB, Link B. CD20-directed antibody-mediated immunotherapy induces responses and facilitates hematologic recovery in patients with Waldenstrom’s macroglobulinemia. J Immunother (1991) 2001;24:272279.

    • Search Google Scholar
    • Export Citation
  • 19

    Keating MJ, O’Brien S, Albitar M. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:40794088.

    • Search Google Scholar
    • Export Citation
  • 20

    Byrd JC, Rai K, Peterson BL. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005;105:4953.

    • Search Google Scholar
    • Export Citation
  • 21

    Hallek MS, Fingerle-Rowson G, Fink AM. First-line treatment with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) improves overall survival (OS) in previously untreated patients (pts) with advanced chronic lymphocytic leukemia (CLL): results of a randomized phase III trial on behalf of an international group of investigators and the German CLL study group [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 535.

    • Search Google Scholar
    • Export Citation
  • 22

    van Oers MH, Klasa R, Marcus RE. Rituximab maintenance improves clinical outcome of relapsed/refractory follicular non-Hodgkin lymphoma in patients both with and without rituximab during induction: results of a prospective randomized phase 3 intergroup trial. Blood 2006;108:32953301.

    • Search Google Scholar
    • Export Citation
  • 23

    Forstpointner R, Unterhalt M, Dreyling M. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood 2006;108:40034008.

    • Search Google Scholar
    • Export Citation
  • 24

    Vidal L, Gafter-Gvili A, Leibovici L. Rituximab maintenance for the treatment of patients with follicular lymphoma: systematic review and meta-analysis of randomized trials. J Natl Cancer Inst 2009;101:248255.

    • Search Google Scholar
    • Export Citation
  • 25

    Salles GA, Seymour JF, Feugier P. Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy [abstract]. Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology; June 4–8, 2010; Chicago, Illinois. Abstract 8004.

    • Search Google Scholar
    • Export Citation
  • 26

    Salles G, Catalano J, Feugier P. Rituximab maintenance for 2-years significantly improves the outcome of patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy: results of the PRIMA study [abstract]. Presented at the 2010 Annual Meeting of the European Hematology Association; June 10–13, 2010; Barcelona, Spain. Abstract 0557.

    • Search Google Scholar
    • Export Citation
  • 27

    Pettengell R, Schmitz N, Gisselbrecht C. Randomized study of rituximab in patients with relapsed or resistant follicular lymphoma prior to high-dose therapy as in vivo purging and to maintain remission following high-dose therapy [abstract]. Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology; June 4–8, 2010; Chicago, Illinois. Abstract 8005.

    • Search Google Scholar
    • Export Citation
  • 28

    Morschhauser F, Dreyling M, Rohatiner A. Rationale for consolidation to improve progression-free survival in patients with non-Hodgkin’s lymphoma: a review of the evidence. Oncologist 2009;14(Suppl 2):1729.

    • Search Google Scholar
    • Export Citation
  • 29

    Morschhauser F, Radford J, Van Hoof A. Phase III trial of consolidation therapy with yttrium-90-ibritumomab tiuxetan compared with no additional therapy after first remission in advanced follicular lymphoma. J Clin Oncol 2008;26:51565164.

    • Search Google Scholar
    • Export Citation
  • 30

    Press OW, Unger JM, Braziel RM. Phase II trial of CHOP chemotherapy followed by tositumomab/iodine I-131 tositumomab for previously untreated follicular non-Hodgkin’s lymphoma: five-year follow-up of Southwest Oncology Group protocol S9911. J Clin Oncol 2006;24:41434149.

    • Search Google Scholar
    • Export Citation
  • 31

    ClinicalTrials.gov. Combination chemotherapy with monoclonal antibody therapy in treating patients with newly diagnosed non-Hodgkin’s lymphoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00006721. Accessed June 30, 2010.

    • Export Citation
  • 32

    ClinicalTrials.gov. Iodine I 131 tositumomab, rituximab, and combination chemotherapy in treating patients with previously untreated stage II, stage III, or stage IV follicular non-Hodgkin lymphoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00770224. Accessed March 31, 2010.

    • Export Citation
  • 33

    Kaminski MS, Tuck M, Estes J. 131I-tositumomab therapy as initial treatment for follicular lymphoma. N Engl J Med 2005;352:441449.

  • 34

    Kaminski MS, Tuck M, Estes J. Tositumomab and iodine I-131 tositumomab for previously untreated, advanced-stage, follicular lymphoma: median 10 year follow-up results [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 3759.

    • Search Google Scholar
    • Export Citation
  • 35

    Flinn IW, Neuberg DS, Grever MR. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup trial E2997. J Clin Oncol 2007;25:793798.

    • Search Google Scholar
    • Export Citation
  • 36

    Catovsky D, Richards S, Matutes E. UK National Cancer Research Institute (NCRI) Haematological Oncology Clinical Studies Group; NCRI Chronic Lymphocytic Leukaemia Working Group. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 trial): a randomised controlled trial. Lancet 2007;370:230239.

    • Search Google Scholar
    • Export Citation
  • 37

    Grever MR, Lucas DM, Dewald GW. 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;25:799804.

    • Search Google Scholar
    • Export Citation
  • 38

    Byrd JC, Peterson BL, Morrison VA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003;101:614.

    • Search Google Scholar
    • Export Citation
  • 39

    Byrd JC, Rai K, Peterson BL. Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 2005;105:4953.

    • Search Google Scholar
    • Export Citation
  • 40

    Keating MJ, O’Brien S, Albitar M. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 2005;23:40794088.

    • Search Google Scholar
    • Export Citation
  • 41

    Wierda W, O’Brien S, Wen S. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 2005;23:40704078.

    • Search Google Scholar
    • Export Citation
  • 42

    Treon SP. How I treat Waldenström macroglobulinemia. Blood 2009;114:23752385.

  • 43

    Treon SP, Branagan AR, Ioakimidis L. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia. Blood 2009;113:36733678.

    • Search Google Scholar
    • Export Citation
  • 44

    Ghobrial IM, Gertz M, Laplant B. Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenstrom macroglobulinemia. J Clin Oncol 2010;28:14081414.

    • Search Google Scholar
    • Export Citation
  • 45

    Ghobrial IM, Hong F, Padmanabhan S. Phase II trial of weekly bortezomib in combination with rituximab in relapsed or relapsed and refractory Waldenstrom macroglobulinemia. J Clin Oncol 2010;28:14221428.

    • Search Google Scholar
    • Export Citation
  • 46

    Leoni LM, Bailey B, Reifert J. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 2008;14:309317.

    • Search Google Scholar
    • Export Citation
  • 47

    Cheson BD, Rummel MJ. Bendamustine: rebirth of an old drug. J Clin Oncol 2009;27:14921501.

  • 48

    Rummel MJ, Niederle N, Maschmeyer G. 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) [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 405.

    • Search Google Scholar
    • Export Citation
  • 49

    Knauf WU, Lissichkov T, Aldaoud A. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 2009;27:43784384.

    • Search Google Scholar
    • Export Citation
  • 50

    Czuczman MS, Rummel MJ. Clinical Roundtable monograph: recent advances in NHL. Highlights from the 51st ASH Annual Meeting and Exposition, December 5–8, 2009, New Orleans, Louisiana. Clin Adv Hematol Oncol 2010;8:A111.

    • Search Google Scholar
    • Export Citation
  • 51

    Kennedy D, Mwamburi M, Ranganathan G. Bendamustine-rituximab combination treatment in relapsed NHL: combined experience from two phase 2 trials and exploration of response predictors [abstract]. Presented at the 2010 Annual Meeting of the European Hematology Association; June 10–13, 2010; Barcelona, Spain. Abstract 0294.

    • Search Google Scholar
    • Export Citation
  • 52

    Burchardt CA, Brugger W, Maschmeyer G. Peripheral blood stem cell mobilization after bendamustine containing chemotherapy in indolent lymphomas is possible. Results from the phase III study of B-R vs. CHOP-R (NHL 1-2003 trial) of the StiL (Study group Indolent Lymphomas, Germany) [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 2679.

    • Search Google Scholar
    • Export Citation
  • 53

    Witzig TE, Wiernik PH, Moore T. Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. J Clin Oncol 2009;27:54045409.

    • Search Google Scholar
    • Export Citation
  • 54

    Fowler N, McLaughlin P, Hagemeister FB. A biologic combination of lenalidomide and rituximab for front-line therapy of indolent B-cell non-Hodgkin’s lymphoma [abstract]. Program and abstracts of the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 1714.

    • Search Google Scholar
    • Export Citation
  • 55

    Fowler NH, McLaughlin P, Hagemeister FB. Complete response rates with lenalidomide plus rituximab for untreated indolent B-cell non-Hodgkin’s lymphoma [abstract]. Presented at the 2010 Annual Meeting of the American Society of Clinical Oncology; June 4–8, 2010; Chicago, Illinois. Abstract 8036.

    • Search Google Scholar
    • Export Citation
  • 56

    Dutia M, DeRoock I, Chee K. R2: preliminary results of a phase II study of lenalidomide and rituximab in relapsed/refractory indolent non-Hodgkin’s lymphoma (NHL) [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 1679.

    • Search Google Scholar
    • Export Citation
  • 57

    Dutia M, DeRoock I, Chee K. Analysis of a phase 2 study of lenalidomide and rituximab in relapsed or refractory non-Hodgkin’s lymphoma [abstract]. Program and abstracts of the 2010 Annual Meeting of the European Hematology Association; June 10–13, 2010; Barcelona, Spain. Abstract 0295.

    • Search Google Scholar
    • Export Citation
  • 58

    Sher T, Miller KC, Lawrence D. Efficacy of lenalidomide in patients with chronic lymphocytic leukemia with high-risk cytogenetics. Leuk Lymphoma 2010;51:8588.

    • Search Google Scholar
    • Export Citation
  • 59

    Fowler N, Kahl BS, Rosen P. Bortezomib, bendamustine, and rituximab in patients with relapsed or refractory follicular lymphoma: encouraging activity in the phase 2 VERTICAL study [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 933.

    • Search Google Scholar
    • Export Citation
  • 60

    Treon SP, Ioakimidis L, Soumerai JD. Primary therapy of Waldenström macroglobulinemia with bortezomib, dexamethasone, and rituximab: WMCTG clinical trial 05-180. J Clin Oncol 2009;27:38303835.

    • Search Google Scholar
    • Export Citation
  • 61

    Hagenbeek A, Fayad L, Delwail V. Evaluation of ofatumumab, a novel human CD20 monoclonal antibody, as single agent therapy in rituximab-refractory follicular lymphoma [abstract]. Presented at the 51st American Society of Hematology Annual Meeting and Exposition; December 5–8, 2009; New Orleans, Louisiana. Abstract 935.

    • Search Google Scholar
    • Export Citation
  • 62

    Czuczman S, Viardot A, Hess G. Ofatumumab in combination with chop (O-CHOP) achieves high response rates in previously untreated follicular lymphoma (FL) patients with high-risk FLIPI scores [abstract]. Presented at the 2010 Annual Meeting of the European Hematology Association; June 10–13, 2010; Barcelona, Spain. Abstract 0237.

    • Search Google Scholar
    • Export Citation
  • 63

    Clinicaltrials.gov. Lumiliximab with fludarabine, cyclophosphamide, and rituximab (FCR) versus fcr alone in subjects with relapsed chronic lymphocytic leukemia (CLL) (LUCID). Available at: http://clinicaltrials.gov/ct2/show/NCT00391066. Accessed: May 10, 2010.

    • Search Google Scholar
    • Export Citation
  • 64

    Salles A, Morschhauser F, Thieblemont C. promising efficacy with the new anti-cd20 antibody ga101 in heavily pre-treated patients—first results from a phase II study in patients with relapsed/refractory indolent NHL (INHL) [abstract]. Presented at the 2010 Annual Meeting of the European Hematology Association; June 10–13, 2010; Barcelona, Spain. Abstract 0558.

    • Search Google Scholar
    • Export Citation
  • 65

    Friedberg JW, Sharman J, Sweetenham J. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood 2010;115:25782585.

    • Search Google Scholar
    • Export Citation
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