Investigational New Drugs

, Volume 27, Issue 5, pp 476–481 | Cite as

Results of a Phase II trial of gemcitabine, mitoxantrone, and rituximab in relapsed or refractory mantle cell lymphoma

  • Lawrence E. Garbo
  • Patrick J. Flynn
  • Margaret A. MacRae
  • Mary A. Rauch
  • Yunfei Wang
  • Kathryn S. Kolibaba


Background: Gemcitabine (G) has shown activity in mantle cell lymphoma (MCL) as a single agent. The combination of mitoxantrone (M) and rituximab (R) is also active in MCL. The primary objective of this study was to determine the efficacy of G+M+R in relapsed or refractory MCL. Patients and Methods: Sixteen patients were enrolled between April 2005 and January 2007, 88% had Stage IV MCL, Median patient age was 74 years. Patients received gemcitabine 900 mg/m2 IV (30–60 min infusion) on Days 1 and 8, mitoxantrone 10 mg/m2 IV (5–10 min infusion) on day 1, and rituximab 375 mg/m2 IV on Day 1 (max 400 mg/hour) of the 21-day cycle. Patients received a median of 6 cycles (range, 1–8). Results: Best responses were CR 20% (95%CI, 0, 40.2), PR 27% (95%CI, 4.3, 49.1), SD 40% (95%CI, 15.2, 64.8), and PD 13% (95%CI, 0, 30.5). Median survival and PFS have not been reached with a median follow-up of 10.7 months. The most common Grade 3–4 toxicities were neutropenia (100%), thrombocytopenia (67%), leukopenia (53%), and anemia (33%). The study was closed early due to slow accrual owing to an alternative treatment which became available at the time. Conclusion: The combination of G+M+R in MCL was well-tolerated with manageable toxicity using growth factors to minimize neutropenia; further studies are warranted.


Multicenter Community-based Lymphoma Phase II 



We thank the patients who participated in this clinical trial, US Oncology physicians, the site coordinators, and data reviewers Denise Elmore-Lockheed, AA, Crystal Grant, BS, Tracy Locke, BS, Jessica Donato, MPH, for help with the statistical analysis, and Kristi A. Boehm, MS, and Maren K. Levin, MS, for editing and writing assistance. Research support was provided by Eli Lilly and Company, Indianapolis IN, USA.


  1. 1.
    Harris NL, Jaffe ES, Diebold J et al (2000) The World Health Organization classification of hematological malignancies report of the Clinical Advisory Committee Meeting, Airlie House, Virginia, November 1997. Mod Pathol 13(2):193–207 doi: 10.1038/modpathol.3880035 PubMedCrossRefGoogle Scholar
  2. 2.
    Jaffe E, Harris N, Stein H, Vardiman JW (eds) (2001) Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC, Lyon, FranceGoogle Scholar
  3. 3.
    Bertoni F, Zucca E, Cotter FE (2004) Molecular basis of mantle cell lymphoma. Br J Haematol 124(2):130–140 doi: 10.1046/j.1365-2141.2003.04761.x PubMedCrossRefGoogle Scholar
  4. 4.
    Hennessy BT, Hanrahan EO, Daly PA (2004) Non-Hodgkin lymphoma: an update. Lancet Oncol 5(6):341–353 doi: 10.1016/S1470-2045(04)01490-1 PubMedCrossRefGoogle Scholar
  5. 5.
    Lenz G, Dreyling M, Hoster E et al (2005) Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol 23(9):1984–1992 doi: 10.1200/JCO.2005.08.133 PubMedCrossRefGoogle Scholar
  6. 6.
    National Comprehensive Cancer Network (NCCN) NCCN Clinical practice guidelines in oncology: Non-hodgkin’s lymphoma, v.2.2008.
  7. 7.
    National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology: Non-hodgkin’s lymphoma, v.1.2005 (effective 6/21/05).Google Scholar
  8. 8.
    Fossa A, Santoro A, Hiddemann W, Truemper L, Niederle N, Buksmaui S, Bonadonna G, Seeber S, Nowrousian MR (1999) Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol 17:3786–3792PubMedGoogle Scholar
  9. 9.
    Santoro A, Bredenfeld H, Devizzi L, Tesch H, Bonfante V, Viviani S, Fiedler F, Parra HS, Benoehr C, Pacini M, Bonadonna G, Diehl V (2000) Gemcitabine in the treatment of refractory Hodgkin’s disease: results of a multicenter phase II study. J Clin Oncol 18:2615–2619PubMedGoogle Scholar
  10. 10.
    Savage DG, Rule SA, Tighe M, Garrett TJ, Oster MW, Lee RT, Ruiz J, Heitjan D, Keohan ML, Flamm M, Johnson SA (2000) Gemcitabine for relapsed or resistant lymphoma. Ann Oncol 11:595–597 doi: 10.1023/A:1008307528519 PubMedCrossRefGoogle Scholar
  11. 11.
    Dumontet C, Morschhauser F, Solal-Celigny P et al (2001) Gemcitabine as a single agent in the treatment of relapsed or refractory low-grade non-Hodgkin’s lymphoma. Br J Haematol 113(3):772–778 doi: 10.1046/j.1365-2141.2001.02795.x PubMedCrossRefGoogle Scholar
  12. 12.
    Maloney D, Grillo-López A, White C et al (1997) IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90:2188–2195PubMedGoogle Scholar
  13. 13.
    Coiffier B, Haioun C, Ketterer N et al (1998) Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood 92(6):1927–1932PubMedGoogle Scholar
  14. 14.
    Foran JM, Rohatiner AZ, Cunningham D et al (2000) 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 18(2):317–324PubMedGoogle Scholar
  15. 15.
    Gams RA, Bryan S, Dukart G et al (1985) Mitoxantrone in malignant lymphoma. Invest New Drugs 3(2):219–222 doi: 10.1007/BF00174174 PubMedCrossRefGoogle Scholar
  16. 16.
    Fortstpointner R, Dreyling M, Repp R et al (2004) The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104(10):3064–3071 doi: 10.1182/blood-2004-04-1323 CrossRefGoogle Scholar
  17. 17.
    Wenger C, Stern M, Herrmann R et al (2005) Rituximab plus gemcitabine: a therapeutic option for elderly or frail patients with aggressive non-Hodgkin’s lymphoma? Leuk Lymphoma 46(1):71–75 doi: 10.1080/10428190400007540 PubMedCrossRefGoogle Scholar
  18. 18.
    Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 92:205–216 doi: 10.1093/jnci/92.3.205 PubMedCrossRefGoogle Scholar
  19. 19.
    Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. JASA 53:457–481Google Scholar
  20. 20.
    Traullé C, Coiffier BB (2005) Evolving role of rituximab in the treatment of patients with non-Hodgkin’s lymphoma. Future Oncol 1(3):297–306 doi: 10.1517/14796694.1.3.297 PubMedCrossRefGoogle Scholar
  21. 21.
    Brody J, Advani R (2006) Treatment of mantle cell lymphoma: current approach and future directions. Crit Rev Oncol Hematol 58(3):257–265 doi: 10.1016/j.critrevonc.2005.10.001 PubMedCrossRefGoogle Scholar
  22. 22.
    Schulz H, Bohlius J, Skoetz N et al (2007) Chemotherapy plus rituximab versus chemotherapy alone for B-cell non-Hodgkin’s lymphoma. Cochrane Database Syst Rev 4:CD003805PubMedGoogle Scholar
  23. 23.
    National Cancer Institute FDA Approval for Bortezomib. (accessed February 12, 2008)
  24. 24.
    Goy A, Younes A, McLaughlin P et al (2005) Phase II study of proteasome inhibitor bortezomib in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J Clin Oncol 23(4):667–675 doi: 10.1200/JCO.2005.03.108 PubMedCrossRefGoogle Scholar
  25. 25.
    O’Connor OA, Wright J, Moskowitz C et al (2005) 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 23(4):676–684 doi: 10.1200/JCO.2005.02.050 PubMedCrossRefGoogle Scholar
  26. 26.
    Kane RC, Dagher R, Farrell A et al (2007) Bortezomib for the treatment of mantle cell lymphoma. Clin Cancer Res 13(18 Pt 1):5291–5294 doi: 10.1158/1078-0432.CCR-07-0871 PubMedCrossRefGoogle Scholar
  27. 27.
    Barr P, Fisher R, Friedberg J (2007) The role of bortezomib in the treatment of lymphomas. Cancer Invest 25(8):766–775 doi: 10.1080/07357900701579570 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Lawrence E. Garbo
    • 1
    • 2
  • Patrick J. Flynn
    • 1
    • 3
  • Margaret A. MacRae
    • 1
    • 4
  • Mary A. Rauch
    • 1
  • Yunfei Wang
    • 1
  • Kathryn S. Kolibaba
    • 1
    • 4
  1. 1.US Oncology Research, Inc.HoustonUSA
  2. 2.New York Oncology HematologyAlbanyUSA
  3. 3.Minnesota Oncology Hematology–MinneapolisMinneapolisUSA
  4. 4.Northwest Cancer Specialists–VancouverVancouverUSA

Personalised recommendations