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Lymphoma

Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma

Leukemia volume 29, pages 1695–1701 (2015)Cite this article

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Abstract

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1–3 prior therapies received Bendamustine (90 mg/m2, day 1+2) and Rituximab (375 mg/m2, day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Cough, diarrhea, pyrexia and rash were observed in five patients (33%) each. Grade 3/4 events included leukopenia in 6 (40%), neutropenia in 4 (27%) and thrombocytopenia in 2 patients (13%). An objective response was observed in 14/15 patients (93%), including 5 complete response (33%; all MCL). After a median follow-up of 19 months, 67% of patients are without signs of progression. Temsirolimus can be safely added to BR with promising preliminary activity. Recruitment in phase II is ongoing.

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References

  1. Coiffier B, Lepage E, Briere 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: 235–242.

    Article  CAS  PubMed  Google Scholar 

  2. Hiddemann W, Dreyling M, Forstpointner R, Kneba M, Woermann B, Lengfelder E et al. Combined immunochemotherpy (R-CHOP) significantly improves time to treatment failure in first line therapy of follicular lymphoma. Results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). Blood 2003; 102: 352a.

    Google Scholar 

  3. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH et al. Treatment of older patients with mantle-cell lymphoma. N Engl J Med 2012; 367: 520–531.

    Article  CAS  PubMed  Google Scholar 

  4. Thomas DW, Owen RG, Johnson SA, Hillmen P, Seymour JF, Wolf MM et al. Superior quality and duration of responses among patients with mantle-cell lymphoma treated with fludarabine and cyclophosphamide with or without rituximab compared with prior responses to CHOP. Leuk Lymphoma 2005; 46: 549–552.

    Article  CAS  PubMed  Google Scholar 

  5. Lenz G, Dreyling M, Hoster E, Wormann B, Duhrsen U, Metzner B et al. 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 2005; 23: 1984–1992.

    Article  CAS  PubMed  Google Scholar 

  6. Advani R, Buggy J, Sharman J, Smith S, Boyd T, 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: 88–94.

    Article  CAS  PubMed  Google Scholar 

  7. 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 370: 1008–1018.

    Article  CAS  PubMed  Google Scholar 

  8. Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S et al. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol 2006; 24: 4867–4874.

    Article  PubMed  Google Scholar 

  9. Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol 2011; 22: 1622–1627.

    Article  CAS  PubMed  Google Scholar 

  10. Hidalgo M, Buckner JC, Erlichman C, Pollack MS, Boni JP, Dukart G et al. A phase I and pharmacokinetic study of temsirolimus (CCI-779) administered intravenously daily for 5 days every 2 weeks to patients with advanced cancer. Clin Cancer Res 2006; 12: 5755–5763.

    Article  CAS  PubMed  Google Scholar 

  11. Drakos E, Rassidakis GZ, Medeiros LJ . Mammalian target of rapamycin (mTOR) pathway signalling in lymphomas. Expert Rev Mol Med 2008; 10: e4.

    Article  PubMed  Google Scholar 

  12. Peponi E, Drakos E, Reyes G, Leventaki V, Rassidakis GZ, Medeiros LJ . Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol 2006; 169: 2171–2180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P et al. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol 2005; 23: 5347–5356.

    Article  CAS  PubMed  Google Scholar 

  14. Ansell SM, Inwards DJ, Rowland KM Jr, Flynn PJ, Morton RF, Moore DF Jr et al. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer 2008; 113: 508–514.

    Article  CAS  PubMed  Google Scholar 

  15. Renner C, Zinzani PL, Gressin R, Klingbiel D, Dietrich PY, Hitz F et al. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica 2012; 97: 1085–1091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Hess G, Romaguera J, Verhoef G, Herbrecht R, Crump M, Strahs A et al. Phase III study of patients with relapsed, refractory mantle cell lymphoma treated with temsirolimus compared with investigator's choice therapy. J Clin Oncol 2008; 27: 3822–3829, (May 20 suppl; abstr 8513).

    Article  Google Scholar 

  17. Hess G . Temsirolimus for the treatment of mantle cell lymphoma. Expert Rev Hematol 2009; 2: 631–640.

    Article  CAS  PubMed  Google Scholar 

  18. Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A et al. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol 2010; 28: 4740–4746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Farag SS, Zhang S, Jansak BS, Wang X, Kraut E, Chan K et al. Phase II trial of temsirolimus in patients with relapsed or refractory multiple myeloma. Leuk Res 2009; 33: 1475–1480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang L, Shi WY, Wu ZY, Varna M, Wang AH, Zhou L et al. Cytostatic and anti-angiogenic effects of temsirolimus in refractory mantle cell lymphoma. J Hematol Oncol 2010; 3: 30.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kiewe P, Thiel E . Impressive response to temsirolimus in a patient with chemotherapy refractory diffuse large B-cell non-Hodgkin's lymphoma. Ann Hematol 2011; 90: 109–110.

    Article  PubMed  Google Scholar 

  22. Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K et al. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol 2011; 12: 361–368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Inwards DJ, Fishkin P, LaPlant BR, Drake MT, Kurtin P, Nikcevich D et al. Phase I trial of Rituximab, Cladribine and Temsirolimus (RCT) for initial therapy of mantle cell lymphoma. ASH Annu Meeting Abstr 2012; 120: 3661.

    Google Scholar 

  24. Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D 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: 3383–3389.

    Article  CAS  PubMed  Google Scholar 

  25. 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: 1203–1210.

    Article  CAS  PubMed  Google Scholar 

  26. Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A et al. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol 2008; 26: 4473–4479.

    Article  CAS  PubMed  Google Scholar 

  27. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ et al. Revised response criteria for malignant lymphoma. J Clin Oncol 2007; 25: 579–586.

    Article  PubMed  Google Scholar 

  28. Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A et al. Analysis of the coding genome of diffuse large B-cell lymphoma. Nat Genet 2011; 43: 830–837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R et al. Combination of Rituximab, Bendamustine, and Cytarabine for patients with mantle-cell non-hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol 2013; 31: 1442–1449.

    Article  CAS  PubMed  Google Scholar 

  30. Weide R, Hess G, Koppler H, Heymanns J, Thomalla J, Aldaoud A et al. High anti-lymphoma activity of bendamustine/mitoxantrone/rituximab in rituximab pretreated relapsed or refractory indolent lymphomas and mantle cell lymphomas. A multicenter phase II study of the German Low Grade Lymphoma Study Group (GLSG). Leuk Lymphoma 2007; 48: 1299–1306.

    Article  CAS  PubMed  Google Scholar 

  31. Friedberg JW, Vose JM, Kelly JL, Young F, Bernstein SH, Peterson D et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011; 117: 2807–2812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Rigacci L, Puccini B, Cortelazzo S, Gaidano G, Piccin A, D’Arco A et al. Bendamustine with or without rituximab for the treatment of heavily pretreated non-Hodgkin’s lymphoma patients. Ann Hematol 2012; 91: 1013–1022.

    Article  CAS  PubMed  Google Scholar 

  33. Ahmadi T, Chong EA, Gordon A, Aqui NA, Nasta SD, Svoboda J et al. Combined lenalidomide, low-dose dexamethasone, and rituximab achieves durable responses in rituximab-resistant indolent and mantle cell lymphomas. Cancer 2014; 120: 222–228.

    Article  CAS  PubMed  Google Scholar 

  34. 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: 716–723.

    Article  PubMed  Google Scholar 

  35. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS et al. Targeting BTK with Ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013; 369: 507–516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia 2013; 27: 1902–1909.

    Article  CAS  PubMed  Google Scholar 

  37. Wang M, Hagemeister F, Westin J, Fayad L, Samaniego F, Turtorro 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. ASH Annu Meeting Abstr 2014 (abstract 627).

  38. Kahl BS, Spurgeon SE, Furman RR, Flinn IW, Coutre SE, Brown JR et al. A phase 1 study of the PI3Kδ inhibitor idelalisib in patients with relapsed/refractory mantle cell lymphoma (MCL). Blood 2014; 123: 3398–3405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Trneny M, Lamy T, Walewski J, Jurczak W, Belada D, Mayer J et al. Phase II randomized, multicenter study of lenalidomide vs best investigator’s choice in relapsed/refractory mantle cell lymphoma: results of the MCL-002 (SPRINT) Study. ASH Annu Meeting Abstr 2014; abstract 626.

  40. Zaja F, De Luca S, Vitolo U, Orsucci L, Levis A, Salvi F et al. Salvage treatment with lenalidomide and dexamethasone in relapsed/refractory mantle cell lymphoma: clinical results and effects on microenvironment and neo-angiogenic biomarkers. Haematologica 2012; 97: 416–422.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C et al. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica 2011; 96: 1008–1014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank the patients, their families, the clinical research staff at the various clinical sites and the IZKS for their contribution to this work. We thank I Schmidt for her assistance in the preparation of the manuscript. This trial was conducted within the German Low Grade Lymphoma Study Group (GLSG). This study was supported by Wyeth (later acquired by Pfizer) and Mundipharma.

Author Contributions

Johannes Atta recruited patients, collected data, and drafted the manuscript. Christian Buske and Christian Scholz recruited patients, collected data, read and approved the manuscript. Martin Dreyling recruited patients, collected and analyzed the data, read and drafted the manuscript. Georg Hess wrote the protocol, recruited patients, collected and analyzed the data and drafted the manuscript. Ulrich Keller and Sebastian Kirschey recruited patients, collected and analyzed the data, read and approved the manuscript. Christoph Medler and Christian Ruckes wrote the protocol, analyzed data, read and approved the manuscript. Matthias Theobald provided administrative support, analyzed data, read and approved the manuscript. Christina van Oordt coordinated the trial, collected data, read and approved the manuscript. Mathias Witzens-Harig wrote the protocol, recruited patients, collected data, read and approved the manuscript.

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Authors and Affiliations

  1. Department of Internal Medicine III (Hematology, Oncology, Pneumology), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    G Hess, S Kirschey, C van Oordt & M Theobald

  2. III. Medical Department, Technical University Munich, Munich, Germany

    U Keller

  3. Department of Hematology, Oncology, Charité - University Medical School Berlin, Berlin, Germany

    C W Scholz

  4. Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany

    M Witzens-Harig

  5. Department of Internal Medicine II, Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, Germany

    J Atta

  6. Institute of Experimental Cancer Research and Department of Internal Medicine III, University Hospital, Ulm, Germany

    C Buske

  7. Interdisciplinary Centre for Clinical Trials (IZKS), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany

    C Ruckes & C Medler

  8. Division of Hematophathology, Christian-Albrechts-University, Kiel, Germany

    W Klapper

  9. Department of Internal Medicine III, Ludwig-Maximilians-University, Munich, Germany

    M Dreyling

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Correspondence to G Hess.

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Competing interests

Johannes Atta received honoraria from Pfizer and Roche. Christian Buske received honoraria and research funding from Roche and Janssen and honoraria from Pfizer and Pharmacyclics. Martin Dreyling received research funding and speaker’s honoraria from Pfizer, Mundipharma and Roche. Georg Hess received research funding and honoraria from and is on the advisory committee of Pfizer, research funding from Mundipharma and honoraria from and is on the advisory committee of Roche. Ulrich Keller received honoraria from and is on the advisory committee of Pfizer and speaker and advisory board honoraria from Mundipharma and Roche. Christian Scholz received honoraria from and is on the advisory committee of Pfizer, research funding and honoraria from and is on the advisory committee of Mundipharma and honoraria from and is on the advisory committee of Roche. Mathias Witzens-Harig received research funding and honoraria from and is on the advirsory committee of Pfizer and Roche and honoraria from Mundipharma. The other authors declare no conflict of interest.

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Presented in part at the 13th International Conference on Malignant Lymphoma, Lugano, Switzerland, 2013.

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Hess, G., Keller, U., Scholz, C. et al. Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma. Leukemia 29, 1695–1701 (2015). https://doi.org/10.1038/leu.2015.60

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