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Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA

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Abstract

Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1–3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.

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References

  1. Leux C, Maynadié M, Troussard X, Cabrera Q, Herry A, Le Guyader-Peyrou S, Le Gouill S, Monnereau A (2014) Mantle cell lymphoma epidemiology: a population-based study in France. Ann Hematol 93:1327–1333

    Article  Google Scholar 

  2. Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Procházka V, di Raimondo F, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH (2012) Treatment of older patients with mantle-cell lymphoma. N Engl J Med 367:520–531

    Article  CAS  Google Scholar 

  3. Le Gouill S, Thieblemont C, Oberic L et al (2017) Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med 377:1250–1260

    Article  Google Scholar 

  4. Jares P, Colomer D, Campo E (2012) Molecular pathogenesis of mantle cell lymphoma. J Clin Invest 122:3416–3423

    Article  CAS  Google Scholar 

  5. Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B (2009) Phase III study to evaluate Temsirolimus compared with Investigator’s choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol 27:3822–3829

    Article  CAS  Google Scholar 

  6. Hess G, Coiffier B, Crump M, Gisselbrecht C, Offner F, Romaguera J, Kang L, Moran PJ (2015) Effect of prognostic classification on temsirolimus efficacy and safety in patients with relapsed or refractory mantle cell lymphoma: a retrospective analysis. Exp Hematol Oncol 4:11

    Article  Google Scholar 

  7. Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S (2016) Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet Lond Engl 387:770–778

    Article  CAS  Google Scholar 

  8. Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA (2013) Targeting BTK with Ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 369:507–516

    Article  CAS  Google Scholar 

  9. Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L, SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network (2016) Lenalidomide versus investigator’s choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol 17:319–331

    Article  Google Scholar 

  10. Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K, Ziesmer SC, Feldman AL, Rao R, Gupta M, Erlichman C, Witzig TE (2011) Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol 12:361–368

    Article  CAS  Google Scholar 

  11. Hess G, Keller U, Scholz CW, Witzens-Harig M, Atta J, Buske C, Kirschey S, Ruckes C, Medler C, van Oordt C, Klapper W, Theobald M, Dreyling M (2015) Safety and efficacy of Temsirolimus in combination with Bendamustine and rituximab in relapsed mantle cell and follicular lymphoma. Leukemia 29:1695–1701

    Article  CAS  Google Scholar 

  12. Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R, Zaja F, Semenzato G, Pizzolo G, D'Amore ESG, Rodeghiero F (2013) Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol Off J Am Soc Clin Oncol 31:1442–1449

    Article  CAS  Google Scholar 

  13. Inwards DJ, Fishkin PA, LaPlant BR, Drake MT, Kurtin PJ, Nikcevich DA, Wender DB, Lair BS, Witzig TE (2014) Phase I trial of rituximab, cladribine, and temsirolimus (RCT) for initial therapy of mantle cell lymphoma. Ann Oncol Off J Eur Soc Med Oncol 25:2020–2024

    Article  CAS  Google Scholar 

  14. Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F, LYM-3002 Investigators (2015) Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med 372:944–953

    Article  CAS  Google Scholar 

  15. Witzens-Harig M, Memmer ML, Dreyling M, Hess G (2013) A phase I/II trial to evaluate the safety, feasibility and activity of salvage therapy consisting of the mTOR inhibitor temsirolimus added to standard therapy of rituximab and DHAP for the treatment of patients with relapsed or refractory diffuse large cell B-cell lymphoma - the STORM trial. BMC Cancer 13:308

    Article  CAS  Google Scholar 

  16. Zhao X, Lwin T, Silva A, Shah B, Tao J, Fang B, Zhang L, Fu K, Bi C, Li J, Jiang H, Meads MB, Jacobson T, Silva M, Distler A, Darville L, Zhang L, Han Y, Rebatchouk D, di Liberto M, Moscinski LC, Koomen JM, Dalton WS, Shain KH, Wang M, Sotomayor E, Tao J (2017) Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma. Nat Commun 8:14920

    Article  CAS  Google Scholar 

Download references

Acknowledgements

• KB, BB, TL, RG, GC, CT, CS, CH, OC, EG, OH, and SLG performed the research.

• SLG designed the research study.

• BT and SLG analyzed the data and wrote the paper.

• CJ performed the statistical analyses.

Funding

This trial was funded by Pfizer, Inc. and LYSARC was the sponsor.

Author information

Authors and Affiliations

  1. Department of Hematology, CHU de Nantes, University Hospital of Nantes, Nantes, France

    Benoît Tessoulin & Steven Le Gouill

  2. INSERM, UMR892, Equipe 10, Nantes, France

    Benoît Tessoulin & Steven Le Gouill

  3. Haematology, CHU de Bordeaux, Bordeaux, France

    Kamal Bouabdallah

  4. Pathology Department, Cochin University Hospital, AP-HP, Paris, France

    Barbara Burroni

  5. INSERM U917, CHU Pontchaillou, Rennes, France

    Thierry Lamy

  6. Hematology, CHU Grenoble, Grenoble, Grenoble, France

    Remy Gressin

  7. Department of clinical hematology, University Hospital Montpellier, Montpellier, France

    Guillaume Cartron

  8. Hôpital Saint-Louis, Paris, France

    Catherine Thieblemont

  9. Hematology, Hospices Civils de Lyon, Pierre Bénite, Lyon, France

    Clémentine Sarkozy

  10. Lymphoid Malignancies Unit, AP-HP, Groupe Hospitalier Mondor, Croéteil, France

    Corinne Haioun

  11. Hematology Department, Hopital Le Bocage, CHU Dijon, Dijon, France

    Olivier Casasnovas

  12. Department of Biostatistics, LYSARC, Lyon, France

    Clementine Joubert

  13. Service d′Hématologie et thérapie cellulaire, Centre Hospitalier Universitaire, Tours, France

    Emmanuel Gyan

  14. Hematology Department, Necker University Hospital, AP-HP, Paris, France

    Olivier Hermine

  15. INSERM, CIC 004, Nantes University Hospital, Nantes, France

    Steven Le Gouill

Authors
  1. Benoît Tessoulin
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  2. Kamal Bouabdallah
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  3. Barbara Burroni
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  4. Thierry Lamy
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  5. Remy Gressin
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  6. Guillaume Cartron
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  7. Catherine Thieblemont
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  8. Clémentine Sarkozy
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  10. Olivier Casasnovas
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  11. Clementine Joubert
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  12. Emmanuel Gyan
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  13. Olivier Hermine
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  14. Steven Le Gouill
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Corresponding author

Correspondence to Steven Le Gouill.

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The authors have no competing interests.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Tessoulin, B., Bouabdallah, K., Burroni, B. et al. Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA. Ann Hematol 99, 1771–1778 (2020). https://doi.org/10.1007/s00277-020-04159-3

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  • DOI: https://doi.org/10.1007/s00277-020-04159-3

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