A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma

Christoph Renner, Pier Luigi Zinzani, Rémy Gressin, Dirk Klingbiel, Pierre Yves Dietrich, Felicitas Hitz, Mario Bargetzi, Walter Mingrone, Giovanni Martinelli, Andreas Trojan, Krimo Bouabdallah, Andreas Lohri, Emmanuel Gyan, Christine Biaggi, Sergio Cogliatti, Francesco Bertoni, Michele Ghielmini, Peter Brauchli, Nicolas Ketterer

Research output: Contribution to journalArticle

Abstract

Background Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). Design and Methods Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Results Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Conclusions Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted. (Clinicaltrials.gov identifier: NCT00516412).

Original languageEnglish
Pages (from-to)1085-1091
Number of pages7
JournalHaematologica
Volume97
Issue number7
DOIs
Publication statusPublished - Jul 1 2012

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Mantle-Cell Lymphoma
Sirolimus
Cyclin D1
Disease-Free Survival
Protein-Serine-Threonine Kinases
B-Cell Lymphoma
Combination Drug Therapy
Neutropenia
Terminology
Thrombocytopenia
Multicenter Studies
Disease Progression
Everolimus
Anemia
Lymphoma
Therapeutics
Drug Therapy
Polymerase Chain Reaction

Keywords

  • Everolimus
  • Mantle cell lymphoma
  • RAD001
  • Refractory
  • Relapsed

ASJC Scopus subject areas

  • Hematology

Cite this

Renner, C., Zinzani, P. L., Gressin, R., Klingbiel, D., Dietrich, P. Y., Hitz, F., ... Ketterer, N. (2012). A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica, 97(7), 1085-1091. https://doi.org/10.3324/haematol.2011.053173

A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. / Renner, Christoph; Zinzani, Pier Luigi; Gressin, Rémy; Klingbiel, Dirk; Dietrich, Pierre Yves; Hitz, Felicitas; Bargetzi, Mario; Mingrone, Walter; Martinelli, Giovanni; Trojan, Andreas; Bouabdallah, Krimo; Lohri, Andreas; Gyan, Emmanuel; Biaggi, Christine; Cogliatti, Sergio; Bertoni, Francesco; Ghielmini, Michele; Brauchli, Peter; Ketterer, Nicolas.

In: Haematologica, Vol. 97, No. 7, 01.07.2012, p. 1085-1091.

Research output: Contribution to journalArticle

Renner, C, Zinzani, PL, Gressin, R, Klingbiel, D, Dietrich, PY, Hitz, F, Bargetzi, M, Mingrone, W, Martinelli, G, Trojan, A, Bouabdallah, K, Lohri, A, Gyan, E, Biaggi, C, Cogliatti, S, Bertoni, F, Ghielmini, M, Brauchli, P & Ketterer, N 2012, 'A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma', Haematologica, vol. 97, no. 7, pp. 1085-1091. https://doi.org/10.3324/haematol.2011.053173
Renner, Christoph ; Zinzani, Pier Luigi ; Gressin, Rémy ; Klingbiel, Dirk ; Dietrich, Pierre Yves ; Hitz, Felicitas ; Bargetzi, Mario ; Mingrone, Walter ; Martinelli, Giovanni ; Trojan, Andreas ; Bouabdallah, Krimo ; Lohri, Andreas ; Gyan, Emmanuel ; Biaggi, Christine ; Cogliatti, Sergio ; Bertoni, Francesco ; Ghielmini, Michele ; Brauchli, Peter ; Ketterer, Nicolas. / A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. In: Haematologica. 2012 ; Vol. 97, No. 7. pp. 1085-1091.
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AU - Klingbiel, Dirk

AU - Dietrich, Pierre Yves

AU - Hitz, Felicitas

AU - Bargetzi, Mario

AU - Mingrone, Walter

AU - Martinelli, Giovanni

AU - Trojan, Andreas

AU - Bouabdallah, Krimo

AU - Lohri, Andreas

AU - Gyan, Emmanuel

AU - Biaggi, Christine

AU - Cogliatti, Sergio

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AU - Brauchli, Peter

AU - Ketterer, Nicolas

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AB - Background Mantle cell lymphoma accounts for 6% of all B-cell lymphomas and is generally incurable. It is characterized by the translocation t(11;14) leading to cyclin D1 over-expression. Cyclin D1 is downstream of the mammalian target of rapamycin threonine kinase and can be effectively blocked by mammalian target of rapamycin inhibitors. We set out to examine the single agent activity of the orally available mammalian target of rapamycin inhibitor everolimus in a prospective, multicenter trial in patients with relapsed or refractory mantle cell lymphoma (NCT00516412). Design and Methods Eligible patients who had received a maximum of three prior lines of chemotherapy were given everolimus 10 mg for 28 days (one cycle) for a total of six cycles or until disease progression. The primary endpoint was the best objective response. Adverse reactions, progression-free survival and molecular response were secondary endpoints. Results Thirty-six patients (35 evaluable) were enrolled and treatment was generally well tolerated with Common Terminology Criteria grade ≥3 adverse events (>5%) including anemia (11%), thrombocytopenia (11%) and neutropenia (8%). The overall response rate was 20% (95% CI: 8-37%) with two complete remissions and five partial responses; 49% of the patients had stable disease. At a median follow-up of 6 months, the median progression-free survival was 5.5 months (95% CI: 2.8-8.2) overall and 17.0 (6.4-23.3) months for 18 patients who received six or more cycles of treatment. Three patients achieved a lasting complete molecular response, as assessed by polymerase chain reaction analysis of peripheral blood. Conclusions Everolimus as a single agent is well tolerated and has anti-lymphoma activity in relapsed or refractory mantle cell lymphoma. Further studies of everolimus in combination with chemotherapy or as a single agent for maintenance treatment are warranted. (Clinicaltrials.gov identifier: NCT00516412).

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