Ian W Flinn1,2, Carole B Miller3, Kirit M Ardeshna4, Scott Tetreault5, Sarit E Assouline6, Jiri Mayer7, Michele Merli8, Scott D Lunin5, Andrew R Pettitt9, Zoltan Nagy10, Olivier Tournilhac11, Karem-Etienne Abou-Nassar12, Michael Crump13, Eric D Jacobsen14, Sven de Vos15, Virginia M Kelly16, Weiliang Shi16, Lori Steelman16, NgocDiep Le17, David T Weaver17, Stephanie Lustgarten17, Nina D Wagner-Johnston18, Pier Luigi Zinzani19. 1. 1 Sarah Cannon Research Institute, Nashville, TN. 2. 2 Tennessee Oncology, Nashville, TN. 3. 3 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD. 4. 4 University College London Hospitals National Health Service Foundation Trust, London, United Kingdom. 5. 5 Florida Cancer Specialists, Tallahassee, FL. 6. 6 McGill University, Montreal, Quebec, Canada. 7. 7 Fakultní Nemocnice Brno, Brno, Czech Republic. 8. 8 Ospedale di Circolo e Fondazione Macchi, Varese, Italy. 9. 9 University of Liverpool, Liverpool, United Kingdom. 10. 10 Semmelweis Egyetem, Budapest, Hungary. 11. 11 Centre Hospitalier Universitaire Estaing, Clermont-Ferrand, France. 12. 12 Centre intégré de santé et de services sociaux de l'Outaouais, Gatineau, Quebec, Canada. 13. 13 Princess Margaret Cancer Centre, Toronto, Ontario, Canada. 14. 14 Dana-Farber Cancer Institute, Boston, MA. 15. 15 Ronald Reagan University of California, Los Angeles, Medical Center, Los Angeles, CA. 16. 16 Infinity Pharmaceuticals, Cambridge, MA. 17. 17 Verastem Oncology, Needham, MA. 18. 18 Washington University in St Louis, St Louis, MO. 19. 19 University of Bologna, Bologna, Italy.
Abstract
PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
PURPOSE: Indolent non-Hodgkin lymphoma (iNHL) remains largely incurable and often requires multiple lines of treatment after becoming refractory to standard therapies. Duvelisib was approved by the Food and Drug Administration for relapsed or refractory (RR) chronic lymphocytic leukemia or small lymphocytic lymphoma (SLL) and RR follicular lymphoma (FL) after two or more prior systemic therapies. On the basis of the activity of duvelisib, a first-in-class oral dual inhibitor of phosphoinositide 3-kinase-δ,-γ, in RR iNHL in a phase I study, the safety and efficacy of duvelisib monotherapy was evaluated in iNHL refractory to rituximab and either chemotherapy or radioimmunotherapy. PATIENTS AND METHODS: Eligible patients had measurable iNHL (FL, SLL, or marginal zone B-cell lymphoma) double refractory to rituximab (monotherapy or in combination) and to either chemotherapy or radioimmunotherapy. All were treated with duvelisib 25 mg orally twice daily in 28-day cycles until progression, unacceptable toxicity, or death. The primary end point was overall response rate (ORR) using the revised International Working Group criteria for malignant lymphoma. RESULTS: This open-label, global phase II trial enrolled 129 patients (median age, 65 years; median of three prior lines of therapy) with an ORR of 47.3% (SLL, 67.9%; FL, 42.2%; MZL, 38.9%). The estimated median duration of response was 10 months, and the estimated median progression-free survival was 9.5 months. The most frequent any-grade treatment-emergent adverse events (TEAEs) were diarrhea (48.8%), nausea (29.5%), neutropenia (28.7%), fatigue (27.9%), and cough (27.1%). Among the 88.4% of patients with at least one grade 3 or greater TEAE, the most common TEAEs were neutropenia (24.8%), diarrhea (14.7%), anemia (14.7%), and thrombocytopenia (11.6%). CONCLUSION: In the DYNAMO study, oral duvelisib monotherapy demonstrated clinically meaningful activity and a manageable safety profile in heavily pretreated, double-refractory iNHL, consistent with previous observations. Duvelisib may provide a new oral treatment option for this patient population of which many are elderly and in need of additional therapies.
Authors: Alix Y L Zackon; Amy A Ayers; Katherine A Yeager; Mary L Somma; Jonathan W Friedberg; Christopher R Flowers; Loretta J Nastoupil Journal: Leuk Lymphoma Date: 2019-06-04
Authors: Manette A W Dinnessen; Marjolein W M van der Poel; Sanne H Tonino; Otto Visser; Nicole M A Blijlevens; Daphne de Jong; King H Lam; Marie José Kersten; Pieternella J Lugtenburg; Avinash G Dinmohamed Journal: Leukemia Date: 2020-10-12 Impact factor: 11.528