Roger G Owen1, Helen McCarthy2, Simon Rule3, Shirley D'Sa4, Sheeba K Thomas5, Olivier Tournilhac6, Francesco Forconi7, Marie José Kersten8, Pier Luigi Zinzani9, Sunil Iyengar10, Jaimal Kothari11, Monique C Minnema12, Efstathios Kastritis13, Thérèse Aurran-Schleinitz14, Bruce D Cheson15, Harriet Walter16, Daniel Greenwald17, Dih-Yih Chen18, Melanie M Frigault18, Ahmed Hamdy18, Raquel Izumi18, Priti Patel18, Helen Wei18, Sun Ku Lee18, Diana Mittag19, Richard R Furman20. 1. St James's University Hospital, Leeds, UK. Electronic address: rogerowen@nhs.net. 2. Royal Bournemouth Hospital, Bournemouth, UK. 3. Plymouth University Medical School, Plymouth, UK. 4. University College London Hospitals NHS Trust, London, UK. 5. University of Texas M. D. Anderson Cancer Center, Houston, TX, USA. 6. Clermont-Ferrand University Hospital, Clermont-Ferrand, France/Lymphomas Study Association. 7. University of Southampton Hospital Trust, Southampton, UK. 8. Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; on behalf of the Lunenburg Lymphoma Phase I/II Consortium - HOVON/LLPC. 9. Institute of Hematology University of Bologna, Bologna, Italy. 10. Royal Marsden Hospital, London, UK. 11. Churchill Hospital, Oxford, UK. 12. University Medical Centre Utrecht Cancer Centre, Utrecht, The Netherlands; on behalf of the Lunenburg Lymphoma Phase I/II Consortium - HOVON/LLPC. 13. Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece. 14. Institut Paoli Calmette, Marseille, France. 15. Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA. 16. Ernest and Helen Scott Haematological Research Institute and Leicester Cancer Research Centre, University of Leicester, Leicester, UK. 17. Cancer Center of Santa Barbara, Santa Barbara, CA, USA. 18. Acerta Pharma, South San Francisco, CA, USA. 19. Acerta Pharma, Oss, The Netherlands. 20. Weill Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA.
Abstract
BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.
BACKGROUND: Chemoimmunotherapy is typically the standard of care for patients with Waldenström macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenström macroglobulinemia. METHODS: This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenström macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenström Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov, number NCT02180724, and is ongoing, but no longer enrolling. FINDINGS: Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0-29·7), 13 (93% [95% CI 66-100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86-98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3-4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3-4 atrial fibrillation occurred in one (1%) patient and grade 3-4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). INTERPRETATION: This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenström macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. FUNDING: Acerta Pharma.
Authors: Julio Delgado; Filip Josephson; Jorge Camarero; Blanca Garcia-Ochoa; Lucia Lopez-Anglada; Carolina Prieto-Fernandez; Paula B van Hennik; Irene Papadouli; Christian Gisselbrecht; Harald Enzmann; Francesco Pignatti Journal: Oncologist Date: 2021-02-10
Authors: Constantine S Tam; Stephen Opat; Shirley D'Sa; Wojciech Jurczak; Hui-Peng Lee; Gavin Cull; Roger G Owen; Paula Marlton; Björn E Wahlin; Ramón Garcia Sanz; Helen McCarthy; Stephen Mulligan; Alessandra Tedeschi; Jorge J Castillo; Jaroslaw Czyz; Carlos Fernández de Larrea; David Belada; Edward Libby; Jeffrey V Matous; Marina Motta; Tanya Siddiqi; Monica Tani; Marek Trneny; Monique C Minnema; Christian Buske; Veronique Leblond; Judith Trotman; Wai Y Chan; Jingjing Schneider; Sunhee Ro; Aileen Cohen; Jane Huang; Meletios Dimopoulos Journal: Blood Date: 2020-10-29 Impact factor: 22.113
Authors: Meletios Dimopoulos; Ramon Garcia Sanz; Hui-Peng Lee; Marek Trneny; Marzia Varettoni; Stephen Opat; Shirley D'Sa; Roger G Owen; Gavin Cull; Stephen Mulligan; Jaroslaw Czyz; Jorge J Castillo; Marina Motta; Tanya Siddiqi; Mercedes Gironella Mesa; Miquel Granell Gorrochategui; Dipti Talaulikar; Pier Luigi Zinzani; Elham Askari; Sebastian Grosicki; Albert Oriol; Simon Rule; Janusz Kloczko; Alessandra Tedeschi; Christian Buske; Veronique Leblond; Judith Trotman; Wai Y Chan; Jan Michel; Jingjing Schneider; Ziwen Tan; Aileen Cohen; Jane Huang; Constantine S Tam Journal: Blood Adv Date: 2020-12-08
Authors: Jorge J Castillo; Jithma P Abeykoon; Joshua N Gustine; Saurabh Zanwar; Kirsten Mein; Catherine A Flynn; Maria G Demos; Maria L Guerrera; Amanda Kofides; Xia Liu; Manit Munshi; Nickolas Tsakmaklis; Rebecca King; Guang Yang; Zachary R Hunter; Ranjana H Advani; Maria Lia Palomba; Stephen M Ansell; Morie A Gertz; Prashant Kapoor; Steven P Treon Journal: Br J Haematol Date: 2020-11-18 Impact factor: 6.998