title: Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.
abstract: BACKGROUND
  In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease.
  
  
  METHODS
  This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete.
  
  
  RESULTS
  Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report.
  
  
  CONCLUSIONS
  The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenström's macroglobulinaemia.
  
  
  BACKGROUND
  Pharmacyclics LLC, an AbbVie Company.
authors.affiliation: National and Kapodistrian University of Athens School of Medicine, Athens, Greece. Electronic address: mdimop@med.uoa.gr.
authors.forename: Meletios A
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: Concord Hospital, University of Sydney, Concord, NSW, Australia.
authors.forename: Judith
authors.initials: J
authors.lastname: Trotman
authors.affiliation: Niguarda Ca' Granda Hospital, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Tedeschi
authors.affiliation: Colorado Blood Cancer Institute, Denver, CO, USA.
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Matous
authors.affiliation: Dalhousie University, Halifax, NS, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Macdonald
authors.affiliation: Peter MacCallum Cancer Centre and St Vincent's Hospital, Melbourne, VIC, Australia.
authors.forename: Constantine
authors.initials: C
authors.lastname: Tam
authors.affiliation: Hématologie Clinique Adulte et Thérapie Cellulaire, CHU de Clermont-Ferrand, Clermont-Ferrand, France; EA 7283, Universite d'Auvergne, Clermont-Ferrand, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Tournilhac
authors.affiliation: Robert H Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Ma
authors.affiliation: Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Oriol
authors.affiliation: Winship Cancer Institute of Emory University, Atlanta, GA, USA.
authors.forename: Leonard T
authors.initials: LT
authors.lastname: Heffner
authors.affiliation: Royal Victoria Hospital at McGill University Health Centre, Montreal, QC, Canada.
authors.forename: Chaim
authors.initials: C
authors.lastname: Shustik
authors.affiliation: Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: García-Sanz
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Cornell
authors.affiliation: Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain.
authors.forename: Carlos Fernández
authors.initials: CF
authors.lastname: de Larrea
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Jorge J
authors.initials: JJ
authors.lastname: Castillo
authors.affiliation: Hospital Sant Pau, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Granell
authors.affiliation: National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Kyrtsonis
authors.affiliation: Hôpital Pitié-Salpêtrière APHP, UPMC Université Paris, Paris, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblond
authors.affiliation: University of Patras Medical School, Patras, Greece.
authors.forename: Argiris
authors.initials: A
authors.lastname: Symeonidis
authors.affiliation: National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: Efstathios
authors.initials: E
authors.lastname: Kastritis
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Singh
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA.
authors.forename: Jianling
authors.initials: J
authors.lastname: Li
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Graef
authors.affiliation: Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bilotti
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Treon
authors.affiliation: Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital of Ulm, Ulm, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Buske
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D010880:Piperidines; D011379:Prognosis; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D000069283:Rituximab / Q000008:administration & dosage; D016879:Salvage Therapy; D015996:Survival Rate; D008258:Waldenstrom Macroglobulinemia / Q000188:drug therapy* / Q000473:pathology
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000069283:Rituximab; D000225:Adenine