Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial

Summary 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 mac...

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Published in:The lancet oncology 2017-02, Vol.18 (2), p.241-250
Main Authors: Dimopoulos, Meletios A, Dr Prof, Trotman, Judith, Prof, Tedeschi, Alessandra, MD, Matous, Jeffrey V, Prof, Macdonald, David, MD, Tam, Constantine, MBBS, Tournilhac, Olivier, Prof, Ma, Shuo, MD, Oriol, Albert, MD, Heffner, Leonard T, MD, Shustik, Chaim, Prof, García-Sanz, Ramón, Prof, Cornell, Robert F, MD, de Larrea, Carlos Fernández, MD, Castillo, Jorge J, MD, Granell, Miquel, MD, Kyrtsonis, Marie-Christine, MD, Leblond, Veronique, Prof, Symeonidis, Argiris, MD, Kastritis, Efstathios, MD, Singh, Priyanka, MS, Li, Jianling, MS, Graef, Thorsten, MD, Bilotti, Elizabeth, MSN, Treon, Steven, MD, Buske, Christian, Prof
Format: Article
Language:English
Subjects:
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Chemotherapy
Drug Resistance, Neoplasm - drug effects
Female
Follow-Up Studies
Hematology
Hematology, Oncology and Palliative Medicine
Hepatitis
Hepatitis B virus
Hepatitis C virus
Human health and pathology
Humans
Infections
Life Sciences
Lymphoma
Male
Middle Aged
Neoplasm Staging
Neutropenia
Patients
Prognosis
Pyrazoles - administration & dosage
Pyrimidines - administration & dosage
Rituximab - administration & dosage
Salvage Therapy
Survival Rate
Waldenstrom Macroglobulinemia - drug therapy
Waldenstrom Macroglobulinemia - pathology
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Summary:Summary 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. Findings 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 9·3–1
ISSN:1470-2045
1474-5488
DOI:10.1016/S1470-2045(16)30632-5