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. 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 9·3–11·7) 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. Interpretation 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. Funding Pharmacyclics LLC, an AbbVie Company. © 2017 Elsevier Ltd

Notes:

Export Date: 18 February 2017References: Treon, S.P., Waldenström's macroglobulinemia: an indolent B-cell lymphoma with distinct molecular and clinical features (2013) Hematol Oncol, 31, pp. 76-80;Dimopoulos, M.A., Kastritis, E., Owen, R.G., Treatment recommendations for patients with Waldenström macroglobulinemia (WM) and related disorders: IWWM-7 consensus (2014) Blood, 124, pp. 1404-1411; Buske, C., Leblond, V., How to manage Waldenström's macroglobulinemia (2013) Leukemia, 27, pp. 762-772; Buske, C., Sadullah, S., Kastritis, E., Treatment and outcome patterns in patients with relapsed Waldenström's macroglobulinemia: development of a large observational Pan-European data platform (2016), The 21st European Hematology Association Annual Congress; Copenhagen, Denmark; June 9–12,. Abstr E1275Castillo, J.J., Kanan, S., Meid, K., Manning, R., Hunter, Z.R., Treon, S.P., Rituximab intolerance in patients with Waldenström macroglobulinaemia (2016) Br J Haematol, 174, pp. 645-684; Treon, S.P., Xu, L., Yang, G., MYD88 L265P somatic mutation in Waldenström's macroglobulinemia (2012) N Engl J Med, 367, pp. 826-833; Yang, G., Zhou, Y., Liu, X., A mutation in MYD88 (L265P) supports the survival of lymphoplasmacytic cells by activation of Bruton tyrosine kinase in Waldenström macroglobulinemia (2013) Blood, 122, pp. 1222-1232; Yang, G., Buhrlage, S.J., Tan, L., HCK is a survival determinant transactivated by mutated MYD88, and a direct target of ibrutinib (2016) Blood, 127, pp. 3237-3252; Treon, S.P., Tripsas, C.K., Meid, K., Ibrutinib in previously treated Waldenström's macroglobulinemia (2015) N Engl J Med, 372, pp. 1430-1440; Kyle, R.A., Treon, S.P., Alexanian, R., Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia (2003) Semin Oncol, 30, pp. 116-120; Owen, R.G., Treon, S.P., Al-Katib, A., Clinicopathological definition of Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia (2003) Semin Oncol, 30, pp. 110-115; Cella, D., The Functional Assessment of Cancer Therapy-Anemia (FACT-An) Scale: a new tool for the assessment of outcomes in cancer anemia and fatigue (1997) Semin Hematol, 34 (3), pp. 13-19; Herdman, M., Gudex, C., Lloyd, A., Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) (2011) Qual Life Res, 20, pp. 1727-1736; http://www.personalis.com/cancer/cancer-panel-dna-rna, (accessed June 27, 2016)Treon, S.P., How I treat Waldenström macroglobulinemia (2009) Blood, 114, pp. 2375-2385; Xu, L., Hunter, Z.R., Tsakmaklis, N., Clonal architecture of CXCR4 WHIM-like mutations in WM (2016) Br J Hematol, 172, pp. 735-744; Castillo, J.J., Garcia-Sanz, R., Hatjiharissi, E., Recommendations for the diagnosis and initial evaluation of patients with Waldenström Macroglobulinemia: a task force from the 8th International Workshop on Waldenström Macroglobulinemia (2016) Br J Hematol, 175, pp. 77-86; Treon, S.P., Xu, L., Hunter, Z., MYD88 mutations and response to ibrutinib in Waldenström's macroglobulinemia (2015) N Engl J Med, 373, pp. 584-586; Treon, S.P., Cao, Y., Yang, G., Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenström macroglobulinemia (2014) Blood, 123, pp. 2791-2796; Gustine, J.N., Meid, K., Dubeau, T.E., Treon, S.P., Castillo, J.J., Atrial fibrillation associated with ibrutinib in Waldenström macroglobulinemia (2016) Am J Hematol, 91, pp. E312-E313; Treon, S.P., Hanzis, C., Tripsas, C., Bendamustine therapy in patients with relapsed or refractory Waldenström's macroglobulinemia (2011) Clin Lymphoma Myeloma Leuk, 11, pp. 133-135; Chen, C.I., Kouroukis, C.T., White, D., Bortezomib is active in patients with untreated or relapsed Waldenstrom's macroglobulinemia: a phase II study of the National Cancer Institute of Canada Clinical Trials Group (2007) J Clin Oncol, 25, pp. 1570-1575; Ghobrial, I.M., Gertz, M., Laplant, B., Phase II trial of the oral mammalian target of rapamycin inhibitor everolimus in relapsed or refractory Waldenström macroglobulinemia (2010) J Clin Oncol, 28, pp. 1408-1414; Ghobrial, I.M., Campigotto, F., Murphy, T.J., Results of a phase 2 trial of the single-agent histone deacetylase inhibitor panobinostat in patients with relapsed/refractory Waldenström macroglobulinemia (2013) Blood, 121, pp. 1296-1303; Treon, S.P., Hunter, Z.R., Matous, J., Multicenter clinical trial of bortezomib in relapsed/refractory Waldenström's macroglobulinemia: results of WMCTG Trial 03–248 (2007) Clin Cancer Res, 13, pp. 3320-3325; Strauss, S.J., Maharaj, L., Hoare, S., Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity (2006) J Clin Oncol, 24, pp. 2105-2112; Treon, S.P., Soumerai, J.D., Branagan, A.R., Lenalidomide and rituximab in Waldenström's macroglobulinemia (2009) Clin Cancer Res, 15, pp. 355-360

Website