Abstract Background: The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Discontinuation of ibrutinib has been associated with an adverse prognosis in patients with chronic lymphocytic leukemia and mantle cell lymphoma. However, reasons for discontinuing ibrutinib therapy and the outcomes following discontinuation in patients with WM has not been previously evaluated. Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM and received ibrutinib therapy. An IgM rebound was defined as a 25% increase in the serum IgM level (with an absolute increase of 500 mg/dl) following the discontinuation of ibrutinib. Time to events was estimated using the Kaplan-Meier method. Univariate and multivariate logistic regression models were fitted to evaluate the association between clinical variables and the occurrence of ibrutinib discontinuation and an IgM rebound. The Cox-proportional hazard regression model was used to fit univariate and multivariate models for overall survival (OS). P-values <0.05 were considered statistically significant. Results: A total of 189 patients with WM who received treatment with ibrutinib were identified, of whom 51 (27%) have discontinued ibrutinib therapy. The overall cumulative incidence of ibrutinib discontinuation at 12, 24, 36, and 48 months was 22%, 25%, 35%, and 43%, respectively. Ibrutinib was discontinued due to progressive disease (PD) in 27 patients (53%). The median time to PD discontinuation was 12 months (95% CI 7-25), and the 12-, 24-, 36-, and 48-month cumulative incidence was 2%, 4%, 7%, and 11%, respectively. Non-PD events caused ibrutinib discontinuation in 24 patients (47%) attributable to toxicity (n=15; 63%), non-response (n=5; 21%), and miscellaneous (n=4; 17%). The median time to non-PD discontinuation was 5 months (95% CI 3-7), and the 12-, 24-, 36-, and 48-month cumulative incidence was 6%, 7%, 10%, and 12%, respectively. A baseline platelet count <100 K/uL (OR 3.85, 95% CI 1.20-12.3; p=0.02) and CXCR4 mutation (OR 3.89, 95% CI 1.74-8.69; p=0.001) were associated with higher odds of ibrutinib discontinuation, whereas a serum IgM level >4,000 mg/dl was associated with lower odds (OR 0.38, 95% CI 0.17-0.86; p=0.02). An IgM rebound was observed in 37 patients (73%) following ibrutinib discontinuation. The cumulative incidence of an IgM rebound at 4 and 8 weeks following discontinuation was 48% and 79%, respectively. An increased risk of an IgM rebound at 4 weeks (72% versus 29%) and 8 weeks (95% versus 66%) was observed for patients with PD versus non-PD discontinuation. Six patients (16%) developed symptomatic hyperviscosity requiring emergent plasmapheresis. Male sex was associated with lower odds of an IgM rebound following ibrutinib discontinuation (OR 0.18, 95% CI 0.03-0.90; p=0.04). Thirty-eight patients (76%) received salvage therapy following ibrutinib discontinuation. The median time to salvage therapy was 5 weeks (95% CI 3.6-8.1). Twenty-seven patients (73%) responded to salvage therapy with the following regimens: combination therapy with an anti-CD20 monoclonal antibody and alkylator (16/22; 73%), proteasome inhibitor (4/5; 80%), or nucleoside analogue (2/2; 100%), BCL2 inhibitor (3/5; 60%), and other (2/5; 40%). Patients without an IgM rebound were more likely to respond to salvage therapy versus those with an IgM rebound (100% versus 62%; p=0.04). Thirteen patients (24%) have not received salvage therapy. Reasons for not receiving salvage therapy include: treatment not required (n=6; 46%), patient choice (n=4; 31%), death (n=2; 15%), and acute myeloid leukemia (n=1; 8%). The median OS was 32 months (95% CI 19-NR) following discontinuation with an estimated 1-, 2-, and 3-year OS of 72%, 56%, and 45%, respectively. Response to salvage therapy was associated with a decreased risk of death following ibrutinib discontinuation (HR 0.18, 95% CI 0.04-0.72; p=0.02) Conclusion: Ibrutinib discontinuation is associated with CXCR4 mutations in WM patients. Rapid increases in serum IgM level often occur following discontinuation, which can result in hyperviscosity syndrome. Patients who must discontinue ibrutinib require close monitoring, and continuation of ibrutinib until initiation of the next therapy should be considered. Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Consultancy, Research Funding.