Decreasing the dose intensity (DI) of ibrutinib may reduce progression-free survival (PFS) among patients with Waldenstrom macroglobulinemia (WM), according to a study in Haematologica.1

Current recommendations for ibrutinib therapy in WM include temporary discontinuation among patients who undergo invasive procedures or experience treatment-related adverse effects. A previous study that investigated the effects of ibrutinib DI reduction in chronic lymphocytic leukemia/small lymphocytic lymphoma showed that this could negatively affect PFS; however, the impact of dose-intensity reduction in WM has not previously been explored.

In this multicenter phase 2 study ( Identifier: NCT01614821) researchers enrolled 63 previously treated patients with WM and treated them with oral ibrutinib 420 mg once daily. Researchers assessed overall DI (defined as the proportion of administered compared with planned doses of ibrutinib) and 8-week DI and 6-month DI (defined as proportion of administered versus planned doses of ibrutinib within the respective treatment durations).

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Of the study participants, 32% (20) reported an overall DI of 100%, 59% (37) reported 95% to 99%, 10% (6) reported under 95%, and only 1.6% (1) reported an overall DI of less than 80%. After a median of 3.9 years of ibrutinib therapy, the mean overall DI was 97%; 30% (19) had mean DI of 97% or less and 70% (44) had a mean DI greater than 97%.

Patients with a lower overall DI had a significantly shorter PFS with 22 months compared with NR-PFS among patients with a higher overall DI (P = .001), and had more than a 3-fold risk of experiencing disease progression. A multivariate analysis factoring in serum IgM, age, beta-2-microglobulin and hemoglobin levels showed that low DI was the only independent variable associated with a reduced PFS (HR, 3.34; 95% CI, 1.34-8.30; P = .009).

The mean 8-week DI and mean 6-month DI was 96% and 98%, respectively; patients who had DIs under the mean for either measure were not associated with reduced PFS.  

Missing ibrutinib treatment for 8 consecutive days or longer led to a significantly lower PFS (35 months) compared with patients who missed less than 8 consecutive days (NR) (P = .005), which represented a 4-fold increase in the risk of progression.

The authors concluded that the “study suggests that, similar to CLL patients, low DI adversely impacts PFS in WM patients. Ibrutinib therapy is indefinite and compliance should be strongly emphasized to optimize outcomes.”


  1. Castillo JJ, Gustine JN, Meid K, et al. Impact of ibrutinib dose intensity on patient outcomes in previously treated Waldenstrom macroglobulinemia [published online May 17, 2018]. Haematologica. doi: 10.3324/haematol.2018.191999