Patient-Reported Symptoms during Ibrutinib Holds: A Withdrawal Syndrome

Background:The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). The management of ibrutinib-related toxicities, such as bleeding and others, are often managed with temporary interruption of therapy. We observed that some WM patients who held ibrutinib developed symptoms during the time they were holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. Our study aims at describing this "ibrutinib withdrawal" phenomenon.

Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM, and received ibrutinib therapy. Medical files were manually reviewed to identify patients who reported new-onset symptoms occurring during a temporary hold of ibrutinib therapy. Pertinent clinical data were gathered. Patient characteristics are summarized descriptively. Univariate association with withdrawal symptoms was evaluated with logistic regression models.

Results: A total of 189 patients with WM who started ibrutinib were identified; 100 patients (53%) have not held ibrutinib, and 89 (47%) held ibrutinib at some point during therapy. The median time on ibrutinib therapy in patients who held ibrutinib was 23 months (95% CI 13-30 months) and 10 months (95% CI 7-12 months) in patients who did not hold ibrutinib. There were no differences between the patients who held and did not hold ibrutinib with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, beta-2-microglobulin (B2M), serum IgM, bone marrow involvement, CXCR4 status, prior treatment and time between WM diagnosis and ibrutinib initiation (p≥0.05 for all factors). From the patients who held ibrutinib, 69 (78%) did not experience withdrawal symptoms and 20 (22%) did. Of the patients who experienced withdrawal symptoms, 17 (85%) were receiving ibrutinib in the relapsed/refractory setting. All patients were holding ibrutinib for the first time since treatment initiation. The median drug hold length was 7 days (range 3-33 days). Reasons for holding ibrutinib included: procedure/surgery (n=12; 60%), toxicity (n=6; 30%), drug interaction (n=1; 5%), and patient choice (n=1; 5%). The median time to symptom development was 2 days (range 0-5 days) from the start of the drug hold. Patient-reported symptoms included: fever (n=16; 80%), body aches (n=6; 30%), chills (n=5; 20%), night sweats (n=5; 20%), headache (n=4; 20%), fatigue (n=2; 10%), arthralgias (n=2; 10%), and weakness (n=1; 5%). There were no differences between patients who became symptomatic and remained asymptomatic during ibrutinib hold with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, B2M, bone marrow involvement, CXCR4 status, prior treatment, time from WM diagnosis and ibrutinib initiation and time on ibrutinib (p≥0.05 for all factors). Patients with serum IgM >4,000 mg/dl had a lower proportion of withdrawal symptoms than patients with serum IgM <4,000 mg/dl (9% vs. 30%; p=0.02). The rates of very good partial response (VGPR), partial response (PR), minor response (MR) and no response (NR) to ibrutinib were 16% (n=13), 57% (n=108), 22% (n=41) and 5% (n=9), respectively. No withdrawal symptoms were reported in patients with MR or NR. The proportion of patients with withdrawal symptoms was higher in patients who achieved VGPR (46%) than in patients who achieved PR (25%). Four patients with fever were admitted to the hospital; no infectious etiology was identified. All patients reported resolution of symptoms the same day ibrutinib was restarted following the drug hold. Nine patients had subsequent drug holds, and reported recurrence of the same symptoms during the hold period. Two patients known to develop these symptoms were treated with corticosteroids during a subsequent hold and reported symptomatic relief.

Conclusion: We describe patient-reported symptoms that develop in about 20% of WM patients who held ibrutinib therapy. The rate of withdrawal symptoms is lower in patients who started ibrutinib with IgM levels >4,000 mg/dl (9%), and higher in patients who had achieved VGPR on ibrutinib (46%). Such symptoms ensue within 2 days of hold and resolve rapidly following reinitiation of therapy. Clinicians should be aware of this phenomenon which may represent an ibrutinib withdrawal syndrome.