Long-Term Follow-up of Previously Treated Patients Who Received Ibrutinib for Symptomatic Waldenstrom's Macroglobulinemia: Update of Pivotal Clinical Trial

MYD88 mutations are present in 95% of WM patients and trigger malignant cell growth through Bruton's Tyrosine Kinase and Hematopoietic Cell Kinase, both targets of ibrutinib. CXCR4 mutations are found in 30-40% of previously treated WM patients and confer in vitro resistance to ibrutinib. We therefore performed a prospective study that examined the activity of ibrutinib in previously treated WM patients (Treon et al, NEJM 2015). The findings showed that ibrutinib was highly active in previously treated WM patients and supported the first ever FDA and EMA drug approval for the treatment of WM. Herein, we provide a long-term follow-up of this study. Sixty-three symptomatic WM patients who received at least one prior therapy were enrolled. Their baseline characteristics were as follows: median age 63 (range 44-86 yrs); 48 (76%) were male, IPSSWM scores were low (n=14; 22%), intermediate (n=27; 43%), and high (n=22; 35%); median serum IgM was 3,520 (range 724-8,390 mg/dL); median hemoglobin level was 10.5 (range 8.2-13.8 g/dL); median serum B₂M level was 3.9 (1.3-14.2 mg/L); adenopathy >1.5 cm (n=37; 59%); splenomegaly >15 cm (n=7; 11%), and median bone marrow disease involvement was 60% (range 3-95%). The median prior therapies was 2 (range 1-9), and 25 (40%) patients were refractory to their previous therapy. MYD88 and CXCR4 genotyping was performed for 63 and 62 patients, respectively and is shown in Table 1. Patients were initiated on 420 mg a day of ibrutinib, and dose de-escalation for toxicity was permitted. Patients received protocol administered ibrutinib for 40 months, and transitioned to commercial supply thereafter. Patients could consent to continue follow-up for response assessment after 40 months on commercial drug supply. Ibrutinib was administered until progression or intolerance. The median time on ibrutinib was 46.6 (range 0.5-60 months). Improvements in categorical responses occurred with prolonged treatment. The overall and major (>PR) response rates were 90.4% and 77.7%, respectively, and were not impacted by prior lines of therapy or relapsed or refractory status. Seventeen (27%) patients achieved a VGPR. No complete responses were observed. At best response, median serum IgM level declined from 3,520 to 821 mg/dL (p<0.0001). At baseline 46/63 (73%) patients had a serum IgM >3,000 mg/dL versus 4/63 (6%) patients at best response (p<0.0001). At best response, median bone marrow involvement declined from 60% to 20% (p<0.0001), and the median hemoglobin level increased from 10.5 to 14.2 g/dL (p<0.0001). The impact of MYD88 and CXCR4 mutation status on responses and time to at least a minor (overall) and PR or better (major) response are shown in Table 1.

Figure 1 shows the Kaplan Meier curves for progression free survival (PFS) for all study participants (A), and those genotyped by MYD88 and CXCR4 mutation status (B). With a median study follow-up of 47.1 months, the median PFS for patients with MYD88^MutCXCR4^WT has not been reached. By comparison, the median PFS was 45 months for patients with MYD88^MutCXCR4^Mut, and 21 months for those with MYD88^WTCXCR4^WT (Log-rank p=0.0093 for 3-way comparison). Three patients died due to disease progression.

Adverse events (Grade >2) that were at least possibly related to protocol therapy in >5% of patients during protocol therapy were as follows: anemia (n=4); atrial fibrillation (n=6); GERD (n=5); hypertension (n=5); neutropenia (n=14); pneumonia (n=6); skin infection (n=3); thrombocytopenia (n=9). Seven patients (11%) had atrial arrhythmia [Grade 1 (n=1); Grade 2 (n=5); Grade 3 (n=1)] on ibrutinib. Six of these patients continued ibrutinib with medical management for their atrial arrhythmia. Four patients came off protocol therapy for toxicity: atrial fibrillation (n=1); infection not related to drug therapy (n=1), procedure related hematoma (n=1), and thrombocytopenia (n=1). The findings from the long-term follow-up of this pivotal study confirm that ibrutinib is highly active in symptomatic patients with relapsed and refractory WM, and produces durable responses. Prolonged ibrutinib therapy is associated with improvements in categorical responses, including attainment of VGPR. Ibrutinib response activity and PFS are impacted by MYD88 and CXCR4 mutation status in this patient population. (ClinicalTrials.gov number, NCT01614821.)

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