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Extended follow-up with the Bruton’s tyrosine kinase inhibitor ibrutinib in previously treated Waldenström’s macroglobulinemia

Waldenstr€ om’s macroglobulinemia (WM) is a subtype of indolent non-Hodgkin lymphoma characterized by lymphoplasmacytic infiltration of the bone marrow, progressive anemia, and immunoglobulin M (IgM) monoclonal gammopathy.[1,2] Current treatments are often associated with significant toxicities, posing a challenge in WM patients, the majority of whom are elderly with comorbidities.[3] This has led to the development of newer agents with durable responses and improved tolerability. Ibrutinib is an oral once-daily, first-in-class inhibitor of Bruton’s tyrosine kinase. In a Phase 1, first-in-human study,[4] objective responses to ibrutinib were observed in 54% of patients with B-cell malignancies, including three of four previously treated WM patients. Subsequently, a trial evaluating single-agent ibrutinib in 63 previously treated WM patients was initiated and reported an overall response rate (MR or better) of 90.5% and a major response rate (PR or better) of 73%,[5] leading to the FDA approval of ibrutinib for the treatment of WM.[6] Herein, we report our >5-year experience with single-agent ibrutinib in the four WM patients enrolled in the Phase 1 study conducted in the United States (NCT00849654 and NCT01109069). The Institutional Review Board at each participating site approved the study, and all patients provided written informed consent. Four male patients with previously treated, histologically confirmed WM, IgM levels 1000mg/dL, and adequate hematologic, renal, and hepatic function received oral ibrutinib between 560mg/day and 12.5mg/kg/day until disease progression or unacceptable toxicity. Baseline characteristics and outcomes are summarized in Table 1. Hemoglobin and IgM levels over time are shown in Figure 1(A–C). Patients with objective responses or stable disease after 6 months of therapy were eligible to continue on an extension study.[4] In the extension study, only AEs grade 3, serious AEs (SAEs), and AEs of any grade leading to dose modification/discontinuation were collected. AEs were reported as the worst grade experienced per patient. During follow-up, a change in data collection resulted in capturing of lymph node measurements only in the event of disease progression. Best clinical response was assessed per the Third International Workshop of WM response criteria.[7] Patient 1, who required plasmapheresis on study, received continuous ibrutinib at 560mg daily. IgM levels trended upward from 5090mg/dL at baseline during cycles 1–7, reaching 10,100mg/dL, despite continued plasmapheresis. Baseline hemoglobin level of 8.6 g/dL improved steadily to 10.6 g/dL at the end of cycle 8. However, given the inability to discontinue plasmapheresis for IgM control, treatment was ended after 8 months. Therapy was tolerated except for an SAE of grade 1 febrile neutropenia between days 8 and 11 of treatment. Patient 2 has received ibrutinib for 71.4 months. He received ibrutinib at 12.5mg/kg/day on the 28-day-on/7day-off schedule for 3 cycles and was subsequently dose reduced per protocol amendment to fixed dosing, and treated with 560mg/day continuously. By the end of cycle 2, baseline IgM of 4820mg/dL declined by 50% and continued to decline to a reduction of 81% (888mg/ dL) at 36 months. Notably, IgM levels dropped over the first year, then fluctuated thereafter. Baseline hemoglobin of 11.2 g/dL improved substantially to 14 g/dL by month 5 and reached a maximum of 15.5 g/dL at month 38, remaining within normal range through month 60. Splenomegaly measuring 23.3 cm at baseline reduced to 21 cm by cycle 4 and was stable at the last available assessment. Substantial reduction in lymphadenopathy was observed from a sum of the product of the longest perpendicular dimensions (SPD) of 110 cm at baseline to 16 cm at the last available assessment. SAEs of grade 1 febrile neutropenia at 8 months (duration: 3 days), grade 3 pneumonia at 53 months (duration: 6 days), and grade 2 pyrexia at month 63 (duration: 3 days) were reported. At 37 months, the patient presented with grade 3 neutropenia and was treated with pegfilgrastim, with resolution. Coincidently, the patient experienced grade 3 aphthous