Ibrutinib therapy for lymphoplasmacytic lymphoma
Authors: Margaret J. Helber, Jeremiah E. Moore, AnnaLynn M. Williams, Philip J. Meacham, Paul G. Rothberg, Clive S. Zent
Journal: American Journal of Hematology (2017)

Lymphoplasmacytic lymphoma (LPL) is a rare indolent B-cell malignancy characterized by an activating mutation of MYD88 (L265P), and is also known as Waldenstrom macroglobulinemia (WM) when producing a detectable serum IgM monoclonal protein.1 LPL commonly causes cytopenias by bone marrow infiltration, and paraproteins can cause hyperviscosity syndromes and antibody mediated toxicities. Ibrutinib, which blocks the downstream effects of MYD88 activation by inhibiting Bruton's tyrosine kinase (BTK), was recently approved by the U.S. Food and Drug Administration (FDA) for treatment of LPL.2, 3 There are published data on the use of ibrutinib to treat WM in clinical trials,2, 4 but limited reported data on the use of ibrutinib to treat LPL in clinical practice ("real world experience"). This observational study was conducted from January 2014 through December 2016 with institutional research board approval. We included all sequential non-selected LPL patients diagnosed according to standard criteria1 and treated with ibrutinib for progressive disease or disease complications in a Lymphoma Clinic with a dedicated specialty pharmacy service. A specialty pharmacist routinely followed all patients on ibrutinib therapy at least monthly in clinic and by telephone, generating consistent, detailed, and prospectively collected and recorded data on ibrutinib compliance, drug interactions, adverse events, and reasons and durations of dose changes and treatment interruptions. Genetic analysis was done in the clinical laboratory of the Department of Pathology at the University of Rochester. Testing for MYD88 L265 used a labeled-oligo melting curve assay with a limit of detection of 1% of cells with a mutation. CXCR4 WHIM-like mutations were detected using Sanger sequencing with a clamp to enhance sensitivity to 1% around codon 338. Ibrutinib response was evaluated using immunoglobulin and hemoglobin levels. The cumulative probability of reaching a target reduction in IgM after initiating ibrutinib therapy was determined by using Kaplan-Meier product limit analysis to account for censored observations. Serum IgM levels, as a percentage of baseline, were plotted against days from starting ibrutinib therapy, and locally weighted regression (LOESS) was used to explore the relationship in more detail. All analyses, including descriptive statistics, were performed using the SAS software system (SAS Institute Inc., Cary, NC, USA; version 9.4). Twenty-three patients (70% male, 61% previously treated, median age 71.9 years, range 41.1–91.7) received ibrutinib (planned dose 420 mg/day) at a median time from diagnosis of LPL of 3.3 years (range 0–21.2). The median duration of ibrutinib therapy at the time of data censoring was 11 months (range 0.5–33.8). All 18 tested patients had MYD88 L265P and five of 16 patients tested had a WHIM-like mutation in the CXCR4 gene (details in Supporting Information Table S1 and Figure S1). All patients had a detectable serum monoclonal protein (22 IgM, 1 IgG). The 21 patients with sequential IgM levels all had objective treatment responses with 19% very good partial responses (≥90% reduction or normalization of IgM), 57% partial responses (≥50% but <90% IgM reduction) and 24% minor responses (≥25% but <50% IgM reduction) using standard response criteria.2 The median maximum IgM decrease was 67% (range 31–96%, Figure 1A). The cumulative probability of reaching a 50% reduction in the serum IgM level by 60 days was 0.51 (95%CI: 0.32, 0.74) and 0.74 (95%CI: 0.53, 0.91) at 90 days (Figure 1B). Four patients had normalization of IgM levels (<230 mg/dL) without clinical evidence of residual LPL but none had the serum protein electrophoresis analysis, re-staging bone marrow studies and imaging required to document a complete remission. The patient with IgG LPL had a clinical response to ibrutinib treatment (37% decrease in IgG level). Anemia (hemoglobin < 10 g/dL) resolved in 6 of 8 patients. No patients had progression of LPL on treatment. Effect of Ibrutinib Therapy on Serum IgM Levels. (A) Changes in serum IgM after initiation of ibrutinib therapy were plotted for the 21 patients with available data during the first 200 days of treatment. Each circle represents a serum IgM measurement at a given time point for each subject, expressed as a percentage of the pretreatment IgM level with all patients at 100% at time 0. The regression line, with a 95% confidence interval band, shows the expected percent of baseline IgM level by follow up time. (B) Shows the cumulative probabilities of reaching at least a 25% or 50% reduction in the serum IgM level compared to the pretreatment level in the 21 patients with evaluable data. The cumulative probability of reaching a 25% reduction in the serum IgM level by 30 days was 0.62 (95%CI: 0.42, 0.82), by 60 days was 0.81 (95%CI: 0.62, 0.94), and by 90 days was 0.95 (95%CI: 0.80, 0.99). Fifteen patients achieved a ≥50% reduction in their serum IgM levels within 150 days of initiation of ibrutinib therapy (range: 7–105 days). By 60 days, the probability of reaching such a reduction was 0.51 (95%CI: 0.32, 0.74), which increased to 0.74 (95%CI: 0.53, 0.91) by 90 days. (C) The effect of ibrutinib treatment interruptions is shown in one representative patient. The serum IgM level was within the normal range (dotted line represents upper level of normal range) after 21 weeks of ibrutinib therapy. A five-week interruption of ibrutinib therapy for interventional procedures was associated with an increased in the serum IgM to the pretreatment level. After resumption of treatment the serum IgM level returned to the normal range Three patients self-discontinued ibrutinib (muscle weakness and pain) and 6 required at least one ibrutinib dose reduction (adverse events/comorbidities n = 5, drug interaction n = 1). Nine patients had 20 therapy interruptions, (procedures n = 10, comorbidities n = 5, adverse events n = 4, hospitalized n = 1). Therapy interruptions were usually associated with rapid increases in IgM levels, with subsequent decreases in IgM levels after resuming ibrutinib therapy (Figure 1C). Many patients in this LPL patient population would have been ineligible for either of the two published clinical trials using ibrutinib in the management of LPL/WM because of poor performance status, co-morbidities, or organ failure.2, 4 Two patients had end stage renal failure (one on long term hemodialysis) prior to initiation of ibrutinib therapy. A 66 year-old male presented with LPL complicated by light chain nephropathy causing severe renal failure and anemia. Ibrutinib therapy was initiated at 140 mg/d and then incrementally increased to 420 mg/d, which resulted in intermittent grade 2 hematuria but was otherwise tolerable. Despite very good IgM and light chain control he did not recover renal function. An 83-year-old female presented with nephrotic syndrome caused by lambda light chain renal amyloidosis. Therapy was initiated at 420 mg per day and then decreased to 280 mg daily because of decreasing renal function without any adverse effects. Paraprotein levels were well controlled on ibrutinib but the patient declined chronic hemodialysis and died of renal failure. To the best of our knowledge, these are the first reports of use of ibrutinib therapy in end stage renal failure. The six patients over the age of 80 tolerated and responded to ibrutinib therapy. Ibrutinib did not cause any treatment-related increases in serum monoclonal protein levels ("flares"),5 which was particularly important for the patients with hyperviscosity syndromes and the three patients treated for neurotoxic complications of LPL (response details in Supporting Information). We observed no serious adverse events from ibrutinib and observed side effects were similar to those previously reported.2, 4, 6 Our experience confirms previous reports of the rapid decrease in the IgM level after initiation of ibrutinib with rapid increases in levels after therapy interruption. This suggests that ibrutinib inhibition of IgM secretion by LPL cells is the primary mechanism for the initial decrease in serum IgM.2 Sustained ibrutinib response is likely to require long-term continuation of treatment in most patients. Funding for this study was provided by the Wilmot Foundation at the University of Rochester Medical Center. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.