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Ibrutinib Therapy for Lymphoplasmacytic Lymphoma

Elaine Xiang, PharmD
Senior Hematology/Oncology Pharmacist
Brigham and Women’s Hospital
Boston, MA

Ibrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, is indicated for treatment of multiple hematologic malignancies, including previously treated mantle cell lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, previously treated marginal zone lymphoma, and Waldenstrom macroglobulinemia (WM). In August 2018 the U.S. Food and Drug Administration (FDA) approved ibrutinib, in combination with rituximab, for treatment of adult patients with WM. WM is a clinical subset of lymphoplasmacytic lymphoma (LPL), which causes an increase in serum immunoglobulin M (IgM) monoclonal proteins. LPL is a rare low-grade B-cell malignancy composed of small lymphocytes, plasmacytoid lymphocytes, and plasma cells that typically involve the bone marrow. It is characterized by an activating mutation of MYD88 (L265P). By inhibiting BTK, ibrutinib is thought to block downstream effects of MYD88 activation. Although some research in the literature supports the use of ibrutinib in WM, limited data are available on ibrutinib use in LPL in a real-life clinical practice setting.

Dr. Helber and colleagues conducted an observational study using ibrutinib in 23 patients with LPL. Included were all sequential nonselected LPL patients who were treated by a dedicated specialty pharmacy service with ibrutinib, at a planned dose of 420 mg daily, for disease progression or disease complications. A pharmacy specialist was responsible for following all patients at least monthly in a lymphoma clinic and by telephone as well as prospectively collecting data. Data points included medication adherence, drug interactions, adverse events, and reasons for treatment interruptions and dose adjustments. MYD88 L265 genetic analysis was performed using a labeled-oligo melting curve assay. The authors evaluated ibrutinib response by monitoring immunoglobulin levels throughout the duration of treatment and hemoglobin levels for resolution of anemia (defined as hemoglobin of ≥10 g/dl or greater). Objective treatment responses were defined as very good partial response (90% or greater reduction or normalization of IgM), partial response (≥50% to <90% IgM reduction), and minor response (≥25% to <50% IgM reduction).

The median age was 71.9 years (range 41.1–91.7). Of the 23 patients, 70% were male, and 61% had been previously treated. The median time of initiating ibrutinib from LPL diagnosis was 3.3 years (range 0–21.2). At the time of data censoring, the median duration of ibrutinib therapy was 11 months (range 0.5–33.8). Twenty-two patients had detectable serum IgM monoclonal proteins, and one patient had immunoglobulin G (IgG) monoclonal proteins. 

Of the 21 patients with sequential IgM levels, 19% had very good partial response, 57% had partial response, and 24% had minor response. The median maximum IgM decrease was 67% (range 31%–96%). Four patients had normalized IgM levels (<230 mg/dl). They had no clinical evidence of residual LPL. However, the authors could not document a complete remission because serum protein electrophoresis analysis or bone marrow restaging studies and images were not performed. The cumulative probability of reaching a 50% reduction in serum IgM level by 60 days and 90 days was 0.51 (95% confidence interval [CI]: 0.32–0.74) and 0.74 (95% CI: 0.53–0.91), respectively. Fifteen patients had a 50% or greater IgM reduction within 150 days of starting ibrutinib therapy (range 7–105). The one patient with IgG LPL had a 37% decrease in IgG levels. Resolution in anemia occurred in six of eight patients. No disease progression during ibrutinib treatment was documented.

In terms of safety, six patients required at least one ibrutinib dose reduction (one for drug interactions and five for adverse events or comorbidities). Three patients self-discontinued ibrutinib because of muscle weakness and pain. Nine patients interrupted therapy because of procedures, comorbidities, adverse events, and hospitalizations. Immunoglobulin levels were monitored during therapy interruptions. It was noted that a rapid increase in IgM levels was associated with ibrutinib interruption, and a subsequent decrease in IgM levels was seen after therapy was restarted. No treatment-related increase of serum monoclonal protein levels, or “flares,” during ibrutinib therapy was reported.

Unique to this observational study is that Dr. Helber and colleagues included many LPL patients who would have been ineligible for the use of ibrutinib in LPL/WM clinical trials because of poor performance status, comorbidities, or organ failure. Two patients with end-stage renal failure were included. One LPL patient with severe renal failure and anemia, secondary to light chain nephropathy, was initiated on a lower dose (140 mg/day) and incrementally increased to 420 mg/day. This patient experienced intermittent grade-2 hematuria but tolerated the full dose. The other patient had nephrotic syndrome caused by lambda light chain renal amyloidosis. Her medication was initiated at the full dose and then decreased to 280 mg/day because of decreased renal function. Although the paraprotein levels were well controlled in ibrutinib therapy, the patient required chronic hemodialysis and died because of renal failure. Additionally, six patients older than 80 years tolerated and responded to ibrutinib therapy appropriately.

The work of Dr. Helber and colleagues provides valuable insight into the use of ibrutinib in LPL. Their work—in which they observed a rapid decrease in IgM levels after the start of ibrutinib therapy and subsequent increases in IgM levels after therapy interruptions—confirms that ibrutinib inhibits IgM secretion by LPL cells. They observed no serious adverse events from ibrutinib therapy or disease progression during treatment. IgM flares have been reported after initiation of rituximab therapy in patients with WM; however, no flares were seen with ibrutinib therapy. This lack of flare with ibrutinib is especially important to note when treating patients with hyperviscosity syndromes. This study was also one of the first reports on using ibrutinib in end-stage renal failure. Last, because each patient was monitored by a dedicated pharmacy specialist, the researchers in this study exemplify the unique and significant role of pharmacy.

Reference

  1. Helber MJ, Moore JE, Williams AM, Meacham PJ, Rothberg PG, Zent CS. Ibrutinib therapy for lymphoplasmacytic lymphoma. Am J Hematol. 2017 Sep;92(9):E542-E544.
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