Ibrutinib Active in Rituximab-Refractory WM

Elizabeth Bilotti, RN, MSN

More than 80% of patients with treatment-refractory Waldenstrom’s macroglobulinemia (WM) responded to single-agent therapy with ibrutinib (Imbruvica), according to results of a preliminary clinical trial.

Treatment with ibrutinib led to an overall response rate of 84% patients, including a major response rate of 65%. The 31 patients in the trial exhibited a trend toward continued improvement in IgM over time.

The data build on a previous study involving less heavily pretreated patients, as reported at the 2015 ASH Annual Meeting.

“These are more treatment-experienced patients who are also rituximab refractory, as compared with the previous study; yet, we continue to see fairly robust responses,” said Elizabeth Bilotti, RN, MSN, associate medical director at Pharmacyclics Inc. “We’re seeing responses early on, with early hemoglobin recovery or symptomatic recovery, which were the primary reasons for initiating treatment.”

Current therapy for WM does not lead to cure, and no standard of care has emerged for the disease. The MYD88L2Y5P mutation associated with WM activates NF-kappaB via the interleukin-1-receptor-associated kinase 1 and Bruton’s tyrosine kinase (BTK) signaling pathways. An oral inhibitor of BTK, ibrutinib has been shown to attenuate interaction between MYD88L2Y5P and BTK, blocking BTK downstream signaling and inducing apoptosis in WM cells (Blood. 2013;122:1222-1232).

A phase II trial of patients with previously treated WM demonstrated an overall response rate in excess of 90% and an estimated 2-year progression-free survival (PFS) of 69.1% (N Engl J Med. 2015;372:1430-1440).

Single-agent rituximab is an option for both untreated and previously treated WM. Response rates have ranged from 48% to 65% (Ann Oncol. 2005;16:132-138). The safety and efficacy of ibrutinib in rituximab-refractory patients had not been evaluated previously, providing a rationale for a clinical trial.

The patients were screened as part of an ongoing randomized trial to compare rituximab alone or in combination with ibrutinib in patients with untreated or previously treated WM. Patients whose disease was refractory to the most recent rituximab-containing regimen were ineligible for the randomized trial but could participate in the open-label trial of ibrutinib.

Patients in the open-label trial received ibrutinib 420 mg/day until disease progression. Reasons for initiating treatment were primarily fatigue that was not relieved by rest (74%), constitutional symptoms (42%), anemia (42%), and lymphadenopathy (23%).

The patients had a median age of 67, median serum IgM of 3830 mg/dL, median beta-2 microglobulin of 3.6 mg/L, median platelet count of 218 x 10⁹/L, and median absolute neutrophil count of 2.9 x 10⁹/L. The patients had received a median of four prior regimens for WM. The most recent therapy was a single agent in 32%, combination therapy without an antibody in 29%, and combination therapy with a monoclonal antibody in 39%.

Investigators used modified response criteria for the trial. Complete response was defined as normal serum IgM, disappearance of monoclonal protein, no histologic evidence of bone marrow involvement, and complete resolution of lymphadenopathy/splenomegaly if present at baseline. Very good partial response: >90% reduction in serum IgM from baseline and a reduction in lymphadenopathy/splenomegaly, if present at baseline. Partial response: >50% reduction in serum IgM and reduction in lymphadenopathy/splenomegaly, if present at baseline; Minor: 25% to 50% reduction in serum IgM.

Single-agent ibrutinib resulted in an overall response rate of 84%, consisting of very good partial response in 13%, partial response in 52%, and minor response in 19%.

Median hemoglobin increased from 10.3 g/dL at baseline to 11.4 g/dL after the first cycle of therapy and continued to improve over time. The baseline median IgM value decreased by more than 50% by the end of the first cycle of therapy and continued to decline with treatment. Patients who achieved at partial or better response had the largest declines in hemoglobin. All patients who had at least a minor response had reductions in hemoglobin from baseline.

Hematologic adverse events (all grades) occurred in 10% to 20% of patients, the most common being neutropenia, followed by thrombocytopenia, and anemia. The most common nonhematologic events (all grades) were diarrhea (35% to 40%, mostly grade 1/2 ), hypertension (20% to 25%), upper respiratory infection (15% to 20%), and pyrexia (10% to 15%). Six patients had serious adverse events.

Four patients required dose reductions, none because of adverse events. One patient discontinued because of earl disease progression and one because of an adverse event unrelated to treatment with ibrutinib.

Dimopoulos MA, Trotman J, Tedeschi A, et al. Ibrutinib therapy in rituximab-refractory patients with Waldenström's macroglobulinemia: initial results from an international, multicenter, open-label phase III substudy (iNNOVATETM). Presented at: 57th American Society of Hematology Annual Meeting; Orlando, FL; December 5-8, 2015. Abstract 2745.

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