'New Era' in the Treatment of Rare Lymphoma

Nick Mulcahy

April 08, 2015

New data on ibrutinib (Imbruvica, Pharmacyclics and Janssen), which recently became the first drug approved for Waldenström's macroglobulinemia, show that the agent provides ongoing control of the rare lymphoma.

In a prospective phase 2 clinical trial of 63 previously treated patients who received ibrutinib monotherapy, the rate of progression-free survival at 2 years was 69.1% and of overall survival was 95.2%.

The overall response rate — the primary end point of the study — was "high" (90.5%), as was the major response rate (73.0%), say the investigators, led by Steven Treon, MD, PhD, director of the Bing Center for Waldenström's Macroglobulinemia at the Dana-Farber Cancer Institute in Boston.

Response was defined as a reduction in serum immunoglobulin (Ig)M of at least 25%. Major response was defined as either a complete response a reduction in IgM of at least 50%.

The results were published in the April 9 issue of the New England Journal of Medicine.

Other monotherapies used to treat patients with relapsed or refractory Waldenström's macroglobulinemia have had response rates of 40% to 80%, with a median progression-free survival of 8 to 20 months, the investigators report.

"These findings herald a new era for the treatment of Waldenström's macroglobulinemia, and show how genome sequencing can lead to the discovery of cancer mutations that can be specifically targeted by new therapies," said Dr. Treon in a press statement.

The investigators were prompted to experiment with ibrutinib, which is also approved for use in mantle cell lymphoma and chronic lymphocytic leukemia, because of the high prevalence in Waldenström's macroglobulinemia of a type of MYD88 genetic mutation, which triggers abnormal activity of Bruton's tyrosine kinase.

Ibrutinib is a first-in-class inhibitor of Bruton's tyrosine kinase.

Waldenström's macroglobulinemia is a type of malignant B-cell lymphoma, which "eventually progresses in most patients," according to the investigators. It has been described as causing B-lymphocytes to grow in the bone marrow, lymph nodes, liver, and spleen. These abnormal B-cells overproduce IgM, which can lead to excess bleeding and problems with vision and the nervous system.

The study participants received a median of two previous therapies, and 40% were refractory to previous treatment. Oral ibrutinib was taken daily until the disease worsened or unacceptable toxic effects occurred. The median duration of treatment was 19 months.

The "response kinetics" with ibrutinib were "rapid," compared with "most other available therapies," the investigators report. Median time to response was 4 weeks.

After patients received ibrutinib, median serum IgM levels decreased from 3520 mg/dL to 880 mg/dL, median hemoglobin levels increased from 10.5 g/dL to 13.8 g/dL, and bone marrow involvement decreased from 60% to 25% (P < .01 for all).

Improvements in serum IgM and hemoglobin levels were seen even in patients with modest or no changes in bone marrow disease burden, the investigators note. "This suggests that a mechanism other than tumor debulking could contribute to the clinical benefit with ibrutinib in patients with Waldenström's macroglobulinemia," they write.

Extramedullary disease was also affected by ibrutinib. For example, 68% of the patients had decreased or resolved adenopathy, and 57% had decreased splenomegaly on serial CT imaging. Also, nine patients in the trial, who had previously received rituximab, had progressive IgM-related peripheral neuropathy. Improvement or stabilization of symptoms occurred during ibrutinib treatment in these patients. "These findings are particularly encouraging given the challenging nature of treating IgM-related peripheral neuropathy in Waldenström's macroglobulinemia," the authors write.

More on Mutations, Plus Adverse Events

The efficacy of ibrutinib was influenced by the mutations detected in the patients' cancer cells.

The investigators explain that, in Waldenström's macroglobulinemia, three genomic groups have been delineated on the basis of clinical manifestations and survival: MYD88L265PCXCR4WT (with WT indicating wild-type); MYD88L265PCXCR4WHIM ; and MYD88WTCXCR4WT .

Table. Response Rates

Genomic Group Overall Response, % Major Response, %
MYD88L265PCXCR4WT 100.0 91.2
MYD88L265PCXCR4WHIM 85.7 61.9
YD88WTCXCR4WT 71.4 28.6

 

The investigators describe ibrutinib as "safe," with "moderate" toxic effects. However, they note that the drug was discontinued in some patients because of adverse events.

Of the nine patients (14%) who experienced neutropenia of grade 3 or higher, seven had received at least three previous therapies (P = .05). Of the eight patients (13%) who experienced thrombocytopenia of grade 3 or higher, seven had received at least three previous therapies (P = .01).

Ibrutinib-related neutropenia and thrombocytopenia were reversible, but necessitated dose reduction in three patients and treatment discontinuation in four patients.

Four patients experienced bleeding events of grade 2 or higher, two of whom had epistaxis. Fish-oil supplements contributed to both grade 2 epistaxis events, and they resolved when these supplements were discontinued. Infections "at least possibly" associated with ibrutinib were "few."

The study was supported by Pharmacyclics; Janssen Pharmaceuticals; Peter S. Bing, MD; the International Waldenström's Macroglobulinemia Foundation; the Leukemia and Lymphoma Society; the Linda and Edward Nelson Fund for Waldenström's Macroglobulinemia Research; the D'Amato Family Fund for Genomic Discovery; the Coyote Fund; and the Bauman Family Foundation. Dr. Treon reports receiving research funding from Pharmacyclics and Janssen. Some of his coauthors report financial ties to industry, as detailed in the publication, and some are employees of Pharmacyclics.

N Engl J Med. 2015;372:1430-1440. Abstract

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