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Ibrutinib active, safe in Waldenström’s macroglobulinemia
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Ibrutinib demonstrated activity and appeared safe among treatment-naive patients with Waldenström’s macroglobulinemia, study data showed.
“Waldenström’s macroglobulinemia is an immunoglobulin M-secreting lymphoplasmacytic lymphoma. Despite treatment advances, disease in most patients eventually progresses and new treatment options are needed,” Steven P. Treon, MD, PhD, director of the Bing Center for Waldenström's Macroglobulinemia at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School, and colleagues wrote. “Ibrutinib is an orally administered, small molecule inhibitor of Bruton tyrosine kinase and hematopoietic cell kinase that triggers apoptosis of MYD88MUT Waldenström’s macroglobulinemia cells.”
Treon and colleagues treated 30 patients with treatment-naive Waldenström’s macroglobulinemia with 420 mg of ibrutinib (Imbruvica; Pharmacyclics, Janssen Biotech) daily until unacceptable toxicity or disease progression.
All patients carried MYD88 mutations. Nearly half (n = 14; 47%) also carried CXCR4 mutations.
After being treated with ibrutinib, patients’ median serum immunoglobulin M levels fell from 4,370 mg/dL to 1,513 mg/dL and bone marrow involvement declined from 65% to 20% (P < .001 for both). The median hemoglobin level increased from 10.3 g/dL to13.9 g/dL (P < .001).
The overall response rate reached 100%, and 83% of patients experienced a major response.
Compared with those who had CXCR4 mutations, patients with wild-type CXCR4 had higher rates of both major response (94% vs. 71%) and very good partial response (31% vs. 7%). These patients also had a shorter time to major response (1.8 vs. 7.3 months; P = .01).
Two patients with CXCR4 mutations experienced disease progression over a median follow-up of 14.6 months.
Ninety-two percent (95% CI, 73-98) of patients achieved 18-month PFS, and all patients were alive when the study was submitted for publication.
The most common grade 2 or grade 3 treatment-related toxicities included hypertension (13%) and atrial fibrillation (10%), follow by arthralgia, bruising, neutropenia, upper respiratory infection and urinary tract infection (7% for each). No patients experienced any grade 4 or unexpected toxicities.
There are several options for patients with Waldenström’s macroglobulinemia, such as combination therapy with rituximab (Rituxan; Genentech, Biogen), cyclophosphamide and dexamethasone, or bortezomib (Velcade, Takeda Oncology), Morie A. Gertz, MD, chair of the department of medicine the Mayo Clinic, wrote in an accompanying editorial.
“The future is bright for patients with Waldenström’s macroglobulinemia who now have many choices for treatment type, and the likely outcome is that few patients will succumb to this disease in the future,” Gertz wrote. –by Andy Polhamus
Disclosures: Treon reports consultant/advisory roles and other relationships with, as well as research funding from Janssen and Pharmacyclics. Please see the study for all other authors’ relevant financial disclosures. Gertz reports no relevant financial disclosures.
Perspective
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Treon and colleagues present a small, yet important, study of ibrutinib for the frontline treatment of Waldenström’s macroglobulinemia. Researchers enrolled 30 untreated patients who were treated at a single institution with 420 mg oral ibrutinib daily. The response was very promising, with 100% of patients showing a response and 83% of patients showing a major response. Responses tended to deepen with continued treatment. Researchers evaluated genetic alterations in MYD88 and CXCR4 for response; all patients were MYD88 mutated and 14 harbored CXCR4 mutations. Those patients harboring CXCR4 mutations were less likely to have a deep response, although all still achieved a response. These patients also represented the only group to progress with treatment. The lower response in CXCR4-mutant disease is consistent with reports in relapsed/refractory disease.
Ibrutinib therapy is planned to continue for 48 4-week cycles — approximately 3.5 years — or until intolerance or progression. With a median follow-up of 14.6 months, the study is not mature enough to determine if ibrutinib can be stopped after 48 cycles, which would need to be done with caution given that prior studies have suggested a flair of immunoglobulin M (IgM) after holding ibrutinib.
Other therapies in the frontline setting include single-agent rituximab or rituximab, bortezomib and dexamethasone (BDR), as well as others. These options have different toxicities than ibrutinib monotherapy, although with similar response rates (85% for BDR) with a defined time on therapy. The kinetics of response are different. Ibrutinib does not appear to be associated with an IgM flair, which can be seen with single-agent or combination rituximab therapy and has a more rapid IgM reduction.
The role of ibrutinib in frontline treatment for Waldenström’s macroglobulinemia remains a question. This study by Treon and colleagues shows that ibrutinib is clearly active in this patient population, but the study is limited by its short follow-up, small numbers and single institution enrollment. The choice of ibrutinib for untreated Waldenström’s macroglobulinemia should be weighed against other treatments that have more data and historical use. These other therapies, particularly BDR, can provide adequate disease control with defined time on therapy, limiting long-term toxicity and costs to health systems. However, patients requiring a rapid response may benefit from the rapid IgM reduction provided by ibrutinib over other therapies.
A randomized trial of ibrutinib — likely in combination with rituximab — compared with BDR in untreated Waldenström’s macroglobulinemia would be a very interesting study to evaluate these subtleties in therapy. Future studies should also include MYD88 and CXCR4 mutations, which may help predict treatment strategies.
Dimopoulos MA, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1802917.
Gavriatopoulou M, et al. Blood. 2017;doi:10.1182/blood-2016-09-742411.
Treon SP, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1501548.
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