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Ibrutinib safe, effective in previously treated Waldenström’s macroglobulinemia
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Treatment with ibrutinib yielded durable responses and proved safe in patients with previously treated Waldenström’s macroglobulinemia, according to study results.
Drug responses were linked to MYD88 and CXCR4 mutation status, the study also found.
“Despite advances in treatment, this disease eventually progresses in most patients,” Steven P. Treon, MD, PhD, of the Bing Center for Waldenström’s macroglobulinemia at Dana-Farber Cancer Institute, and colleagues wrote. “New treatment options are needed.”
Steven P. Treon
MYD88 and CXCR4 mutations are frequently seen in patients with Waldenström’s macroglobulinemia and may affect the patient’s potential response to ibrutinib (Imbruvica; Pharmacyclics, Janssen), according to study background.
Treon and colleagues evaluated data from 63 patients with symptomatic Waldenström’s macroglobulinemia. The median age of the population was 63 years (range, 44-86) and 48 patients were men. All patients received at least one previous treatment (median, 2; range, 1-9).
MYD88 mutations were present in 89% (n = 56) of patients and CXCR4 mutations were present in 34% (n = 21) of patients.
Patients received 420 mg daily ibrutinib for 26 4-week cycles. Treatment lasted until disease progression or the occurrence of unacceptable adverse events.
The overall response rate served as the study’s primary endpoint. Secondary endpoints included PFS and drug safety.
After treatment, researchers observed significant decreases in median serum immunoglobulin M levels (from 3,520 mg/dL to 880 mg/dL) and bone marrow involvement (from 60% to 25%; P ˂ .01 for both). Patient’s hemoglobin levels also significantly increased (from 10.5 g/dL to 13.8 g/dL; P < .01).
Median time to at least a minor response was 4 weeks, and 57% (n = 36) of patients achieved a partial response. The ORR was 90.5% and the major response rate was 73%.
Patients with MYD88 L265P mutations and wild-type CXCR4 demonstrated the greatest response to treatment. The ORR was 100% among these patients and the major response rate was 91.2%.
Response rates were lower among patients with MYD88 L265P and CXCR WHIM mutations (ORR, 87.5%; major response rate, 61.9%) and patients with wild-type MYD88 and CXCR4 (ORR, 71.4%; major response rate, 28.6%).
Nearly all patients (n = 60) were alive at the end of the study period. The estimated PFS at 24 months was 69.1% (95% CI, 53.2-80.5) and the estimated OS rate was 95.2% (95% CI, 86-98.4). Median time to progression was 9.5 months (range, 3.5-19.4) among patients with progressive disease.
The most common grade 3 or worse adverse events were neutropenia (14%) and thrombocytopenia (13%). A significant proportion of patients who experienced these adverse events had received three or more previous therapies (neutropenia, 78%; P = .05; thrombocytopenia, 88%; P = .01).
Researchers noted ibrutinib-related adverse events were reversible; however, three patients required dose reductions and four patients discontinued treatment. – by Cameron Kelsall
Disclosure: The study was funded in part by Pharmacyclics. Please see the full study for a list of all authors’ relevant financial disclosures.
Perspective
Back to TopMark J. Roschewski, MD, and Wyndham H. Wilson, MD, PhD
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase (BTK) with remarkable single-agent activity in a number of B-cell lymphomas, including chronic lymphocytic leukemia, mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). The study by Treon and colleagues expands our understanding of the scope of ibrutinib’s activity and reports an overall response rate of more than 90% in a group of previously treated patients with Waldenström’s macroglobulinemia (WM).In addition to the impressive response rates observed, ibrutinib was extremely well tolerated in patients of all ages and no unexpected toxicities emerged during 19.1 months of therapy. These findings compelled an expansion of FDA approval to include ibrutinib for the treatment of WM, marking the first drug approval for this indication.
An important translational component of the study by Treon and colleagues focused on the predictive nature of individual somatic mutations on the likelihood of response to ibrutinib. The recently described point mutation in MYD88 L265P — which defines the majority of cases of WM — was highly associated with clinical response, whereas patients who lacked the MYD88 mutation were less likely to respond. Although the numbers are too small to draw definitive conclusions, MYD88 mutations can be easily identified by polymerase chain reaction-based methods and could serve as a useful test for distinguishing between patients who benefit from single-agent therapy and those who are best served by combinations.
Based on these results, ibrutinib monotherapy should quickly become the standard of care in relapsed WM, and future studies will likely address its role in front-line therapy and strategies to overcome resistance. Ibrutinib once again proves its potential to be a transformative drug in the treatment of a number of B-cell lymphomas.
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