Ibrutinib Produces High Response Rate in Patients with Refractory Mantle Cell Lymphoma


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[The Bruton’s tyrosine kinase] inhibitor ibrutinib is a highly active new agent showing durable single-agent activity in relapsed and refractory mantle cell lymphoma. Ibrutinib provides the opportunity for treatment with less intensive and more effective regimens.

—Michael L. Wang, MD, and colleagues

Ibrutinib is a first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase, a mediator of the B cell-receptor signaling pathway implicated in the pathogenesis of B-cell cancers. As reported in The New England Journal of Medicine, Michael L. Wang, MD, of The University of Texas MD Anderson Cancer Center, Houston, and colleagues found that single-agent ibrutinib resulted in a high response rate and prolonged responses while exhibiting a favorable toxicity profile in patients with relapsed/refractory mantle cell lymphoma (MCL).1

Dr. Wang told The ASCO Post, “This is a collective effort of bench scientists who devoted many years of data as well as many patients and their families who have bravely fought against mantle cell lymphoma. We owe the success of this study to many clinical investigators, research nurses, and data coordinators. We also received critical support from government and industry.”

Study Details

In a phase II study, 111 patients with relapsed or refractory MCL received ibrutinib at 560 mg/d. Patients were enrolled in two groups consisting of those who had previously received at least two cycles of bortezomib therapy (n = 48) and those who had received fewer than two complete cycles of bortezomib (Velcade) or no prior bortezomib (“no prior bortezomib group,” n = 63).

Patients had a median age of 68 years, 76% were male, 86% had intermediate- or high-risk disease based on simplified Mantle Cell Lymphoma International Prognostic Index (MIPI) score, 86% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, 45% had refractory disease, 72% had advanced disease, and 39% had at least one lymph node ≥ 5 cm in diameter. Patients had received a median of three prior therapies (at least 3 in 55%), with 89% having received rituximab (Rituxan), 30% hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone, 24% lenalidomide (Revlimid), and 11% stem cell transplantation.

5Response was observed in 75 patients (68%), with complete response in 21% of patients and partial response in 47%. Response rates did not differ between patients with no prior bortezomib therapy (68%, including complete response in 19%) and those with prior bortezomib therapy (67%, including complete response in 23%) and also did not vary according to other baseline characteristics or risk factors associated with chemotherapy treatment failure. Response was observed in 63% of patients with lymph nodes ≥ 5 cm and in 63% of those who had received prior lenalidomide. The overall response rate and complete response rate were found to improve over time with continued therapy.

After an estimated median follow-up of 15.3 months, the estimated median response duration among responders was 17.5 months (95% confidence interval [CI] = 15.8 months to not reached), with a median time to response of 1.9 months (range, 1.4–13.7 months) and a median time to complete response of 5.5 months (range, 1.7–11.5 months).

The estimated median progression-free survival was 13.9 months (95% CI = 7.0 months to not reached) among all patients, 17.5 months among those with partial response as best response, and not reached for those with complete response. Median overall survival was not reached. At 18 months, the estimated overall survival rate was 58%.

At the estimated follow-up duration of 15.3 months, 46 patients (41%) were still receiving treatment. Reasons for discontinuation included disease progression in 50 patients (45%, including 2 patients who discontinued treatment within 30 days after the first dose and 1 with unconfirmed progression of disease), patient or investigator decision in 7 patients (6%, including 1 patient who proceeded to stem cell transplantation), and adverse events in 8 patients (7%, including 2 patients with subdural hematoma, and 1 each with pneumonia, elevated bilirubin, sepsis, metastatic adenocarcinoma, respiratory failure, and cardiac arrest).

Favorable Toxicity Profile

The majority of adverse events observed were grade 1 or 2. The most common nonhematologic treatment-related adverse events of any grade were diarrhea (50%), fatigue (41%), nausea (31%), peripheral edema (28%), and dyspnea (27%). The most common grade 3 or higher nonhematologic adverse events were diarrhea (6%), fatigue (5%), abdominal pain (5%), and dyspnea (5%).

Grade 3 or higher hematologic adverse events were also infrequent and included neutropenia in 16% of patents, thrombocytopenia in 11%, and anemia in 10%. Grade 3 bleeding events occurred in five patients (5%). Subdural hematoma occurred in four patients (grade 1 in one patient, grade 2 in one, and grade 3 in two) and were associated with falls, head trauma, or both in all cases; all four patients had received either aspirin or warfarin within 2 days of the event.

A total of 16 patients (14%) died during the trial. Twelve died from disease progression and 4 due to an adverse event (2 from pneumonia, 1 from sepsis, and 1 from a cardiac arrest that was not considered drug-­related).

The investigators concluded, “[The Bruton’s tyrosine kinase] inhibitor ibrutinib is a highly active new agent showing durable single-agent activity in relapsed and refractory mantle cell lymphoma. The favorable toxicity profile suggests that ibrutinib provides the opportunity for treatment with less intensive and more effective regimens than those currently available.” ■

Disclosure: The study was supported by Pharmacyclics, Janssen Biotech; to conduct research only. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Wang ML, Rule S, Martin P, et al: Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. June 19, 2013 (early release online).



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