Ibrutinib Combination Produces High Response Rate in Relapsed/Refractory MCL

Michael Wang, MD,

Almost 90% of patients with relapsed or refractory mantle cell lymphoma (MCL) responded to the targeted combination of ibrutinib and rituximab, according to a study reported at the 2014 ASH Annual Meeting.

Results of the phase II trial showed that 40 of 46 (88%) evaluable patients had objective responses, including complete responses in 18 (40%) patients. The trial also revealed a potential predictor of response, as all patients with lower levels (<50%) of the proliferation marker Ki-67 responded to the combination, reported Michael Wang, MD, professor of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center in Houston.

“Ibrutinib and rituximab are a highly efficacious combination in relapsed and refractory mantle cell lymphoma,” said Wang. “Patients with Ki-67 <50% benefited the most, as all 34 patients responded to treatment. The combination has been well tolerated.”

The results add those reported by Wang and colleagues last year showing a 68% overall response rate in patients with relapsed/refractory MCL treated with ibrutinib monotherapy (N Engl J Med. 2013;369:507-516).

The rationale for combining the Bruton’s tyrosine kinase inhibitor with rituximab came from the registration trial data submitted to the FDA, said Wang. The study showed that ibrutinib induced a transient increase in circulating MCL lymphocytes during the initial phase of tumor reduction. Investigators hypothesized that the cells driven from their home microenvironment would be more sensitive to intravenous rituximab and that the combination of ibrutinib and rituximab would be safe and efficacious.

The trial included patients with tissue-confirmed MCL and both CD20 and cyclin D1 positivity. The disease had to be in relapse but investigators placed no limit on the number of prior therapies.

The primary objective of the phase II study was to assess the efficacy and safety of the combination therapy. Secondarily, Wang and colleagues wanted to determine duration of response with the combination, progression-free survival (PFS), and overall survival.

All patients received ibrutinib at a dose of 540 mg/d. They received four loading doses of rituximab during the first 28-day cycle, followed by a single dose day 1 of cycles 3-8, and then once every other cycle for as long as 2 years.

Patients were evaluated for response by independent radiology review of tumor measurement, in addition to routine radiology reports. Confirmation of complete response required a PET-CT scan in addition to regulate CT imaging, bone marrow biopsy or aspiration, and esophagogastroduodenoscopy/colonoscopy with random biopsies.

The study population consisted of 50 patients who had a median age of 67. Twenty-seven of the 50 patients had received three or more prior therapies. Most of the patients were low or intermediate risk (44% each). Three patients had bulky mass, 17 had at least one node 5 cm or larger, 35 had refractory disease, and 15 had advanced disease.

After a median follow-up of 11 months, 46 patients were evaluable for response. The data showed an overall response rate of 88%, consisting of 22 partial responses and 18 complete responses.

The baseline evaluation included assessment of Ki-67. In the subgroup of 34 patients who had a Ki-67 index <50%, every patient achieved an objective response: partial response in 18 patients and complete response in 16. In contrast, six of the 12 patients with Ki-67 index ≥50% had objective response rate, all but one of which was a partial response.

Neither the median PFS nor median overall survival has been reached.

Grade 1 hematologic toxicity included anemia in 30% of patients and thrombocytopenia in 25%. Treatment-emergent nonhematologic toxicity occurring in >15% of patients included fatigue, diarrhea, myalgia, and dyspnea. Six patients had grade 3 atrial fibrillation. The youngest was 73, and all had cardiovascular risk factors or a history of cardiovascular disease.

Wang M, Hagemeister F, Westin JR, et al. Ibrutinib and Rituximab Are an Efficacious and Safe Combination in Relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical Trial. Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 627

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