Chemotherapy-Free Induction with Ibrutinib plus Rituximab Shows Unprecedented Efficacy in MCL

February 2017 Vol 10, Special Issue: Payers’ Perspectives In Oncology: ASH 2016 Highlights - Leukemia
Charles Bankhead

San Diego, CA—Combination induction therapy with ibrutinib (Imbruvica) and rituximab (Rituxan) in patients with mantle-cell lymphoma (MCL) led to objective responses in each of the first 50 patients who received this combination in an ongoing, phase 2 clinical trial presented at the 2016 American Society of Hematology meeting.

“This chemotherapy-free induction had unprecedented efficacy as frontline therapy for young patients with mantle-cell lymphoma. We have expanded the trial to include an additional 50 patients,” said Michael Wang, MD, M.D. Anderson Cancer Center, Houston, TX. “This therapy may provide a window of opportunity to reduce the use of frontline chemotherapy with improved efficacy and reduced toxicities,” he added.

There were complete responses to the chemotherapy-free combination of ibrutinib and rituximab in 73% of patients. A subgroup analysis showed consistent activity across various patient, clinical, and disease variables.

Intensive chemotherapy induction for MCL often produces objective responses, but at a risk for considerable toxicity, including a risk for second malignancy (solid or hematologic) exceeding 10%. A strategy to reduce or to eliminate chemotherapy without sacrificing the promise of long-term survival would be beneficial.

The concept behind a chemotherapy-free approach with ibrutinib and ri­tuximab involves a 2-step process, said Dr Wang. Treatment of MCL with the Bruton’s tyrosine kinase drives cells from their microenvironment into circulation during initial tumor reduction, a phenomenon known as compartmental shift. Researchers hypothesized that once in circulation, these cells in patients with MCL would become more vulnerable to rituximab therapy.

Precedence for ibrutinib therapy in MCL included a study of 111 patients with relapsed or refractory MCL. Treatment with ibrutinib monotherapy led to an overall response rate of 68%, including complete responses in 21% of patients. The most notable adverse effect was transient lymphocytosis in approximately 33% of patients (Wang M, et al. N Engl J Med. 2013;369:507-516).

Another study evaluated the combination of ibrutinib and rituximab in 50 patients with relapsed MCL with a median treatment history of 3 previous regimens (Wang M, et al. Lancet Oncol. 2015;17:48-56). The combination therapy led to an objective response rate of 88%, including complete responses in 44% of patients. The only grade ≥3 adverse event that occurred in at least 10% of patients was atrial fibrillation.

Impressive Efficacy Results

Favorable results from the previous studies led to the phase 2 clinical trial that involved 50 patients (median age, 55 years) with newly diagnosed MCL. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1.

Induction therapy included ibrutinib 560 mg daily, which continued in 28-day cycles. Treatment with rituximab began with 4 weekly loading doses of 375 mg/m2 during cycle 1, followed by a single dose on day 1 during cycles 3 through 12. On completion of the induction phase of treatment, patients received consolidation therapy with rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone chemoimmunotherapy, alternating every 28 days with rituximab and high-dose methotrexate-Ara C.

“Four cycles of intensive chemotherapy is still toxic, and further improvements are needed,” said Dr Wang.

Patients did not undergo stem-cell transplantation and did not receive maintenance therapy.

Dr Wang reported efficacy data for 45 evaluable patients, showing that 73% of the patients achieved complete response, and 27% achieved a partial response. Analysis of response by the Ki-67 proliferation score, by the MCL International Prognostic Index, and by association with rash yielded consistent results.

“The complete response rate is still rising, and all but 1 of the patients with partial response are still in part 1 (induction) of treatment,” said Dr Wang.

Several patients had dramatic responses that often occurred rapidly after the start of treatment, he added. After a median follow-up of 9 months, the cohort had yet to reach the median duration of response, progression-free survival, or overall survival. No patient had died and no disease progression had occurred.

Hematologic toxicity occurred infrequently and was generally mild (grade 1); the most common hematologic toxicity was anemia, which occurred in approximately 20% of patients. The most common nonhematologic toxicities included fatigue, myalgia, diarrhea, mucositis, skin disorders, dizziness, and peripheral neuropathy.

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