Ibrutinib and Rituximab Are an Efficacious and Safe Combination in Relapsed Mantle Cell Lymphoma: Preliminary Results from a Phase II Clinical Trial

![Graphic][1] Single-agent ibrutinib has been approved by the FDA for patients with mantle cell lymphoma (MCL) who received at least one prior therapy based on a phase II clinical trial in which ibrutinib elicited a response rate of 68% (Wang et al, NEJM, 2013). In this clinical study we found a transient increase in circulating MCL lymphocytes during the initial phase of tumor reduction. We hypothesized that targeting the circulating MCL cells with intravenous rituximab will further improve the efficacy of ibrutinib. We conducted a single-center phase II clinical trial with ibrutinib in combination with rituximab for relapsed MCL with no upper limit for prior lines of therapy. Among 50 patients with MCL, 100% received prior rituximab, 77% received prior Hyper-CVAD, 75% received prior bortezomib, and 20% received prior lenalidomide. Rituximab was dosed at 375 mg/m2 iv weekly X 4 during cycle 1 (cycle = 28 days), then on day 1 of every cycle from 3-8, and thereafter once every other cycle up to 2 years. Ibrutinib was dosed at 560 mg orally daily continuously. With a median follow up time of 6.5 months (range 1-10), 45 patients are evaluable for toxicity and efficacy as of July 21, 2014. Thirty three patients (73% of evaluable patients) have Ki-67 < 50%. Seventeen (17) patients are now off study including 2 patients with secondary malignancies (AML and lung cancer). One (1) patient in CR withdrew consent due to social issues and continued on commercial ibrutinib. Two (2) patients in remission withdrew consent due to their concerns that rituximab-ibrutinib might worsen their atrial fibrillation and both continued on single-agent commercial ibrutinib. One patient was off study due to bleeding. Three (3) patients in remission went off to stem cell transplantation. Eight (8) patients are off study due to progressive MCL (4 never responded: 4 responded then progressed), all of them had Ki-67 greater than 50% (range 50-100%). There were no toxic deaths due to therapy. Grade 3 hematologic toxicity events included neutropenia (1) and thrombocytopenia (1). The most common (≥ 20%) grade 1-2 non-hematologic toxicity events regardless of its relationship with study therapy included fatigue (18), diarrhea (11), myalgia (11), dyspnea (11), blurred vision (10), nausea (9),dry eye (9) and atrial filbrillation (6). The efficacy data is listed in Table 1. The ORR to date is 87% with CR in 17 patients (38%) and PR in 22 patients (49%). The CR rate is high in this study in the context of historical data (21% by single-agent ibrutinib). Median duration of response and PFS has not been reached. Notably, all 10 patients with SD (2) and PD (8) have Ki-67’s ≥ 50%. Excluding the 12 out of 45 evaluable patients with Ki-67 ≥ 50%, the ORR for 33 patients with lower Ki-67 (< 50%) is 100% (48% for CR and 52% for PR) in patients with relapsed/refractory MCL. While this trial is ongoing, preliminary data indicated that Ibrutinib-rituximab combination is well-tolerated and is efficacious, especially in patients with Ki-67 less than 50%. | | All n (%) | Ki-67 < 50% | Ki-67 ≥ 50% | || | Evaluable patients | 45 | 33 | 12 | | ORR | 39 (87%) | 33 (100%) | 6 (50%) | | CR | 17 (38%) | 16 (48%) | 1 (8%) | | PR | 22 (49%) | 17 (52%) | 5 (42%) | | SD | 2 (4%) | | 2 (17%) | | PD | 4 (9%) | | 4 (33%) | | Duration of response | NR | NR | NR | | PFS | NR | NR | NR | Table 1 The best response related to Ki-67 Disclosures Wang: Pharmacyclics and Janssen: Honoraria, Research Funding. Off Label Use: Ibrutinib and Rituximab for mantle cell lymphoma clinical trial. Westin: Pharmaciclics and Janssen: Honoraria, Research Funding. Fayad: Pharmacyclics and Janssen: Research Funding. Samaniego: Pharmacyclics and Janssen: Research Funding. Romaguera: Pharmacyclics and Janssen: Research Funding. [1]: pending:yes