The second is to consider whether combining ibrutinib with chemoimmunotherapy might be so effective as to raise the possibility of cure. 15 month PFS is usually 96 %. Registration trials have been initiated, and the difficult task that remains is usually to determine where in the course of CLL therapy this drug will have the greatest impact and benefit for patients. and refractory disease[17]. Ibrutinib in Previously Untreated CLL/SLL At ASCO 2012, the results of the phase Ib/II study in treatment na?ve CLL patients 65 years of age RU 58841 or older were presented[18]. This study enrolled 26 patients at a dose of 420 mg per day, with median follow-up 14.4 months, and five patients at a dose of 840 mg per day, with 7.4 month median follow-up. The 840 mg cohort halted enrollment early due to the comparable efficacy IGFBP6 and perhaps improved security of the 420 mg dose level in the relapsed or refractory patients; only four patients were actually treated with the 840 mg dose. The median age of all 31 patients was 71, and 60 %60 % experienced Rai 3 C 4 disease, and 43 % unmutated em IGHV /em . Only two patients experienced 17p deletion, however, in this untreated cohort. The therapy was well-tolerated, with the most frequent side effects including very easily manageable diarrhea, nausea, fatigue, rash and contusion. Grade 3 C 4 toxicities included 13 % diarrhea, 10 %10 % contamination and only 12 % hematologic, split between anemia and thrombocytopenia. Interestingly these treatment na?ve patients showed much less increase in complete lymphocyte count, in contrast to the previously treated cohorts. The ORR was 74 %, with 10 %10 % CRs, and an additional 13 % of RU 58841 patients experienced nodal response with lymphocytosis. Fifty percent of patients with pretreatment cytopenias, either anemia or thrombocytopenia, showed significant improvement, defined as improvement by at least 50 %, or Hb 11 g/dL or platelets 100,000/l, sustained for two months. All but five subjects remain on study, with treatment discontinuation due to adverse events in four cases and progressive disease in one case. Compared to the previously treated patients, the treatment na?ve patients showed faster response, and higher overall and complete response rates. The estimated 15 month PFS in this RU 58841 treatment na?ve cohort is an impressive 96 %. Combination Studies of Ibrutinib in CLL The remarkable single agent activity of ibrutinib in CLL raises several possibilities about how to use it in combination. One possibility to consider is usually to try to obviate the need for chemoimmunotherapy entirely, in an effort to create safer and better tolerated therapy. The second is RU 58841 to consider whether combining ibrutinib with chemoimmunotherapy might be so effective as to raise the possibility of cure. Studies to date are starting to explore both possibilities. Ibrutinib C Antibody Combinations The first option of avoiding chemotherapy entirely would probably lead to combination therapy with antibody, most likely CD20 antibody, given the efficacy of the latter in B cell malignancies. Ofatumumab is an anti-CD20 antibody that confers more effective CDC than rituximab against CLL cells that express low levels of CD20. Ofatumumab has been approved for CLL refractory to fludarabine and alemtuzumab based on a 45 % response rate in this setting[19,20]. At ASCO 2012, the Ohio State group offered early results of a single center phase Ib/II study evaluating three different combination dosing regimens of ibrutinib and ofatumumab[21]. Data were presented for one of those dosing schedules, in which ibrutinib is started as a single agent 4 weeks prior to the addition of ofatumumab on cycle 2 day 1. Twenty-seven patients were enrolled with median age 66 years and a median of three prior regimens. Forty-eight percent experienced advanced Rai stage 3 C 4 disease and 41 % were refractory to purine analogues. Ninety-one percent experienced unmutated em IGHV /em , 37 % experienced 17p deletion and 33 %33 % 11q deletion. As might be expected, the addition of ofatumumab brought the early lymphocytosis down rapidly. The ORR was 100 % in the CLL/SLL/PLL RU 58841 patients with 4 % CR (1 CR). Improvement in cytopenias was also seen. Among three patients with Richters syndrome enrolled in the study, two responded and one remained on study in ongoing response at 10.1 months. At a median follow-up of 9.8 months, 89 % of patients remain on study, with one off for progressive disease, one to undergo stem cell transplant and one deceased. Adverse events were similar to the single agent with the exception of neuropathy, which was seen in 25 %25 % of patients, but was more related to ofatumumab than to ibrutinib likely. Ecchymoses had been observed in nearly fifty percent of individuals also, and likely reveal the known truth that ibrutinib inhibits platelet function through a direct impact on BTK. The clinical need for this.