Background: Ibrutinib (Ib), an oral covalent BTK inhibitor, has significant activity in relapsed/refractory (R/R) CLL. Adding ofatumumab (O), an anti-CD20 antibody, to chemotherapy in CLL can improve response and progression free survival (PFS). Here, Ib was given with O in 3 different administration sequences. Methods: Patients (pts) with R/R CLL/SLL, PLL or Richter’s transformation (RT) after ≥2 prior therapies including a purine analog were treated with 420 mg Ib daily and 300/2000 mg O (8 x weekly/then 4 x monthly) in 28-day cycles until progressive disease (PD). Group (G) 1 had 1 cycle of Ib monotherapy, then O was added. G2 started O on Day (D) 1/Cycle (C) 1 and Ib on D2/C1. G3 had 2 cycles of O monotherapy, then Ib was added on D1/C3. Results: 71 pts (27, 20, 24 in G1, 2, 3) were enrolled. Median age was 64 y; 61% had Rai stage III/IV; 65 pts had CLL, 1 SLL, 2 PLL and 3 RT; 75% had lymph nodes ≥5 cm; 44% had del(17p); 31% had del(11q). The most frequent AEs were diarrhea (68%), infusion-related reaction (IRR, 45%), peripheral sensory neuropathy (42%) and stomatitis (37%). In all, 61% had ≥1 AE ≥grade (g) 3; most common g 3-4 AE was neutropenia in 17%. 39% had SAEs including: 1 pt in G2 with ≥g 3 IRR; 6 pts with AEs leading to Ib discontinuation; 9 pts died within 30 days of last dose and 2 within f/u period. Overall response rate in CLL/SLL was 100% in G1, 79% in G2, and 71% in G3. 2 additional pts achieved a partial response with lymphocytosis. 4 pts in G3 progressed before starting Ib. At study end, 52/58 responders (90%) remained progression-free with f/u of 16, 12 and 11 months for G1, 2 and 3, respectively. Three RT pts had disease control followed by PD on Day 471, 168, and 137. At 12 months, PFS was 89%, 85%, and 90% in G1, 2 and 3, respectively; 76% continued on Ib in a long-term extension study; 2 pts had a transplant. Conclusions: Ib combined with O is well tolerated and highly active (83% ORR) in pts with R/R CLL/SLL in all 3 dosing sequences investigated. Because of these compelling results, randomized trials evaluating anti-CD20 antibodies in combination with Ib with a PFS endpoint are ongoing. Clinical trial information: NCT01217749.