Background: IDELA is a first-in-class PI3Kδ inhibitor approved in combination with rituximab for pts with relapsed CLL. Methods: Pts with R/R CLL were treated continuously with 150 mg BID oral IDELA and a limited # of cycles (C) of CIT to evaluate safety and efficacy of combination regimens. Pts could enroll in extension study after 48 wks. Responses were evaluated by published criteria (Hallek 2008; Cheson 2012). Results: 114 pts (37F/77M) median (med) age 65 (range 41-87) yrs enrolled with: extensive prior therapies (med 3, range 1-9), refractory disease (51%), high risk Rai (60%), del17p/TP53 mutation (29%), del11q (13%), unmutated IGHV (79%). Med exposure was 14.6 (range 0-49) mos. 61 pts (54%) enrolled in extension study. 21 (34%) were continuing on study. Most common and select AEs independent of causality (any Grade/Gr ≥ 3): diarrhea/colitis (52%/19%), pyrexia (45%/4%), cough (37%/1%), nausea (29%/1%), fatigue (32%/4%), pneumonia (23%/15%), dyspnea (22%/3%), rash (21%/4%), pneumonitis (4%/4%). AST/ALT elevation Gr ≥ 3 was seen in 12%. Most common reasons for discontinuation were AEs (25%) or PD (25%). 2 pts discontinued due to AST/ALT elevation, 1 due to Richter’s transformation. 20 (18%) deaths were reported on study; 6 pts experienced PD before death. ORR was 82.5% in all pts, 70% in pts with del17p/TP53 mut, and 87% among pts without. SD/PD was reported in 10%/3%. Med overall PFS was 26.1 mos, 20.3 mos for pts with del17p/TP53 mut, and 36.8 mos for pts without. Med OS for all pts or pts with del17p/TP53 mut was not reached. Estimated OS at 36 mos was 73.1% for all pts, 57.3% for pts with del17p/TP53, and 78.3% for pts without. Conclusions: IDELA in combination with CIT shows a manageable safety profile without increased toxicities and has substantial clinical activity in heavily pretreated, refractory, and high-risk CLL including presence of del17p/TP53mutation. Phase 3 trials of IDELA with O or BR in pts with R/R CLL are ongoing (NCT01659021, NCT01732926). Clinical trial information: NCT01088048