Abstract: Toxicity was the most common reason for discontinuation of ibrutinib or idelalisib in treated patients with CLL. KI-intolerant patients, but less so those with CLL progression, can be successfully treated with an alternate KI.

Abstract: Abstract 4618 Background: Front-line regimens for CLL typically include Fludarabine and Rituximab (R), producing ORRs of 90–95% (CR 44–47%) in multicenter trials. Despite these significant responses, patients (pts) invariably relapse and newer regimens are necessary for this relapsed/refractory population. Bendamustine (B) and Lenalidomide (L) have both shown efficacy as single agents in CLL with ORRs of 68–78% and 32–47%, respectively. The combination of these agents, however, has yet to be investigated. In this 2-stage phase I study, we are combining B and L in relapsed/refractory CLL (Stage I) in order to determine the MTD of L for future combination of BLR in CLL (Stage II). We report the preliminary results of the Stage I here. Methods: Pts with relapsed/refractory CLL with adequate performance status and organ function were eligible. This phase I study utilized a standard 3 + 3 dose-escalation design. In Stage I all pts received L 5 mg po daily D-7 through D-1 and allopurinol 300 mg po daily D-2 to D14 of Cycle 1 to minimize the risk of tumor lysis syndrome (TLS). For each 28-day cycle, pts received B 90 mg/m2 IV on D1, 2 with escalating doses of L po daily. Dose levels were 5 mg every other day (Cohort −1), 5 mg daily (Cohort 1), 10 mg daily (Cohort 2), 15 mg daily (Cohort 3), and 20 mg daily (Cohort 4). Pts in Cohorts 2 and higher received L 5 mg po daily during Cycle 1 followed by their respective cohort L doses in subsequent cycles. Pts received 6 cycles of BL followed by 6 cycles of L as long as tolerated or until disease progression. Results: For the 7 pts on study, the median age was 71 years, 100% were male, 43% were Rai Stage III/IV, 43% were CD38+, and 14% had a B-2 microglobulin level 〉 4. Two pts had sole del 13q, 3 had del 11q, and 1 had del 17p cytogenetics. Pts received a median of 1 prior therapy (range, 1–3). One pt had Richter’s transformation and one pt had PLL. The first pt (Richter’s transformation) in Cohort 1 had a DLT of Grade 3 rash. As rash is a common toxicity with L, the protocol was amended so that only Grade 3 rash that did not resolve to 〈 Grade 2 within 10 days despite steroids or any Grade 4 rash were to be considered DLTs. In addition, L administration was reduced to only 21 days of each 28-day cycle. The trial was reinitiated after these amendments, and 3 new pts were enrolled into Cohort 1. There were no DLTs or Grade 3/4 rash found in this cohort. Three pts were enrolled into Cohort 2, but one suffered fatal septic shock during Cycle 2. No MTD has been reached for L. Common 〉 Grade 3 toxicities included neutropenia (71%) and thrombocytopenia (29%). Pts completed a median of 5 cycles of therapy (range, 2–12). The most common reason for discontinuing therapy was toxicity. The ORR was 57% (CR of 14%). Responses were seen in pts with both sole del 13q and del 11q. The median time to response was 6 mos (range, 3–6 mos). Among the responders, the median length of response was 14 months (range, 13–23+ mo). Cohorts 1 and 2 have been completed. Conclusion: BL demonstrates promising efficacy and tolerability in pts with relapsed/refractory CLL. Further evaluation is needed. Disclosures: Cheson: Celphalon: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celegen: Membership on an entity’s Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Research Funding.

Abstract: Ibrutinib demonstrated superior response rates and survival for treatment‐naïve chronic lymphocytic leukemia (CLL) patients in a pivotal study that excluded patients younger than 65 ( 〈 65) and/or with chromosome 17p13 deletion (del[17p13]). We examined outcomes and toxicities of CLL patients who would have been excluded from the pivotal study, specifically 〈 65 and/or those with del[17p13]. This multicenter, retrospective cohort study examined CLL patients treated with front‐line ibrutinib at 20 community and academic centers, categorizing them based on key inclusion criteria for the RESONATE‐2 trial: 〈 65 vs ≥65 and present vs absent del[17p13]. Of 391 included patients, 57% would have been excluded from the pivotal study. Forty‐one percent of our cohort was 〈 65, and 30% had del(17p13). Patients 〈 65 were more likely to start 420 mg of ibrutinib daily; those who started at reduced doses had inferior PFS. The most common adverse events were arthralgias, fatigue, rash, bruising, and diarrhea. Twenty‐four percent discontinued ibrutinib at 13.8 months median follow‐up; toxicity was the most common reason for discontinuation, though progression and/or transformation accounted for a larger proportion of discontinuations in 〈 65 and those with del(17p13). Response rates were similar for 〈 65 and those with del(17p13). However, patients with del(17p13) had inferior PFS and OS. Ibrutinib in the front‐line setting has extended beyond the population in which it was initially studied and approved. This study highlights and compares important differences in ibrutinib dosing, treatment interruptions, toxicities, reasons for discontinuation, and survival outcomes in two important patient populations not studied in RESONATE‐2.

Abstract: Venetoclax-based therapy is a standard-of-care option in first-line and relapsed/refractory chronic lymphocytic leukemia (CLL). Patient management following venetoclax discontinuation remains nonstandard and poorly understood. Experimental Design: To address this, we conducted a large international study to identify a cohort of 326 patients who discontinued venetoclax and have been subsequently treated. Coprimary endpoints were overall response rate (ORR) and progression-free survival for the post-venetoclax treatments stratified by treatment type [Bruton's tyrosine kinase inhibitor (BTKi), PI3K inhibitor (PI3Ki), and cellular therapies]. Results: We identified patients with CLL who discontinued venetoclax in the first-line (4%) and relapsed/refractory settings (96%). Patients received a median of three therapies prior to venetoclax; 40% were BTKi naïve (n = 130), and 81% were idelalisib naïve (n = 263). ORR to BTKi was 84% (n = 44) in BTKi-naïve patients versus 54% (n = 30) in BTKi-exposed patients. We demonstrate therapy selection following venetoclax requires prior novel agent exposure consideration and discontinuation reasons. Conclusions: For BTKi-naïve patients, selection of covalently binding BTKis results in high ORR and durable remissions. For BTKi-exposed patients, covalent BTK inhibition is not effective in the setting of BTKi resistance. PI3Kis following venetoclax do not appear to result in durable remissions. We conclude that BTKi in naïve or previously responsive patients and cellular therapies following venetoclax may be the most effective strategies. See related commentary by Rogers, p. 3501

Abstract: Introduction: Acalabrutinib (acala) is an irreversible, second generation Bruton tyrosine kinase inhibitor (BTKi) approved by the FDA for the treatment of relapsed/refractory (R/R) mantle cell lymphoma, and is in advanced stages of clinical testing for front line (FL) and R/R CLL (Byrd NEJM, Wang NEJM). Ibrutinib (ibr) is a well-established and potent treatment for CLL; however, discontinuation due to intolerance precludes a significant number of patients (pts) in clinical practice from long-term benefit of this targeted therapy (Mato et al Blood 2016, Follows BJH 2017). Acala inhibits BTK more selectively than ibr, and while demonstrating impressive activity, may result in significantly less off-target adverse events (AEs). Although not yet FDA approved, it is being increasingly used in CLL pts with ibr-intolerance or cardiovascular or hematologic comorbidities (atrial fibrillation (AF), hypercoagulable state on long-term anticoagulation, etc.) to potentially avoid ibr-related toxicities. The increasing use of acala in clinical practice provides an opportunity to address various knowledge gaps. Therefore, we conducted a multi-institutional, retrospective analysis in CLL pts treated with acala in the real-world setting. We aimed to report and analyze the main reasons for starting acala, its safety, efficacy, outcome and sequencing. Patients and Methods: This multi-institutional, retrospective analysis included acala-treated CLL pts at 9 US cancer centers. We analyzed and described prior treatments, dosing of acala, discontinuations, toxicities and outcomes. The primary endpoint was progression-free survival (PFS) as predicted by the Kaplan Meier method. Results: 69 CLL pts treated with acala (off clinical trials) were identified. Baseline characteristics are described in Table 1. Median age was 70 years (range 51-89) and 6 (9%) and 63 (91%) pts received acala in the FL and R/R settings, respectively. Of the R/R pts, 49 (78%) had received a prior BTKi, 11 (17%) a phosphoinositide 3-kinase inhibitor (PI3Ki), 14 (22%) venetoclax, 18 (29%) bendamustine, and 17 (27%) fludarabine. Median time from diagnosis of CLL to starting acala was 79.5 months. Most common reasons for choosing acala were prior intolerance to other agents in 47 (68%), disease progression on the prior line of therapy in 19 (28%) and concern for intolerance to other therapies due to age/comorbidities in 9 (13%). Prior intolerance to ibr was the reason for starting acala in 46 (98%) of the intolerant pts; the most common AEs leading to discontinuation of ibr were rash in 10 (22%), AF/flutter in 8 (17%), arthralgia in 8 (17%), bleeding in 6 (13%), infection in 6 (13%) and fatigue in 6 (13%). Almost all pts (99%) started on acala 100 mg orally twice daily, with dose reductions required in 5 (7%). The most common toxicities on acala were fatigue in 9 (13%), infection in 9 (13%), diarrhea/colitis in 7 (10%), nausea/vomiting in 6 (9%), headache in 5 (7%), rash in 5 (7%), bleeding in 2 (3%) and AF/flutter in 1 (1%). The median time from the start of acala to an infection was 3 months. With a median follow-up of 5 months, the acala discontinuation rate was estimated to be 19% (13 pts) with median time to discontinuation of 1 month. The main reason for discontinuation was AEs in 8 pts (12%) (no consistent pattern of AEs), all in R/R pts with median time to discontinuation of 3.5 months; 2 others proceeded to CAR T-cell therapy or allogeneic transplant; 2 died of unrelated causes, 1 from progressive disease off acala. Overall response rate (ORR) was 62% (9% CR, 53% PR, number reported = 66), 50% PR in FL (3/6) and 63% (CR 5%, PR 58%, number reported = 60) in R/R pts. The differences likely reflected small numbers and short follow-up. Median PFS and overall survival were not reached (Figs 1a,b). Conclusion: In this group of largely ibr-intolerant pts, the overall acala discontinuation rate was lower than prior reports from clinical trials, although with relatively short follow up. However, discontinuation rate due to AEs appears to be similar to clinical trial data in an ibr-intolerant pt population (Awan Blood Adv, Rogers ICML 2019). These data demonstrate the need for the results of randomized studies, in order to compare the efficacy and AE profile of acala relative to ibr and other novel agents and Disclosures Yazdy: Genentech: Research Funding; Bayer: Honoraria, Speakers Bureau; Octapharma: Consultancy; Abbvie: Consultancy. Mato:Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; Acerta: Consultancy; Janssen: Consultancy; Gilead: Research Funding; DTRM Biopharma: Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding. Roeker:AbbVie: Equity Ownership; Abbott Laboratories: Equity Ownership. Ujjani:Gilead: Consultancy; Atara: Consultancy; Genentech: Honoraria; AbbVie: Honoraria, Research Funding; PCYC: Research Funding; Pharmacyclics: Honoraria; PCYC: Research Funding; Pharmacyclics: Honoraria; Astrazeneca: Consultancy. Shadman:TG Therapeutics: Research Funding; Gilead: Research Funding; Merck: Research Funding; Bigene: Research Funding; Celgene: Research Funding; Acerta: Research Funding; Emergent: Research Funding; Sunesis: Research Funding; Mustang Biopharma: Research Funding; Atara: Consultancy; Pharmacyclics: Consultancy, Research Funding; Verastem: Consultancy; AbbVIe: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; AstraZeneca: Consultancy; Sound Biologics: Consultancy; ADC Therapeutics: Consultancy. Skarbnik:Genentech: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acerta: Research Funding; Novartis: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Verastem Oncology: Honoraria, Research Funding, Speakers Bureau; Kite Pharma: Honoraria, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; CLL Society: Consultancy, Membership on an entity's Board of Directors or advisory committees. Pagel:AstraZeneca: Consultancy; Gilead Sciences: Consultancy; Pharmacyclics: Consultancy. Patel:Sunesis: Consultancy; Pharmacyclics/Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Genentech: Consultancy, Speakers Bureau. Jacobs:AstraZeneca: Speakers Bureau; Gilead: Consultancy; Genentech: Speakers Bureau; JUNO: Consultancy; TG Therapeutics: Honoraria, Research Funding; AbbVie: Consultancy, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Research Funding, Speakers Bureau. Feldman:Portola Pharma: Research Funding; Roche: Research Funding; Corvus: Research Funding; Eisai: Research Funding; Kyowa Hakko Kirin: Research Funding; Roche: Research Funding; Trillium: Research Funding; Viracta: Research Funding; Pfizer: Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Other: Travel expenses, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Travel expenses, Speakers Bureau; AbbVie: Honoraria, Other: Travel expenses, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Kite Pharma: Honoraria, Other: Travel expenses, Speakers Bureau. Goy:University of Nebraska: Research Funding; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; Hackensack University Medical Center, RCCA: Employment; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Takeda: Other: Grants outside of the submitted work; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Coombs:Pharmacyclics: Honoraria; Loxo: Honoraria; H3 Biomedicine: Honoraria; Octopharma: Honoraria; Dedham Group: Consultancy; Cowen & Co.: Consultancy; Medscape: Honoraria; Abbvie: Consultancy; Covance: Consultancy. Lamanna:Celgene: Consultancy; Infinity/ Verastem: Research Funding; Ming: Research Funding; TG Therapeutics: Research Funding; Oncternal: Research Funding. Weiss:TG Therapeutics: Other: family member with employment and equity) . Cheson:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Portola: Research Funding; Kite: Research Funding; Gilead: Research Funding; Epizyme: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symbios: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Acalabrutinib is an irreversible, second generation Bruton tyrosine kinase inhibitor approved by the FDA for the treatment of relapsed/refractory (R/R) mantle cell lymphoma, and is in advanced stages of clinical development testing for front line (FL) and R/R CLL. Although not yet FDA approved, it is being increasingly used in CLL patients in clinical practice. This highlights the necessity to address various knowledge gaps.

Abstract: The ability of positron emission tomography‐computerized tomography ( PET ‐ CT ) to accurately detect bone marrow involvement ( BMI ) has been suggested in Hodgkin lymphoma ( HL ) and diffuse large B‐cell lymphoma ( DLBCL ), but its abilities in other histologies is less established. The aim of this retrospective study was to confirm the role of PET ‐ CT in detecting BMI in DLBCL and HL , and to explore its usefulness in other subtypes. Of the 149 newly diagnosed patients, common subtypes included DLBCL , follicular lymphoma ( FL ) and HL . In DLBCL , the sensitivity and specificity of PET ‐ CT at diagnosis were 75% and 92%. In FL , the sensitivity and specificity of PET ‐ CT were 67% and 85% at diagnosis, and 73% and 89% at relapse. In HL , the sensitivity and specificity were 100% and 74%. PET ‐ CT was able to detect BMI in patients with negative biopsies. Most of the patients in which PET ‐ CT failed to identify BMI were already advanced stage by imaging. In this analysis, PET ‐ CT was highly accurate for detecting BMI at diagnosis in DLBCL and HL and highly specific in FL at diagnosis and relapse. Results also suggested the diagnostic advantage of PET ‐ CT over bone marrow biopsy in detecting BMI . Prospective evaluation is necessary and may eliminate biopsies in future patients.

Abstract: Determining bone marrow involvement (BMI) is a crucial element for staging of lymphoma. While the standard procedure to evaluate BMI has traditionally been bone marrow biopsy, biopsies are subject to sampling error, particularly if the involvement is focal and outside the pelvis. 18F-FDG PET/CT scans have become an increasingly popular component of the pretreatment evaluation to assess nodal and extramedullary disease. Their ability to accurately detect BMI has been suggested in Hodgkin's lymphoma, but is less well established in other histologies. This retrospective study evaluated whether 18F-FDG PET/CT scans are useful in detecting BMI in different types of lymphoma and, thus, may replace trephine biopsies as part of staging. Methods Between 2005 and 2013, 222 patients (pts) seen at our center underwent coinciding bone marrow biopsies and whole body 18F-FDG PET/CT scans. The most common lymphoma subtypes represented were diffuse large B-cell (DLBCL), follicular, and Hodgkin's lymphoma. Ninety-two pts were referred to our center for a new diagnosis and retrospectively enrolled on study. Unilateral bone marrow biopsy of the iliac crest was used as the standard for detecting BMI. 18F-FDG PET/CT scan was interpreted as positive for BMI when bone marrow 18F-FDG uptake was not otherwise explained by CT findings. Results Of the 92 newly diagnosed pts, there were 44 DLBCL, 28 follicular, and 20 Hodgkin's lymphoma. Most pts underwent 18F-FDG PET/CT scan prior to biopsy (47), as opposed to the same day (13) or after (32). The median age at diagnosis was 48 years (Range 22-89). Fifty-one of the patients were male and 41 were female. Seven of the 44 DLBCL patients had BMI documented by biopsy; 5 DLBCL, 2 follicular. When evaluating for only DLBCL marrow involvement, the sensitivity, specificity, and accuracy (concordance) of 18F-FDG PET/CT scan was 80% (CI 0.28, 0.99), 97% (CI 0.86, 1.00), and 95% (CI 0.84, 0.99) respectively. 18F-FDG PET/CT scan failed to identify 1 patient with focal DLBCL involvement. This pt already had advanced stage disease based on imaging, and would have received the same treatment regimen regardless of the extra information provided by bone marrow biopsy. When accounting for any kind of lymphomatous involvement, the sensitivity dropped to 57% (CI 0.18, 0.90) as 18F-FDG PET/CT scan failed to identify the 2 pts with follicular lymphoma of the marrow. Specificity and accuracy, however, remained high at 97% and 91%. When evaluating pts with relapsed disease, all DLBCL pts in our cohort had negative BMI by both biopsy and 18F-FDG PET/CT. In follicular lymphoma, however, the sensitivity of 18F-FDG PET/CT was 43% (CI 0.21, 0.73), specificity 93% (CI 0.64, 1.00), and accuracy 68% (CI 0.48, 0.84). Of the 9 pts with discordant results, 18F-FDG PET/CT failed to identify 8 pts with marrow involvement, 6 of whom had focal involvement. In the remaining pt, 18F-FDG PET/CT scan indicated appendicular skeletal and vertebral involvement. The bone marrow biopsy was negative in this pt, presumably due to the lack of iliac involvement. Information provided by bone marrow biopsy upstaged one of the 9 pts from limited to advanced stage disease. In the 12 pts with relapsed disease, the sensitivity was 47%, specificity 93%, and accuracy 68% based on 22 coinciding studies. In Hodgkin's lymphoma, the sensitivity, specificity, and accuracy of 18F-FDG PET/CT at diagnosis was 67% (CI 0.09, 0.99), 71% (CI 0.44, 0.90), and 70% (CI 0.46, 0.88) respectively. Of the 5 Hodgkin's pts with discordant results, 18F-FDG PET/CT scans detected marrow involvement in 4 pts with negative bone marrow biopsies. One pt had evidence of marrow involvement by biopsy but not by 18F-FDG PET/CT. As the pt was already stage III by 18F-FDG PET/CT, this information did not impact the treatment regimen. Conclusions In our cohort, 18F-FDG PET/CT was a highly accurate tool for detecting BMI in DLBCL and Hodgkin's lymphoma. As most pts underwent imaging first, the subsequent biopsy was unnecessary. In Hodgkin's, 18F-FDG PET/CT demonstrated the ability to detect BMI in pts who would have otherwise been considered to be negative by biopsy alone. 18F-FDG PET/CT was not as accurate in follicular lymphoma, presumably due to the low-grade nature of the disease. Further evaluation in a prospective manner is warranted, and may eliminate the need for a costly and painful procedure in many pts with lymphoma. Disclosures: No relevant conflicts of interest to declare.

Abstract: Introduction: Ibrutinib (Ibr) is a kinase inhibitor (KI) indicated for treating CLL. Clinical trials that led to its approval showed that its unique side effects differ from traditional chemotherapy toxicities. We previously reported (Mato et al, ASH 2015) that intolerance was the most common reason for discontinuation of Ibr in 123 patients treated in a real world setting. Whether reasons for discontinuation reported in clinical trials mirror those encountered in the real world is unknown and has not been studied. Therefore, we conducted a retrospective analysis of 621 CLL patients treated with Ibr either on clinical studies or commercially. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. Patients and Methods: This multicenter, retrospective analysis included Ibr-treated CLL patients at 9 US cancer centers or the Connect® CLL Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival (PFS) (time from KI treatment to progression, death or last f/u) as determined by the Kaplan Meier method. Comparisons of outcomes data were made using the log rank (LR) test. All other comparisons were descriptive. Results: 621 patients treated with Ibr were identified. Table 1 includes available baseline characteristics stratified by line of therapy. A total of 546 (88%) patients were treated with commercial drug. Clinical trial patients were younger (median age 57 vs. 61 years), had a longer time from diagnosis to Ibr (median 85 vs. 72 months) and were more consistently initiated at 420 mg daily (100% vs. 89%). With a median f/u of 14.5 months, the Ibr discontinuation rate was estimated to be 42% (median time to Ibr discontinuation was 7 months). Reasons for discontinuation are listed in table 2. Notably, Ibr toxicity was the most common reason for discontinuation in all settings. Ibr starting dose (420 mg daily vs. 〈 420 mg daily) did not impact the proportion of patients who discontinued Ibr due to toxicity (51% vs. 50%). In relapsed CLL, the 5 most common Ibr-related toxicities as a reason for discontinuation included: atrial fibrillation (12.3%), infection (10.7%), pneumonitis (9.9%), bleeding (9%), and diarrhea (6.6%). In front line CLL, the 3 most common Ibr-related toxicities as a reason for discontinuation included arthralgia (41.6%), atrial fibrillation (25%), and rash (16.7%). Median times to discontinuation by toxicity were as follows: bleeding (8 months), diarrhea (7.5 months), atrial fibrillation (7 months), infection (6 months), arthralgia (5 months), pneumonitis (4.5 months), and rash (3.5 months). Median PFS and OS for the entire cohort were 35 months and not reached (median f/u 17 months) respectively. Figure 1 describes PFS for Ibr treated patients stratified by line of therapy (A), reason for discontinuation (B), clinical trial participation (C) and depth of response (D). In a multivariable model, complex karyotype was validated as an independent predictor of PFS (HR 1.6, CI 1.1-2.5 p=.04) but not OS (HR 1.6, CI .9-3.1 p=.1). Conclusions: In the largest reported series on Ibr-treated CLL patients, we show that 40% of patients have discontinued Ibr during this observation period. Intolerance as opposed to CLL progression or transformation was the most common reason for discontinuation. As compared to previous reports from clinical trials, the discontinuation rate appears to be higher suggesting (1) a learning curve in terms of toxicity management, (2) a higher incidence of toxicity in clinical practice, (3) or a lower threshold for discontinuation given alternative choices. Outcomes remain excellent and were not impacted by line of therapy and whether patients were treated on studies or commercially. These data strongly argue to find strategies to minimize Ibr intolerance so that efficacy can be further maximized. Figure 1 Figure 1. Disclosures Mato: Abbvie, Acerta Pharma, Gilead Sciences, ProNAi, TG Therapeutics, Theradex: Research Funding; Abbvie, Gilead Sciences, Pharmacyclics, TG Therapeutics: Consultancy. Lamanna:Acerta: Research Funding; TGR Therapeutics: Research Funding; Janssen: Honoraria; Pharmacyclics: Honoraria, Research Funding; Roche-Genentech: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Infinity: Research Funding; Acerta: Research Funding; TGR Therapeutics: Research Funding. Ujjani:Gilead: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy. Brander:TG Therapeutics: Research Funding; Gilead: Honoraria. Howlett:Sandoz: Honoraria; Teva: Speakers Bureau; Amgen: Honoraria; Pfizer: Honoraria; Eisai: Honoraria. Skarbnik:Gilead Sciences: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau; Abbvie: Consultancy; Pharmacyclics: Consultancy. Cheson:Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kiselev:Celgene: Employment, Equity Ownership. Nasta:Millennium Pharmaceuticals: Research Funding. Schuster:Janssen Research & Development: Research Funding; Hoffman-LaRoche: Research Funding; Gilead: Research Funding; Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding. Porter:Novartis: Patents & Royalties, Research Funding; Genentech: Employment. Nabhan:Seattle Genetics: Research Funding; Cardinal Health: Consultancy; Infinity: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Astellas: Research Funding. Barr:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.