Background: Ibrutinib (Ib) is active in relapsed/refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Patients receive indefinite therapy until progression. Published reports describe the occurrence of hypertension (HTN) and Atrial Fibrillation (AF) to be 8% and 6-9% respectively in patients treated with Ib. Methods: We evaluated 176 CLL patients treated on investigational protocols with Ib-based regimens from 2010-14 to determine the incidence of AF and HTN while receiving Ib. All pts gave informed consent and studies were conducted according to the Declaration of Helsinki. Blood pressure (BP) was evaluated at baseline and 6 months (mo). New onset HTN was defined as systolic BP (SBP) >140mmHg or diastolic BP (DBP) >90mmHg at 6mo in a pt with normal baseline BP. An increase in baseline SBP by ≥20mmHg and/or increase in DBP by ≥10mmHg was considered separately to be significant regardless of the absolute BP. AF was defined by an R-R interval following no repetitive pattern with no distinct P wave and an atrial rate of more than 300 beats/min. Electrocardiography (EKG) was reviewed to confirm AF. Baseline EKGs were required, but subsequent EKGs were performed only for symptom evaluation. Echocardiography (echo) was not performed at baseline, but was available in 6 of 9 pts at onset of AF. Results: Baseline characteristics are given below: TableCharacteristicAge (median, range)65 (35-87)Male129 (73)Treatment group:Ib monotherapy, n(%)83 (47)Ib + Rituximab, n(%)78 (44)Ib + Bendamustine + Rituximab, n(%)15 (8)Unmutated IGHV gene, n(%)112 (64)FISH hierarchydel(17p), n(%)59 (34)del(11q), n(%)32 (18)Other, n(%)25 (14) The median follow up of the entire patient cohort is 13 months (mo), range, 1-47mo. 9 patients (5%) developed new onset AF after starting Ibrutinib therapy, 7/9 were not on prior Beta blocker. 5 on Ib monotherapy, 3 patients on Ib + R, 1 on Ib+BR. The median time to AF after starting Ibrutinib was 20 weeks (range, 2-101). Six pts had a Hx of paroxysmal AF pre-dating Ib therapy (3.4%) and were already on treatment with Beta blocker of which none had recurrence of AF after or during Ib therapy, after a median follow up of 24 months (range=2-46). Six of 9 pts with new AF had an echo. Echo was normal in 2 pts, while 4 showed mild-severe left atrial (LA) dilatation; severe LA dilatation had developed during Ib treatment in the 1 pt who had had a normal baseline echo. One pt also had moderate left ventricular (LV) failure in addition to LA dilatation, but LV function was normal in the remaining pts. No pt had thyrotoxicosis as a contributing factor. Serial BP results were available in 111 pts. Median BP was 129/73 at baseline and 137/73 after 6mo of Ib therapy (p<0.001). New onset HTN occurred in 26 pts (23%); this was isolated systolic HTN in 23 pts and both systolic and diastolic in 3. Median change in SBP in pts with new-onset HTN was 27mmHg, range 4-55mmHg. Increase in SBP of >20mmHg occurred in 26 pts (23%); 21 of these pts had new onset HTN, while 5 had exacerbation of pre-existing HTN. Of the 9 pts with new AF, 5 had serial BP measurements. One developed new-onset HTN and 2 had a >20mmHg rise in SBP. Conclusions: In our experience, 5% of pts undergoing treatment with Ib develop new-onset AF. This incidence is comparable to prior reported data. Given that AF may be paroxysmal and asymptomatic, routine surveillance was not performed, the true incidence may be higher. The causative mechanism is unclear. 2/3 of pts with new AF, echo results showed significant structural LA abnormalities which have been associated with AF in the general cardiology literature. Twenty-three % of the pts developed new onset HTN, which was usually isolated systolic HTN. Most of these pts had increases in SBP >20mmHg. New onset HTN is likely therapy-related, although the mechanism is unclear. Development of AF did not appear to be dependent on the development of HT, as only 1 of 5 pts with new AF had new-onset HT. AF and HTN were generally manageable with medical intervention and did not require permanent cessation of Ib. Close monitoring of heart rhythm and blood pressure is recommended during treatment with Ib. Disclosures Jan: pharmacyclics: Research Funding. Wierda:Pharmacyclics: Consultancy. O'Brien:Pharmacyclics: Research Funding.

Background Non-infectious pulmonary syndromes (NIPS) frequently complicate allogeneic stem cell transplantation (alloSCT). The most common and serious is the bronchiolitis obliterans syndrome (BOS), characterized by irreversible fixed airflow obstruction, impaired quality of life and a high mortality. Treatment for established symptomatic disease is relatively ineffective. Although changes in spirometry parameters at day 80 have been shown to correlate with poorer lung function at one year, no screening test has been proven to clearly predict for the development of NIPS. We sought to determine whether early changes in spirometry parameters predict later development of NIPS. Secondary objectives were to determine pre-transplant predictors of NIPS and the impact of NIPS on relapse, treatment-related mortality (TRM) and survival. Methods Spirometry and DLCO were performed pre-alloSCT, at day 100 (D100) and one year post-alloSCT. We retrospectively analyzed spirometry, CT and bronchoalveolar lavage results in consecutive patients having alloSCT from 2004-2010 to identify cases of NIPS. Cases of BOS and cryptogenic organizing pneumonia (COP) were defined as per published guidelines (NIH consensus guidelines, 2005). Spirometry trends and baseline variables were compared between patients with and without NIPS to identify early predictors and risk factors for NIPS. Results Pulmonary function 257 patients underwent allo-SCT during the study period. 235 survived to D100 and were thus assessable for chronic GVHD (cGVHD) and NIPS. Of these, 23 (9.8%) developed NIPS, 18 with BOS and 5 with COP. Median time of onset was day 367 (IQR 144-544 days). All but one case developed prior to two years post-alloSCT. Change in FEV1.0 (ΔFEV1.0), was the best predictor of later NIPS development, while change in pulmonary diffusion capacity for carbon monoxide was not predictive. Median ΔFEV1.0 from pre-transplant to D100 in patients later developing NIPS was -12% (IQR -25% to -1%) vs -1% (IQR -7% to +6%) in those who did not, p=0.002. From pre-transplant to 1 year, it was -19% (IQR -37% to -6%) vs -3% (-10% to +4%), respectively, p<0.001. Median FEV1.0 at diagnosis was 58% predicted (IQR 46-71%). Once fixed airflow obstruction was established, progressive deterioration in lung function with time was the rule; median change in FEV1.0 during follow-up, post-diagnosis of NIPS, was -2% per annum (IQR -7 to 0%). Median follow-up duration post-diagnosis of NIPS was 1 year, range 0-6 years. For those with BOS and >6 months of follow-up, median change in FEV1.0 per year during follow-up was -8% (IQR -14% to -2%). In contrast, 4 of the 5 patients with COP had substantial improvement in FEV1.0 (11-36%) with normalization of FEV1.0 in 3 of these 4. Pre-transplant risk factors Busulfan-based, but not total body irradiation (TBI)-based conditioning increased the risk of NIPS [OR=8.87, 95%CI 3.33-23.63, p<0.001]. No cases of NIPS were seen in 53 patients who received in vivo T-cell depletion with Thymoglobulin as part of their conditioning (p<0.0001). Survival At a median follow-up of 44 months, overall survival was 59.1%. There was a trend towards increased all-cause mortality in those patients developing NIPS [HR = 2.02, 95%CI 0.92-4.44, p=0.08] and an increase in TRM [HR = 5.96, 95%CI 2.14-16.62, p=0.001], with eight patients (35%) with NIPS experiencing TRM. No statistically significant difference in disease relapse was seen between those with and without NIPS [HR = 0.24, 95%CI 0.03–1.80], although only one patient with NIPS experienced disease relapse. This may reflect the small numbers of patients with NIPS. Conclusions Spirometry is a potentially useful screening test for identification of pre-symptomatic NIPS. We recommend 3-monthly spirometry surveillance for up to two years post-transplant, given the moderately severe obstruction at diagnosis (median FEV1.0 58% predicted) and the incidence of 50% of cases between one and two years post-allo-SCT. Our findings require prospective validation to identify patients in whom earlier intervention may potentially modify the natural history of this disease. Disclosures: No relevant conflicts of interest to declare.