Citations

Abstract Background We have previously reported on the high prevalence and severity of insomnia amongst a large international cohort of MPN patients (Emanuel JCO 2012). We sought to further analyze the relationships between insomnia and the MPN disease features (in particular splenomegaly, status of blood counts), individual MPN symptom prevalence and severity, language, and overall quality of life. Methods Data was collected among an international cohort of patients with MPNs. Subjects completed the BFI, MPN-SAF, and EORTC QLQ-C30 instruments. Surveyed symptoms on the MPN-SAF included the patient’s perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. Specifically, the MPN-SAF insomnia item asked about “difficulty sleeping”. Total symptom score (TSS) was computed based on 10 symptom items using the published scoring algorithm on a 0 (all reported symptoms absent) to 100 (all reported symptoms worst imaginable) scale. Pairwise associations between the MPN-SAF insomnia item and continuous and categorical covariates were investigated using Pearson correlations and analysis of variance/t-tests, respectively. Multivariate regression models were used to investigate impact of groups of covariates on the insomnia item with the final multivariate model selected using forward regression. Results Demographics A total of 1992 MPN patients (essential thrombocythemia=834, polycythemia vera=703, myelofibrosis=449, unknown=6) completed the insomnia item. Participants were of typical age (median=61, range-15-94) and gender (female=54%). Overall, 1307 subjects endorsed the MPN insomnia item (score >0) with an overall mean symptom score of 3.0 (median=2.0, SD=3.1. range=0-10); 603/1992 (30%) of patients had severe insomnia related complaints (score >4). Univariate Analysis Among QLQ-C30 functioning scales, emotional functioning most highly correlated with the MPN-SAF insomnia item (r=-.47, p<0.001) with all other domains also having statistically significant but slightly weaker correlation (all p<0.001). Among QLQ-C30 symptom scales, insomnia (r=.79, p<0.001) and fatigue (r=.45, p<0.001) most highly correlated with the MPN-SAF insomnia item with all other QLQ-C30 symptoms having correlations between .13 and .37 (all p<.001). Among MPN-SAF items, the MPN-SAF insomnia item correlated with all MPN-SAF items (all p<0.001) including the TSS (r=0.55, p<0.001) and most highly with depression (r=.52, p<0.001), concentration problems (r=.43, p<0.001), overall QOL (r=.41, p<0.001), night sweats (r=.41, p<0.001), and extremity tingling (r=.40, p<0.001). MPN-SAF insomnia significantly differed by gender (means: M 2.4, F 3.4; p<0.001), language (means ranged from 2.6 [Italian] to 3.6 [German]; p=0.01), anemia (means: absent 2.8, present 3.5; p<0.001), prior hemorrhage (means: no 2.9, yes 3.7; p=0.01), and requiring red blood cell transfusion (means: no 2.9, yes 3.6; p=0.03), with a trend for a difference by MPN type (ET mean=2.7, PV mean=3.0, MF mean=3.2; p=0.06). Multivariate Analysis In a multivariate model of MPN-SAF insomnia containing all QLQ-C30 functioning scales, physical, emotional, and cognitive functioning along with global health status/QOL were all significant (all p<0.001). Numerous symptoms were also significant in a multivariate model of MPN-SAF insomnia containing all other MPN-SAF symptoms (all p<0.05: headaches, extremity tingling, depression, sexual problems, night sweats, pruritus, fever, and QOL). The final multivariate model based on forward regression starting with all demographics, clinical variables, and patient-reported QLQ-C30 scales and MPN-SAF items found age, gender, QLQ-C30 emotional functioning and MPN-SAF items to be significant. Conclusions Insomnia is highly prevalent and severe in MPN patients and closely correlates with most other MPN-related symptoms and functional domains bearing a multi-faceted impact on overall quality of life. Correlations between insomnia and emotional, cognitive, and physical complaints including depression/sad mood, concentration problems, night sweats, and numbness/tingling in the extremities suggest that the cause of MPN-related sleep complaints is likely complex. Future studies should evaluate the impact of interventions on MPN associated insomnia as well as its biological underpinnings. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Celgene: Honoraria; Shire: Speakers Bureau; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.

Abstract Background: The majority of pts with MF present with a mutation in exon 14 of the JAK2 gene (JAK2V617F). Studies have suggested that in pts with MF and this mutation, a lower AB is associated with a myelodepletive phenotype and shortened survival (Tefferi, Leukemia 2008; Guglielmelli Blood 2009; reviewed in Vannucchi, Ther Adv Hematol 2011). For example, in a Cox proportional hazard model for factors predictive of overall survival (OS) in pts with primary MF, a JAK2V617F AB of <25% was associated with a shortened OS (p=0.002; Guglielmelli, Blood 2009). In the phase III trials of ruxolitinib (RUX) therapy in JAK inhibitor-naïve MF, RUX-treated pts had a median decrease in AB of 16% (maximal) in COMFORT-I followed up to 216 weeks and 7% in COMFORT-II at 48 weeks. The median AB at the start of therapy was not reported for COMFORT-I and in COMFORT-II was 84.5% (Cervantes, Blood 2013; Deininger, Blood2015). Methods: In this communication, we report on clinical correlates of quantitative baseline JAK2 mutational status and the effect of treatment on JAK2V617Fmutational burden in the PERSIST-1 trial. This trial enrolled JAK inhibitor-naïve pts with primary or secondary MF without restrictions on baseline platelet counts, randomized 2:1 between PAC and BAT (excluding JAK2 inhibitors) arms. Stratifications included Dynamic International Prognostic Scoring System (DIPSS) risk category, and baseline platelet counts (<50,000/μL, 50,000-100,000/μL, >100,000/μL). Following the 24-week primary analysis, crossover was allowed by physician/pt choice and 90/107 BAT-treated pts (84%) crossed over to receive PAC. Baseline characteristics have been previously reported (Mesa, ASCO 2016) and included 203/327 (62%) pts with Primary MF, 42 (13%) with post-essential thrombocythemia MF and 81 (25%) with post-polycythemia vera MF. 320 of 327 pts had informative PCR testing for JAK2V617F. We report the baseline characteristics of pts with high (≥50%) AB of JAK2V617F, low (<50%) AB of JAK2V617Fand those without a detectable mutation at baseline (<0.1%), as well as the effect of PAC and BAT on AB and correlation with outcome measures. Results: 131 (40.9%) had AB >50% (high AB), 115 (35.9%) had an AB ≥0.1% and ≤50% (low AB), and 74 (23.1%) had AB <0.1% (wild-type JAK2). Median AB values were 80.3% for the high AB group and 30.3% for the low AB group. Baseline characteristics that were significantly different between high and low AB pts are shown in the Table. No differences were noted in the DIPSS risk category or baseline percentage of blasts between pts with low or high AB. There were a higher percentage of pts with a lower AB in the PAC arm (64% vs. 48%; p=0.01). PAC therapy resulted in a median decrement in AB at Week 24 of −15.8% vs −7.9% for pts in the BAT arm (Figure). The median greatest reduction from baseline in AB in PAC-treated pts was −31.6%. Decrease in AB was strongly correlated with spleen volume reduction (p=0.003) and trended towards correlation with improvement in total symptom score (p=0.07) in PAC-treated, but not in BAT-treated pts. Overall survival was shorter in PAC-treated pts with a minimal AB reduction vs pts with greater decreases in AB. Conclusions: In the PERSIST-1 trial, pts with a JAK2V617FAB of <50% had substantially different disease and demographic characteristics when compared with those pts with a >50% AB despite similar distribution of DIPSS scores. In this trial, reduction in AB associated with PAC, but not BAT correlated with clinical benefit. Disclosures Vannucchi: Novartis: Consultancy, Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Shire: Speakers Bureau. Mead:Baxalta: Consultancy, Honoraria. Perkins:Novartis Oncology: Consultancy, Honoraria; Bristol-Myers Squibb: Other: Travel, Accommodations, Expenses. Mayer:CTI BioPharma Corp.: Other: Travel, Accommodations, Expenses, Research Funding. Schouten:Sanofi: Consultancy; Novartis: Consultancy. Farber:Alexion: Equity Ownership; Celgene: Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Acerta: Research Funding; Gilead: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Seattle Genetics: Speakers Bureau; Pharmacyclics: Speakers Bureau. Kiladjian:Novartis: Honoraria, Research Funding; AOP Orphan: Consultancy, Research Funding. Nangalia:Novartis: Consultancy, Other: Travel, Accommodations, Expenses. Dean:CTI BioPharma Corp.: Employment, Equity Ownership. Zhou:CTI BioPharma Corp.: Employment, Equity Ownership. Singer:CTI BioPharma Corp.: Employment, Equity Ownership, Other: Leadership . Mesa:Novartis: Consultancy, Honoraria; Incyte: Research Funding; Gilead: Research Funding; CTI BioPharma: Research Funding; Celgene: Research Funding; Genetech: Research Funding; Promedior: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria, Speakers Bureau; Baxter: Consultancy, Honoraria; Shire: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau.

Abstract Background: Gilteritinib (ASP2215) is a novel, highly selective, potent oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD activating and FLT3-D835 resistance mutations. The objectives of this phase 1/2 study were to assess gilteritinib safety/tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) profiles after single- and multiple-day dosing, and antileukemic effects in patients with R/R AML. Methods: This open-label study (NCT02014558) enrolled patients (≥18 yr) into 1 of 7 dose-escalation cohorts (20-450 mg once daily [QD]) or concomitant dose-expansion cohorts. While confirmed FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 patients with FLT3 mutations (FLT3mut+); 120 and 200 mg dose levels were further expanded with ≥40 FLT3mut+ patients. The choice to expand these dose cohorts was based upon FLT3 inhibition in correlative assays and clinical activity seen during dose escalation. Safety and tolerability were primary endpoints; blood samples were drawn from patients in the dose-escalation cohorts to evaluate gilteritinib PK parameters and PD effects. Antileukemic response rates (eg, complete remission [CR], CR with incomplete platelet recovery [CRp], CR with incomplete hematological recovery [CRi], overall response rate [ORR]) were secondary endpoints. Results: Patients (N=252; 129M:123F, median age 62 yr [range: 21-90]) enrolled between October 2013 and August 2015 received ≥1 dose of gilteritinib. The study population was heavily pretreated: 70% (n=177) had ≥2 prior AML therapies, 29% (n=73) had a prior stem cell transplant, and 25% (n=63) had prior TKI treatment with sorafenib most commonly used. Across the study, 194 patients had a locally confirmed FLT3 mutation (ITD, n=159; D835, n=13; ITD-D835, n=16; other, n=6). For all enrolled patients, progressive disease (n=75), lack of efficacy (n=44), adverse events (n=34), and death (n=29) were the most common reasons for treatment discontinuation. Seven deaths were considered possibly/probably related to treatment: pulmonary embolism, respiratory failure, hemoptysis, intracranial bleed, ventricular fibrillation, septic shock, and neutropenia (all n=1). Maximum tolerated dose was determined to be 300 mg when 2 of 3 patients in the 450 mg cohort experienced diarrhea and/or hepatic transaminase elevation as dose-limiting toxicities. Diarrhea (16%) and fatigue (15%) were the most commonly reported treatment-related adverse events of any grade. Less than 5% of patients (11/252) had a maximum post-baseline QTcF interval >500 msec. Gilteritinib concentrations were generally dose proportional and showed both a long-elimination half-life (45-159 h) and substantial accumulation (3.2-10 fold) by day 15. An exposure-related increase in the inhibition of FLT3 phosphorylation with increasing doses of gilteritinib was also observed. Gilteritinib showed strong antileukemic activity in FLT3mut+ patients (ORR=49%); response was observed less frequently in patients with wild-type FLT3 (ORR=12%). While CR, CRi, and CRp occurred at all doses, responses were enriched among FLT3mut+ patients with gilteritinib steady-state trough concentrations ≥100 ng/mL, which correlated with potent FLT3 inhibition in PD assays and corresponded to doses ≥80 mg. The ORR in 169 FLT3mut+ patients receiving ≥80 mg was 52% (Table); median overall survival in this patient population was ~31 wk (range: 1.7-61; Figure) and median duration of response was 20 wk (range: 1.1-55). Clinical responses occurred in FLT3mut+ patients with -ITD, -D835, and both mutations (ORR: 55%, 17%, and 62%, respectively) as well as in FLT3mut+ patients with or without prior TKI treatment (ORR: 42% vs 56%, respectively). Conclusions: This PD-driven, first-in-human study shows that gilteritinib was well tolerated and generated frequent, prolonged, clinically important responses in FLT3mut+ patients with R/R AML. Antileukemic responses were enriched in FLT3mut+ patients treated at doses that consistently and potently inhibited FLT3 phosphorylation. The survival of these patients appears better than expected for this patient population when treated with standard therapy. Our data suggest that FLT3 inhibition may improve survival in patients with FLT3mut+R/R AML; as such, phase 3 testing of oral gilteritinib 120 mg QD in patients with FLT3mut+R/R AML after first-line therapy is underway (NCT02421939). Disclosures Perl: Astellas US Pharma Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Asana Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Altman:Janssen: Other: advisory board; BMS: Membership on an entity's Board of Directors or advisory committees; Spectrum: Other: advisory board; Ariad: Other: advisory board; Seattle Genetics: Other: advisory board; Syros: Other: advisory board. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Smith:Astellas: Research Funding. Erba:Jannsen: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Agios: Research Funding; Juno: Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Daiichi Sankyo: Consultancy; Ariad: Consultancy; Amgen: Consultancy, Research Funding; Astellas: Research Funding; Gylcomimetics: Other: DSMB; Seattle Genetics: Consultancy, Research Funding; Sunesis: Consultancy; Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Celgene: Consultancy, Speakers Bureau; Pfizer: Consultancy. Gill:Astellas: Employment. Goldberg:Bristol Myers Squibb, Novartis: Speakers Bureau; Novartis: Consultancy; COTA Inc: Employment; Pfizer: Honoraria; Neostem: Equity Ownership. Jurcic:Astellas: Research Funding. Larson:Astellas: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Liu:Astellas: Employment. Ritchie:Celgene: Consultancy, Other: Travel, Accomodations, Expenses, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding, Speakers Bureau; Ariad: Speakers Bureau; Pfizer: Consultancy, Research Funding; Astellas Pharma: Research Funding; Bristol-Meyers Squibb: Research Funding; NS Pharma: Research Funding. Schiller:Incyte Corporation: Research Funding. Strickland:Celator: Research Funding; Cyclacel: Research Funding; Karyopharm Therapeutica: Research Funding; GlaxoSmithKline: Research Funding; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; Ambit: Consultancy; Alexion Pharmaceuticals: Consultancy; Astellas Pharma: Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Sanofi: Research Funding. Wang:Incyte: Speakers Bureau; Immunogen: Research Funding. Stuart:Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Celator: Research Funding; Astellas: Research Funding. Martinelli:Ariad: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Roche: Consultancy, Speakers Bureau; MSD: Consultancy; Genentech: Consultancy; Novartis: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Bahceci:Astellas: Employment. Levis:Millennium: Consultancy, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding.

Abstract Background We have previously reported on the significant, but heterogeneous baseline MPN symptom burden among an international sample of MPN patients (including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF)) utilizing the MPN Symptom Assessment Form (MPN-SAF) and the derivative Total Symptom Score (MPN-SAF TSS). Recent clinical trials have sought to determine optimal MPN symptom response criteria, such as absolute 10 point improvement in MPN SAF TSS for ET/PV (ELN Criteria, Barosi et. al. Blood 2013) and 50% reduction in MPN-SAF TSS for MF (IWG-MRT, Tefferi et. al. Blood 2013). We sought to determine the role of improvement in MPN-SAF TSS quartiles as potential thresholds to assess symptomatic response to therapy. Methods Utilizing prospectively gathered MPN-SAF TSS (Emanuel et. al. JCO 2012) in patients we assessed potential thresholds of response by evaluating quartile thresholds for severity of symptom burden. The MPN-SAF TSS was scored as the average of 10 symptoms (individual symptoms scores of 0-10, with a total score of 0 (best) to 100 (worst)). MPN-SAF TSS quartiles were identified by the percentage of scores between 0-24% (quartile 1 (Q1)), 25-49% (quartile 2 (Q2)), 50-74% (quartile 3 (Q3)), 75-100% (quartile 4 (Q4)). Results MPN-SAF TSS Quartiles: MPN-SAF TSS quartiles were identified among 1858 MPN patients (ET N=775, PV N=654, and MF N=423). Overall MPN-SAF TSS scores of 0 - 7 were designated as Q1, 8 - 17 as Q2, 18 - 31 as Q3, and ≥ 32 was as Q4. MPN-SAF TSS scores were significantly different between clusters (p<0.001). Associations Between Quartiles and Demographic/ Disease Factors: As quartiles increased, the proportion of PV and ET patients diminished and MF increased (Table 1, p<0.001). Cytopenias and transfusion dependence increased in prevalence in the higher quartiles (p<0.001). A history of prior thrombosis was also significantly more prevalent in the quartiles with highest symptom burden (p<0.001). The prevalence of women was significantly higher among the more symptomatic quartiles females 48.9% Q1, 49.4% Q2, 58.4% Q3, and 60.1% Q4; p<0.001). Associations Between Individual Symptoms and MPN-SAF TSS Quartiles: All individual symptoms measured in the MPN-SAF TSS were significantly worse in quartiles as they increased (p<0.0001). Evaluation of Prognostic Scoring and MPN-SAF TSS Quartiles: Comparison of each patients individual risk score (IPSET, PV, DIPSS for MF) and worsening symptom quartile showed the highest correlation with MF patients (DIPSS) (Table 1). However, ET and PV risk scores were not surrogates for symptom burden by quartile. Conclusions Distribution of MPN patient symptomatic burden by MPN-SAF TSS quartiles provides an easy-to-calculate method to cluster and analyze MPN patients of similar burden. Although MF patients are most prevalent in the most severe quartile of MPN symptomatology it is notable that Q4 has many patients with PV and ET. Future prospective efforts are ongoing to assess the potential of using changes in quartile (i.e. improving from Q3 to Q1) as potential symptomatic response thresholds. Disclosures: Etienne: novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Roy:Novartis, BMS: Honoraria. Harrison:Gilead: Honoraria, Membership on an entity’s Board of Directors or advisory committees; S Bio: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Shire: Speakers Bureau; Celgene: Honoraria; YM Bioscience: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Vannucchi:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Birgegard:Vifor Pharma: Honoraria.

Abstract Introduction: ASP2215 is a highly selective inhibitor of AXL and FMS-like tyrosine kinase-3 (FLT3) receptors. ASP2215 is active against both FLT3 internal tandem duplication [ITD] and D835 mutations. Prior analyses of an open-label, dose-escalation/dose-expansion study in subjects with relapsed or refractory acute myeloid leukemia (R/R AML) show ASP2215 was well tolerated from 20-300 mg and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) patients at ≥80 mg with minimal activity observed in wild-type FLT3 subjects. Here we describe the tolerability and potent activity of ASP2215 in a large cohort of FLT3+ patients. Methods: Patients (≥18 years) with R/R AML were assigned to treatment in dose-escalation cohorts or were randomized to an open dose level in the dose-expansion cohorts. Although FLT3 mutation was not an inclusion criterion, each expanded dose level enrolled ≥10 FLT3+ subjects; 120 mg and 200 mg dose levels were further expanded with ≥40 FLT3+ subjects. Tolerability was assessed by adverse event (AE) monitoring. Response assessment was based on modified Cheson criteria and duration of response and overall survival were calculated using Kaplan-Meier estimates. Results: As of June 19, 2015,215 patients with a median age of 61 yr (range: 21-90) had received ≥1 dose of ASP2215 (safety population). Across the safety population, 65% of subjects received ≥2 prior lines of AML therapy, 29% had a hematopoietic stem cell transplant prior to ASP2215 treatment, and 23% had prior tyrosine kinase inhibitor (TKI) treatment. Approximately 73% of patients were FLT3+, of which 137 had FLT3-ITD mutation, 7 were FLT3-D835+, and 9 had both FLT3-ITD and D835. Treatment-related AEs of all Grades, reported in ≥10% of the safety population were diarrhea (16%), fatigue (13%), and increased AST (11%); <2% of subjects reported a Grade ≥3 QTc prolongation. Activity was assessed in the 133 FLT3+ patients treated with ASP2215 ≥80 mg. Overall response rate (ORR; composite complete [CRc] plus partial remission [PR]) for all FLT3+ subjects was 55% (Table). Median overall survival for FLT3+ patients receiving ASP2215 ≥80 mg was ~29 weeks (95% CI: 22-32) and was similar for patients who achieved CRc or PR (Figure). Treatment with ≥80 mg ASP2215 was associated with an ORR of 60% in FLT3-ITD subjects; ORR for the other FLT3 populations was 29% (Table). No difference was observed in median ORR of ASP2215 (≥80 mg) in TKI-naïve patients (55%) and patients with prior TKI treatment (55%). Conclusions: ASP2215, a novel AXL/FLT3 TKI, was well tolerated in subjects with R/R AML and demonstrated a strong antileukemic activity in FLT3+ subjects. Importantly, the ASP2215 response rate in these FLT3+ patients was independent of prior TKI treatment. Even in this heavily pretreated population, the survival of R/R FLT3+ AML patients who received ≥80 mg ASP2215 was longer than prior reports of cytotoxic chemotherapy or other FLT3 inhibitors. Table. ASP2215 Response Assessment 80 mg 120 mg 200 mg 300 mg 450 mg Total All FLT3+ Subjects Population, n 12 52 57 10 2 133 CRc, n (%) 5 (42) 25 (48) 28 (49) 3 (30) 0 61 (46) PR, n (%) 3 (25) 3 (6) 3 (5) 3 (30) 0 12 (9) ORR, n (%) 8 (67) 28 (54) 31 (54) 6 (60) 0 73 (55) Subjects with FLT3-ITD Only Population, n 10 46 50 8 0 114 CRc, n (%) 4 (40) 23 (50) 26 (52) 3 (38) 0 56 (49) PR, n (%) 3 (30) 3 (7) 3 (6) 3 (38) 0 12 (11) ORR, n (%) 7 (70) 26 (57) 29 (58) 6 (75) 0 68 (60) Subjects with FLT3-D835 and Subjects with FLT3-ITD and FLT3-D835 Population, n 2 5 5 1 1 14 CRc, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) PR, n (%) 0 0 0 0 0 0 ORR, n (%) 1 (50) 1 (20) 2 (40) 0 0 4 (29) CRc, composite complete remission (complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete hematologic recovery); ORR, overall response rate; PR, partial response. NR, no response. Subjects with non-evaluable data (N=8) were not included in this curve. Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Figure 1. Overall Survival by Best Overall Response Achieved with ASP2215 ≥80 mg Across All FLT3+ Subjects Disclosures Altman: BMS: Other: Advisory board; Novartis: Other: Advisory board; Spectrum: Other: Advisory board; Ariad: Other: Advisory board; Seattle Genetics: Other: Advisory board; Astellas: Other: Participation in an advisory board December 2013. Off Label Use: ASP2215 is currently under investigation for the treatment of AML and is not yet approved.. Perl:Arog Pharmaceuticals: Consultancy; Asana Biosciences: Consultancy; Actinium Pharmaceuticals: Consultancy; Ambit/Daichi Sankyo: Consultancy; Astellas US Pharma Inc.: Consultancy. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Levis:Arog: Research Funding; Ambit: Research Funding; Takeda: Research Funding; Astellas: Consultancy. Smith:Plexxikon: Research Funding; Astellas: Research Funding. Claxton:NCI: Research Funding; Medimmune, Inc: Research Funding; Ambit Biosciences Corp: Research Funding; Incyte Corporation: Research Funding; Merck Sharp & Dohme Corp: Research Funding; Astellas Pharma: Research Funding. Erba:Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Ariad: Consultancy; Celgene: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Seattle Genetics: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Amgen: Consultancy, Research Funding; Celator: Research Funding; Millennium/Takeda: Research Funding; Astellas: Research Funding; Sunesis: Consultancy; Celator: Research Funding; Pfizer: Consultancy; Astellas: Research Funding; Daiichi Sankyo: Consultancy; Sunesis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; GlycoMimetics: Other: Data Safety and Monitoring Committees ; Jannsen (J&J): Other: Data Safety and Monitoring Committees ; Daiichi Sankyo: Consultancy. Gill:Astellas Pharma US, Inc: Employment. Goldberg:Cyclacel: Research Funding; Celetor: Research Funding; Pfizer: Research Funding; Ambit: Research Funding; Astellas: Research Funding. Jurcic:Astellas Pharma: Research Funding. Larson:Astellas: Consultancy, Research Funding. Lui:Astellas Pharma US, Inc: Employment. Ritchie:Incyte: Speakers Bureau; Novartis: Speakers Bureau; Ariad: Other: Advisory Board; Celgene: Speakers Bureau; Onyx: Speakers Bureau. Sargent:Astellas Pharma US, Inc: Employment. Schiller:Sunesis: Honoraria, Research Funding. Strickland:Sunesis Pharmaceuticals: Other: Steering Committee and Advisory Board Participation; Alexion Pharmaceuticals: Other: Advisory Board Particpation; Amgen: Other: Advisory Board Particpation; Daiichi-Sankyo: Other: Advisory Board Particpation; Boehringer-Ingelheim: Other: Advisory Board Particpation. Wang:Immunogen: Research Funding. Stuart:Sunesis: Honoraria, Other: Advisory Board, Research Funding; Astellas Pharma, Inc: Research Funding. Baldus:Novartis: Research Funding. Martinelli:MSD: Consultancy; ARIAD: Consultancy; BMS: Speakers Bureau; Pfizer: Consultancy; Novartis: Speakers Bureau; Roche: Consultancy. Bahceci:Astellas Pharma Global Development: Employment.

Abstract Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts >80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

Abstract Abstract 788 FLT3 mutations are common in AML and are associated with poor prognosis. Lestaurtinib is a multi-targeted kinase inhibitor with potent activity against FLT3. In an attempt to definitively establish whether or not there is clinical benefit for FLT3 inhibition in the relapse setting, we conducted a randomized trial of chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse. Patients were randomized to receive either chemotherapy alone, consisting of mitoxantrone, etoposide, and cytarabine (MEC) or high-dose cytarabine (HiDAc) depending on the duration of CR1) or chemotherapy followed by 80 mg lestaurtinib orally BID. Patients on the chemotherapy only arm were eligible for crossover if they were refractory to therapy. Patients on the lestaurtinib arm received the drug for up to 112 days on study (they could continue to receive the drug through a separate extension protocol). The primary objective was complete remission (CR/CRp). Secondary objectives included overall survival (OS), safety, and tolerability. From January 2004 through December 2008, 224 patients at 52 different centers were enrolled and randomized, with 220 patients actually receiving therapy. Blood samples from patients on the lestaurtinib arm were obtained at baseline, on Day 15, and on Day 42 for pK studies and for determination of in vivo FLT3 inhibition and measurement of plasma FLT3 ligand (FL) and alpha-1 acid glycoprotein (AGP) levels. The median age for all patients enrolled was 55 years (53.5 in the control arm, 58.5 in the lestaurtinib arm), with 88% having FLT3/ITD mutations, 8% having D835 mutations, and 4% having both. The duration of CR1 was less than 6 months in 47% of patients in each arm. On the lestaurtinib arm, 107 patients received at least 1 week of lestaurtinib (mean 60.1 days, range 8-418), with 17 of these patients receiving drug on the extension protocol. On the chemotherapy only arm, 7 patients crossed over to receive lestaurtinib, and 31 patients went on to receive lestaurtinib on the extension protocol after outcome evaluation. Lestaurtinib was generally well tolerated following chemotherapy, with 104 Grade 3/4 adverse events in the lestaurtinib arm versus 99 in the control arm. There were 61 serious adverse events in the lestaurtinib arm versus 49 in the control arm. Early death (by Day 42) occurred in 22 lestaurtinib patients (2 progressive leukemia, 14 infectious, 6 organ failure) and16 control patients (6 progressive leukemia, 5 infectious, 5 organ failure). By intention to treat analysis, there were 29 CR/CRp in the lestaurtinib arm and 23 in the control arm (26% versus 21%; p = 0.35), with no difference in OS (4.73 months versus 4.57 months) between the two arms. Blood samples from 79 of the 107 lestaurtinib-treated patients obtained on Day 15 were analyzed for FLT3 inhibitory activity (plasma inhibitory activity [PIA] assay), as well as FLT3 ligand (FL), lestaurtinib, and AGP concentrations. Mean lestaurtinib plasma concentration was 12 uM at Day 15 and fell to 7.5 uM on Day 42. Mean lestaurtinib concentration at Day 15 was 13.3 uM in patients achieving CR/CRp and 11.5uM in non-responders. A target of >85% inhibition of FLT3 maintained at trough (pre-dose) was defined from previous studies. Of the 79 patients tested, 46 (58%) achieved this degree of FLT3 inhibition on Day 15. FL concentrations rose from baseline (15.6 pg/mL) to Day 15 (1148 pg/mL), and AGP concentrations rose by an average of 52% over the same period, both of which may have reduced the degree of FLT3 inhibition. Of the 46 patients with target FLT3 inhibition on Day 15, 18 (39%) achieved CR/CRp, while only 3 (9%) of the 32 patients with below target FLT3 inhibition achieved CR/CRp. Thus, in patients with FLT3 mutant AML at first relapse, pharmacokinetic factors and possible physiologic factors (FL and AGP) limit lestaurtinib's ability to effectively inhibit FLT3. FLT3 inhibition by lestaurtinib, when achieved, correlates with better CR rates, but in this trial that benefit was negated by a poor CR rate in those patients for whom the drug did not reach the target level of FLT3 inhibition. Overall, lestaurtinib treatment following re-induction chemotherapy failed to increase response rates or prolong survival of patients with FLT3 mutant AML in first relapse. Disclosures: Levis: Cephalon: Clinical Advisory Board member. Ravandi:Cephalon: Honoraria, Member, clinical advisory board, Research Funding. Erba:Cephalon: Research Funding, Speakers Bureau. Baccarani:Novartis Pharma, Bristol Myers Squibb, Merck Sharp & Dome, Pfizer: Consultancy, Speakers Bureau. Stone:Cephalon: ad hoc consultancy; Novartis: Research Funding, ad hoc consultancy. Advani:Cephalon: Research Funding. Douer:Cephalon: Honoraria, Research Funding, Speakers Bureau. Litzow:Cephalon: Research Funding. Tremmel:Cephalon: Employment, Equity Ownership. Bensen-Kennedy:cephalon: Employment. Smith:Cephalon: Research Funding.

Abstract Background Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by erythrocytosis, splenomegaly and a frequently burdensome symptom profile. Despite current guidelines of aspirin, phlebotomy, and selective cytoreduction, many patients have inadequately controlled PV-related symptoms and/or disease features. We performed a comparison of PV symptom burden/disease feature phenotypes to understand unmet needs in current medical management. Methods Data was collected prospectively amongst an international cohort of PV patients including symptom burden, demographics, and disease features. Subgroups were identified who had previously failed hydroxyurea (PV-HU), required ongoing phlebotomy (PV-P), had palpable splenomegaly (PV-S), or had all 3 features (PV-HUPS). Control groups were derived from the remaining PV patients lacking the specified subgroup trait; patients in whom the trait status was unknown were excluded from each respective control group. All participants completed the MPN specific symptom burden questionnaire (MPN-SAF TSS (MPN-10 – Table 1)) and had no prior history of splenectomy. Surveyed symptoms on the MPN-10 included the patient's perceptions of common MPN-related symptoms and overall quality of life (QOL) on a 0 (absent) to 10 (worst imaginable) scale. PV risk scores were calculated using the 2013 criteria (Leukemia 2013). Comparison of symptoms between groups employed t-tests. Results Patient Demographics and Disease Features Between Phenotypic Groups A total of 1334 PV patients completed the MPN-10, and were assigned to categories of PV-HU (499 [37%]), PV-P (646 [48%]), PV-S (369, [28%]), and PV-HUPS (148 [12%]). The demographics between these groups were similar (comparable age (median range 60-63), PV risk scores (mean risk range: Low 16.4-23.7%; Intermediate 31.4%-36.6%; High 42.8%-47%). Mean hemoglobin was similar among PV subgroups (range 14.4-14.9); PV-HUPS had a higher mean WBC count (20.3 g/dL vs. 8.8-11.8 g/dL) and platelet count (703.5 x 10(9)/L vs. 327.5-462.8 x 10(9)/L), and disease duration (11.5 years vs. 6.4-8.8 years). Prior thrombosis was most common in PV-S patients (28.5% vs. 21.8-25.2%) and prior hemorrhage was most common in PV-HUPS patients (23.8% vs. 13.7-15.8%). Symptom Burden The MPN-10 scores of each problematic PV phenotype (HU, P, S, HUPS) were compared to the remainder of the PV cohort lacking the trait (PV-control; Table 1). Both individual symptom scores and TSS were highest for PV-HUPS patients (mean TSS 32.5 vs. 27.7-29.2). All problematic PV subgroups demonstrated significant differences for individual symptoms and TSS compared to PV-control. Comparing "problematic" subgroup responses, PV-HU patients described more inactivity whereas PV-S patients described more early satiety and pruritus. No statistical differences were noted in PV-HU, PV-P and PV-HUPS patient responses to MPN-10 items of "fever" and "weight loss". Discussion PV patients who have either failed HU, are undergoing phlebotomy and/or have splenomegaly exhibit moderate to severe symptomatology and demonstrate unmet medical need for management. As evidenced in this study, considerable overlap in symptomatology exists in PV-HU, PV-P, PV-S and PV-HUPS. Current randomized trials of JAK inhibitors have demonstrated benefits in a PV-HUPS phenotype. This data suggests that PV patients with any evidence of inadequate control (PV-HU, P, or S) have similarly unmet needs and may be candidates for clinical trials, intensification of medical therapy or perhaps JAK inhibitor therapy. Disclosures Kiladjian: Shire Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Research Funding. Besses:Shire Pharmaceuticals: honoraria for educational lectures Other. Birgegard:Shire Pharmaceuticals: Consultancy, Honoraria, Research Funding. Etienne:Novartis, BMS, Pfizer, Ariad: Honoraria. Roy:Merck: Peg-Interferon provided for academic clinical trial in CML Other. te Boekhorst:Novartis: Consultancy. Griesshammer:Novartis: Honoraria; Shire: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Roche: Honoraria. Mesa:Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding.

Abstract BACKGROUND: Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies, accounting for ~11% of all hematologic neoplasms. Over the last 15 years, a series of phase 3 trials have established that chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) improves both progression free survival (PFS) and overall survival (OS) compared with chemotherapy alone. FCR is the gold standard for young fit patients with treatment naïve CLL. In parallel with the advances in CIT, a profound increase in the understanding of CLL B-cell biology led to new therapeutic approaches.1 Among these, ibrutinib (an irreversible inhibitor of Bruton's Tyrosine Kinase [BTK]) has had the largest impact on clinical practice to date. Initial trials of ibrutinib demonstrated robust and durable efficacy in patients with relapsed/refractory disease. Subsequent phase 3 trials showed improved PFS and OS with ibrutinib relative to chlorambucil in previously untreated, older CLL patients. Despite these advances, the efficacy of ibrutinib as a first-line treatment for younger CLL patients (i.e. <70) relative to the most efficacious CIT regimens, such as FCR, is unknown. METHODS: Eligible patients were treatment-naive individuals with CLL who were age <70 and required therapy. Patients with deletion 17p- were excluded from participating given the poor response of these patients to FCR therapy. Participants were randomly assigned in a 2:1 ratio to receive ibrutinib (420 mg/day until disease progression) and rituximab (50 mg/m2 on day 1 of cycle 2; 325 mg/m2 on day 2 of cycle 2; 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 ) and cyclophosphamide (250 mg/m2) days 1-3 with rituximab (50 mg/m2 on day 1 of cycle 1; 325 mg/m2 on day 2 of cycle 1; 500 mg/m2 on day 1 of cycles 2-6) every 28-days. The planned accrual was 519 patients. Hematologic toxicity was graded according to the 2008 IWCLL Working Group scale. All other adverse events were graded according to the NCI Common Toxicity Criteria (version 4). The primary endpoint was PFS with a secondary endpoint of overall survival (OS). Analysis was by intention to treat. The first planed interim analysis for PFS was scheduled to occur 24-27 months after full accrual with the first interim analysis for OS scheduled to occur if the boundary for PFS was crossed. The primary analysis was a stratified logrank test applied to all patients as randomized. Treatment effect p-values are one-sided. The study was approved by the Central Institutional Review Board for the National Cancer Institute, conducted in accordance with the principles of the Declaration of Helsinki, and registered with ClinicalTrials.gov (NCT02048813). RESULTS: A total of 529 patients were accrued between January 31, 2014 and June 9, 2016. 354 patients were assigned to ibrutinib and rituximab (IR) and 175 to FCR. Nineteen patients did not start protocol therapy. The first interim analysis was performed September 2018. With median follow-up of 33.4 months, we observed 77 PFS events and 14 deaths. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.352; 95% CI 0.223-0.558; p<0.0001) which crossed the pre specified boundary. The HR for OS also favored the IR arm (HR=0.168, 95% CI 0.053-0.538; p=0.0003, pre-specified boundary for superiority p=0.0005). Kaplan-Meier estimates for PFS and OS are shown in Figure 1A and 1B. In subgroup analysis for PFS, IR was superior to FCR independent of age, sex, performance status, disease stage or the presence/absence of del11q23. With current follow-up, IR was also superior to FCR for IGHV unmutated patients (HR=0.262; 95% CI 0.137-0.498; p<0.0001) but not IGHV mutated patients (HR=0.435; 95% CI 0.140-0.1350; p=0.07). Grade 3 and 4 treatment-related adverse events were observed in 58% of IR and 72% of FCR treated patients (p=0.0042). Specifically, FCR was more frequently associated with grade 3 and 4 neutropenia (FCR: 69 [44%] of 158 vs. IR: 80 [23%] of 352; p<0·0001) and infectious complications (FCR: 28/158 [17.7%] vs. IR: 25/352 [7.1%]; p<0.0001). CONCLUSIONS: The combination of ibrutinib and rituximab provides superior PFS and OS relative to FCR for patients with previously untreated CLL age <70. These findings have immediate practice changing implications and establish ibrutinib-based therapy as the most efficacious first-line therapy for patients with CLL. Disclosures Shanafelt: Mayo Clinic: Patents & Royalties: Physician Well-being Index, Medical Student Well-being Index, Well-being index; Celgene: Research Funding; GlaxoSmithKline: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding. Kay:Janssen: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Infinity Pharm: Membership on an entity's Board of Directors or advisory committees. O'Brien:Amgen: Consultancy; Astellas: Consultancy; Celgene: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Aptose Biosciences Inc.: Consultancy; Vaniam Group LLC: Consultancy; Abbvie: Consultancy; Alexion: Consultancy; Kite Pharma: Research Funding; Regeneron: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding. Barrientos:Pharmacyclics/AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Erba:Seattle Genetics: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Incyte: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Janssen: Research Funding; Janssen: Research Funding; Amgen: Research Funding; Amgen: Research Funding; Novartis: Consultancy, Speakers Bureau; Astellas: Research Funding; Incyte: Consultancy, Speakers Bureau; Astellas: Research Funding; Pfizer: Consultancy, Other: grant; Novartis: Consultancy, Speakers Bureau; Juno: Research Funding; Juno: Research Funding; Novartis: Consultancy, Speakers Bureau; MacroGenics: Consultancy; MacroGenics: Consultancy; Amgen: Research Funding; Takeda/Millenium: Research Funding; Amgen: Research Funding; Takeda/Millenium: Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding; Juno: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Daiichi Sankyo: Consultancy, Research Funding. Stone:Juno: Consultancy; Macrogenics: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; FujiFilm: Consultancy; Sumitomo: Consultancy; Ono/Theradex: Consultancy; Otzuka/Astex: Consultancy; Pfizer: Consultancy; Roche: Consultancy; AbbVie: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Celator / Jazz: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cornerstone: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; Daiichi-Sankyo: Other: Advisory board; BioSight: Other: Advisory board; AbbVie: Research Funding; Cellerant: Research Funding; AROG: Research Funding; Orsenix: Other: Advisory board.

Abstract Introduction In general population samples, higher levels of stress and depression have been associated with increased prevalence of smoking in pregnancy. Little is known about the association of prenatal tobacco use, stress, and depression among American Indian or Alaska Native (AI/AN) women. Methods The Healthy Pregnancies Project is a cluster-randomized controlled trial, evaluating a community-level intervention compared with usual care, for reducing tobacco use during pregnancy and postpartum among AN women in 16 villages in western Alaska. This cross-sectional study analyzed baseline data from enrolled pregnant women. Baseline measures included the self-reported, 7-day, point-prevalence current use of any tobacco, Perceived Stress Scale (PSS), and the Center for Epidemiological Studies-Depression (CES-D). Generalized estimating equations (GEE) analyses adjusted for village, participant age, and gestational age. Results Participants (N = 352) were on average (SD) 25.8 (5.0) years of age and at 26.8 (9.8) weeks gestation. 66.5% were current tobacco users, of which 77% used Iqmik, a homemade form of smokeless tobacco. Compared with nonusers, tobacco users reported lower PSS score (p = .020) and less clinical levels of depression (CES-D ≥ 16) (18.1% vs. 9.3%, p = .21). Findings were not accounted for by nicotine dependence severity or self-reported tobacco use before pregnancy. Conclusions In this sample of pregnant AN women, tobacco users report less stress and clinical levels of depression than nonusers. A potential challenge with tobacco treatment for pregnant AN women is to provide alternative ways of deescalating stress and affect management instead of using tobacco. Implications This study contributes novel information on the association of tobacco use, perceived stress, and depression among Alaska Native women enrolled in a clinical trial to promote healthy pregnancies. Most prior studies addressing this topic were conducted among general population samples of pregnant women who smoked cigarettes. Little is known about these associations with prenatal smokeless tobacco, or among American Indian or Alaska Native women. The results are contrary to findings reported previously, because current tobacco use was associated with less stress and depression than nonuse. The study findings have implications for cessation treatment for this tobacco-use disparity group.