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Background: Direct stenting without pre-dilation or post-dilation has been advocated for saphenous vein graft percutaneous coronary intervention to decrease the incidence of distal embolization, periprocedural myocardial infarction, and target lesion revascularization. Methods: We performed a post hoc analysis of patients enrolled in the DIVA (Drug-Eluting Stents Versus Bare Metal Stents in Saphenous Vein Graft Angioplasty; NCT 01121224) prospective, double-blind, randomized controlled trial. Patients were stratified into stent-only and balloon-stent groups. Primary end point was 12-month incidence of target vessel failure (defined as the composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization). Secondary end points included all-cause death, stent thrombosis, myocardial infarction, and target lesion revascularization during follow-up. Results: Of the 575 patients included in this substudy, 185 (32%) patients underwent stent-only percutaneous coronary intervention. Patients in the stent-only versus balloon-stent group had similar baseline characteristics and similar incidence of target vessel failure at 12-months (15% versus 19%; hazard ratio, 1.34 [95% CI, 0.86–2.08]; P =0.19). During long-term follow-up (median of 2.7 years), the incidence of definite stent thrombosis (1% versus 5%; hazard ratio, 9.20 [95% CI, 1.23–68.92]; P =0.0085), the composite of definite or probable stent thrombosis (5% versus 11%; hazard ratio, 2.52 [95% CI, 1.23–5.18]; P =0.009), and target vessel myocardial infarction (8% versus 14%; hazard ratio, 1.92 [95% CI, 1.08–3.40]; P =0.023) was lower in the stent-only group. Multivariable analysis showed that a higher number of years since coronary artery bypass grafting and >1 target saphenous vein graft lesions were associated with increased target vessel failure during entire follow-up, while preintervention Thrombolysis in Myocardial Infarction-3 flow was protective. Conclusions: In patients undergoing percutaneous coronary intervention of de novo saphenous vein graft lesions, there was no difference in target vessel failure at 12 months and long-term follow-up in the stent-only versus the balloon-stent group; however, the incidence of stent thrombosis was lower in the stent-only group, as was target vessel myocardial infarction. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT 01121224.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Treatments include pharmacologic approaches, phlebotomy, and bone marrow transplant. Outcome studies have historically focused on hematologic improvement and survival benefit. Few prospective studies have evaluated patient-reported symptoms and quality of life outcomes after standard therapy. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard treatments. Here we provide updated results for the prospective MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: The MEASURE trial is a prospective international cohort study evaluating responsiveness of the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS or MPN-10) in an anticipated 480 ET, PV, and MF patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF TSS (JCO 2012) for seven consecutive days at enrollment then again for seven days between 90 days and six months later. Patients also complete the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. Physicians report demographic, laboratory, and clinical data. Results: Demographics To date, 340 patients have enrolled and 270 have completed both study visits. Participants include ET (60%), PV (29%), and MF (12%; including 68% primary MF, 12% post-ET, 20% post-PV) patients. Enrolled patients are 51% male. The most common therapies received prior to enrollment were aspirin (34%), phlebotomy (15%), hydroxyurea (14%), and warfarin/clopidogrel/anticoagulation (6%). The most common current MPN therapies were hydroxyurea (67%), aspirin (24%), phlebotomy (9%), and ruxolitinib (8%). Information on mutational analysis was also collected; 77% of patients have a known JAK2 V617F mutation, 3% have an MPL W515 mutation. Symptom Measures On the MPN-SAF TSS, the majority of individual symptoms assessed did not change significantly between the two assessment time points while on standard therapy. Notable exceptions were a significant decrease in weight loss (mean 2.0 vs. 1.7 on a 0=absent to 10=worst imaginable scale, p=0.005) and a significant worsening in quality of life (mean 3.6 vs. 3.8 on a 0=as good as it can be to 10=as bad as it can be scale, p=0.04). No changes were seen in other symptoms including early satiety, abdominal discomfort, night sweats, fatigue, inactivity, poor concentration, bone pain, itching, or fever. Similarly, the cumulative MPN-SAF TSS score remained stable at a mean of 24.4 over the treatment period. These findings were congruent with those observed using the EORTC QLQ-C30 instrument, with no significant changes seen in emotional, physical, role, cognitive, or social functioning. Finally, the MDASI also revealed a lack of change in either symptom severity (mean 2.7) or symptom distress (mean 3.0) scores, which remained stable over the study period. Discussion: Myeloproliferative neoplasms are associated with burdensome symptoms that significantly compromise quality of life. To date, no studies have quantified symptomatic response to standard-of-care treatments. Overall, results from the MEASURE study suggest that standard treatments have limited systematic impact on patient symptomatology over time, with no improvements in overall quality of life. However, we note the relatively low proportion of patients in this cohort treated with ruxolitinib, which has been shown previously to improve symptom burden, and this may have impacted the symptom responses seen in the group as whole; detailed responses by treatment and MPN subtype will be presented. Figure. Figure. Disclosures Dueck: Pfizer: Honoraria; Bayer: Employment; Phytogine: Employment. Ross:BMS: Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding. Tam:Janssen: Honoraria, Research Funding; Gilead: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Travel funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding; Pharmacyclics: Honoraria; Gilead: Honoraria; Roche: Honoraria; Beigene: Honoraria, Other: Travel funding. Radia:Novartis: Speakers Bureau; Blueprint: Consultancy. Mesa:UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; CTI Biopharma: Research Funding; Incyte Corporation: Research Funding; Novartis: Consultancy.

Abstract Background: The oral BTK inhibitor ibrutinib is the only approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). Bing-Neel syndrome (BNS) is a rare complication of WM that results from infiltration of malignant lymphoplasmacytic cells into the central nervous system (CNS) causing neurological deficits. Treatment options in patients with BNS are limited to agents with CNS penetration. Ibrutinib can penetrate into the CNS, but data on its efficacy in BNS is lacking outside case reports. Methods: We performed a multicenter retrospective study evaluating the efficacy of ibrutinib in patients with BNS. The diagnosis of BNS was established in patients with a clinicopathological diagnosis of WM by radiological and/or cytological evidence of CNS involvement by WM, and response was assessed based on recently published criteria. Ibrutinib was given orally at doses of 420-560 mg PO once daily until disease progression or intolerable toxicity. Response was assessed using criteria from the 8th International Workshop for WM (Minnema et al. Haematologica 2017). Events were defined as death from any cause, progression of disease and stopping ibrutinib from any reason. Time to events was estimated using the Kaplan-Meier method. Results: We present data on 24 patients with BNS treated with ibrutinib. The median age at diagnosis of WM was 60 years (range 38-76 years) and 14 patients (58%) were men. The median lines of therapy for WM prior to BNS diagnosis was 1 (range 0-7 lines), and 9 patients (38%) were untreated for WM at the time of BNS diagnosis. Previous WM therapies included anti-CD20 antibodies (n=15), alkylators (n=13), nucleoside analogues (n=8), proteasome inhibitors (n=3), immunomodulators (n=2), and autologous transplant (n=1). The median age at BNS diagnosis was 65 years (range 38-80). The median time from WM to BNS diagnosis was 4 years (range 0-27 years). In 2 patients, the diagnosis of BNS was made concurrently with WM diagnosis. The median number of BNS lines prior to ibrutinib was 1 (range 0-5 lines). Previous BNS therapies included intrathecal chemotherapy (n=9), high-dose methotrexate (n=6), bendamustine (n=3) and radiation therapy (n=3). In 7 patients (29%), ibrutinib was the first line of treatment for BNS. The most common symptoms at BNS presentation were cognitive deficits (n=10), sensory deficits (n=8), ataxia/falls (n=8), motor deficits (n=6), headache (n=5) and seizures (n=5). MRI findings included leptomeningeal enhancement (n=16) and brain masses (n=5). Cerebrospinal fluid (CSF) flow cytometry confirmed the presence of clonal CD19+ in 19 patients (79%). Biopsies were performed in 5 patients (21%) and confirmed presence of WM cells. 4 patients had normal MRI but had abnormal CSF cytology and/or flow cytometry. Tissue was not obtained in 1 patient in whom MRI showed leptomeningeal enhancement. Interestingly, 2 patients were diagnosed with lymphoplasmacytic lymphoma secreting IgG paraprotein. The median serum IgM (n=20) prior to ibrutinib initiation was 1,294 mg/dl (range 125-5,938 mg/dl), and the median hemoglobin level was 11.9 g/dl (7.7-15.2 g/dl). Ten patients (42%) received ibrutinib 560 mg PO once daily, and 14 (58%) received ibrutinib 420 mg PO once daily. At best response, median serum IgM and hemoglobin levels were 340 mg/dl (82-3,330 mg/dl) and 14.6 g/dl (range 9.2-16.0 g/dl). Based on consensus BNS response criteria, complete response was attained in 2 patients (8%), partial response in 14 (58%) and clinical improvement in 3 patients (13%). With a median follow-up time of 13 months (95% CI 8-21 months), 5 patients have stopped ibrutinib, 3 due to BNS progression, 1 due to grade 3 muscle cramps and 1 due to arrhythmia, and 3 patients have died, 2 from infection and 1 from BNS progression. The median event-free survival (EFS) from ibrutinib initiation was not yet reached. The 1-year and 2-year EFS rates were 71% (95% CI 46-86%) and 52% (23-75%), respectively. Conclusion: Ibrutinib is a safe and effective treatment option for patients with BNS. Disclosures Palomba: Pharmacyclics: Consultancy; Celgene: Consultancy. Talaulikar:Amgen: Consultancy, Honoraria; Takeda: Research Funding; Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Buske:Janssen: Honoraria, Research Funding; Bayer: Research Funding; Roche: Honoraria, Research Funding. Tedeschi:Gilead: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau. Simpson:Pharmacyclics LLC, an AbbVie Company: Research Funding; Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Ansell:Affimed: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Pfizer: Research Funding; Trillium: Research Funding; Regeneron: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding. Treon:Johnson & Johnson: Consultancy; BMS: Research Funding; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Other: Travel, Accommodations, Expenses. Castillo:Millennium: Research Funding; Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Abstract Background: Patients (pts) with deletion 17p (del17p) CLL follow an aggressive clinical course and experience poor outcomes with chemoimmunotherapy. Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), is approved for pts with CLL with ≥1 prior therapy and for pts with del17p CLL (including first-line). In the phase 2 RESONATE-17 study (PCYC-1117), ibrutinib demonstrated high efficacy with a favorable risk-benefit profile in del17p CLL/SLL (O'Brien, ASH 2014). We evaluate the baseline genetic features and prognostic factors of these pts to determine their impact on outcome. Methods: Pts with del17p CLL or SLL defined by peripheral blood FISH who failed ≥1 therapy received 420 mg oral ibrutinib once daily until progression or unacceptable toxicity. Using the primary analysis data cut, the overall response rate (ORR; iwCLL 2008 criteria by investigators), progression-free survival (PFS), and overall survival (OS) were assessed by subgroup. Results: Among 144 treated pts (137 CLL, 7 SLL), the median age was 64 (range 36-89). At baseline, 63% of pts had Rai stage III or IV disease, and 39% had received ≥3 prior therapies. Baseline cytogenetics included del11q (16%), del13q (74%), and trisomy 12 (17%), in addition to del17p in all pts. Of 116 pts with valid baseline genomic samples, IGHV status was unmutated in 84%; genomic variants that included mutations, rearrangements, insertions, deletions, and copy number variants affecting coding regions were identified as follows: ATM (14%), BIRC3 (3%), BTK (1%), MYC (2%), MYD88 (2%), NOTCH1 (16%), PLCG2 (3%), SF3B1 (27%), and TP53 (92%), which were consistent with previously identified mutations in pts with CLL (Wang, NEJM 2011; Winkelmann, Haematologica 2015). At a median follow-up of 11.5 months, the investigator-assessed ORR including partial response with lymphocytosis (PR-L) for all treated pts was 83% (17% PR-L). Median PFS and OS were not reached, with 12-month PFS and OS rates of 79% and 84%. Any-grade adverse events (≥15%) included diarrhea (36%), fatigue (31%), cough (24%), arthralgia (22%), nausea (19%), hypertension (19%), anemia (19%), pyrexia (17%), decreased appetite (17%), muscle spasms (17%), neutropenia (17%), and peripheral edema (15%). Serious AEs occurred in 40% of pts (38% ≥ grade 3). ORR, 12-month PFS, and 12-month OS are presented by subgroup for baseline characteristics, cytogenetics, and genomic variants (Table). There were no substantial differences in response rates and survival outcomes in the subgroups with and without baseline cytogenetic aberrations or genomic variants (Table). Response rates were similar for pts with and without NOTCH1 or SF3B1 variants. Of 11 pts with del17p CLL who developed Richter transformation, baseline aberrations included ATM (n=2), SF3B1 (n=3), and/or NOTCH1 (n=3); none had BIRC3 variants. Overall at baseline, there were 3 pts with a PLCG2 mutation (L163F, H193Q, P236L), and 1 with a BTK mutation (R236Q); all achieved a best overall response of PR-L or better. None had received prior therapy with a BTK or PI3K inhibitor. Two pts had a baseline MYD88 mutation (L265P, L142F) with a best overall response of PR in 1 pt. Two pts had baseline MYC amplifications with 5 of 5 exons amplified to 6 and 7 copies, respectively; 1 pt achieved a best overall response of PR. Conclusions: These results provide further evidence of ibrutinib's robust clinical activity and encouraging survival outcomes in this high-risk population regardless of baseline cytogenetic aberrations or genomic variants. The prognostic role of these clinical characteristics and genetic anomalies will continue to be elucidated with longer term follow-up of this population. Figure 1. Investigator-assessed efficacy outcomes by subgroups Figure 1. Investigator-assessed efficacy outcomes by subgroups Disclosures Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jones:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; TA Therapeutics: Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses. Hillmen:AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Osterborg:Gilead: Honoraria; Janssen: Honoraria, Research Funding; GSK: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Thirman:Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment. Hallek:Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract In multiple myeloma, the neoplastic plasma cells are either dispersed throughout the red marrow spaces of the axial and proximal appendicular skeleton or concentrated in discrete, well vascularlized plasmacytomas that stimulate osteoclastic bone resorption and erode into cortical bone. Interactions between bone marrow stromal cells (BMSC) and myeloma cells are clearly important in the pathogenesis of myeloma that diffusely infiltrates the bone marrow and where plasmacytomas are in contact with the bone marrow space. However, these interactions cannot be of major relevance at the centers of expanding plasmacytomas since these sites are devoid of osteoclasts, osteoblasts and other BMSC. Histological sections of skeletal plasmacytomas from 22 patients with multiple myeloma were therefore examined after immunostaining with anti-macrophage antibodies. Hematoxylin and eosin stained sections showed sheets of plasma cells interspersed with numerous small blood vessels. Immunostained sections revealed abundant CD68+, CD163+ macrophage infiltrates in all tumors, and scattered collections of CD3+ T lymphocytes. Tumor-associated macrophages (TAM) accounted for 2 to 12 percent of nucleated cells in these plasmacytomas and were evenly distributed through the parenchyma or clustered around CD34+ blood vessels. In general the TAM had dendritic morphology, and each dendrite was in close contact with multiple plasma cells. In a small percentage of cases, there was a subpopulation of TAM strikingly clustered around CD34+ positive blood vessels. However, vascular mimicry was not seen. Abundant murine CD68+ TAM were also found in subcutaneous KAS6/1 and MM1 myeloma xenografts in SCID mice. To determine whether cells of the monocytic lineage might be exploitable as carriers for systemic delivery of therapeutic agents to plasmacytomas, monocyte-derived dendritic cells were infected with oncolytic measles viruses and administered intravenously to SCID mice bearing subcutaneous KAS6/1 xenografts. Immunostaining for human MHC II antigen revealed that the infused DCs could localize to the KAS6/1 tumors where they heterofused with and transferred MV infection to the myeloma cells. This is the first report of TAM in skeletal plasmacytomas of myeloma patients. Further research into the role of TAM in supporting myeloma growth is warranted since they may offer many potential opportunities for the development of novel approaches to myeloma therapy.

AbstractNerve growth factor (NGF ) can influence mast cell development and function in murine rodents by interacting with its receptors on mast cells. We now report the identification of mRNA transcripts of full-length tyrosine kinase-containing trkA, trkB, and trkC neurotrophin receptor genes in HMC-1 human mast cell leukemia cells. Although HMC-1 cells lacked p75 mRNA, they expressed transcripts for the exon-lacking splice variant of trkA (trkAI), truncated trkB (trkB.T1), and truncated trkC. By flow cytometry, HMC-1 cells exhibited expression of TrkA, TrkB, and TrkC receptor proteins containing full-length tyrosine kinase domains. NGF stimulation of HMC-1 cells induced tyrosine phosphorylation of TrkA protein, increased expression of the early response genes c-fos and NGF1-A, and activation of ERK-mitogen–activated protein (MAP) kinase, results which indicate that TrkA receptors in HMC-1 cells are fully functional. Highly purified populations of human lung mast cells expressed mRNAs for trkA, trkB and trkC, whereas preparations of human umbilical cord blood-derived mast cells expressed mRNAs for trkA and trkC, but not trkB. Moreover, preparations of human umbilical cord blood-derived immature mast cells not only expressed mRNA transcript and protein for TrkA, but exhibited significantly higher numbers of chymase-positive cells after the addition of NGF to their culture medium for 3 weeks. In addition, HMC-1 cells expressed mRNAs for NGF, brain-derived neurotrophic factor (BDNF ), and neurotrophin-3 (NT-3), the cognate ligands for TrkA, TrkB, and TrkC, whereas NGF and BDNF transcripts were detectable in human umbilical cord blood mast cell preparations. Taken together, our findings show that human mast cells express a functional TrkA receptor tyrosine kinase and indicate that NGF may be able to promote certain aspects of mast cell development and/or maturation in humans. Our studies also raise the possibility that human mast cells may represent a potential source for neurotrophins.

Abstract Background: Pev (TAK-924/MLN4924), a novel investigational NAE inhibitor, enhances the anti-leukemic effects of aza in AML cell lines and murine xenografts (Smith et al, Blood 2011). Single-agent pev activity was confirmed in relapsed/refractory AML pts (Swords et al, Br J Haematol 2015). This open-label, multi-center, dose-escalation study (NCT01814826) investigated pev + aza in treatment-naïve older AML pts. Dose-limiting toxicities (DLTs)includedG2 hyperbilirubinemia and G4 AST elevation (n=1 each) at pev 30 mg/m2. The maximum tolerated dose (MTD) for the combination was pev 20 mg/m2 + aza 75 mg/m2 (Swords et al, ASH 2014).We present updated safety/efficacy results for the MTD cohort (fully enrolled). Methods: Primary objectives included safety and tolerability assessments of pev + aza in addition to defining the MTD. Secondary objectives included pharmacokinetics (PK) and disease response assessments. Treatment-naïve pts ≥60 yrs unlikely to benefit from standard induction therapy (defined by ≥1 of: antecedent hematologic disease; known adverse cytogenetic risk; ECOG PS 2; ≥75 yrs), received pev 20 or 30 mg/m2 IV on d 1, 3 and 5, + fixed-dose aza (75 mg/m2 IV/SC) on d 1-5, 8 and 9, every 28 d until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed per NCI-CTCAE v4.03; response per IWG criteria for AML. Bone marrow samples were collected at screening to assess cytogenetic risk (CALGB) and mutation profile; serial samples for PK analysis were drawn in cycle 1. Results: Demographics:As of May 17 2016, 61 pts (median age 75 yrs [range 61-89]; 54% male; 77% ECOG PS 0/1, 23% ECOG PS 2; 57% de novo, 43% secondary AML; median marrow blasts 36% [range 5-92]) had received pev 20 mg/m2, of whom 48% had intermediate-, 30% adverse-, and 3% favorable-risk cytogenetics. Safety/PK: Pts received a median of 4 cycles (range 1-33), and 23/61 pts (38%) received ≥6 cycles of pev + aza. The most common AEs were constipation (46%), nausea (44%), fatigue (43%), and anemia (39%). Fifty pts (82%) experienced ≥G3 AEs; the most frequent (≥15%) were anemia, febrile neutropenia (each 28%), thrombocytopenia (21%), neutropenia (18%), and pneumonia (15%). ≥G3 AST/ALT elevations were reported in 5% of pts. Forty-one pts (67%) experienced serious AEs; the most frequent (≥10%) were febrile neutropenia, neutropenia (each 25%), and pneumonia (11%). Two pts discontinued due to pev related toxicity (G3 febrile neutropenia). There were 11 on-study deaths unrelated to study therapy. In the MTD expansion phase (n=55), 2 pts experienced DLTs of transient G3/4 transaminase elevations, and were successfully re-challenged following dose reduction to remain on study. Pev PK was not altered by the addition of aza. Responses: Overall response rate (ORR) in 52 response-evaluable pts was 60% (18CR, 5CRi, 8PR; Figure 1), with a median duration of remission of 8.3 mos (95% CI: 5.75, 12.06); 19/31 (61%) responses occurred within the first 2 cycles.Of the 23 pts with CR/CRi, 14 had responses lasting ≥4 cycles, 2 went on to have allogeneic stem cell transplant, 9 had intermediate-, 7 adverse-, and 1 favorable-risk cytogenetics. ORR was: 64% (14/22; 7CR, 3CRi, 4PR) vs 57% (17/30; 11CR, 2CRi, 4PR) for pts with low- (<30%) vs high- (≥30%) marrow blasts; 58% (18/31; 11CR, 3CRi, 4PR) vs 62% (13/21; 7CR, 2CRi, 4PR) for de novo vs secondary AML pts; 61% (14/23; 8CR, 1CRi, 5PR) vs 50% (8/16; 5CR, 2CRi, 1PR) for intermediate- vs adverse-risk cytogenetic pts; 83% (19/23; 14CR, 2CRi, 3PR) vs 41% (12/29; 5CR, 3CRi, 4PR) for pts who received ≥6 cycles vs <6 cycles of aza, respectively. Responses were seen in pts with typically refractory disease; 7/11 pts with TP53 mutations achieved either a CR/CRi (n=3) or PR (n=4); 4 stayed on study for >10 cycles. After a median follow-up of 16.4 mos, 6-mo survival was 52%. Median overall survival was: 7.0 mos for the MTD cohort; 8.5 vs 5.2 mos for pts with low- (<30%) vs high- (≥30%) marrow blasts (Figure 2); 5.6 vs 11.2 mos for de novo vs secondary AML pts (Figure 3); and 16.1 vs 5.3 mos for pts aged 65-74 vs ≥75 yrs, respectively. Conclusion: Pev + aza was well tolerated. Response rates and durable remissions were observed with limited additional toxicity beyond what is expected for aza alone. The timing and frequency of responses suggests benefit from the addition of pev compared to aza alone (Dombret et al, Blood 2015). At the time of writing, a randomized phase 2 study in low-blast AML/high-risk myelodysplastic syndromes is ongoing. Disclosures Coutre: Janssen: Consultancy; Pharmacylics, LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Zeidner:Tolero: Research Funding; Merck: Research Funding; Takeda: Research Funding; Otsuka: Consultancy; Agios: Honoraria. Foran:medscape: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; novartis: Honoraria; pfizer: Honoraria; karyopharm: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Cruz:Millennium Pharmaceuticals, Inc.: Honoraria; Millennium Pharmaceuticals, Inc.: Speakers Bureau. Erba:Novartis: Consultancy, Speakers Bureau; Celator: Research Funding; Daiichi Sankyo: Consultancy; Celgene: Consultancy, Speakers Bureau; Juno: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Seattle Genetics: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Amgen: Consultancy, Research Funding; Agios: Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Astellas: Research Funding; Ariad: Consultancy; Jannsen: Consultancy, Research Funding. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Tam:Millennium Pharmaceuticals, Inc.: Consultancy. Vardhanabhuti:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dobler:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Faessel:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dash:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Sedarati:Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Dezube:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment, Equity Ownership. Savona:Takeda: Research Funding; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Research Funding; Sunesis: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Myeloproliferative neoplasms (MPN) including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF) are clonal hemopathies characterized by burdensome symptom profiles and impaired quality of life. Few studies have evaluated patient-reported outcomes during treatment with non-experimental pharmacological regimens. Aims: The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify MPN symptom severity, frequency and quality of life at baseline and throughout treatment with non-experimental therapies utilizing the Myeloproliferative Neoplasm Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS; JCO 2012). In this abstract, we provide updated results for the prospective international cohort trial currently in active enrollment: the MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) trial. Methods: This study aims to recruit 180 international ET, PV, and MF (including primary MF and post-ET or post-PV MF) patients receiving non-experimental medical therapy and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the European Organisation for Research and Treatment of Cancer (EORTC) and M.D. Anderson Symptom Inventory (MDASI) instruments at enrollment and on the first day of the second assessment. At visits, physicians acquired demographic, laboratory, physical examination, and radiographic data. Descriptive statistics were used to summarize data. Results: Clinical Data The MEASURE trial opened for enrollment in 2012 and remains in recruitment phase with 15 participating international sites. To date, 39 patients have been enrolled and 25 have completed both study visits. Participants include ET (28%), PV (24%), and MF (48%; 50% primary MF, 8% post-ET, 42% post-PV) patients. The majority of patients are male (64%) and of expected age (mean 69.3, range 39-89) for the disorders. Seventeen percent had prior thrombosis, 9% required red blood cell transfusion, and none reported prior splenectomy or hemorrhage. Mean hematologic measures included hemoglobin 13.2 g/dL, WBC count 11.4 x109/L, ANC 8.5 x109/L, and platelets 514 x109/L. Therapies received prior to enrollment included aspirin (n=16), hydroxyurea (n=11), phlebotomy (n=8), warfarin/clopidogrel/anticoagulation (n=8), erythropoietin (n=2), and interferon (n=1). The most common current MPN therapies were hydroxyurea (n=9), aspirin (n=9), interferon (n=4), and phlebotomy (n=2). Symptom Assessment In comparing MPN-SAF TSS mean symptom scores, all symptoms except bony pain improved between the first and second visits, including fatigue, early satiety, abdominal discomfort, inactivity, concentration, night sweats, itching, fever, weight loss, and overall quality of life (Figure1). Total MPN-SAF TSS scores improved from a mean of 32.3 to 25.9. On the EORTC, mean scores for physical, role, emotional, and social functioning improved from the first to the second visit (Figure 2). Cognitive functioning showed a slight decline. Global health status measure improved from 60.2 to 72.9. On the MDASI, symptom severity scores decreased from 3.6 to 2.8 from the first to second visit (Figure 3). Symptom distress measure decreased from 4.1 to 3.0. Discussion: Interim results from the MEASURE trial demonstrate that standard, non-experimental treatment regimens offer improvement in quality of life-related symptoms on multiple patient-reported survey instruments including the MPN-SAF TSS, EORTC QLQ-C30, and MDASI. Updated data including symptom correlations and mutational analysis to be presented at the 2016 ASH conference. Disclosures Ross: Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Radia:Novartis: Honoraria; Pfizer: Honoraria. McMullin:Novartis: Honoraria, Speakers Bureau. Cargo:Novartis: Honoraria; Celgene: Honoraria, Research Funding. Sekhar:Novartis: Research Funding. Mesa:Gilead: Research Funding; CTI Biopharma: Research Funding; Galena: Consultancy; Ariad: Consultancy; Incyte: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Promedior: Research Funding.

Abstract Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL). Methods: Patients with del 17p CLL or SLL who failed at least one therapy were enrolled to receive 420 mg oral ibrutinib once daily until progression. All patients receiving at least one dose of ibrutinib were included in the analysis. The primary endpoint was overall response rate (ORR) per an independent review committee (IRC). Other endpoints included duration of response (DOR), progression-free survival (PFS), and safety of ibrutinib. Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib. Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL. Figure 1 Figure 1. Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Jones:Pharmacyclics: Consultancy, Research Funding. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Mato:Pharamcyclics, Genentech, Celegene, Millennium : Speakers Bureau. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Siddiqi:Janssen: Speakers Bureau. Furman:Pharmacyclics: Consultancy, Speakers Bureau. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Stevens-Brogan:Pharmacyclics: Employment. Li:Pharmacyclics: Employment. Fardis:Pharmacyclics: Employment. Clow:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Chu:Pharmacyclics: Employment, Equity Ownership. Hallek:Janssen, Pharmacyclics: Consultancy, Research Funding. Stilgenbauer:Pharmacyclics, Janssen Cilag: Consultancy, Honoraria, Research Funding.

Abstract Background: We sought to retrospectively analyze the clinical differences, at diagnosis and throughout the disease course, between patients with primary myeloifbrosis whom undergo blastic transformation (PMF-BP) and those whom expire from PMF complications without undergoing transformation. Methods: An international collaborative database of patients with PMF which progressed to PMF BP, and a control group of individuals with PMF who expired secondary to PMF was created. Data regarding clinical course, bone marrow, karyotypic, quantitative JAK2V617F analysis (when able), laboratory values, and therapy at the diagnosis of PMF, PMF BP and up to 4 return visits (R1-4) in between these milestones was abstracted. Results: COMPARISON AT DIAGNOSIS OF PMF: 136 cases of PMF who eventually underwent PMF-BP were included, with a control group of 42 PMF patients, were analyzed. Both groups of patients had similar demographic (median age at diagnosis 59 years (range 23–83)/ 59.1 (15–93); and disease parameters (median hemoglobin 10 g/dL (range 2–15.7) /9.8 (4.9–14.6); median platelet count 181 x 109/L (range 7–1400)/168 (16–1916)), and Lille PMF prognostic scores (p = n.s.) for PMF-BP vs. PMF control group respectively. Additionally, blasts (peripheral blood /marrow) were a median of 0% (range 0–18%)/ 2% (range 0–16%) for the study group versus 0.25% (range 0–5%)/ 3% (range 0–4%) (p = n.s. for both) for the control group, respectively. Both groups had similar rates of requiring therapy (86%; 93%) and survival from diagnosis (median 34 months (range 2–441); 29 months (1–236)) (p = n.s.). However, lactate dehydrogenase (LDH) (although high in both groups) was higher at diagnosis (median 802 IU/L (range 83–10353) vs. 416 IU/L (124–2197)) (p=0.04), as well as an abnormal marrow karyotype (85% vs. 25%; p<0.001) amongst the PMF BP group. SUBSEQUENT CLINICAL COURSE: Analyzing the clinical evolution between groups demonstrated persistently higher LDH and worsening thrombocytopenia in the PMF-BP cohort (see figure). Decreasing Platelets Approaching PMF BP Decreasing Platelets Approaching PMF BP Peripheral blood blasts increased in both groups, but values above 10% were unique to the PMF BP group. Additionally marrow karyotype displayed clonal evolution developed in 56% of the PMF-BP patients as opposed to 14% of controls (p<0.001). Initial and serial quantitative JAK2V617F mutation analysis (available from 20 /19 patients from the PMF-BP and control group at diagnosis, with 11 / 12 serial samples) showed no difference between the groups, nor a pattern of mutation burden elevation with transformation to leukemia in the study group. Conclusions: Increasing LDH, peripheral blood blast percentages >10%, and clonal evolution are features commonly seen in PMF patients whom evolve to blast phase and may be a harbinger of movement towards PMF BP.