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Abstract BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Abstract Introduction: Ibrutinib (Imbruvica®), an oral, first-in-class covalent BTK inhibitor, is a new treatment option approved by FDA for chronic lymphocytic leukemia (CLL) patients (pts) with ≥1 prior therapy. We previously reported results from the phase III trial, in which ibrutinib (ibr) significantly improved progression-free and overall survival vs ofatumumab (ofa) in pts with relapsed/refractory CLL or small lymphocytic lymphoma (SLL) (Byrd et al. NEJM, 2014). Here, we report measures of patient well-being, including hematologic, immunologic, and quality of-life parameters, at interim analysis (IA). Methods: Pts with CLL/SLL after ≥1 prior therapy were randomized 1:1 to ibr 420 mg/day until progression or unacceptable toxicity, or to ofa for up to 24 weeks. At IA, secondary efficacy endpoints of hematologic improvement (sustained improvement ≥56 days without transfusions or growth factors) and FACiT-Fatigue (FACiT-F) outcomes were analyzed, along with exploratory endpoints assessing disease-related symptoms (DRS), serum immunoglobulin, patient-reported outcomes (PROs) by EORTC QLQ-C30, and medical resource utilization (MRU). Results: Of 391 enrolled pts (ibr n=195; ofa n=196), 63% had cytopenia(s) at baseline: 45% had anemia (hemoglobin ≤11 g/dL), 35% thrombocytopenia (platelets ≤100×109/L), and 20% neutropenia (absolute neutrophil counts [ANC] ≤1.5×109/L). On the ibr arm, 69% of pts with baseline cytopenias experienced sustained improvement in blood counts compared to 43% on ofa (P<0.0001, table). There was no decrement in serum immunoglobulins (IgA, IgG, IgM) during follow-up. IgA levels increased on the ibrutinib arm only (mean change from baseline: 41% at week 24). Immune cells CD4+ and CD8+ T-cell and NK-cell levels remained relatively stable during treatment. Mean change in FACiT-F score from baseline are shown in the figure for ibr and ofa arms. At week 24, clinically meaningful (≥3 points) improvement in FACiT-F occurred in more pts on ibr than ofa (59% vs 46%, P=0.06); clinically meaningful deterioration was reported by 14% vs 24% (P=0.08), respectively. A larger proportion of ibr vs ofa pts showed clinically meaningful improvement on EORTC-QLQ-C30 global health scores (46% vs 40%). Clinically meaningful improvement (≥10 points) from baseline to week 24 in ibr vs ofa pts was observed for fatigue (median 11 vs 0). A 50% reduction in lymph node based on IRC-assessed CT was observed in 93% (177/190 evaluable) of ibr pts compared with 17% (29/174 evaluable) of ofa pts (P< 0.0001). Splenic response based on IRC-assessed CT was reported for 85% (138/163 evaluable) of ibr pts compared with 54% (82/151 evaluable) of ofa pts. Baseline DRS were comparable between groups; however, improvement by at least 1 grade (G) post-baseline was observed in ibr relative to ofa pts for weight loss (100% vs 93%), fatigue (88% vs 72%), night sweats (95% vs 86%), and anorexia (100% vs 64%), respectively. Cumulative MRU was comparable for growth factors and transfusions, with ibr pts having longer median treatment duration: 8.6 months for ibr vs 5.3 for ofa. Hospitalizations in the first 30 days occurred in 2% ibr vs 15% ofa pts. After adjusting for treatment exposure duration, diarrhea, grade 1-2 bleeding events (e.g petechiae), and atrial fibrillation were among those noted to be more frequent on the ibrutinib arm while events such as fatigue, infusion reaction, and peripheral sensory neuropathy were seen more commonly with ofa. Major hemorrhage events were uncommon, observed in 2 patients on the ibr arm vs 3 on ofa arm without adjusting for exposure time. Exposure-adjusted analysis showed no difference in any-grade infection and a 43% relative reduction for grade 3 or higher infections for ibr. Conclusions: Ibr compared to ofa when administered to previously treated CLL/SLL pts led to improvements in hematologic function and disease burden. A survival benefit with ibr, together with sustained improvements in hematologic endpoints and PRO suggest that ibr enhances quality of life while prolonging survival. Table. Sustained hematologic improvement Parameter, n (%) ITT population Pts with cytopenias at baseline Ibr n=195 Ofa n=196 P value Ibr n=195 Ofa n=196 P value Platelets 60 (31) 19 (10) <0.0001 53/74 (72) 14/64 (22) <0.0001 ANC 52 (27) 19 (10) <0.0001 26/41 (63) 12/38 (32) 0.0047 Hemoglobin 42 (22) 32 (16) 0.1883 42/89 (47) 32/86 (37) 0.1815 Figure. Improvement in FACiT-F by treatment arm. Figure. Improvement in FACiT-F by treatment arm. Disclosures Barrientos: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Kay:Genetech: Research Funding; Pharmacyclics: Research Funding; Hospira: 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. Coutre:Janssen, Pharmacyclics: Honoraria, Research Funding. Tam:Pharmacyclics and Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Mulligan:Roche, Abbvie: Consultancy, Honoraria. Jaeger:Janssen Cilag: Honoraria. Devereux:Pharmacyclics, Janssen: Consultancy, Honoraria. Robak:Janssen: Consultancy, Research Funding. Schuh:Roche, Gilead, GSK, NAPP, Celgene: Honoraria. Bloor:GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Dearden:Roche, GSK, Gilead, Janssen, Napp: Honoraria. Jones:Pharmacyclics: Consultancy, Research Funding. Kierschniak:Pharmacyclics, GmbH: Employment. Eckert:Pharmacyclics: Employment. Suzuki:Pharmacyclics: Employment. Hsu:Pharmacyclics: Employment. James:Pharmacyclics: Employment. Byrd:Pharmacyclics: Research Funding. Hillmen:Pharmacyclics, Janssen, Gilead, Roche: Honoraria, Research Funding.

Abstract Introduction Myelofibrosis (MF) and Post PV/ET MF represents a group of debilitating hematological disorders in which quality of life (QOL) is severely compromised in most patients as a result of persistent constitutional symptoms, progressive cytopenias, and splenomegaly. Conventional therapeutic modalities have largely focused on symptoms palliation rather than cure. Allogeneic stem cell transplantion (ASCT) remains the only potential curative option for intermediate and high risk disease. Till now, outcome data for MF have historically focused on survival benefit. Until now, few studies have evaluated the QOL, financial burden, and symptom response in MF patients undergoing treatment including ASCT. The development of the Myeloproliferative Symptom Assessment Form Total Symptom (MPN-SAF TSS) score in 2012 allows us to objectively quantify with a standardized tool these crucial aspects of patients care. The Myeloproliferative Neoplasm Quality of Life (MPN-QOL) Study Group aims to objectively quantify symptomatic response to standard available treatments by utilizing the MPN-SAF TSS. We introduce two MPN-QOL prospective trials currently in active enrollment: The MPN Experimental Assessment of Symptoms by Utilizing Repetitive Evaluation (MEASURE) Trial and the Symptoms Yielded in Myelofibrosis Patients after Transplant as Objectified by MPN-SAF TSS (SYMPTOMS) Trial. Our intention with these studies is to quantify the QOL and symptom burden of PMF and post PV/ET MF patients undergoing treatment including ASCT. Methods The MEASURES trial is a prospective questionnaire based study evaluating the responsiveness of the MPN-SAF TSS in detecting symptomatic changes in target symptoms for an anticipated 180 ET, PV and MF (including primary MF, post-ET and post PV MF) patients receiving non-experimental medical therapy (aspirin, hydroxyurea, anagrelide, interferon, busulfan, melphalan, cladribine, thalidomide, lenalidomide, prednisone, danazol, ruxolitinib) and/or phlebotomy. Patients complete the MPN-SAF for seven consecutive days at the time of enrollment and repeat the survey for an additional seven consecutive days between 90 days and six months. Patients also complete the MDASI, EORTC and Global Impression of Change Items on the first day of the second assessment. Physicians acquire demographic, laboratory, physical examination and radiographic data, along with serial response assessments. In parallel, the SYMPTOMS trial is prospective questionnaire based study evaluating the QOL of patients undergoing ASCT utilizing MPN-SAF TSS, the FACT-BMT, Global Impression of Change, and a financial questionnaire. Patients will be evaluated at various time points pre-transplant, day 30, day 100 and 1 year post-transplant. Participants (N=110) will be prospectively enrolled from Mayo Clinic Arizona (MCA) with other centers to soon join. To date we have enrolled 5 patients from MCA on the SYMPTOMS trial and 32 patients on the MEASURES trial. Results Both trials began open enrollment in the summer of 2012 and remain in recruitment phase. Our updated preliminary data will be presented at the ASH 2013 meeting Conclusion Myeloproliferative Neoplasms have been associated with debilitating symptom profile that can significantly impair the QOL. We recognize the burden of this disease and treatment and have therefore initiated two ongoing parallel prospective trials with goals to quantify the QOL and symptom burden of MPN patients. By quantifying degree of burden and impairment in QOL in a standardized format in MPN patients undergoing a range of treatments, we will in the future be better able to inform our patients of the likely benefits and toxicities of the available treatment options. Disclosures: Birgegard: Vifor Pharma: Honoraria.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was &gt;95% at all doses. Sustained complete (&gt;95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in &gt;2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

Marrow adipocytes reprogrammed by myeloma cells induce bone lesions.

Purpose: The purpose of this study was to characterize reductions in intraocular pressure (IOP) and the need for IOP-lowering medications following phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy in eyes with angle-closure glaucoma and cataract. Methods: In this retrospective, interventional case series, preoperative, operative, and postoperative data were collected through 6 months of follow-up from 42 eyes of 24 subjects. Outcomes included mean IOP reduction, reduction in IOP-lowering medications, and the proportion of patients achieving IOP reduction ≥20%, IOP≤18 mm Hg, and reduction of ≥1 medication. Results: Preoperatively, mean (SE) IOP was 25.5 (0.7) mm Hg and the mean number of IOP-lowering medications used was 2.3 (0.1) per eye. Through 6 months of follow-up, mean IOP reductions of 10.1 to 12.8 mm Hg (38.4% to 49.5%; P <0.0001) and mean IOP medication reductions of −2.2 to −2.3 (91.7% to 98.4%; P <0.0001) were seen. At month 6, 92.9% of eyes (39/42) achieved IOP≤18 mm Hg, 100% (42/42) achieved IOP reduction of ≥20%, 100% (42/42) required ≥1 fewer medications for IOP control, and 85.7% (36/42) were medication free. Conclusions: Phacoemulsification combined with Kahook Dual Blade-assisted goniosynechialysis and excisional goniotomy safely provides statistically and clinically meaningful reductions in both IOP and the need for IOP-lowering medications in eyes with angle-closure glaucoma.