DSMB Member Research Articles

Implementing a Structured Health Care Transition (HCT) Process for Sickle Cell Disease (SCD) Using Quality Improvement (QI): Early Results of a SCD HCT Learning Collaorative

Background: A regional SCD HCT learning collaborative (SCD-LC) was formed from engaging 14 pediatric and adult paired sites (including required community participation) using a standardized HCT quality improvement process. The SCD-LC involved a kick-off meeting and monthly calls to establish a common understanding of clinical recommendations, QI methods, and implementation of the Six Core Elements of HCT (6CE). Methods: Implementation of 6CE was measured as part of a SCD HCT Study conducted in 14 paired SCD clinical sites with pediatric, adult and community partners who care for 1625 individuals aged 16-25. They represent a variety of clinical programs:12 urban and 2 rural, 12 academic and 2 nonacademic, 6 small and 8 large. Got Transition's Process Measurement Tool (HCTPMT) was customized for SCD and used to assess 6CE implementation. HCTPMT were completed by 14 pediatric and 14 adult sites at baseline (2018) and after 6 months. Pre-post results were compared overall and by type of practice. Results: All 14 participating sites made substantial progress towards implementing a structured HCT process consistent with the within the first 6 months of the project. Overall, baseline scores averaged 19.4 (SD 14.1) and after 6 months of QI support, scores increased to 33.7 (SD 19.4) (average change 14.3, p<0.0001). For the 14 pediatric sites, scores went from 24 to 43 (p 0.0016), and for the 14 adult sites, from 15 to 24 (p 0.0017). Pediatric sites had higher scores at 6 months compared to adult sites (p=0.0068). Although their change over time was higher, it did not reach statistical significance at 0.05 (p=0.0759). Large sites went from 21 to 34 (delta 14, p=0.0048), small went from 18 to 32 (delta 15, p=0.0018). Conclusion: All 14 pediatric and adult sites reported significant progress within 6 months of implementing a structured HCT process aligned with the 6CE. Disclosures Osunkwo: Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Terumo: Speakers Bureau; Micella Biopharma: Other: DSMB Member .

Treatment Discontinuation Patterns for Patients with CLL in the Real-World Settings: Results from a Multi-Center Study

Treatment Discontinuation Patterns for Patients with CLL in the Real-World Settings: Results from a Multi-Center Study

Treatment Sequences and Outcomes of Patients with CLL Treated with Venetoclax and Other Novel Agents Post Introduction of Novel Therapies

Treatment Sequences and Outcomes of Patients with CLL Treated with Venetoclax and Other Novel Agents Post Introduction of Novel Therapies

Treatment Outcomes with Purine Nucleoside Analog Alone or with Rituximab for Hairy Cell Leukemia Patients at First Relapse: A Multi-Center Outcomes Analysis

Treatment Outcomes with Purine Nucleoside Analog Alone or with Rituximab for Hairy Cell Leukemia Patients at First Relapse: A Multi-Center Outcomes Analysis

Use of Buprenorphine/Naloxone in Ameliorating Acute Care Utilization and Chronic Opioid Use in Adults with Sickle Cell Disease

Introduction: Pain is the most common complication of sickle cell disease (SCD) and a frequent cause of acute care utilization. It can be acute due to vaso-occlusive crisis or chronic with over 50% of adults experiencing chronic pain.1 Having chronic pain was associated with both high daily opioid use (≥ 90 MME) and worse quality of life (3,4). High daily opioid use in SCD was also associated with higher acute care utilization5 and ~50% of SCD adults presenting to a large urban acute-care centre were on chronic daily opioids.2 Opioids have been the mainstay of treatment for both acute and chronic pain in SCD however there is emerging evidence of the poor efficacy and high toxicity/morbidity associated with continuous daily use of opioids in any patient. These adverse effects include tolerance, dependency, opioid induced hyperalgesia, worsening of mood disorders, constipation and opioid withdrawal. The current opioid crisis demands that we identify alternatives to reduce daily high-dose opioids for treating SCD chronic pain that may also reduce acute care utilization and quality of life. Buprenorphine is a partial Mu receptor agonist and Kappa receptor antagonist. This product is approved to treat chronic pain. Naloxone is a Mu receptor antagonist. Buprenorphine/naloxone (B/N) combination products have been used to treat opioid use disorders and is increasingly used off-label to treat chronic pain in patients with opioid dependence. There is currently no published data on the use of buprenorphine alone or B/N in the management of chronic pain in adults with SCD. METHODS: We hypothesized that use of B/N in adults with SCD reduce both acute care utilization and daily opioid use while improving overall clinical outcomes. Using a retrospective chart audit we evaluated patients transitioned to B/N between January 1st, 2016 and April 30th, 2018 who had at least six months of follow up post transition. Patients were expected to follow up in clinic at least weekly for the first 4 visits, biweekly for 4 visits, and then monthly with a SCD provider and psychotherapist. We evaluated Morphine Equivalent Daily Dose (MEDD), acute care (ED) visits, inpatient (IP) admissions, length of stay (LOS), comorbid psychiatric diagnosis, hemoglobin S% (HbS) and F% (HbF) as markers of adherence to disease modifying therapy use and serum ferritin. MEDD was calculated by averaging monthly opioid use and included both outpatient prescriptions from the state's-controlled substance database and inpatient opioid doses administered from the electronic medical record, respectively. ED/IP visits (normalized on an annual basis), average LOS, and lab values were compared over two time-periods: from the date of entry into our SCD program to the date of initiation of B/N (switch date), and from the switch date to the last follow-up date. MEDD was compared for the 6 months pre- and post- initiation of B/N. Outcomes were analysed using generalized linear mixed models with the pre- and post-switch date as the fixed factor in the model. A random effect for subject was included to account the repeated observations. Results: Twenty-four patients were evalauted: 67% Female; median age 36 years (range 18 - 65). Genotype distribution: HbSS 15 (63%); HbSC 5 (21%); SB+Thal 4 (17%); 92% had a comorbid psychiatric condition (major depression, bipolar disorder, generalized anxiety disorder). Our results (summarized in Table 1) demonstrate significant reductions in acute care utilization (ED/IP visits, average IP LOS) and MEDD after initiation of B/N (p<0.001). No significant differences were noted in Ferritin level and HbF% between pre- and post-initiation of B/N. There was a trend towards reduced HbS% as a marker of adherence to monthly erythrocytapheresis however sample size was small. Conclusion: These results demonstrate that Buprenorphine/naloxone is effective in reducing acute care utilization among adults with SCD and drastically lowering the amount of daily opioids used to manage chronic pain. The impact of B/N on acute care utilization and daily opioid use was independent of adherence to disease modifying therapy (hydroxycarbamide and chronic erythrocytapheresis). Disclosures Osunkwo: Micella Biopharma: Other: DSMB Member ; Terumo: Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy, Speakers Bureau. Symanowski:Boston Biomedical: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Immatics: Membership on an entity's Board of Directors or advisory committees; Carsgen Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Veneto-STOP Study: Sequential Assessment of Minimal Residual Disease By Next Generation Sequencing to Optimize Outcomes and Minimize Exposure in Venetoclax-Treated CLL Patients

Veneto-STOP Study: Sequential Assessment of Minimal Residual Disease By Next Generation Sequencing to Optimize Outcomes and Minimize Exposure in Venetoclax-Treated CLL Patients

Downregulation of Cytoskeletal Protein Kazrin in Lung Endothelial Cells of Preclinical Sickle Cell Disease Mouse Model - Essential Role of Endothelial Barrier Function

Background: Lung capillary barrier dysfunction is common to all causes of acute chest syndrome (ACS), a leading cause of morbidity and mortality in individuals with sickle cell disease (SCD). Our published data (Haematologica 2017, 102, e26-e29) demonstrated, for the first time, an impaired barrier function in freshly isolated endothelial cells (EC) from the lungs of Townes transgenic sickle cell anemia (SS) mice, compared to heterozygote (AS) or control (AA) mice. In addition, we showed a sub-stimulatory dose (0.05 mg/kg) of bacterial toxin lipopolysaccharide, which did not cause prominent acute lung injury in control AS/AA mice, was fatal to SS mice suggesting an enhanced hypersensitivity of sickle EC to infection. Hemolysis is a fundamental feature of SCD that contributes to its pathophysiology. Hemolysis results in the leakage of vast amounts of hemoglobin, and subsequently, heme into the plasma. Although, previous studies have demonstrated the detrimental effect of heme in SCD, the mechanisms of heme-mediated lung EC barrier dysfunction have not been studied. Recently, Kazrin was identified as a widely expressed protein influencing intercellular adhesion and co-localizes with the cortical actin ring to stabilize cell-cell junctions. In this study, we investigated the mechanisms of heme-induced EC barrier dysfunction related to Kazrin function, using primary EC isolated from the lungs of SCD mice and controls. Methods: Primary EC from the lungs of SS, AS, and AA mice (6-8 weeks old) were isolated according to methods described in our recent publication. The EC barrier function was measured using electrical cell-substrate impedance sensing (ECIS) and Evans blue dye transendothelial permeability was done using a transwell filter assay system. Western blot was performed to measure total and phosphorylated expression levels of protein involved in the regulation of EC barrier function. Immunocytochemistry was performed using specific antibodies and actin cytoskeleton was identified using a known F-actin binding fluorescent marker Phalloidin. Results: Our data demonstrated a significantly reduced basal expression of the Kazrin mRNA and protein in freshly isolated SS-EC compared to AS-EC or AA-EC. To determine the effects of Kazrin downregulation on the EC barrier function, we depleted the Kazrin protein in AS-EC using Kazrin specific siRNA and scrambled control siRNA. Kazrin depleted cells demonstrate an attenuated EC barrier function as evidenced by reduced trans-endothelial electrical resistance by ECIS and increased Evans blue dye leak by transwell filter assay (p<0.05). By contrast, control siRNA treated AS-EC displayed normal barrier function. Therefore, our data, for the first time, suggest that Kazrin is essential for the EC barrier function. Given the crucial role of hemolysis in SCD, we detected that clinically relevant dose of heme (5 µM; 60 min) significantly decreases the AS-EC barrier function (p<0.05) and the heme-mediated decrease of barrier function is dose-dependent. Moreover prolonged treatment of AS-EC with heme (5 µM; 24-48 hrs) downregulated the Kazrin protein levels. These results are intriguing since the SS-EC inherently show downregulated Kazrin when compared with AS-EC. Therefore, it is possible that impaired barrier function in SS-EC that we recently published could be an effect of Kazrin downregulation since hemolysis is a constant process in SCD. We also found that incubation of AS-EC with heme upregulated the efficacy of barrier disruption agent RhoA. Previous studies have indicated that activated RhoA promotes the actin stress fibers by stimulating actin-myosin contractility and increased endothelial permeability. Our immunocytochemistry data reveal that heme incubated AS-EC develop severe actin stress fibers. Studies in progress to determine the mechanistic link between Kazrin downregulation, RhoA activation and impaired EC barrier function in SS-EC. Conclusions and Future Direction: Our findings support the notion that Kazrin participates in the EC barrier function and its downregulation cause an impaired EC barrier function. Our future studies will focus on to identify protective mechanisms of lung EC barrier function in SCD. Disclosures Kutlar: Bluebird Bio: Other: DSMB Member; Novo Nordisk: Research Funding; Novartis: Consultancy; Micelle Biopharma: Other: DSMB Chair; Global Blood Therapeutics, Inc. (GBT): Research Funding.

Crizanlizumab 5.0 Mg/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies

Crizanlizumab 5.0 Mg/Kg Exhibits a Favorable Safety Profile in Patients with Sickle Cell Disease: Pooled Data from Two Phase II Studies

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

A Phase Ia/Ib Study Exploring the Synthetic Lethality of the Orally Administered Novel BTK Inhibitor, Dtrmwxhs-12 (DTRM-12), in Combination with Everolimus and Pomalidomide in Patients with Relapsed/Refractory CLL, DLBCL or Other B-Cell Lymphomas

Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial

Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Characteristics and Potential Biomarkers of Adult Sickle Cell Patients with Chronic Pain

A paradigm shift is occurring in our understanding of pain in patients with sickle cell disease (SCD). Vaso-occlusive episodes (VOEs) are crises of acute nociceptive pain, and have long been recognized as a hallmark of SCD (Brandow et al., 2017). While patients with SCD are traditionally considered to be at “steady state” and pain free between VOEs, recent studies have shown that a significant number of adults with SCD (~30%) experience daily chronic pain (>50% of the time in the past 6 months) (Smith et al., 2008). Although the precise mechanisms underlying this evolution from acute episodic to chronic pain are not well known, some contributing factors include age, chronic inflammation, organ damage, and opioid induced hyperalgesia (Stoicea et al., 2015; Rees et al., 2010). A recent study in a mouse model of SCD showed that mast cell activation was an important contributor to neurogenic inflammation and chronic pain (Vincent et al., 2013). We previously reported that SCD patients with chronic pain were older and had higher levels of mast cell activation markers, plasma tryptase and substance P, compared to those without chronic pain (Kuei et al., 2015). Recently, nerve growth factor (NGF) has been implicated in pathogenesis of some chronic pain syndromes (osteoarthritis), and clinical trials with anti-NGF monoclonal antibodies have been shown to result in superior pain control compared to placebo, opioids and NSAIDs. Here we report the results of our extended study of the evolution of chronic pain in SCD. A total of 72 subjects (age 15-66) were enrolled: 10 in the 15-19 age group, 19 in 20-29, 21 in 30-39, and 22 in ≥ 40. Patients transfused within the past 3 months and those who had an ED visit or hospitalization within the past 2 weeks were excluded. Information on the frequency of VOEs, presence or absence of chronic pain, HU therapy, opioid use (as mg morphine equivalents within the past 6 months), other medications and routine laboratory data (CBC, retics, chemistry panel, HbF) were collected. 4 mL of EDTA blood was collected at steady state and the plasma was separated by centrifugation and kept at -80 C. Plasma tryptase, substance P, and NGF levels were assayed by ELISA using kits from Biomatik inc (catalog# EKU07922), Enzo Life Sciences (catalog# ADI-900-018), and R&D Systems (catalog# DY256), respectively. Pressure pain threshold (PPTh) was measured using a hand-held digital algometer (AlgoMed, Medoc, Israel) four times at each of the following anatomic muscle groups on the left side of the body and then averaged for analysis: masseter, trapezius, and ulna in this consecutive order. Cutaneous mechanical pain was assessed using a Von Frey monofilament on the back of the subject's left hand. A baseline of one stimulus and then two separate series of 10 repeated stimuli each were conducted. The subject was asked to rate the pain on a scale of 0 to 10 (MFB, MF1 and MF2). Overall, 34 patients had chronic pain and 38 did not; there was an age dependent increase in the frequency of chronic pain, VOE frequency, opioid use and Von Frey MF values. Similarly, QST showed significantly lower pressure pain thresholds in subjects with chronic pain at ulna and trapezius (p=0.026 and 0.024 respectively). As expected, opioid use (daily morphine equivalents) was significantly higher in the chronic pain patients (52.8 mg vs 6.94 mg, p=0.009), suggesting a correlation between opioid use and hyperalgesia. Tryptase and substance P levels were higher in chronic pain patients, though the difference did not reach statistical significance. NGF levels were significantly higher in the chronic pain group (1126 pg/ml vs 473 pg/ml, p=0.051). Our results confirm previous observations that there is an age dependent increase in the proportion of patients with chronic pain (Table 1, Fig. 1-3). The trend towards higher levels of tryptase and substance P is in support of mast cell activation and neurogenic inflammation as a contributing factor to chronic pain (Vincent et al., 2013). To our knowledge, this is the first study of NGF as a possible contributing factor to chronic pain in SCD. If confirmed in larger multi-center studies, these observations could provide a rationale for novel interventions for chronic pain in SCD, via inhibition of mast cell activation/c-kit (tyrosine kinase inhibitors) or via repurposing of existing anti-NGF monoclonal antibodies as an alternative to opioids, whose inefficacy in chronic pain is well documented. DisclosuresKutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Bluebird Bio: Other: DSMB Member; Sancilio: Other: DSMB Chair.

Correlation of Serum Ferritin Levels with Liver Iron Concentration By MRI Measurement in Sickle Cell Patients with Transfusional Iron Overload

Background:Recent reports from the thalassemia literature suggest that serum ferritin may be a poor and possibly misleading measure of total iron store in heavily iron overloaded patients. Moreover, the relationship between plasma ferritin and body iron stores is distorted by ascorbate deficiency, fever, infection, inflammation, and hepatic dysfunction, all of which occur in patients with sickle cell disease (SCD). On the other hand, following the results of multiple studies that demonstrated a high correlation of hepatic iron overload determination by magnetic resonance imaging to the values found in specimens from liver biopsy, R2* liver MRI has emerged as the best noninvasive yet highly sensitive and specific method for measuring the level of iron in the liver.The goal of this study was to determine the correlation of liver iron by liver R2* MRI with serum ferritin and by extrapolation assess whether serum ferritin remains to be a useful clinical marker of iron overload in patients with SCD. We also sought to determine the correlation of liver iron concentration with abnormalities in the liver function tests.Methods:We conducted a retrospective analysis of 31 patients with sickle cell disease and transfusional iron overload who are being followed at the Augusta University Comprehensive Sickle Cell Center. Serum ferritin, hepatic R2* MRI liver iron concentration, hepcidin level, and liver function tests (AST, ALT and total bilirubin) were assessed for correlation. We used the Pearson correlation coefficient to determine the relationship between the various variables with hepatic R2* MRI.Results:Serum ferritin levels showed a statistically significant positive correlation with R2* hepatic MRI (r = 0.479 with p = 0.0085) in the patients with SCD and transfusional iron overload . We also saw a positive correlation, although not statistically significant, between hepcidin level and liver iron concentration by liver MRI(r=0.493 with P= 0.399). This may be due to the small sample size of the patients who had hepcidin levels available.On the other hand, no correlation was detected between abnormalities in liver function tests and liver iron concentration. The correlation between liver iron concentration(LIC) and AST was 0.045 with p = 0.816 and the correlation between LIC and ALT was 0.233 with p = 0.224.Conclusion:While R2* MRI is the the most accurate method to diagnose and monitor response to therapy in SCD patients with transfusional iron overload, we have found a statistically significant positive correlation with serum ferritin values. Thus, where R2* liver MRI is unavailable, serum ferritin remains a clinically useful tool that can be used in the diagnosis and monitoring of iron overload in sickle cell patients, despite its limitations.As previously reported, we did not find any correlation between LIC and liver function abnormalities in this population (Harmatz et al, 2000) These findings suggest that patients with SCD may have a different response to iron overload in comparison to patients with thalassemia or hereditary hemochromatosis. DisclosuresKutlar:Bluebird Bio: Other: DSMB Member; Sancilio: Other: DSMB Chair; Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding.

The Association between the Alpha-Fibrinogen Thr312Ala (rs6050) Polymorphism and Risk of Venous Thromboembolism Among Enrollees in the Gate Study

Introduction: The final events of the activated clotting cascade include the conversion of fibrinogen to fibrin and stabilization of the growing fibrin clot by factor XIII (FXIII). A missense variant in the alpha chain of fibrinogen, α-fibrinogen (FGA) Thr312Ala (rs6050, NM_000508.3:c.991A>G, NP_000499.1:p.[Thr331Ala]), has been previously shown to interfere with FXIII-dependent cross-linking, leading to stiffer blood clots. It is believed this pathophysiology underlies the increased risk of venous thromboembolism (VTE) associated with the variant. The Thr312Ala variant has been shown to be significantly associated with VTE among White, Non-Hispanic populations. The only investigation of the variant in a Black population (Rasmussen-Torvik et al 2007) found no significant relationship between Thr312Ala and VTE, but the authors cite the relatively small number of participants included in the analysis as a possible reason for a null finding. We investigated the association between FGA Thr312Ala and VTE in a case-control study enrolling a relatively large racially diverse study population.Methods: Conditional logistic regression was used to assess the association between FGA Thr312Ala and VTE among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, a case-control study enrolling 1,042 VTE cases and 1,213 controls with no history of VTE, frequency-matched on age, sex, and race. Crude models conditioned on the matching factors, and adjusted models conditioned on the matching factors and controlled for patient characteristics found to be associated with both case/control status and FGA Thr312Ala genotype. Among all patient characteristics evaluated, the β-fibrinogen (FGB) promoter region variant -455 G>A (rs1800790, NM_001184741.1:c.-463G>A) was the only patient characteristic associated with both case/control status and FGA Thr312Ala genotype. Potential effect modification was assessed using likelihood ratio tests.Results: Among 660 White controls and 528 White cases in the GATE study, carrying at least one FGA rs6050 G (Ala) allele was associated with increased odds of VTE compared to not carrying a G allele (odds ratio (OR) and 95% confidence interval (CI) 1.2 [1.0-1.5]) in a crude model. This association was strongest when restricting to n=205 idiopathic (unprovoked) cases, n=125 recurrent cases, or n=112 cases exhibiting both deep vein thrombosis (DVT) and pulmonary embolism (PE) (Table 1). This association was modified by obesity status, with the effect among obese enrollees being multiplicative (Table 2). In contrast, there was no association between carrying at least one FGA rs6050 G (Ala) allele and VTE among 553 Black controls and 514 Black cases in the GATE study (OR and 95% CI 1.0 [0.8-1.2]) when assessing the association among all cases (Table 1). However, the odds of VTE was higher among Black participants carrying the G allele compared to those not carrying the allele when restricting to n=103 PE only cases (OR and 95% CI 1.5 [1.0-2.4]). The association between FGA Thr312Ala and VTE did not appear to be modified by obesity status among Black participants (Table 2).Conclusions: These results indicate that the FGA Thr312Ala (rs6050, NM_000508.3:c.991A>G, NP_000499.1:p.[Thr331Ala]) polymorphism is associated with VTE among White participants in the GATE study, with the strongest effect seen in participants exhibiting both DVT and PE. However, the association among Black participants appears limited to PE, indicating further exploration of genetic risk factors for VTE in Black populations is warranted in order to better understand genetic risk factors for all types of VTE in this population. [Display omitted] DisclosuresPayne:Bayer: Other: treatment product donation; Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees. Patel:Daiichi Sankyo: Other: DSMB member.

Differences in Protein S, Protein C, and Antithrombin Levels and Risk of Venous Thromboembolism Among American Black and White Enrollees in the Gate Study

Introduction: Black Americans have been reported to have a higher incidence of venous thromboembolism (VTE) compared to white Americans. The underlying cause of this disparity is not well characterized. Protein S, protein C, and antithrombin deficiency are known risk factors for VTE. There is inconsistent data regarding racial variation on the effect of protein S, protein C, and antithrombin levels and/or deficiency and risk of VTE. Most prior studies have not included a large black study population. The aim of this investigation is to compare levels of protein C, protein S, and antithrombin between VTE cases and controls by race among enrollees in the Genetic Attributes and Thrombosis Epidemiology (GATE) study, accounting for genetic differences such as hemoglobin genotype that may contribute to differences in protein levels by race.Methods: Testing for protein S, protein C, and antithrombin deficiency was performed on a subset of participants enrolled in the GATE study, a case-control study comprised of VTE cases and controls frequency-matched on age, sex, and race (self-identified). Controls had no history of VTE and did not receive anticoagulant therapy. Antigen and activity levels in cases were measured at least one month after completion of anticoagulation therapy. A priori cutoff levels for determining deficiency status were standardized per Centers for Disease Control Hemostasis Laboratory reference ranges. Beta hemoglobin genotype was determined by either a multiplex genotyping assay or sequencing of the beta hemoglobin gene. Differences in protein levels between cases and controls were compared using the Wilcoxon rank sum test. Conditional logistic regression analysis was performed to evaluate the association between protein S, protein C, or antithrombin deficiency and VTE. Crude models were conditioned on the matching factors, and adjusted models were conditioned on the matching factors and controlled for patient characteristics found to be associated with VTE and protein S, protein C, or antithrombin deficiency. Potential effect modification was assessed using likelihood ratio tests.Results: Among 2,454 subjects enrolled in the GATE study, 1,436 subjects (63.6%) had samples available for analysis. Protein S activity and total protein S antigen levels were significantly lower among VTE cases compared to controls in both white and black participants; however, antithrombin levels were higher among VTE cases compared to controls in white participants only. (Table 1) The prevalence of protein S and protein C deficiency was higher among VTE cases compared to controls in both white and black participants in the GATE study (Table 2). The prevalence of antithrombin deficiency was similar between VTE cases compared to controls. Adjusting for the effect of family history of VTE, history of cancer, and hemoglobin genotype, the effect of protein S and protein C deficiency on odds of VTE was stronger among black participants compared to white participants (Table 2).Conclusions: The effects of protein S and protein C deficiency on the odds of being a VTE case were higher among black participants in the GATE study, controlling for confounding variables including hemoglobin genotype. While these results indicate protein S and protein C deficiency may be important contributors to disparities in VTE occurrence, additional investigations using a larger study populations and different study designs are warranted. [Display omitted] DisclosuresPatel:Daiichi Sankyo: Other: DSMB member. Payne:Bioverativ: Other: treatment product donation; Novo Nordisk: Other: treatment product donation; Shire: Other: treatment product donation; Genentech: Membership on an entity's Board of Directors or advisory committees; Bayer: Other: treatment product donation.

Established Prevention of Vaso-Occlusive Crises with Crizanlizumab Is Further Improved in Patients Who Follow the Standard Treatment Regimen: Post-Hoc Analysis of the Phase II Sustain Study

Background: In the 52-week SUSTAIN study, which compared the P-selectin inhibitor crizanlizumab with placebo in patients with sickle cell disease (SCD), crizanlizumab 5.0 mg/kg significantly reduced the frequency of vaso-occlusive crises (VOCs) leading to healthcare utilization versus placebo (Ataga KI et al. N Engl J Med 2017;376:429-39). The overall incidences of adverse events and serious adverse events were similar among the patients treated with crizanlizumab and placebo.Aims: This post-hoc analysis from SUSTAIN evaluated key VOC-related endpoints in crizanlizumab 5.0 mg/kg and placebo groups in the per protocol (PP) population, as a way to assess the effect in patients who are able to follow the standard treatment regimen; data from the intention-to-treat (ITT) population will also be shown for context.Methods: The SUSTAIN study was a randomized, double-blind, placebo-controlled, Phase II study (NCT01895361) that enrolled patients aged 16-65 years with SCD who had experienced 2-10 VOC events in the previous 12 months. Patients were randomized 1:1:1 to receive crizanlizumab 5.0 mg/kg, 2.5 mg/kg or placebo 14 times intravenously over 52 weeks; here we focus on the 5.0 mg/kg dose of crizanlizumab versus placebo. The number and time of VOCs leading to healthcare utilization (e.g., hospital admission, emergency department visit) from randomization to end of treatment were measured for each individual patient. Analyses were conducted on the ITT population (i.e., all patients randomized) and PP population (i.e., all patients randomized who received at least 12/14 planned doses of treatment, and completed the study without major protocol violations that impacted the efficacy assessments).Results: In the crizanlizumab 5.0 mg/kg and placebo groups, there were 67 and 65 patients in the ITT population, and 40 and 41 patients in the PP population, respectively; the main reasons for exclusion from the PP population were associated with violations of the visit schedule. As shown previously (Ataga KI et al. N Engl J Med 2017;376:429-39), the median annual rate of VOCs was 1.63 in the crizanlizumab 5.0 mg/kg group versus 2.98 in the placebo group (stratified Wilcoxon Rank-Sum test, P=0.01; Table) in the ITT population. The median time to first on-treatment VOC was 4.07 versus 1.38 months (stratified log-rank test, P=0.001), respectively, in the crizanlizumab 5.0 mg/kg and placebo groups. Overall, 24/67 (35.8%) and 11/65 (16.9%) patients in the crizanlizumab 5.0 mg/kg and placebo groups (stratified Cochran-Mantel-Haenszel test, P=0.013), respectively, did not experience any VOCs during treatment. In the PP population, the median annual rate of VOCs was 1.04 with crizanlizumab 5.0 mg/kg versus 2.18 with placebo (P=0.02; Table). The median time to first on-treatment VOC was 6.55 months with crizanlizumab 5.0 mg/kg and 1.58 months in the placebo group (P<0.001). Overall, 15/40 (37.5%) and 5/41 (12.2%) patients in the crizanlizumab 5.0 mg/kg and placebo groups, respectively, did not experience any VOCs during treatment (P=0.008). The effect of treatment with crizanlizumab 5.0 mg/kg over placebo, as assessed by the three selected endpoints, is visible on the Figure, i.e., reduced frequency of VOCs, delayed first VOC, and increased number of patients with no VOCs during treatment.Conclusions: This post-hoc analysis of SUSTAIN shows that crizanlizumab 5.0 mg/kg provided benefit over placebo: nearly halving the median annual rate of VOCs, doubling the time to first VOC, and doubling the number of patients with no VOCs during treatment in the ITT population. The effect was even more pronounced in the PP population. This suggests that the superior VOC-related treatment outcomes of crizanlizumab 5.0 mg/kg versus placebo are further improved in patients who are able to follow the standard crizanlizumab treatment regimen. [Display omitted] DisclosuresKanter:NHLBI: Membership on an entity's Board of Directors or advisory committees, Research Funding; Apopharma: Research Funding; Pfizer: Research Funding; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Research Funding; ASH: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Sancilio: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kutlar:Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding; Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member. Bruederle:Novartis: Employment. Shi:Novartis: Employment, Other: Stock owner of Novartis. Campigotto:Novartis: Employment. Ataga:Pfizer: Research Funding; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria; Modus Therapeutics: Honoraria; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

A Multicenter Retrospective Noninterventional Follow-up Study in Patients with Sickle Cell Pain Crisis Who Previously Participated in the Sustain Trial in the United States Successor Study

INTRODUCTIONSUSTAIN was a randomized, double-blind, placebo-controlled, phase 2, 52-week study that compared the effect of crizanlizumab, a P-selectin inhibitor, versus placebo on the frequency of sickle cell pain crises (SCPCs, or vaso-occlusive crises [VOCs] leading to a health care visit) in patients with any genotype of sickle cell disease (SCD). Crizanlizumab 5.0 mg/kg significantly reduced the annual frequency of VOCs versus placebo (1.6 vs 3.0, P=0.01) and increased the time to first on-treatment VOC (4.1 vs 1.4 months, P=0.001). The current study, SUCCESSOR (SUSTAIN Chart-review of Crizanlizumab to Evaluate Sickle-cell Study One-year Retrospective), reviewed medical records of patients who completed the SUSTAIN study at US sites to assess additional cases of significant pain crisis events, and to generate real-world data on treatment patterns and health care resource utilization upon completion of treatment with crizanlizumab.METHODSSUCCESSOR is a retrospective cohort study of adult patients (≥18 years old) who participated in the SUSTAIN study in the United States to evaluate outcomes related to SCD up to 52 weeks following their completion of the trial. SUCCESSOR included the per protocol population from SUSTAIN, which included the intent-to-treat patients who received at least 12 of the 14 planned study drug doses, completed a visit at least 14 days after the final dose of study drug, and had no major protocol violations that impacted the efficacy assessments. The overall study period for the retrospective study was from September 2015 to March 2017 and patient data were obtained from medical records. Crizanlizumab was not administered post-SUSTAIN. Patient consent was obtained prior to data collection if required by local and/or central research ethics review.RESULTSIn this preliminary analysis, a total of 6 patient data sets were extracted. These patients had been randomized to the following treatment arms in the SUSTAIN study: 1 placebo, 1 crizanlizumab 2.5 mg/kg, and 4 crizanlizumab 5.0 mg/kg. The patient who had received placebo during SUSTAIN was a 27-year-old male with HbS/β0-thalassemia SCD. The patient who had received crizanlizumab 2.5 mg/kg was a 42-year-old female with HbSC SCD. The patients who had received crizanlizumab 5.0 mg/kg were: a 28-year-old male with HbSS SCD; a 32-year-old female with HbSS SCD; a 56-year-old female with HbSC SCD; and a 65-year-old female with HbSS SCD. All patients were Black or African-American. In the 52 weeks following completion of the SUSTAIN study, patients who had received placebo or crizanlizumab 2.5 mg/kg reported 4 and 5 VOC events, respectively, while crizanlizumab 5.0 mg/kg patients reported 0-2 VOC events (Table). Four patients (3 crizanlizumab 5.0 mg/kg, 1 placebo) reported hydroxyurea (HU) usage during and after SUSTAIN. One patient who had received crizanlizumab 5.0 mg/kg and did not report HU usage during SUSTAIN reported HU usage post-SUSTAIN. All patients reported opioid usage after SUSTAIN. Transfusions were not allowed during SUSTAIN; 2 patients, 1 who had received crizanlizumab 5.0 mg/kg and 1 who had received placebo, reported transfusions post-SUSTAIN. Five of the 6 patients reported utilizing health care resources (eg, clinic visits, emergency department visits, or hospitalizations) post-SUSTAIN. One patient who received crizanlizumab 5.0 mg/kg did not report utilizing any health care resources post-SUSTAIN and did not report any VOC events in the 52 weeks after SUSTAIN.CONCLUSIONSWe report our initial results from a limited number of patients from SUCCESSOR and therefore summarized post-SUSTAIN outcomes without analysis. In 5 of the 6 patients, the annual frequency of VOC events remained the same or increased in the post-SUSTAIN period compared to that during the SUSTAIN study. Data collection is ongoing in additional eligible patients. DisclosuresShah:Novartis: Consultancy, Research Funding, Speakers Bureau. Boccia:Amgen: Honoraria, Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau. Hardesty:Biomarin: Research Funding; Bioverativ: Research Funding; Global Blood Therapeutics: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Prometic: Research Funding; Sangamo: Research Funding; Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Paulose:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Laine:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Purkayastha:Novartis Pharmaceuticals Corporation: Employment. Nandal:Novartis Pharmaceuticals Corporation: Employment. Kutlar:Sancilio: Other: DSMB Chair; Bluebird Bio: Other: DSMB Member; Novartis: Consultancy, Honoraria, Other: Personal fees, Research Funding.

LB16. Phase 3 Trial of Baloxavir Marboxil in High-Risk Influenza Patients (CAPSTONE-2 Study)

BackgroundBaloxavir marboxil (BXM), an oral selective cap-dependent endonuclease inhibitor, is effective and safe for treating acute influenza in otherwise healthy patients.MethodWe conducted an international, randomized, double-blind, placebo (PLC)- and oseltamivir (Os)-controlled treatment study in patients at higher risk (HR) of influenza complications. Inclusion criteria included age ≥12 years, fever + influenza symptoms of ≤48 hours duration, and presence of at least 1 HR factor adapted from CDC criteria. Patients were randomized (1:1:1) to a single oral dose of BXM (40/80 mg for BW </≥80 kg), PLC, or 75 mg Os BID for 5 days. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in those with RT-PCR confirmed influenza (ITTI population). Secondary endpoints included infectious virus detection in serial nasopharyngeal swabs, prescription of antibiotics, and influenza-related complications.ResultAmong 2,184 randomized patients, 1,163(53%) comprised the ITTI population (47.9% A/H3N2, 6.9% A/H1N1, 41.6% B). The most common risk factors were asthma or chronic lung disease (39.2%) and age ≥65 years (27.4%). TTIIS was significantly shorter in BXM than PLC (median 73.2 hours vs. 102.3 hours, P < 0.0001) and numerically shorter than Os (81.0 hours, P = 0.8347). TTIIS in BXM patients with A/H3N2 virus (median: 75.4 hours) was significantly shorter than in PLC (100.4 hours; P =0.0141) and was significantly shorter in patients with influenza B (74.6 hours) than in either PLC (100.6 hours; P = 0.0138) or Os (101.6 hours; P = 0.0251). Median time to cessation of viral shedding in BXM patients was 48 hours, significantly less than 96 hours in both PLC and Os patients. Systemic antibiotic use and influenza-related complications were significantly fewer in BXM (3.4% and 2.8%, resp.) than PLC (7.5% and 10.4%; P = 0.0112, and P < 0.0001). The incidence of any (25.1–29.7%) or serious adverse events (0.7–1.2%) did not differ significantly across the groups.ConclusionBXM was well-tolerated and associated with faster recovery and reduced risk of complications in HR influenza patients compared with PLC. It proved superior to Os in shortening the duration of virus replication and in resolving influenza B illness. Oral BXM is a promising treatment option for patients with risk factors for influenza complications.Disclosures M. G. Ison, Romark: Investigator, Research support. Shionogi: Scientific Advisor, Paid DSMB Member. Emergent BioScience: Investigator, Research support. Janssen: Investigator and Scientific Advisor, Consulting fee and Research support. GlaxoSmithKlein: Scientific Advisor, Paid DSMB Member. VirBio: Consultant, Consulting fee. Seqirus: Consultant, Consulting fee. S. Portsmouth, Shionogi Inc.: Employee, Salary. Y. Yoshida, Shionogi & Co., Ltd.: Employee, Salary. T. Shishido, Shionogi & Co., Ltd.: Employee, Salary. F. Hayden, Shionogi & Co., Ltd.: Scientific Advisor, Consulting fee (donated) and travel support for attending 6th ESWI meeting, 10–13 September 2017, Latvia, to present phase 3 OWH results. .T. Uehara, Shionogi & Co., Ltd.: Employee, Salary.

1367P - Quality of life (QoL) in elderly NSCLC patients (pts) treated with nab-paclitaxel/carboplatin (nab-P/C) in the ABOUND.70+ trial

Background: Treatment of elderly pts with advanced NSCLC remains challenging, and the impact of therapies on QoL can be an important factor in clinical decisions. nab-P/C demonstrated efficacy in a subset of pts ≥ 70 yrs with NSCLC in a phase 3 trial. ABOUND.70+ was designed to determine whether a 1-wk break can further improve tolerability of nab-P/C in these patients. QoL outcomes are reported here. Methods: Pts ≥ 70 yrs with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-P 100 mg/m2 on d 1, 8, and 15 + C AUC 6 on d 1 of a 21-day cycle (Arm A) or the same regimen with a 1-week break between cycles (Arm B). Primary endpoint: percentage of pts with grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression. Key secondary endpoints: PFS, ORR, OS for which statistical analyses do not control for type I error (P values unadjusted). QoL (exploratory endpoint) was assessed using Lung Cancer Symptom Scale (LCSS) and EuroQoL-5 Dimensions-5 Levels (EQ-5D-5L) at d 1 of each cycle. Results: At interim evaluation, primary endpoint was similar across arms, resulting in early closure of enrollment. In Arms A and B, 78% and 79% completed a baseline and ≥ 1 postbaseline QoL assessment. LCSS item of cough improved with each cycle; at the end of cycle 6, mean change from baseline in Arms A and B was 25.4 and 13.8 mm (visual analog scale). For cough, median time to deterioration (TTD) was 4.4 and 4.7 mos (P = 0.7003). For the composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis, the median TTD was 4.4 and 6.0 mos (P = 0.3347). Mean maximum improvement (at any point during treatment) in EQ-5D-5L visual analog scale was 10.1 and 12.8 points. Table lists key safety, efficacy and QoL data.Table1367PArm A n = 71Arm B n = 72SafetyPrimary endpoint, n (%)52/68 (76)54/70 (77)P value0.9258Grade ≥ 2 peripheral neuropathy25/68 (37)25/70 (36)Grade ≥ 3 myelosuppression48/68 (71)45/70 (64)Neutropenia39/68 (57)39/70 (56)Anemia14/68 (21)17/70 (24)Thrombocytopenia17/68 (25)12/70 (17)EfficacyConfirmed ORR, %2440P value0.0376PFS, median, months3.67.0P value0.0019HR (95% CI)0.48 (0.30 - 0.76)OS, median, months15.216.2P value0.1966HR (95% CI)0.72 (0.44 - 1.19)QoLMean maximum improvement from baseline, mmLCSS Total score5.811.7LCSS Pulmonary symptom9.214.9 Open table in a new tab Conclusions: These results support nab-P/C as a treatment option in elderly pts with NSCLC. Safety (primary endpoint) and OS were similar across the two arms, while there was a signal of improvement in ORR, PFS, and QoL with a 1-wk break. NCT02151149. Clinical trial identification: NCT02151149 Legal entity responsible for the study: Celgene Corporation Funding: Celgene Corporation Disclosure: C.J. Langer: Consultant/Advisor Role: Celgene. J. Goldman, E. Kim: Research funding: Celgene. K. Konduri: Consultant/Advisory Role: Celgene, Boehringer Ingelheim, DAVA – Pharmaceuticals. A. Sanford, K. Amiri: Employment and stock ownership: Celgene. J. Weiss: Astellas: CME & company sponsored trials (CST); AZ, Biodesix, Clovis, Oncoples: consulting; Celgene: IIT support, CST support, SC; EMD Serono: DSMB member; GSK: IIT support; Medimmune, Pfizer: CST support, IIT support; Merck: CS Tsupport, IIT support. All other authors have declared no conflicts of interest.

Combined Treatment with Lenalidomide (LEN) and Epoetin Alfa (EA) Is Superior to Lenalidomide Alone in Patients with Erythropoietin (Epo)-Refractory, Lower Risk (LR) Non-Deletion 5q [Del(5q)] Myelodysplastic Syndrome (MDS): Results of the E2905 Intergroup Study-an ECOG-ACRIN Cancer Research Group Study, Grant CA180820, and the National Cancer Institute of the National Institutes of Health

▪Background: Treatment with rhu-Epo ameliorates anemia in a subset of LR-MDS patients, however, effective salvage therapy is limited. LEN promotes erythroid lineage competence and expansion of primitive erythroid precursors in vitro. In the MDS-002 and MDS-005 trials, treatment with LEN improved erythropoiesis, yielding RBC transfusion-independence in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. We previously reported that LEN restores Epo-responsiveness in MDS progenitors by inducing formation of lipid rafts enriched for signaling competent JAK2/Epo-receptor complexes and excluding large isoforms of the JAK2/lyn kinase-phosphatase CD45 (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In a pilot study of Epo-refractory MDS patients, addition of EA yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome resistance and augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo.Methods: Patients with Low or Intermediate-1 (Int-1) risk IPSS MDS with hemoglobin <9.5 g/dL who were unresponsive to rhEpo treatment or were TD (>2 units/mo) with serum Epo >500mU/mL were eligible for study. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). Primary endpoint was IWG 2006 major erythroid response (MER) rate after 4 cycles. Arm A non-responders were offered cross-over to combined therapy. Secondary endpoints included analysis of response biomarkers.Results: Between April 2009 and May 2016, 248 patients were enrolled and 195 were randomized and will be included in the primary analysis. Interim analysis of 163 patients (Arm A, 81; B, 82) accrued before July 2015 showed that the study met predefined stopping criteria. Baseline characteristics were balanced between arms. Median age was 74 years (range, 47-89) receiving a median of 2 RBC units/mo (0-8). Overall, 64 (39%) patients had Low IPSS risk and 90 (55%) Int-1 risk. Among these, 150 received prior rhuEpo (92%) and 27, azanucleosides (17%). In an ITT analysis, MER rate was significantly higher with combination therapy, Arm B 25.6% (n=21) vs. Arm A 9.9% (n=8) (P=0.015). Among 116 patients evaluable at week 16, 33.3% (20/60) and 14.3% (8/56) achieved MER, respectively (P=0.018), with a median response duration of 25.4 months vs. not reached in Arm A responders. Response to combined treatment was associated with baseline CD45-isoform distribution in erythroid precursors. Patients achieving MER had a significantly lower CD45 RA+RB:RO ratio (median, 1.51) compared to non-responders (median, 4.21; P=0.04), favoring homo-dimerization of the short CD45-RO isoform and inhibition of phosphatase activity. MER rate in Arm B patients with a low isoform ratio (< median) was 72.7% vs. 18.2% in the high ratio group (P=0.03). Thirty-four Arm A non-responders crossed over to combination-therapy with only 1 MER. There was no difference in the frequency or distribution of >Grade 3, non-hematologic AEs.Conclusions: LEN restores sensitivity to rhEpo in Epo-refractory LR-non-del(5q) MDS patients to yield durable and significantly higher rates of erythroid response to combination treatment without added toxicity. Erythroid CD45 isoform profile may serve as a response biomarker for selection of candidates for combination therapy. DisclosuresBennett:Celgne: Membership on an entity's Board of Directors or advisory committees. Altman:Syros: Honoraria; Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Schiffer:Teva: Other: DSMB member; BMS: Research Funding; Ariad: Research Funding; Pfizer: Other: DSMB member.