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Abstract Background. A recent meta-analysis of 9 case-control and 5 cohort studies reported a positive association of transfusion history with risk of NHL (RR=1.20; 95% CI 1.07-1.35), which was only evident in cohort (RR=1.25) and not case-control (RR=1.05) studies (Castillo et al., Blood 2010;116:2897-2907). Risk was similar in men and women, and for transfusions before or after 1992. In subset analyses, elevated risk was only apparent for chronic lymphocytic leukemia (CLL) and not diffuse large B-Cell lymphoma (DLBCL) or follicular lymphoma, but power was low. To further investigate these findings, particularly from studies conducted after 1990, better assess confounding, and address heterogeneity by NHL subtypes, we conducted an individual-level, pooled analysis of 13 case-control studies in the InterLymph Consortium (including 11 studies conducted after 1990; 8 studies were not included in the published meta-analysis). Methods. There were a total of 10,805 cases and 14,026 controls with transfusion data from 13 studies conducted in Europe, North America, and Australia. Transfusion history and other risk factors were self-reported in interviewer-administered or self-administered questionnaires. All risk factor data were harmonized centrally, and cases were grouped into NHL subtypes according to the WHO classification using guidelines from the InterLymph Pathology Working Group. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using logistic regression, adjusted for age, sex, and study center. Results. The median age at diagnosis was 60 years for cases (range, 18-97) and 59 years for controls (range, 16-97). The overall prevalence of a history of any transfusion in controls was 15.5%, was higher in women (18.6%) than men (13.0%), and increased with age, but was not associated with race/ethnicity (Asian, Black, Hispanic, White, other) or geographic region after adjusting for age and sex. Among whites, history of any transfusion was inversely associated with NHL risk among men (OR=0.74; 95% CI 0.65-0.83) but not women (OR=0.92; 95% CI 0.83-1.03); there were no significant results for other race/ethnicity groups, and ORs were highly variable and imprecise due to small sample sizes. Thus analyses were restricted to white men, where there was no trend with the number of transfusions, time since first transfusion, age at first transfusion, or decade of first transfusion. Further adjustment for socioeconomic status, body mass index, smoking, alcohol use or hepatitis C virus (HCV) seropositivity did not alter these results. The associations were stronger in hospital-based (OR=0.56; 95% CI 0.45-0.70) than population-based (OR=0.84; 95% CI 0.72-0.98) studies, and were stronger in studies from Southern Europe (OR=0.53; 95% CI 0.36-0.79) than northern Europe (OR=0.67; 95% CI 0.53-0.83) or North America (OR=0.82; 95% CI 0.70-0.98). For NHL subtypes, statistically significant inverse associations were observed for follicular lymphoma (OR=0.70; 95% CI 0.56-0.88), DLBCL (OR=0.72; 95% CI 0.59-0.87), and CLL/SLL (OR=0.67; 95% CI 0.52-0.87), whereas weaker and non-statistically significant associations were observed for mantle cell (OR=0.81; 95% CI 0.54-1.23), marginal zone (OR=0.78; 95% CI 0.54-1.15), lymphoplasmacytic (OR=0.82; 95% CI 0.47-1.42) and peripheral T-cell (OR=0.83; 95% CI 0.49-1.40) lymphomas. Conclusion. Contrary to earlier results, transfusion history was inversely associated with risk of NHL and the common subtypes of follicular lymphoma, DLBCL and CLL/SLL among white men, whereas associations were null among white women and other racial/ethnic groups. These results were not explained by confounding by lifestyle factors or HCV seropositivity, era of first transfusion, hospital versus population-based study design, or geographic location. Despite dramatic changes in transfusion practice over the past 40 years, results were similar for decade of first transfusion, suggesting secular trends are a less likely explanation. Our results are unexpected and bias cannot be ruled out. Further studies, particularly cohort studies, are needed to clarify the role of transfusion history in NHL risk. Disclosures No relevant conflicts of interest to declare.

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

Abstract Introduction Fedratinib (SAR302503), a JAK2-selective inhibitor, has demonstrated clinical improvements in splenomegaly and constitutional symptoms in patients with MF in Phase I/II trials (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). The aim of this primary analysis was to determine the effect of fedratinib on key MF symptom burden and global assessment of HRQoL in the JAKARTA trial (NCT01437787). Methods JAKARTA is a double-blind, placebo-controlled, international, 3-arm, Phase III study, in which patients ≥18 years of age with intermediate- or high-risk MF, platelet count ≥50 × 109/L, and splenomegaly were randomized (1:1:1) to receive placebo or fedratinib at a dose of 400 or 500 mg, orally, once daily, in consecutive 4-week cycles. Total symptom score (TSS), a key efficacy end point (TSS: averaged daily total score of 6 item measures over 1 week: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain), was assessed through a daily electronic eDiary using the modified Myelofibrosis Symptom Assessment Form (MFSAF; Cancer 2011;117:4869. Blood 2011;118:401), with symptom response defined as a ≥50% reduction in TSS at the end of Cycle 6 (EOC6). HRQoL was assessed using the EuroQOL (EQ)-5D instrument that was completed at baseline and EOC6. Patient performance was assessed using the Eastern Cooperative Oncology Group Performance Scale (ECOG PS). Spleen volume was measured by MRI or CT at baseline and EOC6. Results In JAKARTA, a total of 289 patients were randomized: median age 65 years; 59% male; 63% primary MF; 48% high-risk MF; 67% JAK2V617F positive; 16% platelet count <100 × 109/L. The symptom evaluable population comprised 261 patients (placebo [n=82]; 400 mg [n=89]; 500 mg [n=90]). The mean (SD) baseline TSS was 14.6 (11.9), 17.6, (13.5), and 16.9 (11.9) in the placebo, 400 mg, and 500 mg groups, respectively. At Week 24 (EOC6), the proportion of patients with a symptom response was significantly higher (p<0.0001) in the 400 and 500 mg groups versus placebo (Table). Symptom responses with fedratinib were also higher than placebo in the subgroup of patients with baseline platelets <100 × 109/L (Table). For individual symptoms, the greatest improvements were seen for night sweats and early satiety (Table). Baseline HRQoL (EQ-5D, mean [SD]) was similar in the three groups (placebo: 62.5 [21.2]; 400 mg: 61.3 [22.2]; 500 mg: 60.1 [20.1]). Fedratinib treatment led to improvements in HRQoL from baseline to Week 24, whereas placebo treatment led to slight worsening of HRQoL (Table). At Week 24, the degree of improvement in TSS was greatest in patients with ≥35% reduction in spleen volume from baseline (Figure). Mean TSS improvement was correlated with improvement in HRQoL (TSS reductions were greater in EQ-5D improvers versus non-improvers), and ECOG PS (TSS reductions were greater in patients with ECOG PS 1 or 2 score improvement versus those with ECOG PS worsening). Conclusions Fedratinib treatment over 24 weeks led to significant improvements in MF symptoms versus placebo. Patients treated with fedratinib also experienced substantial improvements in HRQoL versus placebo. Symptom improvements were associated with spleen responses. This study was sponsored by Sanofi. Disclosures: Mesa: Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Jourdan:Sanofi: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Drummond:TargeGen, Novartis: Speakers Bureau; Sanofi, Novartis, Celgene: Honoraria; Sanofi, Novartis, Celgene: Consultancy. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Neumann:Sanofi: Employment. Joulain:Sanofi: Employment. Iqbal:Sanofi: Employment. Harrison:Novartis: Research Funding; Novartis, Sanofi, YM Bioscience, Celgene, SBio, Gilead: Honoraria; Novartis, Sanofi, Shire: Speakers Bureau; Novartis, Sanofi, YM Bioscience, SBio, Gilead: Membership on an entity’s Board of Directors or advisory committees.

Abstract Background: Philadelphia chromosome negative myeloproliferative neoplasms (MPN) include myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). Pertinent to these disorders is the high persistence, prevalence, and severity of fatigue. Overall, excessive fatigue compared to age and gender matched controls occurs in greater than 95% of MPN patients (Blood. 2011;118(2):401-8). Physiologic etiologies of fatigue in these patients include cytokine dysregulation and impaired hematopoiesis, however to date no one has investigated the impact that cofounding medical illnesses have on MPN fatigue burden. Methods: A 70-item internet-based survey was developed by a team of MPN investigators, patient advocates from MPN Forum, and hosted by the Mayo Clinic Survey Research Center. The survey was promoted online via multiple MPN-related webpages including the MPN Forum, MPN Net, MPN Research Foundation, and MPN Voice during late February to March of 2014. Surveyed data included disease demographics such as splenomegaly, thrombosis, hemorrhage transfusions, medications, and phlebotomies. The MPN-SAF (including the MPN 10) was utilized including the 10-item brief fatigue inventory was used to assess disease burden (Blood. 2011 Jul 14;118(2):401-8). Comorbid conditions were assessed, including hypothyroidism, anemias, sleep disturbances, obesity, and heart and lung disorders. Data: Demographics. Overall 1788 MPN patients participated in the survey. Of these, 1676 consented to participate and provided additional data (i.e., completed at least 10 questions). Of these, 555 (33%) patients had ET, 651 (39.0%) had PV, and 417 (25.0%) had MF. Among MF patients, 44.1% had primary MF, 29.7% had post-PV MF, and 26.2% had post-ET MF. Respondents were 68% female with a mean age of 59. Overall brief fatigue inventory score had a mean of 4.4 (range 0-10). MPN-10 score average was 28.4 (range 0-83). Medical Comorbidities. Overall, many patients endorsed having comorbid medical diseases that could contribute to overall fatigue (Table1). Overall 20.2% of patients endorsed having low thyroid function, with 10% indicating they obtained this diagnosis in the last six months. Twenty three percent endorsed having a new sleep disturbance in the last six months. On average, patients tended to have an average to above average BMI (mean =26.3, median = 25.0). However, many patients also experienced a high rate of unintended weight loss (11.8% with >11lb weight loss in the last 6 months). Cytopenias were also frequently encountered, with 14.7% of participants having required previous transfusions. Among these, 46% required transfusions in the last 6 months. Thrombosis (18.3%), hemorrhage (14.7%), and anemia (48.0%) were relatively common. In the last six months, 11.1% of patients required iron supplementation and 2.2% required erythropoietin injections. Many patients also endorsed the use of medications that could contribute to overall fatigue. Correlations. Items significantly correlated with worsened fatigue score (BFI greater than or equal to four) included female gender (<0.001), age (p=0.0047), lower education level (<0.001) and lower BMI (<0.001). Current use of alcohol and tobacco was also significantly associated with greater burden of fatigue (<0.001 and 0.0025, respectively). Items not significantly associated with fatigue included DIPSS (MF only), IPSET (ET only) or PV risk scoring. Conclusions Overall patients with MPN experience an exclusive pattern of disabling fatigue. Many fatigue-related medications and medical comorbidities may contribute to the debilitating fatigue seen among MPN patients, although no specific comorbidities could account for the high prevalence of fatigue. Rates of comorbid disease burden varied widely compared to the general population. For some diseases including diabetes, rates among MPN populations were less than the general population (National Diabetes Statistics Report, 2014), however the rates of other comorbidities, such as hypothyroidism, were higher (J Clin Endocrinol Metab 2002;87:489–99). Similar to our previous studies, females tended to suffer from a higher mean fatigue burden than males (Geyer ASH 2014). Clinical and research-related determination of fatigue should take into account cofounding comorbid medical conditions that can contribute to overall fatigue burden. Disclosures Harrison: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau; CTI: Consultancy; YM Bioscience: Consultancy; Gilead: Consultancy; SBio: Consultancy. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

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

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Background. The syndrome of drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, yet potentially fatal hypersensitivity reaction, most commonly associated with anticonvulsants, sulfonamides, and allopurinol. The reaction commonly manifests as a febrile skin eruption with lymphadenopathy and malaise between two and eight weeks following drug exposure. Internal organ involvement occurs in close to 90 percent of patients, and multiple organs may be involved in approximately half of those affected (most commonly the liver, kidney, and lung). Its long latency period and its variable clinical pattern of presentation have earned it the moniker of “the great mimicker,” with delays in diagnosis leading to higher morbidity and mortality. Although less commonly affected in DRESS syndrome, lung involvement is associated with more severe clinical course and potentially worse outcome. Pulmonary symptoms may precede development of the other more common symptoms and signs of the syndrome, or they might develop later in the course of the disease. Lung involvement in DRESS presents with a plethora of manifestations from mild cough or dyspnea with nonspecific interstitial changes on chest imaging to acute respiratory distress syndrome (ARDS) with life-threatening hypoxic respiratory failure. Methods. We performed a systematic review of literature from the PubMed database and selected cases of definite DRESS syndrome as defined by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) with a score of 6 or more who also had pulmonary involvement. Demographic data, pattern of lung involvement, culprit medication, latency period, laboratory findings, therapy, and outcome were described and compared with the literature. Results. The most common pulmonary radiographic findings in DRESS were interstitial infiltrates in 50% of cases, followed by acute respiratory distress syndrome (ARDS) 31%. Symptoms of cough and shortness of breath (SOB) were present in 72% of patients at the time of presentation. SOB was the more common presenting symptom (81%) compared to cough (19%). In 95% of cases, another visceral organ was involved (most commonly liver or kidneys). 45% of cases were initially misdiagnosed as pneumonia and were treated with empiric antimicrobials. In a multivariate regression, a latency of 30 days or less and an age of 60 or less were associated with development of ARDS. Gender and eosinophil count were not associated with severity of pulmonary manifestations. All patients recovered, and in the vast majority of cases (95%), parenteral steroids were used for treatment in addition to supportive care and symptomatic management. Conclusion. Albeit rare, DRESS is a potentially life-threatening syndrome which may present with a myriad of pulmonary signs and symptoms. Pulmonary manifestations are less common but are typically seen in more severe cases. Pulmonary manifestations may be a presenting sign of DRESS, and timely recognition is important in order to stop offending medication and decrease morbidity and mortality.

AbstractEpidemiologic studies show an increased risk of non‐Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen‐stimulation in one disease leads to another. Here we assess shared genetic risk in genome‐wide‐association‐studies (GWAS).Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B‐cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta‐analysis.Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta‐analysis (combing AD with NHL) implicated genes of apoptosis and telomere length.This GWAS‐based analysis four NHL subtypes and three ADs revealed few weakly‐associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Background:PRM‐151, a recombinant human pentraxin‐2 molecule, prevents and reverses fibrosis in animal models of myelofibrosis (MF) in part by targeting differentiation of fibrocytes from monocytes. In the first stage of a two‐stage trial, treatment of patients (pts) with primary (PMF), post‐essential thrombocythemia/polycythemia vera (post‐ET/PV) MF with PRM‐151 ± ruxolitinib (Rux) was associated with decreases in bone marrow fibrosis (BMF), improvements in hemoglobin (Hgb) and platelets (PLT), reductions in transfusions and symptoms, and modest reductions in splenomegaly.Aims:Here, we report efficacy and safety data from a stage 2 randomized, double‐blind evaluation of single agent PRM‐151.Methods:Pts with DIPPS Int‐1, Int‐2, and high risk PMF or post‐ET/PV MF who were ineligible for, intolerant of, or had an inadequate response to Rux were randomized between 0.3, 3, and 10 mg/kg of PRM‐151 as a sole agent. PRM‐151 was to be administered by IV infusion at one of the three assigned doses on Days 1, 3, and 5 of Cycle 1 and on Day 1 of each subsequent 28‐day cycle for at least 9 cycles. Randomization was stratified according to baseline (BL) Hgb <100 g/L receiving transfusions and/or PLT <50 x 109/L. Bone marrow biopsies and imaging for spleen volume were obtained at BL, C4D1, C7D1, and C9D29. BMF score was evaluated centrally by three independent, blinded hematopathologists. The primary objective of the study was to determine the effect size of three different doses of PRM‐151 on reduction in BMF by ≥ 1 grade at any time during the study.Results:Of the 98 randomized patients, 97 were treated with 0.3 mg/kg (n = 33), 3 mg/kg (n = 32), or 10 mg/kg (n = 32). BL characteristics are provided in Table 1. Forty‐six pts discontinued treatment prior to Cycle 9. Decrease in BMF grade at any time was observed in 10 of 33 pts (30%) at 0.3 mg/kg, 9 of 31 pts (28%) at 3 mg/kg, and 8 of 32 pts (25%) at 10 mg/kg. Decrease in BM collagen grade was observed in 31–37% of pts. In pts who were RBC transfusion dependent or with Hgb <100 g/L and transfusion independent at BL, 16–29% of pts had ≥50% reduction in RBC transfusions or Hgb increases ≥10 g/L for ≥12 consecutive weeks. In pts who were PLT transfusion dependent or with PLT<25 or PLT25‐<50 x 109/L and transfusion independent at BL, 31–40% of pts had ≥50% reduction in PLT transfusions, PLT ≥25 x 109/L or PLT ≥50 x 109/L or doubling of PLT count, without transfusions for ≥12 consecutive weeks. Improvement from BL in MPN‐SAF TSS of ≥25% for ≥12 consecutive weeks was observed in 10–26% of pts. Reduction in spleen volume was observed with a maximum reduction of 34% in one pt. Response rates for BM collagen, Hgb, PLT, MPN‐SAF, and spleen were generally similar across the three dose levels. The most common treatment emergent adverse events (AEs) were fatigue, cough, thrombocytopenia, and abnormal weight loss. A majority of the AEs were Grade 2 or lower in severity and consistent with disease progression. Grade 3 and 4 related AEs were reported in 12% and 6% of pts, respectively.Summary/Conclusion:The study enrolled a large proportion of MF pts with advanced disease (Int‐2 or high risk, BMF grade 3, anemic/transfusion dependent, and PLT <50 x 109/L). Decrease in BMF and collagen grade were observed across all dose levels. Increases in Hgb and PLT count or reduction in transfusion requirements were also reported across all dose levels. Improvements in MPN‐SAF TSS and spleen volume were observed in a proportion of pts. PRM‐151 treatment for up to 9 cycles was well tolerated. These data warrant confirmation in a larger controlled study.image