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Background Standard therapy for COVID-19 is continuously evolving. Autopsy studies showed high prevalence of platelet-fibrin-rich microthrombi in several organs. The aim of the study was therefore to evaluate the safety and efficacy of antiplatelet therapy (APT) in hospitalised patients with COVID-19 and its impact on survival. Methods 7824 consecutive patients with COVID-19 were enrolled in a multicentre international prospective registry (Health Outcome Predictive Evaluation-COVID-19 Registry). Clinical data and in-hospital complications were recorded. Data on APT, including aspirin and other antiplatelet drugs, were obtained for each patient. Results During hospitalisation, 730 (9%) patients received single APT (93%, n=680) or dual APT (7%, n=50). Patients treated with APT were older (74±12 years vs 63±17 years, p<0.01), more frequently male (68% vs 57%, p<0.01) and had higher prevalence of diabetes (39% vs 16%, p<0.01). Patients treated with APT showed no differences in terms of in-hospital mortality (18% vs 19%, p=0.64), need for invasive ventilation (8.7% vs 8.5%, p=0.88), embolic events (2.9% vs 2.5% p=0.34) and bleeding (2.1% vs 2.4%, p=0.43), but had shorter duration of mechanical ventilation (8±5 days vs 11±7 days, p=0.01); however, when comparing patients with APT versus no APT and no anticoagulation therapy, APT was associated with lower mortality rates (log-rank p<0.01, relative risk 0.79, 95% CI 0.70 to 0.94). On multivariable analysis, in-hospital APT was associated with lower mortality risk (relative risk 0.39, 95% CI 0.32 to 0.48, p<0.01). Conclusions APT during hospitalisation for COVID-19 could be associated with lower mortality risk and shorter duration of mechanical ventilation, without increased risk of bleeding. Trial registration number NCT04334291.

PURPOSE Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). RESULTS Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. CONCLUSION In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

7500 Background: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve tolerability. We conducted an open-label, randomized, noninferiority, phase 3 trial to compare Aca vs Ib in patients (pts) with chronic lymphocytic leukemia (CLL). Methods: Previously treated CLL pts with del(17p) or del(11q) by central lab were randomized to receive oral Aca 100 mg BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2 vs ≤1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) as assessed by IRC; secondary endpoints of all grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 pts (Aca, n=268; Ib, n=265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 mo (range 0.0–59.1), Aca was noninferior to Ib with a median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79–1.27). Aca was statistically superior to Ib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection (Aca: 30.8%, Ib: 30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR 0.82 [95% CI 0.59–1.15]), with 63 (23.5%) deaths in the Aca arm and 73 (27.5%) in the Ib arm. Among any-grade AEs in ≥20% of pts in either arm, Aca was associated with a lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of Aca- vs 21.3% of Ib-treated pts. Among any-grade events of clinical interest, cardiac, hypertension, and bleeding events were less frequent with Aca (Table). Conclusions: In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib. Clinical trial information: NCT02477696. [Table: see text]

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Abstract Background: It is not known whether modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. Methods: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer–specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. Results: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (Padj &gt; 0.30). The strongest associations were between all-cause mortality and BMI ≥30 versus 18.5–25 kg/m2 [HR (95% confidence interval (CI), 1.19 (1.06–1.34)]; current versus never smoking [1.37 (1.27–1.47)], high versus low physical activity [0.43 (0.21–0.86)], age ≥30 years versus &lt;20 years at first pregnancy [0.79 (0.72–0.86)]; &gt;0–&lt;5 years versus ≥10 years since last full-term birth [1.31 (1.11–1.55)]; ever versus never use of oral contraceptives [0.91 (0.87–0.96)]; ever versus never use of menopausal hormone therapy, including current estrogen–progestin therapy [0.61 (0.54–0.69)]. Similar associations with breast cancer mortality were weaker; for example, 1.11 (1.02–1.21) for current versus never smoking. Conclusions: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. Impact: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

AbstractPrevious transcriptome‐wide association studies (TWAS) have identified breast cancer risk genes by integrating data from expression quantitative loci and genome‐wide association studies (GWAS), but analyses of breast cancer subtype‐specific associations have been limited. In this study, we conducted a TWAS using gene expression data from GTEx and summary statistics from the hitherto largest GWAS meta‐analysis conducted for breast cancer overall, and by estrogen receptor subtypes (ER+ and ER−). We further compared associations with ER+ and ER− subtypes, using a case‐only TWAS approach. We also conducted multigene conditional analyses in regions with multiple TWAS associations. Two genes, STXBP4 and HIST2H2BA, were specifically associated with ER+ but not with ER– breast cancer. We further identified 30 TWAS‐significant genes associated with overall breast cancer risk, including four that were not identified in previous studies. Conditional analyses identified single independent breast‐cancer gene in three of six regions harboring multiple TWAS‐significant genes. Our study provides new information on breast cancer genetics and biology, particularly about genomic differences between ER+ and ER− breast cancer.

Abstract Introduction Transthyretin amyloidosis (ATTR amyloidosis) is a rare, life-threatening disorder caused by the deposition of amyloid fibrils composed of misfolded transthyretin (TTR). ATTR amyloidosis may arise from mutations in TTR or from aggregation of wild-type TTR (ATTRwt). ATTR amyloidosis with predominantly symptoms of cardiomyopathy (ATTR-CM) includes both hereditary and wild-type forms of the disease. Purpose To describe clinical history and disease presentation in a large population of patients with wild-type ATTR-CM from the Transthyretin Amyloidosis Outcomes Survey (THAOS). THAOS is an ongoing, global, longitudinal, observational survey of patients with ATTR amyloidosis, including both inherited and wild-type disease, and asymptomatic patients with TTR mutations. Methods Data from ATTRwt patients were extracted from THAOS (cut-off date: January 16, 2019) and demographic and clinical characteristics reported using descriptive statistics. Results There were 758 ATTRwt patients in THAOS (95% male). The majority of patients (69.3%) were in the United States, with the remainder in Italy (11.1%), Germany (7.3%), Spain (5.3%), and other countries (7.1%). Most patients (86.3%) were Caucasian, with 3.3% being of African Descent and 3.1% being of other races/ethnicities (7.4% missing data). The median (10–90th percentile) age at symptom onset was 69.7 (54.0–81.3) years and the median (10–90th percentile) time from symptom onset to diagnosis was 3.9 (0.1–17.8) years. Median (10–90th percentile) age at enrollment in THAOS was 76.4 (67.2–85.2) years. Nearly all subjects had either a cardiac (59.6%) or mixed cardiac and neurologic (36.5%) phenotype. At enrollment, 97.1% (577 of 594 patients assessed) had an abnormal ECG, with the prevalence of low voltage being 20.8% (115 of 552) and prevalence of left-ventricular hypertrophy being 2.1% (16 of 758). Atrial fibrillation was documented in 55% of patients (208 of 378). The mean (standard deviation [SD]) left-ventricular septum thickness was 17.5 (3.5) mm (n=505; 94.9% with thickness >12 mm) and mean (SD) left-ventricular ejection fraction (LVEF) was 48.3% (13.2) (n=511; 48.0% with LVEF <50.0%). Other signs and symptoms at enrollment were compatible with a sensory neuropathy in 54.2% of patients, autonomic neuropathy in 33.5% of patients, and motor neuropathy in 29.1% of patients. Gastrointestinal symptoms related to ATTR amyloidosis were present in 10.4% of patients. Conclusions Although patients with wild-type ATTR-CM tend to be older Caucasian men with a mostly cardiac disease phenotype, the clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype. Our findings show that ATTRwt should not be considered an exclusively cardiac disease and there is a need for both cardiologic and neurologic assessment of these patients. Further study is needed to determine if the non-cardiac manifestations are due to amyloidosis or more common causes in this older population. Acknowledgement/Funding This study was sponsored by Pfizer.

Abstract Background The JAK1/JAK2 inhibitor ruxolitinib (RUX) is approved for treatment of myelofibrosis (MF). However, some patients do not respond to RUX, while others lose responsiveness or develop intolerance to RUX over time. Preclinical data also suggest that certain JAK2 mutations (eg the gatekeeper mutation M929I) may confer resistance to RUX (Leukemia 2012;26:708). Options for these RUX resistant/intolerant patients, particularly with regard to further JAK inhibitor therapy, are unclear. Fedratinib (SAR302503) is a JAK2-selective inhibitor which has demonstrated clinically meaningful reductions in splenomegaly and symptom burden in patients with MF, with an acceptable and consistent safety profile (J Clin Oncol 2011;29:789. Haematologica 2013;98:S1113). Fedratinib sensitivity in vitro is unaffected by the M929I mutation. This pre-specified interim analysis of the JAKARTA-2 study (NCT01523171) investigated the efficacy and safety of fedratinib in MF patients previously treated with RUX. Methods JAKARTA-2 is a Phase II, multicenter, open-label, single-arm study of patients who previously received RUX for MF. Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles (permitted dose adjustment to 200–600 mg daily). Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib. Although there is no consensus definition of RUX resistance/intolerance, for the purpose of this study patients were classed (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX. Primary endpoint for the interim analysis: spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]) in the per-protocol (PP) population. Secondary endpoints: symptom RR (≥50% reduction in total symptom score [TSS: modified Myelofibrosis Symptom Assessment Form] from baseline to Wk 12) and safety. Results At the cut-off date for this interim analysis, 27 patients had received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4]): median age 69 yrs; 56% male; 67% primary MF; 63% high-risk MF; 67% JAK2V617F positive; 41% platelet count <100 × 109/L; baseline median spleen volume 3190 mL [1072–7815]; baseline median TSS 19.6 [4.9–46.0]. Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response; median RUX exposure 11.1 months [range 1.9–34.4]) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity; median RUX exposure 9.2 months [2.9–33.2]) to RUX. Median fedratinib exposure to cut-off date: 4 cycles (range 1–10); 19 patients remain on treatment. Spleen RRs were 40% (8/20 PP patients) and 43% (3/7) in patients with baseline platelet count <100 ×109/L. Overall, 19% (5/26 evaluable patients) had a symptom response by Wk 12 (Table). The majority of patients had a reduction in TSS at Wk 12 (Figure). The most common non-hematologic treatment-emergent adverse events (AEs) were gastrointestinal (nausea 67%; diarrhea 56%; vomiting 48%). Grade 3/4 diarrhea occurred in 2 patients; no Grade 3/4 vomiting or nausea. Anemia was the most common hematologic AE (all grades, 93%; Grade 3, 41%; Grade 4, 0%). Thrombocytopenia (all grades) occurred in 19 (70%) patients; Grade 3 in 6 patients and Grade 4 in 2 patients. One patient had Grade 3 AST elevations and 1 patient had Grade 3 hyperbilirubinemia. Seven patients (26%) discontinued treatment due to AEs. There were 2 deaths on study, both due to disease progression. Conclusions Interim results from the JAKARTA-2 study indicate that once-daily fedratinib provides clinical benefit, through reduced splenomegaly and symptom burden, in MF patients previously treated with RUX. The safety profile was acceptable and manageable, with safety results to date consistent with those reported in previous trials of fedratinib. Sponsored by Sanofi. Disclosures: 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. Jourdan:Sanofi: Honoraria. Kiladjian:Novartis, Celgene, AOP Orphan: Research Funding; Novartis, Sanofi, AOP Orphan: Honoraria; Novartis, Sanofi, AOP Orphan: Membership on an entity’s Board of Directors or advisory committees. Cervantes:Novartis: Speakers Bureau; Novartis and Sanofi: Membership on an entity’s Board of Directors or advisory committees. Niederwieser:Novartis Pharma: Consultancy. Cortes:Incyte, Sanofi: Consultancy; Incyte, Sanofi: Research Funding. Passamonti:Novartis, Celgene, Incyte, Sanofi, Roche: Honoraria. Reiter:Sanofi: Honoraria. Heidel:Novartis Inc.: Honoraria; Novartis Inc.: Research Funding; Novartis Inc.: Membership on an entity’s Board of Directors or advisory committees. Silver:Sanofi: Consultancy; Sanofi: Research Funding; Sanofi: Honoraria. Winton:Sanofi: Research Funding. Gupta:Incyte, Novartis: Consultancy; Incyte, Novartis: Research Funding; Novartis: Honoraria. Gisslinger:AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Membership on an entity’s Board of Directors or advisory committees; AOP Orphan Pharmaceuticals, Novartis, Sanofi, Shire, Celgene, Janssen: Honoraria. Vannucchi:Novartis: Membership on an entity’s Board of Directors or advisory committees. Talpaz:Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Research Funding; Novartis, Bristol-Myers Squibb, Ariad, Deciphera: Speakers Bureau. Zhang:Sanofi: Employment. Shi:Sanofi: Employment. Mesa:Incyte, Genentech, Lilly, MS Pharma, Gilead: Research Funding.