scholarly journals The G505A Nonsynonymous Single-Nucleotide Polymorphism (SNP) in TAFI, the Gene Encoding Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) Is Pleiotropically Associated with TAFI Antigen Levels and Coronary Heart Disease (CHD) in Mexican Americans of South Texas

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3217-3217
Author(s):  
Shuchita Jhaveri ◽  
Vincent P. Diego ◽  
Hoang Anh Thi Nguyen ◽  
Satish Kumar ◽  
Marcio A. Almeida ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Mexican Americans ◽  
Research Funding ◽  
Mixed Model ◽  
South Texas ◽  
Elisa Assay ◽  
Systematic Bias ◽  
Advisory Committees ◽  
P Values ◽  
Increased Risk

Abstract Studies have reported that the G505A nonsynonymous (ns)-SNP encoding the Ala147Thr amino acid substitution in TAFI, is associated with a reduction in risk of venous thrombosis and myocardial infarction. Interestingly, homozygosity for the A-allele (AA) of G505A is associated with increased TAFI antigen (TAFI:Ag) levels in plasma. In our study of the genetic determinants of cardiovascular disease (CVD) in Mexican Americans of South Texas, we performed an exome-wide scan in relation to plasma TAFI antigen levels in 784 individuals. While accounting for age, sex, and their interactions as confounders in linear mixed model, we found a heritability of 59% for TAFI:Ag levels (p=1.4E-19), and that ns-SNP G505A was the only variant showing exome-wide significance (p=3.5E-14; Figure A). Figure B shows the quantile-quantile distribution of the p-values from all the exome-wide tests. Clearly, the p-value distribution reveals that there is no systematic bias that may act to skew the p-values, and that the lone exception¾in agreement between observed and expected quantiles¾is due to this TAFI SNP, which strongly suggests a truly significant effect. Consistent with previous reports, the regression coefficient for G505A as a predictor of TAFI:Ag levels showed them to be increasing from the homozygous for the major G-allele (GG), to the heterozygous individuals (GA), to the individuals homozygous for the minor A-allele (AA) (Figure B). We also investigated if G505A is associated with our CHD variable. Using a statistical genetic model for the liability to disease conditional on a threshold, which is equivalent to a probit mixed model, we found that the G505A ns-SNP in TAFI, encoding TAFI Ala147Thr, is significantly associated with a reduction in the risk of CHD (p=0.002). As observed in existing literature, potential limitations of this study include the ELISA assay used for the quantification of TAFI levels. Some ELISA assays measure proTAFI, TAFIa, and TAFIi. However, recent evidence suggests that there may be cross reactivity between TAFIa and TAFIi. This can result in measuring ongoing TAFI activation peptides and elevated levels of TAFIa which ultimately goes on to make resistant fibrin. This is likely the marker that results in the increased risk of venous thromboembolism. To mitigate this confounding factor, an ELISA assay specific to measuring TAFI antigen is needed. In conclusion, we found that TAFI G505A is pleiotropically associated with TAFI:Ag levels and risk of CHD. Figure 1 Figure 1. Disclosures DeFronzo: AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; Intarcia: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding.

scholarly journals VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1835-1835 ◽  
Author(s):  
Katrina M Piedra ◽  
Hani Hassoun ◽  
Larry W. Buie ◽  
Sean M. Devlin ◽  
Jessica Flynn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Venous Thromboembolism ◽  
Board Of Directors ◽  
Research Funding ◽  
High Dose ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cancer Trial ◽  
Oncology Research ◽  
Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

scholarly journals Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-3
Author(s):  
Rita V Masese ◽  
Dominique Bulgin ◽  
Liliana Preiss ◽  
Mitchell Knisely ◽  
Eleanor Stevenson ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Transfusion Requirement ◽  
The United States ◽  
Acute Chest Syndrome ◽  
Maternal Outcomes ◽  
Maternal Complications ◽  
Advisory Committees ◽  
Increased Risk

Introduction Pregnancy in sickle cell disease (SCD) is associated with an exacerbation of SCD-related complications and an increased risk of maternal complications. The increased risk is partly due to physiologic adaptations in pregnancy, which include increased metabolic demands and a hypercoagulable state. The maternal death rate for SCD is 629 per 100,000 deliveries, compared to 12 per 100,000 deliveries in black women and 6 per 100,000 deliveries in the general population (Raider et al., 2016). Studies on maternal and perinatal outcomes of patients with SCD present inconsistent and conflicting results. Some studies have reported an increase in maternal complications such as pre-eclampsia, acute chest syndrome and thromboembolic events, while other studies have reported no significant risk in adverse maternal outcomes. The inconsistent findings reported in prior studies may be attributed to small sample sizes and single-centered sites. Our study aims to determine the prevalence and predictors of maternal morbidity among participants enrolled in the SCD Implementation Consortium (SCDIC) registry, which is the largest, most geographically diverse SCD participant sample in the United States. Methods This cross-sectional study included women enrolled in the SCDIC registry who had at least one pregnancy event. The SCDIC is composed of eight academic SCD centers across the United States and one data-coordinating center. Participants were enrolled in the SCDIC registry if they were 18 to 45 years of age and had a confirmed diagnosis of SCD. Enrolled participants completed a series of surveys that collected sociodemographic information, SCD and pregnancy history and data abstractions of participants' medical records was completed. Medical complications queried during pregnancy included: vaso-occlusive episodes, acute chest syndrome, blood transfusion requirement, preeclampsia, maternal diabetes and deep venous thrombosis. Descriptive analysis of sociodemographic, clinical and maternal characteristics was conducted. Bivariate analysis was performed using Chi-Square test, Mann-Whitney U test, t-test, and logistic regressions, as appropriate. A p-value of ≤ 0.05 was considered statistically significant for all analysis. Results The study sample included 743 women who had at least one pregnancy event, and a total of 1066 live births. Almost all women (96.3%) were African American, with a median age of 21 years (inter-quartile range of 19 to 23 years) at first birth. The majority had Hb SS SCD genotype (69.5%; 513 of the 738 with SCD genotype data). Of all reported pregnancies, participants did not use hydroxyurea during conception (78%), and pregnancy (84.5%). Only 2.7 % of the women reported using fertility drugs or assisted reproductive procedures. Seventy five percent of the pregnancies that ended in live births had maternal complications. The leading complications were vaso-occlusive episodes (61.2%), pregnancy requiring blood transfusion(s) (33.2%), preeclampsia (15.4%), deep venous thrombosis (5.6%) and acute chest syndrome (7.7%). When the pregnancies were stratified by SCD genotype, women with Hb SS had a higher occurrence of acute chest syndrome (63.4% vs. 26.7%), transfusion requirement (70.8% vs. 21%) and preeclampsia (66.7% vs 22.4%). In the univariate logistic regressions, multiparous women, with a history of adverse maternal outcomes in a previous pregnancy, had higher odds of vaso-occlusive episodes (OR: 3.42; 95% CI: 2.42-4.94) acute chest syndrome (OR:4.99; 95% CI:2.56- 9.48), transfusion requirement (OR:3.86; 95% CI:2.64- 5.69), and pre-eclampsia (OR:3.36; 95% CI:2.05-5.45). Conclusion In this large multicenter registry, we found pregnant women with SCD have significant maternal complications. Early antenatal care by healthcare providers knowledgeable about risk factors for adverse maternal outcomes in SCD is essential improve maternal and fetal outcomes and reduce the maternal death rate for SCD. Disclosures Hankins: Novartis: Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria. Treadwell:Global Blood Therapeutics: Consultancy; UpToDate: Honoraria. King:Amphivena Therapeutics: Research Funding; Bioline: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novimmune: Research Funding; RiverVest: Consultancy; Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:SCDAA Medical and Research Advisory Board: Membership on an entity's Board of Directors or advisory committees; AGIOS: Membership on an entity's Board of Directors or advisory committees; BEAM: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; GLG: Honoraria; Jeffries: Honoraria; Cowen: Honoraria; Wells Fargo: Honoraria; NHLBI Sickle Cell Advisory Board: Membership on an entity's Board of Directors or advisory committees; Medscape: Honoraria; Guidepoint Global: Honoraria; bluebird bio, inc: Consultancy, Honoraria; Sanofi: Consultancy. Glassberg:Pfizer: Research Funding; Global Blood Therapeutics: Consultancy; Eli Lilly and Company: Research Funding. Shah:Novartis: Consultancy, Research Funding, Speakers Bureau; Alexion: Speakers Bureau; CSL Behring: Consultancy; Bluebird Bio: Consultancy; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau.

scholarly journals Emicizumab-Kxwh for Previously Untreated Patients with Haemophilia: The Conversation Begins

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2409-2409
Author(s):  
Tiffany Lin Lucas ◽  
Shveta Gupta ◽  
Joanna A. Davis ◽  
Fernando F. Corrales-Medina
Keyword(s):  
Board Of Directors ◽  
Real World ◽  
Research Funding ◽  
Hemophilia A ◽  
The United States ◽  
Haemophilia A ◽  
Advisory Committees ◽  
Inhibitor Development ◽  
Increased Risk ◽  
Prophylaxis Therapy

Introduction: With the Federal Drug and Administration approval of the use of emicizumab from birth to adulthood, clinicians will now grapple with when to choose and offer emicizumab for routine prophylaxis, especially in previously untreated patients (PUPs). Given the overall limited real-world reported data and experience using emicizumab in PUPs, we created and administered a survey to medical providers in the United States who care for paediatric patients with haemophilia to investigate real-world practice strategies and treatment selection for PUPs. Methods: After review and endorsement by the Haemostasis and Thrombosis Research Society (HTRS), the survey was electronically distributed by e-mail to all providers included in the HTRS core member list. The survey was also sent to those providers included in a list of Haemophilia Treatment Centre (HTC) physicians (with duplicate emails reconciled). Providers needed to self-identify as ones that treat pediatric patients to be included. The survey was developed as a tiered survey with questions presented to each recipient based on their prior responses. Results: Seventy-seven completed surveys were included and analysed. All participants were active providers at a comprehensive HTC and the majority (93.4%) were practicing at an academically affiliated site. In terms of characteristics of those that answered the survey, forty-eight percent of responders reported that 1-20% of their patients had expressed interest in emicizumab. 46% of participants (34/74) reported that they would personally consider emicizumab as their prophylaxis recommendation for the majority (>50%) of their hemophilia A patients without inhibitors. 57% (44/76) reported that 1-10% of their non-inhibitor hemophilia A patients were already prescribed emicizumab prophylaxis. Each participant was then asked about his or her consideration of emicizumab as prophylaxis therapy for a 2 month old PUP. Just over the majority were unsure or said no to this consideration (51.3%) and their concerns were lack of information on safety and efficacy in this young age group and increased risk for inhibitor development. If the 2 month old PUP had a high risk of inhibitor, the majority of providers who initially were hesitant to start emicizumab prophylaxis would remain so. Of note, those providers went on to be asked if the patient had gone on to complete 50 exposure days without inhibitor development, they would then become more likely to initiate emicizumab prophylaxis therapy. Use of concurrent factor replacement was posed to all participants and there were varied responses. Discussion: Overall, our results reflect a widespread practice variation and a not yet well-standardized or defined approach for the use of emicizumab in PUPs with haemophilia A. In this survey, patient preference and individual bleeding risk were the top reasons for which a provider would consider using switching to emicizumab prophylaxis in both severe and mild/moderate haemophilia A patients. This pattern of practice reflects the current era of individualized medicine. Overall, our findings reinforce the need for more studies to investigate the outcomes of a combined treatment approach with FVIII concentrates and emicizumab focusing in the potential benefit of this approach in decreasing the risk for inhibitor development PUPs. Clinicians also feel the need for further data to help clarifying the safety of emicizumab in this population. Figure Disclosures Gupta: Novartis: Honoraria, Speakers Bureau; CSL Behring: Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda-Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Davis:Sanofi: Membership on an entity's Board of Directors or advisory committees; Kedrion: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda Shire: Consultancy; Spark Therapeutics: Consultancy. Corrales-Medina:Kedrion: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees.

Peripheral Neuropathy in MGUS and Progression to Amyloid Light-Chain Amyloidosis: A Population-Based Study Including 15,351 MGUS Cases

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5444-5444
Author(s):  
Sæmundur Rögnvaldsson ◽  
Ingemar Turesson ◽  
Magnus Björkholm ◽  
Ola Landgren ◽  
Sigurður Yngvi Kristinsson
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Large Population ◽  
Diagnostic Delay ◽  
Population Based ◽  
Lymphoproliferative Disorders ◽  
First Year ◽  
Advisory Committees ◽  
Population Based Study ◽  
Increased Risk

Introduction Peripheral neuropathy (PN) is a common disorder that can be caused by amyloid light-chain amyloidosis (AL). AL is a rare disorder caused by the deposition of amyloid fibers, originating from malignant plasma cells. Amyloid deposition in peripheral nerves causes PN and is present in 35% of patients with newly diagnosed AL. Diagnosis of AL can be difficult, leading to under-recognition, diagnostic delay, and delayed treatment. Virtually all instances of AL are preceded by monoclonal gammopathy of undetermined significance (MGUS). MGUS is relatively common with a reported prevalence of 4.2% in the general Caucasian population over the age of 50 years. Although MGUS is usually considered asymptomatic, a significant proportion of affected individuals develop PN. However, we are not aware of any studies assessing how PN affects risk of MGUS progression to AL. We were therefore motivated to conduct a large population-based study including 15,351 Swedish individuals with MGUS diagnosed 1986-2013. Methods Participants diagnosed with MGUS between 1986-2013 were recruited from a registry of a nationwide network of hematology- and oncology centers and the Swedish Patient Registry. We then cross-linked data on recorded diagnoses of AL and PN from the Swedish Patient Registry, diagnoses of lymphoproliferative disorders form the Swedish Cancer Registry, and dates of death from the Cause of Death Registry to our study cohort. Individuals with a previous history of other lymphoproliferative disorders were excluded from the study. A multi-state survival model was created. At inclusion, participants started providing person time into the PN or the non-PN states depending on whether they had a previous diagnosis of PN. Those with MGUS who developed PN after inclusion were included into the PN state at the time of PN diagnosis and provided person time in the PN state after that. We then created a Cox proportional hazard regression model with AL as the endpoint. Participants were censored at diagnosis of other lymphoproliferative disorders. We adjusted for sex, age, and year of MGUS diagnosis. Results We included 15,351 participants with MGUS. Of those, 996 participants provided person-time with PN (6.5%). About half of those had PN at MGUS diagnosis (55%). A total of 174 cases of AL were recorded, with AL being more common among those who had PN (2.1% vs 1.0% p=0.002). Those who had PN had a 2.3-fold increased risk of AL as compared to those who did not have PN (hazard ratio (HR): 2.3; 95% confidence interval (95% CI): 1.5-3.7; p<0.001). The results were similar for those who had PN at MGUS diagnosis and those who did not. More than half of AL cases (53%) were diagnosed within one year after MGUS diagnosis. The rate was even higher among those with PN, with 82% of AL cases among those who presented with PN being diagnosed within one year after MGUS diagnosis. In the first year after inclusion, the incidence of AL was 15.2 and 6.1 per 1000 person-years for participants with and without PN respectively (HR: 1.8; 95% CI:1.0-3.4; p=0.04). Participants with PN continued to have an increased risk of progression to AL after the first year with an incidence of AL of 2.6 per 1000 person-years as compared to 1.1 per 1000 person-years among participants who did not have PN (HR:2.4; 95% CI: 1.1-5.0; p=0.02) (Figure). Discussion In this large population-based study, including 15,351 individuals with MGUS, we found that individuals with MGUS who develop PN have an increased risk of progression to AL. In fact, individuals with MGUS who have PN at MGUS diagnosis might already have AL. This risk of AL was highest during the first year after MGUS diagnosis with participants with PN having a higher risk than those who did not have PN. PN continued to be associated with a higher risk of MGUS progression to AL throughout the study period. This is the largest study that we are aware of assessing the association of PN and MGUS progression to AL. Since this is a registry-based study based on recorded diagnoses, some clinical data, including MGUS isotype, is not available. These findings suggest that increased awareness of PN as a feature of MGUS might decrease diagnostic delay and improve outcomes for patients with AL. Figure Disclosures Landgren: Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Genomic Profiling of Smoldering Multiple Myeloma Classifies Molecular Groups with Distinct Pathogenic Phenotypes and Clinical Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 723-723
Author(s):  
Shankara Anand ◽  
Mark Bustoros ◽  
Romanos Sklavenitis-Pistofidis ◽  
Robert A. Redd ◽  
Eileen M Boyle ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Molecular Classification ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Increased Risk ◽  
Risk Of Progression ◽  
Over Time

Abstract Introduction: Multiple Myeloma (MM) is an incurable plasma cell malignancy commonly preceded by the asymptomatic stage smoldering multiple myeloma (SMM). MM is characterized with significant genomic heterogeneity of chromosomal gains and losses (CNVs), translocations, and point mutations (SNVs); alterations that are also observed in SMM patients. However, current SMM risk models rely solely on clinical markers and do not accurately capture progression risk. While incorporating some genomic biomarkers improves prediction, using all MM genomic features to comprehensively stratify patients may increase risk stratification precision in SMM. Methods: We obtained a total of 214 patient samples at SMM diagnosis. We performed whole-exome sequencing on 166 tumors; of these, RNA sequencing was performed on 100. Targeted capture was done on 48 additional tumors. Upon binarization of DNA features, we performed consensus non-negative matrix factorization to identify distinct molecular clusters. We then trained a random forest classifier on translocations, SNVs, and CNVs. The predicted clinical outcomes for the molecular subtypes were further validated in an independent SMM cohort of 74 patients. Results: We identified six genomic subtypes, four with hyperdiploidy (&gt;48 chromosomes, HMC, HKR, HNT, HNF) and two with IgH translocations (FMD, CND) (Table 1). In multivariate analysis accounting for IMWG (20-2-20) clinical risk stages, high-risk (HMC, FMD, HKR) and intermediate-risk (HNT, HNF) genetic subtypes were independent predictors of progression (Hazards ratio [HR]: 3.8 and 5.5, P = 0.016 and 0.001, respectively). The low-risk, CND subtype harboring translocation (11;14) was enriched for the previously defined CD-2 MM signature defined by the B cell markers CD20 and CD79A (FDR = 0.003 ), showed upregulation of CCND1, E2F1, and E2F7 (FDR = 0.01, 0.0004, 0.08), and was enriched for G2M checkpoint, heme metabolism, and monocyte cell signature (FDR = 0.003, 0.003, 0.003, respectively). The FMD subtype with IgH translocations (4;14) and (14;16) was enriched for P53, mTORC1, unfolded protein signaling pathways and plasmacytoid dendritic cell signatures (FDR = 0.01, 0.005, 0.008, respectively). The HKR tumors were enriched for inflammatory cytokine signaling, MYC target genes, T regulatory cell signature, and the MM proliferative (PR) signatures (FDR = 0.02, 0.03, 0.007, 0.02, respectively). The APOBEC mutational signature was enriched in HMC and FMD tumors (P = 0.005), while there was no statistical difference across subtypes in the AID signature. The median follow-up for the primary cohort is 7.1 years. Median TTP for patients in HMC, FMD, and HKR was 3.8, 2.6, and 2.2 years, respectively; TTP for HNT and HNF was 4.3 and 5.2, respectively, while it was 11 years in CND patients (P = 0.007). Moreover, by analyzing the changes in MM clinical biomarkers over time, we found that patients from high-risk subgroups had higher odds of developing evolving hemoglobin and monoclonal protein levels over time (P = 0.01 and 0.002, respectively); Moreover, the absolute increase in M-protein was significantly higher in patients from the high-risk genetic subtypes at one, two, and five years from diagnosis (P = 0.001, 0.03, and 0,01, respectively). Applying the classifier to the external cohort replicated our findings where intermediate and high-risk genetic subgroups conferred increased risk of progression to MM in multivariate analysis after accounting for IMWG staging (HR: 5.5 and 9.8, P = 0.04 and 0.005, respectively). Interestingly, within the intermediate-risk clinical group in the primary cohort, patients in the high-risk genetic subgroups had increased risk of progression (HR: 5.2, 95% CI 1.5 - 17.3, P = 0.007). In the validation cohort, these patients also had an increased risk of progression to MM (HR: 6.7, 95% CI 1.2 - 38.3, P = 0.03), indicating that molecular classification improves the clinical risk-stratification models. Conclusion: We identified and validated in an independent dataset six SMM molecular subgroups with distinct DNA alterations, transcriptional profiles, dysregulated pathways, and risks of progression to active MM. Our results underscore the importance of molecular classification in addition to clinical evaluation in better identifying high-risk SMM patients. Moreover, these subgroups may be used to identify tumor vulnerabilities and target them with precision medicine efforts. Figure 1 Figure 1. Disclosures Bustoros: Janssen, Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria. Casneuf: Janssen: Current Employment. Kastritis: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding. Walker: Bristol Myers Squibb: Research Funding; Sanofi: Speakers Bureau. Davies: Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria. Bergsagel: Genetech: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; GSK: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Yong: BMS: Research Funding; Autolus: Research Funding; Takeda: Honoraria; Janssen: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria; Amgen: Honoraria. Morgan: BMS: Membership on an entity's Board of Directors or advisory committees; Jansen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Getz: IBM, Pharmacyclics: Research Funding; Scorpion Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Evolving Risk of Myelodysplastic Syndromes Among Adolescents and Young Adults Following Radiation Treatment for First Cancers in the United States, 1973 - 2014

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4334-4334
Author(s):  
Remco Molenaar ◽  
Tomas Radivoyevitch ◽  
Hetty E. Carraway ◽  
Jaroslaw P. Maciejewski ◽  
Mikkael A Sekeres ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cancer Diagnosis ◽  
Research Funding ◽  
Second Cancer ◽  
Cancer Risks ◽  
Advisory Committees ◽  
Second Cancers ◽  
Myeloid Neoplasm ◽  
Increased Risk ◽  
Kinetics Of

Abstract Background Adolescents and young adults (AYA; aged 15-39) treated for first cancers are a demographic cohort that are uniquely predisposed to risk of second cancers. This is due to increased sensitivity of exposed tissues to cancer therapies and a longer latency for the development of second cancers due to longer survival resulting from advances in cancer treatments. Radiotherapy is a commonly used modality in several AYA cancers and has been associated with increased risk of subsequent neoplasms including myeloid malignancies. Myelodysplastic syndrome (MDS) is the most common myeloid malignancy in the US but very little is known regarding the risk of MDS in the AYA population. In this study, we analyzed the evolving risk of MDS in the AYA population spanning over 4 decades using the US Surveillance Epidemiology and End Results (SEER) registry. Methods A novel R program, SEERaBomb (Leukemia. 2016;30(2):285-94) was developed to query all 18 SEER registries. We identified all AYA first cancer cases treated with radiation that subsequently developed MDS as second cancers. Diagnosis was derived from the International Classification of Diseases for Oncology Third Revision categories. SEER cancer registries collect information on the initial course of treatment and does not carry information on chemotherapy. SEERaBomb allows merging of all 18 SEER registries - a function not permitted by the NIH-developed SEER*Stat MP-SIR program that limits researchers to use either SEER 9 or SEER 13. This significantly increases the capture of MDS cases. AYA cancer survivor person yrs at risk for developing MDS was based on age at diagnosis of the first cancer, survival time, and age at diagnosis of MDS. Relative risks (RR) for developing MDS were based on observed/expected cases between the cohorts receiving no radiation (control) or radiation. Results In total 569,681 AYA first cancer patients (pts) were identified, of whom 133,829 (23%) received radiation as initial part of their cancer treatment and 426,272 (75%) received no radiotherapy. Mean age at the time of first cancer diagnosis was similar in radiation treated and untreated cohorts (32 yrs vs. 31.2 yrs). Median yrs of follow up after first cancer diagnosis was 5.7 yrs (25-75 interquartile [IQR], 1.9-12.2) in pts receiving radiation and 9.1 yrs (25-75 IQR, 2.7-20.2) in those not treated with radiation. A total of 48 pts developed MDS; 21 in the radiation group and 27 in the cohort that did not receive radiation. Median time to development of MDS after first cancer diagnosis was 3.8 yrs (25-75 IQR, 2.0-6.1) in those who received radiation and 3.1 yrs (25-75 IQR, 1.1-4.2) in non-irradiated pts. MDS cases were classified as RA (n=5), RARS (n=4), RCMD (n=3), RAEB (n=8), MDS with 5q deletion syndrome (n=2), and MDS-U (n=26). Compared with the risk in general population, pts treated with radiotherapy and those who did not receive radiation had an elevated risk of developing MDS within the first 10 yrs (RR=33.3; 95% CI, 20.4-51.5 vs. RR=19.3; 95% CI, 12.6-28.2). The risk of MDS in both radiation-treated and untreated cohort peaked within the first two yrs. The risk of MDS in general was higher in the radiation-treated pts compared to non-radiated pts for up to 7 yrs from exposure and beyond 10 yrs, the risk for MDS steadily fell to baseline rates (Fig 1). The risk kinetics of developing MDS in AYA first cancer survivors mimics the kinetics of MDS development in adults > 40 yrs, whereas the magnitude of the RR is much higher in the first group (Fig 2). When the pooled occurrence of AML and MDS as second cancers was analyzed in AYA first cancer survivors, those who received radiation had a statistically significant increased risk of developing AML or MDS within the first 3 yrs of exposure compared with pts not treated with radiation (RR=22.5; 95% CI, 18.2-27.7 vs. RR=12.5; 95% CI,10.3-15.0; Fig 3). Conclusion AYA cancer pts have a strikingly increased risk of developing MDS in the first 10 yrs after first cancer diagnosis. AYA cancer pts undergoing radiotherapy for first cancers appear to have an even higher risk of developing MDS that can last up to 10 yrs following exposure. Considering the long latency of MDS seen in atomic bomb cohorts and relative young age of AYA pts, MDS rates are likely to continue to rise. Figure 1 Kinetics of MDS second cancer risks in AYA pts. Figure 1. Kinetics of MDS second cancer risks in AYA pts. Figure 2 Kinetics of MDS second cancer risks in patients aged > 40 yrs. Figure 2. Kinetics of MDS second cancer risks in patients aged > 40 yrs. Figure 3 Kinetics of myeloid neoplasm (MN; MDS or AML) second cancer risks in AYA pts. Figure 3. Kinetics of myeloid neoplasm (MN; MDS or AML) second cancer risks in AYA pts. Disclosures Carraway: Baxalta: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding, Speakers Bureau. Maciejewski:Celgene: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 991-991 ◽  
Author(s):  
Julie Kanter ◽  
Darla K Liles ◽  
Kim Smith-Whitley ◽  
Clark Brown ◽  
Abdullah Kutlar ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Pooled Analysis ◽  
Advisory Committees ◽  
Phase Ii Studies ◽  
Increased Risk ◽  
History Of ◽  
Favorable Safety

Background: Crizanlizumab, a humanized monoclonal antibody that binds P-selectin and blocks interaction with its ligands (including leukocyte PSGL-1), is under investigation for preventing vaso-occlusive crises (VOCs) in individuals with sickle cell disease (SCD). Crizanlizumab 5.0 mg/kg was shown to significantly reduce the median annual rate of VOCs by 45.3% versus placebo (Hodges-Lehmann median absolute difference of -1.01 vs placebo, 95% CI [-2.00, 0.00]; P=0.01) (Ataga et al. N Engl J Med 2017). Aims: This pooled analysis evaluated key safety endpoints in patients treated with the recommended dose of crizanlizumab (5.0 mg/kg monthly, following 2 loading doses in the first month). Methods: Data were pooled from 2 Phase II studies of SCD patients (any genotype) with a history of VOCs leading to a healthcare visit. SUSTAIN (NCT01895361) was a randomized, placebo-controlled study in patients aged 16-65 years who had experienced 2-10 VOCs in the previous 12 months. SOLACE-adults (A2202) is an ongoing, open-label PK/PD study (NCT03264989) in patients aged 16-70 years who had experienced at least 1 VOC in the previous 12 months; data cut-off for this analysis was 1 March 2019. Adverse events (AEs) were evaluated based on MedDRA v21.1. AE severity in SOLACE was assessed based on CTCAE v5; in SUSTAIN, severity was collected as mild/moderate/severe but then recategorized for this analysis to a 5-point scale similar to CTCAE grading. AEs of special interest (ie known class effects; AEs identified preclinically or in previous studies; or potentially relevant based on the mechanism of action of crizanlizumab) were also evaluated and included infections, infusion-related reactions (IRRs) and hemostatic effects. As monoclonal antibodies can induce an immune response, anti-drug antibodies (ADAs) were also measured. Results: In total, 111 patients (SUSTAIN, n=66; SOLACE, n=45) received crizanlizumab 5.0 mg/kg: 59 females (53.2%) and 52 males (46.8%). Median age was 29 years (range 16-65). The most common SCD genotypes were HbSS (n=73; 65.8%) and HbSC (n=19; 17.1%), and 75 patients (67.6%) were receiving hydroxyurea (HU). Most patients (n=67; 60.4%) had 1-4 VOCs in the previous 12 months. Median duration of exposure to crizanlizumab was 46 weeks (range 4-58). At least 1 AE was reported in 94 patients (84.7%), the most common (≥15%) being headache (n=22; 19.8%), nausea (n=18; 16.2%) and back pain (n=17; 15.3%). AEs were mild/moderate (grade 1 or 2) and resolved spontaneously in most patients; 23 patients (20.7%) had a grade 3 AE and 1 (0.9%) had a grade 4 AE (neoplasm). At least 1 serious AE was reported in 24 patients (21.6%); serious AEs with a suspected relationship to crizanlizumab were reported in 6 patients (5.4%). Twenty-eight patients (25.2%) discontinued treatment prematurely (n=23 in SUSTAIN, n=5 to date in SOLACE): discontinuations due to AEs (bradycardia and breast cancer) occurred in 2 patients (1.8%); neither was considered related to crizanlizumab. There were 2 on-treatment deaths in SUSTAIN, but neither were considered related to crizanlizumab. Infection events were reported in 51 patients (45.9%), the most common (≥5%) being upper respiratory tract infection (n=13, 11.7%) and urinary tract infection (n=11, 9.9%). There were no grade 4 infections and none led to discontinuation. Data suggest no increased risk or severity of infection in studies with crizanlizumab. Two patients (1.8%) experienced IRRs; the events were not serious and did not lead to discontinuation. Bleeding events were rare, with most observed hemostatic AEs being abnormal laboratory parameters occurring only once. Treatment-induced ADAs were transiently detected in 1 patient (0.9%) and spontaneously resolved. There were no clinically relevant laboratory (hematology, biochemistry, liver) or ECG abnormalities, or vital sign changes, and no notable differences in the AE incidence rates by gender, ethnicity or HU use. Conclusions: This pooled analysis shows that crizanlizumab 5.0 mg/kg was well tolerated, with a favorable safety profile, in patients with SCD and a history of VOCs. Most AEs were mild/moderate, and discontinuations due to AEs were infrequent. The immunogenic potential of crizanlizumab appears low and there is currently no evidence for an increased risk of infection or bleeding. SOLACE-adults and SOLACE-kids (6 months to &lt;18 years) are ongoing, and the randomized Phase III STAND trial is recruiting. Disclosures Kanter: bluebird bio, Inc.: Consultancy; SCDAA: Membership on an entity's Board of Directors or advisory committees; NHLBI: Membership on an entity's Board of Directors or advisory committees; Rockpointe: Honoraria; Peerview: Honoraria; Jeffries: Consultancy; Medscape: Honoraria; GLG: Consultancy; Cowen: Consultancy; Guidepoint Global: Consultancy; Sangamo: Consultancy, Honoraria; Modus: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Imara: Consultancy. Liles:Novartis: Other: PI on clinical trial Sickle cell ; Shire: Other: PI on clinical trial Sickle cell ; Imara: Other: PI on Clinical trial- Sickle cell . Brown:Novartis, Inc: Research Funding. Kutlar:Bluebird Bio: Other: DSMB Member; Micelle Biopharma: Other: DSMB Chair; Novartis: Consultancy; Global Blood Therapeutics, Inc. (GBT): Research Funding; Novo Nordisk: Research Funding. Elliott:Novartis: Employment, Equity Ownership. Shah:Novartis Pharmaceuticals: Employment, Other: Shareholder. Lincy:NOVARTIS PHARMA AG: Employment. Poggio:Novartis: Employment. Ataga:Advisory Board: Global Blood Therapeutics, Novartis: Membership on an entity's Board of Directors or advisory committees, Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE; VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE: Other: VINDICO WILL FORWARD DISCLOSURES ONCE RECEIVED AND SIGNED NOT RECEIVED TO DATE; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Emmaus Life Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals CD20 Is an Unstable Target in Primary-Refractory High-Grade Lymphomas

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1608-1608
Author(s):  
Ryan N Rys ◽  
Dominique Geoffrion ◽  
Christopher Rushton ◽  
Miguel Alcaide ◽  
Raoul Santiago ◽  
...  
Keyword(s):  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Grade ◽  
Advisory Committees ◽  
Increased Risk ◽  
Cd20 Expression ◽  
Anti Cd20

Introduction: A third of patients with diffuse large B cell lymphoma (DLBCL) are not cured with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (RCHOP). Approximately 20% of DLBCLs will lose CD20-protein expression (CD20-neg) at the time of relapse. The incidence of CD20-neg relapses in other aggressive B cell lymphomas is unknown. CD20 is not only targeted by rituximab but other antibody-based therapies that are being investigated in salvage regimens. We hypothesized that prolonged exposure to anti-CD20 containing regimens may lead a CD20-neg relapse. Our goal was to determine the clinical and genetic factors associated with loss of CD20 expression in high-grade lymphomas treated with curative intent. Method: We consented 374 patients with B cell high-grade lymphomas that were treated with RCHOP or more intensive regimens at the time of diagnosis or had a histological transformation from a prior indolent lymphoma (TLy). We recorded the baseline clinical characteristics, histological diagnosis, date of first relapse and the number of treatment regimens prior to their second biopsy. CD20 expression and cell of origin (COO) were determined by immunohistochemistry and, in the latter, using Hans criteria. We performed targeted sequencing of 63 lymphoma-related genes, including MS4A1, the gene that encodes CD20. Sequencing was performed using circulating tumor DNA in the plasma or DNA from the tumor biopsy, both obtained at the time of relapse. Results: Relapse occurred in 170/374 (45%) of patients: 102/253 DLBCL, 55/96 TLy, 6/16 primary mediastinal B cell lymphoma (PMBCL) and 7/9 high grade B cell lymphomas (HGBL) with or without translocations in MYC and BCL2 or BCL6. The median age at diagnosis was 62 years old, 54% were male and 85% had an elevated international prognostic index of ≥ 2. Of these, 104 had a biopsy taken at first (47%) or subsequent relapse (53%) to confirm the diagnosis or performed in the context of a clinical trial. CD20 could be assessed in 100 cases, of which 26 had CD20-neg lymphoma cells: 15/56 (27%) of DLBCL, 7/38 (18%) of TLy, 2/3 (66%) PMBCL and 2/3 (66%) HGBL. Relapsed PMBCL and HGBL combined, appeared to have an increased risk of CD20 negativity at relapse compared to DLBCL and TLy (p=0.043). A GCB phenotype in DLBCL was present in 35% of cases and was not associated with CD20 status. The mean number of therapies given before the second biopsy was similar in both groups (CD20+ = 2.2 and CD20-neg = 2.7, p=0.2). In fact, 11/26 (44%) of CD20-neg cases had biopsies taken after RCHOP alone. Additional chemo-immunotherapy (range 2 to 8) did not increase the risk of having a CD20-neg relapse (p=0.5), suggesting that unlike follicular lymphoma, the emergence of CD20-neg cells occurs early after rituximab exposure in high-grade lymphomas. Supporting this hypothesis, patients with a CD20-neg relapse had a shorter progressive free survival (PFS) after RCHOP (1,7 vs 3,2 years, p=0.025). Patients with primary treatment failure, defined here as a PFS of &lt; 1 year, had a significantly increased risk of having a CD20-neg relapse (hazard ratio 7.9, p= 0.005). Sequencing was performed in 75/100 patients. MS4A1 mutations were present in 16% of CD20-neg cases, while none were present in the CD20+ cases (p=0.003). There was no significant difference in the mutation rate of TP53 (47%) or histone-modifying genes based on CD20 expression status. Conclusion: Decreased CD20 expression occurs early in high-grade lymphomas under the selective pressure of RCHOP, 16% of which are a consequence of MS4A1 mutations, suggesting that other mechanisms also modulate CD20 expression. In patients with a PFS of &lt; 1 year, a repeat biopsy would be recommended if primary anti-CD20-targeted therapy is considered. Disclosures Assouline: F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Johnson:Abbvie: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding; BMS: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BD Biosciences: Other: Provided a significant proportion of the antibodies used in this project free of cost.; Seattle Genetics: Honoraria; Lundbeck: Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel fees, gifts, and others, Research Funding.

scholarly journals Germline-Somatic Interactions in Myelofibrosis Susceptibility

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 313-313
Author(s):  
Derek W Brown ◽  
Youjin Wang ◽  
Andrew St. Martin ◽  
Stephen R. Spellman ◽  
Shu-Hong Lin ◽  
...  
Keyword(s):  
Telomere Length ◽  
Board Of Directors ◽  
Research Funding ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Risk Haplotype ◽  
Advisory Committees ◽  
Genome Wide ◽  
Increased Risk ◽  
V617f Mutation

Abstract Introduction: Myelofibrosis (MF) is a rare myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, progressive bone marrow failure, and increased risk of acute myeloid leukemia. While MF arises from somatic driver mutations in JAK2, MPL, and CALR, some MPN patients may have a heritable component. To comprehensively examine the genetic etiology of MF, we performed the first integrative analysis of SNP array genotyping (using Infinium Global Screening Array), targeted long-read sequencing (using PacBio SMRT sequencing) and telomere length (TL, using qPCR assay). Methods: Our study included 937 MF patients who received an allogeneic hematopoietic cell transplant (HCT) between 2000 and 2016 and had an available pre-HCT blood sample at the Center for International Blood and Marrow Transplant Research Repository. Somatic mosaic chromosomal alterations (mCAs, including deletions, duplications, or copy-neutral losses-of-heterozygosity (CNLOH)) were called with the Mosaic Chromosomal Alteration (MoChA) algorithm using raw genotyping intensity data. A genome-wide association study (GWAS) was restricted to include 827 MF patients of European ancestry and utilized 4,135 genetically-matched healthy controls. Results: GWAS identified six independent MF susceptibility loci at genome-wide significance (P&lt; 5×10 -8); four of which replicate prior MPN susceptibility loci [9p24.1(JAK2), 5p15.33(TERT), 3q25.33(IFT80), and 4q24(TET2)] and two novel MF loci [6p21.35(HLA-DQB1-AS1) and 17p13.1(TP53)] (Figure 1). A transcriptome-wide association analysis using whole blood GTEx data highlighted the 9p24.1 locus with increased JAK2 expression associated with elevated risk of MF (P= 2.18×10 -19). A strong colocalization statistic further indicated shared genetic component between eQTL and this JAK2 locus (HyPrColoc Posterior Probability= 0.6) (Figure 2). Based on the strong signal identified at TERT (Figure 1), we investigated the relationship between MF risk and genetically-inferred telomere length using a panel of 19 germline variants previously found to be associated with telomere length. Of the 19 telomere-length associated variants investigated, 7 were found to be associated with MF risk (binomial P= 2.31×10 -5, linear trend P= 5.48×10 -4) (Figure 3). Both Mendelian randomization and genome-wide genetic correlation analyses further indicated that increased risk of MF was associated with longer inherited telomere length. Utilizing available clinical mutation data on a subset of 185 patients, MF cases carrying the germline risk haplotype of the 9p24.1(JAK2) susceptibility locus were observed to more frequently have the JAK2 V617F mutation (71% vs 59%; P= 0.02). Targeted PacBio long-read sequencing around JAK2 provided further evidence of linkage between the germline risk allele and the JAK2 V617F mutation. Detectable autosomal mCAs were also abundant in MF cases with 67.4% having at least one mCA (compared to ~3% in the general population) and 27.6% having an mCA spanning JAK2 (mostly CNLOH) (Figure 4). In addition, using a binomial test for biased allelic imbalance, a cis relationship was identified at 9p24.1 in which the MF risk haplotype was predominantly duplicated by CNLOH (binomial P=1.36×10 -9). Regional sequencing of JAK2 further confirmed duplication of JAK2 V617F by CNLOH. Finally, we observed an inverse association between autosomal mCAs and qPCR measured telomere length (OR= 0.22, 95% CI= 0.07-0.65, P= 6.40×10 -3). These results were consistent by mCA chromosomal region and copy number state. Conclusion: Our results suggest a molecular framework for the genetic etiology of MF in which both genetically-inferred telomere length and germline variation at JAK2 are associated with increased MF risk. The 9p24.1 risk haplotype predisposes to the acquisition of a somatic JAK2 V617F mutation in cis and subsequent duplication of JAK2 V617F by mCAs (usually CNLOH). This process leads to aberrant JAK2 activity and increased clonal proliferation, accelerating telomere length shortening and increasing genomic instability in patients with MF. Figure 1 Figure 1. Disclosures Gupta: AbbVie: Consultancy, Honoraria; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Lee: Janssen: Other; Incyte: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Syndax: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Saber: Govt. COI: Other.

scholarly journals Risk of Hospitalization for Vaso-Occlusive Episode in Patients with Sickle Cell Disease after out-Patient Exposure to Systemic Corticosteroids

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2048-2048
Author(s):  
Ondine Walter ◽  
Pierre Cougoul ◽  
Julien Maquet ◽  
Pablo Bartolucci ◽  
Maryse Lapeyre-Mestre ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Board Of Directors ◽  
Sickle Cell ◽  
Research Funding ◽  
Cell Disease ◽  
National Health Insurance System ◽  
Advisory Committees ◽  
Systemic Corticosteroids ◽  
Increased Risk ◽  
Case Period

Abstract Introduction : Sickle cell disease (SCD) is an inherited disorder which affects 300,000 newborns per year. Vaso-occlusive episodes (VOEs) cause an important morbi-mortality and a decreased quality of life in patients with SCD. Some risk factors of VOE are well known, like infection, cold exposure, stress, pulmonary diseases and dehydration. Exposure to systemic corticosteroids has been suspected to increase the occurrence of VOEs in few case reports or series. However, no comparative study has been conducted to demonstrate this risk which is still debated, resulting in discrepancies among guidelines on SCD management. This study aimed to assess the risk of hospitalization for VOE associated with out-hospital exposure to systemic corticosteroids in patients with SCD in France. Methods : Data source was the French national health insurance system database, named SNDS (Système National des Données de Santé) between 2010 and 2018. The SNDS links sociodemographic, out- and in-hospital data for the entire French population (&gt;66 million inhabitants). The study population consisted in all patients with SCD with at least one hospitalization for VOE during the study period, identified with a primary discharge diagnosis of VOE (D57.0 code of the international classification of disease, 10 th version; positive predictive value: 98.6%). All genotypes (homozygous SS-SCD and double-heterozygous SCD) were included. Because we assessed out-hospital exposure to corticosteroids, patients hospitalized during the three months before the first VOE were excluded. We performed a case-case-time-control study (Figure 1). This self-controlled design results in self-adjustment for time-independent confounders, including genotype. The outcome was the first hospitalization for VOE. The exposure to oral and injectable corticosteroids, identified using out-hospital reimbursement data, was assessed during a case period (28 days before the outcome) compared to the exposure during a control period (28 days, starting 84 days before the outcome). The same comparison was made among future cases (matched patients hospitalized for VOE the year after the given case), in order to adjust for the trend of exposure to corticosteroids (calendar variations of corticosteroid exposure). Results : Overall, 5,151 cases of VOEs were included in the main analysis. Median age at first VOE was 16.9 years; 317 (6.2%) patients were exposed to corticosteroids during the case period. In the main analysis, corticosteroid exposure was significantly associated with the occurrence of hospitalizations for VOEs: adjusted Odds Ratio (aOR): 3.81, 95% confidence interval (95% CI): 2.44 to 5.61. In patients exposed to hydroxyurea, the aOR was 2.61, 95% CI: 1.07 to 6.39, compared with an aOR of 4.00, 95% CI: 2.53 to 6.30 in unexposed patients. In the subgroup analysis by age, the aOR was 2.81, 95% CI: 1.49 to 5.30 in children, and 4.45, 95% CI: 2.37 to 8.37 in adults. The results were consistent in all sensitivity analyses. Conclusion : This study showed an association between outpatient exposure to systemic corticosteroids with an increased risk of hospitalization for VOE, in both adults and children. Hydroxyurea may reduce this risk in adults. Figure 1 Figure 1. Disclosures Bartolucci: GBT: Consultancy; Emmaus: Consultancy; Fabre Foundation: Research Funding; AGIOS: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Lecture fees, Steering committee, Research Funding; Jazz Pharma: Other: Lecture fees; INNOVHEM: Other: Co-founder; Bluebird: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy; Hemanext: Consultancy; Addmedica: Consultancy, Other: Lecture fees, Research Funding. Moulis: Argenx: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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