The Burden of Atrial Fibrillation in Sickle Cell Disease

Abstract Introduction Life expectancy amongst individuals with sickle cell disease (SCD) has plateaued, with cardiopulmonary complications now becoming a leading cause of death (Fitzhugh et al. Am. J. Hematology 2010). Indeed, SCD is associated with increased rates of pulmonary hypertension (pHTN) and diastolic dysfunction (Sachdev et al. Blood 2005). In the general population, atrial fibrillation (AF) is associated with an increased mortality in the setting of either pHTN or diastolic dysfunction. Although cardiac structural and biochemical changes likely create an electrophysiological substrate for AF in SCD, the prevalence and risk factors for AF in SCD remain unclear. We determined the prevalence, incidence, and clinical characteristics of AF in a large cohort of patients with SCD. Methods We conducted a retrospective, longitudinal cohort study of all adult patients with SCD seen at our large, urban single center from January 2008 to December 2017. SCD patients were identified using a previously described semi-automated system with a subset with direct chart review (Srisuwananukorn et al. Blood Advances 2020). We performed manual review of ~17,000 available electrocardiograms of all enrolled subjects to look for AF. For univariate analyses, the associations of linear and categorical variables with AF were assessed using the Kruskal-Wallis test and Pearson's χ 2 test, respectively. We used Bonferroni correction for categorical variables with greater than two groups. Logistic regression analysis with stepwise addition of variables (p>0.15) was used to evaluate for the effects of previously described AF risk factors, degree of anemia, hydroxyurea use, and genotype on AF development. Results Our cohort consisted of 763 adult SCD patients with a median age of 27.95 years, 59.50% female, 72.4% with Hb SS or Sβ 0-thalassemia genotype, and 61.2% were prescribed hydroxyurea. Mean observation time for the cohort was 8.3 ± 6.3 yrs. We identified AF in 30 out of 763 adult SCD individuals with a mean age onset of 51 ± 10 years (median age 52 years). The period prevalence of AF was 3.93% and the incidence density was 3.02 per 1000 patient years observed. Individuals with AF tended to be older at initial (40 vs. 25 years, p<0.0001) and follow-up (53 vs. 35 years, p<0.0001) visits and were observed for a longer period (13.3 vs. 9.5 years, p=0.0014). There was no difference in gender (p=0.7), ethnicity (p=0.5), or SCD genotype (p=0.03) between groups (see Table 1). Those with AF were more likely to carry diagnoses of chronic obstructive pulmonary disease (p=0.0004), hypertension (p<0.0001), chronic kidney disease (p<0.0001), type 2 diabetes (p<0.0001), and any cancer (p=0.04). However, hydroxyurea use was not associated with AF development (p=0.3). SCD patients with AF were more likely to receive diuretics, atrioventricular nodal blocking agents, antihypertensives, antiplatelets, and statin therapies (see Table 1). AF was associated with worse anemia and reduced renal function. Regression analysis identified significant odds ratios (ORs) for age at initial visit (OR 1.06, p=0.03), serum creatinine per 1 mg/dL increase (OR 2.34, p=0.02), hemoglobin level per 1 g/dL increase (OR 0.52, p=0.0009), fetal hemoglobin level per 1% increment (OR 0.81, p=0.008), and total observation time per year follow up (OR 1.26, p=0.0006). Conclusion We showed that the prevalence and incidence of AF is high in patients with SCD with the median age of onset occurring 1-2 decades earlier than in the general populace (Feinberg et al. JAMA Internal Medicine 1995). AF in patients with SCD is associated with advanced age, worse renal function, a higher degree of anemia, and greater usage of cardio- and nephro-active medications. The high incidence of AF in patients with SCD may contribute to the plateauing of life expectancy and identifying the causative risk factors and the underlying mechanisms may not only improve life expectancy but also the quality of life. Further study is warranted. Figure 1 Figure 1. Disclosures Saraf: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding.

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Clinical and Biomarker Predictors for Avascular Necrosis in Sickle Cell Disease

Blood ◽

10.1182/blood-2021-147829 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3091-3091

Author(s):

Michael Rabaza ◽

Maria Armila Ruiz ◽

Liana Posch ◽

Faiz Ahmed Hussain ◽

Franklin Njoku ◽

...

Keyword(s):

Risk Factors ◽

Sickle Cell Disease ◽

Board Of Directors ◽

Avascular Necrosis ◽

Sickle Cell ◽

Research Funding ◽

Medical Attention ◽

Cell Disease ◽

Advisory Committees ◽

Early Management

Abstract Introduction Sickle cell disease (SCD) affects 1 in 365 African Americans and approximately 25 million people world-wide. A common skeletal system complication is avascular necrosis (AVN), which can cause substantial pain and a reduced quality of life. While early management of AVN is focused on increasing range of motion with physical therapy and pain relief, there are no clear predictors for who is more likely to develop AVN and earlier institution of these preventive measure could help decrease disease progression. Vascular endothelial growth factor (VEGF) is a biomarker of endothelial injury and may indicate reduced vascular supply to the femoral or humeral head. Here we describe potential risk factors and biologic pathways for AVN in SCD, as understanding these may lead to improvements in future monitoring, early detection, and early intervention practices. Methods We investigated clinical and laboratory risk factors associated with AVN in a cohort of 435 SCD patients from our center. Blood samples, clinical, and laboratory data were collected at the time of enrollment during a clinic visit. Genotyping for alpha thalassemia was performed by PCR and the serum concentration of VEGF was measured by ELISA. AVN status was confirmed by review of the medical record and available imaging. We conducted a cross-sectional analysis comparing categorical and linear variables by AVN status using the chi-square and Kruskal-Wallis test, respectively. The independent association of the clinical and laboratory variables with AVN status was determined by logistic regression analysis. The initial model included variables with a P-value < 0.1 on univariate analysis and the final model was ascertained by stepwise forward and backward selection. Median values and interquartile range (IQR) are provided. Results The median age of the cohort was 32 (IQR, 24 - 43) years, 57% (250/435) were female, and 46% (198/435) were on hydroxyurea. AVN was observed in 34% (149/435) of SCD patients. SCD patients with AVN were older, had more frequent vaso-occlusive crises requiring medical attention, and had a higher body mass index (Table I) (P ≤ 0.002). We measured VEGF in 241 of the SCD patients with serum samples available at the time of enrolment. Serum VEGF concentrations trended higher in SCD patients with versus without AVN (420 vs. 359 pg/mL, respectively; P = 0.078). In the multivariate analysis model, AVN was independently associated with increased number of vaso-occlusive crises (OR 1.1, 95% CI: 1.0 - 1.14; P = 0.02), AST concentration (natural log OR 0.5, 95% CI: 0.2 - 0.9; P = 0.03), VEGF concentration (natural log OR 1.4, 95% CI: 1.0 - 1.9; P = 0.047), and tobacco use (OR 1.9, 95% CI: 0.9 - 3.7; P = 0.078). Discussion In conclusion, we demonstrate a high prevalence of AVN in an adult cohort of SCD patients. The presence of AVN was independently associated with a greater frequency of vaso-occlusive pain episodes, which may demonstrate a shared pathophysiology between AVN and vaso-occlusion that merits further investigation. We demonstrate that serum VEGF concentrations are higher in SCD patients with AVN and may be a clinical tool to identify those at high-risk and for earlier intervention for this complication. Figure 1 Figure 1. Disclosures Gordeuk: Modus Therapeutics: Consultancy; Novartis: Research Funding; Incyte: Research Funding; Emmaus: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; CSL Behring: Consultancy. Saraf: Pfizer: Research Funding; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Sex Based Differences in Sickle Cell Disease

Blood ◽

10.1182/blood-2020-140896 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-37

Author(s):

Rita V Masese ◽

Dominique Bulgin ◽

Mitchell Knisely ◽

Liliana Preiss ◽

Eleanor Stevenson ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Categorical Variables ◽

Continuous Variables ◽

Cell Disease ◽

Advisory Committees ◽

Blood Institute ◽

National Heart Lung

Introduction Sickle cell disease (SCD) is the most common inherited blood disorders in the United States. The disease predominantly affects African Americans with 1 out of every 365 individuals born with SCD. The disease is characterized by vascular inflammation and vaso-occlusion leading to numerous complications and multi-organ dysfunction. Previous studies have shown women with SCD tend to outlive their male counterparts. Other than the increased life expectancy, sex-based clinical outcome differences in SCD remain largely unknown. To better characterize sex-based differences in SCD, we assessed sociodemographic characteristics, pain, treatment characteristics, laboratory measures and complications among males and females currently enrolled in the Sickle Cell Disease Implementation Consortium (SCDIC) registry. Methods The SCDIC consists of eight academic and comprehensive SCD centers, and one data-coordinating center that received funding from the National Heart Lung and Blood Institute to improve outcomes for individuals with SCD. Participants were eligible for the enrollment in the SCDIC registry if they were 15 to 45 years of age and had a confirmed diagnosis of SCD. Participants were excluded if they had sickle cell trait or had a successful bone marrow transplant. Enrolled participants completed surveys. Data were also abstracted from the participants' medical records. Data were entered into a REDCap database and analyzed using SAS version 9.4 (SAS Institute; Cary, NC). Categorical variables were presented as frequencies and percentages, continuous variables were presented as medians and interquartile ranges (IQR) or means and standard deviations. Categorical variables were analyzed using Chi-Square or Fisher exact tests when appropriate. Continuous variables were compared using the Mann-Whitney U test or independent sample t-tests depending on the distribution. A two-sided p-value less than 0.05 was deemed significant. Results A total of 2,124 participants were included in the study. The mean (SD) age of our participants was 27.8 (7.9) years. Almost all (95.6%) were Africa American, female (56%) and had hemoglobin SS (68.2%) SCD genotype. More males (55.4 % vs. 44.6%, p <0.0001) were taking hydroxyurea. Females had significantly worse reports of pain frequency and severity (p=0.0002 and <0.0001 respectively), more vaso-occlusive episodes (p=0.01) and a higher occurrence of 3 or more hospital admissions in the past year (30.9 % vs. 25.5, p= 0.03). Males had significantly more skin ulcers and respiratory, musculoskeletal, genitourinary and cardiovascular complications while females had more anxiety, depression and autoimmune conditions. Males also had significantly higher creatinine, blood urea nitrogen, albumin and liver enzymes (alkaline phosphatase, aspartate and alanine aminotransferases). Females had higher fetal hemoglobin levels with and without hydroxyurea use. There were no statistical differences in ethnicity, marital and employment status. Conclusion Key differences in SCD presentation and occurrence of complications exist among males and females. Females had higher rates of depression and anxiety while males had more chronic end-organ complications that are life threatening. Our findings emphasize the need for stratification of data analysis by sex in future SCD studies. Disclosures Hankins: Global Blood Therapeutics: Consultancy, Research Funding; National Heart, Lung, and Blood Institute: Honoraria, Research Funding; LINKS Incorporate Foundation: Research Funding; American Society of Pediatric Hematology/Oncology: Honoraria; MJH Life Sciences: Consultancy, Patents & Royalties; UptoDate: Consultancy; Novartis: Research Funding. Treadwell:UpToDate: Honoraria; Global Blood Therapeutics: Consultancy. King:Tioma Therapuetics: Consultancy; WUGEN: Current equity holder in private company; RiverVest: Consultancy; Celgene: Consultancy; Cell Works: Consultancy; Incyte: Consultancy; Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Bioline: Consultancy; Novimmune: Research Funding; Amphivena Therapeutics: Research Funding. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy. Kanter:bluebird bio, inc: Consultancy, Honoraria; 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; Novartis: Consultancy; Sanofi: Consultancy; Medscape: Honoraria; Guidepoint Global: Honoraria; 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; BEAM: Membership on an entity's Board of Directors or advisory committees. Glassberg:Eli Lilly and Company: Research Funding; Pfizer: Research Funding; Global Blood Therapeutics: Consultancy. Shah:Bluebird Bio: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; CSL Behring: Consultancy; Alexion: Speakers Bureau.

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Sickle-Cell Disease Patients' Attitudes Towards Their Treatment with Hydroxycarbamide

Blood ◽

10.1182/blood-2019-125673 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1013-1013

Author(s):

Frédéric Galactéros ◽

Ersi Voskaridou ◽

Anoosha Habibi ◽

Giovanna Cannas ◽

Laure Joseph ◽

...

Keyword(s):

Sickle Cell Disease ◽

Board Of Directors ◽

Sickle Cell ◽

Research Funding ◽

Fetal Hemoglobin ◽

Treatment Discontinuation ◽

Cell Disease ◽

Advisory Committees

Hydroxyurea (HU) is approved in the EU and USA for prevention of vaso-occlusive crises (VOC) including acute chest syndromes (ACS) in patients over 2 years with sickle-cell disease (SCD). The major benefits of HU in SCD are directly related to its abilities to increase HbF, decrease sickling of red blood cells and hemolysis, leading to reduction of vaso-occlusive episodes, need for blood transfusions and consequently reduction of morbidity and mortality. Adherence to the treatment is paramount for effectiveness, but in spite of proven benefits, barriers to adherence persist.[1] ESCORT-HU study (European Sickle Cell Disease COhoRT - HydroxyUrea), is a multicentric, prospective, non-interventional European study designed to evaluate the safety profile of HU in real life. Patients were enrolled from January 2009 to June 2017 with a follow-up of up to 10 years. All interruptions and resumptions of HU treatment exceeding 15 days were recorded in this study. We hereby present the analysis of the group of patients who self-discontinued HU at least once during the study before informing their caregiver, with a view to identify potential barriers to long-term adherence. In total, 1906 patients were enrolled in ESCORT-HU from 63 centers in France, Germany, Greece and Italy. Of these, 619 patients (32%) stopped HU for over 15 days at least once, and around a third (11% of all patients) were due to patient's will. The mean duration of HU treatment before the first discontinuation was 4.8 ± 5.1 years. Data are summarized in table 1. Compared to the rest of the cohort, the 'treatment discontinuation' group had similar distribution by gender and indication for HU prescription, but a higher proportion of adults stopped HU more than 15 days. It is notable that the proportion of patients with SC genotype was higher in the 'treatment discontinuation' group (4.5% vs 1.7%). The patients in the 'treatment discontinuation' group had more frequent SCD symptoms before enrolment in the study (table 2). Hematological and clinical improvement compared to the baseline was observed in both groups. However, average mean Corpuscular Volume (MCV) and Fetal Hemoglobin percentage (HbF%) were lower and mean percentages of patients with SCD symptoms were higher over the three years of follow-up in the 'treatment discontinuation' group, suggesting that HU daily dose was insufficient (table 2). Sixty patients have no treatment resumption date reported which suggest a permanent interruption of their treatment. Among them 32% preferred to switch to another HU medicinal product and 13% have safety issue (table 3). Understanding and managing self-discontinuation of HU before taking medical advice is challenging for the physician. It is tempting to speculate that it may be due, at least in part, to lack of effectiveness potentially due to an underdosage of the treatment. Resistance to the treatment may also be suggested based on past literature data revealing a great variability in the response (determined by HbF%) to HU therapy. There is evidence that genetic modifiers affect individual response to HU.[2],[3] Finally, weariness from long-term use may also explain the patient's wish to discontinue HU. But treatment at optimal effective should be the primary goal of caregivers. [1]Smaldone A., Manwani D., Green NS, Greater number of perceived barriers to hydroxyurea associated with poorer health-related quality of life in youth with sickle cell disease, Pediatr Blood Cancer. 2019 [2] Steinberg MH, Voskaridou E, Kutlar A, Loukopoulos D, Koshy M, et al. (2003). Concordant fetal hemoglobin response to hydroxyurea in siblings with sickle cell disease. Am J Hematol 72: 121-126 [3] Ware RE, Despotovic JM, Mortier NA, Flanagan JM, He J, et al. (2011) Pharmacokinetics, pharmacodynamics, and pharmacogenetics of hydroxyurea treatment for children with sickle cell anemia. Blood 118: 4985-4991 Disclosures Galactéros: Addmedica: Membership on an entity's Board of Directors or advisory committees. Voskaridou:Celgene Corporation: Consultancy, Research Funding; Protagonist: Research Funding; Genesis: Consultancy, Research Funding; Acceleron: Consultancy, Research Funding; Addmedica: Membership on an entity's Board of Directors or advisory committees. Cannas:Addmedica: Membership on an entity's Board of Directors or advisory committees.

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Real World Evidence of Prescription Patterns and Effect of Oxbryta (voxelotor) for Patients with Sickle Cell Disease

Blood ◽

10.1182/blood-2020-143434 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 31-32

Author(s):

Nirmish Shah ◽

Ahmar Urooj Zaidi ◽

Michael U. Callaghan ◽

Darla Liles ◽

Clarissa E. Johnson ◽

...

Keyword(s):

Clinical Trial ◽

Board Of Directors ◽

Sickle Cell ◽

Real World ◽

Research Funding ◽

Cell Disease ◽

Advisory Committees ◽

Real World Evidence ◽

Disease Modifying

Background: Sickle cell disease (SCD) is a chronic illness characterized by anemia, recurrent severe pain and recurrent organ damage, affecting approximately 100,000 persons in the United States. Prior to November 2019, FDA approved SCD disease-modifying treatments included only hydroxyurea (HU) and L-glutamine. However, voxelotor (Oxbryta®) was recently approved under an accelerated approval based on the HOPE study for the treatment of adult and pediatric patients with SCD 12 years of age and older. We aimed to provide real world evidence of the types of patients prescribed voxelotor and preliminary evidence of potential treatment effects. Methods: Patient records were reviewed from five medical centers with comprehensive sickle cell care. All patients prescribed voxelotor from Nov 25, 2019 to July 31, 2020 were included in our analysis. Data reviewed included: patient demographics, hydroxyurea use, as well as pre- and post- voxelotor changes on red cell transfusion number, vaso-occlusive crisis (VOC) and hemoglobin (Hb) values. In addition, voxelotor dosage changes, side effects, and patients perception on impact on their health were recorded. Descriptive and summary statistics were used to provide results. Results: We reviewed data from 60 patients (18 pediatric and 42 adult), across the five centers, who were prescribed voxelotor. Mean age was 33 (SD 13.8) years old with 63% female patients. All patients were African-American/Black and 96% were HbSS (2% Hb SC and 2% HbSOArab). Eighty (80)% were on hydroxyurea, 20% were on chronic transfusions, and 10% were on erythropoietin stimulating agents when prescribed voxelotor. Mean baseline hemoglobin during the 3 months prior to initiation was 7.38 g/dL (SD 1.46) with all patients started at the recommended dose of 1500mg. Annualized VOC events for the year prior to starting voxelotor was 0.62 (SD) or 7.44 VOCs per year. Across all sites, 31 patients were prescribed voxelotor but had either not initiated drug, not returned for follow up labs at time of analysis, or refused to take drug once approved (n=1). Nine patients had only 1 month of follow labs to review and an additional 18 patients with 3 months of follow up labs. These 27 patients were followed for an average of 6.0 months (SD 7.7) on treatment with 4 patients (15%) requiring dose adjustment to 1000mg. Dose adjustments were for side effects including abdominal pain, diarrhea, loose stools and nausea/vomiting. One patient had dosing changed from daily to three times a day. Average hemoglobin during steady state after 1 and 3 months of treatment were 8.6 g/dL (SD 1.8) and 8.0 g/dL (SD 1.8), respectively. In addition, 52% increased by 1g/dL at 1 month (n=21) and 44% increased by 1g/dL at 3 months (n=18). The mean maximum hemoglobin obtained during the 3-month period following initiation of voxelotor was 8.9 (SD 2.1) g/dL. During follow up visits, several patients reported 'more energy' and improvement in 'morning achiness' and 'quality of life', while a few patients noted no change in stamina or well-being. Three patients (5%) had drug discontinued due to becoming pregnant, unexplained elevation of liver enzymes, and due to excessive abdominal pain and nausea. Annualized VOC rates after voxelotor initiation were numerically decreased, although limited by short follow up. Conclusion: We present real world evidence of prescribing patterns and initial outcomes from the use of newly approved voxelotor. We found the majority of patients prescribed voxelotor were the HbSS genotype, on hydroxyurea, and with a mean baseline Hb <7.5 g/dL, indicating an initial focus on more anemic patients. Interestingly, one-fifth of the prescribed patients where on chronic transfusions. Consistent with the HOPE trial, the average Hb levels was found to have increased at 1 month and 3-month follow up. Our preliminary results support an overall increase in hemoglobin in patients treated with voxelotor and we aim to continue following patients over a longer follow up period. This provides important real-world evidence for this newly approved disease-modifying therapy for SCD. Disclosures Shah: Alexion: Speakers Bureau; CSL Behring: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Global Blood Therapeutics: Consultancy, Research Funding, Speakers Bureau; Bluebird Bio: Consultancy. Zaidi:Global Blood Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Emmaus Life Sciences: Consultancy, Honoraria; Imara: Consultancy, Honoraria; bluebird bio: Consultancy, Honoraria; Cyclerion: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Callaghan:Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Research Funding; Sancillio: Other; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NovoNordisk: Other, Speakers Bureau; Biomarin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Site Investigator/sub-I Clinical Trial, Speakers Bureau; Global Blood Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; Alnylum: Current equity holder in publicly-traded company; Bioverativ: Membership on an entity's Board of Directors or advisory committees; Spark: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Hema Biologics: Honoraria, Membership on an entity's Board of Directors or advisory committees. De Castro:Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; FORMA Therapeutics: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Eculizumab Protects Against TE and Prolongs Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: An International PNH Registry Study

Blood ◽

10.1182/blood.v120.21.3480.3480 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3480-3480

Author(s):

Gérard Socié ◽

Hubert Schrezenmeier ◽

Petra Muus ◽

Jeffrey Szer ◽

Alvaro Urbano-Ispizua ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Board Of Directors ◽

Cumulative Incidence ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Advisory Committees ◽

Significant Protective Effect ◽

Rbc Transfusion

Abstract Abstract 3480 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a chronic and life-threatening hematopoietic stem cell disorder characterized by uncontrolled complement-mediated hemolysis. PNH, in large part due to chronic hemolysis and platelet hyperactivation, is associated with thromboembolism (TE), one of the leading causes of disease mortality. Eculizumab, a monoclonal antibody that inhibits terminal complement activation, has been shown in clinical trials to reduce hemolysis and the incidence of TE. The International PNH Registry provides the opportunity to understand from real world experience the impact of eculizumab on TE reduction in PNH patients. Aim: To assess the risk factors for TE and mortality in PNH patients enrolled in the Registry and to assess the effectiveness of eculizumab in reducing PNH-associated TEs. Methods: Patients are eligible for the Registry if they have a detectable PNH clone, regardless of disease severity, comorbidities, or treatments (past, current or planned). As of June 30, 2012, there were 1547 patients enrolled from 25 countries on 5 continents. Patients were excluded from analysis if they were missing key demographic variables or dates of eculizumab use, or did not yet have follow-up information. The cumulative incidence of TE was determined using competing risks methods to take into account bone marrow transplantation and death, while Kaplan-Meier methods were used for the cumulative incidence of mortality. Risk factors for TE and mortality were explored using a Cox proportional hazards model with stepwise selection (the significance level was relaxed to P=0.20 due to the small number of events for analysis). Variables examined in the models included: ethnicity; prior TEs, bone marrow disorders, impaired renal function, impaired hepatic function (IHF), abdominal pain, dysphagia, dyspnea, easy bruising/bleeding, fatigue, headache, hemoglobinuria, Karnofsky performance score, granulocyte clone size and lactate dehydrogenase (LDH) at enrollment, red blood cell (RBC) transfusions 6 months prior to enrollment as a marker for hemolysis, and treatments after enrollment (eculizumab and warfarin/heparin). Results: The mean age of the 1047 patients eligible for analysis was 45 years; 537 patients (51.3%) were female and 868 were Caucasian (82.9%). Anti-coagulants (heparin/warfarin) were used by 28% of patients and eculizumab was used by 51% during follow-up (18% used both). During a mean (SD) follow-up of 22.5 (18.4) months, 16 patients had a TE and 51 were deceased. Patients taking eculizumab during follow-up had a cumulative incidence of TE at 1 year of 0.41% and 1.35% at 2 years, while patients not taking eculizumab had TE incidence of 1.70% and 2.61% at 1 and 2 years, respectively. In the multivariate Cox model, the greatest associations with TE were RBC transfusions in the 6 months before enrollment (hazard ratio [HR]=9.61), history of IHF (HR=4.78), dyspnea (HR=2.42) and headache (HR=2.33) at enrollment. While controlling for these variables, eculizumab had a significant protective effect (HR=0.23, 95% CI = 0.08–0.66). The cumulative incidence of mortality in eculizumab-treated patients was 2.31% and 4.21% at 1 and 2 years, while in untreated patients it was 4.40% and 7.01%, respectively. In the multivariate model of mortality, the greatest associations were age 60+ years (HR=4.72), Karnofsky score <80 (HR=2.34), fatigue at enrollment (HR=1.94), and recent RBC transfusion (HR=1.75). While controlling for these variable, eculizumab had a significant protective effect (HR=0.41, 95% CI = 0.23–0.73). Conclusions: This analysis of a large international cohort of ‘real world’ patients with PNH showed that eculizumab is associated with a significantly reduced risk of TE and mortality, consistent with prior research. Recent RBC transfusion, a surrogate marker for hemolysis, was associated with increased risk of TE and mortality. Several symptoms and hepatic dysfunction also showed increased risks for these outcomes. As might be expected, older age and low performance status were associated with mortality. These data should be interpreted within the context of a contemporary cohort of PNH patients who may or may not be treated (with either eculizumab and/or anticoagulation). These analyses are limited due to small number of TE and mortality outcomes. Disclosures: Muus: Alexion Pharmaceuticals : Sat on advisory board of Alexion Pharmaceuticals. Other. Urbano-Ispizua:Alexion Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Maciejewski:NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding. Kanakura:Shire: Consultancy. Rosse:Alexion Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara:Alexion Pharmaceuticals, Inc: Employment. Bedrosian:Alexion Pharmaceuticals: Employment, Equity Ownership. Hillmen:Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Validation of the International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET) in Patients with Pre-Fibrotic Primary Myelofibrosis

Blood ◽

10.1182/blood-2019-124302 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1657-1657

Author(s):

Paola Guglielmelli ◽

Alessandra Carobbio ◽

Elisa Rumi ◽

Valerio De Stefano ◽

Lara Mannelli ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Incidence Rate ◽

Research Funding ◽

Risk Model ◽

Univariate Analysis ◽

Thrombotic Event ◽

Advisory Committees ◽

Thrombotic Risk

Introduction. Prefibrotic myelofibrosis (pre-PMF) is a unique entity in the 2016 WHO classification of myeloproliferative neoplasms with distinct clinical phenotype and outcome [Guglielmelli P, Blood 2017]. Compared to essential thrombocythemia (ET), pre-PMF is characterized by more pronounced disease manifestations, adverse mutation profile and worse outcome. Previous studies [Rumi E, Oncotarget 2017] showed that patients (pts) with pre-PMF present a risk of vascular events similar to ET. However, no studies performed a comprehensive assessment of risk factors for thrombosis in pre-PMF. The current study aimed to identify risk factors for thrombosis and bleeding in a large series of pre-PMF pts and explore the effectiveness of contemporary prognostic models developed specifically for ET. Patients and Methods. The study included 382 pre-PMF pts, diagnosed by 2016 WHO criteria, referred by 4 Italian Centers. Previously published methods were used to genotype JAK2, MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2; a high molecular risk (HMR) category was defined according to Vannucchi A, [Leukemia 2013]. Thrombosis‐free survival (TFS) was determined from diagnosis to the first thrombotic event. Pts were grouped according to the conventional risk stratification system [Barbui T, JCO 2011], IPSET‐thrombosis [Barbui T, Blood 2012] and revised IPSET‐thrombosis [Barbui T, BCJ 2015]. Cox-regression model was used for univariate analysis. Harrell's concordance (C) statistic was calculated to measure the incremental accuracy of multivariable models sequentially adjusted for new predictors of thrombotic risk. A P <0.05 was considered statistically significant. Results. At diagnosis, 65 pts (17%) experienced major thrombotic events which included 35 (9%) arterial and 31 (8%) venous thromboses. With a median follow-up of 6.9 y (range 0.08-32.6), 56 (15%) pts developed an arterial or venous thrombotic event, with a total incidence rate of 1.99% pts/year (pt-y); 30 (8%) were arterial and 28 (7%) venous events with incidence rate of 1.00% pt-y and 0.95% pt-y, respectively. Splanchnic vein thrombosis (SVT) represented the most frequent venous events before/at diagnosis (26%). During the follow-up, 16% and 8% of pts experienced myelofibrotic or leukemic progression, and 105 (27%) died, with incidence rate of 2.05% pt-y, 0.95% pt-y and 3.41% pt-y, respectively. In univariate analysis, factors significant for arterial thrombosis after diagnosis were age >65y (HR 2.88; P=0.005), WBC>10x109/L (HR 2.43; P=0.026), presence of >1 generic CV risk factor (HR 2.16; P=0.047), JAK2V617F (HR 3.35; P=0.027) and HMR status (HR 13.1; P=0.027). Conversely, only history of previous thrombosis (HR 3.06; P=0.005) and previous venous event (HR 5.53; P<0.0001) retained significance for predicting venous thrombosis. Pts were effectively stratified according to IPSET and conventional risk model. The risk of thrombosis in IPSET low-, intermediate-, and high-risk categories was 0.67%, 2.05% and 2.95% pt-y, and 1.47% pt-y and 2.71% pt-y in 2-tiered thrombotic risk model. (Figure 1); in revised-IPSET, 0.54%, 2.23%, 2.44% and 2.69 %pt-y in the very low, low, intermediate- and high-risk category. When WBC>10x109/L or HMR variables were incorporated into IPSET model, the C-statistic increased significantly for the prediction of arterial events: from baseline value of 0.68 to 0.74 adding WBC and 0.91 HMR status. The proportion of pts who experienced major bleeding was 3% prior/at diagnosis,and 7% during follow-up, with total incidence rate of 0.94% pt-y. In univariate analysis, predictors for major bleeding during follow-up were age >75y (HR 3.34; P=0.011), WBC>13x109/L (HR 2.33; P=0.035), presence of >1 generic CV risk factor (HR 2.41; P=0.035), particularly hypertension (HR 2.63; P=0.016) and grade-1 fibrosis (HR 2.28; P=0.05). High platelet count and treatment, including antiplatelet and anticoagulant drugs, did not reach statistical significance. Conclusions. Overall, this study identified independent risk factors for major thrombosis and bleeding in pre-PMF. Of interest, we report that HMR status predicted for arterial thrombosis during the follow-up. Pre-PMF pts showed remarkably high rate of venous thrombosis, mostly represented by SVT. The 3-tiered IPSET prognostic model for thrombosis reliably predicted occurrence of thrombotic events in pre-PMF and should be considered as standard reference. Figure 1 Disclosures Rumi: novartis: Honoraria, Research Funding. Thiele:Shire: Research Funding; Incyte: Consultancy, Honoraria, Other: Remuneration, Research Funding; Sanofi: Consultancy, Honoraria, Other: Remuneration; Novartis: Consultancy, Honoraria, Other: Remuneration, Research Funding; AOP Orphan Pharmaceuticals: Consultancy, Research Funding. Vannucchi:Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Preliminary Results of a Phase II Study to Determine the Safety of Defibrotide in Children and Adolescents with Sickle Cell Disease-Associated Acute Chest Syndrome (IND 127812)

Blood ◽

10.1182/blood-2020-139617 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 8-9

Author(s):

Jordan Milner ◽

Deborah Friedman ◽

Marise D'Souza ◽

Krishnan Sankaran ◽

Liana Klejmont ◽

...

Keyword(s):

Chest Pain ◽

Pulmonary Function ◽

Board Of Directors ◽

Research Funding ◽

Pulmonary Infiltrate ◽

Acute Chest Syndrome ◽

Cell Disease ◽

Advisory Committees ◽

The Us

Background: Sickle cell disease (SCD) is a vasculopathy resulting in recurrent vaso-occlusive crises leading to endothelial dysfunction, chronic end-organ damage, poor quality of life, early mortality and the major curative therapy to date is allogeneic stem cell transplantation (AlloSCT) (Talano/Cairo, EJH, 2015). Acute chest syndrome (ACS) can result in pulmonary hypertension and is the leading cause of morbidity and mortality in patients with SCD (Gladwin et al, NEJM, 2008). ACS accounts for 25% of deaths (Vichinsky et al, Blood, 1997). Clinical definition of ACS is chest pain, fever, cough, dyspnea, and new pulmonary infiltrate on chest radiography. Defibrotide was approved in the US for the treatment of severe sinusoidal obstructive syndrome (SOS) with renal or pulmonary dysfunction following HSCT (Cairo et al, BJH, 2020). Defibrotide primarily targets endothelium in microvascular beds and has anti-inflammatory and anti-coagulant activity, which can treat the underlying pathophysiology of ACS (Falanga et al, Leukemia, 2003 and Scallia et al, Clin Pharm, 1996 and Pescador et al, Vasc Pharm, 2013). Objective: To determine the safety and toxicity of defibrotide in children, adolescents, and young adults with SCD-associated ACS. Design/Methods: Patients with SCD aged 2 to 40 years meeting ACS criteria (at least two of the following: fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on chest imaging, decreased oxygen saturation with or without supplemental oxygen requirements) and eligibility were enrolled within 72 hours of diagnosis after consent was obtained (NCT03805581). Baseline studies comprised of chest radiograph, CT chest angiogram, echocardiography with TRJ velocity and brachial artery reactivity, pulmonary function tests, and biomarkers (IFN-a and -g, TNF-a, IL-6, 8, and 10, sCD163, TSP-1, secretory phospholipase A(2), sVCAM-1, sTNFR1, Ang2, sTei-2, PAI-1, sICAM-1, sP-and sE-selectin, sPECAM-1, VEGF-A, C, D and sVEGFR1 and 2). Defibrotide was administered at 6.25mg/kg IV q6 hours and continued for 7 days or until time of discharge, whichever occurred earlier and patients were followed until day +30 following defibrotide. Dose limiting toxicities include Grade III/IV infusion/allergic reaction or hemorrhage probably or directly related to defibrotide. Results: We have enrolled thirteen patients aged 3 to 18 years with a gender ratio (M/F) of 4/9. Patients' genotypes are as follows: hemoglobin SS disease in nine patients, hemoglobin SC disease in two patients, and hemoglobin Sb0/+ thalassemia in two patients. Presenting symptoms included fever, chest pain, cough, dyspnea, tachypnea, pulmonary infiltrate on imaging, and hypoxia.Eight patients completed seven days of treatment, one patient received 6 days of treatment, three patients were discharged after three days of treatment, and one patient withdrew due to recurrent fevers unrelated to defibrotide. All but one patient had resolution of fevers prior to end of treatment. Patients required an average of 1.15 days of oxygen support, with one patient requiring high flow nasal cannula, and no patients required mechanical ventilation. There were no adverse events possibly, probably, or directly related to defibrotide. There was no evidence of hemorrhage in any patient despite four patients receiving concomitant ketorolac or ibuprofen. Of the eleven patients who had pulmonary infiltrates on imaging, eight were evaluated on day +30, two had complete resolution of infiltrate, five had improvements, and one had no change. Seven patients did not follow-up for echocardiography or pulmonary function testing and two of those patients were unable to be evaluated at day +30 due to COVID-19. Discussion: The preliminary data suggest defibrotide is safe and well tolerated in patients with SCD-related ACS. All patients at diagnosis have had baseline studies, which included biomarkers; however, only eight of the thirteen patients have completed all required observations due to poor compliance. After four patients were enrolled and three failed to follow-up, changes to appointment schedules were made with detailed information on all follow-ups. Efforts at improving compliance post therapy are ongoing. Further accrual is needed to determine clinical significance of improvements in cardiac and/or pulmonary function. This study was funded in part by a grant from Jazz Pharmaceuticals. Disclosures Cooke: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cairo:Nektar Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Technology Inc/Miltenyi Biotec: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Miltenyi: Research Funding. OffLabel Disclosure: Defibrotide is utilized in patients with acute chest syndrome to decrease the amount of time they are hospitalized and to assist in alleviating symptoms. Defibrotide is approved in the US for sinusoidal obstructive syndrome with renal or pulmonary dysfunction.

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Engraftment Syndrome in the Setting of Autologous Stem Cell Transplantation for Multiple Myeloma-a Single Institution Review of over 600 Patients

Blood ◽

10.1182/blood-2019-132052 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4576-4576

Author(s):

Sudarsan Kollimuttathuliam ◽

Phyllis McKiernan ◽

David S. Siegel ◽

Scott D. Rowley ◽

Noa Biran ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Clinical Manifestations ◽

Advisory Committees ◽

Autologous Transplant ◽

Engraftment Syndrome ◽

Equity Ownership ◽

Reduced Risk

Engraftment syndrome (ES) is a well-defined entity characterized by non-infectious fever and other clinical manifestations including skin rash, pulmonary infiltrates, diarrhea, weight gain and neurological symptoms which happens in the setting of autologous HSCT during early neutrophil recovery phase. (Spitzer ,2001).These clinical manifestations usually occur immediately before or at the time of neutrophil engraftment possibly due to the release of inflammatory cytokines. ES may require therapy with corticosteroids and other immunosuppressive drugs. Our study cohort included 645 patients with multiple myeloma treated with autologous stem cell transplantation between January 2010 and June 2019. The majority of patients had a single autologous transplant (80%), 18 % received a second autologous transplant and 3 patients had a third autologous transplant. Fifty seven percent of patients were male, 61 % had IgG myeloma and 50 percent had standard risk cytogenetics. Sixty three percent of patients were under the age of 65 years. ES was defined as a combination of at least 2 symptoms not attributed to other causes, including non-infectious fever, diarrhea, skin rash, pulmonary infiltrates or hepatic dysfunction, occurring from 3 days prior to 10 days post engraftment. (Cornell ,2015).One hundred and ninety seven patients in this cohort met the criteria for engraftment syndrome of whom 173 were treated with corticosteroids and 9 required the addition of tacrolimus or cyclosporine. Univariate and multivariate statistical analyses were performed looking at risk factors for the development of ES and the overall effect of ES on patient outcome. Results of our univariate analysis showed that age >65, female sex, use of plerixafor were significant risk factors for developing engraftment syndrome while use of cyclophosphamide-based mobilization had significantly reduced risk. Multivariate analysis using Gray Fine model revealed that patients over 65 years were twice as likely to develop ES than patients who were younger than 65 years (HR=1.881, CI: 1.405 to 2.518). Females had a 36% higher risk of ES than male patients (HR=1.355, CI: 1.011 to 1.815). Patients who were infused with more than 7x106 CD34+ cells/kg had a 40% reduced risk of developing ES (HR=0.559, CI: 0.385 to 0.812). Receiving the new formulation of melphalan: EVOMELAⓇ, as preparative regimen, was associated with a 60% increased risk of developing ES compared to patients treated with the standard formulation (HR=1.597, CI: 1.116 to 2.285). The use of plerixafor was found to be a risk factor for ES even when adjusted for age(HR=1.463,CI:1.024 to 2.089). Follow- up of patients that did not develop ES (n=445) had a median of 59 months (IQR: 29.0 -80.0months), range: 0 - 136 months. Follow-up time of patients that developed ES (n=197) was 41.0 months (IQR: 16.0 - 66.0 months), range: 0.0 - 131 months.An overall survival analysis of patients who developed engraftment syndrome showed a trend for improved survival in patients who did not develop engraftment syndrome, however this did not meet statistical significance and PFS curves were similar with no statistically significant difference between the two groups. Our study of this large cohort of patients suggests that selection of mobilization regimen and conditioning chemotherapy could decrease the incidence of ES, thereby decreasing morbidity and prolonged hospital stay. There can also be a consideration for pre-emptive treatment of patients in the very high risk category based on age, gender and available cell dose. Disclosures Siegel: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy. Biran:Amgen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; Bristol-Myers Squibb: Consultancy; COTA: Equity Ownership. Goy:Takeda: Other: Grants outside of the submitted work; Hackensack University Medical Center, RCCA: Employment; Acerta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Hakensackumc: Research Funding; University of Nebraska: Research Funding; Astrazenca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Other: Grants outside of the submitted work, Research Funding; Pharmacyclics/Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants outside of the submitted work; COTA: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: leadership role for profit healthcare company; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Use of Low Molecular Weight Heparin (LMWH) in Thrombocytopenic Patients with Hematologic Malignancy-Associated Venous Thromboembolism (VTE)

Blood ◽

10.1182/blood.v126.23.3482.3482 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3482-3482 ◽

Cited By ~ 1

Author(s):

Nabin Khanal ◽

R. Gregory Bociek ◽

Baojiang Chen ◽

Julie M. Vose ◽

James O. Armitage ◽

...

Keyword(s):

Platelet Count ◽

Retrospective Study ◽

Board Of Directors ◽

Research Funding ◽

Hematologic Malignancy ◽

Categorical Variables ◽

Advisory Committees ◽

Risk Of Bleeding ◽

Prophylactic Dose

Abstract Introduction: The management of hematologic malignancy-associated VTEin patients with moderate to severe thrombocytopenia is unclear. Clinical trials of anticoagulants in VTE exclude such patients, hence do not inform the risk of bleeding or clot progression. Consensus-based guidelines recommend case-by-case consideration for either platelet transfusion to maintain platelet count >50,000/µL and therapeutic anticoagulation, or 50% dose reduction in LMWH (J Thromb Haemost. 2013 Jan;11(1):56-70.; Curr Oncol. 2015 Apr;22(2):144-55). At our institution, our approach is to use prophylactic dose LMWH for patients with platelet count ≤50,000/µL. Method: This is a single-center retrospective study of 128 adult patients with hematologic malignancies, who were diagnosed with VTE. Patients were identified from hospital research database. The diagnoses were verified after the review of medical records. The platelet count was assessed during the period of anticoagulation for VTE. The outcomes of patients with significant thrombocytopenia (≤50,000/µL) was compared with those without. Bleeding and clot recurrence was assessed until the last follow-up (median of >1 month). Fisher's Exact test was used to test the association between two categorical variables, and Analysis of Variance (ANOVA) was used to test the association between a continuous variable and a categorical variable. Results: Characteristics of the study population were as follows: 51% male, 47% non-Hodgkin lymphoma, 20% acute leukemia/myelodysplastic syndrome, 40% status-post hematopoietic stem cell transplant, 9% with creatinine >2 mg/dl, 36% with pulmonary embolism and 28% with catheter-related VTE. Forty six patients (36%) had a platelet count ≤50,000/µL during a period of time of perceived need for new or continued anticoagulation. The median nadir platelet count in those with significant thrombocytopenia was 9000/µL( range 2000-45,000/µL) versus 166,000/µL (range 50,000-389,000/µL) in those without (p<0.001). The median duration of significant thrombocytopenia in the first group was 10 days (range 1-68 days). Therapy during the period of significant thrombocytopenia included prophylactic dosing of LMWH (46%), therapeutic dose of LMWH or heparin (30%), warfarin (2%), inferior vena cava filter (2%) and observation (17%). Patients without thrombocytopenia were managed with the standard of care therapy. At last follow-up, the risk of bleeding (p=0.65) and clot progression (p=0.81) were similar in the two groups (Table 1). Conclusion: Within the limits of this retrospective study, cautious use of dose-adjusted LMWH in thrombocytopenic patients with hematologic malignancy-associated VTE may be safe. A prospective trial of prophylactic dose LMWH in patients with VTE during thrombocytopenia is required to confirm the safety and, to some extent, efficacy of such an approach. Table 1. Outcome of patients with VTE Outcome Thrombocytopenic cohort (Platelet count ≤50,000/µL) Patients without significant thrombocytopenia (Platelet count >50,000/µL) p-value Bleeding after VTE treatment 0.65 No 38 (82.6%) 75 (91.5%) Minor (without significant clinical implications) 1 (2.2%) 1 (1.2%) Clinically significant (causing drop in hemoglobin; requiring transfusion or other interventions) 4 (8.7%) 5 (6.1%) Missing 3 (6.5%) 1 (1.2%) Clot progression or recurrence at last follow-up 0.81 No 35 (76.1%) 67 (81.7%) Yes 9 (19.6%) 15 (18.3%) Missing 2 (4.3%) 0 Disclosures Vose: Allos Therapeutics/Spectrum: Research Funding; US Biotest, Inc: Research Funding; Janssen Biotech: Research Funding; Celgene: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corp: Research Funding; Acerta Pharma: Research Funding; GlaxoSmithKline: Research Funding. Armitage:Celgene: Consultancy; Ziopharm: Consultancy; Spectrum: Consultancy; Roche: Consultancy; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Conatus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tesaro Bio, Inc: Membership on an entity's Board of Directors or advisory committees. Lunning:Spectrum: Consultancy; Genentech: Consultancy; BMS: Consultancy; Juno: Consultancy; Gilead: Consultancy; TG Therapeutics: Consultancy.

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The Interaction between IPSS Score and JAK2 Mutation Identifies Patients at Different Vascular Risk in Primary Myelofibrosis

Blood ◽

10.1182/blood-2021-145116 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 236-236

Author(s):

Tiziano Barbui ◽

Arianna Ghirardi ◽

Alessandra Carobbio ◽

Arianna Masciulli ◽

Greta Carioli ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Board Of Directors ◽

Research Funding ◽

Primary Myelofibrosis ◽

Vascular Risk ◽

Advisory Committees ◽

Jak2 Mutation ◽

Thrombosis Rate

Abstract BACKGROUND The rate of major arterial and venous thrombosis in primary myelofibrosis (PMF) and post-ET (PET) and post-PV (PPV) secondary myelofibrosis has been evaluated in a limited number of studies. In the present paper we describe the clinical epidemiology of thrombosis in a large series of patients with overt PMF and PPV/PET MF looking at the rate and risk factors. Moreover, we report findings on thrombosis rate in two cohorts of patients treated with Hydroxyurea (HU) or Ruxolitinib (Ruxo). METHODS Patients were registered in the European Registry for Myeloproliferative Neoplasms (ERNEST). This project, promoted by the European LeukemiaNet, is coordinated by FROM - Foundation for Research, Papa Giovanni XXIII Hospital, Bergamo (Italy) and supported by Novartis through a research collaboration . Patients were diagnosed in 6 Centers from Italy, Spain and Sweden, between Jan, 2001 and Dec, 2012, with the required follow-up information. Patients (n= 1010) with PMF (n=584, 59%), PET-MF (n=207, 20%) and PPV-MF (n=219, 21%) were evaluated for incident thrombosis as primary endpoint. Considering death as a competitive event, uni-and multivariate analyses were performed by applying Fine & Gray competing-risk regression models. RESULTS After a median follow-up of 3.8 years (IQR: 1.8-7.1) from diagnosis, 108 thromboses (10.7%) occurred, for an overall incidence rate of 2.0% pts-yr (95% CI: 1.7-2.5). Arterial thromboses were found in 50 patients (46.3%) including cerebral (n=21, 19.4%), myocardial infarction (n=13, 12.0%) and peripheral events (n=9, 8.3%). Venous thromboses were 58 (53.7%), of which 25 (23.0%) were DVT ± PE and 11 (10.2%) were splanchnic. Thrombosis rate was 1.91, 1.60 and 2.79% pts-yr in PMF, PET-MF and PPV-MF, respectively. In univariate analysis, factors significantly associated with an increased thrombotic risk in PMF were age (p=0.013) and the presence of the JAK2 mutation (p=0.003); in addition, a significant higher proportion of PMF patients at low and intermediate-1 vs intermediate-2 or high risk IPSS score, had thrombosis during the follow-up (p=0.008). In multivariate analysis, only JAK2 mutation retained statistical significance (SHR=3.12, 95% CI: 1.40-6.94, p=0.005). Conversely, neither in univariate nor in multivariable analysis, significant risk factors were not found.To investigate the possible interaction of IPSS score and JAK2 mutation we created a model whose results are presented in Fig. 1A: the cumulative incidence function (CIF) of thrombosis was significantly lower in patients with JAK2 wild-type and intermediate-2 or high IPSS score (CIF: 4% projected at 10 years; SHR=1 [reference category]), while patients at the highest risk for thrombosis harbored JAK2 mutation and were categorized at low or intermediate-1 by IPSS score (CIF: 20% projected at 10 years, SHR=7.13, p=0.008). Of note, thrombosis had a significant impact on mortality. After adjusting for sex, age, year of diagnosis, type of MF and IPPS, HR was 1.51, (95% CI. 1.15-1.98, p=0.003).The influence of drug exposure to incident thrombosis was investigated in two cohorts of 559 consecutive patients exposed to HU (n=470) or to Ruxo (n=89), median treatment 2.6 and 3.0 years, respectively. HU- compared to Ruxo-treated patients were older (median age 67 vs. 63 years, p=0.001), more frequently triple negatives (12% vs. 2%, p=0.036), less splenomegalic (spleen length >10 cm: 30% vs. 88%, p <.001) and less symptomatic (49% vs. 79%, p=0.031). Of note, median time from MF diagnosis to therapy start in Ruxo group was 4 years, whereas patients started HU at MF diagnosis. In 56 of 89 Ruxo-treated patients (62.9%), the drug was given after a prior HU therapy. The thrombosis rate from the time of initiation of therapy was 2.40% pts-yr (95% CI 1.78-3.24) under HU and 1.28% pts-yr (95% CI 0.48-3.41) under Ruxo (CIF curves in Fig. 1B). In multivariate analysis corrected for MF type, DIPPS at first drug administration, JAK2 mutation and time from MF diagnosis, exposure to Ruxo showed a non-significant trend towards a protection of approximately 70% compared to HU (SHR=0.33, 95% CI: 0.08-1.32, p=0.117). CONCLUSION IPSS score, in addition to the survival risk assessment, may be useful, if associated with the JAK2 mutation, to recognize patients at vascular risk and to suggest appropriate anti-thrombotic prophylaxis. The trend towards a benefit of Ruxo, compared to HU, warrants a study in larger case series. Figure 1 Figure 1. Disclosures Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Passamonti: Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau. Vannucchi: Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures.

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