Hematuria Is Not a Risk Factor for the Hypertension of Hemophilia

Abstract Introduction: Advances in hemophilia care have led to improved life expectancy and a cohort at risk for age-related comorbidities such as hypertension and cardiovascular diseases. Several studies have shown an increased prevalence of hypertension in patients with hemophilia compared to age-matched general population. However, causes of the increased prevalence of hypertension in patients with hemophilia are unclear. Hemophilia-specific risk factors such as renal bleeding or micro-bleeding may be implicated, but data are limited and conflicting regarding the association between hematuria, renal insufficiency and hypertension. In this two-centre prospective cohort study, we aim to assess the prevalence of gross or microscopic hematuria detected on routine surveillance urinalysis and microscopy, and determine the impact of hematuria on blood pressure and renal function. Methods: 135 adult males with mild-severe hemophilia A and B followed by the British Columbia Adult Bleeding Disorders Program (n=56) and the University of California, San Diego Hemophilia Treatment Center (n=79) were included. Screening urinalysis/microscopy were performed in all patients during routine clinic visits. Hematuria was defined as either a self-reported history of gross hematuria, or > 3 red blood cells per high-power field on urine microscopy in the absence of urinary tract infections. Hypertension was defined as systolic blood pressure (SBP) ≥140mmHg or diastolic blood pressure (DBP) ≥90mmHg on ≥2 occasions, or use of anti-hypertensive medications. Univariate and multivariate logistic regression analysis were used to examine the significance of hematuria and other potential hypertension risk factors. Results: The prevalence of hypertension was 44% in this population, 71% of whom were on anti-hypertensives, of whom 43% achieved blood pressure control (SBP <140 mmHg, and DBP <90mmHg) at last clinic visit. The median age was 42 years (IQR 30-57 years). On univariate analysis, patients with hypertension tended to be older (median age 56 years vs 35 years, P<0.001), had a higher prevalence of diabetes (17% vs 1%, P=0.001), dyslipidemia (35% vs 11%, P<0.001), and obesity (BMI >30; 32% vs 13%, P=0.012) compared to patients without hypertension. Despite the high prevalence of hematuria (34%), chronic kidney disease was rare (2%). On multivariate analysis, only age remains as a significant predictor of hypertension. Hematuria was associated with neither hypertension nor renal insufficiency and was not more prevalent in severe hemophilia. Conclusion: Hypertension was prevalent in our cohort of patients with hemophilia, but not optimally controlled. Hematuria was prevalent, not associated with a diagnosis of hypertension or renal dysfunction, and could not explain the hypertension while renal disease was rare. Larger prospective studies are needed to better elucidate the risk factors and mechanisms for increased prevalence of hypertension in the hemophilia population. Disclosures Sun: Baxter: Other: AHCDC/Baxter fellowship training award. Von Drygalski:Baxalta: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Biogen: Consultancy, Honoraria, Speakers Bureau; CSL Behring: Consultancy, Honoraria, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Speakers Bureau; Grifols: Consultancy, Honoraria, Speakers Bureau; Hematherix LLC: Membership on an entity's Board of Directors or advisory committees. Jackson:Biogen: Honoraria, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees.

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Risk Factors for Thrombosis Among 1,545 Patients with Polycythemia Vera: An International Study.

Blood ◽

10.1182/blood.v120.21.2849.2849 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2849-2849

Author(s):

Guido Finazzi ◽

Elisa Rumi ◽

Alessandro M. Vannucchi ◽

Maria Luigia Randi ◽

Ilaria Nichele ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Myeloproliferative Neoplasms ◽

Univariate Analysis ◽

Abnormal Karyotype ◽

Advisory Committees ◽

Free Survival ◽

History Of

Abstract Abstract 2849 Background We have previously reported on the natural history of polycythemia vera (PV), focusing primarily on overall and leukemia-free survival (ASH Annual Meeting Abstracts. 2011;118(21):277-). In the current study, we present, on behalf of the International Working Group for Myeloproliferative neoplasms Resarch and Treatment (IWG-MRT), our analysis regarding risk factors for thrombosis. Methods Under the auspices of IWG-MRT, seven international centers of excellence for myeloproliferative neoplasms participated in the current study. The two principle investigators (AT and TB) reviewed all the cases and selected 1,545 patients who met the 2008 WHO criteria for PV, were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features Median age was 61 years (range, 18–95; 51% females). Arterial and venous thrombosis history before or at diagnosis was documented in 246 (16%) patients and 114 (7.4%) patients, respectively. Major hemorrhage hemorrhage before or at diagnosis was documented in 17 (4.5%) patients. Other features at diagnosis included pruritus (36%), microvascular disturbances (28.5%), palpable splenomegaly (36%), abnormal karyotype (12%), leukoerythroblastosis (6%), increased LDH (50%), thrombocytosis (53%), extreme thrombocytosis (platelets >1 million mm3; 4%) leukocytosis (49%), JAK2 V617F (95%), other JAK2 mutations (3%), subnormal serum erythropoietin (Epo) level (81%), and endogenous erythroid colonies (EEC; 73%). History of hypertension (46%), hyperlipidemia (18.3%), diabetes (8.4%), and tobacco use (16%) was also obtained. Results II: Clinical Course To date, 347 (23%) deaths, 50 (3%) leukemic progressions, and 138 (9%) fibrotic transformations have been recorded. Overall, cytoreductive treatment was not used in 416 (27%) patients and the remaining were exposed to different agents based on physician discretion. Post-diagnosis arterial or venous thrombosis occurred in 184 (12%) and 137 (9%) patients, respectively. Results III: Risk Factors for thrombosis Arterial and venous thrombosis-free survival, from time of diagnosis, were separately analyzed using the occurrence of thrombosis as the endpoint (uncensored variable) and last follow-up or death before thrombosis as the censored variable. In univariate analysis, the following were significantly associated with post-diagnosis arterial thrombosis: advanced age, leukocyte count, presence of a leukoerythroblastic smear (LES), history of hypertension and history of arterial thrombosis before or at diagnosis; multivariable analysis using all these five parameters identified arterial thrombosis history (RR 2.5, 95% CI 1.6–4.0; p<0.0001), LES (RR 2.3, 95% CI 1.3–4.2; p=0.005) and history of hypertension (RR 1.6, 95% CI 1.1–2.4; p=0.02) as independent predictors of post-diagnosis arterial thrombosis. Only two parameters predicted post-diagnosis venous thrombosis, in univariate analysis, and both remained significant during multivariable analysis: abnormal karyotype (RR 3.1, 95% CI 1.7–5.4; p=0.0001) and history of venous thrombosis (RR 2.4, 95% CI 1.2–4.9). Of note, the type of JAK2 mutation or presence of either subnormal Epo or EEC did not influence either arterial or venous thrombosis. Results IV: Risk Stratification for arterial and venous thrombosis The figures below illustrated arterial or venous thrombosis-free survival of patients stratified by the absence of all risk factors or presence of one or ≥2 risk factors. For arterial thrombosis, the presence of ≥2 risk factors clearly delineated a high risk group (RR 3.1, 95% CI 1.9–5.0) whereas the presence of one (RR 2.4, 95% CI 1.4–4.2) or two risk factors (RR 10.1, 95% CI 3.6–28.2) for venous thrombosis delineated an intermediate and high risk group, respectively. Conclusions: History of arterial thrombosis and venous thrombosis are key risk factors, respectively, for recurrent arterial and venous thrombosis in PV. In addition, abnormal karyotype is a strong independent risk factor for venous thrombosis and the presence of leukoerythroblastosis and hypertension, for arterial thrombosis. This information allows for a simple and practical risk stratification and raises interesting pathogenetic implications that require further clarification. Disclosures: Vannucchi: Novartis: Membership on an entity's Board of Directors or advisory committees. Gisslinger:Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Passamonti:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Impact of Day 28 Absolute Lymphocyte Count on Outcome of Adult Patients with Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v124.21.5256.5256 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5256-5256

Author(s):

Naresh Bumma ◽

Jing Ai ◽

Xuefei Jia ◽

Sean Hobson ◽

Donna Abounader ◽

...

Keyword(s):

Overall Survival ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Lymphocyte Count ◽

Myeloid Leukemia ◽

Univariate Analysis ◽

Absolute Lymphocyte Count ◽

Advisory Committees ◽

The Impact ◽

Acute Myeloid

Abstract Introduction: Lymphocyte recovery after induction chemotherapy (IC) predicts outcome in adult patients (pts) with acute myeloid leukemia (AML) (Behl et al. Leukemia 2006; 20: 29-34). However, it is unknown whether absolute lymphocyte count (ALC) recovery after IC predicts outcome in those pts who are then treated with allogeneic hematopoietic stem cell transplant (AHCT) in first complete remission (CR1). We hypothesized that the prognostic impact of ALC might be nullified by AHCT in CR1 due to the abrogation of normal immunologic recovery. In this study, our aims were to (1) evaluate the impact of Day 28 ALC on all AML pts receiving IC and (2) to specifically, evaluate the impact of Day 28 ALC on the subset of AML pts proceeding to AHCT in CR1. Methods: A retrospective chart review of 180 adult AML pts (≥ 18 years of age) who were treated with IC during the years 2001- 2012 at the Cleveland Clinic was performed. Institutional Review Board approval was obtained. Pts with acute promyelocytic leukemia were excluded . Ninety-four of the 180 pts received AHCT in CR1. A total of 141 AML pts receiving IC and a total of 66 pts receiving IC and then receiving AHCT in CR1 were eligible for data analysis because Day 28 ALC was missing in the remainder of the pts. Prior studies in AML identified an ALC of < 500/ µL at Day 28 of IC as predictive of overall survival. We stratified Day 28 ALC into the following categories: (a)< 250/ µL (b) < 350/ µL (c) < 500/ µL and (d) < 500/ µL for Max ALC [Max ALC was defined as the maximum ALC value between days 26 and 30 after the initiation of IC]. Other variables collected included age at diagnosis, WBC at diagnosis, and cytogenetic (CG) risk. CG risk was ascribed by CALBG criteria. The Kaplan-Meier method was used to summarize overall survival (OS) and relapse-free survival (RFS), which were measured for all pts from the time of diagnosis. The log-rank test was used for univariate analysis of categorical factors and the Cox proportional hazards model was used for measured factors and multivariate analysis. We performed two separate analyses : one for all AML pts (n=141); and a second analysis only focusing on those receiving AHCT in CR1 (n=66). Results: Pt characteristics for the entire AML cohort: The median age was 58.0 years (20.0-80.0); 46.1% female. The median WBC at diagnosis was 11.6 K / µL (range 0.7-220.7) and median Day 28 ALC was 400/ µL (0-2.4). Twenty-seven pts (19.7%) had favorable CG, 84 (61.3%) intermediate, and 26 (19.0%) unfavorable. Most pts (91%) received "7+3" IC and 93 (66%) also received at least 1 cycle of post-remission chemotherapy. On univariate analysis, age ≥60 (HR 2.72, p< 0.001), CG risk (HR 2.13, p < 0.001), Day 28 ALC < 250/ µL (HR 1.60, p=0.022), Day 28 ALC < 350/ µL (HR 1.57, p=0.029), and max ALC < 500/ µL (HR 1.54, p=0.035) were associated with a worse OS from the initiation of treatment. Low ALC was associated with both a higher incidence of refractory disease and death during induction (p=0.015). In our second analysis of pts undergoing AHCT in CR1, although not statistically significant, max ALC < 500/ µL (during IC) was associated with a trend towards decreased OS from the start of treatment on both univariate (HR 1.88,p= 0.13) and multivariate (HR 2.16, p=0.075) analysis. Conclusions: Max ALC < 500/ µL is predictive of outcome in AML pts undergoing IC, and there is a suggestion that this effect may not be abrogated by AHCT. A larger study will be needed to further confirm these findings. Therapies to improve lymphocyte recovery may be important in the treatment of AML. Disclosures Sekeres: Boehringer-Ingelheim Corp: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Corp: Membership on an entity's Board of Directors or advisory committees.

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Risk Factors for Severe Form of COVID-19 after Allogeneic Hematopoietic Stem Cell Transplantation: A SFGM-TC Multicentre Cohort Study

Blood ◽

10.1182/blood-2020-138411 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 34-34

Author(s):

Alienor Xhaard ◽

Constance Xhaard ◽

Maud D'Aveni ◽

Hélène Salvator ◽

Marie-Laure Chabi-Charvillat ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Intensive Care ◽

Platelet Count ◽

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Immunosuppressive Treatment ◽

Severe Form ◽

Advisory Committees

COVID-19 greatly affected Europe between March and May 2020. Initial reports suggest cancer and haematological malignancies as risk factors for severity and mortality, but the role of allogeneic stem cell transplantation (alloHSCT) remains unclear. The Société Francophone de Greffe de Moelle et Thérapie Cellulaire conducted a multicentre retrospective study of alloHSCT recipients diagnosed with COVID-19. We described the COVID-19 disease characteristics in this population and examined risk factors for severity and mortality. Data were collected retrospectively from the patients' charts and the ProMISe database. Diagnosis was retained only if a reverse transcription polymerase chain reaction assay test from a nose swab was positive for SARS-CoV-2. Patients were classified as severe if they were transferred to an intensive care unit (ICU) due to COVID-19 or died of COVID-19, and non-severe in other cases. Comparisons of characteristics were performed using student's t-tests and Mann-Whitney U tests for normally and abnormally distributed data, respectively, for continuous variables and χ2 or Fisher's exact tests, when appropriate for categorical variables. Risk factors associated with a severe form of COVID-19 were assessed using both univariate and multivariate logistic regressions. All analyses were performed using SAS version 9.4.6 (SAS Institute Inc., Cary, NC, USA. A two-tailed significance level p<0.05 was used. Fifty-four patients were diagnosed, including 21 with severe forms (intensive care transfer and/or death). Haematological characteristics did not vary between patients with severe or non-severe forms of COVID-19. Patients with a severe form of COVID-19 were more likely to be diagnosed earlier after alloHSCT (0.78 vs. 2.1 years, p=0.01), to have comorbidities (80.9% vs. 54.5%, p=0.05) and to receive immunosuppressive treatment (81% vs. 51.5%, p=0.03). Severe COVID-19 patients were more likely to have symptoms at COVID-19 diagnosis (100% vs. 81.8%, p=0.04), especially pneumonia and symptoms other than respiratory or digestive (asthenia, neurological symptoms, myalgia, dysgeusia, skin lesions and arthralgia), and to experience co-infection during the course of the disease (52.4% vs. 21.2%, p= 0.001). At COVID-19 diagnosis, patients with a non-severe form were more likely to have a higher platelet count (226 G/L vs. 98 G/L, p= 0.01), while other biological characteristics did not vary between the two cohorts. In univariate analysis, shorter time from transplant to COVID-19 (before 211 days, p=0.01), pneumonia (OR 12.21 [95% CI 2.43 - 61.46], p=0.002), symptoms other than pulmonary or digestive (OR 1.21 [95% CI 1.02 - 11.16], p=0.04), immunosuppressive treatment (OR 5.97 [95% CI 0.75 - 47.42], p=0.03) , co-infection (OR 5.84 [95% CI 1.65-20.63], p=0.006) and comorbidity (OR 3.54 [95% CI 0.98-12.83], p=0.05) were associated with severe COVID-19. The only biological parameter associated with severity was a lower platelet count <71G/L (OR 28.00 [95% CI 2.07-379.25]), p=0.008. In multivariate analysis, pneumonia and other symptoms retained a significant association with severe COVID-19. Thirteen patients died of COVID-19: in univariate analysis, risk factors for death from COVID-19 were similar to the risk factors for severe COVID-19 (i.e. shorter time from alloHSCT, p=0.03; pneumonia, p=0.01; co-infection during the course of COVID-19, p<0.01, and lower platelet count, p<0.01). In multivariate analysis, none of the above mentioned factors remained significantly associated with death from COVID-19. As SARS-CoV-2 continues to spread internationally, given the lack of vaccine or treatment, alloHSCT recipients should maintain a high level of awareness to avoid contamination. Figure Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Bellicum: Consultancy, Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Orchard: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rubio:MSD: Honoraria; Novartis: Honoraria; Neovii: Research Funding; Medac: Consultancy; Gilead: Honoraria.

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Mutations Highly Specific for Secondary AML Are Associated with Poor Outcomes in Patients with NPM1-Mutated ELN Favorable Risk AML

Blood ◽

10.1182/blood-2021-150759 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 686-686

Author(s):

Onyee Chan ◽

Najla Al Ali ◽

Hammad Tashkandi ◽

Austin Ellis ◽

Somedeb Ball ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Prognostic Significance ◽

Cancer Center ◽

Cell Transplant ◽

Intermediate Risk ◽

Advisory Committees ◽

Secondary Aml ◽

The Impact

Abstract Background: NPM1 is commonly mutated in acute myeloid leukemia (AML) and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by European LeukemiaNet (ELN) 2017 criteria. Mutations that are highly specific for secondary AML including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (sMut) (Lindsley et al.) have been shown to confer poor prognosis. The impact of these mutations on NPM1-mutated AML warrants further investigation. Objective: In this study, we explore the outcomes in patients with NPM1-mutated AML. Methods: This was a retrospective study of NPM1-mutated AML patients who were diagnosed and treated at the Moffitt Cancer Center from 2013 to March 2021. Inclusion was restricted to NPM1-mutated patients with mutation analysis (NGS) performed at diagnosis (n=159). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Among 159 patients (78M/81F, median age 63 years at diagnosis), 80.5% had de novo AML. By ELN 2017 criteria, 63.5% (101/159) had favorable risk, 27.7% (44/159) had intermediate risk, and 8.2% (13/159) had adverse risk disease. Almost 90% had intermediate risk cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.2%), FLT3-ITD (35.8%), TET2 (26.4%), IDH1 (17.6%), FLT3-TKD (15.1%), and IDH2 (13.8%). sMut comprised 19.5% (31/159) of patients and 20.8% (21/101) of those with ELN favorable risk. In patients with treatment response data, those with sMut never achieved CR/CRi in 35.7% (10/28) compared to 17.2% (22/128) of patients without sMut (p=0.038). The overall survival (OS) was 43.7 months with a median follow up of 35.5 months. Patients with sMut had worse OS compared to those without sMut (14.7 months vs 57.6 months, p=0.011). Among patients with favorable risk disease, OS was 11.6 months compared to not reached for those with sMut and without sMut, respectively (p<0.0001). Univariate analysis showed sMut and allogeneic hematopoietic cell transplant (HCT) significantly impacted OS (sMut: HR 3.48, 95% CI: 1.80-6.72, p<0.001; HCT: HR 0.17, 95% CI: 0.07-0.44, p<0.001). Multivariate regression using covariates including age, AML type, sMut, and HCT confirmed their prognostic significance on survival (sMut: HR 2.40, 95% CI: 1.17-4.93, p=0.017; HCT: HR 0.26, 95% CI: 0.08-0.56, p=0.002). Conclusions: Our findings suggest NPM1-mutated AML patients with sMut have significantly worse prognosis despite being classified primarily as favorable risk by ELN 2017 at diagnosis. This may have treatment implications altering the need for and/or timing of HCT. These findings should be assessed prospectively and validated in independent datasets. Figure 1 Figure 1. Disclosures Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy. Talati: AbbVie: Honoraria; Pfizer: Honoraria; Astellas: Speakers Bureau; BMS: Honoraria; Jazz: Speakers Bureau. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Celgene/BMS: Honoraria; Abbvie: Honoraria; Blueprint: Honoraria; Pharmaessentia: Honoraria. Padron: Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Agios: Consultancy; Astellas: Consultancy.

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A JAK2V617F Variant Allele Frequency Greater Than 50% Identifies Patients with Polycythemia Vera at High Risk for Venous Thrombosis

Blood ◽

10.1182/blood-2021-147869 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 237-237

Author(s):

Giuseppe Gaetano Loscocco ◽

Paola Guglielmelli ◽

Carmela Mannarelli ◽

Elena Rossi ◽

Francesco Mannelli ◽

...

Keyword(s):

Risk Factors ◽

High Risk ◽

Venous Thrombosis ◽

Board Of Directors ◽

Univariate Analysis ◽

Multivariable Analysis ◽

Advisory Committees ◽

Free Survival ◽

History Of ◽

Independent Risk Factors

Abstract Background: Thrombosis is the main cause of morbidity and mortality in pts with Polycythemia Vera (PV). Current risk stratification is based on 2 variables: age >60y and history of thrombosis. Additional thrombotic risk factors in PV are generic cardiovascular risk factors and leukocytosis. JAK2V617F (JAK2VF) variant allele frequency (VAF) at diagnosis is highly heterogeneous. A VAF>75% was associated with higher rate of all thrombosis after diagnosis (Vannucchi AM et al, Leukemia 2007), and a VAF ≥ 60% correlated with increased rate of venous thrombosis (VT) in high-risk pts (Guglielmelli P et al, ASH 2018); however, predictive role of JAK2VF VAF is still debated. Aim: To evaluate the impact of JAK2VF VAF on rate of arterial and venous thrombosis in PV pts. Patients and methods: A cohort of 576 strictly 2016 WHO-defined PV pts followed at Univ. of Florence (1981-2020) were included. All pts were annotated for JAK2VF VAF, determined <3 years from diagnosis, and thrombosis at diagnosis and follow-up (FU). Arterial thromboses (AT) included stroke, transient ischemic attacks, retinal artery occlusion, coronary artery disease, and peripheral arterial disease; VT included cerebral venous thrombosis, deep vein thrombosis, pulmonary embolism. Splanchnic vein thromboses (SVT) were excluded. Only first occurring event was considered. Cox proportional hazard regression model was used for univariate and multivariable analysis. Kaplan-Meier (KM) analysis was used for time-to-event assessment, compared by log-rank test. Results: Median age was 61.4 y (range, 16.2-91.8), 58.2% were male; 62% were high-risk based on current classification. Median JAK2VF VAF was 41.5% (range, 0.3-100). A total of 76 (13.2%) pts had an AT event before/at PV diagnosis and 49 (8.5%) pts had an AT during FU. As regards VT, 64 (11.1%) and 39 (6.8%) pts had a VT before/at or after PV diagnosis, respectively. We found that JAK2 VAF as a continue variable was correlated with the risk of VT in FU (p=0.003) but not with AT (p=0.8). ROC analysis to determine the best cut-off level for JAK2 VAF predicting VT had an AUC of 0.72 and a best cut-off value of VAF=50%. VT at FU were significantly enriched in pts with VAF >50%: 14.5% versus 2.4%, p=<0.0001. VT -free survival (VT-FS) by KM was significantly shorter in the presence of a JAK2 VAF >50% (HR 4, CI 1.9-8.6, p<0.0001) (Figure 1A), whereas no difference was found for AT (HR 0.9). In addition to JAK2VF VAF>50%, univariate analysis for VT-FS identified history of VT (HR 2.9; CI 1.4-6.1, p=0.006), leukocytosis ≥11x10 9/L (HR 1.9; CI 1.1-3.4, p=0.02) and palpable splenomegaly (HR 1.9, CI 1-3.6; p=0.04) as risk factors. Multivariable analysis confirmed VAF>50% (HR 3.8, CI 1.8-8.1, p=0.0006) and previous VT (HR 2.4, CI 1.1-5.1; p=0.02) as independent risk factors for future VT. In contrast, univariate analysis for AT-free survival (AT-FS) identified history of AT (HR 2.5; CI 1.3-4.9, p=0.007), diabetes (HR 3.3; CI 1.6-6.5, p=0.0007), hyperlipidemia (HR 3.1; CI 1.7-5.6, p=0.0003) and hypertension (HR 2, CI 1.1-3.8; p=0.03) as predictors of future AT; age >60y showed only a trend (p=0.08). Multivariable analysis for AT-FS identified diabetes (HR 2.4, CI 1.2-5; p=0.02), hyperlipidemia (HR 2.3; CI 1.2-4.3, p=0.01) and previous AT (HR 2.1, CI 1-4.2; p=0.04) as independent predictors of future AT. Validation: Our findings were validated in an independent cohort of 315 2016-WHO defined PV pts from Policlinico Gemelli, Catholic Univ., Rome. After exclusion of 26 pts with SVT, analysis was conducted on 289 pts, 38 of them with thrombosis as heralding event (21 AT and 17 VT). Multivariable analysis confirmed JAK2VF VAF >50% (HR 2.3, CI 1.03-5.0, p=0.04) and previous VT (HR 4.5, CI 2.0-10.1; p=0.0003) as independent risk factors for future VT. In pts with VAF >50%, the rate of VT at FU was 19.9% vs 7.7%, P=0.005. KM curve showed that VT-FS was significantly shorter in pts with a JAK2VF VAF >50% (HR 2.2, CI 1.2-4.2; p=0.01) (Figure 1B). Of note, impact of JAK2 VAF>50% on VT at FU was statistically significant particularly in conventionally low-risk pts, accounting for an HR of 9.4 (CI 1.2-72) and HR 3.6 (CI 1.3-10) in Florence and Rome cohorts, respectively. Conclusions: These data support JAK2VF VAF as a strong independent predictor for future venous thrombosis in PV, in association with history of prior venous events, reinforcing that AT and VT are associated with unique risk factors in pts with PV. Supported by AIRC, Project Mynerva n.21267 Figure 1 Figure 1. Disclosures Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees.

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Progression of Albuminuria in Sickle Cell Anemia: A Multicenter, Longitudinal Study

Blood ◽

10.1182/blood-2019-125860 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1004-1004

Author(s):

Omar Niss ◽

Adam Lane ◽

Monika Asnani ◽

Marianne McPherson Yee ◽

Ashok Raj ◽

...

Keyword(s):

Blood Pressure ◽

Board Of Directors ◽

Sickle Cell ◽

Sickle Cell Anemia ◽

Multicenter Study ◽

Univariate Analysis ◽

Prospective Multicenter Study ◽

Advisory Committees ◽

Sickle Cell Nephropathy ◽

Clinic Visits

Introduction Chronic kidney disease (CKD) is a significant cause of morbidity and mortality in patients with sickle cell anemia (SCA). Albuminuria quantified by urinary albumin-to-creatinine ratio (ACR) is predictive of CKD and end-stage renal disease in other settings (non-SCA). As most sickle cell nephropathy studies are retrospective and cross-sectional, little is known about the natural progression of albuminuria in SCA and its correlation with glomerular filtration rate (GFR) decline and development of CKD. Methods We conducted a prospective, multicenter study (between 2009 and 2017) to investigate the longitudinal progression of sickle cell nephropathy (NCT02239016). Participants with SCA (HbSS or HbSb0 thalassemia) of all ages from 11 centers in the United States and the Caribbean were enrolled and provided urine and blood samples during routine clinic visits at steady-state. Urine ACR, cystatin C-estimated GFR (eGFR), and standard biomarkers of SCA and nephropathy in addition to kidney injury molecule (KIM-1) and N-acetyl-b-D-glucosaminidase (NAG) were followed longitudinally. Participants with albuminuria for ≥ 2 annual measurements were considered to have persistent albuminuria. Results A total of 303 participants with SCA were enrolled and followed for a median of 2 years. Participants were 1.6-64 years old (mean 21 years), and 46% were females. Participants provided annual samples (average 14.5-month interval between sample collections) and contributed to 644 patient-years on the study. 175 participants provided at least three annual samples and were included in a longitudinal analysis. The prevalence of albuminuria (ACR>30mg/g) at baseline was 32% (97/303) of which 26% (80/303) had microalbuminuria (UACR 30-300 mg/g) and 6% (17/303) had macroalbuminuria (UACR>300 mg/g). At study entry, 45% of patients were prescribed hydroxyurea, and 20% received chronic transfusion therapy. In univariate analysis, baseline ACR was significantly associated with older age (P<0.0001), sex (P=0.009), higher systolic and diastolic blood pressure (P<0.0001 and P=0.005), lower hemoglobin (P=0.01) and HbF (P=0.0005), higher bilirubin (P=0.001), and higher NAG (P<0.0001) and KIM-1 (P<0.0001). In a longitudinal multivariate analysis (years 0-3) that included the statistically significant variables from univariate analysis in addition to age-adjusted eGFR, only age (P=0.03), female sex (P=0.009), hemoglobin (P=0.01), bilirubin (P=0.002) and KIM-1 (P<0.0001) were significantly associated with ACR. In participants who had at least 3 annual samples, a baseline ACR ≥100mg/g was predictive of persistent albuminuria (ACR>30mg/g for ≥2 annual measurements): 81% of participants with baseline ACR ≥100 mg/g had persistent albuminuria compared to 19% of participants with baseline ACR<100 mg/g. Participants with persistent albuminuria had significantly higher age, blood pressure, and serum creatinine, but were less likely to be on disease-modifying therapy (hydroxyurea or chronic transfusions), and had significantly lower HbF compared to those with non-persistent albuminuria. eGFR correlated with age (P<0.0001) and persistent albuminuria (P=0.002), but not with baseline ACR. Participants with persistent albuminuria were also more likely to have a rapid decline in eGFR (a decline by >3 ml/min/1.73m2 per year) compared to those with non-persistent albuminuria (48% vs 31%, P=0.03). Conclusion In this longitudinal, prospective, multicenter study of sickle nephropathy, albuminuria was strongly associated with age and progressed over time (figure 1). Despite variability in spot urine ACR measurements, high baseline ACR ( ≥100mg/g) was associated with persistent albuminuria. Patients with persistent albuminuria were more likely to have rapid eGFR decline, a high-risk factor for CKD progression. Use of hydroxyurea and chronic transfusions was associated with less incidence of persistent albuminuria. Our results demonstrate that persistent albuminuria and high ACR at baseline predict kidney function decline in SCA. These findings show the feasibility of determining ACR and monitoring sickle nephropathy at routine clinic visits and have important implications for clinical decision-making and the design of future controlled therapeutic trials. Disclosures Saraf: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Quinn:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Other: Research Support.

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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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Allogeneic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma Can Achieve Durable Remissions: An Australasian Bone Marrow Transplant Recipient Registry Study

Blood ◽

10.1182/blood-2020-139076 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

Pietro R Di Ciaccio ◽

Matthew Greenwood ◽

Glen A Kennedy ◽

Sam Milliken ◽

David Gottlieb ◽

...

Keyword(s):

Risk Factors ◽

Board Of Directors ◽

Cumulative Incidence ◽

Univariate Analysis ◽

B Cell Lymphoma ◽

Marrow Transplant ◽

Bone Marrow Transplant Recipient ◽

Advisory Committees ◽

Graft Versus Host ◽

Large B Cell Lymphoma

Introduction A majority of patients with diffuse large B cell lymphoma (DLBCL) will be cured with frontline chemoimmunotherapy, however a significant number of patients will relapse. Although autologous haematopoietic stem cell transplantation (autoHCT) may lead to sustained survival in some relapsing patients, long term survival with relapsed DLBCL is approximately 25% (Larouche et al., J Clin Oncol 2010;28(12):2094). Allogeneic HCT (alloHCT) is a potential treatment strategy in some DLBCL patients with relapsed disease. We performed a retrospective national registry study to examine alloHCT practice and outcomes for DLBCL in Australia and New Zealand in the modern era. Methods Data was collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients receiving an alloHCT for DLBCL between January 2009 and December 2019. Survival was analysed using the Kaplan-Meier method, with comparisons between the transplant periods 2009-2014 and 2015-2019 performed using the log-rank test. Both univariate and Cox proportional hazards regression were performed to determine significant risk factors for transplant outcome. The following risk factors were analysed for impact on outcomes: age, transplant before 2015, previous autoHCT, remission status at transplant, use of myeloablative conditioning (MAC), haploidentical donor (HD) and use of T cell depletion (TCD). Results A total of 154 patients were included in the analysis. The median age was 52 years (range 19-71) and 68% were male. Disease status at transplant was complete remission (CR) in 49%, partial response in 31% and stable or progressive disease in 17% (missing data in 3%). Fifty-five per cent had undergone a previous autoHCT. Approximately equal proportions of donors were HLA-matched siblings or matched unrelated (45% and 46% respectively) and 9% were HDs. MAC was utilised in 26%, and TCD in 24% (alemtuzumab in 3%, anti-thymocyte globulin in 21%) (data missing in 12%). The median times to neutrophil engraftment and platelet engraftment were 16 and 18 days respectively. Non-relapse mortality (NRM) at 1-year and 5-years was 20% (95%CI 7-30%) and 26% (95%CI: 13-38%). The 100-day cumulative incidence of grade II to IV acute graft versus host disease was 15% (95%CI 5-31%). The 3-year cumulative incidence of chronic graft versus host disease (cGVHD) was 56% (95%CI 46-65%) (figure 1). The median duration of follow up for the cohort was 3.98 years (range 0-9.64 years). Median overall survival (OS) post-transplant was 4.01 years, with 5-year OS of 47% (95%CI 38-56%) and 10-year OS of 40% (95%CI 26-54%) (figure 2). The 5-year relapse free survival (RFS) was 45% (95%CI 26-50%) (figure 3). The cumulative incidence of relapse (CIR) was 21% at 1 year and 32% at four years, however relapses were not seen after this point, suggesting a subpopulation with durable remissions (figure 4). On univariate analysis, TCD was associated with both reduced incidence of cGVHD (HR 0.35 95%CI 0.19-0.66, p=0.012) and increased NRM (HR 2.10 95%CI 0.88-4.99 p=0.043). These associations were maintained on multivariate analysis (MVA) (HR 0.29 95%CI 0.16-0.76, p=0.011; HR 2.19 95%CI 1.02-4.70, p=0.045) (figures 5, 6). TCD did not impact on RFS. The vast majority of TCD was given in unrelated donor alloHCTs. CR at time of transplant was associated with improved RFS on univariate analysis (HR 1.65 95%CI 1.04-2.64, p=0.034), however this association was not seen on MVA. No other analysed risk factors impacted OS, RFS, NRM, CIR or GVHD rates on either univariate or MVA. An average of 14 alloHCTs were performed each year, with a trend towards increasing annual numbers over time. There was a significant increase in the proportion of haploidentical transplants between 2009 and 2019 (p=0.003), though total numbers were low (n=14). There was no significant change over time for the use of MAC, TCD, nor in OS, RFS or NRM. Conclusion There has been an increase in the rates of alloHCT with HDs for DLBCL in Australia and New Zealand over the past decade. Survival and relapse rates are relatively favourable compared to the published literature, with sustained remissions observed (5 and 10-year OS of 47% and 40% respectively). TCD is associated with reduced cGVHD rates, as well as increased NRM. Ongoing reporting of alloHCT outcomes in DLBCL is important given the emerging role of novel therapies such as bispecific monoclonal antibodies and chimeric antigen receptor T cell therapy. Figure 1 Disclosures Di Ciaccio: Jansen: Honoraria, Other: travel and accomodation grant. Greenwood:Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Spencer:Celgene, Janssen and Takeda: Speakers Bureau; AbbVie, Amgen, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Honoraria; Amgen, Celgene, Haemalogix, Janssen, Servier and Takeda: Research Funding; AbbVie, Celgene, Haemalogix, Janssen, Sanofi, SecuraBio, Specialised Therapeutics Australia, Servier and Takeda: Consultancy. Arthur:Royal North Shore Hospital: Current Employment. Hamad:Novartis: Honoraria; Abbvie: Honoraria.

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Factors Predicting Intentional Non-Adherence In Chronic Myeloid Leukemia: A Multivariate Analysis On 2546 Patients By The CML Advocates Network

Blood ◽

10.1182/blood.v122.21.4023.4023 ◽

2013 ◽

Vol 122 (21) ◽

pp. 4023-4023 ◽

Cited By ~ 1

Author(s):

Jan Geissler ◽

Fabio Efficace ◽

Felice Bombaci ◽

Jan de Jong ◽

Anthony Michael Gavin ◽

...

Keyword(s):

Multivariate Analysis ◽

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Univariate Analysis ◽

Significant Proportion ◽

First Line ◽

Advisory Committees ◽

Significant Difference ◽

The Impact

Abstract Background Adherence to the prescribed dose of tyrosine kinase inhibitors (TKIs) is critical to maximize treatment effectiveness in chronic myeloid leukemia (CML). While patient-centered outcome studies are lacking in this area, literature has shown that a significant proportion of patients report both intentional and unintentional non-adherence. Objective The main objective of this multivariate analysis was to identify risk factors that might predict intentional non-adherence to TKIs in CML. Methods The CML Advocates Network, connecting 79 CML patient groups from 63 countries, conducted an international project investigating patterns of medication-taking behaviors of CML patients, supported by CML investigator groups in Germany, Italy and France. We sought to demonstrate the relationship between 16 factors and adherence in this multinational cohort. A web-based survey was launched in 12 languages, enrolling CML patients from Sept 2012 to Jan 2013. The identical questionnaire was provided to a cohort of patients recruited in clinics in France, Germany and Italy, returned by patients in a pre-stamped envelope to an independent data center. Questions included potential factors associated with non-adherence as well as on patients' perception of disease and treatment burden. Based on previous literature and on clinical relevance, a pool of 16 candidate factors, potentially predicting intentional non-adherence, was selected for analysis. These included: frequency of CML medication, co-payment for CML treatment, and current TKI therapy. Patients who reported having skipped intentionally one or more doses over the last year were considered as “intentional non-adherers”. Univariate logistic regression analysis was performed to examine the impact of pre-selected candidate factors on the probability of intentional non-adherence. Two multivariate models were fitted based on line of therapy received by patients (i.e. first line and second or greater lines of therapy). Results This patient-led study is the largest study conducted to date on the influencers of non-adherence in CML. Overall, 2546 adult CML patients (47.6% female) under TKI treatment from 79 countries responded to the survey. 2151 patients responded online, 395 questionnaires were returned on paper. No significant difference on intentional non-adherence was observed between paper or online responses. Median age of patients was 51 years (range 18-96) and median time from diagnosis was 4 years (0-27). Overall, 51.6% of all respondents reported having missed at least one dose unintentionally over the last year, and 19.5% did so intentionally. This analysis regards the intentional non-adherent population (n=490). Of those, 60% were on imatinib, 20% on nilotinib, 14% on dasatinib, 6% on other TKIs. Several factors predicted intentional non-adherence in univariate analysis, including education level (P=0.016) and co-payment for TKIs (P=0.005). For patients on first line TKI (n=1551), the following factors independently predicted a higher likelihood of being intentional non-adherers: younger age (P=0.015), longer time since diagnosis (P<0.001), lower satisfaction with information received from healthcare providers (P=0.002), higher burden on social life (P<0.001) and not being fully informed on the importance of adherence (P=0.042). Non-adherence was lower when patients were told every dose was important to make the treatment work (P=0.042). Overall, intentional non-adherers intended to avoid fatigue (13%), diarrhea and GI issues (11%), nausea (10%) and muscle pain (9%). For patients in second or greater lines of therapy (n=985) all of the above factors were still statistically significant except for satisfaction with information received. Being female (P<0.001) also increased the likelihood of intentional non-adherence in this group. Discussion Despite there is clear evidence that survival is close to that of the general population when CML is treated effectively in chronic phase with current therapies, every fifth CML patient deliberately skips doses. Key factors predicting intentional non-adherence can potentially help physicians and patient organisations to identify patients early who should be monitored more closely and informed about the importance of adherence. Managing side effects proactively also reduces reasons for intentional non-adherence. Disclosures: Geissler: Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees. Efficace:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Bombaci:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. de Jong:Novartis: Membership on an entity’s Board of Directors or advisory committees. Gavin:Celgene: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Daban:Ariad: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Pelouchová:Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Sharf:Pfizer: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: 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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The Hypertension of Hemophilia Is Associated with Vascular Joint Remodeling and Cannot be Explained By the Usual Cardiovascular Risk Factors

Blood ◽

10.1182/blood.v126.23.762.762 ◽

2015 ◽

Vol 126 (23) ◽

pp. 762-762

Author(s):

Richard FW Barnes ◽

Thomas J Cramer ◽

Afrah S Sait ◽

Rebecca Kruse-Jarres ◽

Doris V. Quon ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Board Of Directors ◽

Research Funding ◽

Advisory Committees ◽

Maximum Score ◽

Joint Health ◽

Blood Pressures

Patients with hemophilia (PWH) have a higher prevalence of hypertension and intracranial hemorrhage than the general male population. However, the etiology of the hypertension, and to what extent blood pressure and associations with cardiovascular risk factors vary from the general population, is incompletely understood. We therefore investigated the prevalence of hypertension as well as the associations of blood pressure measurements with usual cardiovascular risk factors, in a cross-sectional analysis of a cohort of 486 PWH. The PWH (median age 38 years) came from 3 geographically different areas in the United States. They were compared against males from the contemporary National Health and Nutrition Examination Survey (NHANES), matched for age and race in a 1:5 ratio. Subsequently, at the University of California San Diego, a pilot cohort of PWH (n=28; median age 37 years) was examined prospectively for hypertension and associations with hemophilia-specific risk factors pertaining to joint health. PWH had a significantly higher prevalence of hypertension compared to subjects from NHANES. The prevalence of hypertension was 53.4% in PWH compared to 28.8 % in NHANES (p<0.01). In untreated (not taking anti-hypertensive medications) and treated subjects median systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in PWH than in NHANES. Differences in prevalence of hypertension and blood pressure measurements were most pronounced in the youngest age group (18-29 years). In untreated PWH median SBP and DBP were 125 and 78 mmHg (118 and 72 mmHg in NHANES), and in treated PWH 134 and 84 (127 and 76 mmHg in NAHES), respectively; all p-values <0.0001. However, despite higher blood pressures the usual cardiovascular risk profile was better in PWH compared to NHANES, in that body mass index (BMI), total cholesterol, smoking and diabetes were lower and renal function was better. While the usual cardiovascular risk factors were associated with blood pressure in both PWH and NHANES, they did not account for the differences between the two groups. Whether each risk factor was considered by itself, or in combination with the others in multivariate models, the blood pressure differences remained. Therefore, to elucidate to what extent hemophilia-specific factors might play a role in the pathophysiology of hypertension, we assessed hypertension and blood pressures in association with joint health parameters in a pilot cohort of young adult PWH. These patients underwent prospective baseline examination of 6 joints (both elbows, knees and ankles, n=168) for joint pain (Visual Analogue Scale 0-10), radiographic Pettersson score (maximum score 78), clinical Hemophilia Joint Health Score (HJHS, maximum score 120), severity of hemophilia (severe vs mild/moderate), clotting factor usage, and joint vascular perfusion quantified with Power Doppler (PD, maximum score 54) and high resolution musculoskeletal ultrasound. We found that 54% were hypertensive, similar to the larger cohort. In univariate analysis, PD score was the risk factor most strongly associated with hypertension (p = 0.07). After adjustment for confounders, the odds for hypertension increased by 1.29 (95% CI: 1.04, 1.60; p = 0.02) for each unit increase in PD score. Moreover, there was a strong association of PD scores with SBP when adjusted for confounders. In conclusion, our findings demonstrate that PWH not only have a significantly higher prevalence of hypertension, but also significantly higher blood pressures compared to the general population, even when treated with anti-hypertensive medications. The difference in blood pressures could not be explained by the usual cardiovascular risk factors but appeared to be strongly associated with the degree of vascular changes in the joint. Based on previous findings that vascular remodeling is a prominent feature of hemophilic arthropathy and may be mediated systemically, we postulate that vascular remodeling is associated with the etiology of hypertension in hemophilia. These findings warrant further basic and clinical investigation. Disclosures Kruse-Jarres: Octapharma: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Baxter: Consultancy, Honoraria. Quon:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. von Drygalski:Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hematherix Inc: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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