scholarly journals ABL Tyrosine Kinase Inhibitors (TKIs) Are Associated with Increased Rho-Associated Kinase (ROCK) Activity That May Contribute to Vascular Toxicity in Patients with Chronic Myeloid Leukemia (CML)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1739-1739
Author(s):  
Afaf Osman ◽  
Brian Yu ◽  
Nancy Glavin ◽  
Tamar S. Polonsky ◽  
James K. Liao ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Clinical Studies ◽  
Research Funding ◽  
Total Duration ◽  
Vascular Toxicity ◽  
Downstream Target ◽  
Rock Activity ◽  
Over Time

Abstract Introduction The use of 2nd or 3rd generation ABL TKIs in patients with CML is associated with vascular toxicity, including peripheral arterial occlusive disease and cardiovascular and cerebrovascular events. However, Imatinib, a 1st generation TKI, has not been shown to increase risk of cardiovascular events (Douxfils J et al. JAMA Oncol 2016;2:625). Therefore, there is a need to identify risk factors and predictors of vascular toxicity for patients receiving these TKIs. In mice, inhibition of the Abl kinases results in activation of Rho and its downstream target Rho kinase (ROCK) (Zandy et al. Proc Natl Acad Sci USA 2007;104:17686). Growing evidence suggests that elevated ROCK activity plays a central role in the pathogenesis of cardiovascular disease and stroke in both animal and clinical studies. TKIs used in CML are potent inhibitors of ABL1 and ABL2 kinases. We hypothesized that CML patients receiving 2nd or 3rd generation BCR/ABL1 TKIs have higher ROCK activity than patients not receiving these TKIs, providing a putative mechanism for the vascular toxicity observed in clinical studies. Methods We measured leukocyte ROCK activity in CML patients and analyzed results based on their last TKI dose. We isolated fresh peripheral blood leukocytes from 38 patients (17 females, 21 males) with a median age of 53 years (range, 24-90 years). 4 patients had newly diagnosed untreated CML at the start of the study. One male was receiving Dasatinib for Ph+ ALL and was also included. ROCK activity was assessed in leukocytes by measuring the ratio of phospho-myosin-binding subunit (p-MBS) on myosin light-chain phosphatase, a downstream target of ROCK, to total MBS using an automated Western blotting system (Wes, ProteinSimple, San Jose, CA) (Hata T et al. Atherosclerosis 2011; 214:117). Each patient had 1-6 measurements of leukocyte ROCK activity over 1 - 18 months (n=78 measurements). Information about cardiovascular risk factors, concomitant medications, CML status, and total duration of TKI therapy was collected. For patients with multiple samples over time, ROCK activity was calculated as the mean of all samples taken while receiving the same TKI. Patients in treatment-free remission (TFR) were considered off-TKI, but those in TFR < 1 month were excluded from the analysis to reduce potential confounding effects. Results We analyzed blood samples from 4 untreated CML patients, 8 while in TFR, and 31 who were actively receiving one of the 5 TKIs (7 Imatinib, 12 Dasatinib, 9 Nilotinib, 2 Ponatinib, 1 Bosutinib). 3 patients developed acute coronary syndrome during the study and required coronary revascularization for myocardial infarction. We found no significant difference in ROCK activity when comparing all patients receiving TKIs to those not receiving TKIs. However, we found higher leukocyte ROCK activity when comparing all patients receiving 2nd and 3rd generation TKIs to those not receiving any TKI (Welch's t test, mean leukocyte ROCK activity 1.00 ± 0.06 vs 0.80 ± 0.06; p=0.03). We also found higher leukocyte ROCK activity when comparing patients receiving Dasatinib to patients receiving Imatinib (mean leukocyte ROCK activity 1.05 ± 0.09 vs 0.75 ± 0.10; p=0.04). The comparison of Imatinib to all 2nd and 3rd generation TKIs was not significant (p=0.06). Conclusions We found that patients on 2nd and 3rd generation TKIs have higher leukocyte ROCK activity compared to those not receiving TKIs, and higher leukocyte ROCK activity in patients on Dasatinib compared with patients receiving Imatinib. These results are consistent with the known lower-risk of cardiovascular side-effects observed with Imatinib in comparison to the next generation ABL TKIs. Limitations include small sample size and heterogeneity in the patient population in terms of age, cardiovascular risk factors, specific TKI used, and total duration and sequencing of TKI agents. The study continues to accrue CML subjects in order to follow individual patients over time on TKI therapy. Disclosures Larson: Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

scholarly journals The effect of surgery on fat mass, lipid and glucose metabolism in mild primary hyperparathyroidism

2018 ◽  
Vol 7 (8) ◽  
pp. 941-948 ◽  
Author(s):  
Kristin Godang ◽  
Karolina Lundstam ◽  
Charlotte Mollerup ◽  
Stine Lyngvi Fougner ◽  
Ylva Pernow ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Glucose Metabolism ◽  
Primary Hyperparathyroidism ◽  
Cardiovascular Risk Factors ◽  
Outcome Measures ◽  
Fat Mass ◽  
Lipid Lowering ◽  
Mild Primary Hyperparathyroidism ◽  
Over Time

Context Mild primary hyperparathyroidism has been associated with increased body fat mass and unfavorable cardiovascular risk factors. Objective To assess the effect of parathyroidectomy on fat mass, glucose and lipid metabolism. Design, patients, interventions, main outcome measures 119 patients previously randomized to observation (OBS; n = 58) or parathyroidectomy (PTX; n = 61) within the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH) trial, an open randomized multicenter study, were included. Main outcome measures for this study were the differences in fat mass, markers for lipid and glucose metabolism between OBS and PTX 5 years after randomization. Results In the OBS group, total cholesterol (Total-C) decreased from mean 5.9 (±1.1) to 5.6 (±1.0) mmol/L (P = 0.037) and LDL cholesterol (LDL-C) decreased from 3.7 (±1.0) to 3.3 (±0.9) mmol/L (P = 0.010). In the PTX group, the Total-C and LDL-C remained unchanged resulting in a significant between-group difference over time (P = 0.013 and P = 0.026, respectively). This difference was driven by patients who started with lipid-lowering medication during the study period (OBS: 5; PTX: 1). There was an increase in trunk fat mass in the OBS group, but no between-group differences over time. Mean 25(OH) vitamin D increased in the PTX group (P < 0.001), but did not change in the OBS group. No difference in parameters of glucose metabolism was detected. Conclusion In mild PHPT, the measured metabolic and cardiovascular risk factors were not modified by PTX. Observation seems safe and cardiovascular risk reduction should not be regarded as a separate indication for parathyroidectomy based on the results from this study.

Abstract P373: Trends in Cardiovascular Risk Factors by Clinical Definitions of Prediabetes

Circulation ◽  
2018 ◽  
Vol 137 (suppl_1) ◽  
Author(s):  
Caroline Liu ◽  
Kathryn Foti ◽  
Elizabeth Selvin
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Nutrition Examination Survey ◽  
Risk Factor Management ◽  
Health And Nutrition ◽  
High Prevalence ◽  
Definition Of ◽  
And Control ◽  
Over Time

Introduction: There are five different definitions of prediabetes currently used in clinical practice. How cardiovascular risk may differ by these different definitions of prediabetes and whether trends in cardiovascular risk in persons with prediabetes have changed over time is largely uncharacterized. Hypothesis: We expect the prevalence of cardiovascular risk factors will vary by prediabetes definition and will be highest among those who meet clinical definitions with higher cutoff values. We hypothesize awareness, treatment and control of hypertension and hypercholesterolemia have increased over time among those with prediabetes. Methods: We analyzed data for adults ages ≥ 20 years from the 1999-2014 National Health and Nutrition Examination Survey (NHANES). We used calibrated HbA1c and FPG values to estimate prediabetes prevalence. We examined the prevalence and trends of hypertension and hypercholesterolemia among those who met each clinical definition of prediabetes, as well as awareness, treatment, and control. Results: The prevalence of prediabetes by each definitions remained stable across survey years. The prevalence, awareness, treatment, and control of hypertension and hypercholesterolemia by clinical definition modestly increased over time. Conclusion: The prevalence of hypertension and hypercholesterolemia was higher among individuals who met HbA1c-based definitions of prediabetes than other measures and was highest when more restrictive criteria for prediabetes were used. Awareness, treatment, and control of cardiovascular risk factors increased over time by any definition, but the high prevalence of cardiovascular risk factors highlights the need for improvement in risk factor management in people with prediabetes.

scholarly journals Influence of Connected Health Interventions for Adherence to Cardiovascular Disease Prevention: A Scoping Review

2020 ◽  
Vol 11 (04) ◽  
pp. 544-555
Author(s):  
Dahbia Agher ◽  
Karima Sedki ◽  
Rosy Tsopra ◽  
Sylvie Despres ◽  
Marie-Christine Jaulent
Keyword(s):  
Risk Factors ◽  
Cardiovascular Disease ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Scoping Review ◽  
Health Interventions ◽  
Inclusion Criteria ◽  
Connected Health ◽  
Current Trends ◽  
Over Time

Abstract Background Recent health care developments include connected health interventions to improve chronic disease management and/or promote actions reducing aggravating risk factors for conditions such as cardiovascular diseases. Adherence is one of the main challenges for ensuring the correct use of connected health interventions over time. Objective This scoping review deals with the connected health interventions used in interventional studies, describing the ways in which these interventions and their functions effectively help patients to deal with cardiovascular risk factors over time, in their own environments. The objective is to acquire knowledge and highlight current trends in this field, which is currently both productive and immature. Methods A structured literature review was constructed from Medline-indexed journals in PubMed. We established inclusion criteria relating to three dimensions (cardiovascular risk factors, connected health interventions, and level of adherence). Our initial search yielded 98 articles; 78 were retained after screening on the basis of title and abstract, 49 articles underwent full-text screening, and 24 were finally retained for the analysis, according to preestablished inclusion criteria. We excluded studies of invasive interventions and studies not dealing with digital health. We extracted a description of the connected health interventions from data for the population or end users. Results We performed a synthetic analysis of outcomes, based on the distribution of bibliometrics, and identified several connected health interventions and main characteristics affecting adherence. Our analysis focused on three types of user action: to read, to do, and to connect. Finally, we extracted current trends in characteristics: connect, adherence, and influence. Conclusion Connected health interventions for prevention are unlikely to affect outcomes significantly unless other characteristics and user preferences are considered. Future studies should aim to determine which connected health design combinations are the most effective for supporting long-term changes in behavior and for preventing cardiovascular disease risks.

The Effects of Cardiovascular Risk Factors on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Performance in Cognitively Healthy Older Adults

2019 ◽  
Author(s):  
Alyssa N De Vito ◽  
John P K Bernstein ◽  
Daniel Weitzner ◽  
Matthew Calamia ◽  
Jeffrey N Keller
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Depression Scale ◽  
Aging Research ◽  
Data Set ◽  
Neuropsychological Status ◽  
Repeatable Battery ◽  
The Impact ◽  
Over Time

Abstract Objective The current study investigated the differential impact cardiovascular risk factors (CVRFs) on Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) performance in a large, cognitively healthy, older adult sample across 4 years. Method Participants were 486 individuals recruited through a longitudinal aging research study in the southeastern United States. Participants were 69.3% female, an average of 69.96 years old (SD = 6.58), 16.32 years of education (SD = 2.27), and Mini-Mental Status Exam score of 29.12 (SD = 1.16). Participants completed the RBANS at baseline and yearly thereafter, as well as the Uniform Data Set demographic and health questionnaires and the Geriatric Depression Scale. Results Multilevel modeling was conducted using standardized RBANS index scores. Overall, across indices, performance generally improved across time consistent with practice effects from repeated testing. Some CVRFs were associated with worse performance over time. For example, individuals with hypertension performed more poorly on immediate memory over time (t = −2.06, p < .05). Other CVRFs (e.g., BMI) were not associated with baseline performance or performance over time. (p > .05). Conclusions CVRFs differentially affect RBANS performance over time. These results extend previous cross-sectional findings regarding the impact of different cardiovascular health risks to a large, cognitively healthy, longitudinal sample.

Abstract P347: The Impact of the Length of the Follow-up on the the Strengths of the Associations Between Cardiovascular Risk Factors and Future Myocardial Infarction, Stroke and Heart Failure

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Lars Lind ◽  
Erik Ingelsson ◽  
Johan Sundström ◽  
Johan ärnlöv
Keyword(s):  
Risk Factors ◽  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Cardiovascular Outcomes ◽  
Rapid Decline ◽  
The Impact ◽  
Over Time

Objective: The aim of this study was to investigate how the length of the follow-up period influences the strength of the associations between major cardiovascular risk factors and different cardiovascular outcomes (myocardial infarction [MI], stroke and heart failure). Methods: We examined 1826 men aged 50 regarding cardiovascular risk factors in 1970-74. The follow-up time was 33 years. The hazard ratio (HR) was calculated yearly for each risk factor and outcome. During follow-up, 571 cases of MI, 381 cases of stroke and 384 cases of heart failure occurred. Results: Two major patterns were found regarding influence of the follow-up time on the associations between risk factors and the different cardiovascular outcomes. First, a gradual decline in the HR over time was seen for blood pressure in relation to all three outcomes, with the most rapid decline for heart failure and stroke. This pattern was also seen for BMI in relation to MI and heart failure, and for smoking regarding MI and stroke. Second, we observed a gradual increase in HRs to a maximum at 20-25 years, and thereafter a slight decline. This pattern was seen for the apoB/A1 ratio, HDL, and triglycerides, mainly in relation to MI and heart failure. Conclusion: The length of follow-up influenced the associations between traditional risk factors and cardiovascular outcomes in different ways. The collective influence of the risk factors did however show a substantial decline in discrimination over time for the outcomes stroke and heart failure, but not regarding myocardial infarction.

Incidence of Vascular Thrombotic Events in 183 Consecutive Patients Treated with Nilotinib: A Single Centre Experience

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3147-3147 ◽  
Author(s):  
James Gilbert ◽  
Simona Deplano ◽  
Richard Szydlo ◽  
Renuka Palanicawandar ◽  
Gareth Gerrard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Side Effects ◽  
Adverse Events ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Older Patients ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Advisory Committees

Abstract Introduction The spectrum of adverse events occurring in nilotinib is broadly similar to that of other tyrosine kinase inhibitors but recent reports suggest an increase in the incidence of vascular thrombotic events (VTE) compared to imatinib. Many patients treated with ponatinib, where the association of VTE with treatment is now widely accepted, have previously received nilotinib and it remains unclear as to whether the adverse events are a result of the cumulative use of the two drugs. It is important to clearly delineate the risk of VTE with nilotinib in order to estimate risk and provide better information for patients. Methods We conducted a chart review to identify adverse events in 183 consecutive patients who received nilotinib in our institution from February 2006 until June 2014. Patients were to be considered at risk of side effects in they had received at least 24 hours of treatment. Data were collected from out-patient consultations in which side effects and their severity were self-reported and recorded in the medical case notes. The cohort contained 93 women and 90 men and had a median age of 56 years (range 21-93). 8% of patients received nilotinib as first line therapy: 46% and 39% respectively were treated after failure of imatinib only or imatinib and dasatinib . The remainder were treated for relapse post allogeneic transplant. Of those who were treated after one or two prior tyrosine kinase inhibitors (TKI), 57% and 43% were intolerant or resistant respectively. Results The median duration of treatment with nilotinib was 714 days (range 10 -2816 days). Information was available for pre-existing cardiovascular risk factors in 93% of patients and were present in 59%. We recorded 20 occurrences of VTE in 10% of patients with 9 (5%), 7 (4%) and 4 (2%) episodes of myocardial ischaemia, peripheral arterial occlusive disease and cerebrovascular disease respectively. Only one patient without pre-existing cardiovascular risk factors experienced a VTE, The median age of patients with VTE was 67 years (range 35-79) compared to 55 years (range 21-93) in those without VTE. In contrast to previously reported results VTE were more common (18%) in patients who had received two prior TKI compared to 8% in those who had been treated with a single TKI and 7% who received nilotinib upfront. 75% of VTE occurred in patients who have been treated with nilotinib for more than 2 years but this may in part be because of continuation of treatment at a time of lack of awareness of the association of nilotinib with VTE. The remaining adverse events reported on nilotinib were in accordance with published data. Side effects occurring in >10% of patients are given in the table. Conclusions The incidence of VTE in patients treated with nilotinib in our institution was 10%. VTE was more frequent in older patients, in those with pre-existing cardiovascular risk factors and in those who received prolonged therapy with nilotinib. Without a suitable control group matched for age and cardiovascular risk factors it is difficult to provide an accurate estimate of any potential increased risk of treatment with nilotinib. Nevertheless caution must be exercised in older patients with pre-existing risks for VTE and appropriate counselling and monitoring provided. Table 1Adverse eventIncidence (%)Rash and/or pruritus43Fatigue31Elevated transaminases21Myalgia18Abdominal pain17Headaches17Arthralgia16Nausea14Thrombocytopenia12Neutropenia12Anaemia7 Disclosures Gerrard: Novartis: Research Funding. Foroni:Novartis: Research Funding. Apperley:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Cardiac and Renal Complications of Carfilzomib Therapy in Patients with Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4491-4491 ◽  
Author(s):  
Meletios A. Dimopoulos ◽  
Maria Roussou ◽  
Maria Gavriatopoulou ◽  
Erasmia Psimenou ◽  
Dimitrios Ziogas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Risk ◽  
Cardiovascular Risk Factors ◽  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Toxicity ◽  
Cardiac Events ◽  
Advisory Committees ◽  
Artery Disease ◽  
Higher Doses

Abstract Carfilzomib (CFZ) combinations have shown activity in phase 2 and 3 studies in multiple myeloma (MM) patients but also a small but consistent signal of cardiac and renal toxicity. The aim of our study was to analyze potential cardiac and renal toxicity of CFZ combinations in consecutive MM patients. The analysis included 60 patients treated with different combination of CFZ in a single center (University of Athens, Greece): 48 (80%) had relapsed or refractory (RRMM) and 12 (20%) had newly diagnosed MM (NDMM). All had baseline evaluation of cardiovascular risk factors and echocardiography with a LVEF ≥40%. Regimens included Kd in 31 (52%), KRd in 17 (28%) and KMP in 12 (20%) patients. CFZ dose was 20/27 in 27 (45%) patients, 20/36 in 12 (20%) and 20/56 in 21 (35%). Median age was 72 (range 39-76) years and 65% were males. Median number of prior therapies was 2 (range 0-7). Median baseline eGFR was 88 ml/min (range 16 to> 120 ml/min), 33% had eGFR <60 ml/min and 7% had eGFR <30 ml/min. Median duration of CFZ therapy was 10 (range 1-43) cycles. During therapy with CFZ, 7 (12%) patients had a reduction in LVEF ≥20% within a median of 6 months (range 1-13 months) from initiation of CFZ. In 6/7 patients, dyspnea of grade (gr) ≥2 was also present and was associated with a significant increase of NTproBNP (median 2412, range 2219-10162 pg/ml) without increase in troponins. With discontinuation because of disease progression or other unrelated reasons as a competing event, the incidence of LVEF reduction ≥20% was 5% at 3 months, 8% at 6 months, 10% at 12 months and 12% at 15 months. The respective CFZ discontinuation rate unrelated to cardiac toxicity was 17%, 35%, 41% and 49%, respectively (Figure). Among cardiovascular risk factors (age, smoking, hypertension, hypelipidemia, diabetes, renal dysfunction) only peripheral artery disease was associated more often with cardiac events (3/7, 43% vs 4/53,8%, p=0.02). The use of ACE-I, ARBs or CCBs was not associated with cardiac events, however, the use of b-blockers was more common in patients who had LVEF reduction (3/10, 30% vs 4/50, 8%, p=0.048); patients on b-blockers also experienced LVEF reduction earlier [2% vs 20% at 3 months, 6% vs 20% at 6 months and 6% vs 30% at 12 months (p=0.02)], while non-toxicity discontinuation at 12 months was 44% vs 57% (p=0.66). There was no association with prior anthracycline exposure or prior HDT and the dose of CFZ was not associated with cardiac event frequency or timing. Baseline parameters of cardiac function assessed by echocardiography did not show correlation with cardiac events. Further evaluation in all patients who had EF reduction established the diagnosis of coronary artery disease (CAD) in 3/7. In all patients LVEF improved after holding CFZ (<28 days) and 6/7 patients continued therapy with CFZ with dose reduction; only in one patient reinstitution of CFZ was associated with repeated reduction of LVEF. We also evaluated the effects of CFZ in renal function, excluding renal dysfunction associated with disease progression. Per CTCAE v4.03, 22 (37%) patients had a creatinine increase ≥gr 1 (18% gr1, 17% gr2 and 2% gr3). According to the same criteria for acute kidney injury (AKI), 17 (28%) patients experienced AKI ≥gr 1 (gr1 in 25% and gr3 in 3%) while 21 (35%) had a reduction of their eGFR by ≥25%, which was transient in 13/21 (62%). These events occurred mostly early, within the 1st cycle in 9/21 (43%). Two patients, both in CR, developed TTP, one after 22 and the other after 8 cycles of CFZ. Higher doses of CFZ were associated with higher frequency of eGFR reduction ≥25% (22% vs 33% vs 52% for 20/27, 20/36 and 20/56 doses respectively, p=0.093). Age >65 years was not associated with higher risk of AKI (25% vs 35% for those <65 years, p=0.3). Among patients with baseline eGFR <60 ml/min (n=20), 11 (55%) patients improved their eGFR to >60 ml/min. In conclusion, cardiac toxicity after CFZ occurred in 12% of patients, but was essentially unpredictable and reversible in all patients; standard cardiovascular risk factors were not predictive of cardiac toxicity. However, in about half of the patients was associated with underlying CAD, indicating that further investigation is needed regarding the effects of CFZ to vascular function and endothelium. Decrease in eGFR and low grade AKI is common but transient, and can be associated with higher doses of CFZ. Importantly, 55% of patients with moderate CKD improved their renal function after treatment with CFZ. Figure Figure. Disclosures Dimopoulos: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Genesis: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Kastritis:Genesis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

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