Gender Determines the Myeloproliferative Neoplasms Phenotype Independently of Age, Driver Mutation and JAK2V617F Burden

Philadelphia-negative myeloproliferative neoplasms (MPNs) occur when there is over-production of myeloid cells stemming from hematopoietic stem cells with constitutive activation of JAK/STAT signaling, with JAK2V617F being the most commonly occurring somatic driver mutation. Chronic inflammation is a hallmark feature of MPNs and it is now evident that inflammation is not only a symptom of MPN but can also provoke development and precipitate progression of disease. Herein we have considered major MPN driver mutation independent host, lifestyle, and environmental factors in the pathogenesis of MPN based upon epidemiological and experimental data. In addition to the traditional risk factors such as advanced age, there is evidence to indicate that inflammatory stimuli such as smoking can promote and drive MPN clone emergence and expansion. Diet induced inflammation could also play a role in MPN clonal expansion. Recognition of factors associated with MPN development support lifestyle modifications as an emerging therapeutic tool to restrain inflammation and diminish MPN progression.

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Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Cancers ◽

10.3390/cancers12082100 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2100

Author(s):

Lasse Kjær

Keyword(s):

Myeloproliferative Neoplasms ◽

Philadelphia Chromosome ◽

Clinical Intervention ◽

Driver Mutation ◽

Response Monitoring ◽

Driver Mutations ◽

Clonal Hematopoiesis ◽

Disease Biology ◽

Background Population ◽

The Impact

Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

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Profile of Myeloproliferative Neoplasms in Kuwait: Population-Based Study

Blood ◽

10.1182/blood-2019-128536 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5373-5373

Author(s):

Mazyad Jamal Almazyad ◽

Aisha S Alwehaib ◽

Salem Alshemmari

Keyword(s):

High Risk ◽

Similar Pattern ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Population Based ◽

Driver Mutation ◽

Driver Mutations ◽

Positive Finding ◽

Population Based Study ◽

Arms Pcr

Introduction Myeloproliferative neoplasms (MPNs) are a group of hematopoietic disorders of stem-cell origin, characterized by mutations that disrupt hematopoietic signal-transduction pathways. The Middle East lacks an MPN registry representative of the disease in our area. Here we report on the epidemiology of these neoplasms in our area, including phenotype, clinical features and relevant outcomes. Methods This population-based study reports various demographic characteristics and clinical attributes of all suspected and confirmed MPN patients from all over Kuwait referred to the research hematology lab at Kuwait University & cytogenetic lab in Kuwait Cancer Control Centre (KCCC) during the period from 2007 to 2018. Molecular determination of the patients' driver mutation status currently relies on ARMS-PCR. Confirming a diagnosis follows the WHO criteria, and its refinements, for the diagnosis of MPNs. Data entry and analysis was performed using SPSS (v.22) software. Results Most patients are ≥ 40 years old (79.8%), with a median age of 55 years. Gender distribution is almost equal, with ethnic categorization as Kuwaiti and Non-Kuwaiti showing a similar pattern. ET is the most common diagnosis (40.1%), followed by PRV (32.3%). JAK2 V617F mutation is reported positive in 89.7% of cases, followed by CALR in 8.0% of MPNs. The incidence of MPNs ranged from 0.5 to 2.1 per 100,000 in 2007 through 2018. The lowest rate was recorded in 2007 (0.511) and the highest was observed in 2011 and 2016 (2.417 and 2.101, respectively). The increase in 2011 is likely due to the introduction of a more sensitive technique using ARMS-PCR for the diagnosis of MPNs, whereas the increase in 2017 may be explained by the publication of WHO 2016 modified criteria. Moreover, throughout the years, the distribution of MPNs in different age groups showed similar pattern, with the highest incidence in patients aged ≥ 60. Driver mutations can fit with a general increase in incidence from 2007-2017, which may be attributed to increased awareness among treating physicians asking suspected cases to screen for MPNs using molecular techniques.One hundred and twenty-four (18.5%) cases were documented to have a prior history of thrombosis, with roughly equal distribution between arterial and venous sites. A large proportion (89.5%) of the thrombotic events occurred in those who are ≥ 40 years old, with most events being associated with ET (34.7%) and PRV (33.1%). Almost one-third of cases of thrombosis were associated with undetermined MPN diagnosis. Participating patients were categorized as either low or high risk for thrombotic events, with the latter being defined as age ≥ 55 years and the presence of a previous thrombotic event. The results demonstrate that a total of 46 cases were defined as high risk, most of them being associated with ET (20 cases) and PRV (19 cases). A statistically significant association was reported between gender and site of occurrence of thrombotic events, with males having more arterial thromboses, and females were documented to have more venous thromboses. Conclusion JAK2 V617F driver mutation is the most common positive finding in the participating patients. Roughly one-fifth of the participants encountered thrombotic events, and the site of thrombosis is associated with gender, demonstrating statistical significance. These results should warrant a more thorough evaluation of MPNs in Kuwait to provide a better understanding of its epidemiology. This can be achieved through optimized documentation of patients' data, and testing for additional novel driver mutations and transformation; as well as encourage physicians in primary care centers to refer suspected cases for molecular diagnosis. Disclosures No relevant conflicts of interest to declare.

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Abstract LB-043: Driver mutation and collaborating signaling in phenotype patterning in human myeloproliferative neoplasms

10.1158/1538-7445.am2017-lb-043 ◽

2017 ◽

Author(s):

Chia-Chen Hsu ◽

Jie-Yu You ◽

Cih-En Huang ◽

Yi-Yang Chen ◽

Hsing-Ying Ho ◽

...

Keyword(s):

Myeloproliferative Neoplasms ◽

Driver Mutation

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Spontaneous T-cell responses against Arginase-1 in the chronic myeloproliferative neoplasms relative to disease stage and type of driver mutation

OncoImmunology ◽

10.1080/2162402x.2018.1468957 ◽

2018 ◽

Vol 7 (9) ◽

pp. e1468957 ◽

Cited By ~ 6

Author(s):

Mia Aaboe Jørgensen ◽

Morten Orebo Holmström ◽

Evelina Martinenaite ◽

Caroline Hasselbalch Riley ◽

Hans Carl Hasselbalch ◽

...

Keyword(s):

T Cell ◽

Myeloproliferative Neoplasms ◽

T Cell Responses ◽

Driver Mutation ◽

Disease Stage ◽

Chronic Myeloproliferative Neoplasms ◽

Cell Responses ◽

Arginase 1

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07 / Gender determines the myeloproliferative neoplasms phenotype independently of age, driver mutation and JAK2V617F burden

10.26226/morressier.5b3b802db1b87b000ecedae6 ◽

2018 ◽

Author(s):

Karantanos Theodoros

Keyword(s):

Myeloproliferative Neoplasms ◽

Driver Mutation

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Phylogenetic reconstruction of adult blood cancer reveals early origins and lifelong evolution.

10.21203/rs.3.rs-93830/v1 ◽

2020 ◽

Author(s):

Jyoti Nangalia ◽

Nicholas Williams ◽

Joe Lee ◽

Luiza Moore ◽

E Baxter ◽

...

Keyword(s):

Clinical Presentation ◽

Myeloproliferative Neoplasms ◽

Phylogenetic Reconstruction ◽

Clonal Expansion ◽

In Utero ◽

Driver Mutation ◽

Driver Mutations ◽

New Paradigm ◽

Blood Cancer ◽

Age Related

Abstract Mutations in cancer-associated genes drive tumour outgrowth. However, the timing of driver mutations and dynamics of clonal expansion that lead to human cancers are largely unknown. We used 448,553 somatic mutations from whole-genome sequencing of 843 clonal haematopoietic colonies to reconstruct the phylogeny of haematopoiesis, from embryogenesis to clinical disease, in 10 patients with myeloproliferative neoplasms which are blood cancers more common in older age. JAK2V617F, the pathognomonic mutation in these cancers, was acquired in utero or childhood, with upper estimates of age of acquisition ranging between 4.1 months and 11.4 years across 5 patients. DNMT3A mutations, which are associated with age-related clonal haematopoiesis, were also acquired in utero or childhood, by 7.9 weeks of gestation to 7.8 years across 4 patients. Subsequent driver mutation acquisition was separated by decades. The mean latency between JAK2V617F acquisition and clinical presentation was 34 years (range 20-54 years). Rates of clonal expansion varied substantially (<10% to >200% expansion/year), were affected by additional driver mutations, and predicted latency to clinical presentation. Driver mutations and rates of expansion would have been detectable in blood one to four decades before clinical presentation. This study reveals how driver mutation acquisition very early in life with life-long growth trajectories drive adult blood cancer, providing opportunities for early detection and intervention, and a new paradigm for cancer development.

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Pregnancy Management and Outcomes in Patients with Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-153887 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4615-4615

Author(s):

Iyad Arusi ◽

Vikas Gupta ◽

Ann Kinga Malinowski ◽

Nadine Shehata ◽

Dawn Maze

Keyword(s):

Observational Study ◽

Board Of Directors ◽

Pregnancy Outcomes ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Driver Mutation ◽

Advisory Committees ◽

Consensus Recommendations ◽

Risk Patients ◽

History Of

Abstract Introduction: While BCR-ABL1 negative myeloproliferative neoplasms (MPN) are typically diagnosed in the sixth decade of life, approximately 20% of patients are diagnosed before the age of 40 years. Patients with MPN of reproductive age are being increasingly encountered in clinical practice. Concurrently, there has been increased awareness of the risks of pregnancy complications in patients with MPN and the importance of MPN-specific management to help mitigate these risks. MPN are associated with thrombotic and hemorrhagic complications, and pregnancy may amplify the thrombotic risk. Additionally, MPN may be associated with an increased risk of placental dysfunction and associated complications of preeclampsia, fetal growth restriction, preterm delivery and fetal loss. The aim of this observational study was to report on pregnancy outcomes in a modern cohort of patients with MPN managed according to consensus recommendations. Methods: We conducted a retrospective review of patients with MPN and pregnancy evaluated at either the Princess Margaret Cancer Centre or Mount Sinai Hospital in Toronto, Canada between January 1, 2010 and December 31, 2020. Diagnoses were defined according to the WHO 2016 criteria using information available from hospital records. Descriptive statistics were used to describe selected baseline characteristics. Categorical variables were summarized with counts and percentages. Results: A total of 32 patients with MPN and pregnancy were included in the study (Table 1). The median age at the time of the index pregnancy was 33 (range 21 - 45) years. The most common MPN diagnosis was essential thrombocythemia (ET, n=15), followed by polycythemia vera (PV, n=9) and primary myelofibrosis (PMF, n=8). Driver mutation data was available for 30 patients: 17 (57%) had mutated JAK2, 5 (17%) CALR, and 9 (30%) had no driver mutation identified. Five patients had a prior history of venous thrombosis, all of which were portal vein thrombosis, and 2 patients had a history of bleeding events. Information on antenatal treatment was available for 22 patients: 18 (82%) patients received aspirin, 3 (14%) received antenatal low molecular weight heparin (LMWH) and 3 (14%) received interferon (IFN; interferon alpha 2b in 2 cases and pegylated interferon alfa 2a in 1); 16 (73%) received post-partum LMWH. Information on maternal complications was available for 22 patients. There were 2 thrombotic events (1 antepartum and 1 postpartum) and 1 postpartum hemorrhage. There were no cases of preeclampsia. Of 22 pregnancies, there were 19 live births (86%), 2 first trimester losses (9%) and 1 second trimester loss (5%). Gestational age was 37 weeks or more in 16/17 (94%) and was 33 weeks for 1 patient. Vaginal deliveries were performed in 11/20 (55%) cases and 9/20 (45%) were Cesarean deliveries. Discussion: This observational study represents a modern cohort of MPN patients treated according to consensus recommendations. Our findings highlight that MPN patients have better pregnancy outcomes than those previously described in the literature. Limitations of this retrospective study include a small sample, missing data, and potential underreporting of early pregnancy loss. Pregnancy in patients with MPN is associated with unique risks that may be reduced with interventions such as antepartum aspirin, IFN in higher risk patients, and postpartum LMWH. That not all standard risk patients were managed with aspirin and postpartum LMWH suggests educational opportunities exist for hematologists and maternal-fetal medicine physicians involved in the care of these patients. Figure 1 Figure 1. Disclosures Gupta: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy; Roche: Consultancy; Constellation Pharma: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Malinowski: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding.

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Worse Outcomes in Males with MPN Are Associated with Qualitative and Quantitative Differences in Non-Driver Mutational Burden

Blood ◽

10.1182/blood-2019-125393 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 837-837

Author(s):

Theodoros Karantanos ◽

Evan M Braunstein ◽

Shruti Chaturvedi ◽

Jerry L. Spivak ◽

Linda Resar ◽

...

Keyword(s):

Somatic Mutations ◽

Cox Regression ◽

Myeloproliferative Neoplasms ◽

Multivariable Analysis ◽

Jak2 V617f ◽

Driver Mutation ◽

Molecular Characteristics ◽

Free Survival ◽

Mutational Burden ◽

Male Sex

INTRODUCTION: The chronic myeloproliferative neoplasms (MPN) have variable courses and outcomes despite similar driver mutations. We have found that males present more commonly with primary myelofibrosis (PMF) as opposed to essential thrombocytosis (ET) independently of driver mutation and age, and have demonstrated the independent negative impact of male sex in transformation to secondary MF (sMF), AML, and overall survival. The aim of this study was to examine both driver and non-driver mutational burden as a factor in presentation and outcome in the MPN. PATIENTS AND METHODS: 652 individuals with ET, PV or PMF (394 females and 258 males; 311 with ET, 252 with PV and 89 with PMF) were enrolled in our prospective observational cohort between 2005-2019, with a median follow up of 9 years (Q25-75% 4, 15 years). All JAK2 V617F -positive patients were genotyped for quantitative JAK2 V617F variant allele fractions (VAF) at enrollment and over time, and 76 patients (41 females and 35 males, 43 with ET, 23 with PV and 10 with PMF) had additional sequencing, examining 63 genes implicated in myeloid neoplasms. Multivariable cox regression was used to examine the associations of sex, age and molecular characteristics with venous thrombosis, cerebrovascular events, and MF/AML transformation. Univariate cox regression and Kaplan-Meier (KM) were used to assess the effect of JAK2 V617F VAF change/year on survival. Multivariable logistic regression was used to evaluate the associations of sex, age, phenotype and number of additional somatic mutations. RESULTS: Venous thromboembolism was less common in males (OR 0.44, 95% CI 0.26 - 0.76, P=0.004) independent of age, driver mutation, and MPN diagnosis. Arterial ischemic events were more common in males (OR 1.86, 95% CI 1.14 - 3.02, P=0.013) independent of driver mutation, and initial MPN diagnosis. Male sex was a predictor of sMF transformation (HR 1.5, 95% CI 1.02 - 2.2, P=0.04) independent of age and phenotype at diagnosis, and driver mutation, and transformation to AML (HR 2.63, 95% CI 1.21 - 5.67, P=0.014) independent of age at diagnosis and driver mutation. These results were confirmed with KM analysis (P=0.013 and P=0.018 respectively) (Figures 1A - B). The neutrophil JAK2 V617F VAF or its change/year were not associated with survival in the entire cohort (HR 1, 95% CI 0.99 - 1.01, P=0.082 and HR 1.05, 95% CI 0.97 - 1.12, P=0.22 respectively). However, JAK2 V617F VAF or its change/year was associated with survival in females (HR 1.01, 95% CI 1 - 1.02, P=0.044 and HR 1.12, 95% CI for HR 1.01 - 1.25, P=0.04 respectively). KM analysis confirmed that yearly increases of JAK2 V617F VAF higher than 0.5/year were associated with worse survival only in females (P=0.013). Multivariable analysis showed that males had a higher number of additional somatic mutations (Coef 1.14, 95% CI 0.15 - 2.13, P=0.024) independent of age and diagnosis at the time of sequencing (Figures 1C). Analysis of individual mutations (Figure 1C) showed that males have higher prevalence of ASXL1 (22.9% vs 2.4%, P=0.01) and DNMT3A mutations (11.4% versus 7.3%), mutations associated with MDS/MPN phenotype (CBL, KRAS, EZH2, U2AF1), (22.9% vs 7.3%) and concurrent JAK2 and CALR mutations (11.4% vs 0%, P=0.04). CONCLUSIONS: Males with MPN have higher risk of sMF and AML transformation accounting for their worse survival. Males with MPN are less dependent on the JAK2 V617F VAF as an outcome determinant compared to females, but instead carry a higher risk non-driver mutational burden compared to females. Both quantity and quality of non-driver mutational burden differ between males and females with MPN, with males harboring higher risk burden that underlies higher risk presentation and outcomes. Figure 1. Males have higher frequency of somatic mutations additional to their MPN driver mutation independent of age and MPN diagnosis at the time of the NGS. A. KM analysis showing that males have shorter sMF-free survival (P=0.013). B. KM analysis showing that males have shorter AML-free survival (P=0.018). C. The percentage of males with 1 or more additional somatic mutations is higher compared to females across all MPN at the time of the NGS (ET, PV, PMF, sMF). D. The analysis of the specific additional somatic mutations in our cohort showed that males have higher frequency of high-risk CHIP-related mutations (ASXL1, DNMT3A), mutations in genes related to MDS/MPN phenotype and concurrent mutations in JAK2 and CALR. Disclosures Chaturvedi: Shire/Takeda: Research Funding; Alexion: Consultancy; Sanofi: Consultancy.

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Myeloproliferative Neoplasms (MPN) Clonal Evolution Landscape and Its Impact on Patients' Prognosis

Blood ◽

10.1182/blood-2021-149473 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 317-317

Author(s):

Lin-Pierre Zhao ◽

Marine Cazaux ◽

Nabih Maslah ◽

Rafael Daltro De Oliveira ◽

Emmanuelle Verger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Myeloproliferative Neoplasms ◽

Clonal Evolution ◽

Chronic Phase ◽

Driver Mutation ◽

Advisory Committees ◽

Free Survival

Abstract Introduction: Although myeloproliferative neoplasms (MPN) are driven by three mutually exclusive driver mutations (JAK2, CALR and MPL), targeted deep sequencing studies identified multiple additional somatic mutations potentially impacting MPN evolution. Presence of a high molecular risk (HMR: ASXL1, EZH2, SRSF2 and IDH1/2) or a TP53 mutations has been associated with adverse prognosis. However, to date, the effect of clonal evolution (CEv) on MPN patients' outcome has not been evaluated, as most of the studies assessed mutational-based prognosis stratification from single baseline molecular genotyping. The objective of our study was to describe the clinical and molecular characteristics of patients with CEv in a large cohort of MPN patients and analyze its impact on patients' outcome. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. From this large retrospective cohort, we included in this study 446 patients who had at least 2 molecular analyses during the chronic phase of MPN, performed at diagnosis and/or during follow-up using next generation sequencing (NGS), targeting a panel of 36 genes involved in myeloid malignancies. Significant variants were retained with a sensitivity of 1%. CEv was defined as the acquisition of a new additional non-driver mutation between baseline and subsequent NGS evaluation. Statistical analyses were performed using the STATA software (STATA 17.0 for Mac Corporation, College Station, TX). Results: The median age at MPN diagnosis in our whole cohort was 51 years [IQR 41 - 60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis (MF) respectively. With a median interval of 1.6 years [IQR 1.0 - 2.8] between the first and the second NGS analysis in the whole cohort, CEv occurred in 128 patients (29%). Patients with CEv were significantly older compared to patients without CEv (n=318) (p=0.03). MPN diagnosis, the type of driver mutation and complete blood counts at MPN diagnosis did not differ between the 2 groups. Eighty-one (63%) and 198 (62%) patients with or without CEv respectively had at least one additional non-driver mutation at baseline NGS (p=0.59), while the rate of HMR (n=25 (20%) versus n=79 (25%)) or TP53 (n=7 (5%) versus n=20 (6%)) mutations at baseline NGS did not differ between the 2 groups. Thirty six out of 128 (28%) of patients with CEv had more than 1 acquired mutation. Most recurrently acquired mutations involved the epigenetic regulators TET2 and DNMT3A that were mutated in respectively 33% and 25% of patients with CEv (Figure 1A). Moreover, 38% of CEv patients acquired HMR (ASXL1 (14%), EZH2 (6%), SRSF2 (3%), IDH1/2 (2%)) or TP53 (13%) mutations. After a median follow up of 10.8 years [IQR 6.6 - 17.2] in the whole cohort representing a total of 5635 patient years, 32 (7%) patients died, and 11 (2.5%) and 11 (2.5%) patients with at least 2 NGS performed during MPN chronic phase transformed respectively into secondary MF or myelodysplastic syndrome / acute myeloid leukemia (MDS/AML). Interestingly, CEv (HR 11.27, 95%CI [5.09; 24.96], p<0.001) (Figure 1B), age at MPN diagnosis (HR 1.11, 95%CI [1.07; 1.15], p<0.001) and the presence of HMR mutations at baseline NGS (HR 4.48, 95%CI [2.05; 9.77], p <0.001) independently adversely impacted OS in a COX regression multivariate analysis. CEv also independently adversely impacted MDS/AML free survival (HR 13.15, 95%CI [3.88; 44.47], p<0.001) and secondary MF free survival (HR 21.13, 95%CI [6.18; 72.20], p<0.001) in a COX regression multivariate analysis. Conclusion: Our study on a large retrospective clinically and biologically annotated real-life cohort of MPN patients with long-term follow up shows that CEv independently adversely impacts OS, MDS/AML and secondary MF free survivals. CEv occurred in a clinically relevant proportion of MPN patients (28%) and was associated with patients' age. Acquired mutations mainly involved epigenetic regulators, HMR and TP53 genes. These results suggest that serial molecular monitoring using NGS could be routinely implemented in MPN patients follow up, to assess more accurately disease evolution and potentially update therapeutic management. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; ASTELLAS: Consultancy. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Benajiba: Gilead: Research Funding; Pfizer: Research Funding.

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