RESUMO
Comparative clinical characteristics, molecular landscape and prognosis scoring for primary (PMF) and secondary myelofibrosis (SMF).
Assuntos
Mielofibrose Primária , Humanos , Mielofibrose Primária/genética , PrognósticoAssuntos
DNA (Citosina-5-)-Metiltransferases , DNA Metiltransferase 3A , Humanos , DNA (Citosina-5-)-Metiltransferases/genética , DNA (Citosina-5-)-Metiltransferases/metabolismo , Animais , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Camundongos , Transtornos Mieloproliferativos/patologia , Transtornos Mieloproliferativos/metabolismo , Interferons/metabolismoRESUMO
Myeloproliferative neoplasms (MPN) are blood cancers that appear after acquiring a driver mutation in a hematopoietic stem cell. These hematological malignancies result in the overproduction of mature blood cells and, if not treated, induce a risk of cardiovascular events and thrombosis. Pegylated IFN$\alpha $ is commonly used to treat MPN, but no clear guidelines exist concerning the dose prescribed to patients. We applied a model selection procedure and ran a hierarchical Bayesian inference method to decipher how dose variations impact the response to the therapy. We inferred that IFN$\alpha $ acts on mutated stem cells by inducing their differentiation into progenitor cells; the higher the dose, the higher the effect. We found that the treatment can induce long-term remission when a sufficient (patient-dependent) dose is reached. We determined this minimal dose for individuals in a cohort of patients and estimated the most suitable starting dose to give to a new patient to increase the chances of being cured.
Assuntos
Teorema de Bayes , Interferon-alfa , Transtornos Mieloproliferativos , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Interferon-alfa/administração & dosagem , Conceitos Matemáticos , Relação Dose-Resposta a DrogaRESUMO
Current recommended risk scores to predict thrombotic events associated with myeloproliferative neoplasms (MPN) do not discriminate between arterial and venous thrombosis despite their different physiopathology. To define novel stratification systems, we delineated a comprehensive landscape of MPN associated thrombosis across a large long-term follow-up MPN cohort. Prior arterial thrombosis, age >60 years, cardiovascular risk factors and presence of TET2 or DNMT3A mutations were independently associated with arterial thrombosis in multivariable analysis. ARTS, an ARterial Thrombosis Score, based on these four factors, defined low- (0.37% patients-year) and high-risk (1.19% patients-year) patients. ARTS performance was superior to the two-tiered conventional risk stratification in our training cohort, across all MPN subtypes, as well as in two external validation cohorts. Prior venous thrombosis and presence of a JAK2V617F mutation with a variant allelic frequency ≥50% were independently associated with venous thrombosis. The discrimination potential of VETS, a VEnous Thrombosis Score based on these two factors, was poor, similar to the two-tiered conventional risk stratification. Our study pinpoints arterial and venous thrombosis clinico-molecular differences and proposes an arterial risk score for more accurate patients' stratification. Further improvement of venous risk scores, accounting for additional factors and considering venous thrombosis as a heterogeneous entity is warranted.