RESUMO
Fedratinib hydrochloride is a selective Janus kinase 2 (JAK2) inhibitor approved by the U.S. Food and Drug Administration (FDA) in August 2019 for intermediate- 2 or high-risk primary or secondary myelofibrosis. The approval of this novel oral agent was based on the phase II and III JAKARTA-2 and JAKARTA trials, which both showed significant reduction in splenomegaly and myelofibrosis symptom burden. The most common adverse effects associated with fedratinib include anemia, gastrointestinal symptoms and elevation in liver transaminases. Early clinical trial data was concerning for an increased incidence of Wernicke's encephalopathy (WE), which led the FDA to place a clinical hold on further drug development. However, upon further investigation it was determined that there was no clear evidence that fedratinib causes WE, and the clinical hold was lifted in 2017. This inclusive review provides insight into the pharmacology, safety and efficacy, and future direction of fedratinib use in myeloproliferative neoplasms.
Assuntos
Mielofibrose Primária , Desenvolvimento de Medicamentos , Humanos , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirrolidinas , SulfonamidasRESUMO
While therapy-related (t)-myelodysplastic syndromes (MDS) have worse outcomes than de novo MDS (d-MDS), some t-MDS patients have an indolent course. Most MDS prognostic models excluded t-MDS patients during development. The performances of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Global Prognostic System (MPSS), WHO Prognostic Scoring System (WPSS) and t-MDS Prognostic System (TPSS) were compared among patients with t-MDS. Akaike information criteria (AIC) assessed the relative goodness of fit of the models. We identified 370 t-MDS patients (19%) among 1950 MDS patients. Prior therapy included chemotherapy alone (48%), chemoradiation (31%), and radiation alone in 21%. Median survival for t-MDS patients was significantly shorter than for d-MDS (19 vs 46 months, P<0.005). All models discriminated survival in t-MDS (P<0.005 for each model). Patients with t-MDS had a significantly higher hazard of death relative to d-MDS in every risk model, and had inferior survival compared to patients with d-MDS within all risk group categories. AIC Scores (lower is better) were 2316 (MPSS), 2343 (TPSS), 2343 (IPSS-R), 2361 (WPSS) and 2364 (IPSS). In conclusion, subsets of t-MDS patients with varying clinical outcomes can be identified using conventional risk stratification models. The MPSS, TPSS and IPSS-R provide the best predictive power.
Assuntos
Pesquisa Biomédica , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Medição de Risco/métodos , Terapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Estadiamento de Neoplasias , Prognóstico , Fatores de Risco , Taxa de SobrevidaRESUMO
BACKGROUND: The rheumatologic manifestations of hematologic neoplasms are a collection of diverse syndromes. This review aims to describe the most common syndromes in the context of potential mechanisms of pathogenesis. METHODS: We undertook a structured search of the available peer-reviewed literature describing paraneoplastic phenomena associated with hematologic neoplasms and the most current literature on the biology of inflammation and neoplasm. RESULTS: This review describes the common rheumatologic manifestations and discusses their possible underlying pathogenesis. CONCLUSIONS: This review describes common clinical features of paraneoplastic phenomena prevalent in hematologic malignancies that may help differentiate them from primary rheumatologic disease and discusses the most current understanding of underlying pathogenesis with a specific focus on the biology of inflammation in neoplastic transformation.
Assuntos
Neoplasias Hematológicas/complicações , Síndromes Paraneoplásicas/etiologia , Síndromes Paraneoplásicas/patologia , Doenças Reumáticas/etiologia , Doenças Reumáticas/patologia , HumanosRESUMO
Established prognostic tools in patients with myelodysplastic syndromes (MDS) were largely derived from untreated patient cohorts. Although azanucleosides are standard therapies for higher-risk (HR)-MDS, the relative prognostic performance of existing prognostic tools among patients with HR-MDS receiving azanucleoside therapy is unknown. In the MDS Clinical Research Consortium database, we compared the prognostic utility of the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R), MD Anderson Prognostic Scoring System (MDAPSS), World Health Organization-based Prognostic Scoring System (WPSS) and the French Prognostic Scoring System (FPSS) among 632 patients who presented with HR-MDS and were treated with azanucleosides as the first-line therapy. Median follow-up from diagnosis was 15.7 months. No prognostic tool predicted the probability of achieving an objective response. Nonetheless, all five tools were associated with overall survival (OS, P=0.025 for the IPSS, P=0.011 for WPSS and P<0.001 for the other three tools). The corrected Akaike Information Criteria, which were used to compare OS with the different prognostic scoring systems as covariates (lower is better) were 4138 (MDAPSS), 4156 (FPSS), 4196 (IPSS-R), 4186 (WPSS) and 4196 (IPSS). Patients in the highest-risk groups of the prognostic tools had a median OS from diagnosis of 11-16 months and should be considered for up-front transplantation or experimental approaches.