Assuntos
Benzamidas/uso terapêutico , Mielofibrose Primária/terapia , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Feminino , Seguimentos , Humanos , Janus Quinase 2/imunologia , Masculino , Pessoa de Meia-Idade , Nitrilas , Mielofibrose Primária/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Indução de Remissão , Resultado do TratamentoRESUMO
The discovery of JAK2V617F has rejuvenated interest in Janus kinase (JAK)-signal transducer and activator of transcription (STAT), both as an oncogenic pathway and a drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN). However, the complexity of these diseases in terms of both clonal structure and mutation repertoire makes it unlikely that JAK inhibitor therapy will replicate what has been achieved with imatinib in chronic myeloid leukemia. Consistent with this view, JAK inhibitor therapy in myelofibrosis has not yet produced complete or partial remissions. However, most patients treated with a JAK2 (TG101348) or JAK1/2 (INCB018424) inhibitor experienced substantial improvement in constitutional symptoms and reduction in spleen size; the mechanism of action for INCB018424 includes anti-JAK1-mediated downregulation of proinflammatory cytokines. These observations complicate the choice of primary end points in clinical trials that would be robust enough to support regulatory approval. TG101348 and INCB018424 are the vanguard of JAK inhibitor therapy in myelofibrosis, but newer JAK inhibitors might have a broader spectrum of activity; preliminary results with CYT387 suggest responses in both anemia and splenomegaly. Outstanding issues regarding these drugs include identification of the optimal dosing strategy, their role (if any) in the treatment of polycythemia vera or essential thrombocythemia, and the potential for combining them with other therapeutic agents.
Assuntos
Janus Quinases/antagonistas & inibidores , Mielofibrose Primária/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Nitrilas , Pirazóis/uso terapêutico , Pirimidinas , Pirrolidinas/uso terapêutico , Sulfonamidas/uso terapêutico , Resultado do TratamentoRESUMO
Somatic mutations in Janus kinase 2 (JAK2), including JAK2V617F, result in dysregulated JAK-signal transducer and activator transcription (STAT) signaling, which is implicated in myeloproliferative neoplasm (MPN) pathogenesis. CYT387 is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases (IC(50)=11 and 18 nM, respectively), with significantly less activity against other kinases, including JAK3 (IC(50)=155 nM). CYT387 inhibits growth of Ba/F3-JAK2V617F and human erythroleukemia (HEL) cells (IC(50) approximately 1500 nM) or Ba/F3-MPLW515L cells (IC(50)=200 nM), but has considerably less activity against BCR-ABL harboring K562 cells (IC=58 000 nM). Cell lines harboring mutated JAK2 alleles (CHRF-288-11 or Ba/F3-TEL-JAK2) were inhibited more potently than the corresponding pair harboring mutated JAK3 alleles (CMK or Ba/F3-TEL-JAK3), and STAT-5 phosphorylation was inhibited in HEL cells with an IC(50)=400 nM. Furthermore, CYT387 selectively suppressed the in vitro growth of erythroid colonies harboring JAK2V617F from polycythemia vera (PV) patients, an effect that was attenuated by exogenous erythropoietin. Overall, our data indicate that the JAK1/JAK2 selective inhibitor CYT387 has potential for efficacious treatment of MPN harboring mutated JAK2 and MPL alleles.
Assuntos
Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Policitemia Vera/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Alelos , Animais , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/enzimologia , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/enzimologia , Ensaio de Unidades Formadoras de Colônias , Avaliação Pré-Clínica de Medicamentos , Eritropoetina/farmacologia , Humanos , Concentração Inibidora 50 , Janus Quinase 2/genética , Leucemia Eritroblástica Aguda/patologia , Camundongos , Mutação , Proteínas de Fusão Oncogênica/antagonistas & inibidores , Policitemia Vera/genética , Policitemia Vera/patologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Receptores de Trombopoetina/genética , Fatores de Transcrição STAT/metabolismo , Especificidade por SubstratoRESUMO
In a retrospective cohort, 192 (48%) out of 397 patients with polycythaemia vera had a documented history of pruritus. At diagnosis, the presence of pruritus was significantly associated with a lower mean corpuscular volume and a higher leucocyte count. Among 66 patients with documentation of treatment for pruritus, 389 'patient visits' were reviewed, revealing a significant correlation between active pruritus and low mean corpuscular volume, but not platelet, leucocyte or basophil count. Paroxetine and hydroxyzine were rated by patients to be the most effective drugs in controlling pruritus. These observations suggest a pathogenetic role for both iron deficiency and biogenic amines in polycythaemia vera-associated pruritus.
Assuntos
Policitemia Vera/complicações , Prurido/complicações , Doença Aguda , Volume de Eritrócitos , Feminino , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-Idade , Paroxetina/uso terapêutico , Satisfação do Paciente , Policitemia Vera/tratamento farmacológico , Prevalência , Prurido/tratamento farmacológico , Estudos Retrospectivos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Published data from Europe and North America indicate that for non-iron-deficient adult Caucasian males, the normal mean packed cell volume (PCV) is 0.46 and the 2.5-97.5 percentile interval is 04.0-0.53. Corresponding values for adult Caucasian females are: mean PCV 0.42; 2.5-97.5 percentile interval 0.36-0.48. It is not usually appropriate to undertake studies of polycythemia in adult Caucasian males with PCV < 0.55 (Hb Conc. < 180 g/L) or in adult Caucasian females with PCV < 0.50 (Hb Conc. < 16.5 g/L). Application of this principle will reduce the number of inappropriate and costly studies that would otherwise be performed in patients whose PCV values are only in the upper percentiles of the normal range, and will help to avoid misdiagnoses and therapeutic misadventures.