Yazarlar : Tefferi A, Pardanani A.

Yayın : Blood Rev.

Yayın Yılı : 2012

Pubmed Linki : http://www.ncbi.nlm.nih.gov/pubmed/21742423

Konu : Lösemi

Literatür İçeriği :  

Abstract

JAK-STAT is an appealing but also problematic drug target in BCR-ABL1-negative myeloproliferative neoplasms (MPN) - it is appealing because the majority of patients with MPN harbor gain-of-function JAK2 or MPL mutations - it is problematic because currently available JAK inhibitors do not distinguish between oncogenic and physiologic JAK-STAT activation. Furthermore, JAK-STAT-relevant mutations in MPN do not always constitute the predominant or ancestral mutant clone. Such complexities undermine the value of JAK-STAT as a robust drug target in MPN and partly explain the hitherto lack of histologic or molecular remissions associated with currently available JAK inhibitors. Most of these drugs were, however, effective in alleviating constitutional symptoms and reducing spleen size; the mechanism of action in this instance includes drug-induced down-regulation of inflammatory cytokine activity. In addition, non-specific myelosuppression contributes to both their salutary and detrimental effects on peripheral blood count. Non-hematologic side effects include gastrointestinal disturbances, asymptomatic elevation of liver and pancreatic enzymes, peripheral neuropathy and hyperacute relapse of symptoms during treatment interruption. It is our impression that many more JAK inhibitors need to be evaluated in order to identify the best-in-class in terms of efficacy, toxicity and suitability for future combination treatment programs.

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