bl-4162a and Fibrosis

Ruxolitinib, a JAK1 and JAK2 inhibitor drug, has recently been approved for the treatment of patients with high- or intermediate-risk myelofibrosis with symptomatic splenomegaly. Ruxolitinib is the first clinically useful targeted therapy in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). The aim of this paper is to indicate pharmacobiological aspects of ruxolitinib within the potential context of MPNs. Pharmacobiological assessments, in addition to knowledge of the risk profile for ruxolitinib in MPNs, are required. We propose hypotheses based on our experience in a splenectomized MPN patient with hyperproliferative bone marrow and moderate fibrosis receiving ruxolitinib. We believe that a true clinical development approach for this drug should include pharmacobiological assessments for ruxolitinib in addition to the disease risk profile of MPNs.. Ruxolitinib, JAK1 ve JAK2 inhibitörü olarak işlev gören bir ilaçtır. Semptomatik splenomegalisi olan orta- veya yüksek-risk myelofibrozis hastalarında kullanımı uluslararası onam almıştır. Bu bağlamda ruxolitinib, Philadelphia kromozomu negatif myeloproliferatif neoplaziler (MPN) için klinik yararı gösterilen ilk hedefe yönelik ajan konumundadır. Bu yazının amacı, ruxolitinibin MPN’nin klinik tablolarındaki potansiyel kullanım alanları konusunda farmakobiyolojik yönleri tartışmaktır. Ruxolitinib onamları başlıca hastalık risk faktörleri üzerinden yapılmaktadır. Ancak klinik kullanımda hastalığın ve ilacın farmakobiyolojik yönlerini de dikkate alma gerekliliği vardır. Bu hipotezimizi tartışırken splenektomize bir MPN hastamızda, hiperproliferatif bir kemik iliği ve orta derecede fibrozis mevcutken uyguladığımız ruxolitinib tedavisinden elde ettiğimiz deneyimlere dayandık. İlacın gelecekte klinik geliştirilmesi gerçekleştirilirken MPN risk profili yanı sıra farmakobiyolojik değerlendirmelerin de yapılması gerektiği düşüncesindeyiz.

Topics: Bone Marrow; Combined Modality Therapy; Disease Progression; Female; Fibrosis; Humans; Hydroxyurea; Janus Kinase 2; Leukapheresis; Middle Aged; Myeloproliferative Disorders; Nitriles; Phlebotomy; Point Mutation; Polycythemia Vera; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Quinazolines; Splenectomy; Splenomegaly

We studied 15 patients with essential thrombocythemia (ET) before treatment and after normalization of platelet count by anagrelide. Significantly increased plasma levels of PDGF, TGFbeta, and bFGF were found. Patients with mild reticulin fibrosis in bone marrow had higher PDGF levels. During treatment, plasma TGFbeta and bFGF levels remained elevated in most patients (P < 0.0001 and P < 0.01, respectively). Intraplatelet PDGF levels were low before treatment (P < 0.006) and normal on hematological remission, without relation with the presence or absence of reticulin fibrosis in bone marrow. Intraplatelet TGFbeta levels were normal regardless of the platelet count. Intraplatelet bFGF levels were raised before (P < 0.001) and during treatment (P < 0.01). By immunostaining, TGFbeta and bFGF were seen in megakaryocytes and lymphocytes with a similar pattern of intensity in patients and controls, suggesting that other cells might also contribute to the raised plasma values. We believe that the plasma increment of these cytokines suggests that they play a role in the pathogenesis of ET. The normal PDGF plasma level found during treatment may be in relation with the platelet count. However, the persistent increase of TGF-beta in plasma and bFGF both in plasma and platelets may indicate dysregulation of cytokine synthesis in TE.

Topics: Adolescent; Adult; Aged; Bone Marrow; Female; Fibroblast Growth Factor 2; Fibrosis; Humans; Male; Middle Aged; Platelet Aggregation Inhibitors; Platelet Count; Platelet-Derived Growth Factor; Quinazolines; Reticulin; Thrombocytosis; Transforming Growth Factor beta

Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked increase in the numbers of mature megakaryocytes present in the bone marrow. Thrombohemorrhagic disorders are major morbidities of ET, especially those with mutations in the gene encoding Janus kinase 2 (JAK2). In this study, we report the case of an 18-year-old patient with ET carrying JAK2 mutation who developed acute ST-elevation myocardial infarction (STEMI) 5 months after a commencement of anagrelide. Coronary endothelial dysfunction confirmed by positive acetylcholine provocation test lasted a year after the occurrence of STEMI. Furthermore, intracoronary imaging using optical coherence tomography demonstrated non-atheromatous intimal fibrosis possibly due to chronic endothelial damage. The coronary pathologies reflected chronic change potentially associated with properties of ET and JAK2 mutation in addition to hyperviscosity. These observations suggest that the side effect of anagrelide in our patient was considered causative, while underlying chronic endothelial dysfunction and adverse endothelial remodeling may be predisposing factors to his fatal cardiovascular events.

Topics: Acetylcholine; Adolescent; Coronary Angiography; Coronary Vessels; Echocardiography; Endothelium, Vascular; Fibrinolytic Agents; Fibrosis; Heart Function Tests; Humans; Janus Kinase 2; Magnetic Resonance Imaging; Male; Nitroglycerin; Percutaneous Coronary Intervention; Quinazolines; Radionuclide Imaging; ST Elevation Myocardial Infarction; Thrombectomy; Thrombocythemia, Essential; Tomography, Optical Coherence; Tunica Intima; Vasodilator Agents

First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Disease Progression; Disease-Free Survival; Drug Approval; Female; Fibrosis; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Platelet Aggregation Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Proportional Hazards Models; Quinazolines; Retrospective Studies; Severity of Illness Index; Thrombocythemia, Essential; Thrombosis; Treatment Outcome; Young Adult