Advances in the Therapy of Chronic Idiopathic Myelofibrosis

Abstract

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenesis of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the forefront of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cytoreductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplantrelated mortality. The Oncologist 2006;11:929-943

Hepatic nodule: a case of primary myelofibrosis

“…Other treatment modalities are, at best, palliative and include drugs such as androgen preparations or thalidomide with prednisone for anaemia, lenalidomide in the presence of del(5q), hydroxyurea for splenomegaly, splenectomy or radiation therapy for symptomatic foci of non-hepatosplenic EMH 11 12…”

A 62-Year-Old Woman with Bilateral Pleural Effusions and Pulmonary Infiltrates Caused by Extramedullary Hematopoiesis

“…At present, talc is considered the most efficient sclerosing agent [11], and is also safe if the particle size is not too small [12]. Systemic treatment with hydroxyurea has been reported to be successful in chronic idiopathic myelofibrosis [13,14,15] and apparently induced a regression of the EMH changes including the small right-sided pleural effusion, with a stable situation after a follow-up of >2 years.…”

Biology and Clinical Management of Myeloproliferative Neoplasms and Development of the JAK Inhibitor Ruxolitinib

“…‘Conventional’ drug therapies including corticosteroids, androgen preparations, erythropoiesis stimulating agents (ESA), androgens (danazol), immunomodulators (thalidomide/lenalidomide), splenectomy, splenic irradiation, INF, and cytoreductive therapy (such as HU, busulfan, and melphalan) have been used in patients with MF to address leukocytosis or thrombocytosis, marked splenomegaly, and constitutional symptoms [43, 52]. None of these modalities have ever been shown to consistently, reliably, and durably impact the clinical manifestations (symptoms and signs) of this malignancy in the setting of large, randomized controlled clinical trials.…”

“…JAK2 V617F -mediated cellular transformation seems to involve activation of JAK2-STAT3, JAK2-STAT5, ERK1/2 MAPK, and PI3K/AKT downstream signal transduction pathways, as: (i) STAT3 and BCL X overexpression are characteristic findings in human PV, (ii) human hematopoietic progenitors expressing constitutively active STAT5 and its target BCL X undergo EPO-independent colony formation, and (iii) hematopoietic transformation in murine bone marrow by TEL-JAK2 requires STAT5 [52]. JAK2 V617F can also induce its effects directly, as it can translocate to the nucleus of leukemic cells and primary CD34+ hematopoietic progenitors to phosphorylate histone H3 at tyrosine 41 (H3Y41), decrease the affinity of histone H3 for the transcriptional repressor heterochromatin protein 1a (HP1a), and promote the expression of genes involved in cell proliferation and survival [72].…”