Myelofibrosis-associated complications: pathogenesis, clinical manifestations, and effects on outcomes

Abstract

Myelofibrosis (MF) is a rare chronic BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homologue 1)-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of MF include splenomegaly, consequent to extramedullary hematopoiesis, cytopenias, and an array of potentially debilitating abdominal and constitutional symptoms. Dysregulated Janus kinase (JAK)-signal transducer and activator of transcription signaling underlies secondary disease-associated effects in MF, such as myeloproliferation, bone marrow fibrosis, constitutional symptoms, and cachexia. Common fatal complications of MF include transformation to acute leukemia, thrombohemorrhagic events, organ failure, and infections. Potential complications from hepatosplenomegaly include portal hypertension and variceal bleeding, whereas extramedullary hematopoiesis outside the spleen and liver - depending on the affected organ - may result in intracranial hypertension, spinal cord compression, pulmonary hypertension, pleural effusions, lymphadenopathy, skin lesions, and/or exacerbation of abdominal symptoms. Although allogeneic stem cell transplantation is the only potentially curative therapy, it is suitable for few patients. The JAK1/JAK2 inhibitor ruxolitinib is effective in improving splenomegaly, MF-related symptoms, and quality-of-life measures. Emerging evidence that ruxolitinib may be associated with a survival benefit in intermediate- or high-risk MF suggests the possibility of a disease-modifying effect. Consequently, ruxolitinib could provide a treatment backbone to which other (conventional and novel) therapies may be added for the prevention and effective management of specific MF-associated complications.

Keywords: JAK inhibitor; extramedullary hematopoiesis; myelofibrosis; myeloproliferative neoplasm; ruxolitinib.

Figure 1

Pathogenic mechanisms in myelofibrosis involving dysregulated JAK-STAT signaling. Mutations affecting cytokine receptor function (eg, MPL mutations causing ligand-autonomous activation of the thrombopoietin receptor) or JAK2 mutations resulting in constitutive JAK2 activity lead to over-activation of JAK-STAT signaling in hematopoietic stem cells, with consequent myeloproliferation and excess production of proinflammatory cytokines. Note: Reproduced with permission from Incyte Corporation (Wilmington, DE, USA). Abbreviations: JAK, Janus kinase; MPL, myeloproliferative leukemia virus oncogene; STAT, signal transducer and activator of transcription.

Figure 2

Pathobiology, main clinical manifestations, and common complications of myelofibrosis. Note: Adapted with permission of the American Society of Hematology from: Does primary myelofibrosis involve a defective stem cell niche? From concept to evidence, Lataillade et al. Blood, 2008;112(8):3026–3035. Copyright © 2008. Permission conveyed through Copyright Clearance Center, Inc. Abbreviations: CD34, cluster of differentiation 34; EMH, extramedullary hematopoiesis; Fb, fibroblast; HSC, hematopoietic stem cell; JAK, Janus kinase; MK, megakaryocyte; MO, monocyte; MPL, myeloproliferative leukemia virus oncogene; Ne, neutrophil; Ob, osteoblast; Oc, osteoclast; STAT, signal transducer and activator of transcription.

Figure 3

Mechanisms of the emergence of complications in patients with myelofibrosis (MF). Note: Patients with major clinical manifestations of MF (EMH, constitutional symptoms, and/or cytopenias) typically die prematurely from secondary acute leukemia or bone marrow failure as a consequence of disease progression (symbolized by blue boxes and orange arrows), or from an array of potential disease-related complications (green box, blue arrows), such as infections, thrombohemorrhagic events, or organ failure. Progressive constitutional symptoms have (solid dark orange arrows) and other clinical manifestations may have (dashed dark orange arrows) a strong negative effect on QOL and PS. Abbreviations: EMH, extramedullary hematopoiesis; ET, essential thrombocythemia; PMF, primary myelofibrosis; PS, performance status; PV, polycythemia vera; QOL, quality of life.