The therapy of myelofibrosis: Targeting pathogenesis

Abstract

Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced phases of polycythemia vera and essential thrombocythemia (post polycythemic and post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal, hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly applicable effective therapy have been described. Clinically, these patients experience progressive marrow replacement by fibrotic tissue, ineffective hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly, extramedullary hematopoiesis, profound constitutional symptoms, and a risk of blastic transformation. Historically, therapies have been targeted at palliating symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens, localized radiotherapy). Stem cell transplantation appears promising, but is often toxic and not broadly applicable due to co-morbidities and age of MMM patients. Non-myeloablative approaches to conditioning may broaden the applicability of stem cell transplantation in MMM, yet results to date are preliminary. Although a definitive molecular abnormality responsible for the pathogenesis of MMM has not been described, much has been learned about the aberrant expression of pro-fibrotic cytokines and the presence of increased angiogenesis in MMM. These pathogenetic insights have led to a series of pilot clinical trials with therapeutic agents targeting aberrantly expressed cytokines (and possibly angiogenesis) including Thalidomide (alone or in combination), Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated the most promise (palliating disease associated cytopenia's), whereas the TNF-alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms. Although these later trials have been helpful in a subset of patients, no agent to date has led to solid complete responses in MMM across the spectrum of disease manifestations. Further insights into the pathogenetic mechanisms responsible for myeloproliferation (aberrant cell signaling pathways, apoptotic resistance, other) are necessary to guide selection and testing of the expanding number of novel anti-neoplastic agents in chronic myeloid disorders and MMM.

Allogeneic hematopoietic stem-cell transplantation with reduced-intensity conditioning in intermediate- or high-risk patients with myelofibrosis with myeloid metaplasia

“…Currently, no chemotherapeutic agent has been demonstrated to prolong the survival in this disease, although supportive care with transfusions or treatment with HU, interferon, danazol, or thalidomide may improve the symptoms and possibly improve the quality of life of these patients. 1, [8][9][10][11] Allogeneic bone marrow transplantation, however, is the only curative treatment that by means of the administration of radio/chemotherapy agents, or a graft-versus-tumor effect elicited by donor lymphocytes, is capable of reducing the tumor burden. Nevertheless, previous studies have shown that fully myeloablative preparative regimens, with or without total body irradiation, lead to a transplant-related mortality in 27% to 48% of the patients (Table 3).…”

“…[8][9][10][11][12] Nevertheless, the use of fully myeloablative conditioning regimens has been shown to be associated with a high transplantation-related mortality (TRM) rate, 13-16 especially in advanced and elderly patients. In particular, patients older than 45 years were previously reported to have a significantly worse probability of survival compared with younger patients.…”

Adenoviral-Mediated Gene Transfer into Bone Marrow: An Effective Surgical Technique in Rat

“…The bone marrow reaction is thought to be reactive and cytokine mediated. It has been hypothesized that long-term presence of profibrotic cytokines released from these abnormal cells are capable of inducing irreversible changes in bone marrow stromal cells and the extracellular matrix, leading to bone marrow fibrosis and consequently hematological failure [2,3]. Although the etiopathogenesis of this profound stromal reaction remains equivocal, mediating cytokines such as transforming growth factor-beta 1 (TGF-β 1 ) are believed to be produced by clonal megakaryocytes, monocyte-macrophage cell lineage, or both [4].…”