Myelofibrosis with myeloid metaplasia: targeted therapy

Myelofibrosis with myeloid metaplasia (MMM) is a chronic myeloproliferative stem-cell disorder characterized by dysplastic megakaryocytic hyperplasia, ineffective erythropoiesis, extramedullary hematopoiesis, bone marrow fibrosis, and osteosclerosis.¹  The median age of onset is 65 years and the prognosis is dismal, with a median survival of only 3.5 to 5.5 years, often terminating into leukemia transformation. The only known cure is allogeneic stem cell transplantation, which is limited by the age of onset, lack of healthy matched sibling donors, poor patient performance status, and severely fibrotic bone marrow potentially inhibiting full donor engraftment. Extensive fibrosis and osteosclerosis have been hypothesized, in a murine model of thrombopoietin-overexpressing (TPO^high) mice mimicking MMM, to be secondary to a reactive process mediated by inflammatory mediators, including transforming growth factor β (TGFβ) and osteoprotegerin (OPG) secreted by the clonal proliferation of megakaryocytes and monocytes and stromal-derived cells, respectively.^2,3 

The transcription factor NF-κB regulates the activation of several hundred genes that control the processes of hematopoiesis, immunity, and inflammation. There are 5 NF-κβ family members, including NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA (p65), RelB, and c-Rel, which associate to form various heterodimers and homodimers. These dimers are kept inactive within the cytoplasm in part by their association with ankyrin-containing κB inhibitors (IκBs). IκBs are phosphorylated and degradated by proteosomes allowing release and activation of NF-κB family members (NF-κB1, cRel, RelA) to translocate to the nucleus and activate hematopoietic, inflammatory, and immunoregulatory genes. Specifically, NF-κB stimulates the production of TGFβ1, a potent inducer of fibrosis, and interleukin 1 alpha (ILα), a stimulator of OPG, which inhibits osteoclastogenesis and secondarily leads to osteosclerosis.

Patients with MMM have recently been identified as having activation of the NF-κB pathway in megakaryocytes and circulating CD34 cells.⁴  Bortezomib, a boronic acid dipeptide and a potent, selective inhibitor of the proteosome, was recently approved for the treatment of multiple myeloma and has been shown to inhibit NF-κB activation and the secretion of a large number of cytokines and inflammatory mediators in the bone marrow milieu.⁵  Wagner-Ballon and colleagues hypothesized that bortezomib would inhibit NF-κB activation and subsequently decrease TGFβ1 and OPG secretion, resulting in decreased fibrosis and osteosclerosis in a murine model (TPO^high) of MMM (see figure). Initially, they demonstrated a significant increase in NF-κB activation (NF-κB p65 and NF-κB p50) in TPO-overexpressing mice, and following bortezomib treatment, a significant reduction in TGFβ1, IL-1α, and OPG. Similarly, bortezomib also significantly reduced myeloproliferation, bone marrow and spleen fibrosis, and bone osteosclerosis. The significant reduction in fibrosis and osteosclerosis appeared to be highly correlated with the reduction in levels of TGFβ1 and OPG, respectively. Most importantly, bortezomib also significantly improved the survival of TPO^high mice.

Some limitations of this study include disassociation of bortezomib effects on fibrosis and osteosclerosis and its effects on survival, and that the mechanism of lethality in the TPO^high murine model may be more dependent on myeloproliferation than secondary reactive fibrosis and osteosclerosis, and may not serve as the best model to investigate the effects of bortezomib. Additionally, bortezomib has been associated with the development of thrombocytopenia, which may be a limitation for its chronic use in MMM.

In summary, this study and previous studies by these same investigators have shed new light on the pathogenesis of MMM and a potential targeted therapeutic approach. Currently, few patients with MMM receive curative therapy and current treatment is largely palliative. Inhibition of the NF-κB pathway and subsequent decrease in TGFβ1, IL-1α, and/or OPG by bortezomib or other IκB inhibitors in development may provide the first targeted approach for patients with MMM. Alternatively, inhibitors of TGFβ1, IL-1α, and/or OPG may produce similar results to NF-κB inhibition. These targeted approaches in patients with MMM may potentially, in the future, reduce transfusion requirements, induce remissions and/or prolong survival, or allow more patients to be candidates for allogeneic stem cell transplantation.