Hematopoietic stem cell transplantation and other therapeutic options in primary myelofibrosis: A review and two case reports

Abstract

Primary myelofibrosis (PMF) is BCR/ABL–negative myeloproliferative disorder with splenomegaly, leukoerythroblasts, extramedullary hematopoiesis, reactive bone marrow fibrosis and neoangiogenesis with abnormal cytokine production, generally, affecting elderly persons. PMF may be accomplished by gradual bone marrow failure, splenomegaly, severe general (constitutional) signs, and clinical features of extramedullary hemopoiesis. Acute leukemia develops in up to 30% of PMF. A conventional cytostatic therapy of PMF does not affect the survival rates. Meanwhile, allogeneic hemopoietic stem cell transplantation (allo-HSCT) is the only curative procedure for the PMF. PMF diagnosis is performed by appropriate WHO criteria and includes clinical, morphologic, cytogenetic, and molecular parameters. This disorder should be discerned from other myeloid neoplasias, i.e., polycythemia vera and essential thrombocythemia (ET). Differential diagnosis of PMF should also consider marrow fibrosis caused by other non-neoplastic or neoplastic conditions. In addition to JAK2 V617F or MPL mutations, a more recently found calreticulin (CALR) gene marker have been proposed for the MF (and essential patients with MF and ET). Prognostic aspects are derived from a concept of PMF as a heterogeneous disorder with rather individual manifestation and evolution, with highly variable median survival of up to >20 years. An appropriate scoring scale (IPSS) uses five risk factors to predict prognosis and stratify the patients into risk groups. The risk factors for leukemia-free survival include ≥3% circulating blasts, platelet count <100 x 109/L, and presence of unfavorable karyotype. Drug therapy for PMF is not effective, in terms of overall or event-free survival. AlloHSCT for PMF is potentially curative, but still hazardous. Meanwhile, many patients may be observed for sufficient time without any therapy, whereas some of them are effectively managed by conventional treatment. For low or intermediate-1 risk patients, there is no need for specific therapy in asymptomatic patients. Cytoreductive therapy may be reasonable in cases of extreme leuko- or thrombocytosis. The drug side effects include hepatotoxicity and virilizing effects for androgens, peripheral neuropathy (thalidomide), and myelosuppression (lenalidomide). The first-line therapy with hydroxyurea may reduce the spleen size in 40% of patients, with the spleen response lasting for ca. 1 year. Adverse effects of urea include myelosuppression and mucocutaneous ulcers. Pegylated interferon is currently applied, early on in the course of ET or PV, with a goal of preventing or delaying fibrosis. The patients with intermediate-2 or high risk disease should be treated with investigational drugs, or alloHSCT. E.g., JAK1/JAK2 inhibitors (Ruxolitinib) are highly effective in PMF or ET MF. At the present time, ruxolitinib is the only FDA-approved JAK2 inhibitor for MF and the only modern non-HSCT therapy associated with increased survival. AlloHSCT is quite efficient, however, a hazardous intervention, thus being a method of choice for high-risk symptomatic younger patients with PMF. An evident effect of HSCT in MF is a quick restoration of normal trilineage hematopoiesis and functional microenvironment, with rapid and reversal of the myelofibrosis. In conclusion, considering the lack of long-term effective drug therapies for patients with MF, a potential risk of transplant-related complications seems to be proven in patients with DIPSS plus high- or intermediate 2–risk disease. JAK2 inhibitor provides a unique opportunity of implementing these novel agents into the transplant programs for high-risk patients. The general conclusions are illustrated by two clinical examples from authors’ experience showing successful outcomes of allo-HSCT in PMF.