Management of Myeloproliferative Neoplasms: From Academic Guidelines to Clinical Practice

Abstract

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature cells. In most of the classic Philadelphia-negative MPNs-polycythemia vera (PV), essential thrombocythemia (ET), and MPN-associated myelofibrosis (MPN-MF)-oncogenic mutations affecting JAK2 or MPL lead to constitutive activation of cytokine-regulated intracellular signalling pathways. The traditional therapy for PV and ET is the prevention of thrombotic events with antiproliferative agents in association with aspirin. New drugs such as pegylated interferon and anti-JAK agents are candidates for slowing the evolution to myelofibrosis or leukemia. Conventional therapy for MPN-MF is driven by clinical needs, primarily anemia and splenomegaly. Lenalidomide and pomalidomide are new candidates for treating anemia. JAK2 ATP-competitive inhibitors or drugs that indirectly inhibit the JAK-STAT pathway, like RAD001, are the new candidates for splenomegaly in MPN-MF, but in spite of their strong rationale, they have shown only a palliative benefit. Allogeneic stem cell transplantation remains the only potentially curative approach.

Megakaryocyte pathology and bone marrow fibrosis: the lysyl oxidase connection

“…For ET and PV, the modalities currently in use, 59 which include aspirin, hydroxyurea, busulphan, chlorambucil, and 32 P, lack a specific molecular target. A potential exception is anagrelide, which was shown to inhibit MK polyploidization 60 by a yet undiscovered mechanism.…”

Myelofibrosis patients in Belgium: disease characteristics

“…Subsequent advances in the development of therapies targeting the major symptoms of the disease (splenomegaly, burden of constitutional symptoms) [25][26][27] through inhibition of the JAK-STAT pathway offer new strategies in the management of MF patients. [28][29][30][31] A number of such therapies are now entering clinical phase development. [25][26][27] Only one of these to date, 36 This finding still needs to be confirmed in the ongoing phase III trial where patients are randomized to momelotinib versus ruxolitinib treatment (NCT01969838).…”

Hematopoietic stem cells, progenitor cells and leukemic stem cells in adult myeloproliferative neoplasms

“…Several gene mutations were subsequently associated with Philadelphia/BCR-ABL1 negative (Ph-) myeoloproliferative neoplasms (reviewed in [3] [4]). Most notable of those is the valine to phenylalanine substitution in the JAK2 gene (JAK2V617F) that occurs in ~95% of polycythemia vera (PV), ~ 60% of essential thrombocythemia (ET) and ~50% of idiopathic myelofibrosis (IMF) [5] [6] [7] [8]. These acquired genetic mutations have been incorporated into the diagnostic criteria of myeloproliferative neoplasms as proposed by the World Health Organisation [9], integrating molecular and cytogenetic findings with traditional morphologic pathology in recognition of the importance of specific mutations which lead to constitutively activated kinases that drive disease phenotypes in most myeloproliferative neoplasms [7] [10] [11] [12].…”

“…Allogeneic transplantation is current the only strategy whereby this may occur for CML and Phmyeloproliferative neoplasms. Allogeneic transplantation however, carries significant cost in terms of non-relapse and relapse related morbidity and mortality for both CML [25] and the select group of patients with Phmyeloproliferative neoplasms who have transformed to acute leukaemia or have IMF and who are suitable for the procedure and have appropriately matched donors [8] [26].…”