The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

Abstract

The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

Ruxolitinib in refractory acute and chronic graft-versus-host disease: a multicenter survey study

“…Ruxolitinib is an orally administered selective Janus Kinase (JAK) inhibitor approved for the treatment of myelofibrosis and polycythemia vera [6][7][8][9]. JAK inhibitors relieve symptoms related to an excess of proinflammatory cytokines in these patients [10,11].…”

Programmed Cell Death Deregulation in BCR-ABL1-Negative Myeloproliferative Neoplasms

“…The discovery of JAK2 V617F mutation and its role in constitutive activation of downstream signaling pathways and MPN pathogenesis triggered the search for specific JAK2 kinase inhibitors as potential targeted therapy. One of the first molecules approved for targeted treatment of MPN patients, ruxolitinib/jakafi (RUX), a selective JAK2 and JAK1 inhibitor, is currently used in PV resistant or intolerant to HU, and in intermediate and high risk PMF [99,105]. RUX, approved in 2014 based on the results of the RESPONSE trial [106,107], inhibits ATP-binding catalytic site of JAK kinase domain (both in mutant and wild type JAK), thus leading to a reduction of phosphorylation level of STAT-3/5, ERK, and AKT [108,109].…”

“…RUX effects on the malignant clone are modest, side effects (such as anemia and thrombocytopenia) are reported, and drug resistance may appear. Other therapeutic strategies have been developed; they include the discovery of new inhibitors that target specifically mutant JAK2 and the combination of current therapies with other molecules that inhibit components of signaling pathway [105].…”

Anti-Glucosylsphingosine Autoimmunity, JAK2V617F-Dependent Interleukin-1β and JAK2V617F-Independent Cytokines in Myeloproliferative Neoplasms

“…Most of these symptoms and complications, including bone marrow fibrosis, can be explained by inflammation. Logically, JAK inhibitors that significantly reduce inflammation also reduce clinical symptoms and splenomegaly [ 14 , 15 , 16 , 17 , 18 , 19 ]. Unfortunately, suppression of the MPN clone and significant reduction in the mutation load are typically not obtained with JAK inhibitors [ 17 , 18 , 19 ].…”

“…Logically, JAK inhibitors that significantly reduce inflammation also reduce clinical symptoms and splenomegaly [ 14 , 15 , 16 , 17 , 18 , 19 ]. Unfortunately, suppression of the MPN clone and significant reduction in the mutation load are typically not obtained with JAK inhibitors [ 17 , 18 , 19 ]. In contrast, IFN-α therapy frequently leads to clinical and molecular remission, in PV and also in JAK2 - and CALR -mutated ET [ 20 , 21 , 22 , 23 ].…”