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Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1244-1253
Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications
David M. Ross,1,2,3 Jeffrey J. Babon,4 Denis Tvorogov2 and Daniel Thomas3
1Department of Hematology and Bone Marrow Transplantation, Royal Adelaide Hospital, Adelaide; 2Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide; 3Precision Medicine Theme, South Australian Health & Medical Research Institute, and Adelaide Medical School, University of Adelaide, Adelaide and 4The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Australia.
ABSTRACT
Activation of JAK-STAT signaling is one of the hallmarks of myelofibrosis, a myeloproliferative neoplasm that leads to inflammation, progressive bone marrow failure, and a risk of leukemic transformation. Around 90% of patients with myelofibrosis have a mutation in JAK2, MPL, or CALR: so-called ‘driver’ mutations that lead to activation of JAK2. Ruxolitinib, and other JAK2 inhibitors in clinical use, provide clinical benefit but do not have a major impact on the abnormal hematopoietic clone. This phenomenon is termed ‘persis- tence’, in contrast to usual patterns of resistance. Multiple groups have shown that type 1 inhibitors of JAK2, which bind the active conforma- tion of the enzyme, lead to JAK2 becoming resistant to degradation with consequent accumulation of phospho-JAK2. In turn, this can lead to exacerbation of inflammatory manifestations when the JAK inhibitor is discontinued, and it may also contribute to disease persistence. The ways in which JAK2 V617F and CALR mutations lead to activation of JAK-STAT signaling are incompletely understood. We summarize what is known about pathological JAK-STAT activation in myelofibrosis and how this might lead to future novel therapies for myelofibrosis with greater disease-modifying potential.
Introduction
Primary myelofibrosis is a peculiar illness that has features of both a slowly pro- gressive cancer and a chronic inflammatory disorder. It is a clonal neoplasm driven by a handful of somatic mutations that activate cell signaling, presumably residing in the long-term stem cell compartment,1-3 but it also has a constellation of cytokine-mediated symptoms that are disproportionately severe. Myelofibrosis can also arise from antecedent polycythemia vera or essential thrombocythemia, leading to substantially overlapping clinical features. Progression of myelofibrosis leads to bone marrow failure with extensive marrow fibrosis or transformation to secondary acute myeloid leukemia. After the discovery of activating JAK2 muta- tions in 50-60% of patients with primary myelofibrosis,4,5 clinicians were hopeful that myelofibrosis would respond to tyrosine kinase inhibitor (TKI) therapy in a similar fashion to chronic myeloid leukemia, another myeloproliferative neoplasm (MPN). Chronic myeloid leukemia is driven by the BCR-ABL1 fusion which responds to ABL1 TKI therapy with rapid log-fold reductions in the number of BCR-ABL1-mutated cells in the majority of patients.6-8 Ruxolitinib was the first dual JAK1/JAK2 TKI approved for the treatment of myelofibrosis and was demonstrated to reduce splenomegaly and improve many symptoms related to myelofibrosis but, unlike TKI treatment in chronic myeloid leukemia, it does not result in elimination of the mutant clonal population of cells (a phenomenon termed “disease persist- ence” in contrast to the conventional understanding of TKI resistance) nor does it cause widespread regression of fibrosis. Understanding the molecular basis of clin- ical responses to ruxolitinib is of great relevance to cancer biology and has implica- tions for prescribing (and stopping) therapy, as well as the future design of kinase inhibitors for other cancers. Here we review what is known to date about the
Correspondence:
DAVID M ROSS
david.ross@sa.gov.au
Received: September 15, 2020. Accepted: December 11, 2020. Pre-published: January 21, 2021.
https://doi.org/10.3324/haematol.2020.262691
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