Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib

Abstract

Myeloproliferative neoplasms (MPN) are debilitating stem cell-derived clonal myeloid malignancies. Conventional treatments for the BCR-ABL1-negative MPN including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) have, so far, been unsatisfactory. Following the discovery of dysregulated JAK-STAT signaling in patients with MPN, many efforts have been directed toward the development of molecularly targeted therapies, including inhibitors of JAK1 and JAK2. Ruxolitinib (previously known as INCB018424; Incyte Corporation, Wilmington, Delaware, USA) is a rationally designed potent oral JAK1 and JAK2 inhibitor that has undergone clinical trials in patients with PV, ET, and PMF. Ruxolitinib was approved on November 16, 2011 by the United States Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis (MF), including patients with PMF, post-PV MF, and post-ET MF. In randomized phase III studies, ruxolitinib treatment resulted in significant and durable reductions in splenomegaly and improvements in disease-related symptoms in patients with MF compared with placebo or best available therapy. The most common adverse events were anemia and thrombocytopenia, which were manageable and rarely led to discontinuation. This review addresses the cellular and molecular biology, and the clinical management of MPN.

Fig. (1)

Schematic structure of JAKs. There are seven JAK homology regions (JH) containing the catalytically active kinase domain (JH1), the auto-inhibitory pseudokinase domain (JH2), the SH2 domain (JH3, JH4), and a FERM domain (JH6, JH7) [62]. Reproduced with permission from Wiley-Blackwell.

Fig. (2)

Involvement of the cytokine receptor-tyrosine kinase axis in MPN oncogenesis. The four main myeloid growth factor receptors involved in MPN pathogenesis are represented with their principal downstream signaling event sequences, involving the binding of JAK2, and the phosphorylation of phosphatidyl- inositol-3-kinase (PI3K), protein kinase B (AKT; generally thought to be a cytoplasmic protein), the signal transducers and activators of transcription (STATs), and the mitogen-activated protein kinases (MAPK). The adaptor and E3 ubiquitin ligase c-CBL (casitas B-lineage lymphoma) protein downregulates c-KIT and JAK2 signaling (blue bars). Red stars indicate the oncogenic mutations that occur in MPN resulting in a constitutive or enhanced downstream signaling (red) with eventual modulation of transcription of genes that control and/or modulate cell cycle, proliferation, and apoptosis. Abbreviations: VF, JAK2V617F; Ex12, JAK2 exon 12 mutations; 505 and 515, MPLW515 and MPLS505N mutations, D816V, KITD816V. Several point mutations have been described in c-CBL, resulting in both loss of its inhibitory functions (red crosses) and gain of function properties (red arrow) [71]. Reproduced with permission by the courtesy of International Journal of Hematology.

Fig. (3)

Mutations in MPN. Genes involved in MPN pathogenesis are represented in a schematic linear fashion with their principal functional or conserved domains. Molecular defects are shown in red. Point mutations are indicated by vertical arrows, with horizontal bars spanning the domains where multiple mutations have been identified. Horizontal arrows indicate truncating mutations that may occur anywhere in the downstream coding sequence. Abbreviations: SH, Src homology; JH, JAK homology; Ig, immunoglobulin; TK, tyrosine kinase; Pro, proline; ASXN and ASXM, ASX conserved domains; NR, nuclear receptor; PHD, plant homeodomain [71]. Reproduced with permission by the courtesy of International Journal of Hematology.

Fig. (4)

Effect of ruxolitinib treatment on cytokine levels. Changes in selected cytokines and C-reactive protein (CRP), an acute-phase reactant and a marker for inflammation, are shown in MF patients with a 50% or greater decrease, those with less than a 50% decrease, and those with no change or an increase in the composite symptom score after 6 cycles (months) of ruxolitinib treatment as compared with baseline (ClinicalTrials.gov number, NCT00509899) [101]. Reproduced with permission from the Massachusetts Medical Society.

Fig. (5)

Percent change from baseline in spleen volume at week 24 or last observation for each patient. A significantly larger proportion of patients in the ruxolitinib group achieved a 35% or greater reduction in spleen volume from baseline compared to placebo [103]. Reproduced with permission from the Massachusetts Medical Society.

Fig. (6)

Mean percent change in individual symptom scores at week 24. At week 24, individual symptom scores improved in the ruxolitinib group (decrease from baseline), while scores worsened in the placebo group (increase in score from baseline) (all P <0.01) (reproduced with permission from NEJM) [103]. Reproduced with permission from the Massachusetts Medical Society.