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Published on 23 November 2012

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Ruxolitinib for the treatment of myelofibrosis

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Claire Harrison DM FRCP FRCPath
Department of Haematology,
Guys and St Thomas’ NHS Foundation Trust, London, UK
Email: claire.harrison@gstt.nhs.uk
 

 

Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells that include myelofibrosis (MF), polycythemia vera (PV) and essential thrombocythemia (ET). MF is characterised by bone marrow fibrosis, progressive anaemia, and extramedullary haematopoiesis often resulting in profound splenomegaly. Patients often experience debilitating symptoms including pain, early satiety, and limited mobility, night sweats, and fatigue.(1)
 
Role of JAK in MPNs
A key feature of MPNs is the dysregulation of the JAK/STAT signalling pathway which is involved in normal haematopoiesis, inflammation, and immune function. Dysregulation of the pathway commonly occurs from the presence of the JAK2 V617F mutation(2–5) but mutations in the JAK2 exon 12, MPL, and LNK(6–8) have also been discovered. Regardless of patients’ mutational status, JAK pathway dysregulation has been found to be a key pathophysiological feature of MPNs.
 
Ruxolitinib for MF
Recently, ruxolitinib (JAKAVI®), a potent, oral JAK1 and JAK2 inhibitor has been approved by the European Commission for the treatment of MF-related splenomegaly or symptoms. Starting doses of ruxolitinib are dependent on baseline platelet counts. Patients with platelet counts >200 × 109/l should be started at 20mg twice a day (bid); between 100 × 109/l and ≤200 × 109/l should be started at 15mg bid; and between 50 × 109/l and ≤100 × 109/l should be started at 5mg bid.
 
Pharmacodynamics
In clinical studies, ruxolitinib is rapidly absorbed after oral ruxolitinib administration with maximal plasma concentration (Cmax) achieved within one-to-two hours post-dose. Ruxolitinib is eliminated through metabolism catalysed by CYP3A4 and CYP2C9; strong inhibitors of these enzymes can give rise to increased ruxolitinib exposure. Ruxolitinib results in a decrease in heart rate and an increase in the PR interval and therefore, the concomitant use of ruxolitinib with other drugs that lower heart rate and/or prolong the PR interval should be avoided to the extent possible.
 
Phase III COMFORT studies
The approval of ruxolitinib was based on data from the two pivotal phase III Controlled Myelofibrosis Study with Oral JAK Inhibitor Treatment (COMFORT) trials.(9,10)  COMFORT-I was double-blinded and placebo-controlled,(9) whereas COMFORT-II was an open-label study that compared ruxolitinib to best available therapy (a combination of commercially available agents or no therapy as determined by the physician). 
 
The primary endpoints were met with significantly more patients in the ruxolitinib arms achieving a ≥35% reduction in splenomegaly: COMFORT-I, 41.9% versus 0.7%; and COMFORT-II, 28% versus 0% for ruxolitinib versus control arms, respectively. Importantly, nearly all patients (97% for each study) treated with ruxolitinib had some decrease in spleen size over time, including those with and without the V617F mutation.(9,10) Ruxolitinib resulted in rapid improvements across all measures of health-related quality of life including global health status, physical, role, and social functioning, as well as individual MF-associated symptoms.(9,10)
 
Because JAK-STAT signalling is critical for normal haematopoiesis, effect on red blood cells and/or platelets is an expected consequence of inhibiting this pathway. Accordingly, anaemia, neutropenia, and thrombocytopenia were common and expected adverse events (AEs). In general, cytopenias could be effectively managed with dose reductions and/or interruptions. Treatment should be interrupted for platelet counts less than 50,000/mm3 or absolute neutrophil counts less than 500/mm3. After recovery, dosing may be restarted at 5mg bid and gradually increased based on careful monitoring of blood cell counts to a maximum of 25mg bid. Non-haematologic grade 3 or 4 AEs were infrequent overall and were rarely reported more frequently in the ruxolitinib group than in the control group, attesting to the high degree of safety and tolerability of ruxolitinib observed in these studies.
 
Conclusions
Emerging evidence suggests that ruxolitinib therapy may also impact survival. In COMFORT-I, with a median follow-up of 51 weeks, 13 ruxolitinib- and 24 placebo-treated patients died during the study or during extended follow-up representing a hazard ratio of 0.499 (95% CI, 0.254, 0·98; p=0.0395).(9) Additionally, the overall survival of patients treated with ruxolitinib in a cohort of the phase I/II study conducted at the MDACC (n=107) was significantly better (p=0.005) than that of 310 historical control patients matched on the basis of trial enrolment criteria.(11) These results suggest that ruxolitinib provides an important new treatment option for patients with MF with the potential to alter the natural progression of the disease.
 
Acknowledgments
I thank Daniel Hutta, PhD, for medical editorial assistance funded by Novartis Pharmaceuticals.
 

 

References

 


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