Long-term follow-up data from the COMFORT-I and COMFORT-II Phase III studies in myelofibrosis show that ruxolitinib (INC424/Jakafi?/Jakavi?; Incyte Pharmaceuticals/Novartis) treatment resulted in sustained reductions in spleen size, a hallmark of myelofibrosis, while also improving quality of life and extending overall survival compared to placebo or the best available therapy (BAT). Results were presented at the 54th American Society of Hematology (ASH) Annual Meeting and Exposition in Atlanta.

Myelofibrosis is a life-threatening blood cancer with a poor prognosis and limited treatment options.[7][8] Studies show that patients with myelofibrosis have a decreased life expectancy, with a median overall survival of 5.7 years. [9] Although allogeneic stem cell transplantation may cure myelofibrosis, the procedure is associated with significant morbidity and transplant-related mortality and is available to less than 5% of patients who are young and fit enough to undergo the procedure. [10]

Treatment options
A two-year follow-up analysis of COMFORT-II showed that ruxolitinib was associated with sustained reductions in splenomegaly (enlarged spleen). Overall, 48.3% of patients treated with ruxolitinib achieved a >=35% reduction in spleen volume, and the majority of reductions were sustained with continued treatment over two years.

Survival advantage
In a rigorous intent-to-treat analysis, ruxolitinib-treated patients showed an overall survival advantage compared to patients receiving BAT (HR=0.51; 95% CI, 0.26-0.99; p=0.041)[1], which was defined by protocol as any commercially available agent (monotherapy or in combination) or no therapy at all. A total of 61.6% of BAT patients switched to ruxolitinib treatment, but remained categorized as BAT patients during the follow-up analyses[1].

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“As these Phase III studies continue over the long term, it is encouraging to see how treatment with ruxolitinib consistently alleviates the myelofibrosis disease burden and may improve overall survival,” said Dr. Francisco Cervantes, Hematology Department, Hospital Cl?nic, IDIBAPS, University of Barcelona. “Just one year ago, we didn’t have a truly effective treatment to offer our patients with myelofibrosis. Now, it appears we can significantly improve a patient’s quality of life while also potentially extending their life.”

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Long-term follow-up
In COMFORT-I, which compared the use of ruxolitinib versus placebo, researchers presented long-term follow-up data evaluating the efficacy and safety of ruxolitinib. Similar to COMFORT-II, ruxolitinib was associated with sustained reductions in spleen volume. Mean spleen volume reduction in the ruxolitinib arm was 31.6% at week 24, and maintained through week 96 (34.9%)[2]. Among patients with a >=35% reduction in spleen volume, response was maintained with a median duration of 108 weeks. The study demonstrated a continued overall survival benefit in favor of ruxolitinib, as 83% of patients on ruxolitinib survived at the 102 week follow-up period, compared to 73% of patients on placebo (HR=0.58; 95% CI, 0.36-0.95; p=0.028)[2]. Overall survival favored ruxolitinib across subgroups, including starting dose as well as baseline risk status and hemoglobin[2].

Regulatory approval
“The COMFORT program, which supported the European Commission approval for ruxolitinib, is the most extensive clinical trial program in myelofibrosis to date and continues to demonstrate significant results for Jakavi-treated patients,” said Herv? Hoppenot, President, Novartis Oncology. “We are encouraged by these findings and look forward to evaluating how ruxolitinib may help patients with other myeloproliferative neoplasms associated with a similar mechanism of disease.”

Myelofibrosis develops when uncontrolled signaling in the JAK pathway – which regulates blood cell production – causes bone marrow scarring and faulty blood cell production, resulting in severe complications. Jakavi directly targets an underlying mechanism of myelofibrosis, significantly reducing splenomegaly and improving debilitating symptoms regardless of JAK mutational status, disease subtype or any prior treatment, including hydroxyurea[3],[4],[5],[6].

Disease-modifying effects
While ruxolitinib has proven to provide patient benefits regardless of mutational status, an analysis of patients with the JAK2V617F mutation within the COMFORT-II study was also presented at ASH. Findings demonstrate the disease-modifying effects of ruxolitinib. Patients bearing the JAK2V617F mutation who received ruxolitinib had greater reductions in the presence of cancerous cells with the mutated JAK2V617F allele (allele burden) compared with BAT[5]. Allele burden reductions among ruxolitinib-treated patients were gradual and sustained over the duration of the study, whereas BAT-treated patients demonstrated zero reductions. Among patients with >=20% allele burden reduction, sustained spleen volume reductions were observed to week 72[5].

COMFORT-II Long-Term Study Background
The COMFORT-II (COntrolled MyeloFibrosis Study with ORal JAK Inhibitor Therapy) study randomized 219 patients to receive ruxolitinib (15 or 20 mg BID) or BAT (2:1 randomization for ruxolitinib vs. BAT). A total of 73.3% (107/146) of patients in the ruxolitinib-arm entered the extension phase vs. 61.6% (45/73) in the BAT arm, and 55.5% (81/146) of those originally randomized to ruxolitinib remained on treatment at the time of this analysis[1]. Overall survival was estimated using the Kaplan-Meier method. In the analysis of COMFORT-II data examining JAK2V617 allele burden reduction, allele burden was measured from blood samples using allele-specific quantitative real-time polymerase chain reaction (qPCR)[5].

No specific long-term safety signals emerged during the two-year follow-up period. In the primary analysis of the COMFORT-II study published in The New England Journal of Medicine in February 2012 (median treatment duration of 50.1 weeks; Jakavi, 51.4 weeks; BAT, 45.1 weeks), the most common grade 3/4 hematologic adverse events (AEs) in either arm (ruxolitinib, BAT) were anemia (42.4%; 31.4%) and thrombocytopenia (8.3%; 7.2%), and were manageable with either dose reduction or occasional interruption[4]. In the Jakavi arm, mean hemoglobin levels decreased over the first 12 weeks of treatment and then recovered to levels similar to the BAT from week 24 onward[4].

One patient in each arm discontinued for thrombocytopenia, and no patients discontinued for anemia. One week after discontinuing Jakavi, these patients experienced a return of myelofibrosis symptoms that were present before initiating therapy. Since the core study has completed, all patients either entered the extension phase or discontinued from the study. A total of 107 of the 146 patients on ruxolitinib entered the extension phase in addition to 45 of the 73 patients previously treated with BAT (median treatment duration of 83.3 weeks; ruxolitinib, 111.4 weeks [randomized and extension phases]; BAT, 45.1 weeks [randomized treatment only per primary analysis]. Grade 3/4 hematologic abnormalities in the extension phase for ruxolitinib were consistent with the primary analysis: anemia (40.4%); lymphopenia (22.6%) and thrombocytopenia (9.6%)[1].

COMFORT-I Long-Term Study Background
This study randomized 309 patients to Jakavi or placebo. The primary analysis occurred when all patients completed 24 weeks of therapy, and all patients receiving placebo were eligible to cross over to ruxolitinib after the primary analysis. Quality of life was evaluated beyond week 24 using the European Organization for Resea
rch and Treatment of Cancer QoL Questionnaire-Core 30, and overall survival was assessed according to original randomized treatment[2].

Adverse events
The AE profile with long-term treatment is consistent with what has been previously reported[2]. Of 34 patients randomized to Jakavi who discontinued after the primary analysis, 4 discontinued for an AE. In patients who continued on ruxolitinib therapy, anemia and thrombocytopenia remained the most frequently reported AEs. New onset of grade 3 or 4 anemia and thrombocytopenia was reported in 12 and 5 patients, respectively. One patient discontinued for anemia. Overall, among all patients randomized to Jakavi, grade 3 and 4 anemia – regardless of baseline hemoglobin – was reported in 37.4% and 14.8% of patients, respectively. Similarly, grade 3 and 4 thrombocytopenia was reported in 11.0% and 5.2% of patients, respectively. These rates were similar to those reported in the primary analysis. By week 36, the proportion of patients receiving red blood cell transfusions decreased to the level seen with placebo and remained stable thereafter[2].

Rates of non-hematologic AEs adjusted for increased follow-up duration remained similar to those seen at the time of the primary data analysis[2]. No additional cases of acute myeloid leukemia (AML) in patients randomized to ruxolitinib were reported. Two patients originally randomized to placebo developed AML, 21 and 178 days after crossover to ruxolitinib. There continued to be no reports of a withdrawal syndrome after ruxolitinib discontinuation[2].

References
[1] Cervantes, F, et al. Long-Term Safety, Efficacy, and Survival Findings From COMFORT-II, a Phase 3 Study Comparing Ruxolitinib with Best Available Therapy (BAT) for the Treatment of Myelofibrosis (MF). Blood. 2012. Abstract #801. American Society of Hematology (ASH) 2012 Annual Meeting. Atlanta, GA.
[2] Verstovsek S et al. Long-Term Outcome of Ruxolitinib Treatment in Patients with Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in Quality of Life, and Overall Survival Advantage in COMFORT-I. Blood. 2012. Abstract #800. ASH 2012 Annual Meeting. Atlanta, GA.
[3] Verstovsek S, Mesa RA, Gotlib J, et al. A Double-Blind, Placebo-Controlled Trial of Ruxolitinib for Myelofibrosis. New Eng J Med. 2012 March 1: 366:799-807.
[4] Harrison C, Kiladjian JJ, Al-Ali HK, et al. JAK Inhibition with Ruxolitinib versus Best Available Therapy for Myelofibrosis. New Eng J Med. 2012: March 1;366:787-98.
[5] Vannucchi A, Kiladjian JJ, Gisslinger H, et al. Reductions in JAK2V617F Allele Burden with Ruxolitinib Treatment in COMFORT-II, a Phase III Study Comparing the Safety and Efficacy of Ruxolitinib to Best Available Therapy (BAT). 2012. Abstract #802. ASH 2012. Annual Meeting, Atlanta, GA.
[6] Harrison C, Kiladjian JJ, Gisslinger H, et al. Association of Cytokine Levels and Reductions in Spleen Size in COMFORT-II, a Phase 3 Study Comparing Ruxolitinib to Best Available Therapy (BAT). Abstract # 6625. American Society of Clinical Oncology 2012 Annual Meeting, Chicago, IL.
[7] Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and Efficacy of JAK1 & JAK2 Inhibitor, INCB018424, in Myelofibrosis. New Eng J Med. 2010 September 16;363(12):1117-1127.
[8] Mesa RA, Schwagera S, Radia D, et al. The Myelofibrosis Symptom Assessment Form (MFSAF): an evidence-based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res. 2009;33:1199-1203.
[9] Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
[10] Patriarca F, Bacigalupo A, Sperotto A, et al. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica. 2008;93(10):1514-1522.
[11] Rexolitinib (Jakavi?;Summary of Product Characteristics). Basel, Switzerland: Novartis Pharma AG; 2012.

Clinical trials
NCT00934544 – Controlled Myelofibrosis Study With Oral Janus-associated Kinase (JAK) Inhibitor Treatment-II: The COMFORT-II Trial

NCT01433445– Panobinostat and Ruxolitinib in Primary Myelofibrosis, Post-polycythemia Vera-myelofibrosis or Post-essential Thrombocythemia-myelofibrosis

NCT01251965– Phase l/II Study of Ruxolitinib for Acute Leukemia

NCT01751425– Ruxolitinib for Chronic Myeloid Leukemia (CML) With Minimal Residual Disease (MRD)

NCT01730248– A Study to Find the Maximum Tolerated Dose of the Experimental Combination of the Drugs INC424 and BKM120 in Patients With Primary or Secondary Myelofibrosis

NCT01493414INC424 for Patients With Myelofibrosis, Post Polycythemia Myelofibrosis or Post-essential Thrombocythemia Myelofibrosis (MACS1632/2254)

NCT01243944– Study of Efficacy and Safety in Polycythemia Vera Subjects Who Are Resistant to or Intolerant of Hydroxyurea: JAK Inhibitor INC424 (INCB018424) Tablets Versus Best Available Care: (The RESPONSE Trial) ((RESPONSE))

NCT01392443– Asian Phase II Study of INC424 in Patients With Primary Myelofibrosis (MF), Post-PV MF or Post-ET MF

NCT01558739– Exploratory Phase II Study of INC424 Patients With Primary Myelofibrosis (PMF) or Post Polycythaemia Myelofibrosis (PPV MF) or Post Essential Thrombocythaemia Myelofibrosis (PET-MF) (MACS2030)

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