Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis

Review question

We reviewed the effects of Janus kinase-1 and Janus kinase-2 inhibitors for treating people with myelofibrosis.


Myelofibrosis is a disorder of the bone marrow in which the bone marrow is replaced by fibrous tissue. The symptoms depend on the degree of anemia and enlargement of the spleen. This condition has a poor prognosis and generally its treatment is palliative.

Ruxolitinib is a drug in the class of Janus kinase inhibitors that tries to block the enzyme that derives in the scar tissue.

Study characteristics

We identified two clinical trials that included a limited number of patients comparing ruxolitinib to placebo or standard medical treatment. Both studies were published in 2012, and were conducted in the United States of America (USA) and the United Kingdom (UK). Drug companies sponsored both trials.

Key results

Although the results of the studies only showed a moderate improvement of patients treated with ruxolitinib in terms of their quality of life and a reduction in their spleen size, we could not be sure whether these effects were reliable because of the limitations of the studies and the low number of people they recruited. We also could not be sure whether the drug has an effect on overall survival compared with a placebo, or when it was compared with an active treatment. The effect of ruxolitinib in terms of progression-free survival was also uncertain. In addition, people treated with this drug showed higher rates of anemia, thrombocytopenia and neutropenia compared with patients treated with a placebo, but the rate of adverse effects was similar to those treated with a medical treatment.

Quality of evidence

The confidence in the results of this review is very low. The studies have limitations in the way they were designed and executed. Moreover, the limited number of patients included in the studies led to imprecise results. Larger studies should provide more information about the effect of ruxolitinib.

Researchers from Cochrane searched all available literature up to 13 November 2014.

Authors' conclusions: 

Currently, there is insufficient evidence to allow any conclusions regarding the efficacy and safety of ruxolitinib for treating myelofibrosis. The findings of this Cochrane review should be interpreted with caution as they are based on trials sponsored by industry, and include a small number of patients. Unless powered randomized clinical trials provide strong evidence of a treatment effect, and the trade-off between potential benefits and harms is established, clinicians should be cautious when administering ruxolitinib for treating patients with myelofibrosis.

Read the full abstract...

Myelofibrosis is a bone marrow disorder characterized by excessive production of reticulin and collagen fiber deposition caused by hematological and non-hematological disorders. The prognosis of myelofibrosis is poor and treatment is mainly palliative. Janus kinase inhibitors are a novel strategy to treat people with myelofibrosis.


To determine the clinical benefits and harms of Janus kinase-1 and Janus kinase-2 inhibitors for treating myelofibrosis secondary to hematological or non-hematological conditions.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, the Cochrane Library 2014, Issue 11), Ovid MEDLINE (from 1946 to 13 November 2014), EMBASE (from 1980 to 12 January 2013), and LILACS (from 1982 to 20 November 2014). We searched WHO International Clinical Trials Registry Platform and The metaRegister of Controlled Trials. We also searched for conference proceedings of the American Society of Hematology (from 2009 to October 2013), European Hematology Association (from 2009 to October 2013), American Society of Clinical Oncology (from 2009 to October 2013), and European Society of Medical Oncology (from 2009 to October 2013). We included searches in FDA, European Medicines Agency, and Epistemonikos. We handsearched the references of all identified included trials, and relevant review articles. We did not apply any language restrictions. Two review authors independently screened search results.

Selection criteria: 

We included randomized clinical trials comparing Janus kinase-1 and Janus kinase-2 inhibitors with placebo or other treatments. Both previously treated and treatment naive patients were included.

Data collection and analysis: 

We used the hazard ratio (HR) and 95% confidence interval (95% CI) for overall survival, progression-free survival and leukemia-free survival, risk ratio (RR) and 95% CI for reduction in spleen size and adverse events binary data, and standardized mean differences (SMD) and 95% CI for continuous data (health-related quality of life). Two review authors independently extracted data and assessed the risk of bias of included trials. Primary outcomes were overall survival, progression-free survival and adverse events.

Main results: 

We included two trials involving 528 participants, comparing ruxolitinib with placebo or best available therapy (BAT). As the two included trials had different comparators we did not pool the data. The confidence in the results estimates of these trials was low due to the bias in their design, and their limited sample sizes that resulted in imprecise results.

There is low quality evidence for the effect of ruxolitinib on survival when compared with placebo at 51 weeks of follow-up (HR 0.51, 95% CI 0.27 to 0.98) and compared with BAT at 48 weeks of follow-up (HR 0.70, 95% CI 0.20 to 2.47). Similarly there was very low quality evidence for the effect of ruxolitinib on progression free survival compared with BAT (HR 0.81, 95% CI 0.47 to 1.39).

There is low quality evidence for the effect of ruxolitinib in terms of quality of life. Compared with placebo, the drug achieved a greater proportion of patients with a significant reduction of symptom scores (RR 8.82, 95% CI 4.40 to 17.69), and treated patients with ruxolitinib obtained greater MFSAF scores at the end of follow-up (MD -87.90, 95% CI -139.58 to -36.22). An additional trial showed significant differences in EORTC QLQ-C30 scores when compared ruxolitinib with best available therapy (MD 7.60, 95% CI 0.35 to 14.85).

The effect of ruxolitinib on reduction in the spleen size of participants compared with placebo or BAT was uncertain (versus placebo: RR 64.58, 95% CI 9.08 to 459.56, low quality evidence; versus BAT: RR 41.78, 95% CI 2.61 to 669.75, low quality evidence).

There is low quality evidence for the effect of the drug compared with placebo on anemia (RR 2.35, 95% CI 1.62 to 3.41), neutropenia (RR 3.57, 95% CI 1.02 to 12.55) and thrombocytopenia (RR 9.74, 95% CI 2.32 to 40.96). Ruxolitinib did not result in differences versus BAT in the risk of anemia (RR 1.35, 95% CI 0.91 to 1.99, low quality evidence) or thrombocytopenia (RR 1.20; 95% CI 0.44 to 3.28, low quality evidence). The risk of non-hematologic grade 3 or 4 adverse events (including fatigue, arthralgia, nausea, diarrhea, extremity pain and pyrexia) was similar when ruxolitinib was compared with placebo or BAT. The rate of neutropenia comparing ruxolitinib with standard medical treatment was not reported by the trial.