Ruxolitinib for myelofibrosis: Indication of considerable added benefit

August 19, 2014

Ruxolitinib (trade name: Jakavi) has been approved since August 2012 for the treatment of adults with myelofibrosis. In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) examined whether this new drug offers an added benefit over the appropriate comparator therapy specified by the Federal Joint Committee (G-BA).

According to the results, there is an indication of considerable added benefit in comparison with "best supportive care" (BSC) because ruxolitinib is better at relieving symptoms. Moreover, a hint of an added benefit with regard to survival can be derived from the dossier. Its extent is non-quantifiable, however.

Bone marrow is replaced by connective tissue

Myelofibrosis is a rare disease of the bone marrow, in which the bone marrow is replaced by . As a consequence of this so-called fibrosis, the is no longer able to produce enough blood cells. Sometimes the spleen or the liver takes over some of the blood production. Then these organs enlarge and can cause abdominal discomfort and pain. The typical symptoms also include feeling of fullness, night sweats and itching. Some patients with myelofibrosis develop leukaemia.

Stem cell transplantation is currently the only option to cure myelofibrosis. The drug ruxolitinib aims to relieve the symptoms of myelofibrosis.

G-BA specifies appropriate comparator therapy

Ruxolitinib is an option for patients with so-called primary or secondary myelofibrosis whose spleen is already enlarged (splenomegaly) or who have other disease-related symptoms.

The G-BA specified "best supportive care" (BSC) as appropriate comparator therapy. BSC means a therapy that provides the patient with the best possible, individually optimized, supportive treatment to alleviate symptoms and improve quality of life. This also includes adequate pain therapy.

Relevant study ongoing until 2015

In its assessment, IQWiG could include one (RCT) conducted in 89 centres in Australia, Canada and the United States (COMFORT-I). The 309 patients in total were either treated with ruxolitinib plus BSC or with placebo plus BSC.

The first analysis (primary analysis) was conducted in 2010 after all patients had been treated for 24 weeks and half of them for 36 weeks. Then all participants were unblinded and could switch to the ruxolitinib arm of the study. If their spleen volume had increased by more than 25%, they could also switch earlier. A 3-year analysis was conducted in 2013. The study was prolonged to 2015, however, to obtain long-term data.

Overall survival: results not consistently significant

With regard to survival time, the differences between the two treatment groups were not statistically significant in favour of ruxolitinib in all of the four analysis dates. Because of the high proportion of patients who switched treatment, the survival advantage of ruxolitinib is rather underestimated. Overall, IQWiG therefore considers there to be a hint of an added benefit. The extent of this added benefit is unclear, however.

Morbidity: fewer symptoms in ruxolitinib group

A disease-specific questionnaire (MFSAF v2.0) was used to record symptoms in the COMFORT-I study. This instrument comprises myelofibrosis symptoms and aggregates them to one value (total symptom score, [TSS]). In the ruxolitinib + BSC group, considerably more patients than in the placebo + BSC group reported that their symptoms have improved.

Regarding the occurrence of leukaemia (leukaemic transformation), a typical late complication, there were no differences between the two treatment groups in the study.

For the outcome "morbidity", IQWiG therefore recognizes an indication of an added benefit with the extent "considerable".

No evaluable results on quality of life

The dossier contained no evaluable data on quality of life. Quality of life was recorded in the study using an instrument developed for cancer (EORTC QLQ-C30). However, different proportions of participants in the two treatment groups remained unconsidered in the analysis. As the difference of the missing values was more than 20 percentage points, no reliable conclusions can be derived from the results.

For the same reason, the data on symptoms that were also recorded with EORTC QLQ-C30 are also not evaluable.

Only limited conclusions on side effects possible

Only limited conclusions can be drawn on side effects. This is mainly due to the fact that typical symptoms of , such as night sweats, were also recorded as "adverse events". This means that it remains unclear whether these were side effects of the drug or symptoms of the underlying condition. Such events that are not clearly attributable allow no informative conclusions on side effects.

Although greater harm from ruxolitinib can also not be ruled out completely, the available data contain no signs of harm of a magnitude that might justify downgrading the added benefit as a whole.

Hence the positive effects with regard to symptom relief (indication) and prolongation of life (hint) remain. Overall, IQWiG therefore regards there to be an indication of considerable added benefit of ruxolitinib in comparison with BSC.

First orphan drug with a turnover of over 50 million euros

Ruxolitinib has the status "orphan drug". According to §35a (1), Sentence 10, Social Code Book V [SGB V]), the medical added benefit is regarded as proven if a drug has been approved, as long as the yearly turnover in the statutory health insurance (SHI) funds does not exceed 50 million euros. In this case, the G-BA only has to determine the extent of added benefit. The G-BA made this decision on ruxolitinib in March 2013.

In 2013, ruxolitinib was the first drug for rare diseases to exceed the 50 million euro threshold. The G-BA therefore requested the drug manufacturer to submit proof of the added benefit of ruxolitinib in comparison with the appropriate comparator therapy in a dossier, and commissioned IQWiG with the assessment.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessments supervised by the G-BA. After publication of the manufacturer's dossier and IQWiG's assessment, the G-BA conducts a commenting procedure, which may provide further information and result in a change to the benefit assessment. The G‑BA then decides on the extent of the added benefit, thus completing the early benefit assessment.

Explore further: Enzalutamide: IQWiG assessed data subsequently submitted by the manufacturer

More information: An overview of the results of IQWiG's benefit assessment is given by a German-language executive summary. In addition, the website, published by IQWiG, provides easily understandable and brief German-language information on ruxolitinib.

Related Stories

Enzalutamide: IQWiG assessed data subsequently submitted by the manufacturer

February 21, 2014
Enzalutamide (trade name: Xtandi) has been approved since June 2013 for men with metastatic prostate cancer in whom the commonly used hormone blockade is no longer effective and who have already been treated with the cytostatic ...

Regorafenib: Hint of minor added benefit

January 10, 2014
Regorafenib (trade name: Stivarga) has been approved in Germany since August 2013 for adults with metastatic colorectal cancer in whom previous treatments are no longer effective or for whom these alternatives are not an ...

Radium-223 dichloride in prostate cancer: Major added benefit for certain patients

April 3, 2014
Radium-223 dichloride (radium-223 for short, trade name: Xofigo) has been approved since November 2013 for men with advanced prostate cancer, in whom hormone blockade is no longer effective, and symptomatic bone metastases, ...

Enzalutamide in prostate cancer: Hints of added benefit

December 6, 2013
Enzalutamide (trade name: Xtandi) has been approved since June 2013 for men with metastatic prostate cancer in whom the commonly used hormone blockade is no longer effective and who have already been treated with the cytostatic ...

Dimethyl fumarate for MS: Added benefit is not proven

August 7, 2014
Dimethyl fumarate (trade name: Tecfidera) has been approved since January 2014 for adults with relapsing remitting multiple sclerosis (RRMS). In an early benefit assessment pursuant to the Act on the Reform of the Market ...

Dabrafenib in melanoma: Added benefit not proven

January 7, 2014
Dabrafenib (trade name: Tafinlar) has been approved in Germany since August 2013 for the treatment of advanced melanoma.In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products ...

Recommended for you

Study suggests ending opioid epidemic will take years

July 20, 2017
The question of how to stem the nation's opioid epidemic now has a major detailed response. A new study chaired by University of Virginia School of Law Professor Richard Bonnie provides extensive recommendations for curbing ...

Team-based model reduces prescription opioid use among patients with chronic pain by 40 percent

July 17, 2017
A new, team-based, primary care model is decreasing prescription opioid use among patients with chronic pain by 40 percent, according to a new study out of Boston Medical Center's Grayken Center for Addiction Medicine, which ...

Private clinics' peddling of unproven stem cell treatments is unsafe and unethical

July 7, 2017
Stem cell science is an area of medical research that continues to offer great promise. But as this week's paper in Science Translational Medicine highlights, a growing number of clinics around the globe, including in Australia, ...

Popular heartburn drugs linked to higher death risk

July 4, 2017
Popular heartburn drugs called proton pump inhibitors (PPIs) have been linked to a variety of health problems, including serious kidney damage, bone fractures and dementia. Now, a new study from Washington University School ...

Most reproductive-age women using opioids also use another substance

June 30, 2017
The majority of reproductive-age and pregnant women who use opioids for non-medical purposes also use at least one other substance, ranging from nicotine or alcohol to cocaine, according to a University of Pittsburgh Graduate ...

At-risk chronic pain patients taper opioids successfully with psychological tools

June 28, 2017
Psychological support and new coping skills are helping patients at high risk of developing chronic pain and long-term, high-dose opioid use taper their opioids and rebuild their lives with activities that are meaningful ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.