Does ruxolitinib really prolong survival in individuals with myelofibrosis? The never-ending story

TO THE EDITOR:

We read with interest the recent article by Guglielmelli et al¹  in which they report new evidence showing ruxolitinib prolongs survival in individuals with myelofibrosis. The authors analyzed data from a registry of so-called real-world data from European centers. From 2013 to 2014, 1292 individuals with myelofibrosis were registered, 1010 (78%) of whom were analyzed; 645 (50%) were alive at the study start and were followed for 4 years, including 487 receiving hydroxyurea and 108 receiving ruxolitinib. The authors selected 100 participants (8%) from this cohort for propensity score matching, 50 from each therapy group. They report that those receiving ruxolitinib lived a median of 3 years longer than those receiving hydroxyurea.

The never-ending saga of trying to decipher whether ruxolitinib increases survival began in 2012, when the 2 COMFORT randomized controlled trials were published.^2,3  One-year follow-up data from the COMFORT-I study suggested better survival in participants at intermediate-2 risk or greater compared with controls, a finding confirmed in long-term follow-up.³  No survival benefit was reported in the initial report of the COMFORT-II study, where participants were assigned to receive ruxolitinib versus best available therapy.⁴  In contrast, follow-up at 3 years indicated improved survival with ruxolitinib.⁵ 

Results of these trials were greeted enthusiastically by the scientific community. The claim that ruxolitinib prolongs survival appeared in many commentaries and reviews, despite 3 subsequent publications questioning the validity of this conclusion.^6-8  Using the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach, we downgraded evidence from the COMFORT studies because of performance and attrition biases.^7,9  We argued survival data from these studies failed to meet optimal information size criteria, advising confidence in estimates of a survival advantage should be downgraded for imprecision (too few events). Another analysis using GRADE and a Cochrane systematic review reached similar conclusions.^6,8 

Getting the survival question right is vital because it affects the decision of whether to recommend ruxolitinib therapy when the goal is prolonging survival rather than reducing splenomegaly or improving constitutional symptoms. Six additional studies^1,10-14  addressed the question of whether ruxolitinib or the cognate JAK2 inhibitor momelotinib improves survival, the latest of which is that by Guglielmelli et al.¹  Although designs of these studies differ, they are fundamentally case-control analyses (Table 1). We have discussed limitations of case-control studies elsewhere.¹⁵  Although Guglielmelli et al used propensity score matching, this does not overcome the limitations of such studies, including selection bias for nonconsecutive enrollment and unjustified exclusion of 22% of patients. Another issue is the use of DIPSS to match cases with controls.¹⁶  DIPSS score was an inclusion criterion of the COMFORT trials, and in some countries, it is a criterion for the use of ruxolitinib; however, it is not usually a criterion for decision making regarding ruxolitinib use in individuals who need therapy but are not enrolled in clinical trials. For example, in those with an intermediate- or high-risk DIPSS score with leukocytosis, increased blasts (or elevated CD34⁺ blood cells), anemia, or thrombocytopenia without symptomatic splenomegaly, we and many others prefer hydroxyurea to ruxolitinib. Matching only for DIPSS score ignores prognostic impacts of hemoglobin, white blood cell concentration, and percentage of blood blasts. This bias has been highlighted by others.¹⁰ 

The report by Guglielmelli et al¹  also lacks other data that would make it more credible, such as whether the effect of ruxolitinib on survival correlated with ruxolitinib dose intensity. Moreover, the authors did not report causes of death, thereby preventing us from knowing whether the survival benefit they observed resulted from slowing disease progression, reducing risk of transformation to acute myeloid leukemia, and/or other mechanisms.

Consistency of results is a criterion for quality of evidence in the GRADE platform.⁹  Of the studies we have discussed, 3 reported survival differences^1,10,12  and 3 reported neutral results.^11,13,14  One study reported more new cancers in ruxolitinib receipients.¹⁴ 

Many investigators have stressed the need for a randomized controlled trial specifically designed and powered to evaluate whether ruxolitinib improves survival in myelofibrosis.¹⁰  We agree, and we continue to believe this is an unmet urgent clinical need despite substantial barriers to its execution. Ethical reasons have been put forth against a randomized trial comparing conventional drugs (eg, hydroxyurea) with ruxolitinib in individuals with myelofibrosis requiring therapy for disease progression, because it would contradict the notion of equipoise. We disagree for the reasons we have discussed here. We acknowledge that a randomized controlled trial comparing ruxolitinib with hydroxyurea would face recruitment challenges because most physicians and patients would prefer ruxolitinib, despite uncertainty about a survival benefit. We suggest the solution lies in innovative trial designs, such as partially randomized individual preference trials, which assign potential participants with a preference to that therapy while randomly assigning those without a preference.¹⁷  We also acknowledge a funding problem. Over the last 20 years, there has been a huge shift in the funding of cancer clinical trials from public to pharmaceutical sources.¹⁸  Almost all phase 3 trials are now funded by the pharmaceutical industry. Impartiality is best guaranteed by funding from nonprofit entities.

Contribution: G.B. and R.P.G. wrote and discussed the paper.

Conflict-of-interest disclosure: R.P.G. is a consultant to BeiGene, Ltd, Fusion Pharma, LLC, LaJolla NanoMedical, Inc., Mingsight Parmaceuticals, Inc., Kite Pharma, and CStone Pharmaceuticals; advisor to Antegene Biotech, LLC, Medical Director, and FFF Enterprises, Inc.; partner in AZACA, Inc.; member of the board of directors of the RakFond Foundation for Cancer Research Support; and member of the scientific advisory board of StemRad, Ltd. G.B. declares no competing financial interests.

Correspondence: Giovanni Barosi, Center for the Study of Myelofibrosis, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo Viale Golgi 19, 27100 Pavia, Italy; e-mail barosig@smatteo.pv.it.