Critical appraisal of the role of ruxolitinib in myeloproliferative neoplasm-associated myelofibrosis

The recent approval of molecular-targeted therapies for myeloproliferative neoplasm-associated myelofibrosis (MPN-MF) has dramatically changed its therapeutic landscape. Ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor, is now widely used for first- and second-line therapy in persons with MPN-MF, especially those with disease-related splenomegaly, intermediate- or high-risk disease, and constitutional symptoms. The goal of this work is to critically analyze data supporting use of ruxolitinib in the clinical settings approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). We systematically reviewed the literature and analyzed the risk of biases in the two randomized studies (COMFORT I and COMFORT II) on which FDA and EMA approval was based. Our strategy was to apply the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach by evaluating five dimensions of evidence: (1) overall risk of bias, (2) imprecision, (3) inconsistency, (4) indirectness, and (5) publication bias. Based on these criteria, we downgraded the evidence from the COMFORT I and COMFORT II trials for performance, attrition, and publication bias. In the disease-associated splenomegaly sphere, we upgraded the quality of evidence because of large effect size but downgraded it because of comparator choice and outcome indirectness (quality of evidence, low). In the sphere of treating persons with intermediate- or high-risk disease, we downgraded the evidence because of imprecision in effect size measurement and population indirectness. In the sphere of disease-associated symptoms, we upgraded the evidence because of the large effect size, but downgraded it because of comparator indirectness (quality of evidence, moderate). In conclusion, using the GRADE technique, we identified factors affecting the quality of evidence that were otherwise unstated. Identifying and evaluating these factors should influence the confidence with which physicians use ruxolitinib in persons with MPN-MF.

[1]  M. Cazzola,et al.  A Phase 2 Study of Ruxolitinib in Patients with Splanchnic Vein Thrombosis Associated with Myeloproliferative Neoplasm: A Study from the AGIMM Group , 2014 .

[2]  H. Deeg,et al.  Janus kinase inhibitors and allogeneic stem cell transplantation for myelofibrosis. , 2014, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[3]  M. Griesshammer,et al.  Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) , 2014, Leukemia.

[4]  P. Guglielmelli,et al.  CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients , 2014, Leukemia.

[5]  Yi-yang Chen,et al.  Hepatitis B virus reactivation associated with ruxolitinib , 2014, Annals of Hematology.

[6]  P. Georghiou,et al.  Pneumocystis jiroveci pneumonitis complicating ruxolitinib therapy , 2014, BMJ Case Reports.

[7]  M. Cazzola,et al.  Impact of mutational status on outcomes in myelofibrosis patients treated with ruxolitinib in the COMFORT-II study. , 2014, Blood.

[8]  S. Worswick,et al.  Reactivation of herpes simplex virus infection in a patient undergoing ruxolitinib treatment. , 2014, Journal of the American Academy of Dermatology.

[9]  N. Kröger,et al.  JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis , 2014, Leukemia.

[10]  G. Behre,et al.  Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib , 2014, Bone Marrow Transplantation.

[11]  T. Barbui,et al.  Identifying and addressing unmet clinical needs in Ph-neg classical myeloproliferative neoplasms: a consensus-based SIE, SIES, GITMO position paper. , 2014, Leukemia research.

[12]  G. Barosi,et al.  Rapid and long-lasting decrease of T-regulatory cells in patients with myelofibrosis treated with ruxolitinib , 2014, Leukemia.

[13]  J. D. Fitzpatrick,et al.  Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. , 2013, The New England journal of medicine.

[14]  G. Superti-Furga,et al.  Somatic mutations of calreticulin in myeloproliferative neoplasms. , 2013, The New England journal of medicine.

[15]  T. Barbui,et al.  Three-year efficacy, safety, and survival findings from COMFORT-II, a phase 3 study comparing ruxolitinib with best available therapy for myelofibrosis. , 2013, Blood.

[16]  J. Dipersio,et al.  Efficacy, safety, and survival with ruxolitinib in patients with myelofibrosis: results of a median 3-year follow-up of COMFORT-I , 2013, Haematologica.

[17]  J. Dipersio,et al.  Efficacy, safety and survival with ruxolitinib in patients with myelofibrosis: results of a median 2-year follow-up of COMFORT-I , 2013, Haematologica.

[18]  A. Heine,et al.  Ruxolitinib is a potent immunosuppressive compound: is it time for anti-infective prophylaxis? , 2013, Blood.

[19]  H. Kantarjian,et al.  Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts , 2013, Journal of Hematology & Oncology.

[20]  James M Robins,et al.  Randomized Trials Analyzed as Observational Studies , 2013, Annals of Internal Medicine.

[21]  N. Woolacott,et al.  Ruxolitinib for the Treatment of Myelofibrosis: A NICE Single Technology Appraisal , 2013, PharmacoEconomics.

[22]  N. Kröger,et al.  Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. , 2013, Blood.

[23]  S. Held,et al.  The JAK-inhibitor ruxolitinib impairs dendritic cell function in vitro and in vivo. , 2013, Blood.

[24]  E. Reichel,et al.  Bilateral toxoplasmosis retinitis associated with ruxolitinib. , 2013, The New England journal of medicine.

[25]  A. Shields,et al.  Progressive burden of myelofibrosis in untreated patients: assessment of patient-reported outcomes in patients randomized to placebo in the COMFORT-I study. , 2013, Leukemia research.

[26]  D. Milojković,et al.  Progressive multifocal leukoencephalopathy associated with ruxolitinib. , 2013, The New England journal of medicine.

[27]  Xiaolei Zhou,et al.  Health‐related quality of life and symptoms in patients with myelofibrosis treated with ruxolitinib versus best available therapy , 2013, British journal of haematology.

[28]  J. Dipersio,et al.  The clinical benefit of ruxolitinib across patient subgroups: analysis of a placebo‐controlled, Phase III study in patients with myelofibrosis , 2013, British journal of haematology.

[29]  N. Wysham,et al.  An opportunistic infection associated with ruxolitinib, a novel janus kinase 1,2 inhibitor. , 2013, Chest.

[30]  A. Shields,et al.  Effect of ruxolitinib therapy on myelofibrosis-related symptoms and other patient-reported outcomes in COMFORT-I: a randomized, double-blind, placebo-controlled trial. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[31]  M. Griesshammer,et al.  Myeloproliferative neoplasm (MPN) symptom assessment form total symptom score: prospective international assessment of an abbreviated symptom burden scoring system among patients with MPNs. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[32]  R. Little,et al.  The prevention and treatment of missing data in clinical trials. , 2012, The New England journal of medicine.

[33]  A. Mead,et al.  Guideline for the diagnosis and management of myelofibrosis , 2012, British journal of haematology.

[34]  C. Garnett,et al.  U.S. Food and Drug Administration Approval: Ruxolitinib for the Treatment of Patients with Intermediate and High-Risk Myelofibrosis , 2012, Clinical Cancer Research.

[35]  Jason Gotlib,et al.  A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. , 2012, The New England journal of medicine.

[36]  T. Barbui,et al.  JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. , 2012, The New England journal of medicine.

[37]  G. Guyatt,et al.  GRADE guidelines 6. Rating the quality of evidence--imprecision. , 2011, Journal of clinical epidemiology.

[38]  Z. Estrov,et al.  Evaluating the serial use of the myelofibrosis symptom assessment form for measuring symptomatic improvement , 2011, Cancer.

[39]  Y. Tymofyeyev,et al.  Expansion of the modified Zelen's approach randomization and dynamic randomization with partial block supplies at the centers to unequal allocation. , 2011, Contemporary clinical trials.

[40]  M. Griesshammer,et al.  Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[41]  F. Passamonti,et al.  DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Z. Estrov,et al.  Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. , 2010, The New England journal of medicine.

[43]  H. Kantarjian,et al.  Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. , 2010, Blood.

[44]  M. Cazzola,et al.  A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). , 2010, Blood.

[45]  R. Mesa,et al.  New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. , 2008, Blood.

[46]  D. Altman,et al.  Chapter 8: Assessing risk of bias in included studies , 2008 .

[47]  G. Guyatt,et al.  Going from evidence to recommendations , 2008, BMJ : British Medical Journal.

[48]  Douglas G Altman,et al.  Empirical evidence of bias in treatment effect estimates in controlled trials with different interventions and outcomes: meta-epidemiological study , 2008, BMJ : British Medical Journal.

[49]  A. Liberati,et al.  Developing clinical recommendations for breast, colorectal, and lung cancer adjuvant treatments using the GRADE system: a study from the Programma Ricerca e Innovazione Emilia Romagna Oncology Research Group. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  A. Hrõbjartsson,et al.  Blinded trials taken to the test: an analysis of randomized clinical trials that report tests for the success of blinding. , 2007, International journal of epidemiology.

[51]  David Moher,et al.  Reporting Methods of Blinding in Randomized Trials Assessing Nonpharmacological Treatments , 2007, PLoS medicine.

[52]  Alastair J J Wood,et al.  A proposal for radical changes in the drug-approval process. , 2006, The New England journal of medicine.

[53]  Sandra A. Moore,et al.  MPLW515L Is a Novel Somatic Activating Mutation in Myelofibrosis with Myeloid Metaplasia , 2006, PLoS medicine.

[54]  Mario Cazzola,et al.  A gain-of-function mutation of JAK2 in myeloproliferative disorders. , 2005, The New England journal of medicine.

[55]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[56]  Sandra A. Moore,et al.  Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. , 2005, Cancer cell.

[57]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[58]  Jeffrey P. Krischer,et al.  An automated patient registration and treatment randomization system , 1995, Journal of Medical Systems.

[59]  M. Cazzola,et al.  The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients , 2014, Leukemia.

[60]  D. Sargent,et al.  The role of response evaluation criteria in solid tumour in anticancer treatment evaluation: results of a survey in the oncology community. , 2014, European journal of cancer.

[61]  G. Caocci,et al.  Reactivation of hepatitis B virus infection following ruxolitinib treatment in a patient with myelofibrosis , 2014, Leukemia.

[62]  A. Green,et al.  MPN-associated myelofibrosis (MPN-MF). , 2011, Leukemia research.

[63]  J. Higgins Cochrane handbook for systematic reviews of interventions. Version 5.1.0 [updated March 2011]. The Cochrane Collaboration , 2011 .

[64]  GrADE: an emerging consensus on rating quality of evidence and strength of recommendations , 2022 .

[65]  submit your manuscript | www.dovepress.com , 2022 .