JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis
Open accessAbstract
BACKGROUND: Treatment options for myelofibrosis are limited. We evaluated the efficacy and safety of ruxolitinib, a potent and selective Janus kinase (JAK) 1 and 2 inhibitor, as compared with the best available therapy, in patients with myelofibrosis. METHODS: We assigned 219 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis to receive oral ruxolitinib or the best available therapy. The primary end point and key secondary end point of the study were the percentage of patients with at least a 35% reduction in spleen volume at week 48 and at week 24, respectively, as assessed with the use of magnetic resonance imaging or computed tomography. RESULTS: A total of 28% of the patients in the ruxolitinib group had at least a 35% reduction in spleen volume at week 48, as compared with 0% in the group receiving the best available therapy (P<0.001); the corresponding percentages at week 24 were 32% and 0% (P<0.001). At 48 weeks, the mean palpable spleen length had decreased by 56% with ruxolitinib but had increased by 4% with the best available therapy. The median duration of response with ruxolitinib was not reached, with 80% of patients still having a response at a median follow-up of 12 months. Patients in the ruxolitinib group had an improvement in overall quality-of-life measures and a reduction in symptoms associated with myelofibrosis. The most common hematologic abnormalities of grade 3 or higher in either group were thrombocytopenia and anemia, which were managed with a dose reduction, interruption of treatment, or transfusion. One patient in each group discontinued treatment owing to thrombocytopenia, and none discontinued owing to anemia. Nonhematologic adverse events were rare and mostly grade 1 or 2. Two cases of acute myeloid leukemia were reported with the best available therapy. CONCLUSIONS: Continuous ruxolitinib therapy, as compared with the best available therapy, was associated with marked and durable reductions in splenomegaly and disease-related symptoms, improvements in role functioning and quality of life, and modest toxic effects. An influence on overall survival has not yet been shown. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT00934544.).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Ruxolitinib has promising activity in PMF patients, showing reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival compared with placebo or best available therapy.
“Ruxolitinib, a JAK1/JAK2 inhibitor, has demonstrated promising activity in PMF patients, showing increased benefit across several end points, e.g., reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival, when compared with placebo or best available therapy”
From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as Harrison et al., 2012
The Conclusions report reduced splenomegaly and disease-related symptoms versus best available therapy, but state that an effect on overall survival had not been shown. The Discussion likewise says no overall-survival benefit was observed. This study included patients with primary and other forms of myelofibrosis; it did not compare ruxolitinib with placebo. (LLM, conf=0.90)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
No references could be resolved yet.
Research works printed but not linked: 19
- Tefferi A. Essential thrombocythe- mia, polycythemia vera, and myelofibro- sis: current management and the prospect of targeted therapy. Am J Hematol 2008; 83:491-7.
- Abdel-Wahab OI, Levine RL. Primary myelofibrosis: update on definition, patho- genesis, and treatment. Annu Rev Med 2009;60:233-45.
- 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 My- elofibrosis Research and Treatment. Blood 2009;113:2895-901.
- Baxter EJ, Scott LM, Campbell PJ, et al. Acquired mutation of the tyrosine ki- nase JAK2 in human myeloproliferative disorders. Lancet 2005;365:1054-61. [Er- ratum, Lancet 2005;366:122.]
- Levine RL, Wadleigh M, Cools J, et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential throm- bocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 2005;7:387-97.
- Kralovics R, Passamonti F, Buser AS, et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 2005;352:1779-90.
- James C, Ugo V, Le Couédic JP, et al. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythae- mia vera. Nature 2005;434:1144-8.
- Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 2007;356:459-68.
- Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006;3(7):e270.
- Oh ST, Simonds EF, Jones C, et al. Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 2010;116:988-92.
- Vainchenker W, Delhommeau F, Con- stantinescu SN, Bernard OA. New muta- tions and pathogenesis of myeloprolifera- tive neoplasms. Blood 2011;118:1723-35.
- Quintás-Cardama A, Vaddi K, Liu P, et al. Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 2010;115:3109-17.
- Verstovsek S, Kantarjian H, Mesa RA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibro- sis. N Engl J Med 2010;363:1117-27.
- Swerdlow SH, Campo E, Harris NL, et al. WHO classification of tumours of hae- matopoietic and lymphoid tissues. Vol. 2. 4th ed. Geneva: World Health Organiza- tion, 2008.
- Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-55.
- Tefferi A, Barosi G, Mesa RA, et al. International Working Group (IWG) con- sensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood 2006; 108:1497-503.
- Webster K, Cella D, Yost K. The Func- tional Assessment of Chronic Illness Ther- apy (FACIT) measurement system: proper- ties, applications, and interpretation. Health Qual Life Outcomes 2003;1:79.
- Tefferi A, Vaidya R, Caramazza D, Finke C, Lasho T, Pardanani A. Circulat- ing interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: a comprehen- sive cytokine profiling study. J Clin Oncol 2011;29:1356-63.
- Shi JG, Chen X, McGee RF, et al. The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers. J Clin Pharmacol 2011;51:1644-54.
Cited by
Sorted by citations
JAK inhibition as a therapeutic strategy for immune and inflammatory diseases
Schwartz, D. M., Kanno, Y., Villarino, A., Ward, M., Gadina, M., & O'Shea, J. J. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.201 · Cited by 1,266 · see citing works
Inflammation and cancer: advances and new agents
Crusz, S. M., & Balkwill, F. R. (2015) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2015.105 · Cited by 1,184 · see citing works
Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E. R., Pirtskhalava, T., White, T. A., Johnson, K. O., Stout, M. B., Mezera, V., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1515386112 · Cited by 915 · see citing works
JAKs and STATs in immunity, immunodeficiency, and cancer
O'Shea, J. J., Holland, S. M., & Staudt, L. M. (2013) · New England Journal of Medicine · doi:10.1056/nejmra1202117 · Cited by 927 · see citing works
Targeting senescent cells enhances adipogenesis and metabolic function in old age
Xu, M., Palmer, A. K., Ding, H., Weivoda, M. M., Pirtskhalava, T., White, T. A., Sepe, A., Johnson, K. O., Stout, M. B., Giorgadze, N., et al. (2015) · eLife · doi:10.7554/elife.12997 · Cited by 604 · see citing works
Properties of FDA-approved small molecule protein kinase inhibitors
Roskoski, R. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.03.006 · Cited by 554 · see citing works
Bharadwaj, U., Kasembeli, M. M., Robinson, P., & Tweardy, D. J. (2020) · Pharmacological Reviews · doi:10.1124/pr.119.018440 · Cited by 314 · see citing works
“…PMF patients, showing increased benefit across several end points, e.g., reduction in splenomegaly, improvement in disease-related symptoms, and increased overall survival, when compared with placebo or best available therapy (Harrison et al., 2012; Verstovsek et al., 2012; Vannucchi et al., 2015).”
BackgroundPatient-reported outcomes as primary end points in clinical trials of inflammatory bowel disease
Williet, N., Sandborn, W. J., & Peyrin–Biroulet, L. (2014) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2014.02.016 · Cited by 260 · see citing works
The STAT3 pathway as a therapeutic target in head and neck cancer: barriers and innovations
Geiger, J. L., Grandis, J. R., & Bauman, J. E. (2016) · Oral Oncology · doi:10.1016/j.oraloncology.2015.11.022 · Cited by 193 · see citing works
Ineffective erythropoiesis and regulation of iron status in iron loading anaemias
Camaschella, C., & Nai, A. (2016) · British Journal of Haematology · doi:10.1111/bjh.13820 · Cited by 172 · see citing works
Waugh, K. A., Araya, P., Pandey, A., Jordan, K. R., Smith, K. P., Granrath, R. E., Khanal, S., Butcher, E. T., Estrada, B. E., Rachubinski, A. L., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.10.038 · Cited by 150 · see citing works
Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms
Fisher, D. A. C., Fowles, J. S., Zhou, A., & Oh, S. T. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.683401 · Cited by 115 · see citing works
The European Hematology Association Roadmap for European Hematology Research: a consensus document
Engert, A., Balduini, C., Brand, A., Coiffier, B., Cordonnier, C., Dohner, H., de Wit, T. D., Eichinger, S., Fibbe, W., Green, T., et al. (2016) · Haematologica · doi:10.3324/haematol.2015.136739 · Cited by 81 · see citing works
“The discovery of the JAK2 mutation has been instrumental in rapidly bringing the first JAK1/JAK2 inhibitor into the clinic for the treatment of patients with MPNs.(124,125) European investigators have also played a leading role in the development of hypomethylating agents for the treatment of MDS and AML.”
BackgroundKramann, R., & Schneider, R. K. (2018) · Blood · doi:10.1182/blood-2018-02-834820 · Cited by 62 · see citing works
HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms
Yue, L., Sharma, V., Horvat, N. P., Akuffo, A. A., Beatty, M. S., Murdun, C., Colin, C., Billington, J. M. R., Goodheart, W. E., Sahakian, E., et al. (2020) · Blood · doi:10.1182/blood.2019895326 · Cited by 67 · see citing works
Jeong, W., Doroshow, J. H., & Kummar, S. (2013) · Current Problems in Cancer · doi:10.1016/j.currproblcancer.2013.06.001 · Cited by 59 · see citing works
Gleitz, H. F., Kramann, R., & Schneider, R. K. (2018) · The Journal of Pathology · doi:10.1002/path.5078 · Cited by 23 · see citing works
Hofland, T., de Weerdt, I., ter Burg, H., de Boer, R., Tannheimer, S., Tonino, S. H., Kater, A. P., & Eldering, E. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1900321 · Cited by 21 · see citing works
Chihara, D., Masarova, L., Newberry, K. J., Maeng, H., Ravandi, F., Garcia-Manero, G., Ferrajoli, A., Cortes, J., Kantarjian, H., & Verstovsek, S. (2016) · Leukemia Research · doi:10.1016/j.leukres.2016.06.007 · Cited by 21 · see citing works
- Authors
- Harrison, C., Kiladjian, J.-J., Al-Ali, H. K., Gisslinger, H., Waltzman, R., Stalbovskaya, V., McQuitty, M., Hunter, D. S., Levy, R., Knoops, L., Cervantes, F., Vannucchi, A. M., Barbui, T., & Barosi, G.
- Affiliations
- National Health Service (GB)
- Hôpital Saint-Louis (FR)
- Medical University of Vienna (AT)
- Novartis (Switzerland) (CH)
- Incyte (United States) (US)
- Cliniques Universitaires Saint-Luc (BE)
- Hospital Clínic de Barcelona (ES)
- University of Florence (IT)
- Policlinico San Matteo Fondazione (IT)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2012-03
- Volume
- 366
- Issue
- 9
- Pages
- 787-798
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2115351357
- Cited by
- 1,825
- References
- 0
- Citations by year
- 2026: 81 · 2025: 80 · 2024: 98 · 2023: 115 · 2022: 125 · 2021: 145 · 2020: 129 · 2019: 115 · 2018: 124 · 2017: 133 · 2016: 162 · 2015: 160 · 2014: 130 · 2013: 157 · 2012: 68
- FWCI
- 78.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Florence Research (University of Florence) (submittedVersion, other-oa)
- Digital Access to Libraries (Université catholique de Louvain (UCL), l'Université de Namur (UNamur) and the Université Saint-Louis (USL-B)) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- myelofibrosis, ruxolitinib, JAK inhibition, JAK1/2 inhibitor, splenomegaly, spleen volume reduction, post-polycythemia vera myelofibrosis, post-essential thrombocythemia myelofibrosis, best available therapy, quality of life, thrombocytopenia, anemia
- MeSH terms
- Adult, Aged, Aged, 80 and over, Cause of Death, Female, Follow-Up Studies, Humans, Male, Middle Aged, Nitriles, Organ Size, Pyrazoles, Pyrimidines, Quality of Life, Spleen, Splenomegaly, Survival Analysis, Protein Kinase Inhibitors, Janus Kinase 1, Janus Kinase 2, Primary Myelofibrosis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
