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We report outcomes and high\u2010risk genomic signatures in 149 patients with CALR\u2010mutated MPN. CALR\u2010mutated essential thrombocythaemia (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009106) progressed to myelofibrosis (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200940) at a median of 20.4\u2009years, and 20\u2010year overall survival (OS) was 81%. In 83 patients with myelofibrosis, the median leukaemia\u2010free survival (LFS) was 12.9\u2009years, and OS was 13.9\u2009years. Median survival after leukaemia transformation was 6.8\u2009months. High molecular risk (HMR) mutations included\n                    <jats:italic>ASXL1<\/jats:italic>\n                    ,\n                    <jats:italic>EZH2<\/jats:italic>\n                    ,\n                    <jats:italic>SRSF2<\/jats:italic>\n                    ,\n                    <jats:italic>U2AF1<\/jats:italic>\n                    (Q157),\n                    <jats:italic>IDH1\/2<\/jats:italic>\n                    ,\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>SETBP1<\/jats:italic>\n                    ,\n                    <jats:italic>KRAS<\/jats:italic>\n                    ,\n                    <jats:italic>NRAS<\/jats:italic>\n                    and\n                    <jats:italic>RUNX1<\/jats:italic>\n                    (later five not included in Mutation\u2010Enhanced International Prognostic Score System [MIPSS70]\u2010plus v2.0); and were associated with a significantly higher leukaemic transformation, inferior LFS and OS (hazard ratio [HR]: 3.82, 95% confidence interval [CI]: 1.30\u201311.18); with worst outcomes in patients with \u22652 HMR. Independent of MIPSS70\u2010plus v2.0,\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>KRAS<\/jats:italic>\n                    and\n                    <jats:italic>RUNX1<\/jats:italic>\n                    mutations adversely impacted LFS and OS (HR: 2.87, 95% CI: 1.20\u20136.88; HR: 3.80, 95% CI: 1.37\u201310.54; HR: 5.61, 95% CI: 1.53\u201320.52 respectively). Patients without HMR had a negligible rate of progression. Overall, outcomes are determined not by\n                    <jats:italic>CALR<\/jats:italic>\n                    \u2018driver\u2019 mutation, but by the somatic mutations that can emerge during disease evolution. Hence, serial molecular profiling is important for risk stratification. HMR, including\n                    <jats:italic>TP53<\/jats:italic>\n                    ,\n                    <jats:italic>KRAS<\/jats:italic>\n                    and\n                    <jats:italic>RUNX1<\/jats:italic>\n                    , confer inferior survival and support early transplantation consideration.\n                  <\/jats:p>","DOI":"10.1111\/bjh.70859","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T08:04:07Z","timestamp":1791360247000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Outcome heterogeneity in\n                    <scp>\n                      <i>CALR<\/i>\n                    <\/scp>\n                    \u2010mutated myeloproliferative neoplasms"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4154-9872","authenticated-orcid":false,"given":"Resham","family":"Mawalkar","sequence":"first","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8388-6297","authenticated-orcid":false,"given":"Hua\u2010Ling","family":"Tsai","sequence":"additional","affiliation":[{"name":"Quantitative Sciences Division Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergiu","family":"Pasca","sequence":"additional","affiliation":[{"name":"Department of Oncology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1551-3496","authenticated-orcid":false,"given":"Lukasz P.","family":"Gondek","sequence":"additional","affiliation":[{"name":"Department of Oncology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3557-8753","authenticated-orcid":false,"given":"Eitan","family":"Halper\u2010Stromberg","sequence":"additional","affiliation":[{"name":"Department of Pathology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5532-6524","authenticated-orcid":false,"given":"Rena R.","family":"Xian","sequence":"additional","affiliation":[{"name":"Department of Oncology Johns Hopkins University  Baltimore Maryland USA"},{"name":"Department of Pathology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Gocke","sequence":"additional","affiliation":[{"name":"Department of Oncology Johns Hopkins University  Baltimore Maryland USA"},{"name":"Department of Pathology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6616-5041","authenticated-orcid":false,"given":"Katherine C.","family":"Rappazzo","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6792-8298","authenticated-orcid":false,"given":"Theodoros","family":"Karantanos","sequence":"additional","affiliation":[{"name":"Department of Oncology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0903-7390","authenticated-orcid":false,"given":"B. 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