Comorbidities and mutations including single- and multihit TET2 mutations in relation to outcome in chronic myelomonocytic leukaemia-A population-based study.

To explore the relation between disease characteristics, comorbidities, mutations and overall survival (OS) in chronic myelomonocytic leukaemia (CMML), we collected data from a population-based cohort of 149 consecutive patients. TET2 mutation (TET2MT) was associated with higher haemoglobin, less leucocytosis and longer OS compared to no TET2MT (TET2WT), despite patients being significantly older. Patients with multihit TET2MT had the most favourable outcome (HR 0.55, CI 0.35-0.88, p < 0.05). Multihit TET2MT was associated with lower lactate dehydrogenase and less monocytosis, indicating multihit TET2MT as a separate disease entity. Autoimmune disease (AID) was present in 33.6% of patients, with no association to any mutations. In multivariable analysis, the number of TET2MT was demonstrated to be an independent factor associated with improved OS, and RUNX1MT, myeloproliferative CMML (CMML-MP), ECOG >0 and transfusion dependence remained significant adverse factors. Internal validation including cross-validation and correction for optimism consistently demonstrated that a prognostic model containing the number of TET2MT, RUNX1, CMML-MP, ECOG >0 and transfusion dependence showed better calibration, discrimination and overall performance than CPSS-Mol in predicting OS. Importantly, the addition of TET2 mutation status to CPSS-Mol also improved the CPSS-Mol score performance. Taken together, TET2MT status, especially multihit TET2MT, defines a specific CMML phenotype and should be considered in future prognostic scores.