Myeloid neoplasms with PHF6 mutations: context-dependent genomic and prognostic characterization in 176 informative cases

Recent reports suggest a favorable prognosis for PHF6 mutation (PHF6^MUT) in chronic myelomonocytic leukemia (CMML) and unfavorable in acute myeloid leukemia (AML). We accessed 176 consecutive patients with a spectrum of myeloid neoplasms with PHF6^MUT, including AML (N = 67), CMML (N = 49), myelodysplastic syndromes (MDS; N = 36), myeloproliferative neoplasms (MPN; N = 16), and MDS/MPN (N = 8). PHF6 mutations were classified as nonsense (43%) or frameshift (30%) with the PHD2 domain being the most frequently (64%) affected region. Median follow-up was 25 months with 110 (63%) deaths and 44 allogenic transplants. Our top-line observations include (a) a distinctly superior overall survival (OS; 81 vs. 18 months; p < 0.01) and blast transformation-free survival (BTFS; “not reached” vs. 44 months; p < 0.01) in patients with CMML vs. those with other myeloid neoplasms, (ii) a higher than expected frequency of isolated loss of Y chromosome, in the setting of CMML (16% vs. expected 6%) and MDS (8% vs expected 2.5%), (iii) a significant association, in MDS, between PHF6^MUT variant allele fraction (VAF) > 20% and inferior OS (HR 3.0, 95% CI 1.1–8.1, multivariate p = 0.02) as well as female gender and inferior BTFS (HR 26.8, 95% CI 1.9–368.3, multivariate p = 0.01), (iv) a relatively favorable median post-transplant survival of 46 months. Multivariable analysis also identified high-risk karyotype (HR 5.1, 95% CI 1.2–20.9, p = 0.02), and hemoglobin <10 g/dL (HR 2.7, 95% CI 1.0–7.2, p = 0.04), as independent predictors of inferior OS in patients with MDS. The current study provides disease-specific information on genotype and prognosis of PHF6-mutated myeloid neoplasms.