Recent reports suggest a favorable prognosis for PHF6 mutation (PHF6MUT) in chronic myelomonocytic leukemia (CMML) and unfavorable in acute myeloid leukemia (AML). We accessed 176 consecutive patients with a spectrum of myeloid neoplasms with PHF6MUT, 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 PHF6MUT 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.
近期报告提示，PHF6突变（PHF6MUT）在慢性粒单核细胞白血病（CMML）中预后良好，而在急性髓系白血病（AML）中预后不良。我们纳入了176例连续收治的伴PHF6MUT的系列骨髓肿瘤患者，包括AML（67例）、CMML（49例）、骨髓增生异常综合征（MDS；36例）、骨髓增殖性肿瘤（MPN；16例）以及MDS/MPN（8例）。PHF6突变主要为无义突变（43%）或移码突变（30%），其中PHD2结构域是最常受累的区域（64%）。中位随访时间为25个月，期间共有110例（63%）死亡，44例接受了同种异体移植。我们的主要观察结果包括：（i）与其它骨髓肿瘤患者相比，CMML患者的总生存期（OS；81个月 vs. 18个月；p<0.01）和无原始细胞转化生存期（BTFS；"未达到" vs. 44个月；p<0.01）均显著更优；（ii）在CMML（16% vs. 预期6%）和MDS（8% vs. 预期2.5%）中，单纯Y染色体缺失的发生频率高于预期；（iii）在MDS中，PHF6MUT变异等位基因频率（VAF）>20%与较差的OS显著相关（HR 3.0，95% CI 1.1–8.1，多变量p=0.02），女性与较差的BTFS显著相关（HR 26.8，95% CI 1.9–368.3，多变量p=0.01）；（iv）移植后中位生存期相对较好，为46个月。多变量分析还确定高危核型（HR 5.1，95% CI 1.2–20.9，p=0.02）和血红蛋白<10 g/dL（HR 2.7，95% CI 1.0–7.2，p=0.04）是MDS患者OS较差的独立预测因素。本研究提供了关于PHF6突变骨髓肿瘤的基因型与疾病特异性预后的信息。
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