背景:原发性血小板增多症是一种Janus激酶2(JAK2)突变流行的骨髓增殖性肿瘤,其特征是克隆性血小板增多症;临床过程通常是缓慢的,但可能因血栓性或出血性并发症而中断,微循环症状(例如,头痛,头昏眼花,和肢端感觉异常),and,不那么频繁,通过疾病转化为骨髓纤维化(MF)或急性髓细胞性白血病。
方法:除血小板增多(血小板≥450×109/L)外,正式诊断需要排除其他髓系肿瘤,包括纤维化前的MF,真性红细胞增多症,慢性粒细胞白血病,和骨髓增生异常综合征,伴有环铁皮细胞和血小板增多。骨髓形态通常显示分布在松散簇中的成熟出现的巨核细胞数量增加。
背景:大约80%的患者表达骨髓增殖性肿瘤驱动突变(JAK2,CALR,MPL),以相互排斥的方式;此外,大约50%有其他突变,最常见的是TET2(9%-11%),ASXL1(7%-20%),DNMT3A(7%),和SF3B1(5%)。异常核型见于<10%的患者,包括+9/20q-/13q-。
■预期寿命低于对照人群。中位生存期约为18年,但在年轻患者中超过35年。三A生存风险模型,根据年龄,中性粒细胞绝对计数,和淋巴细胞绝对计数,有效地描绘了高,中间-1-,中间-2-,和低风险疾病,相应的中位生存期为8、14、21和47年。
■考虑了四种风险类别:非常低(年龄≤60岁,无血栓形成史,JAK2野生型),低(与非常低,但JAK2突变存在相同),中级(与低但年龄>60岁相同),和高(血栓形成史或年龄>60岁,JAK2突变)。
■MPL和CALR-1突变与MF转化的风险增加有关;剪接体总体和无MF生存率较差;TP53伴白血病转化,和JAK2V617F与血栓形成。10年时的白血病转化率<1%,但在JAK2突变的血小板严重增多患者和核型异常患者中可能更高。
方法:治疗的主要目标是预防血栓形成。在这方面,所有患者建议每日一次低剂量阿司匹林,对于低危疾病建议每日两次低剂量阿司匹林.对于高风险和中危疾病,建议进行细胞减灭剂治疗。首选的一线细胞还原药物是羟基脲和聚乙二醇化干扰素-α和二线白消安。
■当前的综述包括在极端血小板增多症背景下的具体治疗策略,怀孕,内脏静脉血栓形成,围手术期护理,和原发性血小板增多症MF,以及新的研究药物。
Essential thrombocythemia is a Janus kinase 2 (JAK2) mutation-prevalent myeloproliferative neoplasm characterized by clonal thrombocytosis; clinical course is often indolent but might be interrupted by thrombotic or hemorrhagic complications, microcirculatory symptoms (e.g., headaches, lightheadedness, and acral paresthesias), and, less frequently, by disease transformation into myelofibrosis (MF) or acute myeloid leukemia.
In addition to thrombocytosis (platelets ≥450 × 109 /L), formal diagnosis requires the exclusion of other myeloid neoplasms, including prefibrotic MF, polycythemia vera, chronic myeloid leukemia, and myelodysplastic syndromes with ring sideroblasts and thrombocytosis. Bone marrow morphology typically shows increased number of mature-appearing megakaryocytes distributed in loose clusters.
Approximately 80% of patients express myeloproliferative neoplasm driver mutations (JAK2, CALR, MPL), in a mutually exclusive manner; in addition, about 50% harbor other mutations, the most frequent being TET2 (9%-11%), ASXL1 (7%-20%), DNMT3A (7%), and SF3B1 (5%). Abnormal karyotype is seen in <10% of patients and includes +9/20q-/13q-.
Life expectancy is less than that of the control population. Median survival is approximately 18 years but exceeds >35 years in younger patients. The triple A survival risk model, based on Age, Absolute neutrophil count, and Absolute lymphocyte count, effectively delineates high-, intermediate-1-, intermediate-2-, and low-risk disease with corresponding median survivals of 8, 14, 21, and 47 years.
Four risk categories are considered: very low (age ≤60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (same as low but age >60 years), and high (thrombosis history or age >60 years with JAK2 mutation).
MPL and CALR-1 mutations have been associated with increased risk of MF transformation; spliceosome with inferior overall and MF-free survival; TP53 with leukemic transformation, and JAK2V617F with thrombosis. Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype.
The main goal of therapy is to prevent thrombosis. In this regard, once-daily low-dose aspirin is advised for all patients and twice daily for low-risk disease. Cytoreductive therapy is advised for high-risk and optional for intermediate-risk disease. First-line cytoreductive drugs of choice are hydroxyurea and pegylated interferon-α and second-line busulfan.
The current review includes specific treatment strategies in the context of extreme thrombocytosis, pregnancy, splanchnic vein thrombosis, perioperative care, and post-essential thrombocythemia MF, as well as new investigational drugs.