Mesa Ruben A
Division of Hematology, Mayo Clinic; Rochester, MN, USA.
Int J Hematol. 2002 Aug;76 Suppl 2:296-304. doi: 10.1007/BF03165138.
Myelofibrosis with myeloid metaplasia (MMM) encompasses the diagnoses of agnogenic myeloid metaplasia (idiopathic myelofibrosis), as well as the advanced phases of polycythemia vera and essential thrombocythemia (post polycythemic and post thrombocythemia myeloid metaplasia, respectively). MMM is a clonal, hematopoietic stem cell disorder in which neither the pathogenesis, nor a broadly applicable effective therapy have been described. Clinically, these patients experience progressive marrow replacement by fibrotic tissue, ineffective hematopoiesis, problematic cytopenia's, significant hepato-splenomegaly, extramedullary hematopoiesis, profound constitutional symptoms, and a risk of blastic transformation. Historically, therapies have been targeted at palliating symptoms (i.e. splenectomy, transfusions, hydroxyurea, erythropoietin, androgens, localized radiotherapy). Stem cell transplantation appears promising, but is often toxic and not broadly applicable due to co-morbidities and age of MMM patients. Non-myeloablative approaches to conditioning may broaden the applicability of stem cell transplantation in MMM, yet results to date are preliminary. Although a definitive molecular abnormality responsible for the pathogenesis of MMM has not been described, much has been learned about the aberrant expression of pro-fibrotic cytokines and the presence of increased angiogenesis in MMM. These pathogenetic insights have led to a series of pilot clinical trials with therapeutic agents targeting aberrantly expressed cytokines (and possibly angiogenesis) including Thalidomide (alone or in combination), Etanercept, and STI-571. Amongst these later agents Thalidomide has demonstrated the most promise (palliating disease associated cytopenia's), whereas the TNF-alpha inhibitor Etanercept has aided with MMM associated constitutional symptoms. Although these later trials have been helpful in a subset of patients, no agent to date has led to solid complete responses in MMM across the spectrum of disease manifestations. Further insights into the pathogenetic mechanisms responsible for myeloproliferation (aberrant cell signaling pathways, apoptotic resistance, other) are necessary to guide selection and testing of the expanding number of novel anti-neoplastic agents in chronic myeloid disorders and MMM.
骨髓纤维化伴髓样化生（MMM）包括原发性骨髓化生（特发性骨髓纤维化）的诊断，以及真性红细胞增多症和原发性血小板增多症的晚期阶段（分别为真性红细胞增多症后和原发性血小板增多症后骨髓化生）。MMM是一种克隆性造血干细胞疾病，其发病机制和广泛适用的有效治疗方法均未得到描述。临床上，这些患者会经历骨髓逐渐被纤维组织替代、无效造血、血细胞减少问题、显著的肝脾肿大、髓外造血、严重的全身症状以及发生原始细胞转化的风险。从历史上看，治疗一直以缓解症状为目标（即脾切除术、输血、羟基脲、促红细胞生成素、雄激素、局部放疗）。干细胞移植似乎很有前景，但由于MMM患者的合并症和年龄因素，其往往具有毒性且无法广泛应用。非清髓性预处理方法可能会扩大干细胞移植在MMM中的适用性，但迄今为止的结果仍是初步的。尽管尚未描述导致MMM发病机制的确切分子异常，但关于促纤维化细胞因子的异常表达以及MMM中血管生成增加的情况已有很多了解。这些发病机制的见解引发了一系列针对异常表达细胞因子（可能还有血管生成）的治疗药物的临床试验，包括沙利度胺（单独或联合使用）、依那西普和STI - 571。在这些后期药物中，沙利度胺显示出最有前景的效果（缓解与疾病相关的血细胞减少），而肿瘤坏死因子 - α抑制剂依那西普有助于缓解MMM相关的全身症状。尽管这些后期试验对一部分患者有帮助，但迄今为止，没有一种药物能在MMM的所有疾病表现范围内产生可靠的完全缓解。进一步深入了解导致骨髓增殖的发病机制（异常细胞信号通路、凋亡抵抗等）对于指导慢性髓性疾病和MMM中越来越多新型抗肿瘤药物的选择和测试是必要的。
