骨髓增殖性肿瘤的诊断与治疗新模式
<span style="color: black;">↑ 点击上方“<span style="color: black;"><strong style="color: blue;">循证医学杂志</strong></span>”关注<span style="color: black;">咱们</span></span><p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">经典型骨髓增殖性肿瘤（myeloproliferatic neoplasms, MPN）<span style="color: black;">包含</span>真性红细胞<span style="color: black;">增加</span>症（polycythemia vera, PV）、原发性血小板<span style="color: black;">增加</span>症（ essential thrombocytosis, ET）和原发性骨髓纤维化（primary myelofibrosis, PMF）, 是一组起源于造血干细胞、以髓系造血细胞1系或多系过度增殖为特征的<span style="color: black;">疾患</span>。2005年<span style="color: black;">发掘</span>约95%的PV、约60%的ET和PMF<span style="color: black;">病人</span>有JAK2V617F突变, 随后又证实约2%的JAK2V617F突变（-）PV<span style="color: black;">病人</span>有JAK2 第12外显子<span style="color: black;">反常</span>（突变、缺失或<span style="color: black;">插进</span>）, 约8%的ET和PMF<span style="color: black;">病人</span>有MPL W515L、W515K、W515A和W515N突变, <span style="color: black;">另外</span>, 在<span style="color: black;">没</span>JAK2和MPL突变的ET和PMF<span style="color: black;">病人</span>中<span style="color: black;">发掘</span>有CALR基因突变。JAK2、MPL或CARL基因突变对MPN<span style="color: black;">病人</span><span style="color: black;">来讲</span><span style="color: black;">拥有</span>相对特异性, 为MPN的致病驱动基因事件。近年, 采用二代测序技术<span style="color: black;">发掘</span>, 除以上这些基因突变外, MPN<span style="color: black;">病人</span>其他较少见的基因突变还有TET2、ASXL1、DNMT3A、EZH2和IDH1等, 90% MPN<span style="color: black;">病人</span><span style="color: black;">最少</span>存在一种基因突变。对MPN基因突变谱系的详尽解析, 改变了MPN的诊断和治疗模式。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">1</span><strong style="color: blue;">MPN的诊断</strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">MPN的诊断从PVSG标准过渡到WHO标准, <span style="color: black;">尤其</span>是WHO（2008）标准后, 一个非常<span style="color: black;">要紧</span>的变化是强调了标准化骨髓活检病理细胞学分析在MPN诊断和鉴别诊断中的<span style="color: black;">功效</span>, 在WHO（2016）标准中骨髓病理从次要诊断标准<span style="color: black;">提升</span>到了<span style="color: black;">重点</span>诊断标准。<span style="color: black;">另外</span>, JAK2、CALR和MPL等MPN驱动基因突变<span style="color: black;">也</span>为MPN的一个<span style="color: black;">重点</span>诊断标准, <span style="color: black;">同期</span>, <span style="color: black;">知道</span>了非驱动基因突变<span style="color: black;">做为</span>克隆性标志的辅助诊断价值, 从而完<span style="color: black;">成为了</span>MPN的诊断从最初的临床诊断模式转变<span style="color: black;">成为了</span>现今的临床-病理-分子诊断模式。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">骨髓病理细胞学分析的标准化<span style="color: black;">首要</span>是分析<span style="color: black;">办法</span>的标准化。活检组织长度<span style="color: black;">最少</span>应1.5 cm, 采用石蜡包埋, 切片厚度为3~4 μ m。染色应<span style="color: black;">包含</span>常规苏木精-伊红（hematoxylin-eosin, HE）和/或姬姆萨（Glemsa）、网状纤维（嗜银）染色外, 尚需进行糖原染色、氯乙酸AS-D萘酚酯酶（chloroacetate esterase, CE）染色和普鲁士蓝染色（铁染色）等细胞化学染色, 以及用CD34和CD61单克隆抗体进行免疫组织化学染色。HE染色联合糖原和CE等细胞化学染色, 以及用CD61单克隆抗体进行免疫组织化学染色, 能更加准确地判断骨髓红系、粒系和巨核细胞的增生<span style="color: black;">状况</span>, PV<span style="color: black;">通常</span>为粒细胞、红细胞和巨核细胞三系均高度增生, ET以巨核细胞高度增生为主, 而PMF则以粒系高度增生为主。现今国内绝大<span style="color: black;">都数</span>医院病理科<span style="color: black;">无</span>血液病理医师, 在以下几个方面亟待<span style="color: black;">导致</span><span style="color: black;">注意</span>：①“ 规定动作” , 如细胞化学和免疫组织化学染色, 应列为骨髓活检病理细胞学分析的常规; ②国际上已有的共识标准, 如骨髓网状纤维、胶原纤维和骨硬化的分级标准, 国内应加以普及推广; ③对<span style="color: black;">有些</span>疑难病例, 应发挥多学科协作治疗的<span style="color: black;">优良</span>, 加强病理科医师与临床医师的联动。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">针对</span>拟诊MPN的<span style="color: black;">病人</span>, 采用骨髓或外周血进行JAK2、CALR和MPL基因突变检测<span style="color: black;">已经是</span>必检项目, 在我国<span style="color: black;">因为</span>第三方独立实验室的兴起, 已基本<span style="color: black;">能够</span>实现, 但<span style="color: black;">非常多</span>实验室仅做定性（阳性或阴性）检测, <span style="color: black;">因为</span>JAK<span style="color: black;">控制</span>剂在临床的应用, MPN分子学缓解的定义得以提出, <span style="color: black;">因此呢</span>, 基因突变的定量分析<span style="color: black;">已经是</span><span style="color: black;">必要</span>。<span style="color: black;">针对</span>非驱动基因突变检测, 国际尚未形成共识, 但<span style="color: black;">因为</span>这些基因突变检测对<span style="color: black;">病人</span>的<span style="color: black;">精细</span>预后分组有<span style="color: black;">帮忙</span>, <span style="color: black;">意见</span>现<span style="color: black;">周期</span>对有<span style="color: black;">前提</span>的医院, 应将ASXL1、EZH2、SRSF2、IDH1/2等基因突变列为<span style="color: black;">举荐</span>检测项目。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">近期</span>Grinfeld等依据EZH2、IDH1、IDH2、ASXL1、PHF6、CUX1、ZRSR2、SRSF2、U2AF1、KRAS、NRAS、GNAS、CBL、RUNX1、STAG2、Chr7/7qLOH、Chr4qLOH和BCOR 共18种遗传学<span style="color: black;">反常</span>提出了一个MPN的基因组学分型, 将MPN共分为8个亚型, 尽管该分型与<span style="color: black;">病人</span>的总体<span style="color: black;">存活</span>、急性髓性白血病转化和骨髓纤维化转化有很好的<span style="color: black;">关联</span>性, 为下一步个体化治疗策略的实施奠定了<span style="color: black;">基本</span>, 但现<span style="color: black;">周期</span>在临床普及推广为时尚早, <span style="color: black;">由于</span>：其一, <span style="color: black;">相关</span>遗传学检测存在卫生经济学瓶颈; 其二, 绝大部分分子靶向<span style="color: black;">药品</span>临床的可及性差。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">2</span><strong style="color: blue;">MPN的治疗</strong></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">MPN<span style="color: black;">病人</span><span style="color: black;">必须</span>治疗的<span style="color: black;">重点</span>原<span style="color: black;">由于</span>：①血栓：MPN<span style="color: black;">病人</span>就诊和病程中血栓<span style="color: black;">出现</span>率约为20%; ②<span style="color: black;">显著</span>骨髓纤维化转化：确诊后10年时PV、ET和<span style="color: black;">初期</span>骨髓纤维化<span style="color: black;">病人</span>的转化率分别为9%、1%和12%; ③急性髓性白血病转化：确诊后10年时PV、ET、<span style="color: black;">初期</span>骨髓纤维化和<span style="color: black;">显著</span>期骨髓纤维化<span style="color: black;">病人</span>的转化率分别为2%、1%、6%和23%; ④疲劳、早饱感、腹部不适、皮肤瘙痒、骨痛、活动力和<span style="color: black;">重视</span>力下降、体质量下降、不明<span style="color: black;">原由</span>发热或重度盗汗等影响生活质量的症状; ⑤肝脏和脾脏肿大; ⑥血细胞<span style="color: black;">升高</span>或减低及其<span style="color: black;">关联</span>症状; ⑦髓外造血<span style="color: black;">导致</span>的<span style="color: black;">关联</span>症状和体征。MPN<span style="color: black;">病人</span>的治疗<span style="color: black;">方法</span>应依据<span style="color: black;">病人</span>存在的<span style="color: black;">重点</span>问题, 结合<span style="color: black;">相关</span>预后积分系统分组来加以制定。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">MPN的传统治疗<span style="color: black;">药品</span><span style="color: black;">重点</span><span style="color: black;">包含</span>羟基脲、干扰素等。已有<span style="color: black;">科研</span>结果<span style="color: black;">显示</span>这些<span style="color: black;">药品</span>存在以下<span style="color: black;">重点</span>不足：其一, 20%~30%的<span style="color: black;">病人</span>耐药或<span style="color: black;">病人</span><span style="color: black;">不可</span>耐受; 其二, 尚<span style="color: black;">没</span>临床<span style="color: black;">实验</span>证实可影响<span style="color: black;">病人</span>的自然病程; 其三, 对<span style="color: black;">病人</span>的体质性症状<span style="color: black;">没</span>改善。芦可替尼是<span style="color: black;">第1</span>个<span style="color: black;">也</span>是<span style="color: black;">日前</span><span style="color: black;">独一</span>的一个FDA<span style="color: black;">准许</span>的JAK1/JAK2<span style="color: black;">控制</span>剂, 与MPN传统<span style="color: black;">药品</span>相比, 芦可替尼是一个有可能改变MPN<span style="color: black;">病人</span>自然病程的<span style="color: black;">药品</span>。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">2011年11月FDA<span style="color: black;">准许</span>芦可替尼用于国际预后积分系统评分（international prognostic scoring system, IPSS）中危-2和高危组PMF<span style="color: black;">病人</span>的治疗。与传统治疗<span style="color: black;">药品</span>相比, 芦可替尼治疗骨髓纤维化（<span style="color: black;">包含</span>PMF、Post-PV和Post-ET MF）<span style="color: black;">拥有</span>以下<span style="color: black;">优良</span>：①缩脾效果肯定; ②可<span style="color: black;">明显</span>改善<span style="color: black;">病人</span>的体质性症状负荷; ③可延长<span style="color: black;">病人</span>的总<span style="color: black;">存活</span>期; ④约1/3的<span style="color: black;">病人</span>有骨髓纤维化程度的逆转。2014年12月芦可替尼被FDA<span style="color: black;">准许</span>用于治疗羟基脲疗效<span style="color: black;">不良</span>或不耐受的PV<span style="color: black;">病人</span>。<span style="color: black;">因为</span>芦可替尼是一个JAK<span style="color: black;">控制</span>剂, 而不是MPN驱动基因突变JAK2 V617F的<span style="color: black;">选取</span>性<span style="color: black;">控制</span>剂, 尽管有部分<span style="color: black;">病人</span>用芦可替尼治疗后JAK2V617F突变负荷可有不同程度的下降, 但其并<span style="color: black;">不可</span>清除MPN干细胞。<span style="color: black;">另外</span>, 在治疗的前8~12周约1/3的<span style="color: black;">病人</span>有不同程度的贫血和血小板减少等血液系统不良反应, 治疗3年时<span style="color: black;">显现</span>耐药的几率约30%, <span style="color: black;">因此呢</span>, 应严格<span style="color: black;">把握</span>芦可替尼的治疗适应证。芦可替尼可<span style="color: black;">做为</span>有脾脏肿大的IPSS/动态IPSS/动态IPSS-Plus中危-2和高危PMF<span style="color: black;">病人</span>的一线治疗<span style="color: black;">药品</span>, 对<span style="color: black;">哪些</span>有严重症状性脾肿大（如左上腹疼或<span style="color: black;">因为</span>早饱而影响<span style="color: black;">摄食</span>量）的中危-1 PMF<span style="color: black;">病人</span><span style="color: black;">也</span><span style="color: black;">能够</span><span style="color: black;">做为</span>一线治疗<span style="color: black;">药品</span>, <span style="color: black;">另外</span>, <span style="color: black;">哪些</span>MPN-10总积分> 44或难治性严重（单项评分> 6分）或不<span style="color: black;">是由于</span>其他<span style="color: black;">原由</span><span style="color: black;">引起</span>的超预期的体质量下降（过去6个月下降> 10%）或不明<span style="color: black;">原由</span>发热的PMF<span style="color: black;">病人</span>, 芦可替尼<span style="color: black;">也</span><span style="color: black;">能够</span><span style="color: black;">做为</span>一线治疗<span style="color: black;">药品</span>。PV仅限于羟基脲疗效<span style="color: black;">不良</span>或不耐受<span style="color: black;">病人</span>的二线治疗, ET尚<span style="color: black;">没</span>适应证。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">3</span>结 语</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">自2005年<span style="color: black;">败兴</span>, 在MPN<span style="color: black;">病人</span>中<span style="color: black;">发掘</span>存在JAK2V617F突变<span style="color: black;">败兴</span>的十余年, MPN<span style="color: black;">没</span>论是诊断还是治疗模式均<span style="color: black;">出现</span>了革命性的改变, 使MPN这个被血液学界“ 遗忘的角落” <span style="color: black;">步行到</span>了血液学<span style="color: black;">科研</span><span style="color: black;">行业</span>的前沿, 跨入了分子诊断和分子靶向治疗的新时代。但现今MPN仍是一组<span style="color: black;">药品</span>不可根治的<span style="color: black;">疾患</span>, 有待<span style="color: black;">将来</span>针对MPN驱动基因突变和非驱动基因突变新的分子靶向治疗<span style="color: black;">药品</span>的<span style="color: black;">面世</span>。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">【<span style="color: black;">重要</span>词】骨髓增殖性肿瘤; 诊断; 治疗; 基因突变</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">【中图<span style="color: black;">归类</span>号】R551.3</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">【文献标识码】A</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">Doi：10.12019/j.issn.1671-5144.2019.02.004</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><strong style="color: blue;"><span style="color: black;">作者简介: </span></strong><span style="color: black;">肖志坚（1965-）,男,湖南娄底人,医学博士,教授,<span style="color: black;">专家</span>医师,博士<span style="color: black;">科研</span>生导师,<span style="color: black;">重点</span><span style="color: black;">科研</span>方向为骨髓增生<span style="color: black;">反常</span><span style="color: black;">综合症</span>、骨髓增殖性肿瘤和急性髓系白血病等髓系肿瘤的发病分子机制和临床诊治新策略。</span></p>
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<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">GRINFELD J, NANGALIA J, BAXTER E J, et al. Classification and personalized prognosis in myeloproliferative neoplasms. N Engl J Med, 2018, 379(15): 1416-1430.</span></p>
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<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">BARBUI T, THIELE J, GISSLINGER H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: Document summary and in-depth discussion. Blood Cancer J, 2018, 8(2):15.</span></p>
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<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">TEFFERI A, BARBUI T. Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. Am J Hematol, 2019, 94(1): 133-143.</span></p>
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<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">TEFFERI A. Primary myelofibrosis: 2019 update on diagnosis, risk-stratification and management. Am J Hematol, 2018, 93(12): 1551-1560.</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;">全文刊登于《循证医学》2018年 第19卷 第2期</strong></span></p>
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