[ASCO2015]急性髓系白血病:老年患者如何管理?——C.A. Schiffer教授访谈

作者:  C.A.Schiffer   日期:2015/6/2 20:02:50

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编者按:急性髓系白血病(AML)是最常见的老年急性白血病类型,且其发病率随着年龄的增长而增加。老年AML患者由于对当前的标准化疗药物的原发耐药和(或)不能耐受高强度的诱导化疗及缓解后化疗,且经常并发其他脏器疾病,其早期死亡率较高,预后较差。美国韦恩州立大学Charles Alan Schiffer教授在本届ASCO年会上对于老年AML的管理进行了专题教育讲座,会后《肿瘤瞭望》就此问题对Schiffer教授进行了专访。

美国韦恩州立大学Charles Alan Schiffer教授

 

  《肿瘤瞭望》:急性髓细胞白血病(AML)是一种治疗反应各异的异质性疾病。AML的异质性源于形态学、免疫学、细胞遗传学和分子学异常。在已知的细胞遗传学和突变中,哪些和继发性AML相关?

 

  Schiffer教授:AML的异质性问题十分有趣并且非常重要。它不仅表现在患者之间的差异性,而且在同一个患者中的白血病原始细胞的分型也存在巨大的差异。例如,对于存在FLT3突变的患者,可能同时存在没有突变的细胞,甚至存在两个FLT3突变的细胞,最终一小群克隆性白血病细胞会分立出来,并占主导地位。问题中所提到的继发性AML,确实存在与骨髓增生异常综合征(MDS)类似的特征,例如复杂核型的AML患者白血病细胞中普遍存在P53突变,意味着疾病很难治愈,也有TET2和3A突变,这两种突变也存在于MDS。

 

  The heterogeneity is really very interesting and very important. It is not just heterogeneity between or amongst patients, but in fact there is enormous heterogeneity in the population of leukemic blasts within a single patient. So for a patient who has the FLT3 mutation, for example, you can find cells that are negative. You can find cells that have two FLT3 mutations.

 

  We have learned that some of these small clones can eventually go out and be the dominant clone. Secondary AML, which is the focus of your question, really has similar characteristics to what you see in myelodysplastic syndromes (MDS). Those with complex cytogenetics will frequently have p53 mutations which across all cancers represent an almost impossible entity to cure, but there are also mutations is TET2 and 3A - the kinds of things you see in MDS.

 

  《肿瘤瞭望》:综合预后风险评分系统是基于临床特征、年龄、白细胞计数、表面标记,单核苷酸多态性,细胞遗传学和突变所制定的,对于这一评分系统你有什么看法?

 

  Schiffer教授:这个评分系统目前还没有在临床上正式使用,用它可以帮助我们决策具体每位患者应接受何种治疗,尤其是否能耐受强烈的诱导化疗,并且评估后续是否适合造血干细胞移植。通过它,我们可筛选出化疗有效并预后良好的患者,预后差应尽早移植的患者,以及有特定突变(例如TK突变)、适合靶向治疗的患者。不过,在临床上大多情况下我们都发现自己仍不知所措,因为大部分患者介于预后好与坏之间。

 

  The scoring system is not one I have used formally clinically. They aim to decide what type of therapy a particular patient can tolerate and particularly whether they can tolerate intensive induction therapy and subsequently whether they might be candidates for stem cell transplant.

 

  In terms of all the markers that are used, you are trying to identify groups that can do well with chemotherapy alone and have a favorable outcome, groups that will have a poor outcome and might be considered for transplantation, and groups that have mutations that might be targeted or addressed directly with specific drugs such as mutated TK. The purpose is to get as much information as possible to direct you in one way or another. Unfortunately, most of the time, you find yourself stuck in the middle. You can identify the really good ones and the really bad ones, but there are a lot of subtleties in the middle.

 

  《肿瘤瞭望》:老年患者是一种治疗挑战。有没有新的治疗可能改善目前的治疗现状?

 

  Schiffer教授:老年AML患者的治疗确实是一种挑战,而且由于AML在65~70年龄段的发病率高,老年患者也占大多数。老年患者容易发生耐药,存在更复杂的细胞异常学表现;同时,老年患者多有并发症。确切来说,近10年里,老年患者的预后并没有得到提高。通常,对于存在预后良好的细胞学特征及NPM1突变的患者,如果患者一般情况良好,我们建议标准治疗,或者更强烈的诱导治疗;对于一些预后不良的患者,则需要考虑是否耐受干细胞移植。目前,该类患者最显著的治疗进展,也是最重要的治疗手段,可能是IDH1和IDH2抑制剂,在存在这些基因突变的患者中有显著的治疗反应。阿糖胞苷和阿扎胞苷可能在20%的患者中有效,但是不能治愈,同时它们的治疗反也是暂时的。

 

  That’s right. Older patients are a challenge. And older patients are also the preponderance of patients because disease incidence is highest in the 65-70+ age group. They have more drug-resistant disease. They have more complex cytogenetics. And they have more medical comorbidities. Frankly, we haven’t improved outcomes in those patients in a decade.

 

  Occasional patients will have favorable cytogenetic characteristics and NPM1 mutations and, if possible, they should be considered for standard, more intensive induction therapy. Some of them (and probably more than we actually think) should be considered for and would tolerate transplantation. Probably the most important potential therapy that has come along are the IDH1 and IDH2 inhibitors. They have shown sometimes striking responses in people who have those genes mutated and many of those are older patients. That may be the most potentially dramatic improvement in this group of patients. Therapy with cytarabine and azacitidine can be helpful in perhaps 20+% of patients, but unfortunately it doesn’t cure anyone and the response is transient.

 

  《肿瘤瞭望》:尽管最近关于急性髓细胞白血病的治疗取得了很多进展,但是有关老年患者的最佳治疗仍有很多问题没有解决。对于老年AML患者,缓解后的巩固治疗策略有哪些?

 

  Schiffer教授:对于适合参于临床试验的患者(通常指身体状况良好者),其治愈率最高在10%~15%。此类患者必须进行缓解后的巩固治疗,我们通常给予一个疗程的中等剂量的巩固治疗或者给予几个疗程的低剂量Ara-C (100mg/m2)。然而,一些随机试验显示在年轻患者中经常使用的大剂量Ara-C在老年患者中并没有获益,但是要除外小部分较好细胞遗传学或者有NPM1突变者。

 

  In people eligible for clinical trials (which means they are generally in good health despite their leukemia), there is a cure rate of 10-15% maximum. They have to get some postremission consolidation to accomplish that and we usually give one course of intermediate dose consolidation or sometimes a few courses of lower dose Ara-C (100mg/m2). Unfortunately, a few randomized trials have shown no benefit in older patients for high-dose Ara-C that we would tend to use in younger patients, with the exception of the occasional patient with favorable cytogenetics or possibly a NPM1 mutation.

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