英国纽卡斯尔大学北方癌症研究所Anthony V. Moorman教授

　　《肿瘤瞭望》：您认为最近大家关注的急性淋巴细胞白血病（ALL）免疫表型对预后是否有影响？

　　Moorman教授：肿瘤细胞免疫表型的鉴定是非常重要的，但对于ALL来说其意义可能有限，而基因异常对于明确患者对标准化疗的应答则是更重要的预测因素。染色体的异常和亚缺失可能确定患者接受何种治疗是有帮助的。

　　It is very important to identify the key cell surface prognostic markers. I think their use in acute lymphoblastic leukemia is probably quite limited and the genetic biomarkers are going to be more important in terms of being able to identify patients who will respond very well to standard chemotherapy and also those who won’t respond to standard chemotherapy and consequently have a higher rate of relapse. Chromosomal abnormalities and also submicroscopic deletion are probably the key ways forward in identifying patients who will need alternative therapies.

　　《肿瘤瞭望》：随着靶向治疗的进步，是否有可能治愈高危型ALL，如ph⁺ALL？

　　Moorman教授：是的，我认为的确有可能。对于ph⁺ALL，BCR融合基因并不像在慢性髓系白血病（CML）中是唯一的基因异常，因此酪氨酸激酶抑制剂也不是治疗ALL的唯一化疗药物。对于CLL我们必须考虑其他的基因异常。在标准化疗中加入伊马替尼已显示可以提高预后，并且很多研究显示这种方法对于儿童和成人均有效。值得庆幸的是ALL很多基因异常对于化疗相对敏感有效。其中一个悬而未决问题是BCR-ABL样ALL的治疗，此类患者高表达类似BCR-ABL的基因，但缺乏真正的BCR-ABL融合。理论上酪氨酸抑制剂对此类患者应该有效，但是目前的临床、体内和体外的研究都缺乏确凿的证据支持这一点，仍需要进一步研究。

　　Yes. That is a definite possibility. For Philadelphia-positive ALL， the BCR-ABL fusion is not the only abnormality as in CML， so the use of the tyrosine kinase inhibitors is not going to be possible as single-agent chemotherapy. We have to take into account the additional genomic abnormalities that occur in a higher proportion of patients with Philadelphia-positive ALL. The evidence suggests that we can add imatinib to the standard chemotherapy backbone in order to improve outcomes. There are many studies now that have shown that this is effective in both childhood and adult ALL. There are also a large number of other high-risk genetic abnormalities which can be susceptible to similar types of chemotherapeutic intervention. One topic that has been discussed at length at this conference is BCR-ABL-like ALL. These patients have a gene expression very similar to BCR-ABL but lack the actual BCR-ABL fusion. These patients could theoretically also be targeted with tyrosine kinase inhibitors. There is much less clinical data to support that at the moment but I think there is in vitro and in vivo data that suggests this is an avenue that needs to be explored more fully.

　　《肿瘤瞭望》：微小残留病（MRD）的检测及其意义？

　　Moorman教授：MRD是非常好的预后指标。提高MRD的预测价值第一步需要确定其检测方法。目前可以通过流式细胞术、PCR检测IGH重排、以及新一代的测序都是其检测方法，它们对于患者的临床危险分层都有指导意义。目前，MRD检测技术的标准流程的统一非常重要。所有ALL患者都可以选用其中一种方法来检测，但不能将一种方法的结果去指导长期应用其他方法检测的患者治疗。当一个患者应用多次化疗时，确定流程中的检测方法以鉴定复发危险因素是非常关键的。我非常支持应用MRD作为危险分层的检测，但需要注意的是患者复发的风险还要考虑所选用的化疗方案。很多研究显示高度超二倍体患者的PFS、OS非常良好，但是如果你观察MRD的变化会远远慢于那些有特殊基因如TEL-AML1、ETV6-RUNX1的患者的疗效。其中的原因是体外高度超二倍体对于甲氨蝶呤（MTX）很敏感。大多数患者诱导治疗阶段没有接受MTX，因此超二倍体患者并没有暴露于最敏感的药物下。所以如果只用MRD 来做患者的危险分层，可能会导致过度治疗的风险。未来的危险分层，不论是儿童还是成年患者，都将是结合 MRD 和基因遗传学手段来进行患者治疗应答和预后的预测。

　　MRD is a fantastic predictive marker. The way to improve MRD prediction in ALL is to first identify which technique is going to be used. Are you going to use flow cytometry or IGH PCR rearrangements or go to the next-generation sequencing technology route? All of these can offer clinicians useful biomarkers for risk stratifying patients， but the key thing is to pick your technique and then integrate it into your protocol. That is the key thing. All ALL patients will respond with different kinetics according to what protocol it is. You can’t use an MRD strategy from one protocol and apply it to a different protocol if you are administering drugs at different times and intensities. The key is incorporating it into your own protocol to identify those patients who will have greater risk of relapse based upon your own chemotherapeutic regime. I would say this about MRD， I totally support the use of MRD to risk stratify patients but we must remember that the rate at which patients respond to chemotherapy depends on what chemotherapy is being used. In many studies， patients with high hyperdiploidy， who we know have an excellent response in terms of event-free survival and overall survival， if you look at the kinetics of the MRD response， it is much slower than patients who have TEL-AML1 or ETV6-RUNX1 fusions， for instance. I think the reason behind this is that in vitro there are a high number of high hyperdiploid patients who are particularly sensitive to methotrexate. Most patients do not receive methotrexate during induction， therefore those high hyperdiploid cells haven’t been exposed to the drug they are most sensitive to. So if you just employ MRD to do your risk stratification， you run the risk of overtreating patients . The future of risk stratification in both childhood and adult ALL will be a combination of MRD and genetics in order to identify those patients who are going to respond well and the ones who will need more intensive chemotherapy and the ones who will need targeted chemotherapy.