编者按：一年一度的欧洲血液学协会年会（EHA）于近日在德国法兰克福以线上线下相结合的形式顺利举行。作为欧洲血液学领域规模最大的国际会议，每年都有来自全球100多个国家的10000余名专业人士与会，一起分享并探讨有关血液学的创新理念及最新的科学和临床研究成果。本次大会虽已结束，但会上专家学者们分享的精彩内容仍令人回味无穷。《肿瘤瞭望》特别邀请到美国H.Lee Moffitt癌症中心Rami S.Komrokji教授，就本次大会上有关骨髓增生异常综合征（MDS）的最新进展及相关研究进行分享。

 

Komrokji教授：2022年版更新后MDS有两个分类标准，即WHO分类标准、髓系肿瘤和急性白血病的国际共识分类(ICC)标准。WHO在新版本中修订了一些类别。首先从分子学定义上，除了2016年版中就有的del(5q)（5号染色体缺失）亚型外，2022年版还引入了SF3B1 MDS和双等位基因p53两个亚型。因此，MDS从分子学定义上分为三类，这是WHO 2022年版标准中新增的。从形态学上，WHO仍然保留了环形铁幼粒细胞的概念，但对MDS伴原始细胞增多进行了改名，由过去的“MDS伴原始细胞过多（MDS with excessive blast）”改为“MDS伴原始细胞增多（MDS with increased blast）1型和2型”。最后，WHO还引入了两个新的类别。如果患者骨髓原始细胞少于5％，但骨髓呈低细胞密度，则属于低增生性MDS（hypoplastic MDS）。如果原始细胞增加并伴有纤维化，则属于MDS伴骨髓纤维化（MDS with fibrosis）。这些是2022年版MDS分类相较2016年版的主要变化。

 

Oncology Frontier:Our first question is that World Health Organization updated the classification of MDS，first of all，could you analyze the important differences between the edition of 2016 and edition of 2022 MDS classification.

 

I think this is an important question，because in 2022，now we have two classifications.The WHO and the ICC.The WHO in the newer version have revised some of the categories.It went to first what we call molecularly defined sub categories of MDS.Now，we have，in addition to del(5q)(deletion 5q)that existed in the 2016 version，we have SF3B1 MDS as well as biallelic p53.So we have three categories that are molecularly defined.That’s new in the WHO 2022 criteria.

 

Then based on the morphology，the WHO still maintained ring sideroblasts.They renamed MDS with increased blast，we used to call it MDS with excess blast.Now it’s called MDS with increased blast type one and type two.And finally，they introduced two newer categories.If patients have less than 5%myeloblast，but the bone model is hypocellular.So we have a hypoplastic MDS.If the myeloblast are increased and there is fibrosis，then that’s MDS with fibrosis.So those are really the major changes between the 2016 and the 2022 criteria.

 

Komrokji教授：我们尝试提供基于证据的、数据驱动的证据，使这两种分类方法保持一致。对一种疾病有两种不同的分类是不好的。我们的想法是将它们重新整合在一起。疾病分类应该反映疾病的生物学或共同特征，而不仅仅是患者预后。

 

我们试图收集欧洲和美国的大量数据集。我们收集了近7000例MDS患者，这可能是迄今为止实施的最大的MDS数据库。我们清晰地观察到，携带SF3B1的MDS患者结局最好，在两个研究组中都是这样。而携带双等位基因p53的患者结局最差，两个研究组间有一些不同，我们可能需要将它们重新整合。携带Del（5q）的患者结局很好。我们还发现，不携带SF3B1的环形铁幼粒细胞MDS患者预后不如携带SF3B1的患者，所以可将其从WHO分类中剔除。虽然存在病态造血（dysplasia），但多谱系或单谱系显示无关紧要。ICC也有相关表述，所以我们对其进行保留。骨髓原始细胞百分比的最佳临界值仍存在一些不确定性，因此还未确定。在骨髓中存在纤维化或瘢痕组织与较差的预后相关。我们试图使这两种分类方法保持一致，并从概念上重新考虑分类方法。因此，我提出了一些建议或未来分类的提议，我们可以考虑将MDS分为慢性期（低原始细胞、del(5q)、SF3B1）、更具侵袭性的MDS或加速期（原始细胞增多、p53、MDS伴骨髓纤维化），以及MDS进展为急性髓系白血病（AML）的阶段。

 

Oncology Frontier:Your team used the classification of MDS in WHO 2022 and ICC 2022 to analyze the prognosis and survival of patients with MDS.Could you please share more details?

 

We try to provide the evidence based or data driven evidence in attempt to harmonize those two classifications.It’s not good to have two different classifications for one disease.And the idea is to bring them back together.A classification should reflect the biology of the disease or common features，not just the prognosis.

 

We tried to collect a large data set between Europe and USA.We were able to get together almost 7，000 MDS patients，which is probably the largest MDS database conducted to date.We clearly saw that，for example，MDS with SF3B1 has the best outcome.And it’s correct in both groups.Biallelic p53 has the worst outcome.There are some differences between the two that we probably need to bring them together and Del(5q)has good outcome.Then we saw that ring sideroblasts without SF3B1 is not as good as with SF3B1.So probably that can be dropped from the WHO.While a presence of dysplasia，multi lineage or single lineage displays that didn’t matter.So that’s from the ICC.So we are keeping it.There is a little bit still uncertainty about the best cut off on the blast percentage.So that’s yet to be determined.And then finally，the fibrosis or scarring in the bone model，we were able to show that it is important and is affected with worse outcome.At the end，we are trying to harmonize those two classifications and conceptually think of the classification in a different way.So I presented like some suggestions or proposals for future classification where we can think of a chronic phase MDS those that have low blasts，del(5q)，SF3B1，then a more aggressive MDS or accelerated，like if the myeloblast are increased，that p53，the MDS with fibrosis，and then finally，the AML from MDS.

 

Komrokji教授：我认为今年尤其在低风险MDS的管理方面取得了突破。在本次EHA大会上，我们有两项研究呈现。我们听取了关于Imetelstat和低风险MDS的报告。这是一项随机Ⅲ期临床试验，研究显示Imetelstat在近40%的患者中实现了无输血依赖（transfusion independency）。持续缓解时间超过一年。即使是在基线需要大量输血的患者中，也表明这种治疗可能改变疾病的自然史，因为我们看到某些突变的等位基因负荷减少了。因此，我认为这个报告和随后的发表有望使该药获批。这是低风险MDS患者治疗的一项重大进展。

 

另外一个是关于Luspatercept的研究，即COMMANDS研究。它同样是一项随机Ⅲ期临床试验，在初始治疗中将患者随机分为红系造血刺激剂（ESA）治疗组和Luspatercept治疗组。我们在一周前听到了一些数据。该研究已达到了主要终点，与ESA治疗组相比，Luspatercept治疗组患者缓解率翻倍且持续缓解时间更长。因此，这也可能是一项改变实践的临床试验。在同一场会议上，我们还听取了一些关于完全口服Decitabine/Cedazuridine和Venetoclax联合治疗高风险MDS的有趣数据。虽然这只是一项涉及40、50例患者的小型研究，但显示出了很有前景的活性，对进行骨髓移植的患者而言它是一个很好的过渡方案。

 

因此，我认为在未来，我们可能会为患者（无论风险高低）提供一种完全口服的治疗方案。最后，在同一场会议上，我们还听到了更多关于来那度胺治疗del(5q)患者的信息，即考虑适时停药。尽管传统观点是进行不间断治疗，但现在似乎有一部分患者可以接受适时停药，这将在日常临床实践中产生实际影响。

 

Oncology Frontier:Would you please talk about the advances of MDS treatment at this EHA congress?

 

I think this year had been really a breakthrough in the management of lower risk MDS particularly.So we have two studies presented at this EHA.We heard the presentation on the imetelstat and lower risk MDS.This is a randomized phase three clinical trial that showed imetelstat that was active leading to transfusion independency in almost 40%of the patients.Durable responses are more than a year.Responses，even in patients that are needing a lot of blood transfusions at baseline are suggesting that the treatment could also alter the natural history of the disease，because we are seeing reduction in the allele burden of certain mutations.So I think this presentation and the subsequent publication will hopefully lead to the approval of the drug.So that’s one of the major things in the lower risk.

 

The other one we are gonna hear this afternoon on luspatercept，a study called COMMANDS study.Again，a randomized phase three clinical trial will be presented at the plenary session today，randomizing patients between erythroid stimulating agents and luspatercept in the upfront setting.We heard some of the data a week ago.The study met the primary endpoint that is doubling to the responses than erythroid stimulating agents，more durable responses.So this also could be a practice changing clinical trial.We heard today also during the same session，some kind of interesting data about total oral therapy for higher risk MDS with oral decitabine/cedazuridine combined with venetoclax，again small study with 40，50 patients，but showing promising activity，a very good bridge to transplant.

 

So I think in the future we made it our patients with a total oral regimen，even the higher risk.And finally，in the same session，we heard a little bit more about lenalidomide for del(5q)that sometimes discontinuation could be a possibility.Although，like in the past，the classical dogma was to continue the treatment all the time.But now it seems that there is a subset of patients that treatment could be discontinued，which will have practical implications in everyday practice.

 

Rami S.Komrokji教授

美国佛罗里达州H.Lee Moffitt癌症中心恶性血液学