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不断回响在耳畔。《肿瘤瞭望》特别邀请到安德森癌症中心Nicholas Short教授，就本次大会上有关急性淋巴细胞白血病（ALL）的最新治疗进展及相关研究进行分享。

 

Nicholas Short教授：在ALL患者，尤其是在B淋巴母细胞白血病（B-ALL）患者结局方面取得较多进展。许多新研究评估了使用Blinatumomab（一种抗CD19/CD3双特异性抗体）、Inotuzumab Ozogamicin（一种抗CD22抗体-药物偶联物）不同组合的疗效。此外，还有几种CD19 CAR-T细胞产品在多个国家获批。现在我们也看到了一些其他不同CAR-T细胞产品的数据。针对费城染色体阳性(Ph阳性)ALL，我们有不同靶向BCR-ABL的酪氨酸激酶抑制剂（TKIs）可供选择。特别是研究人员对Ponatinib的兴趣和期待颇高。Ponatinib是一种强效TKI，在整个研究中，它似乎比更早代TKI产生更好的结果。我们进行了一项大型随机研究，结果显示在Ph阳性ALL患者中，Ponatinib相较Imatinib有明显获益，因此这可能代表了对于这类患者的新的治疗标准。

 

Oncology Frontier:Our first question is about，could you please talk about the latest advances of target agents in ALL(acute lymphoblastic leukemia)treatment at this EHA congress?

 

We’ve had a lot of improvements in the outcomes with patients with ALL particularly in B cell ALL.A lot of new studies evaluating different combinations using blinatumomab，which is a CD19/CD3 bispecific engaging antibody，inotuzumab ozogamicin，which is an anti CD 22 antibody drug conjugate.And then also there’s several CD 19 CAR T cell products that are approved in various countries.Now we’re seeing data from some other different CAR T cell constructs.And in Philadelphia Chromosome positive ALL，we have different TKIs available that target BCR-ABL.In particular，we’re seeing a lot of interest and excitement around ponatinib.Ponatinib is a very potent tyrosine kinase inhibitor that across study seems to yield better outcomes than those with earlier generation TKIs.In fact，we had a large randomized study showing the benefit of ponatinib compared to imatinib in Ph positive ALL so that may represent a new standard of care for these patients.

 

Nicholas Short教授：我们在大会上报告了一项目前正在进行的无化疗方案研究的最新数据，该方案将Ponatinib和Blinatumomab联合应用于新诊断的Ph阳性ALL患者。我们给予患者五个周期的免疫治疗（Blinatumomab联合Ponatinib），初始每日剂量为30 mg，一旦患者达到完全分子学缓解（CMR），则将剂量减少至15 mg。我们还进行了12次鞘内预防性化疗。结果显示，患者接受无化疗方案后达到了非常高的治疗反应率。基本上，所有患者都有治疗反应。通过PCR检测BCR-ABL基因的最小残余病（MRD）阴性，我们观察到患者CMR率为87%。进一步采用新一代测序，结果显示MRD阴性率为89%，灵敏度为1x10-6。因此，可以看到是非常深度的MRD缓解，即治疗方案对消除癌细胞的效果极佳。

 

同样重要的是，在我们治疗的60例患者中，只有1例患者进行了移植。因此，我们提供的这种无化疗治疗方案，在首次缓解时也不需要移植。而且，还观察到极少的复发病例。其中，中枢神经系统的复发比例较高，这是无化疗方案的一个担忧，不过我们目前正在修正研究方案，如增加鞘内预防性化疗的总剂量。也就是说，通过这种无化疗方案，患者2年的总生存（OS）率为88%，这非常令人鼓舞，尤其是在无化疗方案可以克服移植需求的情况下。因此，我们认为，这些无化疗方案可能会成为新的治疗标准。对于Ph阳性ALL患者而言，这是一种进步，也希望大多数Ph阳性ALL患者在不久的将来不再需要移植。

 

Oncology Frontier:Could you please talk about an oral study which was reported by your team and evaluated the efficacy of chemotherapy-free combination of ponatinib and blinatumomab for patients with newly diagnosed philadelphia chromosome-positive acute lymphoblastic leukemia.

 

So we presented updated data from our ongoing study of a chemotherapy-free regimen of ponatinib and blinatumomab in patients with newly diagnosed Ph positive ALL.We give five cycles of immunotherapy with blinatumomab in combination with ponatinib，30 milligrams daily initially，then we decrease the dose to 15 milligrams once the patients achieved a complete molecular response.We give 12 doses of intrathecal，chemotherapy prophylaxis.We’ve seen very high rates of response.Essentially，all patients have responded.The complete molecular response rate，which is MRD(minimal residual disease)negativity by PCR for BCR-ABL is 87%.And when we look even more sensitive with next generation sequencing MRD that’s sensitive at one out of a million，we have a MRD negativity rate of 89%，so we see very deep MRD responses.

 

Importantly，we’ve also only transplanted one of the 60 patients that we’ve treated.So we’re delivering this chemotherapy-free regimen also without transplant in first remission.We’ve seen very few relapses of the relapse is that we’ve seen.There’s been disproportionate in the central nervous system.This is a concern with chemotherapy-free regimens，but we’re now amending the study to increase the total doses of intrathecal chemotherapy.But that said the 2 year overall survival is 88%，which is very encouraging，particularly with the chemotherapy-free regimen that can overcome the need for transplants.So we really think that these chemotherapy-free regimens will likely be the new standard of care，going forward for patients with Ph positive ALL and also hopefully most patients with Ph positive ALL won’t need a transplant in the near future.

 

Nicholas Short教授：目前至少有两种不同的CAR-T细胞产品在美国和其他国家获批。它们的靶点都是CD19，其中一个是Tisagenlecleucel，另一个是Brexucabtagene Autoleucel。未来的大问题是我们如何最佳地使用这些药物。例如，我们是否应该将其作为巩固治疗，而不是用于复发/难治性疾病的患者？我们是否应该将其作为巩固治疗的一线治疗，也许它们可以使患者免于干细胞移植？这些都是目前正在探讨的问题。

 

本次大会上公布的一些关于针对T淋巴母细胞白血病（T-ALL）的CAR-T细胞治疗数据非常有趣，这确实是一个未满足的需求。对于ALL患者，目前有许多疗法效果显著。对于B-ALL患者，可以采用Inotuzumab、Blinatumomab、CD19 CAR-T细胞等疗法，但对于T-ALL患者，有效药物则非常少，仅有CD5 CAR-T细胞治疗的数据显示出一些令人鼓舞的应答率。之前也有一些关于CD9/CD7 CAR-T细胞治疗的早期数据。因此，这些领域的未来发展令人期待和兴奋。这些疗法目前尚未获批，这在复发/难治性ALL患者中确实是一个未满足的需求。

 

Oncology Frontier:Could you please introduce us some therapeutic progress or any advance of target treatment in the field of the ALL at this EHA congress?

 

There’s two different CAR-T cell products that are at least approved in the US and around various other countries.These are both target CD19.One is called tisagenlecleucel.One is brexucabtagene autoleucel.The big question going forward is how should we best use these drugs.Should we use them，for example，as consolidation rather than for patients with relapse/refractory disease?Should we move them into the frontline setting again as consolidation，and maybe they can overcome the need for stem cell transplant?Those are all active questions that are being asked now.

 

I think one thing that’s particularly interesting at this particular conference was we’ve seen some data presented about CAR-T cells that can target T cell ALL and this has really been an unmet need.In patients with ALL we have a lot of good therapies now.For patients with B cell ALL，again inotuzumab，blinatumomab，CD19 CAR-T cells，but very few effective drugs for patients with T cell ALL and so there was just data presented about CD5 CAR-T cell that showed some encouraging response rates.We’ve seen previously some other early data of CD9/CD7 CAR-T cells.So it’ll be exciting to see what happens in the future with these.None of these are approved yet，but this is certainly an unmet need in the treatment of patients with relapse/refractory ALL.

 

Nicholas Short教授

安德森癌症中心（MD Anderson Cancer Center）癌症医学部白血病科