摘要：2024年12月7日至10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。在本届大会上，哈佛大学医学院麻省总医院血液科David J Kuter教授团队汇报了LUNA 3研究
编者按：2024年12月7日至10日，第66届美国血液学会（ASH）年会在美国圣迭戈隆重召开，全球血液学专家学者齐聚一堂，共同对血液领域最新研究进展进行深入探讨与交流。在本届大会上，哈佛大学医学院麻省总医院血液科David J Kuter教授团队汇报了LUNA 3研究的最新结果（摘要号：5），深入探索了口服布鲁顿酪氨酸激酶抑制剂（BTKi）rilzabrutinib在既往接受过治疗的原发性免疫性血小板减少症（ITP）成人患者中的疗效与安全性，为ITP治疗领域带来了新的洞见。《肿瘤瞭望-血液时讯》特邀David J Kuter教授分享关键发现，并就ITP治疗中的挑战及患者生活质量的改善等议题进行了深入讨论。
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《肿瘤瞭望-血液时讯》：能否详细介绍一下ITP目前的治疗挑战，特别是在成人患者中？
David J Kuter教授：原发性免疫性血小板减少症（ITP）是一种临床上最为常见的以血小板免疫破坏和血小板生成减少为特征的自身免疫性出血性疾病。长久以来，普遍认为ITP多发于年轻女性，然而，现今的认知已发生转变，该疾病在年轻群体和老年群体中的发病情况愈发普遍，尤其是在老年群体中，其发病率呈现出日益上升的趋势。
回顾ITP的治疗发展历程，早期主要依赖切除患者脾脏以及长期给予类固醇药物的治疗手段。但当下，随着医学的持续进步，针对ITP的各个层面，已涌现出诸多行之有效的疗法。特别是在血小板计数的调控方面，对于大多数ITP患者，现有疗法能够成功地将血小板计数提升至安全水平。
如今，ITP的治疗进程迈入全新阶段，一系列新型药物与前沿疗法的问世，让彻底攻克这一疾病成为可能，实现真正意义上的治愈。
尽管如此，现阶段在成人ITP患者的治疗过程中，依然面临着挑战。首要任务便是探索一种有效的治疗方案，既要将血小板计数提升至安全水平，减少出血风险，又要保证患者的生活质量。
Oncology Frontier-Hematology Frontier：Could you introduce in detail the current treatment challenges of ITP, especially among adult patients?
Dr. David J Kuter：Immune thrombocytopenia (ITP) is the most common autoimmune hemorrhagic disease clinically, characterized by immune destruction of platelets and decreased platelet production. For a long time, it was generally believed that ITP mostly occurred in young women. However, the current understanding has changed. The incidence of this disease is becoming more common in both the young and the elderly populations. Especially among the elderly, the incidence rate is showing an increasing trend.
Looking back on the treatment history of ITP, in the early days, the main treatment methods relied on splenectomy and long-term administration of steroid drugs. But now, with the continuous progress of medicine, there have emerged a great number of effective medical therapies for various aspects of ITP. Especially in the regulation of platelet count, for most ITP patients, the existing therapies can successfully increase the platelet count to a safe range.
Today, the treatment of ITP has entered a new stage. The advent of a series of new drugs and cutting-edge therapies makes it possible to completely overcome this disease and achieve a real cure.
Nevertheless, at present, there are still challenges in the treatment of adult ITP patients. The top priority is to explore an effective treatment plan that can not only increase the platelet count to a safe range to prevent bleeding, but also ensure the quality of life of patients.
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《肿瘤瞭望-血液时讯》：根据LUNA 3研究的结果，rilzabrutinib在成人ITP患者中的疗效如何？您能否分享一些关键的数据和结果？这些结果对临床治疗有何意义？
David J Kuter教授：LUNA 3是一项随机、多中心的3期研究，旨在评估rilzabrutinib与安慰剂相比，对持续性或慢性ITP成人和青少年患者的疗效和安全性。这些患者患病时间在6-8年，且既往平均接受过5种以上不同的治疗方法均未成功。患者的基线血小板计数中位数为1.5万/μL（正常血小板计数水平通常在15万-45万/μL之间）。试验的主要终点是持久的血小板应答，接受rilzabrutinib治疗的患者中，有65%的患者在没有使用挽救疗法的情况下，在24周盲法治疗期的最后12周中，至少有8周血小板计数达到或超过5万/μL。次要终点包括血小板应答时间、挽救治疗的使用情况以及身体疲劳和出血评分。分析结果显示，接受每日两次口服400 mg rilzabrutinib治疗的ITP患者中，达到持久血小板应答这一主要终点的比例显著更高，为29%。此外，次要终点的积极结果也凸显了rilzabrutinib为患有持续性和慢性ITP的患者带来具有临床意义上的获益。
Oncology Frontier-Hematology Frontier：According to the results of the LUNA 3 study, what is the efficacy of Rilzabrutinib in adult ITP patients? Could you share some key data and results? What's the significance of these results for clinical treatment?
Dr. David J Kuter：LUNA 3 is a randomized, multicenter phase 3 study designed to evaluate the efficacy and safety of rilzabrutinib compared with placebo in adult and adolescent patients with persistent or chronic ITP. These patients have had the disease for 6 - 8 years and, on average, have failed more than five different treatment methods previously. The median baseline platelet count of the patients was 15×109/L (the normal platelet count level is usually between 150×109/L and 450 ×109/L ).
The primary endpoint of the trial was a durable platelet response. Among the patients treated with rilzabrutinib, 65% of them achieved a platelet count of 50×109/L or more for at least 8 weeks out of the last 12 weeks of the 24-week blinded treatment period without the use of rescue therapy. Secondary endpoints included the number of weeks and time to platelet response, the use of rescue therapy, and physical fatigue and bleeding scores.
The analysis results showed that the proportion of ITP patients who achieved the primary endpoint of durable platelet response was significantly higher, at 29%, among those treated with 400 mg of rilzabrutinib orally twice a day. In addition, the positive results of the key secondary endpoints also highlight the potential of rilzabrutinib to bring clinically meaningful benefits to patients with persistent and chronic ITP.
03
《肿瘤瞭望-血液时讯》：除了血小板计数改善等，ITP 患者生活质量也是衡量治疗成功与否的隐性 “标尺”。研究有无跟踪观察患者出血症状缓解程度、日常活动能力恢复情况等生活质量指标？若有，rilzabrutinib在这些维度交出怎样的 “答卷”，又是如何彰显临床价值的？
David J Kuter教授：目前，ITP治疗的主要目标之一是快速提升血小板计数至安全水平以减少出血风险。本研究的独特之处在于，rilzabrutinib不仅能够提升血小板计数和减少出血风险，还能改善患者的生活质量。ITP患者普遍存在疲劳症状，而本研究是首个对药物治疗导致的疲劳状态变化进行分析的研究。
我们发现，达到试验的主要终点，即持久的血小板应答的患者，其抗疲劳能力显著增强。相比之下，安慰剂组患者的疲劳状况不仅没有改善，甚至有所恶化。令人惊讶的是，即便对于血小板应答不理想的患者，其疲劳状况也有所改善。这表明rilzabrutinib可能通过其他机制（例如抗炎作用）发挥作用，进而提升患者的生活质量。
总体而言，我们清晰地观察到了这些难治性患者生活质量的改善。如果我们能在早期阶段使用rilzabrutinib，这种改善效果可能更为显著。
Oncology Frontier-Hematology Frontier：Besides the improvement of platelet count, the quality of life of ITP patients is also a hidden "ruler" to measure the success of treatment. Did the research track the relief of bleeding symptoms and the recovery of daily activity ability of patients? If so, what kind of "answer sheet" did Rilzabrutinib present in these aspects and how did it demonstrate its clinical value?
Dr. David J Kuter：At present, most of the treatments for ITP aim to increase platelet count and reduce bleeding events. The uniqueness of this study lies in that rilzabrutinib can not only elevate platelet count and decrease bleeding, but also improve the quality of life of patients. Fatigue symptoms are prevalent among ITP patients, and this study is the first one to analyze the changes in fatigue state caused by drug treatment.
We found that patients who achieved the primary endpoint of the trial, that is, a durable platelet response, had a significantly enhanced anti-fatigue ability. In contrast, the fatigue status of patients in the placebo group not only did not improve but even worsened. Surprisingly, even for those patients whose platelet response was not very satisfactory, their fatigue status also improved. This indicates that rilzabrutinib may function through other mechanisms (such as anti-inflammatory effects) to further enhance the quality of life of patients.
Overall, we clearly observed the improvement in the quality of life of these refractory patients. If we start using rilzabrutinib in the early stage, we may find that the improvement effect is even more remarkable.
04
《肿瘤瞭望-血液时讯》：LUNA 3试验中，rilzabrutinib出现的常见不良应答类型、发生率数据详情如何？尤其是BTK抑制剂类药物常涉的出血风险、感染隐患，各等级不良事件在患者群体里的分布态势怎样，是否可控？
David J Kuter教授：BTK抑制剂在肿瘤治疗中得到了广泛的应用。然而，现有的BTK抑制剂通常会对血小板功能造成影响或降低其效能，导致出血成为常见并发症之一。rilzabrutinib在设计上巧妙地规避了这些问题，与其他BTK抑制剂不同，它不会对血小板功能产生任何影响。此外，rilzabrutinib也没有引起其他BTK抑制剂可能引发的心律失常或心房颤动等心脏问题。
在本研究中，rilzabrutinib的主要副作用与安慰剂组相比略有差异，少数患者可能会轻度腹泻，但与安慰剂组相比，并未观察到感染风险的增加。在ITP的相关临床试验中，出血通常被视为不良事件，但在本研究中，出血风险显著降低。
Oncology Frontier-Hematology Frontier：In the LUNA 3 trial, what are the details of the types and incidence rates of common adverse reactions of Rilzabrutinib? Especially for the bleeding risks and infection risks often involved in BTK inhibitor drugs, what's the distribution of adverse events of different grades among the patient group and are they controllable?
Dr. David J Kuter：BTK inhibitors have been widely used in cancer treatment. However, existing BTK inhibitors usually affect or reduce platelet function, making bleeding one of the common complications. Rilzabrutinib is ingeniously designed to avoid these problems. Unlike other BTK inhibitors, it does not have any impact on platelet function. In addition, rilzabrutinib does not cause cardiac problems such as arrhythmia or atrial fibrillation, which may be induced by other BTK inhibitors.
In this study, the main side effects of rilzabrutinib are slightly different from those of the placebo group. A small number of patients may experience mild diarrhea. However, compared with the placebo group, no increase in the risk of infection was observed. In clinical trials of ITP, bleeding is usually regarded as an adverse event, but in this study, the bleeding events were significantly reduced.
来源：肿瘤瞭望