酪氨酸激酶抑制剂（TKIs）的问世改变了慢性髓性白血病（CML）的治疗格局，改善了CML患者的预后，提高了其生命质量。然而，随着一些患者出现药物不耐受或耐药性，探索新一代TKIs或其他新型药物势在必行。在刚刚落幕的2023年第65届美国血液学会（ASH）大会上，美国德克萨斯州大学MD安德森癌症中心Fadi Haddad教授口头报告了《达沙替尼治疗早期慢性期慢性粒细胞白血病（ECP-CML）患者的II期研究》。会后，《肿瘤瞭望–血液时讯》特别邀请到Fadi Haddad教授就CML的治疗进展做进一步分享。
Photographer: Tianmeng Liu
伊马替尼时代
在2000年之前，CML面临着巨大挑战，治疗仅限于干扰素和羟基脲等药物，这些药物可改善患者血象和缓解症状，但不能延迟疾病进展。大多数患者最后都会进入加速期和急变期，最终死亡。异基因造血干细胞移植是当时唯一有效的治疗手段。直到2000年，第一代TKI药物伊马替尼的出现，给CML治疗带来转折。这种突破性的治疗方法彻底改变了CML的治疗，患者获得了完全细胞遗传学反应和分子学反应，生存率显著提高并接近正常人群。然而，随着一些患者出现药物不耐受或耐药性，CML治疗再次面临挑战，促使对第二代TKIs的探索。
英文原文：
Before the year 2000, CML presented a formidable challenge with limited treatment options, including interferon and hydroxyurea. Unfortunately, many patients progressed to advanced stages and succumbed to the disease, with allogeneic stem cell transplantation being the sole curative option.The turning point came in 2000 with the advent of the first-generation TKI, imatinib. This groundbreaking therapy revolutionized CML treatment, leading to complete cytogenetic and molecular responses. Patient survival significantly improved, approaching that of the normal population. However, challenges emerged as some patients developed treatment intolerance or resistance, necessitating the exploration of second-generation TKIs.
第二代TKIs
达沙替尼、尼洛替尼和博舒替尼作为第二代TKIs出现，在挽救治疗中显示出比伊马替尼更大的优越性。这促使对这三种药物进行一线治疗评估，最终它们均获得了美国食品药品监督管理局（FDA）的批准。因此，目前CML的一线治疗包括伊马替尼、达沙替尼、尼洛替尼和博舒替尼。在治疗中，需根据患者的具体情况选择合适的TKI。例如，患有心血管疾病的患者可能要避免使用尼洛替尼，因为它与心血管毒性有关；而患有肺部疾病的患者则可能要避免使用达沙替尼，以降低肺毒性的风险。
英文原文：
Desatinib, nilotinib, and bosutinib emerged as second-generation TKIs, demonstrating superiority over imatinib in salvage settings. Their success prompted evaluations in the frontline setting, resulting in FDA approval for all three. Current options for frontline CML treatment include imatinib, desatinib, nilotinib, and bosutinib. Choosing the appropriate TKI involves considering patient-specific factors such as comorbidities. For instance, patients with cardiovascular disease may avoid nilotinib due to its association with cardiovascular issues, while those with lung problems might steer clear of desatinib to mitigate the risk of pulmonary toxicity.
第三代TKIs
在前线治疗中，通过最佳监测以及依从性，CML患者总生存率接近95%。针对复发患者，目前已有两种第三代TKIs——普纳替尼和asciminib获批。尽管普纳替尼因心血管和胰腺毒性需谨慎管理剂量，但其对重度预处理患者，特别是T315I突变患者有效。
英文原文：
In the frontline setting, the overall survival rate approaches 95% with optimal monitoring and compliance. In cases of relapse, two third-generation TKIs, ponatinib and asciminib, have been approved. Ponatinib is effective in heavily pretreated patients, particularly those with the T315I mutation, though careful dose management is essential due to associated cardiovascular and pancreatic toxicities.
新型药物
阿西米尼是首个具有独特作用机制的激酶抑制剂，通过特异性靶向ABL肉豆蔻酰口袋(STAMP)发挥作用。在既往接受TKI治疗的患者中，与博舒替尼相比，阿西米尼显示出积极结果。针对阿西米尼正在进行的研究旨在阐明其长期毒性，并在三线治疗中确定最佳排序。此外，还有多项针对CML治疗的临床试验正在进行中，以期探索其他新药物和治疗组合。长期随访研究将为这些新药物的耐受性和安全性提供重要依据，指导未来的治疗决策。
英文原文：
Asciminib stands out as the first TKI with a distinct mechanism of action—acting as an allosteric drug targeting a different pocket. While it has shown positive outcomes compared to bosutinib in patients with prior TKI treatments, ongoing research aims to elucidate its long-term toxicities and determine the optimal sequence in the third-line setting.The landscape of CML treatment continues to evolve, with ongoing clinical trials exploring new drugs and combinations. Long-term follow-up studies will provide crucial insights into the durability and safety profiles of newer agents, guiding future treatment decisions.
小结
以TKI为标志的CML治疗之旅，已经将过去极差的预后转变为患者可以渴望接近正常预期寿命的前景。根据患者的具体情况量体裁衣选择合适的TKI，体现了现代CML治疗的个体化原则。随着研究的进展，临床医生和患者同样可以期待治疗策略的进一步完善，为治愈这种恶性血液肿瘤带来希望。
英文原文：
The journey of CML treatment, as discussed by Dr. Fadi Haddad, marked by the introduction of TKIs, has transformed a once dire prognosis into a landscape where patients can aspire to a near-normal life expectancy. The nuanced approach to selecting TKIs based on individual patient factors underscores the personalized nature of modern CML care. As research advances, clinicians and patients alike can anticipate further refinements in treatment strategies, bringing hope to those affected by this hematologic malignancy.
专家简介
Fadi Haddad教授
美国德克萨斯州大学MD安德森癌症中心癌症医学部白血病科