肿瘤细胞治疗研究
英文原题：The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades.
The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades.
过去四十年中，急性淋巴细胞白血病（ALL）的治疗取得了显著进展。
成人急性淋巴细胞白血病（ALL）的研究和治疗进展正在加快。本分析总结MD Anderson癌症中心1985至2022年开展的ALL各亚型临床试验数据。对于费城染色体阳性ALL，自2000年以来，在强化化疗中加入BCR::ABL1酪氨酸激酶抑制剂（TKI）改善了治疗结局。近期，无化疗方案blinatumomab联合ponatinib使完全分子学缓解率达到85%，估计3年生存率达到90%，有望降低缓解后异基因干细胞移植（SCT）的作用和需求。对于较年轻的费城染色体阴性前B细胞ALL患者，将blinatumomab和inotuzumab纳入一线治疗后，各风险类别患者估计3年生存率提高至85%。我们的未来策略是在一线治疗中尽早联合两种免疫治疗药物inotuzumab和blinatumomab与低剂量化疗（剂量密集型mini-Hyper-CVD-inotuzumab-blinatumomab），随后对高危患者以CAR-T细胞巩固治疗，不再进行额外维持治疗。对于老年患者，较低强度化疗（mini-Hyper-CVD）联合inotuzumab和blinatumomab已将5年生存率提高至50%。在65–70岁患者中，完全缓解（CR）期间死亡率仍较高，且原因多样，包括高龄、CR期间感染死亡，以及发生骨髓增生异常综合征或急性髓系白血病。无化疗的inotuzumab联合blinatumomab方案正在研究中。采用新一代测序（NGS）评估可测量残留病（MRD）优于传统检测；NGS检测早期MRD阴性与最佳生存结局相关。我们预计，未来B-ALL治疗将采用强度更低、疗程更短的化疗方案，并联合靶向CD19（blinatumomab）、CD20和CD22（inotuzumab）的药物。CAR-T疗法可能在疾病负荷较低时使用更为理想；未来试验将评估对高危患者采用CAR-T巩固治疗以替代异基因SCT的作用。总之，过去40年ALL治疗取得显著进展。包含新一代BCR::ABL1 TKI和新型抗体的联合方案，使人们重新审视强化化疗及异基因SCT的必要性和疗程。
Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients 65-70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.
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