嵌合抗原受体T细胞治疗成人复发/难治急性B淋巴细胞白血病的长期疗效分析

Long-term efficacy of chimeric antigen receptor-modified T-cell therapy in adults with relapsed/refractory acute B lymphoblastic leukemia

目的:评价嵌合抗原受体T细胞(CAR-T)序贯治疗复发/难治成人急性B淋巴细胞白血病(B-ALL)的长期疗效。方法:收集接受CAR19/22 T细胞序贯治疗的35例复发/难治B-ALL成人患者的临床资料。统计分析其CAR-T疗效、不良反应和转归,应用Kaplan-Meier法分析患者总生存率和无进展生存率的特征。随访截至2023年2月28日。结果:所有患者的CAR-T治疗总反应率为77.1%(27/35),中位总生存期为12.2(0.3~59.5)个月,中位无进展生存期为7.5(0.3~57.3)个月。治疗无反应组患者回输前均伴高肿瘤负荷和高危遗传学/分子学异常,其总生存期和无进展生存期显著低于有反应组(P均<0.0001)。27例(77.1%)携带高危遗传学异常患者的总生存期(P=0.0344)和无进展生存期(P=0.0244)显著低于低危组。回输后细胞因子释放综合征和免疫效应细胞相关神经毒性综合征的发生率分别为91.4%(32/35)和17.1%(6/35)。10例(28.6%)CAR-T治疗后复发患者的CD19/CD22表达仍为双阳性(2例CD19弱表达)。结论:CAR19/22 T细胞序贯治疗能有效降低抗原逃逸复发率,不良反应可控。伴高肿瘤负荷或高危遗传学异常的患者预后不佳,回输前降低肿瘤负荷、回输后予以积极抗炎治疗以及长期病情监测有助于改善其预后。此外,回输2年后处于存活状态患者的长期生存率可能更好。

Objective:To evaluate the long-term outcomes of chimeric antigen receptor T-cell(CAR-T)sequential therapy in adults with relapsed/refractory acute B lymphoblastic leukemia(B-ALL).Methods:A retrospective analysis was performed on the clinical data of 35 adult patients with relapsed/refractory B-ALL who underwent sequential CAR19/22 T cell therapy.The CAR-T efficacy,adverse effects and long-term outcomes were analyzed.The Kaplan-Meier method was applied to analyze overall survival and progression-free survival of patients.The date of the last follow-up was February 28,2023.Results:The overall response rate was 77.1%(27/35)in all patients,with a median overall survival of 12.2(0.3-59.5)months and a median progression-free survival of 7.5(0.3-57.3)months.Patients in the non-response group were found to hold high tumor burden and high-risk genetic abnormalities prior to CAR-T therapy,and they had significantly worse overall survival and progression-free survival than those achieving complete remissions(all P<0.0001).A total of 27 patients(77.1%)carrying high-risk genetic abnormalities also had significantly worse overall survival(P=0.0344)and progression-free survival(P=0.0244)than those in the low risk group.Cytokine release syndrome and immune effect or cell-associated neurotoxicity syndrome developed in 91.4%(32/35)and 17.1%(6/35)of patients,respectively.A total of 10 patients(10/35,28.6%)who relapsed after this sequential CAR-T therapy remained double positive in CD19/CD22 expression(2 cases with CD19+dim).Conclusions:Sequential CAR19/22 T-cell therapy can effectively reduce the rate of antigen escape relapse with manageable adverse effects.Patients with high tumor burden or high-risk genetic abnormalities might have poor outcomes.Therefore,tumor load reduction before CAR-T cell infusion,early onset of anti-inflammatory therapy after infusion,and long-term disease monitoring may help improve their prognosis.In addition,long-term survival may be longer in patients who survive for 2 years after CAR-T therapy.