CLAE强烈化疗序贯异基因造血干细胞移植治疗复发难治急性白血病的疗效观察

Efficacy of CLAE Chemotherapy Regimen Followed by Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Relapsed/Refractory Acute Leukemia

目的:观察CLAE强烈化疗方案序贯异基因造血干细胞移植(allo-HSCT)治疗复发难治急性白血病(relapsed/refractory acute leukemia,R/R AL)的疗效与安全性。方法:采用CLAE方案[克拉屈滨5 mg/(m^(2)·d),d 1-5;阿糖胞苷1.5 g/(m^(2)·d),d 1-5;依托泊苷100 mg/(m^(2)·d),d 3-5]序贯allo-HSCT治疗3例R/R AL患者。3例患者在复发难治状态接受CLAE化疗后行骨髓穿刺判断骨髓增生程度,间歇3-5 d后,序贯allo-HSCT预处理方案[氟达拉滨30mg/(m^(2)·d),d-7至d-3;白消安注射液0.8 mg/kg q6h,d-6至d-3或d-5至d-2。若骨髓增生低下,原始细胞小于10%,应用3 d白消安注射液;若骨髓增生活跃,原始细胞大于10%,应用4 d白消安注射液],采用环孢素、麦考酚吗乙酯、短程甲氨蝶呤预防GVHD。3例患者移植后规律监测微小残留病与骨髓嵌合状态,并于移植后3个月应用去甲基化药物或达沙替尼预防复发。结果:2例患者为t(11;19)易位的复发难治急性髓系白血病,均在诱导缓解后半年内复发,分别接受CLAE方案强烈化疗序贯单倍体与非血缘供者allo-HSCT,移植后半年再次复发,采用供者淋巴细胞输注、干扰素、白介素-2等方法再次获得缓解,移植后无病生存2年。1例为慢性粒细胞白血病患者,在口服酪氨酸激酶抑制剂治疗过程中发生急淋变,伴有ABL1激酶区T315I、E255K突变及附加染色体异常,经诱导化疗获得形态学缓解后并发中枢神经系统白血病,微小残留病阳性状态下采用CLAE方案强烈化疗序贯同胞全相合allo-HSCT,移植后3个月再次复发,采用CAR-T治疗后获得缓解,并发严重细胞因子反应综合征(CRS)与GVHD,于移植后5个月死亡。结论:CLAE方案序贯allo-HSCT可以延长R/R AL患者的总生存期,可能是R/R AL患者挽救治疗的一种选择。

Objective:To observe the efficacy and safety of CLAE intensive chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with relapsed/refractory acute leukemia (R/R AL).Methods:CLAE regimen[cladribine 5 mg/(m^(2)·d),d 1-5;cytarabine 1.5 g/(m^(2)·d),d 1-5;etoposide 100 mg/(m^(2)·d),d 3-5]followed by allo-HSCT was used to treat 3 R/R AL patients.The patients received CLAE chemotherapy in relapsed or refractory status and underwent bone marrow puncture to judge myelodysplastic state.After an interval of 3 to 5 days,followed by preconditioning regimen for allo-HSCT[fludarabine 30 mg/(m^(2)·d),d-7 to d-3;busulfan 0.8 mg/kg q6h,d-6to d-3 or d-5 to d-2.If the bone marrow hyperplasia was not active and the blasts were less than 10%,busulfan should be used for 3 days.If the bone marrow hyperplasia was active and the blasts were more than 10%,busulfan should be used for 4 days].Cyclosporin A,mycophenolate mofetil and short-term methotrexate were used for graft-versus-host disease (GVHD)prevention.After transplantation,the status of minimal residual disease (MRD) and bone marrow chimerism were regularly monitored in all 3 patients,and demethylation drugs or dasatinib were used to prevent recurrence 3 months after transplantation.Results:2 patients with t(11;19) translocation and relapse/refractory acute myeloid leukemia recurred within 6 months after induction of remission,and received intensive chemotherapy with CLAE regimen followed by haploidentical allo-HSCT and unrelated donor allo-HSCT,respectively.The two patients both relapsed 6 months after transplantation,then achieved complete remission by donor lymphocyte infusion,interferon,interleukin-2 and other methods,and disease-free survival was 2 years after transplantation.The other patient was chronic myelogenous leukemia who developed acute lymphoblastic leukemia during oral administration of tyrosine kinase inhibitor,accompanied by T315I and E255K mutations in ABL1 kinase region and additional chromosomal abnormalities.After morphological remission by induction chemotherapy,central nervous system leukemia was complicated.Intensive chemotherapy with CLAE regimen followed by sibling allo-HSCT was performed in the positive state of MRD.The patient relapsed 3months after transplantation,and achieved remission after chimeric antigen receptor T-cell (CAR-T) therapy,however,he died 5 months after transplantation because of severe cytokine release syndrome (CRS) and GVHD.Conclusion:CLAE regimen followed by allo-HSCT may be an effective salvage treatment option for R/R AL patients to prolong the overall survival.