贝林妥欧单抗治疗复发难治急性B淋巴细胞白血病效果分析

Efficacy analysis of blinatumomab in treatment of relapsed/refractory B-cell acute lymphoblastic leukemia

目的探讨贝林妥欧单抗治疗复发难治急性B淋巴细胞白血病(B-ALL)的效果和安全性。方法回顾性分析2020年9月至2021年12月上海闸新中西医结合医院接受贝林妥欧单抗治疗的8例复发难治B-ALL患者资料,分析其临床特征、生存时间、治疗反应、淋巴细胞亚群、细胞因子、联合移植情况以及不良反应。结果 8例患者中位随访时间143 d(41~534 d)。8例患者中5例生存,其中贝林妥欧单抗停药时评估为微小残留病(MRD)阴性完全缓解(CR)的6例患者中4例生存,评估为未缓解的2例患者中1例生存。贝林妥欧单抗治疗的中位时间为28 d(10~56 d),其中基线MRD阳性患者的中位治疗时间为23 d(10~56 d),4例未缓解患者的中位治疗时间为28 d(25~31 d)。6例患者治疗后达到MRD阴性CR,其中4例基线评估为MRD阳性,2例基线评估为未缓解。4例MRD阳性CR患者经过贝林妥欧单抗治疗后均达到MRD阴性CR,其中1例费城染色体阳性(Ph+)ALL患者桥接自体造血干细胞移植,1例Ph+ ALL患者和1例Ph- ALL患者序贯异基因造血干细胞移植,疾病呈持续MRD阴性CR。4例未缓解患者经过贝林妥欧单抗治疗后,2例达MRD阴性CR,其中1例Ph+ ALL患者桥接自体造血干细胞移植,1例Ph- ALL患者序贯异基因造血干细胞移植,2例患者均持续MRD阴性CR。接受贝林妥欧单抗治疗后MRD阳性CR和未缓解患者的白细胞计数和中性粒细胞均有下降。MRD阳性CR患者CD3+ T和CD3+ CD8+ T淋巴细胞占淋巴细胞比例和绝对数均高于未缓解患者,且在用药后均有所下降。治疗第3周时MRD阳性CR和未缓解患者的中位白细胞介素6(46.23、1.42 pg/ml)、白细胞介素8(17.85、2.10 pg/ml)、白细胞介素10(7.43、1.49 pg/ml)和干扰素γ(11.82、0.39 pg/ml)水平均升高。发生1级细胞因子释放综合征1例,其临床表现为发热,暂停用药后好转。3例发生感染,其中2例为肺部感染,1例为上呼吸道感染。未观察到免疫效应细胞相关神经毒性综合征。结论贝林妥欧单抗对于复发难治B-ALL的MRD清除效果好,不良反应可控,为桥接造血干细胞移植延长患者生存提供了有效的治疗选择。

Objective To explore the efficacy and safety of blinatumomab in treatment of relapsed/refractory B-cell acute lymphoblastic leukemia(B-ALL).Methods The data of 8 patients with relapsed/refractory B-ALL treated with blinatumomab in Shanghai Zhaxin Traditional Chinese and Western Medicine Hospital from September 2020 to December 2021 were retrospectively analyzed,and their clinical characteristics,overall survival,lymphocyte subsets,cytokines,tandem transplantation and adverse reactions were analyzed.Results The median follow-up time of 8 patients was 143 d(range:41-534 d).Five of the 8 patients were alive;among them,4 of 6 patients assessed to be in minimal residual disease(MRD)-negative complete remission(CR)and 1 of 2 patients assessed to be in non-remission at the time of belintuzumab discontinuation were alive.The median duration of treatment with belintuzumab was 28 d(10-56 d),and it was 23 d(10-56 d)for patients with MRD-positive at baseline and 28 d(25-31 d)for the 4 non-remission patients.Six patients achieved MRD-negative CR after treatment,of which 4 were assessed as MRD-positive at baseline and 2 were assessed as non-remission at baseline.All 4 patients with MRD-positive CR achieved MRD-negative CR after treatment with belintuzumab,including 1 patient with Philadelphia chromosome-positive(Ph+)ALL bridged to autologous hematopoietic stem cell transplantation,and 1 patient with Ph+ALL and 1 patient with Ph-ALL received sequential allogeneic hematopoietic stem cell transplantation and had persistent MRD-negative CR.Two of the 4 non-remission patients achieved MRD-negative CR after treatment with belintuzumab,including 1 patient with Ph+ALL bridged to autologous hematopoietic stem cell transplantation,and 1 patient with Ph-ALL received sequential allogeneic hematopoietic stem cell transplantation,and the 2 patients had persistent MRD-negative CR.Leukocyte counts and neutrophils decreased in both MRD-positive CR and non-remission patients after receiving belintumomab.The proportion and absolute number of CD3+T and CD3+CD8+T lymphocytes in patients with MRD-positive CR were higher than those in patients without remission,and both decreased after drug administration.Median interleukin-6(46.23,1.42 pg/ml),interleukin-8(17.85,2.10 pg/ml),interleukin-10(7.43,1.49 pg/ml)and interferon-γ(11.82,0.39 pg/ml)levels were elevated in MRD-positive CR and non-remission patients at week 3 of treatment.Grade 1 cytokine release syndrome occurred in 1 case with clinical manifestations of fever,which improved after drug suspension.Three cases developed infections,2 of which were pulmonary and 1 of which was upper respiratory tract infection.No immune effector cell-associated neurotoxic syndrome was observed.Conclusions Belintumomab is effective for MRD clearance in relapsed/refractory B-ALL with manageable adverse reactions,providing an effective therapeutic option for bridging hematopoietic stem cell transplantation to prolong the survival of patients.