伊布替尼治疗伴MyD88突变难治性弥漫大B细胞淋巴瘤患者预后的临床分析

Clinical prognosis analysis of refractory diffuse large B-cell lymphoma patients with MyD88 mutation treated by ibrutinib

目的探讨伊布替尼对伴髓样分化因子(MyD)88突变难治性弥漫大B细胞淋巴瘤(DLBCL)患者的疗效及预后。方法选择2018年8月至2020年8月南方医科大学珠江医院肿瘤科收治的134例难治性DLBCL患者为研究对象,按照随机数表法将患者按2∶1分为训练集(n=94)和测试集(n=40)。其中,训练集患者年龄为60~78岁,男、女性患者分别为41、53例,根据MyD88基因型将训练集患者分为MyD88突变型组(n=33)和MyD88野生型组(n=61)。测试集患者年龄为62~80岁,男、女性患者分别为18、22例。收集患者的临床病例资料,如性别、年龄、病变部位、DLBCL结外累及部位、Hans分型、Ann-Arbor分期、东部肿瘤协作组(ECOG)评分、血清乳酸脱氢酶(LDH)水平、β2-微球蛋白(MG)水平、CD5表达情况、Ki-67指数、治疗方案、既往治疗方案种类、MyD88突变等。采用χ^(2)检验比较2组患者的临床资料、伊布替尼疗效等定性资料;采用Kaplan-Meier法绘制不同患者生存曲线,采用log-rank检验进行不同患者生存曲线比较。采用Cox比例风险回归模型进行难治性DLBCL患者预后影响因素的单因素及多因素分析,建立列线图模型,并采用受试者工作特征(ROC)曲线,校准曲线,临床决策曲线分别对模型的区分度、准确性和有效性进行评价,同时建立预测患者预后的危险分层系统。2组患者性别构成比、年龄等一般资料分别比较,差异均无统计学意义(均P>0.05)。本研究经南方医科大学珠江医院伦理委员会审核批准(批准文号:32846),所有患者均签署临床研究知情同意书。结果①MyD88突变型组难治性DLBCL患者采取伊布替尼治疗后的客观缓解率(ORR)和疾病控制率(DCR)分别为60.6%(20/33)和97.0%(32/33),均高于MyD88野生型组的34.4%(21/61)和82.0%(50/61),并且差异有统计学意义(χ^(2)=5.97,P=0.015;χ^(2)=4.33,P=0.037)。训练集94例难治性DLBCL中MyD88野生型组患者的2年无进展生存(PFS)率和总体生存(OS)率分别为64.8%和63.7%,MyD88突变型组分别为63.6%和62.3%,2组患者中位PFS期分别为16.0和11.7个月,中位OS期分别为18.1和13.2个月,2组分别比较,差异均无统计学意义(均P>0.05)。②采用伊布替尼联合其他药物治疗的患者中,MyD88野生型者(n=25)的2年PFS和OS率分别为57.5%和54.7%,均高于MyD88突变型者(n=21)的50.3%和48.2%,并且差异均有统计学意义(χ^(2)=9.37、P=0.002,χ^(2)=7.79、P=0.005)。③对难治性DLBCL患者PFS、OS率进行多因素Cox比例风险回归模型分析结果显示,ECOG评分≥2分(HR=1.846,95%CI:1.476~2.283,P=0.036),LDH水平≥250 IU/L(HR=2.983,95%CI:2.525~3.358,P=0.008),β2-MG表达呈阳性(HR=3.241,95%CI:2.508~3.956,P=0.005),既往治疗方案种类>2种(HR=3.062,95%CI:2.547~3.618,P=0.011),伴MyD88突变(HR=3.742,95%CI:3.028~4.439,P=0.041)是难治性DLBCL患者PFS率的独立危险因素。ECOG评分≥2分(HR=3.726,95%CI:1.842~3.677,P=0.014),β2-MG表达呈阳性(HR=2.529,95%CI:1.927~3.124,P=0.027),既往治疗方案种类>2种(HR=2.796,95%CI:2.145~3.425,P=0.018),伴MyD88突变(HR=2.483,95%CI:2.139~2.917,P=0.024)是难治性DLBCL患者OS率的独立危险因素。④构建预测患者PFS和OS率的列线图模型,训练集和测试集的ROC曲线下面积分别为0.856(95%CI:0.801~0.924)和0.849(95%CI:0.795~0.918),灵敏度分别为90.28%和88.46%,特异度分别为87.42%和85.93%,对患者预后情况区分度较好。预测患者PFS和OS率的列线图模型的校准曲线评价结果显示,训练集、测试集的预测值和实际观测值拟合度良好(χ^(2)=1.21、P=0.093,χ^(2)=1.31、P=0.085),一致性、准确性均较好。预测患者PFS和OS率的列线图模型的临床决策曲线评价结果显示,训练集和测试集在高风险阈值为0~0.9时,净获益值均为正值,即具有明显的正向净收益,具有良好的临床实用性。⑤根据对难治性CLBCL患者危险评分总分,将40例测试集患者分为3个危险组:低风险组(n=12,总分<65分),中风险组(n=16,5分≤总分<105分),高风险组(n=12,总分≥105分),其中低、中、高风险组难治性DLBCL患者比例分别为30%(12/40),40%(16/40)和30%(12/40)。3组患者的OS率比较,差异有统计学意义(Z=6.15,P=0.010),提示该危险分层系统能较好区分患者生存情况。结论MyD88突变与难治性DLBCL患者的临床特征及伊布替尼疗效有关,采用伊布替尼联合其他药物治疗可改善伴MyD88突变患者的预后。预测患者DFS和OS率的列线图模型对预测难治性DLBCL患者预后的区分度较高,准确性和有效性较好。

Objective To investigate efficacy and prognosis of ibrutinib treatment in refractory diffuse large B-cell lymphoma(DLBCL)patients with myeloid differentiation factor(MyD)88 mutation.Methods From August 2018 to August 2020,a total of 134 patients with refractory DLBCL who were admitted to Department of Oncology,Zhujiang Hospital,Southern Medical University were selected as the study subjects.Using random number table method,the patients were divided into training set(n=94)and test set(n=40)according to ratio of 2∶1.Among them,patients in training set were aged 60-78 years,with 41 male patients and 53 females.According to the MyD88 genotype,they were divided into MyD88 mutant group(n=33)and MyD88 wild-type group(n=61).Patients in test set were aged 62-80 years,with 18 males and 22 females.Collect clinical data of patients,such as gender,age,lesion site,extranodal involvement site,Hans classification,Ann-Arbor staging,Eastern Tumor Collaborative Group(ECOG)score,serum lactate dehydrogenase(LDH),β2-microglobulin(MG)and CD5 expression levels,Ki-67 index,treatment plan,type of previous treatment plan,MyD88 mutation,etc..Compare qualitative data,such as the clinical data,efficacy of ibrutinib treatment between two groups of patients using chi-square test.Kaplan-Meier method was used to draw survival curves for different patients,and the log-rank test was used to compare the survival curves of different patients.Use the Cox proportional hazard regression model for univariate and multivariate analysis of prognostic factors in refractory DLBCL patients.Establish a column chart model,and the discrimination,accuracy,and effectiveness of the model were evaluated using receiver operating characteristic(ROC)curves,calibration curves,and clinical decision curves,respectively.At the same time,the risk stratification system to predict patients'prognosis was established.There was no statistically significant difference in general data such as gender composition ratio and age between the two groups of patients(P>0.05).This study was reviewed and approved by the Ethics Committee of Zhujiang Hospital,Southern Medical University(Approval No.32846),and all patients signed the informed consent for clinical research.Results①Objective remission rate(ORR)and disease control rate(DCR)of refractory DLBCL patients in MyD88 mutant group after treatment with ibutinib were 60.6%(20/33)and 97.0%(32/33),respectively,which were higher than those of 34.4%(21/61)and 82.0%(50/61)of MyD88 wild-type group,and the differences were statistically significant(χ^(2)=5.97,P=0.015;χ^(2)=4.33,P=0.037).Among 94 patients with refractory DLBCL in training set,the 2-year progression-free survival(PFS)and overall survival(OS)rate of patients in MyD88 wild-type group were 64.8%and 63.7%,and the MyD88 mutant group were 63.6%and 62.3%,respectively.Median PFS time of patients in two groups were 16.0 and 11.7 months,and the median OS time were 18.1 and 13.2 months,respectively.There was no statistically significant difference between the two groups(all P>0.05).②Among patients treated with ibrutinib in combination with other drugs,MyD88 wild-type(n=25)patients'2-year PFS and OS rate were 57.5%and 54.7%,respectively,which were higher than those of 50.3%and 48.2%in MyD88 mutant patients(n=21),and the differences between the two were also statistically significant(χ^(2)=9.37,P=0.002;χ^(2)=7.79,P=0.005).③Multivariate Cox proportional hazard regression model analysis of PFS and OS rates in patients with refractory DLBCL showed that the ECOG score≥2 points(HR=1.846,95%CI:1.476-2.283,P=0.036),LDH level≥250 IU/L(HR=2.983,95%CI:2.525-3.358,P=0.008),positive expression ofβ2-MG(HR=3.241,95%CI:2.508-3.956,P=0.005),more than 2 types of previous treatment regimens(HR=3.062,95%CI:2.547-3.618,P=0.011),and with MyD88 mutation(HR=3.742,95%CI:3.028-4.439,P=0.041)were independent risk factors affecting PFS rate of refractory DLBCL patients.ECOG score≥2 points(HR=3.726,95%CI:1.842-3.677,P=0.014),positive expression ofβ2-MG(HR=2.529,95%CI:1.927-3.124,P=0.027),more than 2 types of previous treatment regimens(HR=2.796,95%CI:2.145-3.425,P=0.018),and with MyD88 mutation(HR=2.483,95%CI:2.139-2.917,P=0.024)were independent risk factors affecting the OS rate of refractory DLBCL patients.④A nomogram was constructed to predict patients'PFS and OS rate.Results showed that the areas under the ROC curves corresponding to the training set and test set were 0.856(95%CI:0.801-0.924)and 0.849(95%CI:0.795-0.918),respectively,with sensitivity of 90.28%and 88.46%,specificity of 87.42%and 85.93%,and good discrimination.Accuracy of using calibration curves to evaluate nomogram predicting patient'PFS and OS rate showed that the predicted values of the training set and test set fit well with the actual observation values(χ^(2)=1.21,P=0.093;χ^(2)=1.31,P=0.085),with good consistency and accuracy.Effectiveness of the nomogram predicting patient'PFS and OS rate was evaluated using clinical decision curves.Results showed that the training set and test set had positive net benefit values when the high-risk threshold was 0-0.9,indicating a significant positive net benefit and good clinical practicality.⑤Risk stratification system of refractory DLBCL patients divided patients into 3 risk groups:low risk group(n=12,with a total score<65),medium risk group(n=16,with a total score of 65 to 105),and high risk group(n=12,with a total score≥105).Proportion of low-,medium-and high-risk refractory DLBCL patients were 30%(12/40),40%(16/40)and 30%(12/40).OS rate analysis showed that the risk stratification system can effectively distinguish the survival status of patients(Z=6.15,P=0.010).Conclusions MyD88 mutation is related to the clinical characteristics of refractory DLBCL patients and the efficacy of ibrutinib.Application of ibrutinib combined with other drugs could improve the prognosis of patients with MyD88 mutation.Nomogram predicting patient'PFS and OS rate could predict the prognosis of refractory DLBCL patients with high differentiation,accuracy and effectiveness.