Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities were found in 84% of the patients, among whom IKZF1 deletion was most frequently detected (60%). IKZF1 deletion frequently co-occurred with other copy-number abnormalities (IKZF1plus, 46%) and was significantly associated with unfavorable overall survival (OS) (false discovery rate < 0.1) and increased cumulative incidence of relapse (p = 0.01). In a multivariate analysis, dasatinib therapy, lack of achievement of 3-month complete molecular response, and the presence of IKZF1plus status were significantly associated with poor OS. The differential impact of IKZF1plus was largely restricted to patients given Hyper-CVAD plus ponatinib; dasatinib-based regimens had unfavorable outcomes regardless of the molecular abnormalities. Overall design: Samples were either bone marrow samples obtained from previously untreated patients.

研究已在费城染色体（Philadelphia chromosome, Ph）阳性急性淋巴细胞白血病（acute lymphoblastic leukemia, ALL）中发现复发性遗传异常。其中，IKZF1缺失（IKZF1 deletion）与接受伊马替尼（imatinib）或达沙替尼（dasatinib）方案治疗的患者不良预后相关。然而，接受普纳替尼（ponatinib）治疗的患者其临床结局的分子决定因素仍未明确。本研究系统分析了在临床试验中统一接受达沙替尼方案或普纳替尼方案治疗的费城染色体阳性急性淋巴细胞白血病成人患者的遗传改变，并通过采集自接受Hyper-CVAD联合达沙替尼或普纳替尼治疗的费城染色体阳性急性淋巴细胞白血病成人患者的预处理标本，探究了治疗结局的分子决定因素。研究对标本实施了DNA测序与单核苷酸多态性微阵列（SNP microarray）检测，结果显示84%的患者存在复发性遗传异常，其中IKZF1缺失检出率最高（60%）。IKZF1缺失常与其他拷贝数异常共存（即IKZF1plus表型，占比46%），且与不良总生存期（overall survival, OS）（错误发现率<0.1）及更高的累积复发率（p=0.01）显著相关。多变量分析（multivariate analysis）显示，达沙替尼治疗、未达到3个月完全分子学缓解（complete molecular response）以及存在IKZF1plus表型，均与不良总生存期显著相关。IKZF1plus表型的差异化影响主要局限于接受Hyper-CVAD联合普纳替尼治疗的患者；而接受达沙替尼方案治疗的患者，无论携带何种分子异常，其预后均不佳。研究整体设计：标本均来源于初治患者的骨髓样本。