Dept. of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavska 20, 625 00, Brno, Czech Republic.
Dept. of Molecular Medicine, Central European Institute of Technology (CEITEC), Masaryk University, Kamenice 5, 625 00, Brno, Czech Republic.
Leuk Res. 2019 Jun;81:75-81. doi: 10.1016/j.leukres.2019.04.015. Epub 2019 Apr 25.
The impact of genetic aberrations on rituximab-based therapeutic regimens has been intensely studied in chronic lymphocytic leukemia (CLL). According to the current consensus chemoimmunotherapy consisting of rituximab and DNA-damaging drugs is not suitable for patients with TP53 defects. In our study, we focused on CLL patients with an intact TP53 gene and investigated four recurrently mutated genes in CLL, genomic aberrations by FISH, and IGHV status with the aim of analyzing their impact on progression-free survival (PFS) after front-line therapy with FCR (fludarabine, cyclophosphamide, rituximab) or BR (bendamustine, rituximab) regimens. Using next-generation sequencing, we analyzed 120 patients treated with FCR and 57 patients treated with BR at a university hospital. We used a 10% cut-off for variant allele frequency and recorded the following mutation frequencies in the pre-therapy samples: ATM 23%, SF3B1 20%, NOTCH1 19% and BIRC3 11%. The data on cytogenetic aberrations (11q22, 13q14, trisomy 12) and IGHV mutation status were also considered in PFS analyses. In univariate analyses, we observed a negative impact of BIRC3 mutations and 11q22 deletion in both regimens, while the unmutated IGHV status was associated with a significantly shorter PFS only in the FCR-treated cohort. In a multivariate analysis, only deletion 11q22 in both regimens, and the unmutated IGHV in the FCR cohort maintained an independent association with the reduced PFS. Notably, sole 11q22 deletion, without an ATM mutation on the other allele, manifested the shortest PFS of all analyzed markers. Deletion 11q22 and IGHV status predict PFS in previously untreated CLL patients.
在慢性淋巴细胞白血病（CLL）中，已深入研究了遗传异常对基于利妥昔单抗的治疗方案的影响。根据目前的共识，含利妥昔单抗和 DNA 损伤药物的化疗免疫疗法不适合 TP53 缺陷的患者。在我们的研究中，我们专注于 TP53 基因完整的 CLL 患者，并研究了 CLL 中四个经常发生突变的基因、FISH 检测的基因组异常以及 IGHV 状态，旨在分析它们对一线 FCR（氟达拉滨、环磷酰胺、利妥昔单抗）或 BR（苯达莫司汀、利妥昔单抗）方案治疗后的无进展生存期（PFS）的影响。我们使用下一代测序技术分析了在一所大学医院接受 FCR 治疗的 120 例患者和接受 BR 治疗的 57 例患者。我们使用变异等位基因频率 10%的截止值，记录了治疗前样本中的以下突变频率：ATM 23%、SF3B1 20%、NOTCH1 19%和 BIRC3 11%。在 PFS 分析中还考虑了细胞遗传学异常（11q22、13q14、12 三体）和 IGHV 突变状态的数据。在单变量分析中，我们观察到在两种方案中 BIRC3 突变和 11q22 缺失均有负面影响，而未突变的 IGHV 状态仅在 FCR 治疗组中与较短的 PFS 显著相关。在多变量分析中，只有两种方案中的 11q22 缺失和 FCR 队列中的未突变 IGHV 与降低的 PFS 保持独立相关性。值得注意的是，所有分析标志物中，仅存在 11q22 缺失且另一条等位基因上无 ATM 突变，提示最短的 PFS。11q22 缺失和 IGHV 状态可预测未经治疗的 CLL 患者的 PFS。
