Institute of Regenerative Medicine and Biotherapy, INSERM, U1183, University of Montpellier, Montpellier, France.
Department of Clinical Hematology, University Hospital Montpellier, Montpellier, France.
Front Immunol. 2022 Oct 17;13:983771. doi: 10.3389/fimmu.2022.983771. eCollection 2022.
During many years, chemo-immunotherapy fludarabine-cyclophosphamide-rituximab (FCR) was the gold standard for first line treatment of medically fit patients with symptomatic B-chronic lymphocytic leukemia (CLL). Over the last decade, targeted biotherapies have revolutionized the treatment of B-CLL patients and almost entirely supplanted FCR. However, no biomarker still exists to predict the complete remission (CR) with undetectable minimal residual disease (uMRD) in bone marrow (BM), which remains the best predictive factor for survival. MicroRNAs represent a class of molecular biomarkers which expression is altered in B-CLL. Our study aimed at identifying before treatment blood miRNAs that predict treatment outcome in previously untreated B-CLL patients (NCT01370772, https://clinicaltrials.gov/ct2/show/NCT01370772). Using hierarchical clustering of miRNA expression profiles discriminating 8 patients who achieved CR with BM uMRD from 8 patients who did not achieve CR and displayed detectable BM MRD, we identified 25 miRNAs differentially expressed before treatment. The expression of 11 miRNAs was further validated on a larger cohort (n=123). Based on the dosage of 5 miRNAs at diagnosis, a decision tree was constructed to predict treatment outcome. We identified 6 groups of patients with a distinct probability of being CR with BM uMRD to FCR treatment, ranging from 72% (miR-125b, miR-15b and miR-181c high) to 4% (miR-125b and miR-193b low). None of the patients displaying high expression levels of miR-125b, miR-15b and miR-181c relapsed during study follow-up. In contrast, patients with low miR-15b and high miR-412, or with low miR-125b and miR-193b, demonstrated significant low PFS. RNA sequencing of blood at diagnosis identified that patients relapsing after treatment are characterized by significant enrichment of gene signatures related to cell cycle, target genes, metabolism and translation regulation. Conversely, patients achieving CR with BM uMRD displayed significant enrichment in genes related to communication between CLL cells and the microenvironment, immune system activation and upregulation of polycomb PRC2 complex target genes. Our results suggest that blood miRNAs are potent predictive biomarkers for FCR treatment efficacy and might be implicated in the FCR efficacy in B-CLL patients, providing new insight into unmet need for the treatment of B-CLL patients and identifying pathways predictive of patients' remission.
ClinicalTrials.gov, identifier NCT01370772.
在许多年里，氟达拉滨-环磷酰胺-利妥昔单抗（FCR）化疗免疫疗法一直是有症状的 B 慢性淋巴细胞白血病（CLL）患者的一线治疗金标准。在过去的十年中，靶向生物疗法彻底改变了 B-CLL 患者的治疗方法，几乎完全取代了 FCR。然而，目前仍没有生物标志物可以预测骨髓（BM）中不可检测的微小残留疾病（uMRD）的完全缓解（CR），这仍然是生存的最佳预测因素。miRNA 代表一类分子生物标志物，其表达在 B-CLL 中发生改变。我们的研究旨在鉴定在未经治疗的 B-CLL 患者中，治疗前血液 miRNA 是否可以预测治疗结果（NCT01370772，https://clinicaltrials.gov/ct2/show/NCT01370772）。通过 miRNA 表达谱的层次聚类，将 8 例达到 BM uMRD 完全缓解的患者与 8 例未达到 CR 且显示 BM MRD 可检测的患者区分开来，我们鉴定出 25 个在治疗前表达差异的 miRNA。在更大的队列（n=123）中进一步验证了 11 个 miRNA 的表达。基于 5 个 miRNA 的诊断剂量，构建了一个决策树来预测治疗结果。我们确定了 6 组患者，他们在接受 FCR 治疗后达到 BM uMRD 完全缓解的可能性具有明显差异，范围从 72%（miR-125b、miR-15b 和 miR-181c 高）到 4%（miR-125b 和 miR-193b 低）。在研究随访期间，没有任何高表达 miR-125b、miR-15b 和 miR-181c 的患者复发。相比之下，miR-15b 低而 miR-412 高，或 miR-125b 低而 miR-193b 高的患者，PFS 明显较低。在诊断时对血液进行 RNA 测序，发现治疗后复发的患者表现出与细胞周期、靶基因、代谢和翻译调节相关的基因特征显著富集。相反，达到 BM uMRD 完全缓解的患者在与 CLL 细胞和微环境之间的通信、免疫系统激活以及多梳 PRC2 复合物靶基因上调相关的基因方面表现出显著富集。我们的结果表明，血液 miRNA 是 FCR 治疗效果的有效预测生物标志物，可能与 B-CLL 患者的 FCR 疗效有关，为 B-CLL 患者的治疗需求提供了新的见解，并确定了预测患者缓解的途径。
