Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal.
Eradication of Measurable Residual Disease in AML: A Challenging Clinical Goal.
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DOI：
10.3390/cancers13133170
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发表时间：
2021-06-25
期刊：
影响因子：
5.2
通讯作者：
Borsani O
中科院分区：
文献类型：
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作者：
Bernasconi P;Borsani O
复发仍然是AML的一个主要问题，因为它发生在大约60-80%的患者中，即使是那些先前达到完全缓解（CR）的患者，根据骨髓（BM）白血病细胞的存在≤5%来定义。因此，由于CR无法预测复发风险，因此开发了更敏感的技术，旨在识别BM或外周血中的AML细胞，称为可测量残留疾病（MRD）的参数。其中，分析合适分子标记的RT-qPCR和分析异常表达抗原的多参数流式细胞术（multiparameter flow cytometry， MFC）已被确定为MRD检测的首选方法。如今，通过这些技术评估MRD的各种研究已经提供了令人信服的证据，表明在标准诱导/巩固化疗后和同种异体造血干细胞移植前的MRD阳性（MRD+）预示着非常差的临床结果。此外，其他研究表明，即使在病程的后期，MRD+的清除也可能改善疾病的临床预后，这进一步加强了MRD+的相关性。因此，完全根除MRD，有可能通过新颖的创新治疗实现，已经成为AML未满足的临床需求，并有望改善患者的预后。在非早幼粒细胞（非m3） AML中，通过多参数流式细胞术和分子技术检测可测量的残留疾病（MRD），在基于共识的指南指导下，发现非常低的白血病细胞数量远低于形态学评估的5%阈值，已成为临床结果最相关的预测指标。目前，MRD阳性在标准诱导和巩固化疗后，以及在同种异体造血干细胞移植（alloo - hsct）之前的一段时间，预示着一个明显较差的无复发生存期（RFS）和总生存期（OS）。此外，从MRD阳性到MRD阴性状态的转化提供了与早期MRD阴性相关的有利临床结果，这一点已经变得非常清楚。因此，彻底根除MRD，即清除少数白血病干细胞（由于其化疗-放疗耐药性，可能最终导致疾病复发）已成为AML尚未满足的临床需求。如今，由于新的创新治疗策略的发展，这一目标有可能实现，包括那些针对驱动突变、细胞凋亡、甲基化模式和白血病蛋白的治疗策略。本综述的目的是分析这些策略，并提出在造血干细胞移植前后能够诱导MRD阴性的任何潜在组合。
Relapse is still a major problem in AML because it occurs in about 60–80% of patients, even those who have previously achieved complete remission (CR), defined by the presence of ≤5% bone marrow (BM) leukemic cells. Thus, since CR is unable to predict the relapse risk, significantly more sensitive techniques aimed at identifying AML cells in BM or peripheral blood, a parameter termed measurable residual disease (MRD), have been developed. Among them, RT-qPCR, which analyses appropriate molecular markers, and multiparameter flow cytometry (MFC), which analyses aberrantly expressed antigens, have been identified as the methods of choice for MRD detection. Nowadays, various studies that assessed MRD by these techniques have provided compelling evidence that MRD positivity (MRD+) after standard induction/consolidation chemotherapy and before allo-HSCT is predictive of a very poor clinical outcome. In addition, other studies, which showed that MRD+ clearance even at late time points of the course of the disease may improve the disease clinical outcome, have further strengthened the relevance of MRD+. Thus, a complete MRD eradication, potentially attainable through novel innovative treatments, has emerged as an un-met clinical need in AML and is expected to improve our patients’ prognosis. In non-promyelocytic (non-M3) AML measurable residual disease (MRD) detected by multi-parameter flow cytometry and molecular technologies, which are guided by Consensus-based guidelines and discover very low leukemic cell numbers far below the 5% threshold of morphological assessment, has emerged as the most relevant predictor of clinical outcome. Currently, it is well-established that MRD positivity after standard induction and consolidation chemotherapy, as well as during the period preceding an allogeneic hematopoietic stem cell transplant (allo-HSCT), portends to a significantly inferior relapse-free survival (RFS) and overall survival (OS). In addition, it has become absolutely clear that conversion from an MRD-positive to an MRD-negative state provides a favorable clinical outcome similar to that associated with early MRD negativity. Thus, the complete eradication of MRD, i.e., the clearance of the few leukemic stem cells—which, due to their chemo-radiotherapy resistance, might eventually be responsible of disease recurrence—has become an un-met clinical need in AML. Nowadays, this goal might potentially be achieved thanks to the development of novel innovative treatment strategies, including those targeting driver mutations, apoptosis, methylation patterns and leukemic proteins. The aim of this review is to analyze these strategies and to suggest any potential combination able to induce MRD negativity in the pre- and post-HSCT period.