Baleydier Frédéric, Domenech Carine, Thomas Xavier
Institut d'hématologie et oncologie pédiatrique, Hospices civils de Lyon, France.
Bull Cancer. 2011 Aug;98(8):901-13. doi: 10.1684/bdc.2011.1412.
Cytogenetic, molecular and phenotyping features of malignant hematologic diseases succeeded in improving their management by a more accurate stratification of patients according to several groups of risk and by providing a rational for targeted therapy. Three major types of treatment (excluding cellular therapy) are currently available in onco-hematology: conventional chemotherapy, small molecules for targeted therapy and monoclonal antibodies. Conventional chemotherapy with optimization of doses and multidrug-based regimens allowed to substantially improve survival of patients and keeps a place of choice in treatment of these diseases. Targeted treatments came from the cytogenetic and molecular characterization of hemopathies. Thus, the kinase Bcr-Abl, as a result of the translocation t(9;22)(q34;q11), has been successfully targeted by tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia. Molecular abnormalities like internal-tandem duplication/point activating mutations in FLT3 in some acute myeloblastic leukemia or epigenetic dysregulations in some blood malignancies can also be targeted by small molecules. Hematopoietic malignant cells are phenotypically characterized by expression of cluster of differentiation (CD) on their surface. These CD are detected by flow cytometry using specific antibodies. Monoclonal antibodies targeting different CD have been developed for treatment. Rituximab, an anti-CD20 antibody, was the first monoclonal antibody successfully developed for treatment of malignant hematologic diseases. Since rituximab, many other monoclonal antibodies are being developed. Trends in malignant hematologic diseases presented here will include treatments, which have at least entered phase I/II clinical trials in adult or childhood leukemia. They include some novel drugs of conventional chemotherapy like second-generation nucleoside analogues. We will give an overview of the small molecules targeting the different cellular pathways and we will highlight those appearing as the most promising like novel TKIs. The large field of monoclonal antibodies will be also approached focusing on antibodies developed in leukemias.
恶性血液病的细胞遗传学、分子学和表型特征通过根据几组风险对患者进行更准确的分层，并为靶向治疗提供理论依据，成功改善了其治疗管理。目前肿瘤血液学中有三种主要的治疗类型（不包括细胞治疗）：传统化疗、靶向治疗小分子药物和单克隆抗体。优化剂量和基于多种药物的方案的传统化疗能够显著提高患者的生存率，并在这些疾病的治疗中保持首选地位。靶向治疗源于血液病的细胞遗传学和分子特征。因此，由于易位t(9;22)(q34;q11)产生的激酶Bcr-Abl，已在慢性髓性白血病和Ph+急性淋巴细胞白血病中被酪氨酸激酶抑制剂（TKI）成功靶向。一些急性髓性白血病中FLT3的内部串联重复/点激活突变等分子异常，或一些血液恶性肿瘤中的表观遗传失调，也可以被小分子药物靶向。造血恶性细胞在表型上的特征是其表面表达分化簇（CD）。这些CD通过使用特异性抗体的流式细胞术进行检测。已开发出针对不同CD的单克隆抗体用于治疗。利妥昔单抗，一种抗CD20抗体，是首个成功开发用于治疗恶性血液病的单克隆抗体。自利妥昔单抗以来，许多其他单克隆抗体也在研发中。这里呈现的恶性血液病治疗趋势将包括至少已进入成人或儿童白血病I/II期临床试验的治疗方法。它们包括一些传统化疗的新药，如第二代核苷类似物。我们将概述针对不同细胞途径的小分子药物，并重点介绍那些最有前景的药物，如新型TKI。单克隆抗体的广阔领域也将围绕白血病中开发的抗体进行探讨。
