Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
Curr Treat Options Oncol. 2020 Jun 29;21(8):66. doi: 10.1007/s11864-020-00765-5.
Relapse is still a common scenario in acute myeloid leukemia (AML) treatment and occurs in 40-50% of younger and the great majority of elderly patients. The prognosis in relapsed AML patients is generally poor but depends largely on the timing of relapse (early versus late) and the possibility of allogeneic hematopoietic stem cell transplantation (HSCT). At the time of relapse, we again perform a mutational screening and cytogenetic analysis in all AML patients as clonal evolution of disease is frequent. Clinical trials should be first priority in all relapsed patients. In fit patients without prior transplant, we aim to perform HSCT after salvage therapy. In AML patients relapsing after HSCT and good performance status, intensive therapy can be considered with subsequent cellular therapy such as donor lymphocyte infusion (DLI) or a second HSCT. However, less than 20% of these patients are alive after 5 years. For those patients that are unfit, the therapeutic aim is to prolong life with acceptable quality of life. Here, hypomethylating agents (HMA), low-dose AraC (LDAC), and solely cytoreductive therapy with hydroxurea are options depending on first-line therapy. For those patients that have not been treated with venetoclax in first line, the combination therapy of venetoclax with demethylating agents achieves encouraging response rates. Venetoclax is currently also studied in combination with intensive salvage therapy. Importantly, for patients with isocitrate dehydrogenase (IDH) 1/2-mutated AML, ivosidenib, an IDH1 inhibitor, and enasidenib, an IDH2 inhibitor, present well-tolerated options in the setting of refractory or relapsed (r/r) disease even in elderly and heavily pre-treated patients with response rates of 30-40%. Both substances have been approved by the U.S. Food and Drug Administration (FDA) for r/r AML patients with IDH1/2 mutations (but not yet by the European Medicines Agency (EMA)). For patients with FMS-like tyrosine kinase 3 (FLT3) mutations, treatment with the selective FLT3 inhibitor gilteritinib is well tolerated and leads to improved outcome compared with standard salvage therapy. The approval has been granted by the FDA and the EMA. Generally, we would recommend targeted therapy for IDH1/2- and FLT3-mutated AML if available. In order to improve outcome in relapsed AML, it will be important to intelligently combine novel substances with each other as well as chemotherapy in prospective clinical trials. The development of therapies with bispecific antibodies or chimeric antigen receptor T cells (CAR-T) are still in early development.
复发仍然是急性髓系白血病（AML）治疗中的常见情况，在年轻患者中约占 40-50%，在老年患者中则更为常见。复发 AML 患者的预后一般较差，但主要取决于复发的时间（早期与晚期）以及是否有可能进行异基因造血干细胞移植（HSCT）。在复发时，我们会再次对所有 AML 患者进行基因突变筛查和细胞遗传学分析，因为疾病的克隆演变很常见。临床试验应是所有复发患者的首要治疗选择。对于没有接受过移植的合适患者，我们的目标是在挽救治疗后进行 HSCT。对于在 HSCT 后且身体状况良好的 AML 患者复发，可以考虑进行强化治疗，随后进行细胞治疗，如供者淋巴细胞输注（DLI）或二次 HSCT。然而，只有不到 20%的这些患者在 5 年后仍然存活。对于那些不适合治疗的患者，治疗目的是延长生命，同时保持可接受的生活质量。在这里，低甲基化剂（HMA）、低剂量阿糖胞苷（LDAC）和单纯的羟基脲细胞减灭性治疗是根据一线治疗方案的选择。对于那些没有在一线治疗中接受 venetoclax 治疗的患者，venetoclax 联合去甲基化剂的联合治疗可达到令人鼓舞的缓解率。Venetoclax 目前也在与强化挽救性治疗联合进行研究。重要的是，对于异柠檬酸脱氢酶（IDH）1/2 突变的 AML 患者，IDH1 抑制剂ivosidenib 和 IDH2 抑制剂enasidenib 是在难治性或复发性（r/r）疾病中耐受性良好的选择，即使是在老年和接受过多线治疗的患者中，缓解率也达到 30-40%。这两种药物都已被美国食品和药物管理局（FDA）批准用于 IDH1/2 突变的 r/r AML 患者（但尚未被欧洲药品管理局（EMA）批准）。对于有 FMS 样酪氨酸激酶 3（FLT3）突变的患者，选择性 FLT3 抑制剂 gilteritinib 的治疗耐受性良好，与标准挽救性治疗相比可改善预后。该批准已获得 FDA 和 EMA 的批准。一般来说，如果有条件，我们会建议对 IDH1/2-和 FLT3-突变的 AML 患者进行靶向治疗。为了提高复发 AML 的治疗效果，在前瞻性临床试验中明智地将新型药物与化疗相结合将非常重要。双特异性抗体或嵌合抗原受体 T 细胞（CAR-T）的治疗方法仍处于早期开发阶段。
