Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.
Evidence for Clinical Differentiation and Differentiation Syndrome in Patients With Acute Myeloid Leukemia and IDH1 Mutations Treated With the Targeted Mutant IDH1 Inhibitor, AG-120.
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DOI：
10.1016/j.clml.2016.04.006
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
DiNardo CD
中科院分区：
文献类型：
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作者：
Birendra KC;DiNardo CD
我们描述了 3 名复发/难治性急性髓性白血病患者，他们在使用 AG-120（一种突变型异柠檬酸脱氢酶 1 的新型口服抑制剂）单药治疗期间出现了临床明显的分化，同时出现了临床反应。症状包括明显的白细胞增多和中性粒细胞旺盛恢复以及其他临床明显的体质表现。认识到此类抑制剂引起分化综合征的可能性，并及时识别和干预，对于促进临床解决至关重要。癌症相关的异柠檬酸脱氢酶 (IDH) 突变通过产生致癌代谢物 R-2-羟基戊二酸来阻止正常细胞分化。据传闻，在接受靶向突变 IDH 抑制剂治疗的急性髓系白血病 (AML) 患者中，中性粒细胞在临床分化综合征 (DS) 情况下恢复。我们描述了 3 名在接受突变 IDH1 抑制剂 AG-120 单一疗法治疗复发/难治性 AML 时出现临床明显 DS 的患者。 AG-120 诱导的分化在治疗的前 60 天内开始，特别是在与临床反应相同的时间范围内，通过成功的骨髓成熟强化了靶向突变 IDH 抑制剂治疗的据称机制。 DS 的症状是非特异性的，除了明显的中性粒细胞为主的白细胞增多外，还包括培养阴性的发热、水肿、低血压、不适、胸腔和/或心包积液。 DS 可能在使用靶向突变 IDH1 抑制剂治疗期间发生。患者可能会出现非特异性临床表现，通常与中性粒细胞恢复旺盛相关的白细胞增多有关。及时识别并开始治疗干预措施，包括羟基脲、皮质类固醇和/或考虑暂时停止治疗，对于促进迅速解决很重要。
We describe 3 patients with relapsed/refractory acute myeloid leukemia who developed clinically-apparent differentiation concurrent with clinical response during monotherapy with AG-120, a novel, oral inhibitor of mutant isocitrate dehydrogenase 1. Symptoms included marked leukocytosis and exuberant neutrophil recovery among other clinically-apparent constitutional manifestations. Awareness of the potential for differentiation syndrome with such inhibitors, and prompt identification and intervention, are essential to facilitate clinical resolution. Cancer-associated isocitrate dehydrogenase (IDH) mutations block normal cellular differentiation via production of the oncometabolite, R-2-hydroxyglutarate. In patients with acute myeloid leukemia (AML) receiving targeted mutant IDH inhibitor therapy, neutrophil recovery within the setting of clinical differentiation syndrome (DS) has been anecdotally described. We describe 3 patients who developed clinically apparent DS while on monotherapy with the mutant IDH1 inhibitor, AG-120, for relapsed/refractory AML. AG-120-induced differentiation commenced within the first 60 days of treatment, notably in the same timeframe as clinical response, strengthening the purported mechanism of targeted mutant IDH-inhibitor therapy via successful myeloid maturation. Symptoms of DS were non-specific and included culture-negative fever, edema, hypotension, malaise, and pleural and/or pericardial effusions, in addition to marked neutrophil-predominant leukocytosis. DS can occur during treatment with targeted mutant IDH1 inhibitor therapy. Patients may present with non-specific clinical manifestations often in the setting of leukocytosis related to exuberant neutrophil recovery. Prompt identification and initiation of treatment interventions, including hydroxyurea, corticosteroids and/or consideration of temporary treatment discontinuation, are important to facilitate prompt resolution.