Soignet S L, Benedetti F, Fleischauer A, Parker B A, Truglia J A, Ra Crisp M, Warrell R P
Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Cornell University Medical College, New York, NY 10021, USA.
Leukemia. 1998 Oct;12(10):1518-21. doi: 10.1038/sj.leu.2401150.
The use of all-trans retinoic acid (RA) for remission induction markedly increases survival of patients with acute promyelocytic leukemia (APL) compared to patients treated solely with cytotoxic chemotherapy. However, clinical resistance to this agent develops rapidly, which has been associated with a progressive decline in plasma drug concentrations. Previous studies suggested that 9-cis RA, a retinoid receptor 'pan agonist' did not induce its own catabolism to the same extent as all-trans RA. Therefore, we conducted a dose-ranging study of this compound in patients with both relapsed and newly diagnosed APL. We treated 18 patients with morphologically diagnosed APL (13 relapsed, five newly diagnosed). The daily dose of 9-cis RA ranged from 30 to 230 mg/m2/day given as a single oral dose. Four of 12 (33%) relapsed patients (three of whom were previously treated with all-trans RA) and four of five (80%) newly diagnosed patients achieved complete remission. The sole failure in the newly diagnosed group died early from an intracranial hemorrhage. One other patient with t(9;12) translocation had substantial hematologic improvement. The drug was generally well tolerated; headache and dry skin were the most common adverse reactions. Three patients were treated with corticosteroids for signs of incipient 'RA syndrome.' These preliminary data suggest that 9-cis RA is an effective agent for remission induction and deserves further investigation in patients with retinoid-sensitive APL.
与仅接受细胞毒性化疗的患者相比，使用全反式维甲酸（RA）进行缓解诱导可显著提高急性早幼粒细胞白血病（APL）患者的生存率。然而，对该药物的临床耐药性迅速出现，这与血浆药物浓度的逐渐下降有关。先前的研究表明，一种类视黄醇受体“泛激动剂”9-顺式RA不会像全反式RA那样在同等程度上诱导自身的分解代谢。因此，我们对复发和新诊断的APL患者进行了该化合物的剂量范围研究。我们治疗了18例经形态学诊断为APL的患者（13例复发，5例新诊断）。9-顺式RA的日剂量范围为30至230mg/m²/天，采用单次口服给药。12例复发患者中有4例（33%）（其中3例曾接受全反式RA治疗）以及5例新诊断患者中有4例（80%）实现了完全缓解。新诊断组中唯一未缓解的患者因颅内出血过早死亡。另一名患有t(9;12)易位的患者血液学有显著改善。该药物总体耐受性良好；头痛和皮肤干燥是最常见的不良反应。3例患者因出现早期“RA综合征”迹象而接受了皮质类固醇治疗。这些初步数据表明，9-顺式RA是一种有效的缓解诱导药物，值得在对类视黄醇敏感的APL患者中进一步研究。
