Quintás-Cardama Alfonso, Kantarjian Hagop, Garcia-Manero Guillermo, O'Brien Susan, Faderl Stefan, Estrov Zeev, Giles Francis, Murgo Anthony, Ladie Nakia, Verstovsek Srdan, Cortes Jorge
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Cancer. 2007 Jan 15;109(2):248-55. doi: 10.1002/cncr.22398.
Homoharringtonine (HHT) is a cephalotaxus alkaloid that inhibits the synthesis of proteins leading to apoptosis. Intravenous HHT has demonstrated activity in patients with chronic myeloid leukemia (CML) after failure with interferon.
A Phase I study was completed of subcutaneous (s.c.) HHT in patients with CML in accelerated or blast phases and demonstrated efficacy and good tolerance at the same doses used by intravenous (i.v.) administration. The maximal tolerated dose (MTD) was 1.25 mg/m(2) s.c. twice daily. The cohort was then expanded to treated at the MTD to include patients in late chronic phase CML after imatinib failure. Therapy consisted of an i.v. loading dose of HHT 2.5 mg/m(2) over 24 hours, followed by 1.25 mg/m(2) s.c. twice daily for 14 days every 28 days until remission, then for 7 days every 28 days. Six patients (median age, 53 years) who had failed imatinib were treated and 5 were evaluable. Patients received a median of 4.5 courses of s.c. HHT.
Complete hematologic remission was obtained in all 5 evaluable patients and 3 had cytogenetic (CG) responses: 1 complete and 2 minor. The 2 patients with BCR-ABL kinase domain mutations at the start of therapy with HHT had a CG response and in both instances the mutations became undetectable. All patients developed myelosuppression and 3 had their HHT dose reduced due to prolonged neutropenia. Nonhematologic toxicity was mild and manageable.
Subcutaneous HHT is well tolerated and may have clinical activity in patients with CML after imatinib failure.
高三尖杉酯碱（HHT）是一种从三尖杉属植物中提取的生物碱，可抑制蛋白质合成并诱导细胞凋亡。静脉注射HHT已被证明对干扰素治疗失败的慢性髓性白血病（CML）患者具有活性。
完成了一项针对加速期或急变期CML患者皮下注射（s.c.）HHT的I期研究，结果表明，皮下注射与静脉注射（i.v.）使用相同剂量时疗效相同且耐受性良好。最大耐受剂量（MTD）为1.25mg/m²，皮下注射，每日两次。随后将队列扩大至以MTD进行治疗，纳入伊马替尼治疗失败的晚期慢性期CML患者。治疗方案为静脉注射负荷剂量的HHT 2.5mg/m²，持续24小时，随后皮下注射1.25mg/m²，每日两次，共14天，每28天重复一次，直至缓解，然后每28天注射7天。6例（中位年龄53岁）伊马替尼治疗失败的患者接受了治疗，5例可评估。患者接受皮下注射HHT的疗程中位数为4.5个。
所有5例可评估患者均获得完全血液学缓解，3例有细胞遗传学（CG）反应：1例完全缓解，2例部分缓解。2例在HHT治疗开始时具有BCR-ABL激酶域突变的患者出现了CG反应，且两种情况下突变均变得不可检测。所有患者均出现骨髓抑制，3例因长期中性粒细胞减少而降低了HHT剂量。非血液学毒性轻微且可控。
皮下注射HHT耐受性良好，对伊马替尼治疗失败的CML患者可能具有临床活性。
