O'Brien Susan, Talpaz Moshe, Cortes Jorge, Shan Jianqin, Giles Francis J, Faderl Stefan, Thomas Deborah, Garcia-Manero Guillermo, Mallard Susie, Beth Mary, Koller Charles, Kornblau Steve, Andreeff Michael, Murgo Anthony, Keating Michael, Kantarjian Hagop M
Department of Leukemia and Bioimmunotherapy, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cancer. 2002 Apr 1;94(7):2024-32. doi: 10.1002/cncr.10436.
Homoharringtonine (HHT) has antileukemic activity in patients with Philadelphia chromosome (Ph) positive chronic myelogenous leukemia (CML). Combinations of HHT, interferon-alpha (IFN-alpha), and cytarabine (ara-C) have been studied in various CML phases. The objectives of this study were to evaluate the efficacy and toxicity profiles of a combination regimen of simultaneous HHT and IFN-alpha therapy in patients with chronic-phase CML who were not exposed previously to either agent.
Forty-seven patients were treated: 37 patients with early chronic-phase CML (2 patients with clonal evolution) and 10 patients with late chronic-phase CML. Their median age was 62 years (range, 23-73 years). HHT was given at a dose of 2.5 mg/m(2) by continuous intravenous infusion over 24 hours daily for 5 days every month, and IFN-alpha was given daily at a target dose of 5 x 10(6) units/m(2) subcutaneously. Response, survival, and treatment toxicity were analyzed.
Overall, the complete hematologic response (CHR) rate was 85%; the cytogenetic response rate was 66%, with major cytogenetic responses (Ph positive in < 35% of metaphases) in 49% of patients and complete cytogenetic responses in 21% of patients. The CHR rate, cytogenetic response rate, and major cytogenetic response rate were 84%, 69%, and 52%, respectively, in patients with early chronic-phase CML. Among the 10 patients with late chronic-phase CML, the CHR rate, cytogenetic response rate, and major cytogenetic response rate were 80%, 50%, and 40%, respectively. Response rates in patients age > 60 years were 84%, 62%, and 49% for CHR, cytogenetic response, and major cytogenetic response. Myelosuppression was frequent but manageable: Anemia with hemoglobin < 8.0 g/dL occurred in 36% of patients, requiring dose adjustments and erythropoietin therapy. Nonhematologic toxicities were mainly fatigue, aches, and gastrointestinal disturbances. Dose reductions with multiple courses were significant and were due to myelosuppression: After 6-24 courses, the median daily IFN-alpha dose was 1 MU/m(2), and the median number of days on HHT per month was 2 days. With a median follow-up of 26 months, the estimated 2-year survival rate was 90% (95% confidence interval, 79-100%).
The simultaneous combination of HHT and IFN-alpha is safe and effective, but the dose schedules that actually were delivered were significantly lower than the planned dose schedules. With the availability of signal-transduction inhibitor 571 (imatinib mesylate), studies of combination of HHT and IFN-alpha chemotherapy in patients with CML who have disease that fails to respond to imatinib mesylate and of combinations with imatinib mesylate need to be explored.
高三尖杉酯碱（HHT）对费城染色体（Ph）阳性的慢性粒细胞白血病（CML）患者具有抗白血病活性。HHT、α干扰素（IFN-α）和阿糖胞苷（ara-C）的联合应用已在CML的各个阶段进行了研究。本研究的目的是评估在既往未接触过这两种药物的慢性期CML患者中，同时使用HHT和IFN-α治疗的联合方案的疗效和毒性特征。
47例患者接受治疗：37例早期慢性期CML患者（2例有克隆演变）和10例晚期慢性期CML患者。他们的中位年龄为62岁（范围23 - 73岁）。HHT的给药剂量为2.5mg/m²，每月连续静脉输注24小时，每日1次，共5天；IFN-α的目标剂量为5×10⁶单位/m²，皮下注射，每日1次。分析疗效、生存率和治疗毒性。
总体而言，完全血液学缓解（CHR）率为85%；细胞遗传学缓解率为66%，49%的患者有主要细胞遗传学缓解（中期分裂相中Ph阳性率<35%），21%的患者有完全细胞遗传学缓解。早期慢性期CML患者的CHR率、细胞遗传学缓解率和主要细胞遗传学缓解率分别为84%、69%和52%。在10例晚期慢性期CML患者中，CHR率、细胞遗传学缓解率和主要细胞遗传学缓解率分别为80%、50%和40%。年龄>60岁患者的CHR、细胞遗传学缓解和主要细胞遗传学缓解率分别为84%、62%和49%。骨髓抑制很常见但可控制：36%的患者出现血红蛋白<8.0g/dL的贫血，需要调整剂量并进行促红细胞生成素治疗。非血液学毒性主要为疲劳、疼痛和胃肠道不适。多疗程治疗后剂量减少显著，原因是骨髓抑制：6 - 24个疗程后，IFN-α的中位每日剂量为1MU/m²，每月HHT的中位使用天数为2天。中位随访26个月，估计2年生存率为90%（95%置信区间，79 - 100%）。
HHT和IFN-α同时联合应用是安全有效的，但实际给药剂量明显低于计划剂量。随着信号转导抑制剂571（甲磺酸伊马替尼）的应用，需要探索在对甲磺酸伊马替尼治疗无效的CML患者中HHT与IFN-α化疗联合应用以及与甲磺酸伊马替尼联合应用的研究。
