Talpaz M, O'Brien S, Rose E, Gupta S, Shan J, Cortes J, Giles F J, Faderl S, Kantarjian H M
Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, TX, USA.
Blood. 2001 Sep 15;98(6):1708-13. doi: 10.1182/blood.v98.6.1708.
Interferon alpha (IFN-alpha) therapy improves prognosis in Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Polyethylene glycol (PEG) attached to IFN-alpha prolongs its half-life and may offer better therapy. The aims of this phase 1 study were to define the maximal tolerated dose (MTD), dose-limiting toxicities (DLTs), and response with PEG IFN-alpha-2b. Twenty-seven adults with Ph(+) CML in chronic or accelerated phases, in whom IFN-alpha treatment had failed, were studied. Patients had hematologic (9 patients) or cytogenetic resistance (12 patients) or intolerance to IFN-alpha (6 patients). PEG IFN-alpha-2b was given as a weekly subcutaneous injection starting at 0.75 microg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5, and 9.0 microg/kg. The MTD was defined at 7.5 to 9 microg/kg; DLT included severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression. Longer administration of PEG IFN-alpha-2b resulted in chronic side effects not observed earlier, which defined the MTD and DLT. The proposed phase 2 dose of PEG IFN-alpha-2b was 6 microg/kg weekly. Among 19 patients with active disease, 7 (37%) achieved complete hematologic response (CHR); 2 (11%) had a cytogenetic response (complete). Among 8 patients treated in CHR, 7 (87%) improved cytogenetic response to complete (4 patients) or partial (3 patients). All 6 patients intolerant to IFN-alpha tolerated PEG IFN-alpha-2b; 4 improved their cytogenetic response. The results show that PEG IFN-alpha-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-alpha.
α干扰素（IFN-α）治疗可改善费城染色体（Ph）阳性慢性粒细胞白血病（CML）的预后。与IFN-α结合的聚乙二醇（PEG）可延长其半衰期，并可能提供更好的治疗效果。这项1期研究的目的是确定聚乙二醇化干扰素α-2b的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和疗效。研究了27例处于慢性期或加速期的Ph（+）CML成年患者，这些患者的IFN-α治疗均失败。患者存在血液学耐药（9例）或细胞遗传学耐药（12例）或对IFN-α不耐受（6例）。聚乙二醇化干扰素α-2b每周皮下注射一次，起始剂量为0.75μg/kg，每周递增至1.5、3、4.5、6、7.5和9.0μg/kg。MTD确定为7.5至9μg/kg；DLT包括严重疲劳、神经毒性、肝功能异常和骨髓抑制。聚乙二醇化干扰素α-2b的长期给药导致了早期未观察到的慢性副作用，这确定了MTD和DLT。建议的聚乙二醇化干扰素α-2b 2期剂量为每周6μg/kg。在19例活动性疾病患者中，7例（37%）实现了完全血液学缓解（CHR）；2例（11%）有细胞遗传学缓解（完全缓解）。在8例接受CHR治疗的患者中，7例（87%）细胞遗传学缓解改善至完全缓解（4例）或部分缓解（3例）。所有6例对IFN-α不耐受的患者均耐受聚乙二醇化干扰素α-2b；4例改善了细胞遗传学缓解。结果表明，聚乙二醇化干扰素α-2b给药更简便（每周一次），耐受性更好，可能比IFN-α更有效。
