Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia
Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia
复制标题
DOI：
10.1182/blood-2010-02-272039
复制
发表时间：
2010-08-12
期刊：
影响因子：
20.3
通讯作者：
Ravandi, Farhad
中科院分区：
文献类型：
--
作者：
Balakrishnan, Kumudha;Verma, Dushyant;Ravandi, Farhad
呋咯地辛是一种新的嘌呤核苷磷酸化酶（PNP）抑制剂。对基于氟达拉滨的治疗原发性耐药或疾病进展的慢性淋巴细胞白血病（CLL）患者有资格口服呋咯地辛（200 mg/d）长达24周。接受治疗的8例患者的中位淋巴细胞计数为35.9 × 10（9）/L，中位血清β 2微球蛋白水平为6.45 mg/L。6例患者患有Rai III至IV期，既往接受过大量治疗（中位既往治疗= 5）。2例患者淋巴细胞计数一过性下降至正常，而5例患者疾病进展。不良事件为轻度。呋咯地辛的稳态水平范围为200至1300 nM，未达到所需的2 μ M水平。PNP抑制范围为57%至89%，稳态2 '-脱氧鸟苷（dGuo）浓度中位数为1.8 μ M。细胞内脱氧鸟苷三磷酸（dGTP）的增加是非常温和的，从6 μ M到10 μ M的中位数。与体内相比，CLL淋巴细胞与10或20 μ M dGuo和呋咯地辛（2 μ M）的体外孵育导致更高水平的dGTP（40-250 μ M）积累，这导致凋亡增加。呋咯地辛在CLL中具有生物活性;药效学参数表明，替代给药方案和/或更高剂量以实现更大的细胞内dGTP可能对该患者人群有益。
Forodesine is a new and potent purine nucleoside phosphorylase (PNP) inhibitor. Patients with chronic lymphocytic leukemia (CLL) with primary resistance to fludarabine-based therapy or with progressive disease were eligible for oral forodesine (200 mg/d) for up to 24 weeks. Eight patients with median lymphocyte count of 35.9 x 10(9)/L and median serum beta 2 microglobulin level of 6.45 mg/L were treated. Six had Rai stage III to IV and were previously heavily treated (median prior therapy = 5). Two had transient decrease in lymphocyte count to normal, whereas in 5, disease progressed. Adverse events were mild. Steady-state level of forodesine ranged from 200 to 1300nM and did not reach desired 2 mu M level. PNP inhibition ranged from 57% to 89% and steady-state 2'-deoxyguanosine (dGuo) concentration median was 1.8 mu M. Intracellular deoxyguanosine triphosphate (dGTP) increase was very modest, from median of 6 mu M to 10 mu M. Compared with in vivo, in vitro incubations of CLL lymphocytes with 10 or 20 mu M dGuo and forodesine (2 mu M) resulted in accumulation of higher levels of dGTP (40-250 mu M) which resulted in increase in apoptosis. Forodesine has biologic activity in CLL; pharmacodynamic parameters suggest that an alternate dosing schedule and/or higher doses to achieve greater intracellular dGTP may be beneficial in this patient population.