Cooper Brenda W, Veal Gareth J, Radivoyevitch Tomas, Tilby Michael J, Meyerson Howard J, Lazarus Hillard M, Koc Omer N, Creger Richard J, Pearson Graham, Nowell Geoff M, Gosky David, Ingalls Stephen T, Hoppel Charles L, Gerson Stanton L
Department of Medicine, University Hospitals of Cleveland, Ireland Cancer Center, Case Western Reserve University, Cleveland, Ohio 44109, USA.
Clin Cancer Res. 2004 Oct 15;10(20):6830-9. doi: 10.1158/1078-0432.CCR-04-0097.
A novel regimen designed to maximize antileukemia activity of carboplatin through inhibiting repair of platinum-DNA adducts was conducted in poor prognosis, acute leukemia patients.
Patients received fludarabine (10 to 15 mg/m(2) x 5 days), carboplatin (area under the curve 10 to 12 by continuous infusion over 5 days), followed by escalated doses of topotecan infused over 72 hours (fludarabine, carboplatin, topotecan regimen). Twenty-eight patients had acute myelogenous leukemia (7 untreated secondary acute myelogenous leukemia, 11 in first relapse, and 10 in second relapse or refractory), 1 patient had refractory/relapsed acute lymphoblastic leukemia, and 2 patients had untreated chronic myelogenous leukemia blast crisis. Six patients had failed an autologous stem cell transplant. Patients ranged from 19 to 76 (median 54) years. Measurement of platinum-DNA adducts were done in serial bone marrow specimens.
Fifteen of 31 patients achieved bone marrow aplasia. Clinical responses included 2 complete response, 4 complete response with persistent thrombocytopenia, and 2 partial response. Prolonged myelosuppression was observed with median time to blood neutrophils >/=200/microl of 28 (0 to 43) days and time to platelets >/=20,000/microl (untransfused) of 40 (24 to 120) days. Grade 3 or greater infections occurred in all of the patients, and there were 2 infection-related deaths. The nonhematologic toxicity profile was acceptable. Five patients subsequently received allografts without early transplant-related mortality. Maximum tolerated dose of fludarabine, carboplatin, topotecan regimen was fludarabine 15 mg/m(2) x 5, carboplatin area under the curve 12, and topotecan 2.55 mg/m(2) over 72 hours. An increase in bone marrow, platinum-DNA adduct formation between the end of carboplatin infusion and 48 hours after the infusion correlated with bone marrow response.
Fludarabine, carboplatin, topotecan regimen is a promising treatment based on potential pharmacodynamic interactions, which merits additional study in poor prognosis, acute leukemia patients.
在预后不良的急性白血病患者中开展一种新方案，旨在通过抑制铂 - DNA加合物的修复来最大化卡铂的抗白血病活性。
患者接受氟达拉滨（10至15mg/m²×5天）、卡铂（曲线下面积10至12，持续输注5天），随后是分阶段递增剂量的拓扑替康在72小时内输注（氟达拉滨、卡铂、拓扑替康方案）。28例患者患有急性髓系白血病（7例未经治疗的继发性急性髓系白血病、11例首次复发、10例第二次复发或难治性），1例患者患有难治性/复发性急性淋巴细胞白血病，2例患者患有未经治疗的慢性髓系白血病急变期。6例患者自体干细胞移植失败。患者年龄在19至76岁（中位年龄54岁）之间。在系列骨髓标本中检测铂 - DNA加合物。
31例患者中有15例出现骨髓抑制。临床反应包括2例完全缓解、4例伴有持续性血小板减少的完全缓解和2例部分缓解。观察到长期骨髓抑制，中性粒细胞计数≥200/μl的中位时间为28（0至43）天，血小板计数≥20,000/μl（未输血）的时间为40（24至120）天。所有患者均发生3级或更高级别的感染，有2例与感染相关的死亡。非血液学毒性情况可接受。5例患者随后接受了同种异体移植，无早期移植相关死亡率。氟达拉滨、卡铂、拓扑替康方案的最大耐受剂量为氟达拉滨15mg/m²×5天、卡铂曲线下面积12以及拓扑替康2.55mg/m²在72小时内输注。卡铂输注结束至输注后48小时之间骨髓中铂 - DNA加合物形成的增加与骨髓反应相关。
基于潜在的药效学相互作用，氟达拉滨、卡铂、拓扑替康方案是一种有前景的治疗方法，值得在预后不良的急性白血病患者中进一步研究。
