Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies
Clinical experience with intravenous and oral formulations of the novel histone deacetylase inhibitor suberoylanilide hydroxamic acid in patients with advanced hematologic malignancies
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DOI：
10.1200/jco.2005.01.9679
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发表时间：
2006-01-01
影响因子：
45.3
通讯作者：
Kelly, WK
中科院分区：
文献类型：
--
作者：
O'Connor, OA;Heaney, ML;Kelly, WK
目的记录组蛋白脱乙酰酶抑制剂辛二酰苯胺异羟肟酸（SAHA）在接受过预治疗的恶性血液病患者中的毒性和活性。患者和方法在两项连续的I期试验中评估了SAHA的两种制剂（静脉注射[IV]和口服）。在这两项试验中，在实体瘤和恶性血液病患者中平行和独立进行剂量递增。符合条件的患者需要有足够的肝肾功能，中性粒细胞绝对计数> 500/μ L，血小板计数> 25，000/mL。结果共纳入39例恶性血液病患者（14例接受静脉SAHA治疗，25例接受口服SAHA治疗），其中35例接受了治疗。疾病谱包括弥漫性大B细胞淋巴瘤（n = 12）、霍奇金病（HD; n = 12）、多发性骨髓瘤（n = 2）、T细胞淋巴瘤（n = 3）、套细胞淋巴瘤（n = 2）、小淋巴细胞淋巴瘤（n = 2）和髓性白血病（n = 2）患者。口服制剂的主要不良事件包括疲劳、腹泻、厌食和脱水，而静脉制剂的骨髓抑制和血小板减少症更为突出。通常，血液学毒性在SAHA停止后不久消退。无血小板减少性发热或血小板减少性脓毒症，5例患者观察到可测量的肿瘤缩小。1例转化型小淋巴细胞淋巴瘤达到完全缓解标准，另1例达到部分缓解标准，1例难治性HD患者达到PR，3例病情稳定达9个月。结论SAHA对血液系统恶性肿瘤包括HD和非霍奇金淋巴瘤的某些亚型有治疗作用。
Purpose To document the toxicity and activity of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in patients with pretreated hematologic malignancies.Patients and Methods Two formulations of SAHA (intravenous [IV] and oral) have been assessed in two consecutive phase I trials. In both trials, dose escalation was performed in parallel and independently in patients with solid tumors and hematologic malignancies. Eligible patients were required to have adequate hepatic and renal function, an absolute neutrophil count > 500/mu L and a platelet count more than 25,000/mL. All patients provided informed consent for study Inclusion.Results A total of 39 patients with hematologic malignancy were enrolled (14 on IV SAHA and 25 on oral SAHA), of whom 35 were treated. The spectrum of diseases included patients with diffuse large B-cell lymphoma (n = 12), Hodgkin's disease (HD; n = 12), multiple myeloma (n = 2), T-cell lymphoma (n = 3), mantle cell lymphoma (n = 2), small lymphocytic lyniphoma (n = 2), and myeloid leukemia (n = 2). Major adverse events with the oral formulation included fatigue, diarrhea, anorexia, and dehydration, whereas myelosuppression and thrombocytopenia were more prominent with the IV formulation. Typically, the hematologic toxicities resolved shortly after SAHA was stopped. There was no neutropenic fever or neutropenic sepsis, Reduction in measurable tumor was observed in five patients. One patient with transformed small lymphocytic lymphoma met criteria for complete response, whereas another met the criteria for partial response (PR), One patient with refractory HD had a PR, whereas three patients had stable disease for up to 9 months.Conclusion These results suggest that SAHA has activity in hematologic malignancies including HD and select subtypes of non-Hodgkin's lymphoma.