Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkin's lymphoma.
Flavopiridol can be safely administered using a pharmacologically derived schedule and demonstrates activity in relapsed and refractory non-Hodgkin's lymphoma.
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DOI：
10.1002/ajh.23568
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发表时间：
2014-01
影响因子：
12.8
通讯作者：
Byrd, John C.
中科院分区：
文献类型：
--
作者：
Jones, Jeffrey A.;Rupert, Amy S.;Poi, Ming;Phelps, Mitch A.;Andritsos, Leslie;Baiocchi, Robert;Benson, Don M.;Blum, Kristie A.;Christian, Beth;Flynn, Joseph;Penza, Sam;Porcu, Pierluigi;Grever, Michael R.;Byrd, John C.
黄吡哆醇是一种广泛的细胞周期蛋白依赖性激酶抑制剂(CDKI)，可在体外和小鼠淋巴瘤模型中诱导恶性淋巴细胞的凋亡。我们进行了一项I期剂量递增研究，以确定按药动学派生的混合剂量方案对复发和难治性非霍奇金淋巴瘤患者单药黄烷醇的最大耐受剂量(MTD)。在四个队列中的一个中，剂量独立递增：惰性B细胞(队列1)、套细胞(队列2)、包括转化淋巴瘤的中等级别B细胞(队列3)和不包括原发皮肤病的T/NK细胞(队列4)。共有46例患者入选。大多数患者(60%)出现3级或4级白细胞减少，但感染很少见。常见的非血液毒性包括腹泻和乏力。只有2名患者观察到生化肿瘤溶解，没有患者需要血液透析进行治疗。剂量递增在两个队列中完成(惰性和攻击性B细胞)。没有观察到剂量限制毒性，在测试的最高剂量(50 mg/m2推注+50 mg/m2每周持续输注，6周周期中连续4周)，两组均未达到MTD。在43例可评价疗效的患者中，有26%的患者临床受益，包括14%的部分反应(2例套细胞，3例惰性B细胞，1例弥漫性大B细胞)。这种第一代CDKI的单药活性表明，这类药物中的其他药物值得单独或联合应用于淋巴系统恶性肿瘤的进一步研究。
Flavopiridol is a broad cyclin-dependent kinase inhibitor (CDKI) that induces apoptosis of malignant lymphocytes in vitro and in murine lymphoma models. We conducted a phase I dose-escalation study to determine the maximum tolerated dose (MTD) for single-agent flavopiridol administered on a pharmacokinetically derived hybrid dosing schedule to patients with relapsed and refractory non-Hodgkin’s lymphoma. Dose was escalated independently in one of four cohorts: indolent B-cell (cohort 1), mantle cell (cohort 2), intermediate grade B-cell including transformed lymphoma (cohort 3), and T-/NK-cell excluding primary cutaneous disease (cohort 4). Forty-six patients were accrued. Grade 3 or 4 leukopenia was observed in the majority of patients (60%), but infection was infrequent. Common non-hematologic toxicties included diarrhea and fatigue. Biochemical tumor lysis was observed in only 2 patients, and no patients required hemodialysis for its management. Dose escalation was completed in two cohorts (indolent and aggressive B-cell). Dose-limiting toxicities were not observed, and the MTD was not reached in either cohort at the highest dose tested (50 mg/m2 bolus + 50 mg/m2 continuous infusion weekly for 4 consecutive weeks of a 6 week cycle). Clinical benefit was observed in 26% of 43 patients evaluable for response, including 14% with partial responses (2 mantle cell, 3 indolent B-cell, and 1 diffuse large B-cell). The single-agent activity of this first-generation CDKI suggests that other agents in this class merit further study in lymphoid malignancies, both alone and in combination.
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影响因子：
45.3
作者：
Freyer, G;Delozier, T;Trillet-Lenoir, V
通讯作者：
Trillet-Lenoir, V
影响因子：
20.3
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
通讯作者：
Grever, Michael R.
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
2
作者：
Myatt, Daniel;Johnson, Louise;Siligardi, Giuliano
通讯作者：
Siligardi, Giuliano
影响因子：
20.3
作者：
Karp, Judith E.;Smith, B. Douglas;Rudek, Michelle A.
通讯作者：
Rudek, Michelle A.