A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.
A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.
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DOI：
10.1007/s00277-016-2683-1
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发表时间：
2016-06
影响因子：
3.5
通讯作者：
Andritsos LA
中科院分区：
文献类型：
--
作者：
Awan FT;Jones JA;Maddocks K;Poi M;Grever MR;Johnson A;Byrd JC;Andritsos LA
接受化学免疫治疗且未达到完全缓解的慢性淋巴细胞白血病（CLL）患者的无进展间期（PFS）显著缩短。此外，大多数接受复发性疾病治疗的患者表现出可测量疾病的证据。根除微小残留病（MRD）可改善PFS和总生存期。维持治疗可能导致MRD的根除并改善缓解持续时间，但可能与感染并发症的发生率增加相关。Flavopiridol是一种广泛的细胞周期蛋白依赖性激酶（CDK）抑制剂，在复发性CLL患者，特别是具有高风险细胞遗传学特征的患者中具有确定的安全性和有效性。在本I期研究中，采用了一种基于Flavopiridol的方案作为巩固治疗，以评估低肿瘤负荷患者门诊使用Flavopiridol治疗的安全性和可行性。Flavopiridol以30 mg/m2的30分钟负荷剂量给药，随后以30 mg/m2的4小时输注，每周一次，持续3周，每5周（1个周期），计划在10例患者中进行2个周期。治疗耐受性非常好，没有患者发生急性肿瘤溶解综合征。最常见的毒性反应为胃肠道反应。在这些患者中，22%的患者的反应从PR改善为CR。88%的患者通过骨髓受累程度（包括del 17 p和复杂核型患者）测量肿瘤负荷减轻。该研究确定了Flavopiridol作为CLL患者化学免疫治疗后巩固治疗的安全性和有效性。需要在更大规模的试验中进一步评估CDK抑制剂作为巩固或维持策略的效用。在ClinicalTrials.gov注册号：NCT 00377104。
Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/ m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies. Registration number at ClinicalTrials.gov: NCT00377104.