Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies.
Phase I and correlative study of combination bryostatin 1 and vincristine in relapsed B-cell malignancies.
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发表时间：
2003-12
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通讯作者：
A. Dowlati;H. Lazarus;P. Hartman;J. Jacobberger;C. Whitacre;S. Gerson;Pamela Ksenich;B. Cooper;P. S. Frisa;Megan Gottlieb;A. Murgo;S. Remick
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作者：
A. Dowlati;H. Lazarus;P. Hartman;J. Jacobberger;C. Whitacre;S. Gerson;Pamela Ksenich;B. Cooper;P. S. Frisa;Megan Gottlieb;A. Murgo;S. Remick
苔藓抑素1（Bryostatin 1）在短期暴露时激活蛋白激酶C（PKC），长期暴露时导致PKC耗竭。临床前体外和体内研究表明，在B细胞恶性肿瘤中，当长时间输注苔藓抑素1后再输注长春新碱时，具有协同活性并增加肿瘤细胞凋亡。实验设计：我们开始了苔藓抑素1作为24小时连续输注，然后推注长春新碱在难治性B细胞恶性肿瘤而不是急性白血病患者中的I期试验。入组了24例可评价患者。结果剂量限制性毒性为肌痛。苔藓抑素1的MTD和推荐的II期剂量为50 μ g/m2/24 h，随后为长春新碱1.4 mg/m2（最大总剂量为2 mg），每2周一次重复。在该复发人群中观察到显著的抗肿瘤活性，包括高剂量化疗失败的患者。这包括5例持久的完全和部分缓解和5例持续≥ 6个月（范围，6-48+个月）的稳定疾病患者。中位缓解时间为8个月。相关研究表明，输注苔藓抑素1后血清白细胞介素-6逐渐升高，长春新碱后进一步升高。流式细胞术检测B和T细胞的凋亡显示，在输注苔藓抑素1后6小时内，CD 5+细胞的凋亡频率最初降低，这与大多数患者中PKC活性的已知增加相一致，随后在输注完成后，凋亡频率恢复至基线或总体增加。所有（5/5）CD 5+细胞凋亡频率总体增加的患者均获得临床缓解或疾病长期稳定。这5例患者中有4例在6 h时细胞凋亡没有初始减少。结论：由于缺乏骨髓抑制和临床疗效的早期证据，在非霍奇金淋巴瘤和多发性骨髓瘤中进一步探索该方案是必要的。
PURPOSE Bryostatin 1 activates protein kinase C (PKC) with short-term exposure and results in depletion of PKC with prolonged exposure. Preclinical in vitro and in vivo studies demonstrate synergistic activity and increased tumor apoptosis in B-cell malignancies when a prolonged infusion of bryostatin 1 is followed by vincristine. EXPERIMENTAL DESIGN We embarked on a Phase I trial of bryostatin 1 as a 24-h continuous infusion followed by bolus vincristine in patients with refractory B-cell malignancies other than acute leukemias. Twenty-four evaluable patients were enrolled. RESULTS The dose-limiting toxicity was myalgia. The MTD and recommended Phase II dose of bryostatin 1 was 50 microg/m2/24 h followed by vincristine 1.4 mg/m2 (maximum total dose of 2 mg) repeated every 2 weeks. Significant antitumor activity was observed in this relapsed population, including patients who had failed high-dose chemotherapy. This included 5 durable complete and partial responses and 5 patients with stable disease lasting > or =6 months (range, 6-48+ months). Median time to response was 8 months. Correlative studies demonstrated a progressive increase in serum interleukin-6 with bryostatin 1 infusion followed by an additional increase after vincristine. Flow cytometry for detection of apoptosis in B and T cells showed an initial decrease in apoptotic frequency in CD5+ cells within 6 h of bryostatin 1 infusion compatible with its known increase in PKC activity in the majority of patients followed by a return to baseline or overall increase in apoptotic frequency after completion of infusion. All (5 of 5) patients who had an overall increase in apoptotic frequency in CD5+ cells achieved either a clinical response or prolonged stable disease. Four of these 5 patients did not have the initial decrement in apoptosis at 6 h. CONCLUSIONS Given the lack of myelosuppression and early evidence of clinical efficacy, additional exploration of this regimen in non-Hodgkin's lymphoma and multiple myeloma is warranted.