CML（慢性粒细胞性白血病）治疗最新进展系列报道之（二）

2007-02-08 08:19:00 文字大小：【大】【中】【小】

标题：FDA批准了达沙替尼（Sprycel）在慢性阶段，加速阶段，或者急髓变、急淋变阶段的慢性粒细胞白血病治疗上的使用。

来源：FDA官方网站

翻译：陈锋（北京大学阳光志愿者协会）

2006年6月28日，美国食品药品管理局（FDA）向达沙替尼（Sprycel，百时美施贵宝公司）颁发了加速审批核准，准许其使用于对先前的包括伊马替尼在内的治疗有抗药性或者无法忍受的慢性阶段（CP），加速阶段（AP），急髓变（MB）或急淋变（LB）阶段的慢性粒细胞白血病（CML）的成人患者。正在进行的研究得到的后续数据的进一步提交将把这一加速审批核准转变为正式审批核准。另外，FDA对达沙替尼使用于对先前的治疗有抗药性或无法忍受的费城染色体呈阳性的急性淋巴细胞白血病（Ph+ ALL）患者颁发了正式审批核准。

达沙替尼的效力在四项无对照研究中得到证实。总共445名患者以每天两次一次70毫克的起始剂量服用达沙替尼进行治疗。从早期诊断到开始达沙替尼服用的平均时间分别是64个月（CP），91个月（AP），49个月（MB），28个月（LB），20个月（Ph+ ALL）。

患者群体曾被广泛治疗过。先前的治疗包括伊马替尼、化疗、干扰素、羟基脲、阿那格雷、以及骨髓移植。伊马替尼服用中断的患者，82％是因为抗药性，18％是因为无法忍受。伊马替尼的最大剂量是大约50％的患者为每日400到600毫克，剩下的大约50％患者为每日大于600毫克。

CP患者研究中的首要效力指标是显著细胞生成反应，定义为Ph阳性的造血细胞的消失或者大量减少（至少减少65％）。CP患者的显著细胞生成反应是45％（95％置信区间： 37％到52％）。AP、MB、和LB/Ph+ ALL患者研究的首要指标是血液反应。显著血液反应定义为完全血液反应或者没有白血病的证据。显著血液反应分别为AP患者59％（95％置信区间：49％到68％）、MB患者32％（95置信区间：22％到44％）、LB患者31％（95％置信区间：18％到47％）、Ph+ ALL患者42％（95％置信区间：26％到59％）。

在数据截止的时刻，CP、AP、MB阶段患者的平均反应持续时间因大多数相关患者仍在作出反应而无法确定。LB阶段患者的平均反应持续时间是3.7个月（95％置信区间：2.79到不确定上限），而Ph+ ALL患者是4.8个月（95％置信区间：2.89到不确定上限）。

可靠患者总体包括911名CML和Ph+ ALL患者。肠胃上的（腹泻、恶心、腹痛、呕吐）和体质上的（发烧、头痛、疲劳、无力、厌食）影响是最常见的副作用。50％的患者发生了体液停滞。最常见的影响包括表面浮肿（36％）和胸腔积液（22％）。40％的患者发生出血；14％的患者经历了肠胃出血。

血液毒性是最常见的3级或4级副作用。大约48-83％的患者发生嗜中性白血球减少和血小板减少；18-70％的患者发生贫血。这些副作用在CP阶段患者中比其它阶段CML或者Ph+ ALL患者更为少见。其它的常发3级或4级副作用包括出血（10％），体液停滞（9％），发热引起的嗜中性白血球减少症（8％），呼吸困难（6％），发烧（5％），胸腔积液（5％），和腹泻（5％）。1％的患者发生3级或者4级的中枢神经出血。六名患者被观测到致命的中枢神经出血。

完整的处方信息，包括临床试验信息、安全性、剂量、药间相互作用和禁忌症候的信息，可以在Drugs@FDA找到。

医疗专业人士应当将所有被怀疑与任何药品和仪器使用相关的严重副作用，通过电话1-800-FDA-1088、传真1-800-FDA-0178或使用http：//www.fda.gov/medwatch.index.html提供的3500表格通过邮件报告于

FDA的药品监察报告部门。

原文：

FDA approves dasatinib (Sprycel) for use in the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia

On June 28, 2006, the U. S. Food and Drug Administration granted accelerated approval to dasatinib (Sprycel, Bristol-Myers Squibb) for use in the treatment of adults with chronic phase (CP), accelerated phase (AP), or myeloid or lymphoid blast (MB or LB) phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy, including imatinib mesylate. Submission of further follow-up data from ongoing studies will convert this accelerated approval to regular approval. In addition, the FDA granted regular approval to dasatinib for use in the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

Efficacy was demonstrated in four single-arm studies. A total of 445 patients were treated with dasatinib at a starting dose of 70 mg twice daily. Median times from initial diagnosis were 64, 91, and 49 months in CP, AP, and MB patients, respectively, and 28 and 20 months in LB and Ph+ ALL patients, respectively. The patient population was extensively pre-treated. Prior treatment included imatinib, chemotherapy, interferon, hydroxyurea and/or anagrelide, and bone marrow transplantation. Imatinib was discontinued in 82% of patients because of resistance; 18% discontinued imatinib because of drug intolerance. The maximum imatinib dose was 400 – 600 mg/day in approximately 50% of patients and > 600 mg/day in the remaining patients.

The primary efficacy endpoint in CP studies was major cytogenetic response, defined as elimination or substantial diminution (by at least 65%) of Ph+ hematopoietic cells. The major cytogenetic response rate in CP patients was 45% (95% CI: 37%, 52%). Primary endpoints in AP, MB, and LB /Ph+ ALL studies were hematologic responses. Major hematologic response was defined as either a complete hematologic response or no evidence of leukemia. Major hematological response rates were 59% (95% CI: 49%, 68%) in AP, 32% (95% CI: 22%, 44%) in MB, 31% (95% CI: 18%, 47%) in LB, and 42% (95% CI: 26%, 59%) in Ph+ ALL.

At the time of data cutoff, the median response duration for CP, AP, or MB phase patients could not be determined since most responding patients had remained in response. The median response duration was 3.7 months (95% CI: 2.79, upper limit not reached) for LB patients and 4.8 months (95% CI: 2.89, upper limit not reached) for Ph+ ALL patients.

The safety population included 911 patients with CML and Ph+ ALL. Gastrointestinal (diarrhea, nausea, abdominal pain, and vomiting) and constitutional (pyrexia, headache, fatigue, asthenia, and anorexia) events were the most common adverse events. Fluid retention occurred in 50% of patients; the most common events included superficial edema (36%) and pleural effusion (22%). Bleeding occurred in 40% of all patients; 14% of patients experienced gastrointestinal bleeding.

Hematological toxicities were the most common grade 3/4 adverse events. Neutropenia and thrombocytopenia occurred in approximately 48-83% of patients and anemia in 18-70%. These events were less common in CP patients than in advanced-stage CML or Ph+ ALL patients. Other common grade 3/4 events included bleeding (10%), fluid retention (9%), febrile neutropenia (8%), dyspnea (6%), pyrexia (5%), pleural effusion (5%), and diarrhea (5%). Grade 3/4 CNS hemorrhage occurred in 1% of patients. Fatal CNS hemorrhage was observed in six patients.

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