University of Minnesota, Minneapolis, MN, USA,
Invest New Drugs. 2013 Oct;31(5):1311-20. doi: 10.1007/s10637-013-9978-z. Epub 2013 May 23.
Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death.
Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750-1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity.
The median age was 70.5 years; 51 % had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32 % had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5 %) patients; all 7 were among the 47 patients able to remain on vatalanib for at least 3 months (hematological improvement achieved in 15 % of these 47 patients). For patients with low risk and high risk MDS, respectively, median progression-free survivals were 15 and 6 months, median times to transformation to AML were 28 and 6 months, and median overall survivals were 36 and 10 months. The most frequent non-hematological adverse events grade ≥ 2 were fatigue, nausea or vomiting, dizziness, anorexia, ataxia, diarrhea, and pain. Two deaths (one intra-cerebral hemorrhage and one sudden death) were possibly related to vatalanib.
Vatalanib induces improvement in blood counts in a small proportion of MDS patients. Clinical applicability is limited by side effects.
血管生成与骨髓增生异常综合征（MDS）的病理生理学和进展有关。Vatalanib（PTK787/ZK222584；诺华和先灵 AG）抑制血管内皮生长因子、血小板衍生生长因子和 c-Kit 的受体酪氨酸激酶。我们研究了 Vatalanib 是否能诱导 MDS 患者的血液学反应，以及是否能延迟向急性髓系白血病（AML）或死亡进展。
研究了两个队列。155 例 MDS 患者接受 1250 毫克 Vatalanib 口服，每日一次（队列 1）或根据患者情况每日递增剂量 750-1250 毫克，28 天为一周期（队列 2）；142 例患者可评估疗效，153 例患者可评估毒性。
中位年龄为 70.5 岁；51%为低危（国际预后评分系统[IPSS]低/中-1），32%为高危（IPSS 中-2/高）MDS。142 例患者中有 7 例（5%）达到血液学改善；这 7 例均来自 47 例能至少持续服用 Vatalanib 3 个月的患者（这 47 例患者中 15%达到血液学改善）。低危和高危 MDS 患者的无进展生存期中位数分别为 15 和 6 个月，转化为 AML 的时间中位数分别为 28 和 6 个月，总生存期中位数分别为 36 和 10 个月。最常见的非血液学不良反应≥2 级为疲劳、恶心或呕吐、头晕、厌食、共济失调、腹泻和疼痛。2 例死亡（1 例为颅内出血，1 例为猝死）可能与 Vatalanib 有关。
Vatalanib 可诱导一小部分 MDS 患者的血液计数改善。由于副作用，临床应用受到限制。
