难治性和复发性急性淋巴细胞白血病(ALL)患者需要新型药物。Combotox是两种免疫毒素(IT)的1:1混合物,通过将去糖基化的蓖麻毒素A链(dgRTA)与针对CD22(RFB4-dgRTA)和CD19(HD37-dgRTA)的单克隆抗体偶联来制备。临床前数据表明,Combotox可有效杀死B-ALL前细胞系和B-ALL患者的细胞。一项针对儿科患者的临床研究,其中17例ALL患者中有3例完全缓解,支持临床前工作并推动这项研究。这项研究是第一阶段,在难治性或复发性B谱系ALL成人中使用Combotox的剂量递增试验。一个周期由三个剂量组成,每隔一天给一个剂量。剂量水平为每剂量3、5、6、7和8mg/m(2)。17名患者,19-72岁,参加了这项多机构研究。最大耐受剂量为7mg/m(2)/剂量(21mg/m(2)/周期),血管渗漏综合征为剂量限制性毒性。两名患者在肝功能测试中出现可逆的3级升高。一名患者获得部分缓解,并进行异基因干细胞移植。在施用Combotox后,所有具有外周母细胞的患者的母细胞计数均减少。因此,Combotox可以安全地用于患有难治性白血病的成人。
Novel agents are needed for patients with refractory and relapsed acute lymphoblastic leukaemia (ALL). Combotox is a 1:1 mixture of two immunotoxins (ITs), prepared by coupling deglycosylated
ricin A chain (dgRTA) to monoclonal antibodies directed against CD22 (RFB4-dgRTA) and CD19 (HD37-dgRTA). Pre-clinical data demonstrated that Combotox was effective in killing both pre-B-ALL cell lines and cells from patients with pre-B ALL. A clinical
study of paediatric patients in which 3 of 17 patients with ALL experienced complete remission, supported the preclinical work and motivated this
study. This
study was a Phase I, dose-escalation
trial using Combotox in adults with refractory or relapsed B-lineage-ALL. A cycle consisted of three doses, with one dose given every other day. Dose levels were 3, 5, 6, 7 and 8 mg/m(2) per dose. Seventeen patients, aged 19-72 years, were enrolled in this multi-institution
study. The maximum tolerated dose was 7 mg/m(2) /dose (21 mg/m(2) /cycle) and vascular leak syndrome was the dose-limiting toxicity. Two patients developed reversible grade 3 elevations in liver function tests. One patient achieved partial remission and proceeded to allogeneic stem cell transplantation. All patients with peripheral blasts experienced decreased blast counts following the administration of Combotox. Thus, Combotox can be safely administered to adults with refractory leukaemia.