STI571治疗慢性髓系白血病的临床疗效与毒副作用观察

Clinical Efficacy and Side Effects of STI571 in Treatment of Patients with Chronic Myeloid Leukemia

背景与目的:bcr-abl融合基因翻译的蛋白产物P210bcr-abl的酪氨酸激酶(proteintyrosinekinase,PTK)活性异常增高被认为是导致慢性髓系白血病(chronicmyeloidleukmeia,CML)发病的根本原因。STI571能高效特异性抑制P210bcr-abl的PTK活性,在临床应用中获得了显著的疗效,但对急变期患者的治疗效果维持时间短。本研究观察和比较了STI571治疗慢性期与加速/急变期CML患者的临床疗效和所发生的不良反应,并从细胞遗传学的角度对急变期患者STI571耐药机制进行初步的分析。方法:选择接受STI571治疗的CML患者22例,其中慢性期6例,加速/急变期16例。按照血液学缓解和细胞遗传学缓解的标准,结合骨髓细胞形态学分析、骨髓细胞G显带技术分析和间期荧光原位杂交检测结果,对患者STI571治疗前和治疗3个月后的血液学和细胞遗传学缓解情况进行分析,并对3个月内出现耐药复发的患者进行核型演化分析。同时密切观察各系统发生的不良反应及严重程度。结果:6例(100%)慢性期CML患者获血液学完全缓解和细胞遗传学缓解,4例(25%)加速/急变期CML患者获血液学完全缓解,8例(50%)获不同程度的细胞遗传学反应。获血液学完全缓解和细胞遗传学反应的百分率两组比较均有统计学差异(P<0.05)。3例急变期CML患者出现耐药复发。

BACKGROUND & OBJECTIVE: The aberrant regulation of the protei n tyrosine kinase (PTK) activity of P210BCR- ABL, which is the protein product of Bcr- Abl fusion gene leads to the pathogenesis of chronic myeloid leukemia (CM L). Though STI571 can inhibit specifically the PTK activity of P210Bcr- Abl and greatly improve the clinic curative effect on CML in chronic phase, its effect on CML in accelerated phase and blast crisis is not clear. In this article, we a ttempted to analyze the clinic efficacy and side effect of STI571 treatment on C ML patients in different phase. In addition, we analyzed the potential mechanism of STI571 resistance in accelerated/blast crisis CML with genetic methods. METH ODS: A total of 22 cases of CML, 14 cases male and 8 female, 6 cases in chronic phase and 16 cases in accelerated/blast crisis phase, were treated with STI571. According to the efficacy standard, the hematological and cytogenetic response o f 22 cases CML were analyzed, by determining the positive rate of Ph chromosome in bone marrow from the patients treated with STI571 for 3 months. Furthermore, the karyotype evolution of those patients showing STI571 resistance was analyzed . At the same time, the side effects and adverse events of STI571 treatment were evaluated. RESULTS: 6/6(100% ) cases of CML patients in chronic phase acquired hematological CR and cytogenetic response. 4/16(25% ) cases in accelerated pha se or blast crisis acquired hematological CR and 8/16(50% ) cases acquired cyto genetic response. 3 CML patients in blast crisis showed secondary STI571 resista nce. The karyotype analysis shows 2 with 2 Ph chromosome and other additional ab normality. Ⅰ /Ⅱ grade non- hematological toxicity was observed in all the pa tients, including edema (77.3% ), side effects of digestive system (36.4% ) an d myalgia (22.7% ) et al. Severe hematological toxicities includes:(1)Ⅲ /Ⅳ g rade neutropenia (9 cases):1/6 cases of CML patients in chronic phase, 8/16 case s in accelerated phase or blast crisis; (2)Ⅲ /Ⅳ grade thrombocytopenia (6 cas es): 6/16 cases in accelerated phase or blast crisis. The percentage of Ⅲ /Ⅳ grade neutropenia/thrombocytopenia in chronic phase and accelerated/blast crisis phase was compared and no significant statistical difference was observed. CONC LUSIONS: Hematological and cytogenetic responses of different degrees can be acq uired in CML- CP and CML- AP/BC patients treated with STI571 and showing stati stic difference. STI571 improves the clinic curative effect greatly on CML in ch ronic phase. CML patients in blast crisis have secondary STI571 resistance with novel 2 Ph chromosome and other additional abnormality, it furnishes the evidenc e of the gene changes. The slightness of non- hematological toxicity of STI571 in the treatment of chronic myeloid leukemia suggests this drug is relatively s afe. Severe hematological toxicities, such as Ⅲ / Ⅳ neutropenia and thrombocytopenia, are more common in accelerated/blast cr isis than in chronic phase.