【ASH 2012】急性髓系白血病基因型可预测治疗相关性死亡率
发布时间：2012-12-13 | 来源：医脉通
关键词：
ASH 2012
急性髓系白血病
AML
WT1基因
rs16754
SNP
癌症研究中心助理研究员Phoenix Ho 博士
在某些急性髓系白血病儿童患者人群中，一种特异性基因标记可能与较低的化疗药物毒性反应相关。
据第54届美国血液病学会年会上发表的研究数据表明，在某些特定种族人群中，WT1基因中的rs16754单核苷酸多态性（SNP）与其预后改善相关——在亚裔或黑人急性髓系白血病（AML）患儿中表现尤为突出。
本研究的首席作者、华盛顿州西雅图市西雅图儿童医院主治医师、西雅图Fred Hutchinson 癌症研究中心助理研究员Phoenix Ho 博士解释道，WT1基因在血液系统及泌尿生殖系统正常组织的发育过程中起一定作用，在儿童AML患者中，有81%其WT1基因异常过表达，有8%在WT1基因的锌指区内存在基因突变。
Ho博士在大会报告前的一次新闻发布会上做了上述表述。
新闻发布会的主持人、佐治亚州亚特兰大市儿童保健机构Aflac癌症中心及血液疾病部Daniel P. Amos儿科主席、儿童血液/肿瘤科主任William G. Woods博士表示，该研究对于AML的治疗具有重要的启示意义。他同时向媒体表示，似乎“具有正常SNP的患者，其能够接受的药物治疗剂量较低”。
种族差异
研究者们发现，儿童AML患者的成功治疗有赖于强力诱导治疗药物+多种药物联合化疗。患儿的治疗相关性死亡率仍是一个令人担忧的大问题，但它受患者多种不同特异性因素的影响。
此外，不同种族及不同民族的成人及儿童AML患者之间，其疾病预后也存在差异。Ho博士解释道：“这可能是由生物学和非生物学因素共同造成的。”
在不同人群之间，rs16754 SNP的出现频率存在明显差异。
Ho博士及其同事研究发现，上述SNP的发生率在不同人群中分别为：白人患者25%，黑人患者21%，拉丁裔患者34%，美国亚裔患者53%。他表示：“这与此种SNP在该人种正常人群中发生率一致。”
某些特定人群的治疗相关性死亡率较低
研究人员对rs16754基因型与患者5年总体生存率、完全缓解率、复发风险以及治疗相关死亡率之间的相关关系进行了评估分析。为了检测rs16754 SNP基因型，他们在参与儿童肿瘤组CCG-2961试验的492例确诊AML患儿样本中，对WT1基因外显子7进行了直接基因测序。
研究表明，此SNP并不与患者的治疗缓解率增高和复发率降低相关，但将患者按种族分层并观察其治疗相关性死亡率时，发现在亚裔及非洲裔患儿中，该SNP阳性者未发生一例药物毒性致死事件。
Ho博士补充道，这与同种族SNP阴性患儿的结果恰好相反，其因药物毒性导致的死亡率较高。
他解释道：“由于此类患者多使用多药联合化疗方案，因而很难具体判断治疗毒性反应主要是由哪种药物所引起的。”
在等位基因中，至少含有1个G碱基的患者为rs16754 SNP阳性，而含有A碱基纯合子型基因者则为rs16754 SNP阴性。研究者们按种族和SNP基因型差异对患者进行分层，随后分析了其预后情况。
治疗相关性死亡多发生于最初的2个化疗周期内，研究者们对上述两治疗组患者的治疗相关死亡率分别进行了评估。
在5年总体生存率方面，SNP阳性组患者（占28%）明显优于SNP阴性组患者（分别为61%和44%，P=0.009）。然而，SNP差异对于患者的其他预后评估指标（如无疾病生存期、治疗缓解率）并无显著性影响。
在不同种族亚组患者中，SNP阳性患者的5年总体生存率均优于SNP阴性患者：拉丁裔患者（49%和37%， P=0.433），黑人患者（56%和30%，P=0.207），亚裔（88%和29%，P=0.037），白人患者（65%和48%，P=0.051）。其中，在白人患者亚组中，该差异近似有统计学意义；而在亚裔患者亚组中，该差异具有统计学显著性。
对于参试患者总体来说，rs16754基因型并不会影响患者的治疗相关性死亡率。然而，在黑人和亚裔患者组的综合治疗相关死亡率方面，SNP阳性患者明显低于SNP阴性患者。在黑人患者中，SNP阴性者的治疗相关死亡率明显高于SNP阳性患者（分别为25%和0%）；在亚裔患者中亦是如此（分别为43%和0%）。
研究者表示，本研究结果表明，在非洲裔和亚裔AML患儿中，rs16754 SNP对患者的保护效应更加明显，它可以减轻化疗相关的毒性反应。
研究者们将在一项更大型的同步临床试验中验证种族特异性SNP状态与患者治疗相关死亡率之间的相关关系。Ho博士解释道，他们还将在其
他类型癌症患者中评估rs16754 SNP与患者治疗效应之间的关系。
文章摘要：1385 WT1 snp rs16754 Genotype Predicts Treatment Related Mortality (TRM) in African-American and Asian Pediatric AML Patients: A Report From the Children’s Oncology Group
Background: Successful treatment of childhood acute myeloid leukemia (AML) requires multi-agent chemotherapy, beginning with intensive induction regimens. Treatment-related mortality (TRM) remains a significant concern, and may be influenced by patient-specific factors. Outcomes in adult and pediatric AML differ among ethnicities. We reported that the minor (G) allele of the WT1 synonymous SNP rs16754 is associated with improved outcome. Racial frequencies of SNP rs16754 vary significantly. Here we explore rs16754 genotype and 5-year rates of overall survival (OS), complete remission (CR), relapse risk (RR) and TRM in the Children’s Cancer Group trial CCG-2961, in the context of ethnicity.
Methods: To assess SNP rs16754 genotype, we directly sequenced WT1 exon 7 on available diagnostic specimens (N=492) from pediatric AML patients enrolled on CCG-2961. Patients with at least one minor (G) allele were considered SNP+, while patients homozygous for the major (A) allele were considered SNP?. We stratified SNP genotype by ethnicity and analyzed outcomes. In the 2961 trial, Induction Course 1 consisted of an intensively-timed hybrid regimen (Ida-DCTER: idarubicin / daunorubicin, dexamethasone, cytarabine, thioguanine, and etoposide). Patients with at least partial remission (<30% marrow blasts) were randomized to receive Induction Course 2 consisting of either a repeat course of Ida-DCTER (Regimen A) or Ida-FLAG (idarubicin, fludarabine, cytarabine; Regimen B). As most TRM events occurred within the first two cycles of chemotherapy, TRM was further examined separately on each of these two study arms.
Results: Twenty-eight percent of patients were SNP+; SNP positivity correlated with improved overall survival (5 year OS, 61% vs. 44%, p=0.009), although other outcome measures (CR, RR, DFS) were not significantly different between SNP+ and SNP? groups in the 2961 study. Prevalence of the SNP G allele varied significantly across ethnic groups (p=0.034): Asian (n=8/15, 53%), Hispanic (n=28/82, 34%), Caucasian (n=81/322, 25%), and African-American (n=10/47, 21%). When examining rs16754 genotype within ethnic subgroups, SNP+ patients had higher 5 year OS in each population (Hispanic: 49% vs. 37%, p=0.433; African-American: 56% vs. 30%, p=0.207; Asian: 88% vs. 29%, p=0.037; and Caucasian: 65% vs. 48%, p =0.051); statistical significance was approached in the Caucasian group and was achieved only in the Asian group. When patients of all ethnicities were considered together, TRM rates did not vary by rs16754 genotype. However, TRM rate was significantly lower in SNP+ African-American and Asian patients taken together compared to their SNP? counterparts (p=0.020) with a trend to significance taken individually (Asian: 0% vs. 43%, p=0.063; African-American: 0% vs. 25%, p=0.105). Further, for patients who survived Induction 1 and underwent Induction 2 randomization, SNP? Asian and African-American patients experienced higher rates of TRM from randomization disproportionately on Arm B (p=0.107), where TRM in SNP+ vs. SNP? patients was 0% vs 60% in Asian patients (Arm B n=9, p=0.110) and 0% vs. 14% in African-American patients (Arm B n=21, p=0.305).
Conclusions: As CCG-2961 comprised blocks of intensive inpatient therapy, this clinical trial provides a setting in which to study the effects of ethnicity on outcome while minimizing confounding non-biologic factors. African-American and Asian patients who were negative for SNP rs16754 experienced disproportionate TRM, particularly on experimental Arm B, which tested the then-novel agent fludarabine; conversely, the TRM rate was 0% for SNP+ patients of these two ethnicities. The biologic mechanism for this observation bears further study, as biomarkers predictive of drug-specific toxicity may inform treatment decisions in certain ethnic populations.
Disclosures: No relevant conflicts of interest to declare.
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