酪氨酸激酶抑制剂治疗期间Ph-细胞出现克隆性染色体异常对慢性髓性白血病患者预后的影响

Prognosis of clonal chromosomal abnormalities in Philadelphia negative metaphases cells in chronic myeloid leukemia with tyrosine kinase inhibitor therapy

目的探讨酪氨酸激酶抑制剂(TKI)治疗期间Ph-细胞间期出现克隆性染色体异常(CCA/Ph-)的特征以及对慢性髓性白血病(CML)患者预后的影响。方法回顾性分析河南省肿瘤医院2007年8月至2017年7月期间接受TKI治疗并出现CCA/Ph-的30例CML患者的临床资料。结果 30例CML患者,男性19例(63.3%)。首次出现CCA/Ph-时患者中位年龄44(14~68)岁,TKI中位治疗13(2~94)个月。TKI治疗3个月BCR-ABLIS≤10%者占46.7%(14/30)。60.0%(18/30)的患者首次出现CCA/Ph-的克隆比例≥50%。63.3%(19/30)的患者CCA/Ph-呈一过性出现(仅出现1次),36.7%(11/30)呈反复出现(出现次数≥2)。CCA/Ph-类型:+8为主异常占60.0%,-7/7q-为主异常占13.3%,-Y异常占6.7%。中位随访50个月,76.7%(23/30)的患者维持完全细胞遗传学反应;63.3%(19/30)获主要分子学反应,其中43.3%(13/30)达分子学无法检测(UMRD)。30例患者中位无事件生存(EFS)时间为44个月,2年和5年EFS率分别为(82.1±7.3)%和(52.4±12.8)%,中位总生存(OS)时间为50个月,2年和5年OS率分别为(92.6±5.0)%和(77.2±14.7)%。单因素分析显示:男性、CCA/Ph-出现≥2次、3个月BCR-ABLIS>10%的CML患者2年EFS率分别较女性、CCA/Ph-一过性出现、3个月BCR-ABLIS≤10%者显著降低(P值均<0.05);CCA/Ph-出现≥2次者2年OS率较CCA/Ph-一过性出现者显著降低(P<0.05)。多因素分析显示:CCA/Ph-出现频率是影响CML患者EFS率的独立危险因素(RR=4.741,95%CI 1.21~18.571,P=0.018)。结论 TKI治疗期间出现CCA/Ph-以+8最常见,其次为-7/7q-和-Y;CCA/Ph-克隆比例多≥50%;可呈反复出现或一过性出现,以一过性出现更常见。CCA/Ph-反复出现(≥2次)是影响CML患者EFS和OS的独立危险因素。

Objective To investigate the characteristics and prognosis of clonal chromosomal abnormalities appearing in Philadelphia negative metaphases (CCA/Ph-) cells in chronic myeloid leukemia (CML) with tyrosine kinase inhibitor (TKI) therapy. Methods The clinical data of 30 cases with CCA/Ph- during TKI treatment in Henan Cancer Hospital from August 2007 to July 2017 were retrospectively analyzed. The univariate factor was analyzed by Kaplan-Meier method. Multiple-factor was analyzed by Cox proportional risk model. Results Of the 30 cases, 19 (63.3%) were males. At the first detection of CCA/Ph- the median age was 44 (rang 14-68) years old and the median treatment of TKI was 13 (rang 2-94) months. The clones proportion of first detected CCA/Ph-≥ 50% was found in 18 (60.0%) cases. TKI treatment for 3 months with BCR-ABLIS less than 10% was seen in 14 (46.7%) patients. 63.3%(19/30) of CCA/Ph- was transient (only one time) and 36.7%(11/30) was repeated (≥2 times). Trisomy 8 dominant accounted for 60.0%(18/30),-7/7q- for 13.3%(4/30), loss of chromosome Y 6.7%. With a median of follow-up 50 months, 76.7%(23/30) cases were in complete cytogenetic response (CCyR);63.3%(19/30) in major molecular response (MMR), 43.3%(13/30) in undetectable minimal residual disease (UMRD). The median event-free survival rate of (EFS) were 44 months, and 2-year and 5-year EFS were (82.1±7.3)% and (52.4±12.8)%, respectively. The median overall survival (OS) were 50 months, and 2-year and 5-year OS rates were (92.6±5.0)% and (77.2±14.7)%, respectively. Univariate analysis shows that the 2-year EFS of who in males, more than 2 times CCA/Ph-, BCR-ABLIS>10% at 3 months after TKI were significantly lower than women, transient CCA/Ph-, and BCR-ABLIS≤10%(P<0.05). The 2-year OS rate in whom the occurrence frequency of CCA/Ph- more than twice was significantly lower than those with transient CCA/Ph-(P<0.05). Multivariate analysis showed that CCA/Ph- was an independent risk factor (RR=4.741, 95%CI 1.21-18.571, P=0.018) for EFS in CML patients. Conclusion Trisomy 8,-7/7q-, and -Y were the most common CCA/Ph- during TKI treatment, with high clones proportion of ≥50%. CCA/Ph- mainly occurred transiently or was permanent occasionally. CCA/Ph- recurrence (≥2 times) was an independent risk factor for EFS and OS in CML with TKI.