伴Ph阳性附加染色体异常慢性髓性白血病的生物学特征及疗效分析

Analysis of clinical features and prognosis of patients with chronic myelogenous leukemia harboring additional chromosomal abnormalities in Ph-positive cells

目的探讨Ph阳性附加染色体异常(ACA/Ph^(+))对初诊慢性期(CP)和治疗中进展为加速期和急变期慢性髓性白血病(CML-AP/BP)患者生物学特征、疗效和预后的影响。方法回顾性分析2013年1月至2020年6月河南省人民医院收治的410例Ph^(+)CML[初诊CML-CP 348例,治疗中进展为AP/BP(进展期CML)62例]患者的临床资料,根据ELN2020标准将其分为高危、非高危和无ACA/Ph^(+)三组,并比较分析高危/非高危ACA/Ph^(+)对其生物学特征、疗效和预后的影响。结果①348例初诊CML-CP患者,合并ACA/Ph^(+)者20例(5.75%),其中高危ACA/Ph^(+)组3例,非高危ACA/Ph^(+)组17例;无ACA/Ph^(+)组328例。伴ACA/Ph^(+)和无ACA/Ph^(+)组患者的基本临床特征差异无统计学意义(P值均>0.05);非高危ACA/Ph^(+)组和无ACA/Ph^(+)组间完全血液学缓解(CHR)率、完全细胞遗传学反应(CCyR)率、主要分子学反应(MMR)率和5年总生存(OS)率差异均无统计学意义(P值均>0.05);非高危ACA/Ph^(+)组5年无进展生存(PFS)率显著低于无ACA/Ph^(+)组(42.0%对74.5%,χ^(2)=4.766,P=0.029)。②62例进展期CML患者,合并ACA/Ph^(+)者41例(66.13%),其中高危ACA/Ph^(+)组28例,非高危ACA/Ph^(+)组13例;无ACA/Ph^(+)组21例。高危ACA/Ph^(+)组患者中位PLT水平(42.5×10^(9)/L)低于非高危(141×10^(9)/L)和无ACA/Ph^(+)组(109×10^(9)/L)(χ^(2)=4.968,P=0.083);三组间ABL激酶区点突变发生率差异无统计学意义(P=0.652)。高危ACA/Ph^(+)组CCyR率显著低于无ACA/Ph^(+)组(5.3%对46.7%,χ^(2)=5.851,P=0.016)。高危ACA/Ph^(+)组5年OS率为46.2%,非高危ACA/Ph^(+)组为64.3%,无ACA/Ph^(+)组为77.8%,其中高危ACA/Ph^(+)组患者5年OS率明显低于无ACA/Ph^(+)组(χ^(2)=3.878,P=0.049)。亚组分析显示高危Ⅰ组(^(+)8,^(+)Ph或含^(+)8/^(+)Ph的复杂ACA)CML患者的5年OS率为54.5%,与无ACA/Ph^(+)组相比差异无统计学意义(χ^(2)=1.514,P=0.219);高危Ⅱ组[含-7/7q-或i(17q)或含2个及以上高危ACA的复杂核型]为28.6%,显著低于无ACA/Ph^(+)组(χ^(2)=8.035,P=0.005)。结论因ACA类型和疾病分期不同,伴ACA/Ph^(+)CML患者的治疗反应和预后存在差异,治疗过程中高危ACA的出现意味着更差的治疗反应和预后,严格、规范的细胞遗传学监测对此类患者的早期发现和精准诊疗具有重要意义。

Objective To investigate the effects of additional chromosomal abnormalities(ACA)in Philadelphia chromosome-positive(Ph^(+))cells on biological characteristics,therapy efficacy,and prognosis of patients with primary chronic myeloid leukemia(CML)-chronic phase(CP)and those who developed CML-accelerated phase/blast phase(AP/BP)during therapy.Methods The clinical data of 410 patients with Ph^(+)CML,including 348 patients with primary CML-CP and 62 patients who progressed to CML-AP/BP during treatment,who were admitted to Henan People's Hospital from January 2013 to June 2020 were retrospectively analyzed to categorize into high-risk,non-high-risk,and non-ACA groups according to the ELN2020 criteria.The effects of high-and non-high-risk ACA on biological characteristics,therapy efficacy,and prognosis were compared.Results①Among the 348 patients with primary CML-CP,20 patients(5.75%)had ACA,including 3 and 17 patients with high-risk and non-high-risk ACA,respectively,whereas the remaining 328 patients did not have ACA.There were no significant differences in baseline clinical characteristics between those with and without ACA(P>0.05 for all).The rates of complete hematological response,complete cytogenetic response,major molecular remission,and 5-year overall survival(OS)were not significantly different between the non-high-risk ACA and non-ACA groups(P>0.05 for all);however,the 5-year progression-free survival of the non-high-risk ACA group(42.0%)was significantly lower than that of the non-ACA group(74.5%)(χ^(2)=4.766,P=0.029).②Of the 62 patients who progressed to CML-AP/BP during treatment,41 patients(66.13%)had ACA,including 28 and 13 patients with high-risk and non-high-risk ACA,respectively,whereas the remaining 21 patients did not have ACA.Platelet counts of the high-risk ACA group(42.5×10^(9)/L)were lower than those of the non-high-risk(141×10^(9)/L)and non-ACA groups(109×10^(9)/L)(χ^(2)=4.968,P=0.083).There was no significant difference in the incidence of point mutations in ABL kinase among the three groups(P=0.652).The complete cytogenetic response of the high-risk ACA group(5.3%)was significantly lower than that of the non-ACA group(46.7%)(χ^(2)=5.851,P=0.016).The 5-year OS of the high-risk ACA group was lower than that of the non-ACA group(46.2%vs 77.8%,χ^(2)=3.878,P=0.049).Subgroup analysis revealed that the 5-year OS rate of the high-risk groupⅡ,which included-7/7q-,i(17q),and complex karyotype comprising≥2 high-risk ACA,was significantly lower than that of the non-ACA group(28.6%vs 77.8%,χ^(2)=8.035,P=0.005)whereas the 5-year OS rate was not significantly different between high-risk groupⅠ,which included^(+)8,^(+)Ph,and complex ACA with^(+)8/^(+)Ph,and the non-ACA group(54.5%vs 77.8%,χ^(2)=1.514,P=0.219).Conclusion Due to different disease stages and ACA/Ph^(+)types,treatment response and prognosis vary among patients with CML harboring ACA/Ph^(+).The emergence of high-risk ACA during therapy suggests worse therapy efficacy and prognosis.Strict and standardized cytogenetic monitoring is critical for early detection,precise diagnosis,and treatment of these patients.