细胞遗传学异常检测对多发性骨髓瘤危险度分层及预后评估
|
摘要
目的探讨细胞遗传学异常分析对多发性骨髓瘤(MM)患者危险度分层及预后评估的作用。方法回顾性分析2015年1月至2017年12月200例初治的MM患者临床资料,采用原位荧光杂交法(FISH)对骨髓标本进行分子遗传学异常检测,分析不同染色体异常与临床指标、浆细胞表面免疫表型、治疗效果及预后的关系。结果FISH细胞遗传学异常检出率为77. 00%,其中IGH重排、RB1缺失、P53缺失、1q21扩增检出率分别为48. 50%、57. 00%、14. 50%、51. 50%。IGH重排阳性组浆细胞比例、国际分期系统(ISS)Ⅲ期、Durier-Salmon分期(DS)Ⅲ期比例高于阴性组; RB1缺失阳性组CD28表达率高于阴性组; P53缺失阳性组血钙(Ca2+)水平、骨髓中浆细胞比例、CD28表达率及ISSⅢ期、DSⅢ期比例高于阴性组,而CD117表达率低于阴性组(P <0. 05)。1q21扩增阳性组与阴性组临床指标比较差异均无统计学意义(P> 0. 05)。T-VAD方案(沙利度胺,长春新碱,吡柔比星,地塞米松)中IGH重排、P53缺失阳性组有效率均低于阴性组(P <0. 05); PD方案(硼替佐米,地塞米松)中P53缺失阳性组有效率低于阴性组(P <0. 05)。IGH重排阳性组总生存时间(OS)短于阴性组(P <0. 05); P53缺失阳性组OS与无进展生存时间(PFS)均短于阴性组(P <0. 05)。结论 MM患者细胞遗传学异常发生率高,且多种遗传学异常并存;细胞遗传学异常与临床指标、免疫表型、治疗效果及预后存在一定的相关性,其中P53缺失是OS及PFS减低,预后不良的因素,临床应重视对MM患者进行细胞遗传学异常的检测,以此指导临床治疗及预后分层评估。
Objective To investigate the role of cytogenetic abnormality analysis in risk stratification and prognosis assessment for patients with multiple myeloma( MM). Methods The clinical data of 200 newly treated patients with MM from January 2015 to December 2017 were retrospectively analyzed. In situ fluorescence hybridization( FISH) was used to detect molecular cytogenetic abnormalities in the bone marrow specimen,and the relationship between different chromosomal abnormalities and clinical index,cytoplasmic surface immunophenotype,treatment efficacy and prognosis was analyzed. Results FISH result showed that the detection rate of cytogenetic abnormalities was 77. 00% in which the detection rates of IGH rearrangement,RB1 deletion,P53 deletion and 1 q21 amplification were 48. 50%,57. 00%,14. 50%and 51. 50%,respectively. Plasma cell ratio,the ratio of International Staging System( ISS) Ⅲ stage,the ratio of DurierSalmon Staging System( DS) Ⅲ stage in IGH rearrangement positive group were significantly higher than those in negative group. The expression rate of CD28 in RB1 deletion positive group was significantly higher than that in RB1 deletion negative group. The blood calcium( Ca2 +) level,plasma cell ratio in bone marrow,CD28 expression rate,the ratio of ISS Ⅲstage and DS Ⅲ stage in P53 deletion positive group were significantly higher than those in P53 deletion negative group,while CD117 expression rate in P53 deletion positive group was significantly lower than that in P53 deletion negative group( all P < 0. 05). There was no significant difference in the clinical indexes between 1 q21 amplification positive and negative groups( P > 0. 05). In T-VAD regimen( thalidomide,vincristine,pirarubicin,dexamethasone),the effective rates of IGH rearrangement positive and P53 deletion positive were significantly lower than those of IGH rearrangement negative and P53 deletion negative( all P < 0. 05). In PD regimen( bortezomib,dexamethasone),the effective rate of P53 deletion positive was significantly lower than that of P53 deletion negative( P < 0. 05). The overall survival time( OS) in IGH rearrangement positive group was significantly shorter than that in IGH rearrangement negative group( P < 0. 05). The OS and the progression free survival time( PFS) in P53 deletion positive group were significantly lower than those in P53 deletion negative group( all P < 0. 05). Conclusions The MM patients have high incidence of cytogenetic abnormalities and coexistence of multiple genetic abnormalities. The cytogenetic abnormality is related to clinical indicator,immunophenotype,therapeutic effect and prognosis. P53 deletion is a factor of poor prognosis with shorter OS and PFS. The detection of cytogenetic abnormalities should be paid attention in clinic for guiding the clinical treatment and prognosis stratified evaluation of MM patients.
Objective To investigate the role of cytogenetic abnormality analysis in risk stratification and prognosis assessment for patients with multiple myeloma( MM). Methods The clinical data of 200 newly treated patients with MM from January 2015 to December 2017 were retrospectively analyzed. In situ fluorescence hybridization( FISH) was used to detect molecular cytogenetic abnormalities in the bone marrow specimen,and the relationship between different chromosomal abnormalities and clinical index,cytoplasmic surface immunophenotype,treatment efficacy and prognosis was analyzed. Results FISH result showed that the detection rate of cytogenetic abnormalities was 77. 00% in which the detection rates of IGH rearrangement,RB1 deletion,P53 deletion and 1 q21 amplification were 48. 50%,57. 00%,14. 50%and 51. 50%,respectively. Plasma cell ratio,the ratio of International Staging System( ISS) Ⅲ stage,the ratio of DurierSalmon Staging System( DS) Ⅲ stage in IGH rearrangement positive group were significantly higher than those in negative group. The expression rate of CD28 in RB1 deletion positive group was significantly higher than that in RB1 deletion negative group. The blood calcium( Ca2 +) level,plasma cell ratio in bone marrow,CD28 expression rate,the ratio of ISS Ⅲstage and DS Ⅲ stage in P53 deletion positive group were significantly higher than those in P53 deletion negative group,while CD117 expression rate in P53 deletion positive group was significantly lower than that in P53 deletion negative group( all P < 0. 05). There was no significant difference in the clinical indexes between 1 q21 amplification positive and negative groups( P > 0. 05). In T-VAD regimen( thalidomide,vincristine,pirarubicin,dexamethasone),the effective rates of IGH rearrangement positive and P53 deletion positive were significantly lower than those of IGH rearrangement negative and P53 deletion negative( all P < 0. 05). In PD regimen( bortezomib,dexamethasone),the effective rate of P53 deletion positive was significantly lower than that of P53 deletion negative( P < 0. 05). The overall survival time( OS) in IGH rearrangement positive group was significantly shorter than that in IGH rearrangement negative group( P < 0. 05). The OS and the progression free survival time( PFS) in P53 deletion positive group were significantly lower than those in P53 deletion negative group( all P < 0. 05). Conclusions The MM patients have high incidence of cytogenetic abnormalities and coexistence of multiple genetic abnormalities. The cytogenetic abnormality is related to clinical indicator,immunophenotype,therapeutic effect and prognosis. P53 deletion is a factor of poor prognosis with shorter OS and PFS. The detection of cytogenetic abnormalities should be paid attention in clinic for guiding the clinical treatment and prognosis stratified evaluation of MM patients.
引文
[1] Daudignon A,Quilichini B,Ameye G,et al. Cytogenetics in the man-agement of multiple myeloma:an update by the Groupe francophonede cytogénétique hématologique(GFCH)[J]. Ann Biol Clin(Par-is),2016,74(5):588-595.
[2]胡凯,王晶,朱明霞,等.不同预后分层的多发性骨髓瘤患者免疫表型特征分析[J].中国实验血液学杂志,2014,22(6):1624-1627.
[3] Mikhael JR,Dingli D,Roy V,et al. Management of newly diagnosedsymptomatic multiple myeloma:updated Mayo Stratification of Myelo-ma and Risk-Adapted Therapy(m SMART)consensus guidelines2013[J]. Mayo Clin Proc,2013,88(4):360-376.
[4] Rajkumar SV,Dimopoulos MA,Palumbo A,et al. International Mye-loma Working Group updated criteria for the diagnosis of multiplemyeloma[J]. Lancet Oncol,2014,15(12):e538-e548.
[5] Greipp PR,San Miguel J,Durie BG,et al. International staging sys-tem for multiple myeloma[J]. J Clin Oncol,2005,23(15):3412-3420.
[6] Durie BGM,Salmon SE. A clinical staging system for multiple myelo-ma correlation of measured myeloma cell mass with presenting clini-cal features,response to treatment,and survival[J]. Cancer,1975,36(3):842-854.
[7] Rajkumar SV. Multiple myeloma:2016 update on diagnosis,risk-stratification,and management[J]. Am J Hematol,2016,91(7):719-734.
[8] Scott EC,Hari P,Sharma M,et al. Post-transplant outcomes in high-risk compared with non-high-risk multiple myeloma:a CIBMTR anal-ysis[J]. Biol Blood Marrow Transplant,2016,22(10):1893-1899.
[9] Avet-Loiseau H,Leleu X,Roussel M,et al. Bortezomib plus dexam-ethasone induction improves outcome of patients with t(4; 14)mye-loma but not outcome of patients with del(17p)[J]. J Clin Oncol,2010,28(30):4630-4634.
[10] Cleynen A,Szalat R,Kemal Samur M,et al. Expressed fusion genelandscape and its impact in multiple myeloma[J]. Nat Commun,2017,8(1):1893.
[11] Smol T,Daudignon A. Comparison of IGH profile signals using t(4;14)and IGH break-apart probes by FISH in multiple myeloma[J].Cytogenet Genome Res,2017,153(1):18-21.
[12] Hermansen NE,Borup R,Andersen MK,et al. Gene expression risksignatures maintain prognostic power in multiple myeloma despitemicroarray probe set translation[J]. Int J Lab Hematol,2016,38(3):298-307.
[13] Sergentanis TN,Kastritis E,Terpos E,et al. Cytogenetics and surviv-al of multiple myeloma:isolated and combined effects[J]. Clin Lym-phoma Myeloma Leuk,2016,16(6):335-340.
[14] Chan H,Phillips M,Maganti M,et al. Single-center experience intreating patients with t(4; 14)multiple myeloma with and withoutplanned frontline autologous stem cell transplantation[J]. Clin Lym-phoma Myeloma Leuk,2018,18(3):225-234.
[15] Chavan SS,He J,Tytarenko R,et al. Bi-allelic inactivation is moreprevalent at relapse in multiple myeloma,identifying RB1 as an in-dependent prognostic marker[J]. Blood Cancer J,2017,7(2):e535.
[16]李燕,杨涛,李静,等.细胞肿瘤高危遗传学异常在多发性骨髓瘤危险度分层中的应用[J].中国老年学杂志,2015,35(14):3843-3845.
[17]辛雪,傅琤琤,孙爱宁.多发性骨髓瘤细胞遗传学及预后相关分析[J].中华临床医师杂志(电子版),2013,7(6):2474-2479.
[18]蒙珊,赵万红,杨云,等. i FISH技术检测多发性骨髓瘤遗传学异常及其临床意义[J].现代肿瘤医学,2018,26(3):440-445.
[19]杨璐璐,聂玉,刘欣,等.免疫组织化学联合荧光原位杂交技术检测多发性骨髓瘤分子细胞遗传学异常[J].中华临床医师杂志(电子版),2013,7(8):3345-3350.
[20] Abramova TV,Obukhova TN,Mendeleeva LP,et al. Prognostic valueof 1q21 amplification in multiple myeloma[J]. Ter Arkh,2017,89(7):32-38.
[21] Weinhold N,Kirn D,Seckinger A,et al. Concomitant gain of 1q21and MYC translocation define a poor prognostic subgroup of hyper-diploid multiple myeloma[J]. Haematologica,2016,101(3):116-119.
[2]胡凯,王晶,朱明霞,等.不同预后分层的多发性骨髓瘤患者免疫表型特征分析[J].中国实验血液学杂志,2014,22(6):1624-1627.
[3] Mikhael JR,Dingli D,Roy V,et al. Management of newly diagnosedsymptomatic multiple myeloma:updated Mayo Stratification of Myelo-ma and Risk-Adapted Therapy(m SMART)consensus guidelines2013[J]. Mayo Clin Proc,2013,88(4):360-376.
[4] Rajkumar SV,Dimopoulos MA,Palumbo A,et al. International Mye-loma Working Group updated criteria for the diagnosis of multiplemyeloma[J]. Lancet Oncol,2014,15(12):e538-e548.
[5] Greipp PR,San Miguel J,Durie BG,et al. International staging sys-tem for multiple myeloma[J]. J Clin Oncol,2005,23(15):3412-3420.
[6] Durie BGM,Salmon SE. A clinical staging system for multiple myelo-ma correlation of measured myeloma cell mass with presenting clini-cal features,response to treatment,and survival[J]. Cancer,1975,36(3):842-854.
[7] Rajkumar SV. Multiple myeloma:2016 update on diagnosis,risk-stratification,and management[J]. Am J Hematol,2016,91(7):719-734.
[8] Scott EC,Hari P,Sharma M,et al. Post-transplant outcomes in high-risk compared with non-high-risk multiple myeloma:a CIBMTR anal-ysis[J]. Biol Blood Marrow Transplant,2016,22(10):1893-1899.
[9] Avet-Loiseau H,Leleu X,Roussel M,et al. Bortezomib plus dexam-ethasone induction improves outcome of patients with t(4; 14)mye-loma but not outcome of patients with del(17p)[J]. J Clin Oncol,2010,28(30):4630-4634.
[10] Cleynen A,Szalat R,Kemal Samur M,et al. Expressed fusion genelandscape and its impact in multiple myeloma[J]. Nat Commun,2017,8(1):1893.
[11] Smol T,Daudignon A. Comparison of IGH profile signals using t(4;14)and IGH break-apart probes by FISH in multiple myeloma[J].Cytogenet Genome Res,2017,153(1):18-21.
[12] Hermansen NE,Borup R,Andersen MK,et al. Gene expression risksignatures maintain prognostic power in multiple myeloma despitemicroarray probe set translation[J]. Int J Lab Hematol,2016,38(3):298-307.
[13] Sergentanis TN,Kastritis E,Terpos E,et al. Cytogenetics and surviv-al of multiple myeloma:isolated and combined effects[J]. Clin Lym-phoma Myeloma Leuk,2016,16(6):335-340.
[14] Chan H,Phillips M,Maganti M,et al. Single-center experience intreating patients with t(4; 14)multiple myeloma with and withoutplanned frontline autologous stem cell transplantation[J]. Clin Lym-phoma Myeloma Leuk,2018,18(3):225-234.
[15] Chavan SS,He J,Tytarenko R,et al. Bi-allelic inactivation is moreprevalent at relapse in multiple myeloma,identifying RB1 as an in-dependent prognostic marker[J]. Blood Cancer J,2017,7(2):e535.
[16]李燕,杨涛,李静,等.细胞肿瘤高危遗传学异常在多发性骨髓瘤危险度分层中的应用[J].中国老年学杂志,2015,35(14):3843-3845.
[17]辛雪,傅琤琤,孙爱宁.多发性骨髓瘤细胞遗传学及预后相关分析[J].中华临床医师杂志(电子版),2013,7(6):2474-2479.
[18]蒙珊,赵万红,杨云,等. i FISH技术检测多发性骨髓瘤遗传学异常及其临床意义[J].现代肿瘤医学,2018,26(3):440-445.
[19]杨璐璐,聂玉,刘欣,等.免疫组织化学联合荧光原位杂交技术检测多发性骨髓瘤分子细胞遗传学异常[J].中华临床医师杂志(电子版),2013,7(8):3345-3350.
[20] Abramova TV,Obukhova TN,Mendeleeva LP,et al. Prognostic valueof 1q21 amplification in multiple myeloma[J]. Ter Arkh,2017,89(7):32-38.
[21] Weinhold N,Kirn D,Seckinger A,et al. Concomitant gain of 1q21and MYC translocation define a poor prognostic subgroup of hyper-diploid multiple myeloma[J]. Haematologica,2016,101(3):116-119.