急性髓系白血病WHO分型及治疗
魏辉中国医学科学院
血液病医院(血液学研究所)
WHO
分型
FAB与WHO
分型
newly diagnosed patients with newlydiagnosedpatientswith“AMLAML,
NOS.”BLOOD,2013 121: 2424-2431
FAB与WHO
分型
NPM1–and NPM1–/CEBPA–NPM1andNPM1/CEBPApatients patients
with newly diagnosed “AML, NOS.”BLOOD,2013 121: 2424-2431
due to the lack of prognostic significance of multilineagedysplasia in patients without MDS-associated cytogenetic findings and with a mutation of NPM1 or biallelicmutation of CEBPA 87-89, these mutations now supersede the presence of multilineage
dysplasia in the classification.
AML with mutated CEBPA or NPM1•
CEBPA要求双突变,需要排除单突变•NPM1和CEBPA突变的AML诊断分型要优和突变的诊断分型要优
先于伴有多系增生异常AML的分型。
NPM1 and Multilineage
dysplasia2010 Dec 23;116(26):6147-8
CEBPAmutationAML
CEBPA mutation AML
J ClinOncol28:2739-2747
CEBPA
mutation
单突变双突变单突变
双突变
de novo AML with BCR-ABL1•一个新的建议分个新的建议分类
•可能从TKI治疗中获益Ph+AMLPh+ AML
CML-MBC
Am J ClinPathol2007;127:642-650
Ph(+)AML vs
CML/BCL
•Ph(+)AML 常伴有免疫球蛋白及T细胞受体基因的隐性缺失。
Br J Haematol. 2013 May;161(4):541-50
Ann Hematol (2016) 95:1211–1221
AML‐MRC
•由于NPM1突变及CEBPA双突变常伴发
del(9q),并且这种情况下的del(9q)没有预后意义因此预后意义,因此,dl(9)从定义MDS相关del(9q)从定义MDS相关
的细胞遗传学异常中去除
RFS
CEBPA and karyotypeCEBPAandkaryotype
abnormalities
OS
Blood. 2013;122(9):1576-1582
NPM1 and karyotypeabnormalities
EFS
OS
Blood. 2009;114:3024-3032
AML with mutated RUNX1
•一个新的建议分类
•主要见于细胞遗传学中危组,尤其是正常核型非复杂核型的核型,非复杂核型的+8。高危组中发生率高危组中发生率低。
•RUNX1突变与MDS相关的细胞遗传学改变没有相关性
J ClinOncol2011,29:1364-1372
RUNX1 and karyotype
FavorableIntermediateUnfavorableNormalSimpleComplex-7/7q-+8+21-5/5q-+11+13
[***********]211131
0 (0.0)48(147)48 (14.7)8 (12.1)32 (13.9)19 (11.2)5 (9.4)3 (30.0)6 (27.3)2(182)2 (18.2)0 (0.0)0 (0.0)0 (0.0)
59 (100.0)279(853)279 (85.3)58 (87.9)198 (86.1)150 (88.8)48 (90.6)7 (70.0)16 (72.7)9(818)9 (81.8)1 (100.0)3 (100.0)1 (100.0)
Blood. 2009;114:5352-5361
RUNX1mutationRUNX1 mutation
•发生率:5.6%,
(6.3% in CN AML)•CR:RUNX1突变型和野生型的CR率分别为60.4%and73.4%60.4% and 73.4% (
P=0.055)
J ClinOncol2011,29:1364-1372
RUNX1mutationRUNX1 mutation
RFS
OS
J ClinOncol2011,29:1364-1372
AML, not otherwise specified
•急性红白血病(AML,
erythroid/myeloid type从分类中删从分类中删除
•纯红血病(Pure erythroidleukemia)仍然保留在
AML, NOS亚型中。AMLNOS亚型中
BM erythroid precursors
Myeloblast % in BM (or PB)
Prior Therapy
Recurring genetic abnormality
Meets criteria for AML-MRC
Fourth edition diagnosis Therapy-related myeloidneoplasm AML with recurring genetic abnormality
Updated fourth edition diagnosis Therapy-related myeloid neoplasm AML with recurring genetic abnormality
≥50% ≥50% ≥50% ≥50%
NA ≥20% ≥20% ≥20%
Yes No No No
NA Yes No No
NA Yes No NA
AML with MRC
AML, NOS, acute erythroid leukemia (erythroid/ myeloid type) AML, NOS, acute erythroid leukemia (erythroid/ myeloid subtype)
AML with MRC AML, NOS (non erythroid subtype) MDS
≥50
<20%, but ≥20% of nonerythroi d cells <20%, and <20% of nonerythroi d cells
No
No
NA
≥50%
No
No
NA
MDS
MDS
≥80% immature erythroid precursors with ≥30% proerythroblasts
<20%
No
No
NA
AML, NOS, acute erythroid leukemia (pure erythroid type)
AML, NOS, acute erythroid leukemia (pure erythroid type)
Genetic G ti alteration lt ti in i AML‐ M6(WHO2008)
Leukemia (2013) 27, 1940–1943;
11 genes and counting
• Hematologic malignancies only
AML: CEBPA MDS/AML: DDX41 MPNs/AML: ATG2B/GSKIP
•
Cytopenias and/or platelet dysfunction
FPD/AML: RUNX1 MDS/AML: GATA2 Thrombocytopenia:ETV6, ANKRD26
•
Bone marrow f B failure il syndromes
Telomere syndromes: TERT, TERC, ACD AA/MDS:SRP72
Blood. 2016 Feb 25;127(8):960-1
Familial AML with germline CEBPA mutations
Blood. 2015;126(10):1214-1223
MPAL
• 诊断AML或ALL,并不需要按照MPAL的系列 标志标准进行分型诊断。 • 对于两群细胞的白血病,每 对于两群细胞的白血病,每一个符合T、B 个符合T、B 或髓系标准即可,不一定要有特异性系列 标志表达
AML‐M0
• 例,FCM, one blast population : cCD3 dim, , CD33, , CD34, , CD56 bright, g , and CD13 dim, CD117. • Negative: CD1a CD1a, CD2, CD2 mCD3 mCD3, CD5 CD5, CD4 CD4, CD7, CD8, CD11b, CD11c, CD14, CD16, C 1 C CD41, CD61, 61 C CD64, 6 glycophorin A, HLADR, MPO, and TdT • 核型:46,XY
Am J Clin Pathol 2015;144:361-376
BPDCN
AML的治疗
成人AML的诱导治疗
NCRI AML17 GOELAMS LAM-2001
DA45
DA90
=
DA60
IA8X5
ECOG1900
N Engl J Med 2009;361:1249-1259. Blood. 2015;125(25):3878-3885 Blood. 2011;117(8):2358 Leukemia. 2014; 28(2):440-4433
DA50X5
IA12
JALSG AML201
蒽环剂量与NPM1
突变
Blood. 2016;127(12):1551-1558
CALGB8525CALGB 8525
INDUCTION
R
ANCRD
O
MIZE
INTENSIFICATION
Ara‐C, 4 courses100mg/m2, d1‐5400mg/m2, d1‐53g/m2/12h, d1, 3, 5
AMLn=10881088
DNR 45mg/m2, d1‐3(≤60y)
30mg/m2, d1‐3(>60y)Ara‐C 200mg/m2, d1‐7
N Engl J Med. 1994 Oct 6;331(14):896‐903
成人AML的巩固治疗
MRCAML15MRC AML15CAGB9222ALFA 9802德国AML2003血研所
诱导两疗程DA(45)
MACE
MidAC
HDACCTX+VP16
MTZ+AZQ
TSC
Amsa+Ara-c
TSC
DA双诱导
MAC(1g/m2)MAMAC
MA
MAC
HAD
DA/MA中剂量X2
HA
J ClinOncol. 2013; 31(27):3360 J ClinOncol2013;31:2094-2102 Blood. 2011;118(7):1754-1762 Blood. 2005;105:3420-3427
大剂量阿糖胞苷的剂量
MRCAML15
MRC-AML 15
J Clin Oncol. 2013; 31(27):3360
23g/m2
vs 1.5g/mAra-c
P=0.6
P
=0
0.11
J Clin Oncol. 2013; 31(27):3360
AML缓解后应予几个疗程的巩
固治疗
MRCAML15
MRC-AML 15
J Clin Oncol. 2013; 31(27):3360
巩固治疗(4疗程vs 5vs5疗程)OS
P=0.9
RFS
P
=0. 7
J Clin Oncol. 2013; 31(27):3360
Toxicityy
consolidation (110 patients)C1(110)
Median duration with
ffeverMedian duration with antibioticsMedian duration with WBC count≤1×10 9/LMedian duration with ANC≤0.5×109/L
3 days8 days13 days15 days
C2(95)4 days10 days14 days14 days
C3(81)2 days8 days12 days14 days
C4(74)2 days8 days13 days14 days
20 (18%), 17 (18%), 17 (21%) and 13 (18%) experienced no single febrile episode during HDAC consolidation courses
Leukemia & Lymphoma, June 2012; 53(6): 1068–1076
小结•遗传学在WHO急性髓系白血病分型中越来越重要•强烈的诱导治疗提高AML预后中危组的总生存•HDAC是AML
理想的巩固治疗方案
急性髓系白血病WHO分型及治疗
魏辉中国医学科学院
血液病医院(血液学研究所)
WHO
分型
FAB与WHO
分型
newly diagnosed patients with newlydiagnosedpatientswith“AMLAML,
NOS.”BLOOD,2013 121: 2424-2431
FAB与WHO
分型
NPM1–and NPM1–/CEBPA–NPM1andNPM1/CEBPApatients patients
with newly diagnosed “AML, NOS.”BLOOD,2013 121: 2424-2431
due to the lack of prognostic significance of multilineagedysplasia in patients without MDS-associated cytogenetic findings and with a mutation of NPM1 or biallelicmutation of CEBPA 87-89, these mutations now supersede the presence of multilineage
dysplasia in the classification.
AML with mutated CEBPA or NPM1•
CEBPA要求双突变,需要排除单突变•NPM1和CEBPA突变的AML诊断分型要优和突变的诊断分型要优
先于伴有多系增生异常AML的分型。
NPM1 and Multilineage
dysplasia2010 Dec 23;116(26):6147-8
CEBPAmutationAML
CEBPA mutation AML
J ClinOncol28:2739-2747
CEBPA
mutation
单突变双突变单突变
双突变
de novo AML with BCR-ABL1•一个新的建议分个新的建议分类
•可能从TKI治疗中获益Ph+AMLPh+ AML
CML-MBC
Am J ClinPathol2007;127:642-650
Ph(+)AML vs
CML/BCL
•Ph(+)AML 常伴有免疫球蛋白及T细胞受体基因的隐性缺失。
Br J Haematol. 2013 May;161(4):541-50
Ann Hematol (2016) 95:1211–1221
AML‐MRC
•由于NPM1突变及CEBPA双突变常伴发
del(9q),并且这种情况下的del(9q)没有预后意义因此预后意义,因此,dl(9)从定义MDS相关del(9q)从定义MDS相关
的细胞遗传学异常中去除
RFS
CEBPA and karyotypeCEBPAandkaryotype
abnormalities
OS
Blood. 2013;122(9):1576-1582
NPM1 and karyotypeabnormalities
EFS
OS
Blood. 2009;114:3024-3032
AML with mutated RUNX1
•一个新的建议分类
•主要见于细胞遗传学中危组,尤其是正常核型非复杂核型的核型,非复杂核型的+8。高危组中发生率高危组中发生率低。
•RUNX1突变与MDS相关的细胞遗传学改变没有相关性
J ClinOncol2011,29:1364-1372
RUNX1 and karyotype
FavorableIntermediateUnfavorableNormalSimpleComplex-7/7q-+8+21-5/5q-+11+13
[***********]211131
0 (0.0)48(147)48 (14.7)8 (12.1)32 (13.9)19 (11.2)5 (9.4)3 (30.0)6 (27.3)2(182)2 (18.2)0 (0.0)0 (0.0)0 (0.0)
59 (100.0)279(853)279 (85.3)58 (87.9)198 (86.1)150 (88.8)48 (90.6)7 (70.0)16 (72.7)9(818)9 (81.8)1 (100.0)3 (100.0)1 (100.0)
Blood. 2009;114:5352-5361
RUNX1mutationRUNX1 mutation
•发生率:5.6%,
(6.3% in CN AML)•CR:RUNX1突变型和野生型的CR率分别为60.4%and73.4%60.4% and 73.4% (
P=0.055)
J ClinOncol2011,29:1364-1372
RUNX1mutationRUNX1 mutation
RFS
OS
J ClinOncol2011,29:1364-1372
AML, not otherwise specified
•急性红白血病(AML,
erythroid/myeloid type从分类中删从分类中删除
•纯红血病(Pure erythroidleukemia)仍然保留在
AML, NOS亚型中。AMLNOS亚型中
BM erythroid precursors
Myeloblast % in BM (or PB)
Prior Therapy
Recurring genetic abnormality
Meets criteria for AML-MRC
Fourth edition diagnosis Therapy-related myeloidneoplasm AML with recurring genetic abnormality
Updated fourth edition diagnosis Therapy-related myeloid neoplasm AML with recurring genetic abnormality
≥50% ≥50% ≥50% ≥50%
NA ≥20% ≥20% ≥20%
Yes No No No
NA Yes No No
NA Yes No NA
AML with MRC
AML, NOS, acute erythroid leukemia (erythroid/ myeloid type) AML, NOS, acute erythroid leukemia (erythroid/ myeloid subtype)
AML with MRC AML, NOS (non erythroid subtype) MDS
≥50
<20%, but ≥20% of nonerythroi d cells <20%, and <20% of nonerythroi d cells
No
No
NA
≥50%
No
No
NA
MDS
MDS
≥80% immature erythroid precursors with ≥30% proerythroblasts
<20%
No
No
NA
AML, NOS, acute erythroid leukemia (pure erythroid type)
AML, NOS, acute erythroid leukemia (pure erythroid type)
Genetic G ti alteration lt ti in i AML‐ M6(WHO2008)
Leukemia (2013) 27, 1940–1943;
11 genes and counting
• Hematologic malignancies only
AML: CEBPA MDS/AML: DDX41 MPNs/AML: ATG2B/GSKIP
•
Cytopenias and/or platelet dysfunction
FPD/AML: RUNX1 MDS/AML: GATA2 Thrombocytopenia:ETV6, ANKRD26
•
Bone marrow f B failure il syndromes
Telomere syndromes: TERT, TERC, ACD AA/MDS:SRP72
Blood. 2016 Feb 25;127(8):960-1
Familial AML with germline CEBPA mutations
Blood. 2015;126(10):1214-1223
MPAL
• 诊断AML或ALL,并不需要按照MPAL的系列 标志标准进行分型诊断。 • 对于两群细胞的白血病,每 对于两群细胞的白血病,每一个符合T、B 个符合T、B 或髓系标准即可,不一定要有特异性系列 标志表达
AML‐M0
• 例,FCM, one blast population : cCD3 dim, , CD33, , CD34, , CD56 bright, g , and CD13 dim, CD117. • Negative: CD1a CD1a, CD2, CD2 mCD3 mCD3, CD5 CD5, CD4 CD4, CD7, CD8, CD11b, CD11c, CD14, CD16, C 1 C CD41, CD61, 61 C CD64, 6 glycophorin A, HLADR, MPO, and TdT • 核型:46,XY
Am J Clin Pathol 2015;144:361-376
BPDCN
AML的治疗
成人AML的诱导治疗
NCRI AML17 GOELAMS LAM-2001
DA45
DA90
=
DA60
IA8X5
ECOG1900
N Engl J Med 2009;361:1249-1259. Blood. 2015;125(25):3878-3885 Blood. 2011;117(8):2358 Leukemia. 2014; 28(2):440-4433
DA50X5
IA12
JALSG AML201
蒽环剂量与NPM1
突变
Blood. 2016;127(12):1551-1558
CALGB8525CALGB 8525
INDUCTION
R
ANCRD
O
MIZE
INTENSIFICATION
Ara‐C, 4 courses100mg/m2, d1‐5400mg/m2, d1‐53g/m2/12h, d1, 3, 5
AMLn=10881088
DNR 45mg/m2, d1‐3(≤60y)
30mg/m2, d1‐3(>60y)Ara‐C 200mg/m2, d1‐7
N Engl J Med. 1994 Oct 6;331(14):896‐903
成人AML的巩固治疗
MRCAML15MRC AML15CAGB9222ALFA 9802德国AML2003血研所
诱导两疗程DA(45)
MACE
MidAC
HDACCTX+VP16
MTZ+AZQ
TSC
Amsa+Ara-c
TSC
DA双诱导
MAC(1g/m2)MAMAC
MA
MAC
HAD
DA/MA中剂量X2
HA
J ClinOncol. 2013; 31(27):3360 J ClinOncol2013;31:2094-2102 Blood. 2011;118(7):1754-1762 Blood. 2005;105:3420-3427
大剂量阿糖胞苷的剂量
MRCAML15
MRC-AML 15
J Clin Oncol. 2013; 31(27):3360
23g/m2
vs 1.5g/mAra-c
P=0.6
P
=0
0.11
J Clin Oncol. 2013; 31(27):3360
AML缓解后应予几个疗程的巩
固治疗
MRCAML15
MRC-AML 15
J Clin Oncol. 2013; 31(27):3360
巩固治疗(4疗程vs 5vs5疗程)OS
P=0.9
RFS
P
=0. 7
J Clin Oncol. 2013; 31(27):3360
Toxicityy
consolidation (110 patients)C1(110)
Median duration with
ffeverMedian duration with antibioticsMedian duration with WBC count≤1×10 9/LMedian duration with ANC≤0.5×109/L
3 days8 days13 days15 days
C2(95)4 days10 days14 days14 days
C3(81)2 days8 days12 days14 days
C4(74)2 days8 days13 days14 days
20 (18%), 17 (18%), 17 (21%) and 13 (18%) experienced no single febrile episode during HDAC consolidation courses
Leukemia & Lymphoma, June 2012; 53(6): 1068–1076
小结•遗传学在WHO急性髓系白血病分型中越来越重要•强烈的诱导治疗提高AML预后中危组的总生存•HDAC是AML
理想的巩固治疗方案