MONOSOMAL KARYOTYPE AND TRISOMY 8 ARE POOR PROGNOSTIC FACTORS IN PEDIATRIC AML: AN AML-BFM 2004 TRIAL REPORT ON GENOTYPE-OUTCOME CORRELATIONS
(Abstract release date: 05/19/16)
EHA Library. Rasche M. 06/11/16; 135239; S483
Dr. Mareike Rasche
Contributions
Contributions
Abstract
Abstract: S483
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A2
Background
Conflicting data on poor risk factors in pediatric acute myeloid leukemia (AML) hamper risk stratification systems and the improvement of risk-adapted therapeutic strategies.
Aims
We aimed to unravel the prognostic impact of specific chromosomal aberrations including complex and hypodiploid as well as monosomal karyotypes and trisomy 8 in pediatric patients with AML.
Methods
Karyotypes of a population-based cohort of 643 patients <18 years with de novo AML treated on the AML-BFM 2004 study protocol (excluding Down’s Syndrome and patients with t(15;17)/PML-RARA fusion gene) were analyzed. For cytogenetic definitions see Table 1.
Results
Our analysis revealed overlapping groups of patients with monosomal (MK+), complex (CK+) or hypodiploid (HK+) karyotypes. Multivariate regression confirmed MK+ (n=25) as new independent poor risk factor for event-free survival (EFS) with a reduced EFS of 23±9% (p=0.008), even after exclusion of monosomy 7 (MKno-7; n=19; EFS 25±10%, p=0.007). As expected, Monosomy 7 (n=8; pEFS 13%±12%; p=0.0026) was associated with poor outcome and resistance to induction chemotherapy. Importantly, after exclusion of MK, patients with CK did not experience a significantly worse outcome (n=47; 42±7%, p=0.12), while CK+/MK+ patients did poorly (n=11; EFS 24±14%, p =0.04). Similarly, hypodiploid karyotype (HK) did not predict worse outcome overall (n=38; EFS 43±8%, p=0.26). However, after exclusion of HK+ patients with concurrent t(8;21) (n=21; pEFS 70±10%), the remaining HK+ patients showed very poor prognosis (n=17, pEFS 9±8%, p=<0.0001). Finally Trisomy 8 without additional cytogenetic aberrations was associated with poor outcome (n=16; EFS 25±11%; p=0.009).
* in comparison to other patients with cytogenetic data, + 3 or more aberrations, at least one structural aberration; without favorable genetics; without MLL rearrangement, † Two or more autosomal monosomies or one autosomal monosomy with at least one structural abnormality. No favorable cytogenetics (t(15;17)(q22;q21); (t(8;21)(q22;q22); inv(16)(p13q22)/t(16;16)(p13;q22)), ¬ < 46 chromosomes, SE = standard error, pOS = probability of OS, pEFS = probability of ES
Conclusion
Our study identified monosomal karyotype and isolated trisomy 8 for the first time as strong and independent prognostic factors in a pediatric AML cohort that are associated with poor outcome. In contrast, complex karyotype alone without MK or hypodiploidy per se does not seem to confer dismal prognosis. These results have important implications for risk stratification including the indication for stem cell transplantation and should be validated in ongoing pediatric trials.
Session topic: Standard Treatment Results in AML
Keyword(s): AML, Cytogenetics, Pediatric
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A2
Background
Conflicting data on poor risk factors in pediatric acute myeloid leukemia (AML) hamper risk stratification systems and the improvement of risk-adapted therapeutic strategies.
Aims
We aimed to unravel the prognostic impact of specific chromosomal aberrations including complex and hypodiploid as well as monosomal karyotypes and trisomy 8 in pediatric patients with AML.
Methods
Karyotypes of a population-based cohort of 643 patients <18 years with de novo AML treated on the AML-BFM 2004 study protocol (excluding Down’s Syndrome and patients with t(15;17)/PML-RARA fusion gene) were analyzed. For cytogenetic definitions see Table 1.
Results
Our analysis revealed overlapping groups of patients with monosomal (MK+), complex (CK+) or hypodiploid (HK+) karyotypes. Multivariate regression confirmed MK+ (n=25) as new independent poor risk factor for event-free survival (EFS) with a reduced EFS of 23±9% (p=0.008), even after exclusion of monosomy 7 (MKno-7; n=19; EFS 25±10%, p=0.007). As expected, Monosomy 7 (n=8; pEFS 13%±12%; p=0.0026) was associated with poor outcome and resistance to induction chemotherapy. Importantly, after exclusion of MK, patients with CK did not experience a significantly worse outcome (n=47; 42±7%, p=0.12), while CK+/MK+ patients did poorly (n=11; EFS 24±14%, p =0.04). Similarly, hypodiploid karyotype (HK) did not predict worse outcome overall (n=38; EFS 43±8%, p=0.26). However, after exclusion of HK+ patients with concurrent t(8;21) (n=21; pEFS 70±10%), the remaining HK+ patients showed very poor prognosis (n=17, pEFS 9±8%, p=<0.0001). Finally Trisomy 8 without additional cytogenetic aberrations was associated with poor outcome (n=16; EFS 25±11%; p=0.009).
| Pts n(%) | 5y pEFS (SE) % | p-value (Logrank)* | 5ypOS (SE)% | p-value (Logrank)* | |
| monosomal karyotype† (MK+) | 25(4) | 23(9) | 0.0008 | 43(10) | 0.0008 |
| monosomal karyotype†excl. -7 | 19(3) | 25(10) | 0.0066 | 47(12) | 0.0070 |
| MK+/CK+ | 11(2) | 24(14) | 0.041 | 36(15) | 0.0013 |
| MK+/CK- | 14(2) | 21(11) | 0.0047 | 50(13) | 0.070 |
| MK+/HK+ | 11(2) | 9(9) | < 0.0001 | 36(15) | 0.0031 |
| MK+/HK- | 14(2) | 34(13) | 0.22 | 49(14) | 0.057 |
| hypodiploid karyotype¬ (HK+) | 38 (6) | 43(8) | 0.26 | 62(8) | 0.27 |
| HK+/MK- | 27(4) | 57(10) | 0.60 | 73(9) | 0.59 |
| complex karyotypes+(CK+) | 58(9) | 42(7) | 0.12 | 62(7) | 0.30 |
| CK+/MK- | 47(7) | 47(7) | 0.33 | 68(8) | 0.94 |
Conclusion
Our study identified monosomal karyotype and isolated trisomy 8 for the first time as strong and independent prognostic factors in a pediatric AML cohort that are associated with poor outcome. In contrast, complex karyotype alone without MK or hypodiploidy per se does not seem to confer dismal prognosis. These results have important implications for risk stratification including the indication for stem cell transplantation and should be validated in ongoing pediatric trials.
Session topic: Standard Treatment Results in AML
Keyword(s): AML, Cytogenetics, Pediatric
Abstract: S483
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A2
Background
Conflicting data on poor risk factors in pediatric acute myeloid leukemia (AML) hamper risk stratification systems and the improvement of risk-adapted therapeutic strategies.
Aims
We aimed to unravel the prognostic impact of specific chromosomal aberrations including complex and hypodiploid as well as monosomal karyotypes and trisomy 8 in pediatric patients with AML.
Methods
Karyotypes of a population-based cohort of 643 patients <18 years with de novo AML treated on the AML-BFM 2004 study protocol (excluding Down’s Syndrome and patients with t(15;17)/PML-RARA fusion gene) were analyzed. For cytogenetic definitions see Table 1.
Results
Our analysis revealed overlapping groups of patients with monosomal (MK+), complex (CK+) or hypodiploid (HK+) karyotypes. Multivariate regression confirmed MK+ (n=25) as new independent poor risk factor for event-free survival (EFS) with a reduced EFS of 23±9% (p=0.008), even after exclusion of monosomy 7 (MKno-7; n=19; EFS 25±10%, p=0.007). As expected, Monosomy 7 (n=8; pEFS 13%±12%; p=0.0026) was associated with poor outcome and resistance to induction chemotherapy. Importantly, after exclusion of MK, patients with CK did not experience a significantly worse outcome (n=47; 42±7%, p=0.12), while CK+/MK+ patients did poorly (n=11; EFS 24±14%, p =0.04). Similarly, hypodiploid karyotype (HK) did not predict worse outcome overall (n=38; EFS 43±8%, p=0.26). However, after exclusion of HK+ patients with concurrent t(8;21) (n=21; pEFS 70±10%), the remaining HK+ patients showed very poor prognosis (n=17, pEFS 9±8%, p=<0.0001). Finally Trisomy 8 without additional cytogenetic aberrations was associated with poor outcome (n=16; EFS 25±11%; p=0.009).
* in comparison to other patients with cytogenetic data, + 3 or more aberrations, at least one structural aberration; without favorable genetics; without MLL rearrangement, † Two or more autosomal monosomies or one autosomal monosomy with at least one structural abnormality. No favorable cytogenetics (t(15;17)(q22;q21); (t(8;21)(q22;q22); inv(16)(p13q22)/t(16;16)(p13;q22)), ¬ < 46 chromosomes, SE = standard error, pOS = probability of OS, pEFS = probability of ES
Conclusion
Our study identified monosomal karyotype and isolated trisomy 8 for the first time as strong and independent prognostic factors in a pediatric AML cohort that are associated with poor outcome. In contrast, complex karyotype alone without MK or hypodiploidy per se does not seem to confer dismal prognosis. These results have important implications for risk stratification including the indication for stem cell transplantation and should be validated in ongoing pediatric trials.
Session topic: Standard Treatment Results in AML
Keyword(s): AML, Cytogenetics, Pediatric
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 16:15 - 16:30
Location: Hall A2
Background
Conflicting data on poor risk factors in pediatric acute myeloid leukemia (AML) hamper risk stratification systems and the improvement of risk-adapted therapeutic strategies.
Aims
We aimed to unravel the prognostic impact of specific chromosomal aberrations including complex and hypodiploid as well as monosomal karyotypes and trisomy 8 in pediatric patients with AML.
Methods
Karyotypes of a population-based cohort of 643 patients <18 years with de novo AML treated on the AML-BFM 2004 study protocol (excluding Down’s Syndrome and patients with t(15;17)/PML-RARA fusion gene) were analyzed. For cytogenetic definitions see Table 1.
Results
Our analysis revealed overlapping groups of patients with monosomal (MK+), complex (CK+) or hypodiploid (HK+) karyotypes. Multivariate regression confirmed MK+ (n=25) as new independent poor risk factor for event-free survival (EFS) with a reduced EFS of 23±9% (p=0.008), even after exclusion of monosomy 7 (MKno-7; n=19; EFS 25±10%, p=0.007). As expected, Monosomy 7 (n=8; pEFS 13%±12%; p=0.0026) was associated with poor outcome and resistance to induction chemotherapy. Importantly, after exclusion of MK, patients with CK did not experience a significantly worse outcome (n=47; 42±7%, p=0.12), while CK+/MK+ patients did poorly (n=11; EFS 24±14%, p =0.04). Similarly, hypodiploid karyotype (HK) did not predict worse outcome overall (n=38; EFS 43±8%, p=0.26). However, after exclusion of HK+ patients with concurrent t(8;21) (n=21; pEFS 70±10%), the remaining HK+ patients showed very poor prognosis (n=17, pEFS 9±8%, p=<0.0001). Finally Trisomy 8 without additional cytogenetic aberrations was associated with poor outcome (n=16; EFS 25±11%; p=0.009).
| Pts n(%) | 5y pEFS (SE) % | p-value (Logrank)* | 5ypOS (SE)% | p-value (Logrank)* | |
| monosomal karyotype† (MK+) | 25(4) | 23(9) | 0.0008 | 43(10) | 0.0008 |
| monosomal karyotype†excl. -7 | 19(3) | 25(10) | 0.0066 | 47(12) | 0.0070 |
| MK+/CK+ | 11(2) | 24(14) | 0.041 | 36(15) | 0.0013 |
| MK+/CK- | 14(2) | 21(11) | 0.0047 | 50(13) | 0.070 |
| MK+/HK+ | 11(2) | 9(9) | < 0.0001 | 36(15) | 0.0031 |
| MK+/HK- | 14(2) | 34(13) | 0.22 | 49(14) | 0.057 |
| hypodiploid karyotype¬ (HK+) | 38 (6) | 43(8) | 0.26 | 62(8) | 0.27 |
| HK+/MK- | 27(4) | 57(10) | 0.60 | 73(9) | 0.59 |
| complex karyotypes+(CK+) | 58(9) | 42(7) | 0.12 | 62(7) | 0.30 |
| CK+/MK- | 47(7) | 47(7) | 0.33 | 68(8) | 0.94 |
Conclusion
Our study identified monosomal karyotype and isolated trisomy 8 for the first time as strong and independent prognostic factors in a pediatric AML cohort that are associated with poor outcome. In contrast, complex karyotype alone without MK or hypodiploidy per se does not seem to confer dismal prognosis. These results have important implications for risk stratification including the indication for stem cell transplantation and should be validated in ongoing pediatric trials.
Session topic: Standard Treatment Results in AML
Keyword(s): AML, Cytogenetics, Pediatric
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