Contributions
Abstract: S1567
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:30 - 08:45
Location: Room K1
Background
Impressive improvements of survival rates in pediatric acute lymphoblastic leukemia (ALL) have been achieved during the last decades, but a significant proportion of patients still suffers from relapse and therapy-related toxicities. Further improvement of therapy can be achieved by better personalized adjustment of treatment to the risk of relapse.
Aims
While most research activities on genetic prognostic factors have focused on somatic features, relatively little is known on hereditary contributions to treatment response and outcome in pediatric ALL. Therefore, we conducted a genome-wide association study (GWAS) of relapse in B cell precursor (BCP) ALL.
Methods
Our study included 1152 patients from AIEOP-BFM ALL 2000 (Schrappe et al. Blood 2011). On this trial, patients were stratified into three risk groups, mainly by minimal residual disease (MRD) analyses. Treatment employed standard drugs. Complete remission (CR) was defined as the absence of physical signs of leukemia or detectable leukemia cells on blood smears, <5% leukemia blast cells present in the bone marrow, and normal cerebrospinal fluid (CSF). The diagnosis of relapse was only made after CR has been achieved before and was defined as isolated bone marrow, combined bone marrow, CNS or testicular relapse. Of the 1152 patients included, 145 relapsed (cases) and 1007 patients remained in long-term CR (controls). DNA isolated from remission samples was genotyped by Illumina Human1M-Duo BeadChips containing 1.048.711 single SNV markers. For GWAS analyses gPLINK v2.050, PLINK v.1.09 and RStatistics v3.3.1 were used. Replication analyses were conducted in a cohort of 73 relapsed and 615 non-relapsed patients treated on trial AIEOP-BFM ALL 2009.
Results
After quality control assessment, the analysis of the initial cohort included 751.432 SNPs among 130 relapsed compared to 889 control patients. Twenty candidate SNVs demonstrating promising associations with risk of relapse were selected for replication analysis, including intronic SNVs in the Ankyrin repeat and SOCS box protein 3 (ASB3, rs1549749, P=8.593×10−7, odds ratio, OR, 2.48) and the inositol polyphosphate multikinase (IPMK, rs7919168, P=1.266×10−5, OR 2.06). One additional SNV in ASB3 and six additional SNVs in IPMK were in linkage disequilibrium with rs1549749 and rs7919168 and demonstrated significant levels of P ≤1.7×10−5. Replication analyses in an independent cohort from AIEOP-BFM ALL 2009 confirmed the initial observations for risk of relapse conferred by rs1549749 and rs7919168 and - in combined analysis of the initial and replication cohort - revealed genome-wide significance (rs1549749, P=4.98×10−8 OR=2.09; rs7919168, P=1.3×10−8 OR=3.13). In further analysis of the initial cohort from AIEOP-BFM ALL 2000, rs1549749 and rs7919168 risk alleles were associated with a significantly lower 5-year-event-free survival (EFS) compared to wildtype (0.75±0.03 vs. 0.9±0.01, P<0.0001; 0.79±0.09 vs. 0.99±0.01, P=0.008). Multivariate Cox analyses of the above ASB3 and IPMK SNVs demonstrated independence of the observed relapse risk associations (hazard ratio rs1549749: 1.55, 95% CI 1.15-2.10; hazard ratio rs7919168: 2.10, 95% CI 1.48-2.97).
Conclusion
We identified genome-wide significant associations of ASB3 and IPMK germline variations with risk of relapse in BCP ALL patients treated on BFM protocols for pediatric ALL. These results suggest that germline genetic variation influences effectiveness of chemotherapy in pediatric ALL and represent an important additional step in defining the hereditary contribution to the risk of relapse in pediatric ALL.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, Childhood, Relapse, SNP
Abstract: S1567
Type: Oral Presentation
Presentation during EHA23: On Sunday, June 17, 2018 from 08:30 - 08:45
Location: Room K1
Background
Impressive improvements of survival rates in pediatric acute lymphoblastic leukemia (ALL) have been achieved during the last decades, but a significant proportion of patients still suffers from relapse and therapy-related toxicities. Further improvement of therapy can be achieved by better personalized adjustment of treatment to the risk of relapse.
Aims
While most research activities on genetic prognostic factors have focused on somatic features, relatively little is known on hereditary contributions to treatment response and outcome in pediatric ALL. Therefore, we conducted a genome-wide association study (GWAS) of relapse in B cell precursor (BCP) ALL.
Methods
Our study included 1152 patients from AIEOP-BFM ALL 2000 (Schrappe et al. Blood 2011). On this trial, patients were stratified into three risk groups, mainly by minimal residual disease (MRD) analyses. Treatment employed standard drugs. Complete remission (CR) was defined as the absence of physical signs of leukemia or detectable leukemia cells on blood smears, <5% leukemia blast cells present in the bone marrow, and normal cerebrospinal fluid (CSF). The diagnosis of relapse was only made after CR has been achieved before and was defined as isolated bone marrow, combined bone marrow, CNS or testicular relapse. Of the 1152 patients included, 145 relapsed (cases) and 1007 patients remained in long-term CR (controls). DNA isolated from remission samples was genotyped by Illumina Human1M-Duo BeadChips containing 1.048.711 single SNV markers. For GWAS analyses gPLINK v2.050, PLINK v.1.09 and RStatistics v3.3.1 were used. Replication analyses were conducted in a cohort of 73 relapsed and 615 non-relapsed patients treated on trial AIEOP-BFM ALL 2009.
Results
After quality control assessment, the analysis of the initial cohort included 751.432 SNPs among 130 relapsed compared to 889 control patients. Twenty candidate SNVs demonstrating promising associations with risk of relapse were selected for replication analysis, including intronic SNVs in the Ankyrin repeat and SOCS box protein 3 (ASB3, rs1549749, P=8.593×10−7, odds ratio, OR, 2.48) and the inositol polyphosphate multikinase (IPMK, rs7919168, P=1.266×10−5, OR 2.06). One additional SNV in ASB3 and six additional SNVs in IPMK were in linkage disequilibrium with rs1549749 and rs7919168 and demonstrated significant levels of P ≤1.7×10−5. Replication analyses in an independent cohort from AIEOP-BFM ALL 2009 confirmed the initial observations for risk of relapse conferred by rs1549749 and rs7919168 and - in combined analysis of the initial and replication cohort - revealed genome-wide significance (rs1549749, P=4.98×10−8 OR=2.09; rs7919168, P=1.3×10−8 OR=3.13). In further analysis of the initial cohort from AIEOP-BFM ALL 2000, rs1549749 and rs7919168 risk alleles were associated with a significantly lower 5-year-event-free survival (EFS) compared to wildtype (0.75±0.03 vs. 0.9±0.01, P<0.0001; 0.79±0.09 vs. 0.99±0.01, P=0.008). Multivariate Cox analyses of the above ASB3 and IPMK SNVs demonstrated independence of the observed relapse risk associations (hazard ratio rs1549749: 1.55, 95% CI 1.15-2.10; hazard ratio rs7919168: 2.10, 95% CI 1.48-2.97).
Conclusion
We identified genome-wide significant associations of ASB3 and IPMK germline variations with risk of relapse in BCP ALL patients treated on BFM protocols for pediatric ALL. These results suggest that germline genetic variation influences effectiveness of chemotherapy in pediatric ALL and represent an important additional step in defining the hereditary contribution to the risk of relapse in pediatric ALL.
Session topic: 2. Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, Childhood, Relapse, SNP