EARLY IMMATURE T-ALL AS DETERMINED BY ABSENCE OF BI-ALLELIC DELETION AT THE TCR GAMMA LOCUS IS NOT AN ADVERSE PROGNOSTIC FACTOR ON THE MRC UKALL2003 TRIAL
(Abstract release date: 05/19/16)
EHA Library. Farah N. 06/11/16; 135256; S500
Dr. Nadine Farah
Contributions
Contributions
Abstract
Abstract: S500
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:00 - 17:15
Location: Auditorium 2
Background
Despite a marked improvement in the survival of children with T-cell acute lymphoblastic leukaemia (T-ALL), a significant proportion of patients will experience refractory disease or relapse. Previous studies using immunophenotyping and gene expression profiling identified the early T-cell precursor (ETP) phenotype as a subgroup of T-ALL with an inferior outcome. However, the diagnosis of ETP by immunophenotyping remains difficult to standardise, and gene expression profiling on T-ALL cases is not widely utilised. An alternative marker of immature T-ALL is Absence of Bi-allelic Deletion (ABD) at the TCRγ locus which has been shown to be associated with a very poor outcome. It is a marker that can potentially be standardised and assessed in real time for clinical use.
Aims
To investigate whether ABD status at the TCRγ locus adds prognostic information to paediatric T-ALL patients treated on the MRC UKALL2003 trial.
Methods
After informed consent, diagnostic DNA from 152 paediatric patients with T-ALL on the UKALL2003 trial was analysed by qPCR to amplify the region between the most 3’ V region (TRGV11) and the most 5’ J region (TRGJP1) of the TCRγ locus. Presence of an undeleted sequence in this region would indicate developmental arrest of the thymocyte at an early immature stage prior to V-J recombination. Patients were assigned to the ABD and non-ABD groups if fold change was ≥0.5 and <0.25 respectively. The undetermined group (fold change 0.25-0.5) were excluded from further analysis. Results were validated using the Illumina CytoSNP-850K array. Overall Survival (OS) and Relapse-free Survival (RFS) were plotted using Kaplan-Meier survival analysis. Cox regression and the log rank test were used to compare groups.
Results
Of 152 patients analysed by qPCR, 23 (15%) had ABD, 110 (72%) were non-ABD, and 19 (13%) were undetermined. Of the 133 informative patients, 118 had SNP array data that was consistent with the qPCR findings. There was no statistical difference in OS by ABD group (HR for ABD 1.34 (0.37–4.79); p=0.65). RFS was also very similar between the two groups (HR for ABD 1.68 (0.54-5.22); p=0.36) (Fig 1). MRD results were available for 102 patients. Median MRD levels were higher in the ABD group than the non-ABD group (2.5% positive cells at day 29 vs 0.02% respectively, p=0.031). The proportion of patients with indeterminate MRD was also higher in the ABD group (n=13, 57%) than in the non-ABD group (n=18, 19%) (p<0.0001). All eight ABD patients with high risk MRD received regimen C compared to 29 of 53 (55%) MRD high risk non-ABD patients (p=0.01). The good OS in ABD patients could not be attributed to coincidence of a favourable–risk NOTCH/FBXW7 genotype, as only 9% (2/23) of ABD patients were double mutant as compared to 31% (34/110) of non-ABD patients (p=0.03).
Conclusion
We found no evidence that the molecular marker ABD added further prognostic value to the outcome of paediatric patients with T-ALL treated on the UKALL2003 trial. Therefore escalation of treatment to more intensive regimens based on ABD status is not justified on this protocol. Our failure to confirm previous reports of a poor outcome for the ABD patients could be due to the fact that this trial employed MRD risk directed therapy.
Session topic: Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, MRD, T-ALL, TCR
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:00 - 17:15
Location: Auditorium 2
Background
Despite a marked improvement in the survival of children with T-cell acute lymphoblastic leukaemia (T-ALL), a significant proportion of patients will experience refractory disease or relapse. Previous studies using immunophenotyping and gene expression profiling identified the early T-cell precursor (ETP) phenotype as a subgroup of T-ALL with an inferior outcome. However, the diagnosis of ETP by immunophenotyping remains difficult to standardise, and gene expression profiling on T-ALL cases is not widely utilised. An alternative marker of immature T-ALL is Absence of Bi-allelic Deletion (ABD) at the TCRγ locus which has been shown to be associated with a very poor outcome. It is a marker that can potentially be standardised and assessed in real time for clinical use.
Aims
To investigate whether ABD status at the TCRγ locus adds prognostic information to paediatric T-ALL patients treated on the MRC UKALL2003 trial.
Methods
After informed consent, diagnostic DNA from 152 paediatric patients with T-ALL on the UKALL2003 trial was analysed by qPCR to amplify the region between the most 3’ V region (TRGV11) and the most 5’ J region (TRGJP1) of the TCRγ locus. Presence of an undeleted sequence in this region would indicate developmental arrest of the thymocyte at an early immature stage prior to V-J recombination. Patients were assigned to the ABD and non-ABD groups if fold change was ≥0.5 and <0.25 respectively. The undetermined group (fold change 0.25-0.5) were excluded from further analysis. Results were validated using the Illumina CytoSNP-850K array. Overall Survival (OS) and Relapse-free Survival (RFS) were plotted using Kaplan-Meier survival analysis. Cox regression and the log rank test were used to compare groups.
Results
Of 152 patients analysed by qPCR, 23 (15%) had ABD, 110 (72%) were non-ABD, and 19 (13%) were undetermined. Of the 133 informative patients, 118 had SNP array data that was consistent with the qPCR findings. There was no statistical difference in OS by ABD group (HR for ABD 1.34 (0.37–4.79); p=0.65). RFS was also very similar between the two groups (HR for ABD 1.68 (0.54-5.22); p=0.36) (Fig 1). MRD results were available for 102 patients. Median MRD levels were higher in the ABD group than the non-ABD group (2.5% positive cells at day 29 vs 0.02% respectively, p=0.031). The proportion of patients with indeterminate MRD was also higher in the ABD group (n=13, 57%) than in the non-ABD group (n=18, 19%) (p<0.0001). All eight ABD patients with high risk MRD received regimen C compared to 29 of 53 (55%) MRD high risk non-ABD patients (p=0.01). The good OS in ABD patients could not be attributed to coincidence of a favourable–risk NOTCH/FBXW7 genotype, as only 9% (2/23) of ABD patients were double mutant as compared to 31% (34/110) of non-ABD patients (p=0.03).
Conclusion
We found no evidence that the molecular marker ABD added further prognostic value to the outcome of paediatric patients with T-ALL treated on the UKALL2003 trial. Therefore escalation of treatment to more intensive regimens based on ABD status is not justified on this protocol. Our failure to confirm previous reports of a poor outcome for the ABD patients could be due to the fact that this trial employed MRD risk directed therapy.
Session topic: Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, MRD, T-ALL, TCR
Abstract: S500
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:00 - 17:15
Location: Auditorium 2
Background
Despite a marked improvement in the survival of children with T-cell acute lymphoblastic leukaemia (T-ALL), a significant proportion of patients will experience refractory disease or relapse. Previous studies using immunophenotyping and gene expression profiling identified the early T-cell precursor (ETP) phenotype as a subgroup of T-ALL with an inferior outcome. However, the diagnosis of ETP by immunophenotyping remains difficult to standardise, and gene expression profiling on T-ALL cases is not widely utilised. An alternative marker of immature T-ALL is Absence of Bi-allelic Deletion (ABD) at the TCRγ locus which has been shown to be associated with a very poor outcome. It is a marker that can potentially be standardised and assessed in real time for clinical use.
Aims
To investigate whether ABD status at the TCRγ locus adds prognostic information to paediatric T-ALL patients treated on the MRC UKALL2003 trial.
Methods
After informed consent, diagnostic DNA from 152 paediatric patients with T-ALL on the UKALL2003 trial was analysed by qPCR to amplify the region between the most 3’ V region (TRGV11) and the most 5’ J region (TRGJP1) of the TCRγ locus. Presence of an undeleted sequence in this region would indicate developmental arrest of the thymocyte at an early immature stage prior to V-J recombination. Patients were assigned to the ABD and non-ABD groups if fold change was ≥0.5 and <0.25 respectively. The undetermined group (fold change 0.25-0.5) were excluded from further analysis. Results were validated using the Illumina CytoSNP-850K array. Overall Survival (OS) and Relapse-free Survival (RFS) were plotted using Kaplan-Meier survival analysis. Cox regression and the log rank test were used to compare groups.
Results
Of 152 patients analysed by qPCR, 23 (15%) had ABD, 110 (72%) were non-ABD, and 19 (13%) were undetermined. Of the 133 informative patients, 118 had SNP array data that was consistent with the qPCR findings. There was no statistical difference in OS by ABD group (HR for ABD 1.34 (0.37–4.79); p=0.65). RFS was also very similar between the two groups (HR for ABD 1.68 (0.54-5.22); p=0.36) (Fig 1). MRD results were available for 102 patients. Median MRD levels were higher in the ABD group than the non-ABD group (2.5% positive cells at day 29 vs 0.02% respectively, p=0.031). The proportion of patients with indeterminate MRD was also higher in the ABD group (n=13, 57%) than in the non-ABD group (n=18, 19%) (p<0.0001). All eight ABD patients with high risk MRD received regimen C compared to 29 of 53 (55%) MRD high risk non-ABD patients (p=0.01). The good OS in ABD patients could not be attributed to coincidence of a favourable–risk NOTCH/FBXW7 genotype, as only 9% (2/23) of ABD patients were double mutant as compared to 31% (34/110) of non-ABD patients (p=0.03).
Conclusion
We found no evidence that the molecular marker ABD added further prognostic value to the outcome of paediatric patients with T-ALL treated on the UKALL2003 trial. Therefore escalation of treatment to more intensive regimens based on ABD status is not justified on this protocol. Our failure to confirm previous reports of a poor outcome for the ABD patients could be due to the fact that this trial employed MRD risk directed therapy.
Session topic: Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, MRD, T-ALL, TCR
Type: Oral Presentation
Presentation during EHA21: On Saturday, June 11, 2016 from 17:00 - 17:15
Location: Auditorium 2
Background
Despite a marked improvement in the survival of children with T-cell acute lymphoblastic leukaemia (T-ALL), a significant proportion of patients will experience refractory disease or relapse. Previous studies using immunophenotyping and gene expression profiling identified the early T-cell precursor (ETP) phenotype as a subgroup of T-ALL with an inferior outcome. However, the diagnosis of ETP by immunophenotyping remains difficult to standardise, and gene expression profiling on T-ALL cases is not widely utilised. An alternative marker of immature T-ALL is Absence of Bi-allelic Deletion (ABD) at the TCRγ locus which has been shown to be associated with a very poor outcome. It is a marker that can potentially be standardised and assessed in real time for clinical use.
Aims
To investigate whether ABD status at the TCRγ locus adds prognostic information to paediatric T-ALL patients treated on the MRC UKALL2003 trial.
Methods
After informed consent, diagnostic DNA from 152 paediatric patients with T-ALL on the UKALL2003 trial was analysed by qPCR to amplify the region between the most 3’ V region (TRGV11) and the most 5’ J region (TRGJP1) of the TCRγ locus. Presence of an undeleted sequence in this region would indicate developmental arrest of the thymocyte at an early immature stage prior to V-J recombination. Patients were assigned to the ABD and non-ABD groups if fold change was ≥0.5 and <0.25 respectively. The undetermined group (fold change 0.25-0.5) were excluded from further analysis. Results were validated using the Illumina CytoSNP-850K array. Overall Survival (OS) and Relapse-free Survival (RFS) were plotted using Kaplan-Meier survival analysis. Cox regression and the log rank test were used to compare groups.
Results
Of 152 patients analysed by qPCR, 23 (15%) had ABD, 110 (72%) were non-ABD, and 19 (13%) were undetermined. Of the 133 informative patients, 118 had SNP array data that was consistent with the qPCR findings. There was no statistical difference in OS by ABD group (HR for ABD 1.34 (0.37–4.79); p=0.65). RFS was also very similar between the two groups (HR for ABD 1.68 (0.54-5.22); p=0.36) (Fig 1). MRD results were available for 102 patients. Median MRD levels were higher in the ABD group than the non-ABD group (2.5% positive cells at day 29 vs 0.02% respectively, p=0.031). The proportion of patients with indeterminate MRD was also higher in the ABD group (n=13, 57%) than in the non-ABD group (n=18, 19%) (p<0.0001). All eight ABD patients with high risk MRD received regimen C compared to 29 of 53 (55%) MRD high risk non-ABD patients (p=0.01). The good OS in ABD patients could not be attributed to coincidence of a favourable–risk NOTCH/FBXW7 genotype, as only 9% (2/23) of ABD patients were double mutant as compared to 31% (34/110) of non-ABD patients (p=0.03).
Conclusion
We found no evidence that the molecular marker ABD added further prognostic value to the outcome of paediatric patients with T-ALL treated on the UKALL2003 trial. Therefore escalation of treatment to more intensive regimens based on ABD status is not justified on this protocol. Our failure to confirm previous reports of a poor outcome for the ABD patients could be due to the fact that this trial employed MRD risk directed therapy.
Session topic: Acute lymphoblastic leukemia - Clinical
Keyword(s): Acute lymphoblastic leukemia, MRD, T-ALL, TCR
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