COMPOSITE INDEX FOR RISK PREDICTION IN RELAPSED CHILDHOOD ACUTE LYMPHOBLASTIC LEUKAEMIA
Author(s): ,
Anthony V Moorman
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Julie AE Irving
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Amir Enshaei
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Catriona A Parker
Affiliations:
Institute of Cancer,The University of Manchester,Manchester,United Kingdom
,
Rosemary Sutton
Affiliations:
Children’s Cancer Institute Australia,University of New South Wales,Sydney,Australia
,
Roland Kuiper
Affiliations:
Department of Human Genetics,Radboud University Nijmegen Medical Centre,Nijmegen,Netherlands
,
Amy Erhorn
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Lynne Minto
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Nicola C Venn
Affiliations:
Children’s Cancer Institute Australia,University of New South Wales,Sydney,Australia
,
Tamara Law
Affiliations:
Children’s Cancer Institute Australia,University of New South Wales,Sydney,Australia
,
Jiangyan Yu
Affiliations:
Department of Human Genetics,Radboud University Nijmegen Medical Centre,Nijmegen,Netherlands
,
Claire Schwab
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Rosanna Davies
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle-upon-Tyne,United Kingdom
,
Edwin Sonneveld
Affiliations:
Dutch Childhood Oncology Group (DCOG),The Hague,Netherlands
,
Monique L den Boer
Affiliations:
Department of Paediatric Oncology and Haematology,Erasmus MC-Sophia Children's Hospital,Rotterdam,Netherlands;Dutch Childhood Oncology Group (DCOG),The Hague,Netherlands
,
Sharon B Love
Affiliations:
Centre for Statistics in Medicine,University of Oxford,Oxford,United Kingdom
,
Christine J Harrison
Affiliations:
Northern Institute for Cancer Research,Newcastle University,Newcastle upon Tyne,United Kingdom
,
Peter M Hoogerbrugge
Affiliations:
Children’s Hospital,Radboud University Nijmegen Medical Centre,Nijmegen,United Kingdom;Dutch Childhood Oncology Group (DCOG),The Hague,Netherlands
,
Tomas Revesz
Affiliations:
Department of Haematology-Oncology,SA Pathology at Women’s and Children’s Hospital and University of Adelaide,Adelaide,Australia
Vaskar Saha
Affiliations:
Institute of Cancer,The University of Manchester,Manchester,United Kingdom;Tata Translational Cancer Research Centre,Kolkata,India
(Abstract release date: 05/21/15) EHA Library. Moorman A. 06/13/15; 103109; S517 Disclosure(s): None
Prof. Anthony Moorman
Prof. Anthony Moorman
Contributions
Abstract
Abstract: S517

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:00 to 13.06.2015 16:15

Location: Room Lehar 1 + 2

Background

Somatic genetic abnormalities are key initiators and drivers of disease in acute lymphoblastic leukaemia (ALL). Several chromosomal abnormalities have proven clinical utility as prognostic and predictive biomarkers at initial diagnosis. However, the role of genetic biomarkers in relapsed ALL is less well understood and has rarely been studied comprehensively within a clinical trial.



Aims

To evaluate the role of genetics in predicting outcome among children with relapsed B-cell precursor ALL treated on the international trial, ALLR3.



Methods

We analysed cytogenetic, copy number alteration (CNA) and sequence mutation data at relapse in representative cohorts of patients. Patients with a very early relapse (<18 months from first diagnosis) and those patients with an isolated marrow relapse who had an early relapse (<6 months from stopping frontline therapy) were treated as clinical high risk (HR) whereas all other patients were treated as clinical standard risk (SR).



Results
Clinical HR patients accounted for 25% of the cohort and had a significantly inferior overall survival (OS) compared to SR patients: 25% (95% CI 15-37) v 65% (57-72), p<0.0001. A total of 427 patients were assigned to pre-defined cytogenetic risk groups which were predictive of survival post-relapse in both univariate and multivariate analysis adjusting for clinical risk: good risk (GR) cytogenetics (ETV6-RUNX1, high hyperdiploidy) 5 years OS 68% (60-75); intermediate risk (IR) cytogenetics (TCF3-PBX1, IGH translocations, B-other ALL) 47% (38-55); and HR cytogenetics (BCR-ABL1, MLL translocations, near haploidy, low hypodiploidy, iAMP21, TCF3-HLF) 26% (14-40), p<0.001. However, the prognostic effect of cytogenetic risk group was strongest within the clinical SR group. A representative cohort of 240 patients with marrow involvement was screened for CNA and mutations affecting key genes in ALL. Over 75% patients harboured at least one CNA or mutation: CDKN2A/B (39%), IKZF1 (22%), PAX5 (20%), TP53 (17%), ETV6 (16%), KRAS (12%), NRAS (12%), NR3C1 (9%), PAR1 (8%), PTPN11 (8%), RB1 (4%), EBF1 (4%), BTG1 (4%), FLT3 (4%), CBL (1%). Cox models adjusted for clinical risk revealed that only four genes were associated with outcome. Patients with a TP53 alteration or a deletion of either NR3C1 or  BTG1 had an inferior progression free survival (PFS) with hazard ratios of 2.07 (95% CI 1.20-3.58), p=0.009 and 2.26 (1.38-3.70), p=0.001, respectively. In addition, cytogenetic GR patients with a NRAS mutation had an inferior PFS compared with other GR cytogenetic patients 2.54 (1.24-5.22), p=0.01. The integration of clinical and cytogenetic risk groups with TP53, NR3C1, BTG1 and NRAS gene status revealed three groups: (1) Favourable - clinical SR patients with GR cytogenetics and without a TP53, NR3C1, BTG1 or NRAS abnormality; (2) Intermediate - clinical SR patients with GR cytogenetics and a TP53, NR3C1, BTG1 or NRAS abnormality plus clinical SR patients with IR cytogenetics; and (3) Adverse - all clinical and cytogenetic HR patients. The three groups accounted for 35%, 35% and 30% patients, respectively, and had markedly distinct OS rates: 78% (61-89), 56% (46-65) and 27% (19-35), p<0.001, respectively. Multivariate Cox models including variables for treatment and minimal residual disease did not materially alter the results. Receiver operating characteristic (ROC) curve analysis revealed that the new index had significantly greater predictive power than clinical risk alone for both PFS and OS: area under the curve (AUC) = 0.73 v 0.67, p=0.02 and 0.75 v 0.69, p=0.03, respectively.

Summary

In conclusion, we have integrated key genetic information with clinical risk to improve risk prediction in relapsed ALL and propose a three-tier index which could be used to develop risk-directed therapy in future trials.



Keyword(s): Cytogenetic abnormalities, Prognostic factor, Relapsed acute lymphoblastic leukemia, Risk factor

Session topic: Biological pathway deregulation in B Cell Precursor ALL
Abstract: S517

Type: Oral Presentation

Presentation during EHA20: From 13.06.2015 16:00 to 13.06.2015 16:15

Location: Room Lehar 1 + 2

Background

Somatic genetic abnormalities are key initiators and drivers of disease in acute lymphoblastic leukaemia (ALL). Several chromosomal abnormalities have proven clinical utility as prognostic and predictive biomarkers at initial diagnosis. However, the role of genetic biomarkers in relapsed ALL is less well understood and has rarely been studied comprehensively within a clinical trial.



Aims

To evaluate the role of genetics in predicting outcome among children with relapsed B-cell precursor ALL treated on the international trial, ALLR3.



Methods

We analysed cytogenetic, copy number alteration (CNA) and sequence mutation data at relapse in representative cohorts of patients. Patients with a very early relapse (<18 months from first diagnosis) and those patients with an isolated marrow relapse who had an early relapse (<6 months from stopping frontline therapy) were treated as clinical high risk (HR) whereas all other patients were treated as clinical standard risk (SR).



Results
Clinical HR patients accounted for 25% of the cohort and had a significantly inferior overall survival (OS) compared to SR patients: 25% (95% CI 15-37) v 65% (57-72), p<0.0001. A total of 427 patients were assigned to pre-defined cytogenetic risk groups which were predictive of survival post-relapse in both univariate and multivariate analysis adjusting for clinical risk: good risk (GR) cytogenetics (ETV6-RUNX1, high hyperdiploidy) 5 years OS 68% (60-75); intermediate risk (IR) cytogenetics (TCF3-PBX1, IGH translocations, B-other ALL) 47% (38-55); and HR cytogenetics (BCR-ABL1, MLL translocations, near haploidy, low hypodiploidy, iAMP21, TCF3-HLF) 26% (14-40), p<0.001. However, the prognostic effect of cytogenetic risk group was strongest within the clinical SR group. A representative cohort of 240 patients with marrow involvement was screened for CNA and mutations affecting key genes in ALL. Over 75% patients harboured at least one CNA or mutation: CDKN2A/B (39%), IKZF1 (22%), PAX5 (20%), TP53 (17%), ETV6 (16%), KRAS (12%), NRAS (12%), NR3C1 (9%), PAR1 (8%), PTPN11 (8%), RB1 (4%), EBF1 (4%), BTG1 (4%), FLT3 (4%), CBL (1%). Cox models adjusted for clinical risk revealed that only four genes were associated with outcome. Patients with a TP53 alteration or a deletion of either NR3C1 or  BTG1 had an inferior progression free survival (PFS) with hazard ratios of 2.07 (95% CI 1.20-3.58), p=0.009 and 2.26 (1.38-3.70), p=0.001, respectively. In addition, cytogenetic GR patients with a NRAS mutation had an inferior PFS compared with other GR cytogenetic patients 2.54 (1.24-5.22), p=0.01. The integration of clinical and cytogenetic risk groups with TP53, NR3C1, BTG1 and NRAS gene status revealed three groups: (1) Favourable - clinical SR patients with GR cytogenetics and without a TP53, NR3C1, BTG1 or NRAS abnormality; (2) Intermediate - clinical SR patients with GR cytogenetics and a TP53, NR3C1, BTG1 or NRAS abnormality plus clinical SR patients with IR cytogenetics; and (3) Adverse - all clinical and cytogenetic HR patients. The three groups accounted for 35%, 35% and 30% patients, respectively, and had markedly distinct OS rates: 78% (61-89), 56% (46-65) and 27% (19-35), p<0.001, respectively. Multivariate Cox models including variables for treatment and minimal residual disease did not materially alter the results. Receiver operating characteristic (ROC) curve analysis revealed that the new index had significantly greater predictive power than clinical risk alone for both PFS and OS: area under the curve (AUC) = 0.73 v 0.67, p=0.02 and 0.75 v 0.69, p=0.03, respectively.

Summary

In conclusion, we have integrated key genetic information with clinical risk to improve risk prediction in relapsed ALL and propose a three-tier index which could be used to develop risk-directed therapy in future trials.



Keyword(s): Cytogenetic abnormalities, Prognostic factor, Relapsed acute lymphoblastic leukemia, Risk factor

Session topic: Biological pathway deregulation in B Cell Precursor ALL

By clicking “Accept Terms & all Cookies” or by continuing to browse, you agree to the storing of third-party cookies on your device to enhance your user experience and agree to the user terms and conditions of this learning management system (LMS).

Cookie Settings
Accept Terms & all Cookies