TY - JOUR
T1 - Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials
AU - Eckert, C.
AU - Parker, C.
AU - Moorman, A.V.
AU - Irving, J.A.
AU - Kirschner-Schwabe, R.
AU - Groeneveld-Krentz, S.
AU - Révész, T.
AU - Hoogerbrugge, P.
AU - Hancock, J.
AU - Sutton, R.
AU - Henze, G.
AU - Chen-Santel, C.
AU - Attarbaschi, A.
AU - Bourquin, J.-P.
AU - Sramkova, L.
AU - Zimmermann, M.
AU - Krishnan, S.
AU - von Stackelberg, A.
AU - Saha, V.
N1 - Funding Information:
The authors would like to thank all clinicians who enrolled patients into the trial and the children and families who agreed to take part; the Children's Cancer Research Institute (St. Anna Kinderkrebsforschung), Vienna, Austria; the molecular genetics and immunophenotyping laboratory technicians for their excellent work and all members of the ALLR3 and ALL-REZ BFM trial centres for reliable comprehensive data management. The authors acknowledge the contribution of past and present members of the Leukaemia Research Cytogenetics Group (LRCG) for helping to establishing this data set. Primary childhood leukaemia samples used in this study were provided by the Leukaemia and Lymphoma Research Childhood Leukaemia Cell Bank (United Kingdom [UK]), the Tumour Bank at Children's Cancer Institute (Australia) and DCOG (The Netherlands). ALLR3 was funded in part by Bloodwise (formerly Leukaemia and Lymphoma Research), Cancer Research UK (CRUK A6791), Sporting Chance Cancer Foundation, the National Health and Medical Research Council Australia and Kinderen Kankervrij (KiKa) for ALLR3. The ALL-REZ BFM 2002 Study Group / Arend von Stackelberg received funding from the German Childhood Cancer Foundation (DKS 2007.02/2012.21/2016.08/2019.05) and the German Jose Carreras Foundation (DJCLS A09/01). This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration (grant 278514?IntReALL) and a DBT-Wellcome India Alliance Margdarshi Fellowship (IA/M/12/500755). The ALLR3 trial was sponsored by Manchester University NHS Foundation Trust, UK. The ALLR3 in Australia was supported by Cancer Council NSW (PG16-01) and NHMRC Australia (APP1024232).
Funding Information:
The authors would like to thank all clinicians who enrolled patients into the trial and the children and families who agreed to take part; the Children's Cancer Research Institute (St. Anna Kinderkrebsforschung), Vienna, Austria; the molecular genetics and immunophenotyping laboratory technicians for their excellent work and all members of the ALLR3 and ALL-REZ BFM trial centres for reliable comprehensive data management. The authors acknowledge the contribution of past and present members of the Leukaemia Research Cytogenetics Group (LRCG) for helping to establishing this data set. Primary childhood leukaemia samples used in this study were provided by the Leukaemia and Lymphoma Research Childhood Leukaemia Cell Bank (United Kingdom [UK]), the Tumour Bank at Children's Cancer Institute (Australia) and DCOG (The Netherlands). ALLR3 was funded in part by Bloodwise (formerly Leukaemia and Lymphoma Research), Cancer Research UK (CRUK A6791), Sporting Chance Cancer Foundation, the National Health and Medical Research Council Australia and Kinderen Kankervrij (KiKa) for ALLR3. The ALL-REZ BFM 2002 Study Group / Arend von Stackelberg received funding from the German Childhood Cancer Foundation (DKS 2007.02/2012.21/2016.08/2019.05) and the German Jose Carreras Foundation (DJCLS A09/01). This research has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration (grant 278514 –IntReALL) and a DBT-Wellcome India Alliance Margdarshi Fellowship (IA/M/12/500755). The ALLR3 trial was sponsored by Manchester University NHS Foundation Trust, UK. The ALLR3 in Australia was supported by Cancer Council NSW (PG16-01) and NHMRC Australia (APP1024232).
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/7
Y1 - 2021/7
N2 - Aim: Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). Methods: Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. Results: Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10
−3), HR cytogenetics and TP53 alterations in BCP-ALL. Conclusion: Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT. Trial registration: ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348
AB - Aim: Outcomes of children with high-risk (HR) relapsed acute lymphoblastic leukaemia (ALL) (N = 393), recruited to ALLR3 and ALL-REZ BFM 2002 trials, were analysed. Minimal residual disease (MRD) was assessed after induction and at predetermined time points until haematopoietic stem cell transplantation (SCT). Methods: Genetic analyses included karyotype, copy-number alterations and mutation analyses. Ten-year survivals were analysed using Kaplan-Meier and Cox models for multivariable analyses. Results: Outcomes of patients were comparable in ALLR3 and ALL-REZ BFM 2002. The event-free survival of B-cell precursor (BCP) and T-cell ALL (T-ALL) was 22.6% and 26.2% (P = 0.94), respectively, and the overall survival (OS) was 32.6% and 28.2% (P = 0.11), respectively. Induction failures (38%) were associated with deletions of NR3C1 (P = 0.002) and BTG1 (P = 0.03) in BCP-ALL. The disease-free survival (DFS) and OS in patients with good vs poor MRD responses were 57.4% vs 22.6% (P < 0.0001) and 57.8% vs 32.0% (P = 0.0004), respectively. For BCP- and T-ALL, the post-SCT DFS and OS were 42.1% and 56.8% (P = 0.26) and 51.6% and 55.4% (P = 0.67), respectively. The cumulative incidences of post-SCT relapse for BCP- and T-ALL were 36.9% and 17.8% (P = 0.012) and of death were 10.7% and 25.5% (P = 0.013), respectively. Determinants of outcomes after SCT were acute graft versus host disease, pre-SCT MRD (≥10
−3), HR cytogenetics and TP53 alterations in BCP-ALL. Conclusion: Improvements in outcomes for HR ALL relapses require novel compounds in induction therapy to improve remission rates and immune targeted therapy after induction to maintain remission after SCT. Trial registration: ALLR3: NCT00967057; ALL REZ-BFM 2002: NCT00114348
KW - Acute lymphoblastic leukaemia
KW - High-risk
KW - Minimal residual disease
KW - Outcomes
KW - Stem cell transplantation
U2 - 10.1016/j.ejca.2021.03.034
DO - 10.1016/j.ejca.2021.03.034
M3 - Article
SN - 0959-8049
VL - 151
SP - 175
EP - 189
JO - European Journal of Cancer
JF - European Journal of Cancer
ER -
