EARLY RESPONSE AND GENETICS DEFINE RELAPSE RISK AFTER FRONTLINE BLINATUMOMAB IN CHILDHOOD B-ALL: A COHORT STUDY

Blinatumomab is increasingly incorporated into frontline therapy for B-cell acute lymphoblastic leukaemia (B-ALL), yet risk stratification remains based on chemotherapy-era factors that may not apply in the immunotherapy setting. We analysed a national cohort to define determinants of relapse following frontline blinatumomab. Children and young people (1-24 years) in the UK and Ireland diagnosed with B-ALL between 2018 and 2025 who were chemotherapy-intolerant or resistant received blinatumomab in place of selected components of the frontline chemotherapy backbone. Outcomes were analysed according to conventional prognostic variables, genetic features, and response to blinatumomab. Among 225 patients, 195 received chemotherapy following blinatumomab (Blin-CT) and 30 underwent first-remission HSCT. In the Blin-CT cohort, traditional risk factors, including age, white cell count, high-risk genetics, and pre-blinatumomab end-of-induction measurable residual disease (MRD) did not predict relapse. On univariable analysis, relapse risk was increased with detectable MRD after blinatumomab cycle 1 (C1-END; hazard ratio HZR 6.61, p<0.001), IKZF1plus (HZR 3.64, p=0.04), JAK-STAT abnormalities (HR 3.56, p=0.05), and DUX4 rearrangements (HZR 4.24, p=0.03). In multivariable modelling, C1-END MRD and IKZF1plus remained independently associated with relapse, whereas DUX4-rearranged cases were strongly associated with persistent MRD at C1-END. An integrated model incorporating C1-END MRD, IKZF1plus, and DUX4-r defined a high-risk subgroup (33%) with an 18% 2-year relapse rate versus 0% in remaining patients (bootstrapped HZR 12.82, p=0.001, C-index=0.81). Relapse following frontline blinatumomab is determined by early treatment response and genetic subtype rather than conventional chemotherapy-derived risk factors. These findings support immunotherapy-specific risk stratification to guide treatment intensity.

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Journal
Blood Advances
Published
2026-09-01
DOI
https://doi.org/10.1182/bloodadvances.2026021026
Primary Topic
Acute Lymphoblastic Leukemia research
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article
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article

EARLY RESPONSE AND GENETICS DEFINE RELAPSE RISK AFTER FRONTLINE BLINATUMOMAB IN CHILDHOOD B-ALL: A COHORT STUDY

John Moppett, Anna Castleton, Ismail Elbeshlawi, Galina Jigoulina et al.
Blood Advances
Acute Lymphoblastic Leukemia research
article

EARLY RESPONSE AND GENETICS DEFINE RELAPSE RISK AFTER FRONTLINE BLINATUMOMAB IN CHILDHOOD B-ALL: A COHORT STUDY

John Moppett, Anna Castleton, Ismail Elbeshlawi, Galina Jigoulina, Angus Hodder, David Devenney, Jude Gibson, Anthony V. Moorman, Jeremy Hancock, Stuart Adams, Amir Enshaei, Alison Spence, Danielle Ingham, Katherine Clesham, Michael Gattens, David O’Connor, Subramaniam Ramanathan, Miguel Vieira Martins, Emma Nicholson, Majid Madni, Rachael Hough, Sanjay Tewari, Jayashree Motwani, Susan Baird, Andrea Malone, Philip Connor, Katherine Lindsay, Katharine Hodby, Katharine Patrick, Ajay Vora, Sujith Samarasinghe, Christopher Dalley, Clare Rowntree, Kaljit Bhuller, Lindsay C. George, Bethany Rose Mitchell, Yang Yang Wang, Denise Kathleen Bonney, Andrew King
article en

Abstract

Blinatumomab is increasingly incorporated into frontline therapy for B-cell acute lymphoblastic leukaemia (B-ALL), yet risk stratification remains based on chemotherapy-era factors that may not apply in the immunotherapy setting. We analysed a national cohort to define determinants of relapse following frontline blinatumomab. Children and young people (1-24 years) in the UK and Ireland diagnosed with B-ALL between 2018 and 2025 who were chemotherapy-intolerant or resistant received blinatumomab in place of selected components of the frontline chemotherapy backbone. Outcomes were analysed according to conventional prognostic variables, genetic features, and response to blinatumomab. Among 225 patients, 195 received chemotherapy following blinatumomab (Blin-CT) and 30 underwent first-remission HSCT. In the Blin-CT cohort, traditional risk factors, including age, white cell count, high-risk genetics, and pre-blinatumomab end-of-induction measurable residual disease (MRD) did not predict relapse. On univariable analysis, relapse risk was increased with detectable MRD after blinatumomab cycle 1 (C1-END; hazard ratio HZR 6.61, p<0.001), IKZF1plus (HZR 3.64, p=0.04), JAK-STAT abnormalities (HR 3.56, p=0.05), and DUX4 rearrangements (HZR 4.24, p=0.03). In multivariable modelling, C1-END MRD and IKZF1plus remained independently associated with relapse, whereas DUX4-rearranged cases were strongly associated with persistent MRD at C1-END. An integrated model incorporating C1-END MRD, IKZF1plus, and DUX4-r defined a high-risk subgroup (33%) with an 18% 2-year relapse rate versus 0% in remaining patients (bootstrapped HZR 12.82, p=0.001, C-index=0.81). Relapse following frontline blinatumomab is determined by early treatment response and genetic subtype rather than conventional chemotherapy-derived risk factors. These findings support immunotherapy-specific risk stratification to guide treatment intensity.

Blood Advances
North Bristol NHS Trust (GB), Royal Marsden NHS Foundation Trust (GB), Nottingham University Hospitals NHS Trust (GB), University College London Hospitals NHS Foundation Trust (GB), University of Liverpool (GB), Leeds Teaching Hospitals NHS Trust (GB), Great Ormond Street Hospital (GB), Leicester Royal Infirmary (GB), Great Ormond Street Hospital for Children NHS Foundation Trust (GB), Royal Hospital for Children (GB), University Hospitals Bristol NHS Foundation Trust (GB), University Hospital of Wales (GB), Royal Belfast Hospital for Sick Children (GB), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Bristol Royal Hospital for Children (GB), Cambridge University Hospitals NHS Foundation Trust (GB), University Hospital Southampton NHS Foundation Trust (GB), Food for Health Ireland (IE), Birmingham Children's Hospital (GB), Noah's Ark Children's Hospital for Wales (GB), Southampton Children's Hospital (GB), Royal Marsden Hospital (GB), Newcastle upon Tyne Hospital (GB), The Christie Hospital (GB), The Christie NHS Foundation Trust (GB), NIHR Surgical Reconstruction and Microbiology Research Centre (GB), Great North Children's Hospital (GB), Oxford University Hospitals NHS Trust (GB), Addenbrooke's Hospital (GB), Alder Hey Children's Hospital (GB), Royal Manchester Children's Hospital (GB), Sheffield Children's Hospital (GB), University Hospitals Bristol and Weston NHS Foundation Trust (GB), University College London (GB), Newcastle University (GB)
Good health and well-being
Openalex Percentile: Top 9%
Acute Lymphoblastic Leukemia research
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