Skip to main content
SpringerLink
Log in

ACUTE LYMPHOBLASTIC LEUKEMIA

Temporal changes in incidence of relapse and outcome after relapse of childhood acute lymphoblastic leukemia over three decades; a Nordic population-based cohort study

  • Article
  • Published:
Leukemia Submit manuscript

Abstract

Relapse remains the main obstacle to curing childhood acute lymphoblastic leukemia (ALL). The aims of this study were to compare incidence of relapse, prognostic factors, and survival after relapse between three consecutive Nordic Society of Pediatric Hematology and Oncology trials. Relapse occurred as a primary event in 638 of 4 458 children (1.0–14.9 years) diagnosed with Ph-negative ALL between 1992 and 2018. The 5-year cumulative incidence of relapse was 17.3% (95% CI 15.4–19.2%) and 16.5% (95% CI 14.3–18.8%) for patients in the ALL1992 and ALL2000 trials, respectively, but decreased to 8.4% (95% CI 7.0–10.1%) for patients in the ALL2008 trial. No changes in duration of first complete remission and site of relapse were observed over time; however, high hyperdiploidy, and t(12;21) decreased in the ALL2008 trial. The 4-year overall survival after relapse was 56.6% (95% CI 52.5–60.5%) and no statistically significant temporal improvements were observed. Age ≥10 years, T-cell immunophenotype, bone-marrow involvement, early and very early relapse, hypodiploidy, and Down syndrome all independently predicted worse outcome after relapse. Improvements in the primary treatment of childhood ALL has resulted in fewer relapses. However, failure to improve outcome of remaining relapses suggests a selection of harder-to-cure relapses and calls for new therapeutic strategies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Flow diagram of the study population.
Fig. 2: Cumulative incidence of ALL relapse by NOPHO trial.
Fig. 3: Cumulative incidence of ALL relapse by NCI risk groups.
Fig. 4: Survival after relapse.
Fig. 5: Survival after relapse stratified by immunophenotype.
Fig. 6: Second event after relapse.

Similar content being viewed by others

References

  1. Toft N, Birgens H, Abrahamsson J, Griskevicius L, Hallbook H, Heyman M, et al. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Leukemia. 2018;32:606–15.

    Article  CAS  Google Scholar 

  2. Schmiegelow K, Forestier E, Hellebostad M, Heyman M, Kristinsson J, Soderhall S, et al. Long-term results of NOPHO ALL-92 and ALL-2000 studies of childhood acute lymphoblastic leukemia. Leukemia. 2010;24:345–54.

    Article  CAS  Google Scholar 

  3. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016;34:2591–601.

    Article  Google Scholar 

  4. Smith L, Glaser AW, Kinsey SE, Greenwood DC, Chilton L, Moorman AV, et al. Long-term survival after childhood acute lymphoblastic leukaemia: population-based trends in cure and relapse by clinical characteristics. Br J Haematol. 2018;182:851–8.

    Article  Google Scholar 

  5. Oskarsson T, Soderhall S, Arvidson J, Forestier E, Frandsen TL, Hellebostad M, et al. Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2018;65. https://doi.org/10.1002/pbc.26909.

  6. Oskarsson T, Soderhall S, Arvidson J, Forestier E, Montgomery S, Bottai M, et al. Relapsed childhood acute lymphoblastic leukemia in the Nordic countries: prognostic factors, treatment and outcome. Haematologica. 2016;101:68–76.

    Article  CAS  Google Scholar 

  7. Parker C, Waters R, Leighton C, Hancock J, Sutton R, Moorman AV, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376:2009–17.

    Article  CAS  Google Scholar 

  8. Parker C, Krishnan S, Hamadeh L, Irving JAE, Kuiper RP, Révész T, et al. Outcomes of patients with childhood B-cell precursor acute lymphoblastic leukaemia with late bone marrow relapses: long-term follow-up of the ALLR3 open-label randomised trial. Lancet Haematol. 2019;6:e204–e16.

    Article  Google Scholar 

  9. Coustan-Smith E, Gajjar A, Hijiya N, Razzouk BI, Ribeiro RC, Rivera GK, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia after first relapse. Leukemia. 2004;18:499–504.

    Article  CAS  Google Scholar 

  10. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2008;22:2142–50.

    Article  CAS  Google Scholar 

  11. Henze G, Fengler R, Hartmann R, Kornhuber B, Janka-Schaub G, Niethammer D, et al. Six-year experience with a comprehensive approach to the treatment of recurrent childhood acute lymphoblastic leukemia (ALL-REZ BFM 85). A relapse study of the BFM group. Blood. 1991;78:1166–72.

    Article  CAS  Google Scholar 

  12. Schroeder H, Garwicz S, Kristinsson J, Siimes MA, Wesenberg F, Gustafsson G. Outcome after first relapse in children with acute lymphoblastic leukemia: a population-based study of 315 patients from the Nordic Society of Pediatric Hematology and Oncology (NOPHO). Med Pediatr Oncol. 1995;25:372–8.

    Article  CAS  Google Scholar 

  13. Tallen G, Ratei R, Mann G, Kaspers G, Niggli F, Karachunsky A, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90. J Clin Oncol. 2010;28:2339–47.

    Article  CAS  Google Scholar 

  14. Lawson SE, Harrison G, Richards S, Oakhill A, Stevens R, Eden OB, et al. The UK experience in treating relapsed childhood acute lymphoblastic leukaemia: a report on the medical research council UKALLR1 study. Br J Haematol. 2000;108:531–43.

    Article  CAS  Google Scholar 

  15. Roy A, Cargill A, Love S, Moorman AV, Stoneham S, Lim A, et al. Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol. 2005;130:67–75.

    Article  Google Scholar 

  16. Irving JA, Enshaei A, Parker CA, Sutton R, Kuiper RP, Erhorn A, et al. Integration of genetic and clinical risk factors improves prognostication in relapsed childhood B-cell precursor acute lymphoblastic leukemia. Blood. 2016;128:911–22.

    Article  CAS  Google Scholar 

  17. Lew G, Chen Y, Lu X, Rheingold SR, Whitlock JA, Devidas M, et al. Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children’s Oncology Group phase III study AALL0433. Haematologica. 2021;106:46–55.

    Article  CAS  Google Scholar 

  18. Paganin M, Zecca M, Fabbri G, Polato K, Biondi A, Rizzari C, et al. Minimal residual disease is an important predictive factor of outcome in children with relapsed ‘high-risk’ acute lymphoblastic leukemia. Leukemia. 2008;22:2193–200.

    Article  CAS  Google Scholar 

  19. von Elm E, Altman DG, Egger M, Pocock SJ, Gotzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344–9.

    Article  Google Scholar 

  20. Smith M, Arthur D, Camitta B, Carroll AJ, Crist W, Gaynon P, et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. 1996;14:18–24.

    Article  CAS  Google Scholar 

  21. Arend von Stackelberg CQ, Saha V, Locatelli F, Moschandreas J, Love S. IntReALL SR 2010: An international randomised phase III study for the treatment of standard risk childhood relapsed acute lymphoblastic leukaemia (abstract). NCRI Cancer Conference; Nov 5-8, 2017; Glasgow.

  22. Inaba H, Pui CH. Immunotherapy in pediatric acute lymphoblastic leukemia. Cancer Metastasis Rev. 2019;38:595–610.

    Article  Google Scholar 

  23. Dunsmore KP, Winter SS, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed T-Cell Acute Lymphoblastic Leukemia. J Clin Oncol. 2020;38:3282–93.

    Article  CAS  Google Scholar 

  24. Borowitz MJ, Devidas M, Hunger SP, Bowman WP, Carroll AJ, Carroll WL, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children’s Oncology Group study. Blood. 2008;111:5477–85.

    Article  CAS  Google Scholar 

  25. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grumayer R, Moricke A, et al. Molecular response to treatment redefines all prognostic factors in children and adolescents with B-cell precursor acute lymphoblastic leukemia: results in 3184 patients of the AIEOP-BFM ALL 2000 study. Blood. 2010;115:3206–14.

    Article  CAS  Google Scholar 

  26. Li B, Brady SW, Ma X, Shen S, Zhang Y, Li Y, et al. Therapy-induced mutations drive the genomic landscape of relapsed acute lymphoblastic leukemia. Blood. 2020;135:41–55.

    Article  Google Scholar 

  27. Bailey LC, Lange BJ, Rheingold SR, Bunin NJ. Bone-marrow relapse in paediatric acute lymphoblastic leukaemia. Lancet Oncol. 2008;9:873–83.

    Article  Google Scholar 

  28. Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008;322:1377–80.

    Article  CAS  Google Scholar 

  29. Dobson SM, García-Prat L, Vanner RJ, Wintersinger J, Waanders E, Gu Z, et al. Relapse-Fated Latent Diagnosis Subclones in Acute B Lineage Leukemia Are Drug Tolerant and Possess Distinct Metabolic Programs. Cancer Discov. 2020;10:568–87.

    Article  CAS  Google Scholar 

  30. Brown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, et al. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. Jama. 2021;325:833–42.

    Article  CAS  Google Scholar 

  31. Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. Jama. 2021;325:843–54.

    Article  CAS  Google Scholar 

  32. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia .2019;33:884–92.

    Article  CAS  Google Scholar 

  33. Brivio E, Locatelli F, Lopez-Yurda M, Malone A, Díaz-de-Heredia C, Bielorai B, et al. A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study). Blood. 2021;137:1582–90.

    Article  CAS  Google Scholar 

  34. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl J Med. 2014;371:1507–17.

    Article  Google Scholar 

  35. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N. Engl J Med. 2018;378:439–48.

    Article  CAS  Google Scholar 

  36. McMahon CM, Luger SM. Relapsed T Cell ALL: Current Approaches and New Directions. Curr Hematol Malignancy Rep. 2019;14:83–93.

    Article  Google Scholar 

  37. Pan J, Tan Y, Wang G, Deng B, Ling Z, Song W, et al. Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial. J Clin Oncol. 2021;39:3340–51.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Danish Cancer Society, the A.P. Møller Foundation, and Tømrermester Jørgen Holm & Hustru Elisa F. Hansens Foundation. The funders had no role in the design or conduct of the study.

We thank all clinicians assisting with the data collection and the Nordic Society of Paediatric Haematology and Oncology (NOPHO).

Author information

Author notes

  1. These authors contributed equally: Henrik Schrøder, Birgitte Klug Albertsen.

Authors and Affiliations

  1. Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark

    Karen Schow Jensen, Henrik Schrøder & Birgitte Klug Albertsen

  2. Department of Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden

    Trausti Oskarsson, Petter Svenberg & Mats Heyman

  3. Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden

    Trausti Oskarsson & Päivi M. Lähteenmäki

  4. Department of Pediatric and Adolescent Hematology/Oncology, Turku University Hospital, FICAN-west, and Turku University, Turku, Finland

    Päivi M. Lähteenmäki

  5. Department of Pediatrics, Institute of Clinical Medicine, University of Tromsø, Tromsø, Norway

    Trond Flaegstad

  6. Department of Pediatrics, University Hospital of North Norway, Tromsø, Norway

    Trond Flaegstad

  7. Children’s Hospital, Landspitali University Hospital, Reykjavik, Iceland

    Ólafur Gísli Jónsson

  8. Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital, Copenhagen, Denmark

    Kjeld Schmiegelow

  9. Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Kjeld Schmiegelow

  10. Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, Sweden

    Ulrika Norén-Nyström

  11. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Birgitte Klug Albertsen

Authors
  1. Karen Schow Jensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Trausti Oskarsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Päivi M. Lähteenmäki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Trond Flaegstad
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ólafur Gísli Jónsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Petter Svenberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kjeld Schmiegelow
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mats Heyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ulrika Norén-Nyström
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Henrik Schrøder
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Birgitte Klug Albertsen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KSJ designed the study, analyzed and interpreted data and wrote the manuscript; TO designed the study, interpreted data and edited the manuscript; PML designed the study, interpreted data and edited the manuscript; TF designed the study, interpreted data and edited the manuscript; OGJ designed the study, interpreted data and edited the manuscript; PS designed the study, interpreted data and edited the manuscript; KS designed the study, interpreted data and edited the manuscript; MH designed the study, interpreted data and edited the manuscript; UNN designed the study, reviewed cytogenetics, interpreted data and edited the manuscript; BA designed the study, interpreted data and edited the manuscript; HS designed the study, interpreted data and edited the manuscript. All authors approved the final manuscript.

Corresponding author

Correspondence to Birgitte Klug Albertsen.

Ethics declarations

Competing interests

BA declares the following: sponsor for the investigator-initiated NOR-GRASPALL 2016 study; speaker and/or advisory board honoraria from Erytech (2020) and Servier (2021). Kjeld Schmiegelow declares the following: speaker and/or advisory board honoraria from Jazz Pharmaceuticals (2020) and Servier (2020); speaker’s fee from Amgen (2020) and Medscape (2020); educational grant from Servier (2020). The remaining authors have no competing interests to declare.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jensen, K.S., Oskarsson, T., Lähteenmäki, P.M. et al. Temporal changes in incidence of relapse and outcome after relapse of childhood acute lymphoblastic leukemia over three decades; a Nordic population-based cohort study. Leukemia 36, 1274–1282 (2022). https://doi.org/10.1038/s41375-022-01540-1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-022-01540-1

  • Springer Nature Limited

Search

Navigation