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The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia

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Abstract

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease whose prognostic factors include minimal residual disease (MRD) and cytogenetic abnormalities. To explore the significance of MRD in ALL subtypes, we analyzed the outcomes of 1126 children treated with risk-stratified therapy based on sequential MRD monitoring. MRD distributions and treatment outcomes differed between distinct leukemia subtypes. Patients with ETV6-RUNX1 or hyperdiploidy had the best prognosis (5-year OS: 97 ± 1.5% and 89.2 ± 2.7%). However, hyperdiploidy patients with MRD ≥ 10% on day 15 had a higher risk of relapse (36.4%) than those with ETV6-RUNX1. TCF3-PBX1 patients had the fastest disease clearance (negative MRD rate on day 33: 92.1%), but the overall prognosis was intermediate (5-year OS: 82.5%). Patients with high-risk characteristics and ALL-T had inferior outcomes: even with undetectable MRD on day 33, cumulative incidence of relapse was 19.9% and 23.4%, respectively. Moreover, those with poor early-treatment response and detectable week-12 MRD had a worse prognosis. After adjusting for other risk factors, re-emergent MRD was the most significant adverse prognostic indicator overall. Sequential MRD measurement is important for MRD-guided therapy, and integration of MRD values at different timepoints based on leukemia subtype could allow for more refined risk stratification.

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References

  1. Bonaventure A, Harewood R, Stiller CA, Gatta G, Clavel J, Stefan DC, et al. Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries. Lancet Haematol. 2017;4:e202–17.

    Article  Google Scholar 

  2. Campana D, Pui CH. Minimal residual disease-guided therapy in childhood acute lymphoblastic leukemia. Blood. 2017;129:1913–8.

    Article  CAS  Google Scholar 

  3. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. Jama Oncol. 2017;3:e170580.

    Article  Google Scholar 

  4. 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 

  5. Pui CH, Pei D, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, et al. Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: a prospective study. Lancet Oncol. 2015;16:465–74.

    Article  Google Scholar 

  6. Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33:2938–48.

    Article  CAS  Google Scholar 

  7. Pui CH, Pei D, Campana D, Cheng C, Sandlund JT, Bowman WP, et al. A revised definition for cure of childhood acute lymphoblastic leukemia. Leukemia. 2014;28:2336–43.

    Article  CAS  Google Scholar 

  8. Vora A, Goulden N, Mitchell C, Hancock J, Hough R, Rowntree C, et al. Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): a randomised controlled trial. Lancet Oncol. 2014;15:809–18.

    Article  Google Scholar 

  9. Pui CH, Pei D, Raimondi SC, Coustan-Smith E, Jeha S, Cheng C, et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with response-adapted therapy. Leukemia. 2017;31:333–9.

    Article  Google Scholar 

  10. Bene MC, Castoldi G, Knapp W, Ludwig WD, Matutes E, Orfao A, et al. Proposals for the immunological classification of acute leukemias. European Group for the Immunological Characterization of Leukemias (EGIL). Leukemia. 1995;9:1783–6.

    CAS  PubMed  Google Scholar 

  11. Pui CH, Evans WE. Acute lymphoblastic leukemia. N Engl J Med. 1998;339:605–15.

    Article  CAS  Google Scholar 

  12. Qin Y, Zhu H, Jiang B, Li J, Lu X, Li L, et al. Expression patterns of WT1 and PRAME in acute myeloid leukemia patients and their usefulness for monitoring minimal residual disease. Leuk Res. 2009;33:384–90.

    Article  CAS  Google Scholar 

  13. Qin YZ, Zhu HH, Liu YR, Wang YZ, Shi HX, Lai YY, et al. PRAME and WT1 transcripts constitute a good molecular marker combination for monitoring minimal residual disease in myelodysplastic syndromes. Leuk Lymphoma. 2013;54:1442–9.

    Article  CAS  Google Scholar 

  14. Cui L, Li ZG, Chai YH, et al. Outcome of children with newly diagnosed acute lymphoblastic leukemia treated with CCLG-ALL 2008: The first nation-wide prospective multicenter study in China. Am J Hematol. 2018;93:913–20.

    Article  Google Scholar 

  15. Liu YR, Zhang LP, Chang Y, Cheng YF, Fu JY, Li LD, et al. (2006) Clinical significance for minimal residual disease detection by 4 color flow cytometry in adult and childhood B lineage acute lymphoblastic leukemia. Zhonghua Xue Ye Xue Za Zhi 27:302–305.

  16. Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, et al. Monitoring MRD with flow cytometry: an effective method to predict relapse for ALL patients after allogeneic hematopoietic stem cell transplantation. Ann Hematol. 2012;91:183–92.

    Article  CAS  Google Scholar 

  17. Xue YJ, Suo P, Huang XJ, Lu AD, Wang Y, Zuo YX, et al. Superior survival of unmanipulated haploidentical haematopoietic stem cell transplantation compared with intensive chemotherapy as post-remission treatment for children with very high-risk philadelphia chromosome negative B-cell acute lymphoblastic leukaemia in first complete remission. Br J Haematol. 2020;188:757–67.

    Article  CAS  Google Scholar 

  18. Winick N, Devidas M, Chen S, Maloney K, Larsen E, Mattano L, et al. Impact of initial CSF findings on outcome among patients with national cancer institute standard- and high-risk b-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. J Clin Oncol. 2017;35:2527–34.

    Article  CAS  Google Scholar 

  19. Yeoh AE, Ariffin H, Chai EL, Kwok CS, Chan YH, Ponnudurai K, et al. Minimal residual disease-guided treatment deintensification for children with acute lymphoblastic leukemia: results from the Malaysia-Singapore acute lymphoblastic leukemia 2003 study. J Clin Oncol. 2012;30:2384–92.

    Article  CAS  Google Scholar 

  20. 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 

  21. Takahashi H, Kajiwara R, Kato M, Hasegawa D, Tomizawa D, Noguchi Y, et al. Treatment outcome of children with acute lymphoblastic leukemia: the Tokyo Children’s Cancer Study Group (TCCSG) Study L04–16. Int J Hematol. 2018;108:98–108.

    Article  Google Scholar 

  22. Pemmaraju N, Kantarjian H, Jorgensen JL, Jabbour E, Jain N, Thomas D, et al. Significance of recurrence of minimal residual disease detected by multi-parameter flow cytometry in patients with acute lymphoblastic leukemia in morphological remission. Am J Hematol. 2017;92:279–85.

    Article  Google Scholar 

  23. Del PM, Buzzatti E, Piciocchi A, Forghieri F, Bonifacio M, Lessi F, et al. Clinical significance of occult central nervous system disease in adult acute lymphoblastic leukemia. HAEMATOLOGICA: A multicenter report from the campus all network; 2019.

    Google Scholar 

  24. Taskinen M, Oskarsson T, Levinsen M, Bottai M, Hellebostad M, Jonsson OG, et al. The effect of central nervous system involvement and irradiation in childhood acute lymphoblastic leukemia: Lessons from the NOPHO ALL-92 and ALL-2000 protocols. Pediatr Blood Cancer. 2017;64:242–9.

    Article  Google Scholar 

  25. Schrappe M, Hunger SP, Pui CH, Saha V, Gaynon PS, Baruchel A, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366:1371–81.

    Article  CAS  Google Scholar 

  26. O’Connor D, Enshaei A, Bartram J, Hancock J, Harrison CJ, Hough R, et al. Genotype-Specific Minimal Residual Disease Interpretation Improves Stratification in Pediatric Acute Lymphoblastic Leukemia. J Clin Oncol. 2018;36:34–43.

    Article  CAS  Google Scholar 

  27. Gao C, Zhao XX, Li WJ, Cui L, Zhao W, Liu SG, et al. Clinical features, early treatment responses, and outcomes of pediatric acute lymphoblastic leukemia in China with or without specific fusion transcripts: a single institutional study of 1,004 patients. Am J Hematol. 2012;87:1022–7.

    Article  Google Scholar 

  28. Pui CH, Campana D, Pei D, Bowman WP, Sandlund JT, Kaste SC, et al. Treating childhood acute lymphoblastic leukemia without cranial irradiation. N Engl J Med. 2009;360:2730–41.

    Article  CAS  Google Scholar 

  29. Biondi A, Schrappe M, De Lorenzo P, Castor A, Lucchini G, Gandemer V, et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. 2012;13:936–45.

    Article  CAS  Google Scholar 

  30. Schultz KR, Carroll A, Heerema NA, Bowman WP, Aledo A, Slayton WB, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children’s Oncology Group study AALL0031. Leukemia. 2014;28:1467–71.

    Article  CAS  Google Scholar 

  31. Conter V, Bartram CR, Valsecchi MG, Schrauder A, Panzer-Grümayer R, Möricke 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 

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Acknowledgements

This work was supported by the Foundation of 2018 Beijing Key Clinical Specialty Construction Project-Pediatrics (2199000726).

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Author notes

  1. Yu-juan Xue and Yu Wang contributed equally to this work.

  2. Ai-dong Lu and Le-ping Zhang contributed equally as last authors.

Authors and Affiliations

  1. Department of Pediatrics, Peking University People’s Hospital, Peking University, No. 11, Xizhimen South Street, Xicheng District, Beijing, 100044, China

    Yu-juan Xue, Yu Wang, Yue-ping Jia, Ying-xi Zuo, Jun Wu, Ai-dong Lu & Le-ping Zhang

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  1. Yu-juan Xue
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Xue, Yj., Wang, Y., Jia, Yp. et al. The role of minimal residual disease in specific subtypes of pediatric acute lymphoblastic leukemia. Int J Hematol 113, 547–555 (2021). https://doi.org/10.1007/s12185-020-03063-w

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  • DOI: https://doi.org/10.1007/s12185-020-03063-w

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