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Acute lymphoblastic leukemia

Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy

Leukemia volume 31, pages 333–339 (2017)Cite this article

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Abstract

To determine the clinical significance of minimal residual disease (MRD) in patients with prognostically relevant subtypes of childhood acute lymphoblastic leukemia (ALL), we analyzed data from 488 patients treated in St Jude Total Therapy Study XV with treatment intensity based mainly on MRD levels measured during remission induction. MRD levels on day 19 predicted treatment outcome for patients with hyperdiploid >50 ALL, National Cancer Institute (NCI) standard-risk B-ALL or T-cell ALL, while MRD levels on day 46 were prognostic for patients with NCI standard-risk or high-risk B-ALL. Patients with t(12;21)/(ETV6-RUNX1) or hyperdiploidy >50 ALL had the best prognosis; those with a negative MRD on day 19 had a particularly low risk of relapse: 1.9% and 3.8%, respectively. Patients with NCI high-risk B-ALL or T-cell ALL had an inferior outcome; even with undetectable MRD on day 46, cumulative risk of relapse was 12.7% and 15.5%, respectively. Among patients with NCI standard-risk B-ALL, the outcome was intermediate overall but was poor if MRD was ⩾1% on day 19 or MRD was detectable at any level on day 46. Our results indicate that the clinical impact of MRD on treatment outcome in childhood ALL varies considerably according to leukemia subtype and time of measurement.

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References

  1. Campana D . Minimal residual disease monitoring in childhood acute lymphoblastic leukemia. Curr Opin Hematol 2012; 19: 313–318.

    Article  CAS  Google Scholar 

  2. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grümayer R, Möricke A et al. Late MRD response determines relapse risk overall and in subsets of childhood T-cell ALL: results of the AIEOP-BFM-ALL 2000 study. Blood 2011; 118: 2077–2084.

    Article  CAS  Google Scholar 

  3. Bowman WP, Larsen EL, Devidas M, Linda SB, Blach L, Carroll AJ et al. Augmented therapy improves outcome for pediatric high risk acute lymphocytic leukemia: results of Children's Oncology Group trial P9906. Pediatr Blood Cancer 2011; 57: 569–577.

    Article  Google Scholar 

  4. 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: 3206–3214.

    Article  CAS  Google Scholar 

  5. Stow P, Key L, Chen X, Pan Q, Neale GA, Coustan-Smith E et al. Clinical significance of low levels of minimal residual disease at the end of remission induction therapy in childhood acute lymphoblastic leukemia. Blood 2010; 115: 4657–4663.

    Article  CAS  Google Scholar 

  6. Basso G, Veltroni M, Valsecchi MG, Dworzak MN, Ratei R, Silvestri D et al. Risk of relapse of childhood acute lymphoblastic leukemia is predicted by flow cytometric measurement of residual disease on day 15 bone marrow. J Clin Oncol 2009; 27: 5168–5174.

    Article  Google Scholar 

  7. Sutton R, Venn NC, Tolisano J, Bahar AY, Giles JE, Ashton LJ et al. Clinical significance of minimal residual disease at day 15 and at the end of therapy in childhood acute lymphoblastic leukaemia. Br J Haematol 2009; 146: 292–299.

    Article  CAS  Google Scholar 

  8. 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: 5477–5485.

    Article  CAS  Google Scholar 

  9. Cavé H, van der Werff ten Bosch J, Suciu S, Guidal C, Waterkeyn C, Otten J et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European Organization for Research and Treatment of Cancer—-Childhood Leukemia Cooperative Group. N Engl J Med 1998; 339: 591–598.

    Article  Google Scholar 

  10. van Dongen JJ, Seriu T, Panzer-Grümayer ER, Biondi A, Pongers-Willemse MJ, Corral L et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet 1998; 352: 1731–1738.

    Article  CAS  Google Scholar 

  11. Coustan-Smith E, Behm FG, Sanchez J, Boyett JM, Hancock ML, Raimondi SC et al. Immunological detection of minimal residual disease in children with acute lymphoblastic leukaemia. Lancet 1998; 351: 550–554.

    Article  CAS  Google Scholar 

  12. Ribera JM, Oriol A, Morgades M, Montesinos P, Sarrà J, González-Campos J et al. Treatment of high-risk Philadelphia chromosome-negative acute lymphoblastic leukemia in adolescents and adults according to early cytologic response and minimal residual disease after consolidation assessed by flow cytometry: final results of the PETHEMA ALL-AR-03 trial. J Clin Oncol 2014; 32: 1595–1604.

    Article  CAS  Google Scholar 

  13. Beldjord K, Chevret S, Asnafi V, Huguet F, Boulland ML, Leguay T et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood 2014; 123: 3739–3749.

    Article  CAS  Google Scholar 

  14. Bassan R, Spinelli O, Oldani E, Intermesoli T, Tosi M, Peruta B et al. Improved risk classification for risk-specific therapy based on the molecular study of minimal residual disease (MRD) in adult acute lymphoblastic leukemia (ALL). Blood 2009; 113: 4153–4162.

    Article  CAS  Google Scholar 

  15. Paganin M, Fabbri G, Conter V, Barisone E, Polato K, Cazzaniga G et al. Postinduction minimal residual disease monitoring by polymerase chain reaction in children with acute lymphoblastic leukemia. J Clin Oncol 2014; 32: 3553–3558.

    Article  Google Scholar 

  16. Vora A, Goulden N, Wade R, Mitchell C, Hancock J, Houghet R et al. Treatment reduction for children and young adults with low-risk acute lymphoblastic leukaemia defined by minimal residual disease (UKALL 2003): a randomised controlled trial. Lancet Oncol 2013; 14: 199–209.

    Article  CAS  Google Scholar 

  17. 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: 809–818.

    Article  Google Scholar 

  18. 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: 2384–2392.

    Article  CAS  Google Scholar 

  19. 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: 465–474.

    Article  Google Scholar 

  20. Attarbaschi A, Panzer-Grümayer R, Mann G, Möricke A, König M, Mecklenbräuker A et al. Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: the experience of the ALL-BFM 2000 trial. Klin Padiatr 2014; 226: 338–343.

    Article  Google Scholar 

  21. Roberts KG, Pei D, Campana D, Payne-Turner D, Li Y, Cheng C et al. Outcomes of children with BCR-ABL1-like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol 2014; 32: 3012–3020.

    Article  CAS  Google Scholar 

  22. Mullighan CG, Jeha S, Pei D, Payne-Turner D, Coustan-Smith E, Roberts KG et al. Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood 2015; 126: 2896–2899.

    Article  Google Scholar 

  23. 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: 2730–2741.

    Article  CAS  Google Scholar 

  24. Pui CH, Evans WE . Acute lymphoblastic leuikemia. N Engl J Med 1998; 339: 605–615.

    Article  CAS  Google Scholar 

  25. Coustan-Smith E, Song G, Clark C, Key L, Liu P, Mehrpooya M et al. New markers for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2011; 117: 6267–6276.

    Article  CAS  Google Scholar 

  26. Neale GA, Coustan-Smith E, Stow P, Pan Q, Chen X, Pui CH et al. Comparative analysis of flow cytometry and polymerase chain reaction for the detection of minimal residual disease in childhood acute lymphoblastic leukemia. Leukemia 2004; 18: 934–938.

    Article  CAS  Google Scholar 

  27. Faham M, Zheng J, Moorhead M, Carlton VE, Stow P, Coustan-Smith E et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood 2012; 120: 5173–5180.

    Article  CAS  Google Scholar 

  28. Kalbfleisch JD, Prentice RL . The Statistical Analysis of Failure Time Data. Wiley: New York, USA, 2002, 1–439.

    Book  Google Scholar 

  29. Gray RJ . A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154.

    Article  Google Scholar 

  30. 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: 2938–2948.

    Article  CAS  Google Scholar 

  31. Vora A, Andreano A, Pui CH, Hunger SP, Schrappe M, Moericke A et al. Influence of cranial radiotherapy on outcome in children with acute lymphoblastic leukemia treated with contemporary therapy. J Clin Oncol 2016; 34: 919–926.

    Article  CAS  Google Scholar 

  32. 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: 1371–1381.

    Article  CAS  Google Scholar 

  33. Bartram J, Wade R, Vora A, Hancock J, Mitchell C, Kinsey S et al. Excellent outcome of minimal residual disease-defined low-risk patients is sustained with more than 10 years follow-up: results of UK paediatric acute lymphoblastic leukaemia trials 1997-2003. Arch Dis Child 2016; 101: 449–454.

    Article  Google Scholar 

  34. Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children's Oncology Group study AALL0232. Blood 2015; 126: 964–971.

    Article  CAS  Google Scholar 

  35. Wu D, Sherwood A, Fromm JR, Winter SS, Dunsmore KP, Loh ML et al. High-throughput sequencing detects minimal residual disease in acute T lymphoblastic leukemia. Sci Transl Med 2012; 4: 134ra63.

    Article  Google Scholar 

  36. Jeha S, Pei D, Raimondi SC, Onciu M, Campana D, Cheng C et al. Increased risk for CNS relapse in pre-B cell leukemia with the t(1;19)/TCF3-PBX1. Leukemia 2009; 23: 1406–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants (CA21765, CA36401, and GM115279) from the National Institutes of Health and by the American Lebanese Syrian Associated Charities.

Author contributions

C-HP and DC designed the study, reviewed and interpreted data and wrote the paper; C-HP, SJ, WPB, JTS, RCR, JER, HI, TAG and WHL enrolled patients and revised the manuscript; DP and CC provided statistical expertize, analyses and data interpretation; SCR performed genetic analyses and EC-S minimal residual disease determination. All authors made substantial contributions to the concept, design and conduct of the clinical trial, were involved in the writing and critical revision of the manuscript, and gave final approval of the revision to be submitted.

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Author notes

  1. E Coustan-Smith & D Campana

    Present address: 8Current address: Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,

Authors and Affiliations

  1. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    C-H Pui, E Coustan-Smith, S Jeha, J T Sandlund, R C Ribeiro, J E Rubnitz, H Inaba, T A Gruber & D Campana

  2. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    C-H Pui, S C Raimondi & J R Downing

  3. The University of Tennessee Health Science Center, Memphis, TN, USA

    C-H Pui

  4. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    D Pei & C Cheng

  5. Department of Pediatrics, University of North Texas Health Science Center, Fort Worth, TX, USA

    W P Bowman

  6. Department of Bone Marrow Transplantation & Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    W H Leung

  7. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital, Memphis, TN, USA

    J J Yang, W E Evans & M V Relling

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Correspondence to C-H Pui.

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Pui, CH., Pei, D., Raimondi, S. et al. Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia 31, 333–339 (2017). https://doi.org/10.1038/leu.2016.234

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