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Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG)

Leukemia volume 32, pages 1370–1379 (2018)Cite this article

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Abstract

Minimal residual disease (MRD) after initial therapy is integral to risk stratification in B-precursor and T-precursor acute lymphoblastic leukemia (B-ALL, T-ALL). Although MRD determines depth of remission, remission remains defined by morphology. We determined the outcomes of children with discordant assessments of remission by morphology vs. flow cytometry using patients age 1–30.99 years enrolled on Children’s Oncology Group ALL trials who underwent bone marrow assessment at the end of induction (N = 9350). Morphologic response was assessed locally as M1 (<5% lymphoblasts; remission), M2 (5–25%), or M3 (>25%). MRD was centrally measured by flow cytometry. Overall, 19.8% of patients with M2/M3 morphology had MRD < 5%. M1 with MRD ≥ 5% was less common in B-ALL (0.9%) than T-ALL (6.9%; p < 0.0001). In B-ALL, M1/MRD ≥ 5% was associated with superior 5-year event-free survival (EFS) than M2/MRD ≥ 5% (59.1% ± 6.5% vs. 39.1% ± 7.9%; p = 0.009), but was inferior to M1/MRD < 5% (87.1% ± 0.4%; p < 0.0001). MRD levels were higher in M2/MRD ≥ 5% than M1/MRD ≥ 5% patients. In T-ALL, EFS was not significantly different between M1/MRD ≥ 5% and M2/MRD ≥ 5%. Patients with morphologic remission but MRD ≥ 5% have outcomes similar to those who fail to achieve morphological remission, and significantly inferior to those with M1 marrows and concordant MRD, suggesting that flow cytometry should augment the definition of remission in ALL.

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References

  1. 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  PubMed  PubMed Central  CAS  Google Scholar 

  2. 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  PubMed  PubMed Central  CAS  Google Scholar 

  3. 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;126:964–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. 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 teh AIEOP-BFM ALL 2000 study. Blood. 2010;115:3206–14.

    Article  PubMed  CAS  Google Scholar 

  5. Schrappe M, Valsecchi MG, Bartram CR, Schrauder A, Panzer-Grumayer R, Moricke 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;118:2077–84.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Van der Velden VH, Corral L, Valsecchi MG, Jansen MW, De Lorenzo P, Cazzaniga G, et al. Prognostic significance of minimal residual disease in infants with acute lymphoblastic leukemia treated within the Interfant-99 protocol. Leukemia. 2009;23:1073–9.

    Article  PubMed  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  PubMed  Google Scholar 

  9. 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  PubMed  PubMed Central  CAS  Google Scholar 

  10. Kreft A, Holtmann H, Schad A, Kirkpatrick CJ. Detection of residual leukemic blasts in adult patients with acute T-lymphoblastic leukemia using bone marrow trephine biopsies: Comparison of fluorescent immunohistochemistry with conventional cytologic and flow-cytometric analysis. Pathol Res Pract. 2010;206:560–4.

    Article  PubMed  CAS  Google Scholar 

  11. Longacre TA, Foucar K, Crago S, Chen IM, Griffith B, Dressler L, et al. Hematogones: a multiparameter analysis of bone marrow precursor cells. Blood. 1989;73:543–52.

    PubMed  CAS  Google Scholar 

  12. O’Connor D, Moorman AV, Wade R, Hancock J, Tan RMR, Bartram J, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35:660–7.

    Article  PubMed  Google Scholar 

  13. Larsen EC, Devidas M, Chen S, Salzer WL, Raetz EA, Loh ML, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk b-acute lymphoblastic leukemia: a report from children’s oncology group study AALL0232. J Clin Oncol. 2016;34:2380–8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Winter SS, Dunsmore KP, Devidas M, Eisenberg N, Asselin BL, Wood BL, et al. Safe integration of nelarabine into intensive chemotherapy in newly diagnosed T-cell acute lymphoblastic leukemia: Children’s Oncology Group Study AALL0434. Pediatr Blood Cancer. 2015;62:1176–83.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Schultz KR, Pullen DJ, Sather HN, Shuster JJ, Devidas M, Borowitz MJ, et al. Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG). Blood. 2007;109:926–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Wood BL. Flow cytometric monitoring of residual disease in acute leukemia. In: Czader M, editor. Hematologic malignancies. New York: Springer Science and Business; 2013. p. 999.

  17. Roshal M, Fromm JR, Winter SS, Dunsmore KP, Wood BL. Immaturity associated antigens are lost during induction for T cell lymphoblastic leukemia: implications for minimal residual disease detection. Cytom B Clin Cytom. 2010;78:139–45.

    Article  CAS  Google Scholar 

  18. Heerema NA, Carroll AJ, Devidas M, Loh ML, Borowitz MJ, Gastier-Foster JM, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk Children’s oncology group studies: a report from the children’s oncology group. J Clin Oncol. 2013;31:3397–402.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Coustan-Smith E, Mullighan CG, Onciu M, Behm FG, Raimondi SC, Pei D, et al. Early T-cell precursor leukaemia: a subtype of very high-risk acute lymphoblastic leukaemia. Lancet Oncol. 2009;10:147–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Kaplan E, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53:457–81.

    Article  Google Scholar 

  21. Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977;35:1–39.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127:2391–405.

    Article  PubMed  CAS  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;360:2730–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Vrooman LM, Sevenson KE, Supko JG, O’Brien J, Dahlberg SE, Asselin BL, et al. Post-induction dexamethasone and individualized dosing of Escherichia coli L-asparaginase each improve outcome of children and adolescents with newly diagnosed acute lymphoblastic leukemia: results from a randomized study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01. J Clin Oncol. 2013;31:1202–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. McKenna RW, LaBaron WT, Aquino DB, Picker LJ, Kroft SH. Immunophenotypic analysis of hematogones (B-lymphocyte precursors) in 662 consecutive bone marrow specimens by 4-color flow cytometry. Blood. 2001;98:2498–507.

    Article  PubMed  CAS  Google Scholar 

  26. Karawajew L, Dworzak M, Ratei R, Rhein P, Gaipa G, Buldini B, et al. Minimal residual disease analysis by eight-color flow cytometry in relapsed childhood acute lymphoblastic leukemia. Haematologica. 2015;100:935–44.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Inaba H, Coustan-Smith E, Cao X, Pounds SB, Shurtleff SA, Wang KY, et al. Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30:3625–32.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This study was supported by National Institutes of Health, National Cancer Institute grants (U10CA098543, U10CA098413, U10CA180886, and U10CA180899) and by St. Baldrick’s Foundation. In-kind support was also provided by Becton Dickinson Biosciences (San Jose, CA). SG is supported by a young investigator grant from the Alex’s Lemonade Stand Foundation. MLL is the Benioff Chair of Childhood Health and the Deborah and Arthur Ablin Chair of Pediatric Molecular Oncology at the Benioff Children’s Hospitals, UCSF SF, CA. SPH is the Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics, Children’s Hospital of Philadelphia

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Author notes

  1. Stephen P. Hunger

    Present address: Department of Genetics, Children’s Hospital of Alabama, Birmingham, AL, USA

  2. These authors contributed equally: Sumit Gupta, Meenakshi Devidas

  3. These authors jointly supervised this work: Michael J. Borowitz, Brent L. Wood

Authors and Affiliations

  1. Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada

    Sumit Gupta

  2. Department of Biostatistics, University of Florida, Gainesville, FL, USA

    Meenakshi Devidas, Si Chen & Cindy Wang

  3. Division of Hematology Oncology, University of California at San Francisco, San Francisco, CA, USA

    Mignon L. Loh

  4. Division of Pediatric Hematology-Oncology, Primary Children’s Hospital, Salt Lake City, UT, USA

    Elizabeth A. Raetz

  5. Johns Hopkins University/Sidney Kimmel Cancer Center, Baltimore, MD, USA

    Patrick Brown

  6. Department of Genetics, Children’s Hospital of Alabama, Birmingham, AL, USA

    Andrew J. Carroll

  7. Department of Pathology, The Ohio State University, Columbus, OH, USA

    Nyla A. Heerema

  8. Department of Pathology, Nationwide Children’s Hospital, Columbus, OH, USA

    Julie M. Gastier-Foster

  9. Department of Pediatrics, University of Virginia Cancer Center, Norton, VA, USA

    Kimberly P. Dunsmore

  10. Maine Children’s Cancer Program, Scarborough, ME, USA

    Eric C. Larsen

  11. Children’s Hospital Colorado, Aurora, CO, USA

    Kelly W. Maloney

  12. HARP Pharma Consulting, Mystic, CT, USA

    Leonard A. Mattano Jr.

  13. University of New Mexico Cancer Center, Albuquerque, NM, USA

    Stuart S. Winter

  14. Department of Pediatrics, University of Texas Southwestern/Simmons Cancer Center, Dallas, TX, USA

    Naomi J. Winick

  15. Laura and Isaac Perlmutter Cancer Center, New York, NY, USA

    William L. Carroll

  16. Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Stephen P. Hunger

  17. Division of Hematologic Pathology, John Hopkins University, Baltimore, MD, USA

    Michael J. Borowitz

  18. Seattle Children’s Hospital, Seattle, WA, USA

    Brent L. Wood

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  1. Sumit Gupta
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  2. Meenakshi Devidas
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  15. Stuart S. Winter
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  20. Brent L. Wood
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Correspondence to Sumit Gupta.

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Gupta, S., Devidas, M., Loh, M.L. et al. Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG). Leukemia 32, 1370–1379 (2018). https://doi.org/10.1038/s41375-018-0039-7

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