Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission

Bone Marrow Transplantation volume 56, pages 2779–2787 (2021)Cite this article

Subjects

Abstract

Pretransplant measurable residual disease (MRD) has been shown to be associated with relapse incidence following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML). However, it remains less clear whether pretransplant MRD status affects transplant outcomes in core binding factor AML (CBF-AML). We retrospectively evaluated the effect of pretransplant MRD, which was measured by a polymerase chain reaction of RUNX1-RUNX1T1 or CBFB-MYH11 fusion transcripts, on transplant outcomes for a cohort of 959 adult patients with t(8;21) or inv(16) AML treated by allogeneic HCT during complete remission (CR), between 2000 and 2018. Multivariate analysis showed the absence of pretransplant MRD was significantly associated with lower relapse (hazard ratio [HR], 0.46; P < 0.001), treatment failure (HR, 0.66; P = 0.004), and overall mortality (HR, 0.72; P = 0.037) among patients with t(8;21). However, pretransplant MRD negativity was not associated with relapse (HR, 0.73; P = 0.420), treatment failure (HR, 0.64; P = 0.063), or overall mortality (HR, 0.69; P = 0.149) among patients with inv(16). In subgroup analysis, pretransplant MRD status significantly affected relapse and LFS only in patients with t(8;21) undergoing allogeneic HCT during CR2. In conclusion, our data demonstrate the different prognostic values of pretransplant MRD for CBF-AML, highlighting the need to develop effective therapeutic strategies for such MRD-positive patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The probability of overall survival (OS) and leukemia-free survival (LFS) in patients with t(8;21) or inv(16) acute myeloid leukemia, according to pretransplant measurable residual disease (MRD) status.
Fig. 2: The cumulative incidence of relapse and non-relapse mortality (NRM) in patients with t(8;21) or inv(16) acute myeloid leukemia, according to pre-transplant measurable residual disease (MRD) status.

Similar content being viewed by others

References

  1. Schuurhuis GJ, Heuser M, Freeman S, Béné MC, Buccisano F, Cloos J, et al. Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party. Blood 2018;131:1275–91.

    Article  CAS  Google Scholar 

  2. Dillon R, Potter N, Freeman S, Russell N. How we use molecular minimal residual disease (MRD) testing in acute myeloid leukaemia (AML). Br J Haematol. 2021;193:231–44.

    Article  CAS  Google Scholar 

  3. Cloos J, Ossenkoppele GJ, Dillon R. Minimal residual disease and stem cell transplantation outcomes. Hematol Am Soc Hematol Educ Program. 2019;2019:617–25.

    Article  Google Scholar 

  4. Gaut D, Mead M. Measurable residual disease in hematopoietic stem cell transplantation-eligible patients with acute myeloid leukemia: clinical significance and promising therapeutic strategies. Leuk Lymphoma. 2021;62:8–31.

    Article  CAS  Google Scholar 

  5. Yin JA, O’Brien MA, Hills RK, Daly SB, Wheatley K, Burnett AK. Minimal residual disease monitoring by quantitative RT-PCR in core binding factor AML allows risk stratification and predicts relapse: results of the United Kingdom MRC AML-15 trial. Blood 2012;120:2826–35.

    Article  CAS  Google Scholar 

  6. Jourdan E, Boissel N, Chevret S, Delabesse E, Renneville A, Cornillet P, et al. Prospective evaluation of gene mutations and minimal residual disease in patients with core binding factor acute myeloid leukemia. Blood 2013;121:2213–23.

    Article  CAS  Google Scholar 

  7. Corbacioglu A, Scholl C, Schlenk RF, Eiwen K, Du J, Bullinger L, et al. Prognostic impact of minimal residual disease in CBFB-MYH11-positive acute myeloid leukemia. J Clin Oncol. 2010;28:3724–9.

    Article  CAS  Google Scholar 

  8. Zhu HH, Zhang XH, Qin YZ, Liu DH, Jiang H, Chen H, et al. MRD-directed risk stratification treatment may improve outcomes of t(8;21) AML in the first complete remission: results from the AML05 multicenter trial. Blood 2013;121:4056–62.

    Article  CAS  Google Scholar 

  9. Willekens C, Blanchet O, Renneville A, Cornillet-Lefebvre P, Pautas C, Guieze R, et al. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial. Haematologica 2016;101:328–35.

    Article  CAS  Google Scholar 

  10. Rücker FG, Agrawal M, Corbacioglu A, Weber D, Kapp-Schwoerer S, Gaidzik VI, et al. Measurable residual disease monitoring in acute myeloid leukemia with t(8;21)(q22;q22.1): results from the AML Study Group. Blood 2019;134:1608–18.

    Article  Google Scholar 

  11. Ishikawa Y, Kawashima N, Atsuta Y, Sugiura I, Sawa M, Dobashi N, et al. Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11. Blood Adv. 2020;4:66–75.

    Article  CAS  Google Scholar 

  12. Puckrin R, Atenafu EG, Claudio JO, Chan S, Gupta V, Maze D, et al. Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia. Haematologica 2021;106:56–63.

    Article  CAS  Google Scholar 

  13. Wang Y, Wu DP, Liu QF, Qin YZ, Wang JB, Xu LP, et al. In adults with t(8;21)AML, posttransplant RUNX1/RUNX1T1-based MRD monitoring, rather than c-KIT mutations, allows further risk stratification. Blood 2014;124:1880–6.

    Article  CAS  Google Scholar 

  14. Tang FF, Xu LP, Zhang XH, Chen H, Chen YH, Han W, et al. Monitoring of post-transplant CBFB-MYH11 as minimal residual disease, rather than KIT mutations, can predict relapse after allogeneic haematopoietic cell transplantation in adults with inv(16) acute myeloid leukaemia. Br J Haematol. 2018;180:448–51.

    Article  Google Scholar 

  15. Yalniz FF, Patel KP, Bashir Q, Marin D, Ahmed S, Alousi AM, et al. Significance of minimal residual disease monitoring by real-time quantitative polymerase chain reaction in core binding factor acute myeloid leukemia for transplantation outcomes. Cancer 2020;126:2183–92.

    Article  CAS  Google Scholar 

  16. Halaburda K, Labopin M, Mailhol A, Socié G, Craddock C, Aljurf M, et al. Allogeneic stem cell transplantation in second complete remission for core binding factor acute myeloid leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2020;105:1723–30.

    Article  CAS  Google Scholar 

  17. Atsuta Y. Introduction of Transplant Registry Unified Management Program 2 (TRUMP2): scripts for TRUMP data analyses, part I (variables other than HLA-related data). Int J Hematol. 2016;103:3–10.

    Article  Google Scholar 

  18. Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649–55.

    Article  CAS  Google Scholar 

  19. Giralt S, Ballen K, Rizzo D, Bacigalupo A, Horowitz M, Pasquini M, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transpl. 2009;15:367–9.

    Article  Google Scholar 

  20. Marcucci G, Mrózek K, Ruppert AS, Maharry K, Kolitz JE, Moore JO, et al. Prognostic factors and outcome of core binding factor acute myeloid leukemia patients with t(8;21) differ from those of patients with inv(16): a Cancer and Leukemia Group B study. J Clin Oncol. 2005;23:5705–17.

    Article  Google Scholar 

  21. Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.

    Article  CAS  Google Scholar 

  22. Araki D, Wood BL, Othus M, Radich JP, Halpern AB, Zhou Y, et al. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia: time to move toward a minimal residual disease-based definition of complete remission? J Clin Oncol. 2016;34:329–36.

    Article  Google Scholar 

  23. Oran B, Jorgensen JL, Marin D, Wang S, Ahmed S, Alousi AM, et al. Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia. Haematologica 2017;102:110–7.

    Article  CAS  Google Scholar 

  24. Walter RB, Gyurkocza B, Storer BE, Godwin CD, Pagel JM, Buckley SA, et al. Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 2015;29:137–44.

    Article  CAS  Google Scholar 

  25. Gilleece MH, Labopin M, Yakoub-Agha I, Volin L, Socié G, Ljungman P, et al. Measurable residual disease, conditioning regimen intensity, and age predict outcome of allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first remission: A registry analysis of 2292 patients by the Acute Leukemia Working Party European Society of Blood and Marrow Transplantation. Am J Hematol. 2018;93:1142–52.

    Article  Google Scholar 

  26. Qin YZ, Wang Y, Xu LP, Zhang XH, Chen H, Han W, et al. The dynamics of RUNX1-RUNX1T1 transcript levels after allogeneic hematopoietic stem cell transplantation predict relapse in patients with t(8;21) acute myeloid leukemia. J Hematol Oncol. 2017;10:44.

    Article  Google Scholar 

  27. Papaemmanuil E, Gerstung M, Bullinger L, Gaidzik VI, Paschka P, Roberts ND, et al. Genomic Classification and Prognosis in Acute Myeloid Leukemia. N. Engl J Med. 2016;374:2209–21.

    Article  CAS  Google Scholar 

  28. Kuwatsuka Y, Miyamura K, Suzuki R, Kasai M, Maruta A, Ogawa H, et al. Hematopoietic stem cell transplantation for core binding factor acute myeloid leukemia: t(8;21) and inv(16) represent different clinical outcomes. Blood 2009;113:2096–103.

    Article  CAS  Google Scholar 

  29. Armand P, Kim HT, Zhang MJ, Perez WS, Dal Cin PS, Klumpp TR, et al. Classifying cytogenetics in patients with acute myelogenous leukemia in complete remission undergoing allogeneic transplantation: a Center for International Blood and Marrow Transplant Research study. Biol Blood Marrow Transpl. 2012;18:280–8.

    Article  Google Scholar 

  30. Hu GH, Cheng YF, Lu AD, Wang Y, Zuo YX, Yan CH, et al. Allogeneic hematopoietic stem cell transplantation can improve the prognosis of high-risk pediatric t(8;21) acute myeloid leukemia in first remission based on MRD-guided treatment. BMC Cancer. 2020;20:553.

    Article  CAS  Google Scholar 

  31. Duan W, Liu X, Jia J, Wang J, Gong L, Jiang Q, et al. The loss or absence of minimal residual disease of <0·1% at any time after two cycles of consolidation chemotherapy in CBFB-MYH11-positive acute myeloid leukaemia indicates poor prognosis. Br J Haematol. 2021;192:265–71.

    Article  CAS  Google Scholar 

  32. Wang T, Zhou B, Zhang J, Zhang X, Liu T, Qiu H, et al. Allogeneic hematopoietic stem cell transplantation could improve survival for pure CBF-AML patients with minimal residual disease positive after the second consolidation. Leuk Lymphoma. 2021;62:995–8.

    Article  CAS  Google Scholar 

  33. Hourigan CS, Dillon LW, Gui G, Logan BR, Fei M, Ghannam J, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38:1273–83.

    Article  CAS  Google Scholar 

  34. Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N. Engl J Med. 2016;375:944–53.

    Article  Google Scholar 

  35. Byrd JC, Weiss RB, Arthur DC, Lawrence D, Baer MR, Davey F, et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 1997;15:466–75.

    Article  CAS  Google Scholar 

  36. Baer MR, Stewart CC, Lawrence D, Arthur DC, Byrd JC, Davey FR, et al. Expression of the neural cell adhesion molecule CD56 is associated with short remission duration and survival in acute myeloid leukemia with t(8;21)(q22;q22). Blood 1997;90:1643–8.

    Article  CAS  Google Scholar 

  37. Duployez N, Marceau-Renaut A, Boissel N, Petit A, Bucci M, Geffroy S, et al. Comprehensive mutational profiling of core binding factor acute myeloid leukemia. Blood 2016;127:2451–9.

    Article  CAS  Google Scholar 

  38. Opatz S, Bamopoulos SA, Metzeler KH, Herold T, Ksienzyk B, Bräundl K, et al. The clinical mutatome of core binding factor leukemia. Leukemia 2020;34:1553–62.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank all the physicians and staff at the participating hospitals, the Japan Marrow Donor Program, and the cord blood banks for providing clinical data to the Transplant Registry Unified Management Program of the Japanese Data Center for Hematopoietic Cell Transplantation. This work was supported in part by the Practical Research Project for Allergic Diseases and Immunology (Research Technology of Medical Transplantation) from the Japan Agency for Medical Research and Development, AMED under grant 18ek0510023h0002.

Author information

Authors and Affiliations

  1. Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Takaaki Konuma

  2. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Tadakazu Kondo

  3. Department of Hematopoietic Cell Transplantation, Niigata University Medical and Dental Hospital, Niigata, Japan

    Masayoshi Masuko

  4. Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan

    Hiroaki Shimizu

  5. Department of Hematology, Hokkaido University Hospital, Sapporo, Japan

    Souichi Shiratori

  6. Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

    Takahiro Fukuda

  7. Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan

    Jun Kato

  8. Department of Hematology and Oncology, Anjo Kosei Hospital, Anjo, Japan

    Masashi Sawa

  9. Department of Hematology, Japanese Red Cross Nagoya First Hospital, Nagoya, Japan

    Yukiyasu Ozawa

  10. Department of Haematology, Sapporo Hokuyu Hospital, Sapporo, Japan

    Shuichi Ota

  11. Department of Hematology, Toranomon Hospital, Tokyo, Japan

    Naoyuki Uchida

  12. Division of Hematology, Jichi Medical University, Tochigi, Japan

    Yoshinobu Kanda

  13. Division of Hematology, Jichi Medical University Saitama Medical Center, Saitama, Japan

    Yoshinobu Kanda & Shinichi Kako

  14. Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan

    Shin Fujisawa

  15. Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan

    Kentaro Fukushima

  16. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    Tatsuo Ichinohe

  17. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan

    Yoshiko Atsuta

  18. Department of Healthcare Administration, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshiko Atsuta

  19. Department of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan

    Masamitsu Yanada

Authors
  1. Takaaki Konuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadakazu Kondo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Masayoshi Masuko
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroaki Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Souichi Shiratori
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Takahiro Fukuda
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jun Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masashi Sawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yukiyasu Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shuichi Ota
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Naoyuki Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yoshinobu Kanda
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Shinichi Kako
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Shin Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Kentaro Fukushima
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Tatsuo Ichinohe
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Yoshiko Atsuta
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Masamitsu Yanada
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for the Adult Acute Myeloid Leukemia Working Group of the Japan Society for Hematopoietic Cell Transplantation

Corresponding author

Correspondence to Takaaki Konuma.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Konuma, T., Kondo, T., Masuko, M. et al. Prognostic value of measurable residual disease at allogeneic transplantation for adults with core binding factor acute myeloid leukemia in complete remission. Bone Marrow Transplant 56, 2779–2787 (2021). https://doi.org/10.1038/s41409-021-01409-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41409-021-01409-4

This article is cited by

Search

Advanced search

Quick links