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Donor cell leukemia: evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient

Leukemia volume 31, pages 1637–1640 (2017)Cite this article

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Acute myeloid leukemia (AML) is an aggressive malignant disorder of hematopoietic stem and (HSCs) progenitor cells. The development of AML involves the serial acquisition of mutations in HSCs in epigenetic genes such as DNMT3A, TET2 or IDH1/2. These preleukemic HSCs acquire further mutations in genes affecting transcription, differentiation and proliferation (for example, FLT3, NPM1) consequently leading to leukemic transformation (reviewed in Grimwade et al.1). More recently, somatic mutations in DNMT3A and TET2 have been detected in healthy individuals and evidence of clonal hematopoiesis,2, 3, 4 a condition called clonal hematopoiesis of indeterminate potential (CHIP).5 CHIP increases with age, reaching 10% at 60 years, and is associated with an increased risk of developing hematologic malignancies.4 There are extensive studies about clonal evolution in AML, but mainly restricted to diagnosis, remission and relapse samples. Little is known about the evolutionary processes prior to overt leukemia. Here we present a seven-year follow-up study of a CHIP-derived donor cell AML (DCL) developing in parallel, but with very distinct features in the recipient and his related donor after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The sequential monitoring of mutational burden in the recipient provides unique insights into clonal dynamics and reveals the progression and persistence of diverse preleukemic clones over more than 7 years in this patient until the emergence of overt leukemia.

In detail, a 43-year-old male patient (P1) was diagnosed with chronic lymphocytic leukemia (1996). Chemo-immunotherapy was started, and after first relapse alemtuzumab-based treatment was initiated. Due to the short response duration, an allo-HSCT from his HLA-identical sister (P2; age 54 years) was performed (11/2004) following reduced-intensity conditioning (busulfan/fludarabine).6 Full donor chimerism (DC) assessed by short tandem repeat analysis7 was reported from day +27 onwards. Graft-versus-host disease prophylaxis had been performed with CsA/Methotrexate for 12 months without clinical signs of graft-versus-host disease. More than 7 years after allo-HSCT (02/2012), P1 was diagnosed with normal female karyotype [46,XX] AML (M1). Chimerism analysis confirmed complete DC indicating DCL. P1 received standard ‘3+7’ daunorubicin+cytarabine induction chemotherapy, reached complete remission (CR) and received a second allo-HSCT from an HLA-compatible unrelated donor. Interestingly, the sibling donor (P2) had been also diagnosed with AML (M2), only 3 months earlier (11/2011). In this case, cytogenetics revealed an abnormal karyotype [47,XX,+8]. P2 initially also achieved CR after standard chemotherapy, but relapsed (07/2012) and received an allo-HSCT from an HLA-compatible unrelated donor after successful reinduction treatment. At the time of reporting (12/2016), P1 is alive in remission, whereas P2 died from second relapse (09/2014). The parallel development of distinct leukemias with such a long latency in two individuals prompted us to investigate the clonal relationship of both diseases.

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References

  1. Grimwade D, Ivey A, Huntly BJ . Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance. Blood 2016; 127: 29–42.

    Article  CAS  Google Scholar 

  2. Xie M, Lu C, Wang J, McLellan MD, Johnson KJ, Wendl MC et al. Age-related mutations associated with clonal hematopoietic expansion and malignancies. Nat Med 2014; 12: 1472–1478.

    Article  Google Scholar 

  3. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Townsley D et al. Somatic mutations and clonal hematopoiesis in aplastic anemia. N Engl J Med 2015; 373: 35–47.

    Article  CAS  Google Scholar 

  4. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med 2014; 371: 2488–2498.

    Article  Google Scholar 

  5. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP et al. Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes. Blood 2016; 126: 9–17.

    Article  Google Scholar 

  6. Schetelig J, Thiede C, Bornhäuser M, Schwerdtfeger R, Kiehl M, Beyer J et al. Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 2003; 21: 2747–2753.

    Article  CAS  Google Scholar 

  7. Bornhäuser M, Oelschlaegel U, Platzbecker U, Bug G, Lutterbeck K, Kiehl MG et al. Monitoring of donor chimerism in sorted CD34+ peripheral blood cells allows the sensitive detection of imminent relapse after allogeneic stem cell transplantation. Haematologica 2009; 94: 1613–1617.

    Article  Google Scholar 

  8. Hahn CN, Ross DM, Feng J, Beligaswatte A, Hiwase DK, Parker WT et al. A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone. Leukemia 2015; 29: 2101–2104.

    Article  CAS  Google Scholar 

  9. Yasuda T, Ueno T, Fukumura K, Yamato A, Ando M, Yamaguchi H et al. Leukemic evolution of donor-derived cells harboring IDH2 and DNMT3A mutations after allogeneic stem cell transplantation. Leukemia 2014; 28: 426–428.

    Article  CAS  Google Scholar 

  10. Sala-Torra O, Hanna C, Loken MR, Flowers ME, Maris M, Ladne PA et al. Evidence of donor-derived hematologic malignancies after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2006; 12: 511–517.

    Article  Google Scholar 

  11. Wiseman DH . Donor cell leukemia: a review. Biol Blood Marrow Transplant 2011; 17: 771–789.

    Article  Google Scholar 

  12. Rezvani AR, Storer BE, Guthrie KA, Schoch HG, Maloney DG, Sandmaier BM et al. Impact of donor age on outcome after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2015; 21: 105–112.

    Article  Google Scholar 

  13. Walter RB, Pagel JM, Gooley TA, Petersdorf EW, Sorror ML, Woolfrey AE et al. Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 2010; 24: 1276–1282.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The skillful technical assistance by M Karger and M Hartwig is highly acknowledged. We also thank Rob Saunders (biomed context) for providing medical writing support. This study was supported in part by grant BMBF 01GS0872 to CT and by grant BMBF 031A424 to CT, MB and IR.

Author contributions

SH, MB and CT designed the study; SH, MB, MvB, MK and CT wrote the manuscript; SH, MK, CH, TS, IR, AD, CT performed the experiments and analyzed the data; UP, JR, TL, KS, KG, JS, CR, BM, MvB, HS, CB and GE provided patient materials, clinical and/or experimental data; all authors read and approved the final manuscript.

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Author notes

  1. S Herold, M Kuhn, M v Bonin, M Bornhäuser and C Thiede: These authors contributed equally to this work.

Authors and Affiliations

  1. Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl Gustav Carus der TU Dresden, Dresden, Germany

    S Herold, M v Bonin, U Platzbecker, J Radke, K Sockel, J Schetelig, C Röllig, C Schuster, B Mohr, G Ehninger, M Bornhäuser & C Thiede

  2. Institut für Medizinische Informatik und Biometrie,

    M Kuhn, T Stange & I Roeder

  3. TU Dresden, Dresden, Germany

    M Kuhn, T Stange & I Roeder

  4. Deutsches Konsortium für Translationale Krebsforschung (DKTK), Dresden, Germany

    M v Bonin

  5. Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany

    M v Bonin

  6. Abteilung Hämatologie, Universitätsklinikum Leipzig AöR, Leipzig, Germany

    T Lange

  7. Klinik für Hämatologie und Onkologie, Städtisches Klinikum Görlitz, Görlitz, Germany

    K Gutsche

  8. Deep Sequencing Core Facility, Center for Regenerative Medicine, TU Dresden, Dresden, Germany

    A Dahl

  9. Medizinische Klinik II, Klinikum der Johann-Wolfgang-Goethe-Universität, Frankfurt am Main, Germany

    H Serve & C Brandts

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  1. S Herold
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Corresponding author

Correspondence to C Thiede.

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Competing interests

CT is CEO and co-owner of AgenDix GmbH, a company performing molecular diagnostics. The remaining authors declare no conflict of interest.

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Herold, S., Kuhn, M., Bonin, M. et al. Donor cell leukemia: evidence for multiple preleukemic clones and parallel long term clonal evolution in donor and recipient. Leukemia 31, 1637–1640 (2017). https://doi.org/10.1038/leu.2017.104

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