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Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia

Bone Marrow Transplantation volume 56, pages 1908–1918 (2021)Cite this article

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Abstract

The impact of adverse risk genetic profiles on outcomes in acute myeloid leukemia (AML) patients following allogeneic hematopoietic stem cell transplantation (HCT) has not been fully elucidated. Accordingly, we have profiled somatic mutations at diagnosis using next-generation sequencing (NGS) in 178 AML patients who received allogeneic HCT. NGS revealed 598 somatic mutations in 165/178 patients (92.7%). Frequently mutated genes include DNMT3A, TET2, NPM1, RUNX1, IDH2, and FLT3. Commonly detected cytogenetic profiles include normal karyotype, trisomy 8, monosomal karyotype (MK), deletion 5, complex karyotype (CK), and monosomy 7. In univariate analyses, TP53 mutation, MK, CK, and monosomy 7 were associated with decreased overall survival (OS), relapse-free survival (RFS), and a higher relapse incidence (RI). We defined adverse molecular-genetic profile as harboring at least one of the molecular/genetic abnormalities of TP53 mutation, MK, CK, monosomy 7, and deletion 5. The patients harboring adverse molecular-genetic profile (n = 30) showed a lower 2-year OS (24.9% vs. 57.9%; p = 0.003), RFS (23.7% vs. 57.9%; p = 0.002), and higher RI (47.2% and 17.2%; p = 0.001) after HCT when compared to patients without those lesions. Multivariate analysis confirmed adverse molecular-genetic profile as an independent prognostic factor, associated with decreased OS (HR 2.19), RFS (HR 2.23), and higher RI (HR 2.94).

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Fig. 1: Spectrum of somatic mutations and patterns of their co-occurrence/mutual exclusiveness in 178 AML patients treated with allogeneic hematopoietic cell transplantation.
Fig. 2: Association between the composite adverse profile and outcome of allogeneic hematopoietic cell transplantation.
Fig. 3: Transplant outcome of allogeneic hematopoietic cell transplantation in a subgroup of the patients with the adverse molecular-genetic profile according to the intensity of conditioning regimen.

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References

  1. Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5:33.

    Article  Google Scholar 

  2. Kouchkovsky ID, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J. 2016;6:e441.

    Article  Google Scholar 

  3. Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol. 2015;19:A68–77.

    Google Scholar 

  4. Network TCGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

    Article  Google Scholar 

  5. Metzeler KH, Herold T, Rothenberg-Thurley M, Amler S, Sauerland MC, Görlich D, et al. Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia. Blood. 2016;128:686–98.

    Article  CAS  Google Scholar 

  6. 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.

  7. Ilyas AM, Ahmad S, Faheem M, Naseer MI, Kumosani TA, Al-Qahtani MH, et al. Next generation sequencing of acute myeloid leukemia: influencing prognosis. BMC Genom. 2015;16:S5.

    Article  Google Scholar 

  8. DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology. 2016;2016:348–55.

    Article  Google Scholar 

  9. Moarii M, Papaemmanuil E. Classification and risk assessment in AML: integrating cytogenetics and molecular profiling. ASH Educ Program Book. 2017;2017:37–44.

    Google Scholar 

  10. Koreth J, Schlenk R, Kopecky KJ, Honda S, Sierra J, Djulbegovic BJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301:2349–61.

    Article  CAS  Google Scholar 

  11. Mohr B, Schetelig J, Schäfer-Eckart K, Schmitz N, Hänel M, Rösler W, et al. Impact of allogeneic haematopoietic stem cell transplantation in patients with abnl(17p) acute myeloid leukaemia. Brit J Haematol. 2013;161:237–44.

    Article  Google Scholar 

  12. Guo RJ, Atenafu EG, Craddock K, Chang H. Allogeneic hematopoietic cell transplantation may alleviate the negative prognostic impact of monosomal and complex karyotypes on patients with acute myeloid leukemia. Biol Blood Marrow Transplant. 2014;20:690–5.

    Article  Google Scholar 

  13. Oran B, Dolan M, Cao Q, Brunstein C, Warlick E, Weisdorf D. Monosomal karyotype provides better prognostic prediction after allogeneic stem cell transplantation in patients with acute myelogenous leukemia. Biol Blood Marrow Transplant. 2011;17:356–64.

    Article  CAS  Google Scholar 

  14. Lindsley RC, Saber W, Mar BG, Redd R, Wang T, Haagenson MD, et al. Prognostic mutations in myelodysplastic syndrome after stem-cell transplantation. N Engl J Med. 2017;376:536–47.

    Article  CAS  Google Scholar 

  15. Yoshizato T, Nannya Y, Atsuta Y, Shiozawa Y, Iijima-Yamashita Y, Yoshida K, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129:2347–58.

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

    Article  CAS  Google Scholar 

  17. Grimwade D, Hills RK, Moorman AV, Walker H, Chatters S, Goldstone AH, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116:354–65.

    Article  CAS  Google Scholar 

  18. 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 

  19. Grimwade D, Walker H, Oliver F, Wheatley K, Harrison C, Harrison G, et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children’s Leukaemia Working Parties. Blood. 1998;92:2322–33.

    Article  CAS  Google Scholar 

  20. Breems DA, Putten WLJV, Greef GED, Zelderen-Bhola SLV, Gerssen-Schoorl KBJ, Mellink CHM, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol. 2008;26:4791–7.

    Article  Google Scholar 

  21. Consortium 1000 Genomes Project, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526:68–74.

  22. Fu W, O’Connor TD, Jun G, Kang HM, Abecasis G, Leal SM, et al. Analysis of 6,515 exomes reveals the recent origin of most human protein-coding variants. Nature. 2013;493:216–20.

    Article  CAS  Google Scholar 

  23. Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

  24. Sherry ST, Ward M-H, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29:308–11.

    Article  CAS  Google Scholar 

  25. Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424–47.

  26. Wang M, Lindberg J, Klevebring D, Nilsson C, Mer AS, Rantalainen M, et al. Validation of risk stratification models in acute myeloid leukemia using sequencing-based molecular profiling. Leukemia. 2017;31:2029–36.

    Article  CAS  Google Scholar 

  27. Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, et al. Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood. 2000;96:4075–83.

    Article  CAS  Google Scholar 

  28. Byrd JC, Mrózek K, Dodge RK, Carroll AJ, Edwards CG, Arthur DC, et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood. 2002;100:43–4336.

  29. Haferlach C, Alpermann T, Schnittger S, Kern W, Chromik J, Schmid C, et al. Prognostic value of monosomal karyotype in comparison to complex aberrant karyotype in acute myeloid leukemia: a study on 824 cases with aberrant karyotype. Blood. 2012;119:2122–5.

    Article  CAS  Google Scholar 

  30. Poiré X, Labopin M, Maertens J, Yakoub-Agha I, Blaise D, Ifrah N, et al. Allogeneic stem cell transplantation in adult patients with acute myeloid leukaemia and 17p abnormalities in first complete remission: a study from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). J Hematol Oncol. 2017;10:20.

    Article  Google Scholar 

  31. Castro PD, Liang JC, Nagarajan L. Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Blood. 2000;95:2138–43.

    Article  CAS  Google Scholar 

  32. Armand P, Kim HT, Zhang M-J, Perez WS, Cin PSD, 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 Transplant. 2012;18:280–8.

    Article  Google Scholar 

  33. Middeke JM, Fang M, Cornelissen JJ, Mohr B, Appelbaum FR, Stadler M, et al. Outcome of patients with abnl(17p) acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. Blood. 2014;123:2960–7.

    Article  CAS  Google Scholar 

  34. Middeke JM, Herold S, Rücker-Braun E, Berdel WE, Stelljes M, Kaufmann M, et al. TP53 mutation in patients with high‐risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation. Brit J Haematol. 2016;172:914–22.

    Article  CAS  Google Scholar 

  35. Yanada M, Emi N, Naoe T, Sakamaki H, Iseki T, Hirabayashi N, et al. Allogeneic myeloablative transplantation for patients aged 50 years and over. Bone Marrow Transplant. 2004;34:29–35.

    Article  CAS  Google Scholar 

  36. Ringdén O, Horowitz MM, Gale RP, Biggs JC, Gajewski J, Rimm AA, et al. Outcome after allogeneic bone marrow transplant for leukemia in older adults. JAMA. 1993;270:57–60.

    Article  Google Scholar 

  37. Cahn J-Y, Labopin M, Schattenberg A, Reiffers J, Willemze R, Zittoun R, et al. Allogeneic bone marrow transplantation for acute leukemia in patients over the age of 40 years. Leukemia. 1997;11:416–9.

    Article  CAS  Google Scholar 

  38. Stelljes M, Beelen DW, Braess J, Sauerland MC, Heinecke A, Berning B, et al. Allogeneic transplantation as post-remission therapy for cytogenetically high-risk acute myeloid leukemia: landmark analysis from a single prospective multicenter trial. Haematologica. 2011;96:972–9.

    Article  Google Scholar 

  39. Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–8.

    Article  CAS  Google Scholar 

  40. Lima M, de, Anagnostopoulos A, Munsell M, Shahjahan M, Ueno N, Ippoliti C, et al. Nonablative versus reduced-intensity conditioning regimens in the treatment of acute myeloid leukemia and high-risk myelodysplastic syndrome: dose is relevant for long-term disease control after allogeneic hematopoietic stem cell transplantation. Blood. 2004;104:865–72.

    Article  Google Scholar 

  41. Wahid SFA, Ismail N-A, Mohd-Idris M-R, Jamaluddin FW, Tumian N, Sze-Wei EY, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev. 2014;23:2535–52.

    Article  Google Scholar 

  42. Bornhäuser M, Kienast J, Trenschel R, Burchert A, Hegenbart U, Stadler M, et al. Reduced-intensity conditioning versus standard conditioning before allogeneic haemopoietic cell transplantation in patients with acute myeloid leukaemia in first complete remission: a prospective, open-label randomised phase 3 trial. Lancet Oncol. 2012;13:1035–44.

    Article  Google Scholar 

  43. Alyea EP, Kim HT, Ho V, Cutler C, DeAngelo DJ, Stone R, et al. Impact of conditioning regimen intensity on outcome of allogeneic hematopoietic cell transplantation for advanced acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2006;12:1047–55.

    Article  Google Scholar 

  44. Paun O, Lazarus HM. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission. Curr Opin Hematol. 2012;19:95–101.

    Article  Google Scholar 

  45. Savani BN. Transplantation in AML CR1. Blood. 2010;116:1822–3.

    Article  CAS  Google Scholar 

  46. Gupta V, Tallman MS, Weisdorf DJ. Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns. Blood. 2011;117:2307–18.

  47. Wong TN, Ramsingh G, Young AL, Miller CA, Touma W, Welch JS, et al. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia. Nature. 2015;518:552–5.

  48. Wattel E, Preudhomme C, Hecquet B, Vanrumbeke M, Quesnel B, Dervite I, et al. p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood. 1994;84:3148–57.

    Article  CAS  Google Scholar 

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Acknowledgements

TK is supported by scholarship from the Natural Sciences and Engineering Research Council of Canada (NSERC) (PGS-D). ZZ acknowledges support from NSERC (RGPIN-2017-06743). DDHK acknowledges support from the Leukemia & Lymphoma Society of Canada, New Idea Award (2017-522193), and from the Princess Margaret Cancer Foundation. Lastly, authors would like to thank anonymous reviewers for providing valuable and detailed comments on our manuscript.

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Author notes

  1. These authors contributed equally: Georgina Daher-Reyes, TaeHyung Kim

  2. These authors jointly supervised this work: Andre Schuh, Dennis D. H. Kim

Authors and Affiliations

  1. Department of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Georgina Daher-Reyes, TaeHyung Kim, Igor Novitzky-Basso, Kyuoung Ha Kim, Zeyad Al-Shaibani, Ivan Pasic, Arjun Law, Wilson Lam, Fotios V. Michelis, Armin Gerbitz, Auro Viswabandya, Jeffrey Lipton, Rajat Kumar, Jonas Mattsson, Aaron Schimmer, Caroline McNamara, Tracy Murphy, Dawn Maze, Vikas Gupta, Hassan Sibai, Steven Chan, Karen Yee, Mark Minden, Andre Schuh & Dennis D. H. Kim

  2. Department of Computer Science, University of Toronto, Toronto, ON, Canada

    TaeHyung Kim & Zhaolei Zhang

  3. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada

    TaeHyung Kim & Zhaolei Zhang

  4. Department of Internal Medicine, Soonchunhyang University Hospital, Seoul, Korea

    Kyuoung Ha Kim

  5. Clinical Lab Genetics Division, Laboratory of Molecular Pathology, Toronto General Hospital, University Health Network, Toronto, ON, Canada

    Adam Smith & Tracy Stockley

  6. Advanced Molecular Diagnostics Laboratory, Princess Margaret Cancer Centre, Toronto, ON, Canada

    Tracy Stockley & Jose-Mario Capochichi

  7. Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada

    Zhaolei Zhang

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Contributions

A. Schuh and DK designed the study; GD-R, A. Schuh, and DK collected samples and performed experiments; TK, TS, J-MC, ZZ, and DK analyzed the sequencing data and performed computational analyses; GD-R, TK, IN-B, KHK, A. Schuh, and DK interpreted the data and statistical analyses; and GD-R, TK, IN-B, ZZ, A. Schuh, and DK wrote the paper. All authors reviewed and approved the paper.

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Correspondence to Dennis D. H. Kim.

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Daher-Reyes, G., Kim, T., Novitzky-Basso, I. et al. Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia. Bone Marrow Transplant 56, 1908–1918 (2021). https://doi.org/10.1038/s41409-021-01255-4

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