Prognostic impact of the adverse molecular-genetic profile on long-term outcomes following allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia.
Journal
Bone marrow transplantation
ISSN: 1476-5365
Titre abrégé: Bone Marrow Transplant
Pays: England
ID NLM: 8702459
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
received:
05
08
2020
accepted:
19
02
2021
revised:
03
02
2021
pubmed:
27
3
2021
medline:
14
10
2021
entrez:
26
3
2021
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 33767401
doi: 10.1038/s41409-021-01255-4
pii: 10.1038/s41409-021-01255-4
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1908-1918Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature Limited.
Références
Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. 2016;5:33.
doi: 10.3390/jcm5030033
Kouchkovsky ID, Abdul-Hay M. ‘Acute myeloid leukemia: a comprehensive review and 2016 update’. Blood Cancer J. 2016;6:e441.
doi: 10.1038/bcj.2016.50
Tomczak K, Czerwińska P, Wiznerowicz M. The Cancer Genome Atlas (TCGA): an immeasurable source of knowledge. Contemp Oncol. 2015;19:A68–77.
Network TCGAR. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.
doi: 10.1056/NEJMoa1301689
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.
doi: 10.1182/blood-2016-01-693879
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.
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.
doi: 10.1186/1471-2164-16-S1-S5
DiNardo CD, Cortes JE. Mutations in AML: prognostic and therapeutic implications. Hematology. 2016;2016:348–55.
doi: 10.1182/asheducation-2016.1.348
Moarii M, Papaemmanuil E. Classification and risk assessment in AML: integrating cytogenetics and molecular profiling. ASH Educ Program Book. 2017;2017:37–44.
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.
doi: 10.1001/jama.2009.813
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.
doi: 10.1111/bjh.12253
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.
doi: 10.1016/j.bbmt.2014.01.027
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.
doi: 10.1016/j.bbmt.2010.05.012
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.
doi: 10.1056/NEJMoa1611604
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.
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.
doi: 10.1182/blood-2016-03-643544
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.
doi: 10.1182/blood-2009-11-254441
Kanda Y. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transpl. 2013;48:452–8.
doi: 10.1038/bmt.2012.244
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.
doi: 10.1182/blood.V92.7.2322
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.
doi: 10.1200/JCO.2008.16.0259
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.
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.
doi: 10.1038/nature11690
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.
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.
doi: 10.1093/nar/29.1.308
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.
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.
doi: 10.1038/leu.2017.48
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.
doi: 10.1182/blood.V96.13.4075
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.
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.
doi: 10.1182/blood-2011-10-385781
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.
doi: 10.1186/s13045-017-0393-3
Castro PD, Liang JC, Nagarajan L. Deletions of chromosome 5q13.3 and 17p loci cooperate in myeloid neoplasms. Blood. 2000;95:2138–43.
doi: 10.1182/blood.V95.6.2138
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.
doi: 10.1016/j.bbmt.2011.07.024
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.
doi: 10.1182/blood-2013-12-544957
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.
doi: 10.1111/bjh.13912
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.
doi: 10.1038/sj.bmt.1704518
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.
doi: 10.1001/jama.1993.03510010063030
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.
doi: 10.1038/sj.leu.2400573
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.
doi: 10.3324/haematol.2011.041004
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.
doi: 10.1038/sj.leu.2404037
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.
doi: 10.1182/blood-2003-11-3750
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.
doi: 10.1089/scd.2014.0123
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.
doi: 10.1016/S1470-2045(12)70349-2
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.
doi: 10.1016/j.bbmt.2006.06.003
Paun O, Lazarus HM. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission. Curr Opin Hematol. 2012;19:95–101.
doi: 10.1097/MOH.0b013e32834ff54b
Savani BN. Transplantation in AML CR1. Blood. 2010;116:1822–3.
doi: 10.1182/blood-2010-06-291500
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.
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.
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.
doi: 10.1182/blood.V84.9.3148.3148