Clonal hematopoiesis and measurable residual disease assessment in acute myeloid leukemia

Blood - Tập 135 Số 20 - Trang 1729-1738 - 2020
Robert P. Hasserjian1, David P. Steensma2, Timothy A. Graubert1, Benjamin L. Ebert2
1Massachusetts General Hospital, Boston, MA; and
2Dana-Farber Cancer Institute, Boston, MA

Tóm tắt

Abstract Current objectives regarding treatment of acute myeloid leukemia (AML) include achieving complete remission (CR) by clinicopathological criteria followed by interrogation for the presence of minimal/measurable residual disease (MRD) by molecular genetic and/or flow cytometric techniques. Although advances in molecular genetic technologies have enabled highly sensitive detection of AML-associated mutations and translocations, determination of MRD is complicated by the fact that many treated patients have persistent clonal hematopoiesis (CH) that may not reflect residual AML. CH detected in AML patients in CR includes true residual or early recurrent AML, myelodysplastic syndrome or CH that is ancestral to the AML, and independent or newly emerging clones of uncertain leukemogenic potential. Although the presence of AML-related mutations has been shown to be a harbinger of relapse in multiple studies, the significance of other types of CH is less well understood. In patients who undergo allogeneic hematopoietic cell transplantation (HCT), post-HCT clones can be donor-derived and in some cases engender a new myeloid neoplasm that is clonally unrelated to the recipient’s original AML. In this article, we discuss the spectrum of CH that can be detected in treated AML patients, propose terminology to standardize nomenclature in this setting, and review clinical data and areas of uncertainty among the various types of posttreatment hematopoietic clones.

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Tài liệu tham khảo

Steensma, 2015, Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes, Blood, 126, 9, 10.1182/blood-2015-03-631747

Cargo, 2015, Targeted sequencing identifies patients with preclinical MDS at high risk of disease progression, Blood, 126, 2362, 10.1182/blood-2015-08-663237

Malcovati, 2017, Clinical significance of somatic mutation in unexplained blood cytopenia, Blood, 129, 3371, 10.1182/blood-2017-01-763425

Jaiswal, 2014, Age-related clonal hematopoiesis associated with adverse outcomes, N Engl J Med, 371, 2488, 10.1056/NEJMoa1408617

Steensma, 2018, Clinical consequences of clonal hematopoiesis of indeterminate potential, Blood Adv, 2, 3404, 10.1182/bloodadvances.2018020222

Jaiswal, 2017, Clonal hematopoiesis and atherosclerosis, N Engl J Med, 377, 1401

Schuurhuis, 2018, Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party, Blood, 131, 1275, 10.1182/blood-2017-09-801498

Obrochta, 2018, Identifying patients with genetic predisposition to acute myeloid leukemia, Best Pract Res Clin Haematol, 31, 373, 10.1016/j.beha.2018.09.014

Cheson, 2003, Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia [published correction appears in J Clin Oncol. 2004;22(3):576], J Clin Oncol, 21, 4642, 10.1200/JCO.2003.04.036

Döhner, 2017, Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel, Blood, 129, 424, 10.1182/blood-2016-08-733196

Ouyang, 2015, The clinical significance of negative flow cytometry immunophenotypic results in a morphologically scored positive bone marrow in patients following treatment for acute myeloid leukemia, Am J Hematol, 90, 504, 10.1002/ajh.23988

Engel, 1997, Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow-up of patients in clinical remission, Br J Haematol, 99, 64, 10.1046/j.1365-2141.1997.3323151.x

Baron, 2006, Chimerism and outcomes after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning, Leukemia, 20, 1690, 10.1038/sj.leu.2404335

Levine, 2019, Next-generation sequencing in the diagnosis and minimal residual disease assessment of acute myeloid leukemia, Haematologica, 104, 868, 10.3324/haematol.2018.205955

Morita, 2018, Clearance of somatic mutations at remission and the risk of relapse in acute myeloid leukemia, J Clin Oncol, 36, 1788, 10.1200/JCO.2017.77.6757

Jongen-Lavrencic, 2018, Molecular minimal residual disease in acute myeloid leukemia, N Engl J Med, 378, 1189, 10.1056/NEJMoa1716863

Platzbecker, 2017, Improved outcomes with retinoic acid and arsenic trioxide compared with retinoic acid and chemotherapy in non-high-risk acute promyelocytic leukemia: final results of the randomized Italian-German APL0406 trial, J Clin Oncol, 35, 605, 10.1200/JCO.2016.67.1982

Yin, 2012, 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, 120, 2826, 10.1182/blood-2012-06-435669

Willekens, 2016, 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, 101, 328, 10.3324/haematol.2015.131946

Yin, 2003, Monitoring AML1-ETO and CBFbeta-MYH11 transcripts in acute myeloid leukemia, Curr Oncol Rep, 5, 399, 10.1007/s11912-003-0026-6

Inaba, 2012, Comparative analysis of different approaches to measure treatment response in acute myeloid leukemia, J Clin Oncol, 30, 3625, 10.1200/JCO.2011.41.5323

Matsuo, 2018, Monitoring of fusion gene transcripts to predict relapse in pediatric acute myeloid leukemia, Pediatr Int, 60, 41, 10.1111/ped.13440

Huang, 2016, Prognostic significance of mixed-lineage leukemia (MLL) gene detected by real-time fluorescence quantitative PCR assay in acute myeloid leukemia, Med Sci Monit, 22, 3009, 10.12659/MSM.900429

Platzbecker, 2018, Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial, Lancet Oncol, 19, 1668, 10.1016/S1470-2045(18)30580-1

Chou, 2006, Nucleophosmin mutations in de novo acute myeloid leukemia: the age-dependent incidences and the stability during disease evolution, Cancer Res, 66, 3310, 10.1158/0008-5472.CAN-05-4316

Patel, 2019, Clinicopathologic and genetic characterization of nonacute NPM1-mutated myeloid neoplasms, Blood Adv, 3, 1540, 10.1182/bloodadvances.2019000090

Montalban-Bravo, 2019, NPM1 mutations define a specific subgroup of MDS and MDS/MPN patients with favorable outcomes with intensive chemotherapy, Blood Adv, 3, 922, 10.1182/bloodadvances.2018026989

Wong, 2019, Molecular measurable residual disease testing of blood during AML cytotoxic therapy for early prediction of clinical response, Front Oncol, 8, 669, 10.3389/fonc.2018.00669

Ivey, 2016, Assessment of minimal residual disease in standard-risk AML, N Engl J Med, 374, 422, 10.1056/NEJMoa1507471

Gorello, 2006, Quantitative assessment of minimal residual disease in acute myeloid leukemia carrying nucleophosmin (NPM1) gene mutations, Leukemia, 20, 1103, 10.1038/sj.leu.2404149

Zhou, 2018, Deep NPM1 sequencing following allogeneic hematopoietic cell transplantation improves risk assessment in adults with NPM1-mutated AML, Biol Blood Marrow Transplant, 24, 1615, 10.1016/j.bbmt.2018.04.017

Venditti, 2019, GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia, Blood, 134, 935, 10.1182/blood.2018886960

Hourigan, Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease [published online ahead of print 20 December 2019], J Clin Oncol

Ricci, 2010, RAS mutations contribute to evolution of chronic myelomonocytic leukemia to the proliferative variant, Clin Cancer Res, 16, 2246, 10.1158/1078-0432.CCR-09-2112

Al-Kali, 2013, Prognostic impact of RAS mutations in patients with myelodysplastic syndrome, Am J Hematol, 88, 365, 10.1002/ajh.23410

Haferlach, 2012, Amount of bone marrow blasts is strongly correlated to NPM1 and FLT3-ITD mutation rate in AML with normal karyotype, Leuk Res, 36, 51, 10.1016/j.leukres.2011.04.026

Xie, 2014, Age-related mutations associated with clonal hematopoietic expansion and malignancies, Nat Med, 20, 1472, 10.1038/nm.3733

Hirsch, 2017, Precision and prognostic value of clone-specific minimal residual disease in acute myeloid leukemia, Haematologica, 102, 1227, 10.3324/haematol.2016.159681

Press, 2019, Next-generation sequencing-defined minimal residual disease before stem cell transplantation predicts acute myeloid leukemia relapse, Am J Hematol, 94, 902, 10.1002/ajh.25514

Vedula, 2017, Measurement of residual disease in acute myeloid leukemia, Curr Hematol Malig Rep, 12, 574, 10.1007/s11899-017-0428-4

Höllein, 2018, NPM1 mutated AML can relapse with wild-type NPM1: persistent clonal hematopoiesis can drive relapse, Blood Adv, 2, 3118, 10.1182/bloodadvances.2018023432

Klco, 2015, Association between mutation clearance after induction therapy and outcomes in acute myeloid leukemia, JAMA, 314, 811, 10.1001/jama.2015.9643

Ravandi, 2018, Is it time to routinely incorporate MRD into practice?, Best Pract Res Clin Haematol, 31, 396, 10.1016/j.beha.2018.09.013

Ley, 2013, Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia, N Engl J Med, 368, 2059, 10.1056/NEJMoa1301689

Welch, 2012, The origin and evolution of mutations in acute myeloid leukemia, Cell, 150, 264, 10.1016/j.cell.2012.06.023

Shlush, 2014, Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia [published correction appears in Nature. 2014;508(7496):420], Nature, 506, 328, 10.1038/nature13038

Wong, 2016, Rapid expansion of preexisting nonleukemic hematopoietic clones frequently follows induction therapy for de novo AML, Blood, 127, 893, 10.1182/blood-2015-10-677021

Shlush, 2017, Tracing the origins of relapse in acute myeloid leukaemia to stem cells, Nature, 547, 104, 10.1038/nature22993

Lindsley, 2015, Acute myeloid leukemia ontogeny is defined by distinct somatic mutations, Blood, 125, 1367, 10.1182/blood-2014-11-610543

Petrova, 2018, IDH1 and IDH2 mutations in patients with acute myeloid leukemia: suitable targets for minimal residual disease monitoring? [published correction appears in Clin Biochem. 2019;63:161], Clin Biochem, 61, 34, 10.1016/j.clinbiochem.2018.08.012

Debarri, 2015, IDH1/2 but not DNMT3A mutations are suitable targets for minimal residual disease monitoring in acute myeloid leukemia patients: a study by the Acute Leukemia French Association, Oncotarget, 6, 42345, 10.18632/oncotarget.5645

Ferret, 2018, Clinical relevance of IDH1/2 mutant allele burden during follow-up in acute myeloid leukemia. A study by the French ALFA group, Haematologica, 103, 822, 10.3324/haematol.2017.183525

Ok, 2019, Persistent IDH1/2 mutations in remission can predict relapse in patients with acute myeloid leukemia, Haematologica, 104, 305, 10.3324/haematol.2018.191148

Kohlmann, 2014, Monitoring of residual disease by next-generation deep-sequencing of RUNX1 mutations can identify acute myeloid leukemia patients with resistant disease, Leukemia, 28, 129, 10.1038/leu.2013.239

Getta, 2017, Multicolor flow cytometry and multigene next-generation sequencing are complementary and highly predictive for relapse in acute myeloid leukemia after allogeneic transplantation, Biol Blood Marrow Transplant, 23, 1064, 10.1016/j.bbmt.2017.03.017

Yilmaz, 2019, Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia?, Blood Cancer J, 9, 7, 10.1038/s41408-019-0170-3

van Galen, 2019, Single-cell RNA-Seq reveals AML hierarchies relevant to disease progression and immunity, Cell, 176, 1265, 10.1016/j.cell.2019.01.031

Jaiswal, 2019, Clonal hematopoiesis in human aging and disease, Science, 366, 10.1126/science.aan4673

Murphy, 2019, Impact of preleukemic mutations and their persistence on hematologic recovery after induction chemotherapy for AML, Blood Adv, 3, 2307, 10.1182/bloodadvances.2019000306

Aynardi, 2018, JAK2 V617F-positive acute myeloid leukaemia (AML): a comparison between de novo AML and secondary AML transformed from an underlying myeloproliferative neoplasm. A study from the Bone Marrow Pathology Group, Br J Haematol, 182, 78, 10.1111/bjh.15276

Machiela, 2017, Mosaic chromosome 20q deletions are more frequent in the aging population, Blood Adv, 1, 380, 10.1182/bloodadvances.2016003129

Herold, 2017, Evolution of NPM1-negative therapy-related myelodysplastic syndromes following curative treatment of NPM1-mutant AML, Leukemia, 31, 2247, 10.1038/leu.2017.217

Vosberg, 2019, Clonal evolution of acute myeloid leukemia from diagnosis to relapse, Genes Chromosomes Cancer, 58, 839, 10.1002/gcc.22806

Platt, 2015, Detection of dual IDH1 and IDH2 mutations by targeted next-generation sequencing in acute myeloid leukemia and myelodysplastic syndromes, J Mol Diagn, 17, 661, 10.1016/j.jmoldx.2015.06.004

Krönke, 2013, Clonal evolution in relapsed NPM1-mutated acute myeloid leukemia, Blood, 122, 100, 10.1182/blood-2013-01-479188

Arber, 2016, The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia [published correction appears in Blood. 2016;128(3):462-463], Blood, 127, 2391, 10.1182/blood-2016-03-643544

Tuval, 2019, Evolutionary trajectory of leukemic clones and its clinical implications, Haematologica, 104, 872, 10.3324/haematol.2018.195289

Rojek, 2016, Identifying inherited and acquired genetic factors involved in poor stem cell mobilization and donor-derived malignancy, Biol Blood Marrow Transplant, 22, 2100, 10.1016/j.bbmt.2016.08.002

Engel, 2019, European experience and risk factor analysis of donor cell-derived leukaemias/MDS following haematopoietic cell transplantation, Leukemia, 33, 508, 10.1038/s41375-018-0218-6

Hahn, 2015, A tale of two siblings: two cases of AML arising from a single pre-leukemic DNMT3A mutant clone, Leukemia, 29, 2101, 10.1038/leu.2015.67

Uy, 2017, Dynamic changes in the clonal structure of MDS and AML in response to epigenetic therapy, Leukemia, 31, 872, 10.1038/leu.2016.282

Gaidzik, 2018, DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia, Leukemia, 32, 30, 10.1038/leu.2017.200

Rothenberg-Thurley, 2018, Persistence of pre-leukemic clones during first remission and risk of relapse in acute myeloid leukemia, Leukemia, 32, 1598, 10.1038/s41375-018-0034-z

Thol, 2018, Measurable residual disease monitoring by NGS before allogeneic hematopoietic cell transplantation in AML, Blood, 132, 1703, 10.1182/blood-2018-02-829911