Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

•This updated ESMO Clinical Practice Guideline provides key recommendations on the management of acute myeloid leukaemia (AML) including acute promyelocytic leukaemia (APL).•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•A summary of recommendations is provided, including levels of evidence and grades of recommendation where applicable.•Recommendations take the approval status of AML drugs in Europe into account until the year 2019.•Detailed guidance on diagnosis, classification, response assessment, treatment and follow-up is provided for adults with AML and APL. Acute myeloid leukaemia (AML) incidence is age dependent, rising markedly in patients aged ≥60 years. Ageing of the European population may therefore contribute to the reported increase in AML incidence in Europe from 3.48 in 1976 to 5.06 patients per 100 000 people in 2013.1Roman E. Smith A. Appleton S. et al.Myeloid malignancies in the real-world: occurrence, progression and survival in the UK's population-based Haematological Malignancy Research Network 2004-15.Cancer Epidemiol. 2016; 42: 186-198Crossref PubMed Scopus (9) Google Scholar Across all age groups, the incidence of AML is higher in males than in females.2Juliusson G. Abrahamsson J. Lazarevic V. et al.Prevalence and characteristics of survivors from acute myeloid leukemia in Sweden.Leukemia. 2017; 31: 728-731Crossref PubMed Scopus (11) Google Scholar The median age at diagnosis is ∼70 years.2Juliusson G. Abrahamsson J. Lazarevic V. et al.Prevalence and characteristics of survivors from acute myeloid leukemia in Sweden.Leukemia. 2017; 31: 728-731Crossref PubMed Scopus (11) Google Scholar The 2016 World Health Organization (WHO) classification identifies distinct categories of AML (see supplementary Table S1, available at Annals of Oncology online).3Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar Notably, AML is primarily categorised by recurrent genetic abnormalities, with morphological classification reserved for patients not otherwise classifiable. With advanced age, the relative incidence of AML with recurrent genetic abnormalities decreases,4Bullinger L. Dohner K. Dohner H. Genomics of acute myeloid leukemia diagnosis and pathways.J Clin Oncol. 2017; 35: 934-946Crossref PubMed Scopus (169) Google Scholar while the relative incidence of other AML categories [such as AML with myelodysplasia-related changes (MRC-AML) or therapy-related AML (tAML)] increases with age, comprising about 19% and 7% of AML cases, respectively.5Granfeldt Ostgard L.S. Medeiros B.C. Sengeløv H. et al.Epidemiology and clinical significance of secondary and therapy-related acute myeloid leukemia: a national population-based cohort study.J Clin Oncol. 2015; 33: 3641-3649Crossref PubMed Scopus (173) Google Scholar, 6Hulegardh E. Nilsson C. Lazarevic V. et al.Characterization and prognostic features of secondary acute myeloid leukemia in a population-based setting: a report from the Swedish Acute Leukemia Registry.Am J Hematol. 2015; 90: 208-214Crossref PubMed Google Scholar, 7Kayser S. Döhner K. Krauter J. et al.The impact of therapy-related acute myeloid leukemia (AML) on outcome in 2853 adult patients with newly diagnosed AML.Blood. 2011; 117: 2137-2145Crossref PubMed Scopus (254) Google Scholar The prognosis and long-term survival rates of patients <65 years have incrementally improved with time, largely based upon improved supportive care and increased utilisation of allogeneic haematopoietic cell transplantation (alloHCT). Despite this progress, age-standardised relative 5-year survival for adult patients diagnosed between the years 2000 and 2007 was as low as 17% (16.6–17.7),8De Angelis R. Minicozzi P. Sant M. et al.Survival variations by country and age for lymphoid and myeloid malignancies in Europe 2000-2007: results of EUROCARE-5 population-based study.Eur J Cancer. 2015; 51: 2254-2268Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar mainly attributable to the minimal progress attained in AML patients >65 years. Patients suspected of a diagnosis of AML must undergo prompt cytogenetic and molecular investigations to inform risk stratification and, increasingly, treatment strategies. It is vital to urgently differentiate acute promyelocytic leukaemia (APL) from other forms of AML by cytomorphology (dysplastic promyelocytes, binucleated blasts, faggot cells), signs of hyperfibrinolysis and molecular evidence of PML-RARA fusion. AML is defined based on morphological inspection revealing a myeloid blast count of ≥20% out of 500 bone marrow (BM) cells,9Vardiman J.W. Thiele J. Arber D.A. et al.The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes.Blood. 2009; 114: 937-951Crossref PubMed Scopus (3126) Google Scholar although counting fewer cells is sufficient in patients with high blast count.10Abdulrahman A.A. Patel K.H. Yang T. et al.Is a 500-cell count necessary for bone marrow differentials?: a proposed analytical method for validating a lower cutoff.Am J Clin Pathol. 2018; 150: 84-91Crossref PubMed Scopus (1) Google Scholar Blast counts should include myeloblasts, monoblasts/promonocytes and megakaryoblasts, but not abnormal monocytes. According to the latest WHO classification, all nucleated cells in the BM serve as a denominator, even in cases where the BM is enriched with erythroid precursors.3Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar Supplementary Table S2, available at Annals of Oncology online, lists all mandatory clinical and laboratory tests that should be carried out at presentation. Past medical history should be carefully reviewed to reveal signs of an antecedent BM disease and previous exposure to radiation, chemotherapy (ChT) or leukaemogenic toxins such as benzene and organochlorine insecticides. Blood count results preceding AML diagnosis should be collected, but even if abnormal, are insufficient to make a definitive diagnosis of MRC-AML. A history of a myelodysplastic syndrome (MDS) or a myelodysplastic/myeloproliferative neoplasm or the presence of one of several MDS-related cytogenetic abnormalities, or ≥50% dysplastic cells in at least two cell lineages (except when combined with NPM1 or double CEBPA mutations), is required for the diagnosis of MRC-AML.3Arber D.A. Orazi A. Hasserjian R. et al.The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Blood. 2016; 127: 2391-2405Crossref PubMed Google Scholar Despite progress in immunophenotyping allowing recognition of dysplasia by aberrant flow cytometry patterns, cytomorphology remains the gold standard for diagnosis of dysplasia and MDS.11Bene M.C. Nebe T. Bettelheim P. et al.Immunophenotyping of acute leukemia and lymphoproliferative disorders: a consensus proposal of the European LeukemiaNet Work Package 10.Leukemia. 2011; 25: 567-574Crossref PubMed Scopus (0) Google Scholar The authors recommend a BM aspirate for cytology and cytochemistry, including Sudan Black B, myeloperoxidase and esterase staining, immunophenotyping and a trephine biopsy for histology at diagnosis. Cytochemistry is especially helpful while cytogenetic and molecular results are awaited [V, B]. A BM biopsy is mandatory in patients with dry-tap. Interpretation of morphological changes may be challenging. Presence of an AML-related recurrent genetic abnormality [e.g. t(8:21)] overrules morphological uncertainties. Multiparameter flow cytometry (MFC), using a minimum of six colours and following an established flow cytometry protocol such as the European LeukemiaNet (ELN) criteria for immunophenotypic leukaemia classification,12Dohner H. Estey E. Grimwade D. et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447Crossref PubMed Scopus (1796) Google Scholar is required for the diagnosis of specific entities, such as mixed phenotype acute leukaemia (MPAL), AML not otherwise specified (NOS) with minimal differentiation, acute megakaryoblastic leukaemia or blastic plasmacytoid dendritic cell neoplasm (BPDCN, positive for CD4, CD56, CD123 and TCL1).13van Dongen J.J. Lhermitte L. Böttcher S. et al.EuroFlow antibody panels for standardized n-dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes.Leukemia. 2012; 26: 1908-1975Crossref PubMed Scopus (449) Google Scholar,14Johansson U. Bloxham D. Couzens S. et al.Guidelines on the use of multicolour flow cytometry in the diagnosis of haematological neoplasms. British Committee for Standards in Haematology.Br J Haematol. 2014; 165: 455-488Crossref PubMed Scopus (0) Google Scholar In general, genetic aberrations overrule immunophenotypic changes. Cytogenetic classification should be based on the evaluation of at least 20 metaphases. An abnormal clone is reported only if at least 2/20 cells are identified as carrying the same karyotypic abnormality. Karyotype analysis may miss clinically significant cryptic aberrations [e.g. MLL/KMT2A, inv(16), chromosome 3 aberrations], thus complementary fluorescent in situ hybridisation (FISH) analysis is recommended and should be considered mandatory when conventional cytogenetic analysis fails. Molecular studies to detect the presence of mutations in the FLT3 gene [internal tandem duplication (ITD) or tyrosine kinase domain (TKD)] should be carried out immediately to allow timely initiation of an FLT3 inhibitor. Additional molecular studies to measure the FLT3-ITD allelic ratio (AR), and detection of NPM1, PML-RARA, RUNX1-RUNX1T1, CBFB-MYH11 and double CEBPA mutations should be carried out at diagnosis given their prognostic significance. The presence of TP53, RUNX1 and ASXL1 mutations classifies patients to the adverse ELN risk group; testing is therefore advised. IDH1 and IDH2 should also be assessed for mutations to identify patients who may benefit from pharmacological inhibitors when these become available in Europe. If available, next-generation sequencing (NGS) of a panel of genes commonly mutated in AML provides important additional prognostic and therapeutic information. The new WHO diagnosis of myeloid neoplasms with germline predisposition is often overlooked in patients with newly diagnosed AML (see supplementary Table S1, available at Annals of Oncology online). Genetic counselling is recommended in case of a positive cancer family history or if an inherited condition potentially associated with leukaemia has been diagnosed in any relative. There are also specific medical conditions that should draw physicians' awareness regarding potential germline predisposition (supplementary Table S3, available at Annals of Oncology online).15Godley L.A. Shimamura A. Genetic predisposition to hematologic malignancies: management and surveillance.Blood. 2017; 130: 424-432Crossref PubMed Scopus (0) Google Scholar All candidates for alloHCT and their siblings should undergo human leucocyte antigen (HLA) typing at diagnosis. Sperm cryopreservation should be systematically proposed before starting ChT, especially in patients due to undergo alloHCT. In females, ovarian tissue cryopreservation (OTC) may be carried out before haematopoietic cell transplantation (HCT) if patients are in complete remission (CR).16Shapira M. Raanani H. Cohen Y. Meirow D. Fertility preservation in young females with hematological malignancies.Acta Haematol. 2014; 132: 400-413Crossref PubMed Scopus (25) Google Scholar The main concern about the safety of autologous transplantation of ovarian fragments is possible contamination with leukaemic cells that may lead to AML recurrence.16Shapira M. Raanani H. Cohen Y. Meirow D. Fertility preservation in young females with hematological malignancies.Acta Haematol. 2014; 132: 400-413Crossref PubMed Scopus (25) Google Scholar Fertility preservation is further discussed in ‘Follow-up, long-term implications and survivorship’ section in supplementary Material, available at Annals of Oncology online. The initial assessment of newly diagnosed AML patients should focus on patient fitness for standard induction and consolidation ChT. Pre-existing heart, kidney, lung or liver disease, mental illness, an Eastern Cooperative Oncology Group (ECOG) performance score ≥3 and age ≥75 years are the strongest predictors for nonrelapse induction-related mortality and should be considered to determine ineligibility to intensive induction and consolidation ChT [V, B].17Ferrara F. Barosi G. Venditti A. et al.Consensus-based definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a project of SIE, SIES and GITMO group on a new tool for therapy decision making.Leukemia. 2013; 27: 997-999Crossref PubMed Scopus (30) Google Scholar The risk of early death of older AML patients upon induction ChT can be calculated using seven clinical parameters: body temperature, age, de novo versus secondary leukaemia, haemoglobin level, platelet count, fibrinogen level and serum concentration of lactate dehydrogenase.18Krug U. Röllig C. Koschmieder A. et al.Complete remission and early death after intensive chemotherapy in patients aged 60 years or older with acute myeloid leukaemia: a web-based application for prediction of outcomes.Lancet. 2010; 376: 2000-2008Abstract Full Text Full Text PDF PubMed Scopus (205) Google Scholar The HCT-specific comorbidity index (HCT-CI) score predicts treatment-related mortality in patients treated with induction ChT, as well as transplant outcome.19Sorror M.L. Storer B.E. Fathi A.T. et al.Development and validation of a novel acute myeloid leukemia-composite model to estimate risks of mortality.JAMA Oncol. 2017; 3: 1675-1682Crossref PubMed Scopus (47) Google Scholar,20Giles F.J. Borthakur G. Ravandi F. et al.The haematopoietic cell transplantation comorbidity index score is predictive of early death and survival in patients over 60 years of age receiving induction therapy for acute myeloid leukaemia.Br J Haematol. 2007; 136: 624-627Crossref PubMed Scopus (173) Google Scholar The final decision concerning the role of intensive ChT is taken after careful consultation between an experienced clinician and the patient. The presence of extramedullary involvement should be evaluated clinically, although its prognostic value is debatable.21Ganzel C. Manola J. Douer D. et al.Extramedullary disease in adult acute myeloid leukemia is common but lacks independent significance: analysis of patients in ECOG-ACRIN Cancer Research Group Trials, 1980-2008.J Clin Oncol. 2016; 34: 3544-3553Crossref PubMed Scopus (41) Google Scholar Extramedullary AML involvement has been found in 17% of patients when using positron emission tomography (PET).22Stölzel F. Lüer T. Löck S. et al.The prevalence of extramedullary AML detected by 18-FDG/PET-CT: results from the prospective PET-AML Trial.Blood. 2014; 124: 2270Crossref Google Scholar In case of any neurological signs or symptoms, diagnostic lumbar puncture should be carried out when blasts are reduced in peripheral blood, and cranial magnetic resonance imaging (MRI) [or computed tomography (CT) if MRI is unavailable] should be conducted. In APL patients, lumbar puncture should be delayed until recovery of bleeding diathesis. In patients with hypoproliferative disease or those who can be safely treated with hydroxycarbamide cytoreduction, it may be feasible to await cytogenetic and molecular genetic results before commencing treatment, if these results are likely to influence the choice of therapeutic modalities. Genetic classification of AML is essential to guide clinical decisions and predict prognosis. The 2017 ELN recommendations identify three risk groups, based on karyotype and mutational analysis (ELN favourable, intermediate and adverse risk, see supplementary Table S4, available at Annals of Oncology online).12Dohner H. Estey E. Grimwade D. et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447Crossref PubMed Scopus (1796) Google Scholar The favourable-risk AML group comprises all patients in whom a relapse risk is predicted to be low if treated with induction and consolidation ChT alone. This group includes patients with mutated NPM1 (NPM1mut) without FLT3-ITD or with FLT3-ITD presenting with AR <0.5, t(8;21)(q22;q22.1)/RUNX1-RUNX1T1, inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB-MYH11, or presenting with double-mutant CEBPA. However, a large retrospective analysis showed that 3.6% of NPM1mut/FLT3-ITDlow patients have adverse cytogenetic aberrations, which confer an equally poor prognosis as adverse cytogenetics in NPM1wildtype patients.23Angenendt L. Röllig C. Montesinos P. et al.Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: a pooled analysis of individual patient data from nine international cohorts.J Clin Oncol. 2019; 37: 2632-2642Crossref PubMed Scopus (5) Google Scholar The intermediate-risk AML group comprises patients with molecular or cytogenetic abnormalities not classified as favourable or adverse, and includes patients with NPM1mut and a high AR of FLT3-ITD. The adverse-risk AML group includes patients with complex cytogenetics and other poor-risk genetic aberrations.12Dohner H. Estey E. Grimwade D. et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447Crossref PubMed Scopus (1796) Google Scholar All patients failing to achieve CR after 2 induction cycles should also be considered as adverse-risk patients, regardless of genetics/cytogenetics.24Ferguson P. Hills R.K. Grech A. et al.An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.Haematologica. 2016; 101: 1351-1358Crossref PubMed Scopus (14) Google Scholar Accurate risk stratification plays a critical role in guiding selection of the optimal postremission approach and of indications for alloHCT in first CR (CR1).25Cornelissen J.J. Gratwohl A. Schlenk R.F. et al.The European LeukemiaNet AML Working Party consensus statement on allogeneic HSCT for patients with AML in remission: an integrated-risk adapted approach.Nat Rev Clin Oncol. 2012; 9: 579-590Crossref PubMed Scopus (253) Google Scholar A comprehensive risk classification integrating clinical, genetic and treatment data is available as an online tool that simulates the individual patient's risk and predicts outcome with and without alloHCT (https://cancer.sanger.ac.uk/aml-multistage/).26Gerstung M. Papaemmanuil E. Martincorena I. et al.Precision oncology for acute myeloid leukemia using a knowledge bank approach.Nat Genet. 2017; 49: 332-340Crossref PubMed Scopus (105) Google Scholar The ELN has defined response categories to induction ChT.12Dohner H. Estey E. Grimwade D. et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447Crossref PubMed Scopus (1796) Google Scholar In addition to conventional CR, CR with incomplete haematological recovery (CRi) and CR without measurable residual disease (CRMRD–) were proposed (supplementary Table S5, available at Annals of Oncology online). ELN MRD recommendations recently proposed CR with molecular persistence at low copy numbers (CRMRDlow) to account for NPM1 and core binding factor leukaemia patients with positive MRD at low copy numbers (<100–200 copies/104 ABL copies corresponding to <1%–2% of target to reference gene or variant allele burden), who have completed their treatment and have a low risk of relapse despite MRD positivity. The authors recommend handling these patients the same way as patients with complete molecular remission. In addition, CR with partial haematological recovery (CRh) is proposed by other groups, to be used in the context of clinical studies [<5% blasts in the BM, without evidence of extramedullary disease, platelets ≥50 × 109/l and absolute neutrophil count (ANC) ≥0.5 × 109/l]. The term CRp, also used in clinical studies, indicates a CR with platelets <100 × 109/l and with ANC recovery ≥1.0 × 109/l, but is now covered by CRi. Morphological leukaemia-free state (MLFS) consists of <5% BM blasts, absence of blasts with Auer rods, no extramedullary disease and a lack of haematological recovery of both neutrophils and platelets where the BM may not be merely aplastic and at least 200 cells should be counted or cellularity at trephine biopsy should be at least 10%. By comparison, CRi requires recovery of at least one lineage (either ANC ≥1.0 × 109/l or platelets ≥100 × 109/l). BM cellularity <10% should be defined as BM aplasia in patients without count recovery, and response assessment repeated after 2–4 weeks. It is unclear if prognosis differs between patients reaching CRi or MLFS. In clinical practice, it is recommended to use CRMRD−, CR, CRi and MLFS. The authors introduce an operational definition of refractoriness for patients not achieving CR/CRi/MLFS after the first induction cycle: blast persistence after induction 1 defined by ≥5% blasts in BM. Consistent with ELN 2017 recommendations, patients are considered primary refractory to induction ChT if they have ≥5% blasts in BM after the second induction cycle. It was shown that patients with >15% BM blasts or <50% reduction of BM blasts after the first induction cycle constitute a group with an equally poor prognosis as patients with primary refractory disease and who may benefit from direct alloHCT.24Ferguson P. Hills R.K. Grech A. et al.An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.Haematologica. 2016; 101: 1351-1358Crossref PubMed Scopus (14) Google Scholar Relapse is defined by BM blasts ≥5% in patients who have been in CR previously, or reappearance of blasts in the blood or development of extramedullary AML.12Dohner H. Estey E. Grimwade D. et al.Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.Blood. 2017; 129: 424-447Crossref PubMed Scopus (1796) Google Scholar,24Ferguson P. Hills R.K. Grech A. et al.An operational definition of primary refractory acute myeloid leukemia allowing early identification of patients who may benefit from allogeneic stem cell transplantation.Haematologica. 2016; 101: 1351-1358Crossref PubMed Scopus (14) Google Scholar Molecular relapse is defined by an increase of the MRD level of ≥1 log10 between two positive samples in a patient who previously tested negative. Morphological enumeration of the blast percentage should be refined by immunophenotypic or molecular MRD assessment in patients with <10% blasts.27Freeman S.D. Hills R.K. Russell N.H. et al.Induction response criteria in acute myeloid leukaemia: implications of a flow cytometric measurable residual disease negative test in refractory adults.Br J Haematol. 2019; 186: 130-133Crossref PubMed Scopus (2) Google Scholar ELN recommendations on MRD assessment in AML specify its clinical use and technical requirements.28Schuurhuis G.J. Heuser M. Freeman S. et al.Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.Blood. 2018; 131: 1275-1291Crossref PubMed Scopus (316) Google Scholar It is recommended to assess MRD by reverse transcriptase polymerase chain reaction (RT-PCR) for patients positive for NPM1mut, RUNX1-RUNX1T1, CBFB-MYH11 or PML-RARA fusion genes; ∼40% of all AML patients. In the remaining patients, MRD should be assessed by MFC, which relies on antigens aberrantly expressed by leukaemic cells that can be found in >90% of AML patients. Many clinical studies have shown the strong prognostic impact of MRD, as measured by MFC, with levels ≥0.1% defined as positive.29Buccisano F. Maurillo L. Spagnoli A. et al.Cytogenetic and molecular diagnostic characterization combined to postconsolidation minimal residual disease assessment by flow cytometry improves risk stratification in adult acute myeloid leukemia.Blood. 2010; 116: 2295-2303Crossref PubMed Scopus (89) Google Scholar, 30Zeijlemaker W. Kelder A. Oussoren-Brockhoff Y.J. et al.Peripheral blood minimal residual disease may replace bone marrow minimal residual disease as an immunophenotypic biomarker for impending relapse in acute myeloid leukemia.Leukemia. 2016; 30: 708-715Crossref PubMed Scopus (46) Google Scholar, 31Freeman S.D. Hills R.K. Virgo P. et al.Measurable residual disease at induction redefines partial response in acute myeloid leukemia and stratifies outcomes in patients at standard risk without NPM1 mutations.J Clin Oncol. 2018; 36: 1486-1497Crossref PubMed Scopus (66) Google Scholar Laboratories should report results of MRD studies according to recently published guidelines.28Schuurhuis G.J. Heuser M. Freeman S. et al.Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.Blood. 2018; 131: 1275-1291Crossref PubMed Scopus (316) Google Scholar More than 90% of AML patients harbour a molecular marker that could potentially be used for MRD assessment by molecular methods. NGS enables simultaneous testing of multiple genes in a single assay,32Jongen-Lavrencic M. Grob T. Hanekamp D. et al.Molecular minimal residual disease in acute myeloid leukemia.N Engl J Med. 2018; 378: 1189-1199Crossref PubMed Scopus (271) Google Scholar and sensitivity approaches 10–4 with recent protocols.33Thol F. Gabdoulline R. Liebich A. et al.Measurable residual disease (MRD) monitoring by NGS before allogeneic hematopoietic cell transplantation in AML.Blood. 2018; 132: 1703-1713Crossref PubMed Scopus (0) Google Scholar Residual positivity for nonclonal haematopoiesis-related gene mutations (thus excluding DNMT3A, TET2 and ASXL1) after 2 cycles of induction ChT and before alloHCT predicted AML relapse in a recent study, which also showed that NGS-MRD and MFC are complementary techniques.32Jongen-Lavrencic M. Grob T. Hanekamp D. et al.Molecular minimal residual disease in acute myeloid leukemia.N Engl J Med. 2018; 378: 1189-1199Crossref PubMed Scopus (271) Google Scholar However, NGS-MRD needs thorough standardisation and validation before recommendation for clinical use. In APL patients, MRD assessment is recommended at the end of consolidation treatment, before starting maintenance. In non-high-risk APL patients treated with arsenic trioxide (ATO) and all-trans-retinoic acid (ATRA), all patients were MRD negative at the end of consolidation.34Platzbecker U. Avvisati G. Cicconi L. et al.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. 2017; 35: 605-612Crossref PubMed Scopus (174) Google Scholar If MRD is negative in these patients, no further MRD assessment is recommended in view of the very low relapse risk.28Schuurhuis G.J. Heuser M. Freeman S. et al.Minimal/measurable residual disease in AML: a consensus document from the European LeukemiaNet MRD Working Party.Blood. 2018; 131: 1275-1291Crossref PubMed Scopus (316) Google Scholar In high-risk APL patients treated with ChT and ATRA, a variable proportion of 1%–5% of patients were MRD positive at the end of consolidation.35Grimwade D. Jovanovic J.V. Hills R.K. et al.Prospective minimal residual disease monitoring to predict relapse of acute promyelocytic leukemia and to direct pre-emptive arsenic trioxide therapy.J Clin Oncol. 2009; 27: 3650-3658Crossref PubMed Scopus (236) Google Scholar Continuous MRD monitoring is therefore recommended in high-risk APL patients to predict impending haematological relapse and thereby prevent bleeding complications and to allow administration of pre-emptive therapy at the time of molecular relapse, prior to the occurrence of haematological relapse. The authors recommend performing up to two BM assessments during the first cycle of standard induction ChT, the first between day 14 and day 21 as early response assessment to guide further treatment in case of insufficient response, and the second after recovery of BM to document CR. BM aspirates are usually sufficient, but trephine biopsy is recommended if smears are not evaluable. If a first response assessment gives an uncertain result, it is advisable to repeat BM aspirations until a clearer picture is obtained and the attainment of morphological CR can be more reliably assessed, at least when the nonattainment of CR would have therapeutic consequences. If a second induction cycle is applied, BM should be assessed after haematological recovery or between days 28 and 35 if haematological recovery is still lacking. Morphological assessment of BM is recommended before each consolidation cycle and before alloHCT. After the end of intensive induction and consolidation treatment, BM morphology may be repeated every 3 months for 24 months. 3-monthly differential blood counts are recommended for a total of 5 years after the end of treatment. Assessment of MRD is recommended at diagnosis to establish the aberrant marker profile, after 2 cycles of ChT and after the end of treatment. In addition, molecular MRD may be assessed every 3 months after the end of treatment from BM or every 4–6 weeks from peripheral blood for 24 months in patients with a molecular marker. Flow cytometric MRD should be assessed from BM, while molecular MRD should be as