Special Report Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN ohner,1 Andrew H. Wei,2 Frederick R. Appelbaum,3 Charles Craddock,4 Courtney D. DiNardo,5 Herv Hartmut D€ e Dombret,6 Benjamin L. Ebert,7 Pierre Fenaux,8 Lucy A. Godley,9 Robert P. Hasserjian,10 Richard A. Larson,11 Ross L. Levine,12 Yasushi Miyazaki,13 Dietger Niederwieser,14 Gert Ossenkoppele,15 Christoph R€ ollig,16 Jorge Sierra,17 Eytan M. Stein,18 Martin S. Tallman,18 Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Hwei-Fang Tien,19 Jianxiang Wang,20 Agnieszka Wierzbowska,21 and Bob L€ owenberg22 1 Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany; 2Department of Haematology, Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Australia; 3University of Washington and the Fred Hutchinson Cancer Research Center, Seattle, WA; 4Centre for Clinical Haematology, Queen Elizabeth Hospital, University of Birminham, Birmingham, UK; 5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 6Department of Hematology, Saint-Louis Institute for Research, Universit e de Paris, H^ opital Saint-Louis, Assistance Publique-H^opitaux de Paris, Paris, France; 7Dana-Farber Cancer Institute, Boston, MA; 8Service d’H ematologie S eniors, H^opital Saint-Louis, Assistance Publique-H^opitaux de Paris, Paris, France; 9Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL; 10Department of Pathology, Massachusetts General Hospital, Boston, MA; 11Department of Medicine and Comprehensive Cancer Center, University of Chicago, Chicago, IL; 12 Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; 13 Department of Hematology, Atomic Bomb Disease Institute, Nagasaki University, Nagasaki, Japan; 14University of Leipzig, Leipzig, Germany; 15Department of Haematology, Amsterdam UMC, Location VU University Medical Center, Amsterdam, The Netherlands; 16Department of Internal Medicine I, University Hospital Carl Gustav Carus TU Dresden, Dresden, Germany; 17Hematology Department, Hospital Santa Creu i Sant Pau, Barcelona, Spain; 18Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York; 19Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 20Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; 21Department of Hematology, Medical University of Lodz, Lodz, Poland; and 22Department of Hematology, Erasmus University Medical Center Rotterdam and Erasmus MC Cancer Institute, Rotterdam, The Netherlands The 2010 and 2017 editions of the European LeukemiaNet classification, technological progress in genomic (ELN) recommendations for diagnosis and management of diagnostics and assessment of measurable residual acute myeloid leukemia (AML) in adults are widely disease, and the successful development of new recognized among physicians and investigators. There therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 have been major advances in our understanding of inhibitors. These advances have prompted this update that AML, including new knowledge about the molecular includes a revised ELN genetic risk classification, revised pathogenesis of AML, leading to an update of the disease response criteria, and treatment recommendations. Introduction Methods Since the 2017 report from the European LeukemiaNet (ELN),1 The panel included international members with recognized there has been substantial progress in our knowledge of acute clinical and research expertise in AML. Literature and relevant myeloid leukemia (AML). Recent advances significantly influence abstract review, categorization of evidence, and arrival at con- clinical practice. These advances include insights into the clinical sensus recommendations were developed as previously value of genomic abnormalities for diagnosis and prognosis, the reported.1,3 For diagnosis and management of acute promy- clinical significance of inherited predisposition to AML, techno- elocytic leukemia (APL), readers are referred to the respective logical advancements in the quantitative assessment of measur- recommendations.4 able residual disease (MRD) and their utility for assessing therapeutic response and disease risk, the development of a range of novel therapeutic agents, and developments in alloge- neic hematopoietic cell transplantation (HCT), resulting in new AML classification disease classification,2 diagnostic and prognostic algorithms, Molecular landscape and updated therapeutic practices. The current report highlights Somatic mutations drive the development of AML. Although the these advances and updates their implications for the standard epigenetic state of leukemia cells, the bone marrow microenvi- of care and for clinical trials in AML. ronment, the health of normal hematopoietic cells, and other blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1345 features are important for leukemia biology, somatic mutations MPN, or therapy-related), have most relevance in classifying bio- can be assessed readily with current techniques. Leukemia logically distinct AML subgroups.6,26 Dysplastic morphology, develops from the serial acquisition of somatic mutations in currently used as a criterion for AML-MRC, lacks independent hematopoietic stem and progenitor cells with the capacity to prognostic significance.27-29 Thus, although a prior history of self-renew and propagate the neoplastic clone.5,6 Initiating MDS or MDS/MPN and prior exposure to therapy are still impor- mutations may lead to an expanded clone of cells that is appar- tant features to note in the diagnosis, they are now applied as ent in the peripheral blood, termed clonal hematopoiesis, a diagnostic qualifiers to the AML-defining category (Table 1; common pre-malignant state that increases in prevalence with Figure 1). age.7 Although some mutations, such as those in DNMT3A, TET2, and ASXL1, are more common in clonal hematopoiesis AML with recurrent genetic abnormalities and appear to be relatively early events in leukemogenesis, This category has been expanded to include additional variant others tend to be acquired later in the course of leukemia devel- translocations involving RARA, KMT2A, and MECOM, as well as opment, including mutations in FLT3, NRAS, and RUNX1. The other rare recurring translocations, which are now recognized as combinations of mutations that ultimately drive leukemogenesis AML-defining entities (Table 1).14,30,31 Recent studies show that are influenced by biological cooperativity and mutual exclusivity in-frame mutations affecting the basic leucine zipper (bZIP) between mutated genes. region of CEBPA confer a favorable outcome, irrespective of Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 their occurrence as biallelic or monoallelic mutations.32-35 General classification In-frame bZIP variants are found in 90% and 35% of cases with The International Consensus Classification of AML2,8 that biallelic and monoallelic CEBPA mutations, respectively. Gene updated the prior revised fourth edition World Health Organiza- expression analyses support a distinct biology associated with tion (WHO) classification of AML9 introduced changes in the CEBPA bZIP mutation in AML. Accordingly, this AML subtype blast thresholds and new genetic entities to define AML, further has been redefined to only require an in-frame bZIP CEBPA expanding the spectrum of classification identified by cytoge- mutation for classification rather than the previous requirement netic and mutational profiles (Table 1). Because of their overrid- for biallelic CEBPA abnormalities. ing impact on disease phenotype and disease outcome, genetic aberrations are given priority in defining AML disease classifica- AML with mutated TP53, AML with tion, with additional predisposing features (therapy-related, prior myelodysplasia-related gene mutations, and myelodysplastic syndrome [MDS] or MDS/myeloproliferative AML with myelodysplasia-related cytogenetic neoplasm [MPN], germline predisposition) appended as quali- abnormalities fiers of the primary diagnosis. A summary of the hierarchical Accumulating evidence indicates that from both a clinical and classification is depicted in Figure 1. molecular perspective, TP53-mutant AML and MDS represent a distinct disease entity. The vast majority of TP53-mutant cases Changes to the blast thresholds defining AML have complex karyotypes, and in about half, TP53 mutations All recurrent genetic abnormalities (Table 1) that define specific occur in the absence of other AML-associated gene mutations. subtypes of AML, with the exception of AML with Clinically, these myeloid neoplasms are associated with a very t(9;22)(q34.1;q11.2)/BCR::ABL1, are now considered to establish poor prognosis.6,36-41 The presence of a pathogenic TP53 muta- a diagnosis of AML if there are $10% blasts in the bone marrow tion (at a variant allele fraction of at least 10%, with or without or blood. The clinical behavior of myeloid neoplasms with these loss of the wild-type TP53 allele) defines the new entity AML rearrangements reflects the specific genetic abnormality, even with mutated TP53. for cases presenting with ,20% blasts.10-18 This 10% blast threshold aligns with previously AML-defining abnormalities, Cases lacking TP53 mutation, but with mutations in ASXL1, such as PML::RARA, CBFB::MYH11, and RUNX1::RUNX1T1.19 BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or To avoid potential overlap with chronic myeloid leukemia in ZRSR2, are categorized as AML with myelodysplasia-related accelerated phase, AML with BCR::ABL1 still requires $20% gene mutations, irrespective of any prior history of MDS. These blasts. mutations are highly associated with AML following prior MDS or MDS/MPN and confer an adverse prognosis even if they Although all other AML subtypes require $20% blasts for diag- occur in de novo AML.6,26,42-45 AML with myelodysplasia-related nosis, a new category of MDS/AML has been introduced in gene mutations encompasses the prior provisional category of association with defined genomic abnormalities to include cases AML with mutated RUNX1. with 10% to 19% blasts in the bone marrow or blood to recog- nize the fact that these cases lie on the border between AML The new category AML with myelodysplasia-related cytogenetic and MDS in terms of their biology and prognosis (Table 1).20-25 abnormalities now includes cases previously classified as AML- Patients diagnosed with MDS/AML should be eligible for either MRC due to the presence of myelodysplasia-associated cytoge- MDS or AML clinical trials and treatment approaches. netic findings, but lacking TP53 or myelodysplasia-related gene mutations.46 Antecedent AML history An important change to the classification is the removal of the Of note, the classification is hierarchical (Figure 1); ie, “AML with former categories AML with myelodysplasia-related changes mutated TP53” takes precendence over “AML with (AML-MRC) and therapy-related myeloid neoplasms. Recent myelodysplasia-related gene mutations,” and the latter su- data indicate that genetic characteristics, rather than clinical his- percedes “AML with myelodysplasia-related cytogenetic tory (de novo, secondary after an antecedent MDS or MDS/ abnormalities.” 1346 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al t10% myeloid blasts or blast equivalents in the bone marrow or blooda Complex karyotype and/or Mutated ASXL1, del(5q)/t(5q)/add(5q), AML-defining No No BCOR, EZH2, RUNX1, No –7/del(7q), +8, del(12p)/ No Mutated TP53 AML not otherwise recurrent genetic VAF t10% SF3B1, SRSF2, STAG2, t(12p)/add(12p), i(17q), specified abnormalitiesb U2AF1, and/or ZRSR2 –17/add(17p)/del(17p), del(20q), or idic(X)(q13) 10–19% t20% 10–19% t20% 10–19% t20% 10–19% t20% blasts blasts blasts blasts blasts blasts blasts blasts MDS/AML with MDS/AML with MDS/AML with myelodysplasia-related MDS/AML not myelodysplasia-related mutated TP53 gene mutation cytogenetic abnormality otherwise specified Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 AML with AML with AML with AML with myelodysplasia- AML not recurrent genetic myelodysplasia-related mutated TP53 related cytogenetic otherwise specified abnormalityb gene mutation abnormality Diagnostic qualifiers appended to any of the above diagnosesc Prior MDS or Germline Therapy-related MDS/MPN predispositionc Figure 1. Hierarchical classification of the International Consensus Classification of AML. The classification is hierarchical (ie, AML with recurrent genetic abnormalities takes precedence over all other categories); among the remaining categories, AML with mutated TP53 supersedes AML with myelodysplasia-related gene mutations, and the latter supersedes AML with myelodysplasia-related cytogenetic abnormalities. aMyeloblasts, monoblasts, and megakaryoblasts are included in the blast count. Monoblasts and promonocytes, but not abnormal monocytes, are counted as blast equivalents in AML with monocytic or myelomonocytic differentiation, and promyelocytes in the setting of PML::RARA or variant RARA rearrangement. Cases with prior diagnosis of MPN are excluded and are classified as accelerated (10%-19% blasts) or blast phase ($20% blasts) MPN. For patients who already have a history of MDS/MPN (eg, CMML), the diagnosis of MDS/MPN should be retained until there are $20% blasts/blast equivalents; however, once an AML-defining recurrent genetic abnormality (eg, KMT2A rearrangement or NPM1 mutation) is detected and the blast count is $10%, AML-type therapy is recommended. bAML-defining recurrent genetic abnormalities are t(15;17)(q24.1;q21.2)/PML::RARA; t(8;21)(q22;q22.1)/ RUNX1::RUNX1T1; inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11; t(9;11)(p21.3;q23.3)/MLLT3::KMT2A; t(6;9)(p22.3;q34.1)/DEK::NUP214; inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1); mutated NPM1; in-frame bZIP mutated CEBPA; t(9;22)(q34.1;q11.2)/BCR::ABL1; other recurrent rearrangements involving RARA, KMT2A, MECOM, and other rare rearrangements as listed in Table 1. The entity is named with the specific genetic abnormality. Cases with BCR::ABL1 rearrangement and 10% to 19% blasts are classified as CML in accelerated phase, and cases with history of CML and $20% blasts are classified as CML in myeloid blast phase. cExamples how to append diagnostic qualifiers: AML with myelodysplasia-related cytogenetic abnormality, therapy-related; AML with myelodysplasia-related gene mutation, prior myelodys- plastic syndrome; AML with myelodysplasia-related gene mutation, germline RUNX1 mutation (ie, gene or syndrome should be specified). The remaining AML cases are categorized as “AML, not other- numbers of cancer survivors at risk.47 As mentioned above, wise specified” (irrespective of the presence or absence of multi- “therapy-related AML” is no longer considered a disease entity, lineage dysplasia). The 4 categories described above are but the term “therapy-related” is now used as a diagnostic qual- designated as AML/MDS if the bone marrow or blood blast ifier to the disease entities that are primarily defined by their count is 10% to 19% and as AML with $20% blasts (Table 1; genetic profile. Figure 1). Cases that have both a specific AML-defining recurrent genetic abnormality and TP53 mutation and/or These neoplasms have been thought to be the direct conse- myelodysplasia-related gene mutations or cytogenetics quence of mutational events induced by cytotoxic therapy and/ should be classified according to the defined recurrent or selection of chemotherapy-resistant clones.48-50 In general, genetic abnormality. Although complex karyotypes and cer- these AMLs are associated with adverse genetic lesions, and tain co-mutation profiles confer adverse prognosis to some more than 90% show an abnormal karyotype.51,52 The more genetic AML subtypes, these are captured in the prognostic common subtype, seen in 75% of cases, typically presents 5 to stratification scheme and do not affect their primary diag- 7 years after first exposure to alkylating agents or radiation, is nostic classification. often preceded by MDS, and is frequently accompanied by chromosome 5 and/or 7 abnormalities, complex karyotype, and Therapy-related AML TP53 mutations.48,49,52,53 Some individuals develop AML after Currently comprising 10% to 15% of all newly diagnosed AML, treatment with topoisomerase II inhibitors, with breakage at the incidence of cases showing relatedness to previous therapy topoisomerase II sites leading to abnormal recombination and for another disease continues to rise due in part to increasing balanced translocations involving KMT2A at 11q23.3, RUNX1 at 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1347 Table 1. AML and related neoplasms and acute leukemias of ambiguous lineage AML and related neoplams AML with recurrent genetic abnormalities (requiring ‡10% blasts in BM or PB)* Myeloid sarcoma  APL with t(15;17)(q24.1;q21.2)/PML::RARA†  AML with t(8;21)(q22;q22.1)/RUNX1::RUNX1T1 Acute leukemia of ambiguous lineage  AML with inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11  Acute undifferentiated leukemia  AML with t(9;11)(p21.3;q23.3)/MLLT3::KMT2A‡  MPAL with t(9;22)(q34.1;q11.2)/BCR::ABL1  AML with t(6;9)(p22.3;q34.1)/DEK::NUP214  MPAL with t(v;11q23.3)/KMT2A-rearranged  AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM(EVI1)§  MPAL, B/myeloid, not otherwise specified  AML with other rare recurring translocationsjj  MPAL, T/myeloid, not otherwise specified  AML with mutated NPM1  AML with in-frame bZIP mutated CEBPA¶  AML with t(9;22)(q34.1;q11.2)/BCR::ABL1* Categories designated AML (if ‡20% blasts in BM or PB) or MDS/AML Myeloid proliferations related to Down syndrome (if 10-19% blasts in BM or PB)  Transient abnormal myelopoiesis associated with Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023  AML with mutated TP53# Down syndrome  AML with myelodysplasia-related gene mutations  Myeloid leukemia associated with Down syndrome Defined by mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and/or ZRSR2 Blastic plasmacytoid dendritic cell neoplasm  AML with myelodysplasia-related cytogenetic abnormalities**  AML not otherwise specified Diagnostic qualifiers†† Therapy-related‡‡  Prior chemotherapy, radiotherapy, immune interventions Progressed from MDS  MDS should be confirmed by standard diagnostics and .3 mo prior to AML diagnosis Progressed from MDS/MPN (specify type)  MDS/MPN should be confirmed by standard diagnostics and .3 mo prior to AML diagnosis Germline predisposition (specify type) Classification adopted from reference 2. BM, bone marrow; MPAL, mixed phenotype acute leukemia. *Bone marrow or peripheral blood blast count of $ 10% required, except for AML with t(9;22)(q34.1;q11.2)/BCR::ABL1 which requires bone marrow or peripheral blood blast count of $ 20% due to its overlap with progression of chronic myeloid leukemia, BCR::ABL1-positive. †Other recurring translocations involving RARA should be reported accordingly: eg, APL with t(1;17)(q42.3;q21.2)/IRF2BP2::RARA; APL with t(5;17)(q35.1;q21.2)/NPM1::RARA; APL with t(11;17)(q23.2;q21.2)/ZBTB16::RARA; APL with cryptic inv(17) or del(17)(q21.2q21.2)/STAT5B::RARA; STAT3::RARA; other genes rarely rearranged with RARA: TBL1XR1 (3q26.3); FIP1L1 (4q12); BCOR (Xp11.4). ‡Other recurring translocations involving KMT2A should be reported accordingly: eg, AML with t(4;11)(q21.3;q23.3)/AFF1::KMT2A; AML with t(6;11)(q27;q23.3)/AFDN::KMT2A; AML with t(10;11)(p12.3;q23.3)/MLLT10::KMT2A; AML with t(10;11)(q21.3;q23.3)/TET1::KMT2A; AML with t(11;19)(q23.3;p13.1)/KMT2A::ELL; AML with t(11;19)(q23.3;p13.3)/KMT2A::MLLT1. §Other recurring translocations involving MECOM should be reported accordingly: eg, AML with t(2;3)(p1123;q26.2)/MECOM::?; AML with t(3;8)(q26.2;q24.2)/MYC, MECOM; AML with t(3;12)(q26.2;p13.2)/ETV6::MECOM; AML with t(3;21)(q26.2;q22.1)/MECOM::RUNX1. jjOther rare recurring translocations: AML with t(1;3)(p36.3;q21.3)/PRDM16::RPN1; AML (megakaryoblastic) with t(1;22)(p13.3;q13.1)/RBM15::MRTFA; AML with t(3;5)(q25.3;q35.1)/ NPM1::MLF1; AML with t(5;11)(q35.2;p15.4)/NUP98::NSD1; AML with t(7;12)(q36.3;p13.2)/ETV6::MNX1; AML with t(8;16)(p11.2;p13.3)/KAT6A::CREBBP; AML with t(10;11)(p12.3;q14.2)/PICALM::MLLT10; AML with t(11;12)(p15.4;p13.3)/NUP98::KMD5A; AML with NUP98 and other partners; AML with t(16;21)(p11.2;q22.2)/FUS::ERG; AML with t(16;21)(q24.3;q22.1)/RUNX1::CBFA2T3; AML with inv(16)(p13.3q24.3)/CBFA2T3::GLIS2. ¶AML with in-frame mutation in the bZIP domain of the CEBPA gene, either monoallelic or biallelic. #The presence of a pathogenic somatic TP53 mutation (at a variant allele fraction of at least 10%, with or without loss of the wild-type TP53 allele) defines the entity AML with mutated TP53. **Cytogenetic abnormalities sufficient for the diagnosis of AML with MDS-related cytogenetic abnormalities and the absence of other AML-defining disease categories. Complex karyotype: $3 unrelated chromosome abnormalities in the absence of other class-defining recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or polysomies) without structural abnormalities. Unbalanced clonal abnormalities: del(5q)/t(5q)/add(5q); 27/del(7q); 18; del(12p)/t(12p)/(add)(12p); i(17q), 217/add(17p) or del(17p); del(20q); and/or idic(X)(q13). ††Examples: AML with myelodysplasia-related cytogenetic abnormality, therapy-related; AML with myelodysplasia-related gene mutation, prior myelodysplastic syndrome; AML with myelodysplasia-related gene mutation, germline RUNX1 mutation. ‡‡Prior therapy for nonmyeloid neoplasms. 21q22.1, or RARA at 17q21.2. In these cases, the latency period is frequent somatic drivers in pediatric AML related to previous shorter, often it is only 1 to 3 years, and antecedent MDS is rare. therapy, but unlike in adults, most cases appear to represent independent clones arising as a consequence of cytotoxic ther- Another pathogenetic pathway is represented by cases with a apy and not preexisting minor clones.50 preexisting myeloid clone that is resistant to chemotherapy.52 Clonal hematopoiesis of indeterminate potential may be the first Deleterious mutations typical of familial cancer predisposi- step in a multi-hit model.54,55 Cases were identified in which the tion syndromes in the homologous recombination DNA exact TP53 mutation found at diagnosis was already present at repair pathway, particularly BRCA1, BRCA2, PALB2, TP53, or low frequency in blood or bone marrow many years before CHEK2, are observed in 20% of cases.58,59 The identifica- AML development.52 These data suggest a model in which tion of such preexisting conditions facilitates screening and hematopoietic stem cells carrying mutations in TP53 or PPM1D counseling of patients prior to treatment of their primary dis- undergo positive selection by cytotoxic therapy, ultimately lead- ease, family donor selection for allogeneic HCT, cancer/ ing to AML.56,57 Mutations in the RAS/MAPK pathway, altera- organ surveillance strategies, and cascade testing within tions in RUNX1 or TP53, and KMT2A rearrangements are also families.60 1348 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Germline predisposition genes will advance our ability to provide the best treatments for Increasingly, individuals are being recognized as having an patients and their families and will facilitate strategies to main- inherited germline predisposition to hematopoietic malignancies tain health for them throughout their lifetimes. (Table 2).61,62 Recognition of such hereditary predispositions impacts patient management, especially if there is consideration for an allogeneic HCT and health surveillance strategies for the Diagnostic procedures patient and relatives who share the causative variant. Clinical All tests necessary to establish the diagnosis, risk classification, testing for these syndromes is difficult for most clinicians given and the other procedures recommended to be performed at their relative lack of experience regarding these conditions, diagnosis are listed in Table 4. requirement for obtaining germline DNA for testing (Table 3), and a lack of standardization in the field regarding which Immunophenotyping patients and which genes should be tested.63 Immunophenotyping by multiparameter flow cytometry (MFC) is required to diagnose AML accurately by identifying cell surface Germline predisposition risk should be considered for all and intracellular markers (Table 5). Because of the heterogeneity patients diagnosed with a hematopoietic malignancy regardless of AML, no marker is expressed in all cases. It is also important Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 of age, because some germline predisposition alleles, like those to identify leukemia-associated immunophenotypes (LAIP) for in DDX41, can drive hematopoietic malignancies in older subsequent MRD monitoring by MFC. In cases where an age.64,65 When identified, germline predisposing disorders aspirate is unobtainable and circulating blasts are absent, should be applied as diagnostic qualifiers to the specific AML myeloid phenotype may be confirmed on a core biopsy disease category. Key features of the clinical presentation that should prompt consideration of germline testing are given in using immunohistochemistry. Table 3. Clinicians should familiarize themselves with academic and commercial testing options, including the culture and Cytogenetic and molecular studies sequencing of skin fibroblasts, thereby excluding somatic muta- Conventional cytogenetic analysis is mandatory in the evaluation tions in hematopoietic cells, and the panel of genes to be ana- of AML. If conventional cytogenetics fails, fluorescence in situ lyzed (Table 2).63 Germline variants are categorized as hybridization is an alternative to detect specific abnormalities pathogenic, likely pathogenic, variant of uncertain significance, like RUNX1::RUNX1T1, CBFB::MYH11, KMT2A (MLL), and likely benign, or benign; only pathogenic and likely pathogenic MECOM (EVI1) gene fusions, or myelodysplasia-related chromo- variants are considered causative of disease and are followed some abnormalities, eg, loss of chromosome 5q, 7q, or 17p clinically in families. However, gene variant classification can material (Table 1). change over time as additional information regarding gene/ allele function and/or segregation data from families becomes Molecular genetic testing should screen for all the genetic available, and variants of uncertain significance in particular are abnormalities that define disease and risk categories or that are often reclassified as likely pathogenic or pathogenic. needed for targeted treatment modalities (Table 4). These tests can be performed by commercially available gene panel diag- Certain germline disorders are associated with specific charac- nostics or platforms simultaneously testing for mutations and teristics that are important for clinicians to recognize (Table 2), rearrangements. When AML with germline predisposition is sus- those associated with quantitative and qualitative platelet pected, a dedicated gene panel including known predisposing defects: ANKRD26, ETV6, and RUNX1, and those associated alleles should be used. However, caution should be used in with other organ dysfunction: GATA2 with immunodeficiency; interpreting data from tumor-based panels, because hematopoi- Shwachman Diamond syndrome with exocrine pancreas insuffi- etic tissues undergo somatic reversion frequently leading to ciency and skeletal dysplasia; Fanconi anemia with facial dysmor- false-negative results, and panel-based testing is often not able phism, squamous cell carcinomas, and liver tumors; and to detect germline copy number variants, which are relatively dyskeratosis congenita with pulmonary fibrosis, liver cirrhosis, common predisposition alleles. and vascular anomalies; among others. Some disorders are asso- ciated only with myeloid malignancies (eg, CEBPA), whereas For patients with mutant NPM1 and core-binding factor (CBF)- others confer risk to a variety of hematopoietic malignancies AML, it is recommended to perform baseline molecular assess- and solid tumors. The tumor spectrum associated with each dis- ment by quantitative polymerase chain reaction (qPCR) or order may expand over time as more individuals and families droplet digital PCR (dPCR) to facilitate MRD monitoring after are identified. Germline predisposition alleles that confer risk to treatment. lymphoid malignancies are emerging and often overlap with the myeloid malignancy risk genes. Biobanking Because the treatment plan for many patients with AML includes At least in clinical studies, but preferably also outside this con- allogeneic HCT and relatives are the preferred donors, testing text, bone marrow and blood samples should be obtained at for germline risk alleles should be performed as early as possible time of diagnosis, at remission, and at relapse and stored under during clinical management. Use of hematopoietic donor stem appropriate conditions (DNA and RNA stored at 280 C and via- cells from carriers of deleterious RUNX1 and CEBPA variants is ble cells stored at 2196 C). Broad informed consent should be prohibitive, but we lack data for most predisposition genes and obtained to allow for performance of correlative laboratory stud- whether any variants are permissive to transplantation.66 Future ies. In addition, a sample from healthy tissue should be stored studies that lead to a comprehensive list of all predisposition to enable delineation of germline from somatic mutations. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1349 1350 Table 2. Myeloid neoplasms with germline predisposition Predisposition to Syndrome name Gene Inheritance Age of onset other cancers Clinical features Myeloid neoplasms with germline predisposition without a preexisting platelet disorder or organ dysfunction Germline predisposition due to CEBPA* AD Wide range Not yet described 2nd allele mutations are common, CEBPA P/LP variants* typically at the 39 end Without allogeneic HCT, individuals are susceptible to additional malignancies Germline predisposition due to DDX41 AD Adult . childhood Likely Male mutation carriers appear to DDX41 P/LP variants develop myeloid malignancies more often than female mutation carriers Age of onset of myeloid malignancies similar to the general population R525H hotspot occurs commonly in blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 myeloid malignancies as a somatic mutation Li-Fraumeni syndrome TP53 AD Wide age range Yes Predisposition to several tumor types Myeloid neoplasms with germline predisposition and preexisting platelet disorders† Germline predisposition due to RUNX1‡ AD Wide age range Myeloid malignancies . Life-long thrombocytopenia and RUNX1 P/LP variants‡ T-ALL . B-cell qualitative platelet defects malignancies Germline predisposition due to ANKRD26 AD Adult . childhood Not yet described Life-long thrombocytopenia, various ANKRD26 P/LP variants platelet function abnormalities No syndromic features Germline predisposition due to ETV6 ETV6 AD Wide age range ALL . myeloid Life-long thrombocytopenia P/LP variants malignancies AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic. *Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 59 -end mutation, although rare 39 -end germline mutations have been described. Germline 59 -end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 39 -end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 59 end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 39 -end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients. †Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies . T-cell ALL . B-cell malignan- cies; germline ETV6 mutations cause B-cell ALL . myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date. ‡Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1. §Emerging disorders are so-named due to limited numbers of cases from the published literature at this time. € DOHNER et al Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Table 2. (continued) Predisposition to Syndrome name Gene Inheritance Age of onset other cancers Clinical features Myeloid neoplasms with germline predisposition and potential organ dysfunction Germline predisposition due to GATA2 AD Adolescents and Yes Associated with immunodeficiencies, GATA2 P/LP variants young adults lymph edema, and many other phenotypes Severe congenital neutropenia ELANE, G6PC3GFI1, HAX1, JAGN, AD, AR Adolescents and Not yet described Severe opportunistic infections without 2022 ELN AML RECOMMENDATIONS TCRG1, VPS45A young adults growth factor support Shwachman-Diamond syndrome SBDS (. 90%), DNAJC21, EFL1, SRP54 AR Childhood . adult Not yet described Exocrine pancreas dysfunction, variable cytopenias, skeletal dysplasia, hepatomegaly and transaminitis in early childhood, may present as nonsyndromic AA or MDS/AML Fanconi anemia FANC A-W AR Childhood . adult Yes Congenital malformations, facial dysmorphism, BM failure, squamous cell carcinomas and liver tumors, sensitivity to genotoxic agents Telomere biology disorders/short ACD, CTC1, DKC1, MDM4, RTEL1, AD, AR, and X- Wide age range Yes Mucocutaneous triad of nail/hair telomere syndromes TERC, TERT, TINF2, ACD, NHP2, linked abnormalities, skin rash, leukoplakia NOP10, NPM1, PARN, WRAP53, BM failure, pulmonary fibrosis, liver RPA1, Apollo cirrhosis, vascular anomalies, squamous cell carcinoma May present as nonsyndromic AA or monosomy 7 MDS CBL syndrome CBL AD Early childhood Not yet described JMML/Noonan syndrome-like: facial dysmorphism, cardiac disease, musculoskeletal anomalies, cognitive deficits, vasculopathy; variable syndrome expressivity Noonan syndrome PTPN11, NRAS, KRAS AD Early childhood ALL, AML, various non- Facial dysmorphism, cardiopathy, hematologic cancers chylothorax, hygroma, and later in life short stature Neurofibromatosis type I NF1 AD Childhood . adult Yes Caf e au lait, neurofibromas Noonan syndrome-like disorder AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic. *Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 59 -end mutation, although rare 39 -end germline mutations have been described. Germline 59 -end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 39 -end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 59 end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 39 -end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients. †Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies . T-cell ALL . B-cell malignan- cies; germline ETV6 mutations cause B-cell ALL . myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date. blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 ‡Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1. §Emerging disorders are so-named due to limited numbers of cases from the published literature at this time. 1351 Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 1352 Table 2. (continued) Predisposition to Syndrome name Gene Inheritance Age of onset other cancers Clinical features Germline predisposition due to SAMD9 AD Childhood . adult Not yet described MIRAGE syndrome: MDS with SAMD9 P/LP variants Infections, Renal abnormalities, Adrenal Insufficiency, Genitourinary anomalies, Enteropathy May present as non-syndromic monosomy 7 MDS or BM failure Germline predisposition due to SAMD9L AD Childhood . adult Not yet described Ataxia-pancytopenia syndrome SAMD9L P/LP variants May present as non-syndromic monosomy 7 MDS or BM failure Bloom syndrome BLM AR Childhood . adult Yes Prenatal growth deficiency, mild immunodeficiency, excessive photosensitivity with facial lupus-like skin lesions, type 2 diabetes mellitus, hypogonadism blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 Germline predisposition genes causing multiple cancer types including myeloid neoplasms Germline predisposition due to CHEK2 AD Adult . childhood Yes Predisposition to clonal hematopoiesis CHEK2 P/LP variants and several tumor types Germline predisposition due to MPL MPL AR, AD Adult . childhood Also associated with Thrombocytopenia: AR (homozygous P/LP variants lymphoid malignancies and compound heterozygous); thrombocytosis: AD Germline predisposition due to RECQL4 AR Adult . childhood Yes Atrophic skin and pigment changes RECQL4 P/LP variants Alopecia, osteopenia, cataracts Hereditary breast and ovarian cancer BRCA1 AD Adult . childhood Yes Predisposition to several tumor types Hereditary breast and ovarian cancer BRCA2 AD Adult . childhood Yes Predisposition to several tumor types Lynch syndrome MLH1, MSH2, MSH6, PMS2 AD, AR Adult . childhood Yes Tumors show microsatellite instability AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic. *Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 59 -end mutation, although rare 39 -end germline mutations have been described. Germline 59 -end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 39 -end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 59 end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 39 -end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients. †Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies . T-cell ALL . B-cell malignan- cies; germline ETV6 mutations cause B-cell ALL . myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date. ‡Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1. §Emerging disorders are so-named due to limited numbers of cases from the published literature at this time. € DOHNER et al Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Table 2. (continued) Predisposition to Syndrome name Gene Inheritance Age of onset other cancers Clinical features Nijmegen breakage syndrome NBN AR Childhood . adult Yes .90% are homozygous for a 5-base pair deletion founder mutation Microcephaly at birth and progressive 2022 ELN AML RECOMMENDATIONS with age, dysmorphic facial features, mild growth retardation, intellectual disability, combined cellular and humoral immunodeficiency with recurrent sino-pulmonary infections, females with hypergonadotropic hypogonadism Wiskott-Aldrich syndrome WAS X-linked Adult . childhood Yes Immunodeficiency with microthrombocytopenia and neutropenia, eczema, recurrent infections, autoimmunity Emerging disorders§ Germline predisposition due to CSF3R AD Adult . childhood Not yet described Full syndrome description awaits CSF3R P/LP variants publication of additional cases Germline predisposition due to ERCC6L2 AR Adult . childhood Not yet described Full syndrome description awaits ERCC6L2 P/LP variants (homozygous) publication of additional cases Germline predisposition due to JAK2 JAK2 AD Adult . childhood Not yet described Associated with thrombocythemia P/LP variants Germline predisposition due to MBD4 MBD4 AD Adult . childhood Likely Myeloid malignancies have a high P/LP variants mutational rate Somatic mutation of DNMT3A is common AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic. *Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 59 -end mutation, although rare 39 -end germline mutations have been described. Germline 59 -end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 39 -end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 59 end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 39 -end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients. †Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies . T-cell ALL . B-cell malignan- cies; germline ETV6 mutations cause B-cell ALL . myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date. ‡Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1. §Emerging disorders are so-named due to limited numbers of cases from the published literature at this time. blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1353 Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 1354 Table 2. (continued) Predisposition to Syndrome name Gene Inheritance Age of onset other cancers Clinical features Germline predisposition due to MECOM/EVI1 AD Childhood . adult Not yet described Radioulnar synostosis, clinodactyly, MECOM/EVI1 P/LP variants cardiac and renal malformations, presenile hearing loss BM failure, B-cell deficiency Germline predisposition due to NPM1 NPM1 AD Childhood . adult Not yet described Full syndrome description awaits blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 P/LP variants publication of additional cases Germline predisposition due to RBBP6 AD Adult . childhood Not yet described Full syndrome description awaits RBBP6 P/LP variants publication of additional cases Germline predisposition due to SRP72 SRP72 AD Wide age range Not yet described Full syndrome description awaits P/LP variants publication of additional cases Germline predisposition due to TET2 TET2 AD, AR Childhood . adult Not yet described Full syndrome description awaits P/LP variants publication of additional cases AA, aplastic anemia; AD, autosomal dominant; ALL, acute lymphoblastic leukemia; AR, autosomal recessive; JMML, juvenile myelomonocytic leukemia; LP, likely pathogenic; P, pathogenic. *Approximately 10% of patients with bi-allelic CEBPA-mutant AML have one of those alleles as a germline allele, typically the 59 -end mutation, although rare 39 -end germline mutations have been described. Germline 59 -end CEBPA mutations have a penetrance of close to 100%, in contrast to germline 39 -end mutations, which have lower penetrance. Because of the high penetrance of leukemia development in those with 59 end germline mutations, some advocate pre-emptive allogeneic HCT. Leukemia survival appears to be longer for those with a germline mutation compared with those with two acquired mutations. The presence of the acquired CEBPA mutation serves as a molecular marker of AML, and these 39 -end acquired mutations are distinct in AML that re-emerge in germline CEBPA-mutation carriers, suggesting that they are independent primary AMLs rather than relapses. Therefore, individuals with germline CEBPA mutations who develop AML and are treated only with chemotherapy are at risk for developing independent AML, since their germline mutation remains. For this reason, some argue for allogeneic HCT in first remission for these patients. †Among these, all show phenotypic variability even within the same family. People with germline ANKRD26 mutations generally have the lowest platelet counts. Germline RUNX1 mutations cause myeloid malignancies . T-cell ALL . B-cell malignancies; germline ETV6 mutations cause B-cell ALL . myeloid malignancies; and germline ANKRD26 mutations have been associated only with myeloid malignancies to date. ‡Thirty percent of germline RUNX1-mutated patients have clonal hematopoiesis prior to leukemia development, where BCOR mutations predominate. When leukemias develop, somatic mutations in the wild-type RUNX1 allele are seen commonly along with acquired mutations in ASXL1, FLT3, GATA2, PHF6, SRSF2, and WT1. §Emerging disorders are so-named due to limited numbers of cases from the published literature at this time. € DOHNER et al Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Table 3. Clinical features prompting consideration of clinical testing for a germline predisposition allele(s) Clinical features Personal history of $2 cancers, 1 of which is a hematopoietic malignancy (order does not matter) Personal history of a hematopoietic malignancy plus:  Another relative within two generations with another hematopoietic malignancy, or  Another relative within two generations with a solid tumor diagnosed at age 50 or younger, or  Another relative within two generations with other hematopoietic abnormalities Presence of a deleterious gene variant in tumor profiling that could be a germline allele, especially if that variant is present during remission* Age of diagnosis of hematopoietic malignancy at an earlier age than average (eg, MDS diagnosed # 40 y) Germline status of a variant is confirmed by: Its presence in DNA derived from a tissue source not likely to undergo somatic mutation frequently (eg, cultured skin fibroblasts or hair follicles) AND at a variant allele frequency consistent with the germline (generally considered between 30-60%), or Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Its presence in at least two relatives at a variant allele frequency consistent with the germline *Certain gene alleles (eg, CHEK2 I200T and truncating DDX41 variants) are overwhelmingly likely to be germline and should prompt consideration of germline testing when identified even once. 2022 European LeukemiaNet genetic shown that in-frame mutations affecting the basic leucine zipper region of CEBPA confer the favorable outcome, irrespective of risk classification at diagnosis their occurrence as biallelic or monoallelic mutations and there- Since 2017, new data have emerged that prompted the need to fore are now categorized in the favorable-risk group.32,34,35 (5) adjust the risk classification. In addition to baseline genetic char- Additional disease-defining recurring cytogenetic abnormalities acterization, the importance of response to initial therapy and are included in the adverse-risk group, including t(3q26.2;v) assessment of early MRD in individual risk assignment are involving the MECOM gene,31,73 or t(8;16)(p11.2;p13.3) associ- highlighted.67 In clinical practice, a patient with favorable-risk ated with KAT6A::CREBBP gene fusion.14 (6) Finally, hyperdi- AML may be reclassified as intermediate-risk or vice versa, ploid karyotypes with multiple trisomies (or polysomies) are no based on the presence or absence of MRD, respectively. For longer considered complex karyotypes and as adverse risk.74 instance, this is particularly relevant for patients with NPM1- mutant AML.68-70 Although numerous reports have studied mutations in other genes, for example, IDH1/IDH2 or DNMT3A, current evi- The most important changes made to the previous risk classifica- dence does not yet warrant their assignment to a distinct tion are outlined in Table 6. (1) The FLT3-ITD allelic ratio is no ELN prognostic group. Also, the emerging therapeutic use longer considered in the risk classification; consequently, AML with FLT3-ITD (without adverse-risk genetic lesions) are now cat- of targeted inhibitors might impact prognostic outcome in egorized in the intermediate-risk group, irrespective of the allelic IDH1/IDH2-mutated AML. Finally, it should be emphasized ratio or concurrent presence of NPM1 mutation. The reason for that the ELN AML risk classification has been developed this change relates to methodological issues with standardizing based on data from intensively treated patients and may the assay to measure the FLT3-ITD allelic ratio, the modifying warrant modifications for patients receiving less intensive impact of midostaurin-based therapy on FLT3-ITD without therapies. NPM1 mutation,71 and the increasing role of MRD in treatment decisions. (2) AML with myelodysplasia-related gene mutations is now categorized in the adverse-risk group. These mutations, Monitoring of measurable typically associated with AML following an antecedent hemato- logic disease, are also prevalent in de novo AML and indicate residual disease MRD assessment in AML is used to (1) provide a quantitative adverse risk even in the absence of myelodysplasia-related cytogenetic abnormalities.6,26,42,44,45 Beyond the previously methodology to establish a deeper remission status; (2) refine considered ASXL1 and/or RUNX1 genes, this category of postremission relapse risk assessment; (3) identify impending myelodysplasia-related gene mutations now includes pathologic relapse to enable early intervention; and (4) as a surrogate end variants in at least one of the ASXL1, BCOR, EZH2, RUNX1, point to accelerate drug testing and approval.75 SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 genes. (3) The pres- ence of adverse-risk cytogenetic abnormalities in NPM1-mutated Currently, the 2 most extensively evaluated methodologies are AML now defines adverse risk. A meta-analysis has shown that multiparameter flow cytometry-based MRD (MFC-MRD) and NPM1-mutated AML with adverse cytogenetic abnormalities is molecular MRD (Mol-MRD) assessed by qPCR.76 Emerging associated with a poor outcome.72 Whether other genetic exploratory technologies are next-generation sequencing (NGS) abnormalities (eg, myelodysplasia-related gene mutations) also and dPCR (Table 7).77 The current update of the ELN recom- confer unfavorable outcome to NPM1-mutated AML is under mendation on MRD includes new technical recommendations investigation. (4) As mentioned previously, recent studies have for standardized MFC-MRD and Mol-MRD analysis, MRD 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1355 Table 4. Tests and procedures at diagnosis for a patient with AML Tests and procedures Tests to establish the diagnosis Additional tests and procedures Complete blood count and differential count* Complete physical examinationc Bone marrow aspirate† Performance status (ECOG/WHO score) Bone marrow trephine biopsy‡ Geriatric assessmentd (optional) Immunophenotyping by flow cytometry (see Table 5) Biochemistry, coagulation testse Genetic analyses Results preferably available within Hepatitis A, B, C; HIV-1 testing; CMV, EBV, HSV, VZV Cytogenetics§  5-7 d Serum pregnancy testf Screening for gene mutations Eligibility assessment for allogeneic HCT (incl. HLA-typing)g required for establishing the Chest x-ray, 12-lead electrocardiogram, echocardiography diagnosis and to identify or MUGA (on indication) Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 actionable therapeutic targets#  FLT3,¶ IDH1, IDH2  3-5 d Computed tomography of the chest (on indication)h  NPM1  3-5 d Lumbar puncture (on indication)i  CEBPA,# DDX41, TP53; ASXL1,  1st cycle BCOR, EZH2, RUNX1, SF3B1, Information on oocyte and sperm cryopreservationj SRSF2, STAG2, U2AF1, ZRSR2 Biobankingk Screening for gene rearrangements**  PML::RARA, CBFB::MYH11,  3-5 d RUNX1::RUNX1T1, KMT2A rearrangements, BCR::ABL1, other fusion genes (if available) Additional genes recommended to test at diagnosis††  ANKRD26, BCORL1, BRAF, CBL, CSF3R, DNMT3A, ETV6, GATA2, JAK2, KIT, KRAS, NRAS, NF1, PHF6, PPM1D, PTPN11, RAD21, SETBP1, TET2, WT1 Medical history Demographics and medical history‡‡ Detailed family historya Patient bleeding historyb Analysis of comorbidities CMV, cytomegalovirus; EBV, Epstein-Barr virus; ECOG, Eastern Cooperative Oncology Group; HSV, herpes simplex virus; MUGA, multigated acquisition; VZV, varicella-zoster virus. *Two hundred nucleated cells on blood smears should be counted. †Five hundred nucleated cells on bone marrow smears should be counted. Myeloblasts, monoblasts, and megakaryoblasts are included in the blast count. Monoblasts and promonocytes, but not abnormal monocytes, are counted as blast equivalents in AML with monocytic or myelomonocytic differentiation. ‡In patients with a dry tap (punctio sicca); touch preparations from the core biopsy should be performed if a dry tap is suspected. §At least 20 bone marrow metaphases are needed to define a normal karyotype and recommended to describe an abnormal karyotype. Normal and abnormal karyotypes may be diagnosed from blood specimens with circulating blasts. In case of no analyzable metaphases, fluorescence in-situ hybridization is an alternative method to detect genetic abnormalities like RUNX1::RUNX1T1, CBFB::MYH11, KMT2A, and MECOM gene fusions, or myelodysplasia-related chromosome abnormalities, eg, loss of chromosome 5q, 7q, or 17p material. #Screening for gene mutations is an evolving field of research; screening for single genes is increasingly replaced by gene panel diagnostics. ¶FLT3: mutational screening should include the analysis of internal tandem duplications (ITD) and of tyrosine kinase domain (TKD) mutations. Longer FLT3-ITDs may be missed by next-generation sequencing, therefore, we recommend continuing to use capillary electrophoresis. #The report should specify type of mutation: only in-frame mutations affecting the basic leucine zipper (bZIP) region of CEBPA, irrespective whether they occur as monoallelic or biallelic mutations, have been associated with favorable outcome. **Screening for gene rearrangements should be performed if rapid information is needed for recommendation of suitable therapy, if chromosome morphology is of poor quality, or if there is typical morphology but the suspected cytogenetic abnormality is not present. ††Results from these genes are not required for establishing the diagnosis or for the identification of actionable therapeutic targets, rather they may be used for subsequent monitoring of the disease by next-generation sequencing-based techniques (with the exception of mutations consistent with pre-malignant clonal hematopoiesis, eg, DNMT3A, TET2, ASXL1); although these techniques are still investigational, this is a rapidly evolving field. ‡‡Including race or ethnicity, prior exposure to toxic agents, prior malignancy, therapy for prior malignancy, information on smoking. a Thorough family history needed to identify potential myeloid neoplasms with germline predisposition. b History of bleeding episodes may inform cases of myeloid neoplasms with germline predisposition and preexisting platelet disorders. c Special attention for skin (bleeding symptoms, leukemia cutis, Sweet syndrome), gingival hyperplasia, lymphadenopathy, testis enlargement, signs of infection (eg, pulmonary, perianal, mouth/teeth); symptoms of central nervous system involvement; signs of abnormalities associated with germline predisposition syndromes (Table 2). d Tests for objectively measured physical and cognitive function are particularly useful in the context of trials. e Biochemistry: glucose, sodium, potassium, calcium, creatinine, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline phosphatase, lactate dehydrogenase (LDH), bilirubin, urea, total protein, uric acid, total cholesterol, total triglycerides, creatinine phosphokinase (CPK). Special attention should be given to tumor lysis syndrome. Coagulation tests: prothrombin time (PTT), international normalized ratio (INR) where indicated, activated partial thromboplastin time (aPTT). f In women with childbearing potential. 1356 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al g HLA typing and CMV testing should be performed in those patients eligible for allogeneic HCT. In patients in whom allogeneic HCT is likely to be indicated, it is also important to commence a search for sibling or volunteer unrelated donor at diagnosis. h If suspicion of pulmonary infection. i Required in patients with clinical symptoms suspicious of central nervous system involvement; patient should be evaluated by imaging study for intracranial bleeding, leptomeningeal disease, and mass lesion; lumbar puncture considered optional in other settings (eg, high white blood cell count). j Cryopreservation to be done in accordance with the wish of the patient. k Pretreatment leukemic bone marrow and blood sample; preferably also normal tissue (eg, skin biopsy, nail clippings). thresholds, definitions of MRD response, and suggestions for to disease below the MRD test threshold in the tested sample. clinical implications.67 Conversely, not all patients who are MRD positive will relapse. Of note, Mol-MRD may remain detectable at low levels Multiparameter flow cytometry (CRMRD-LL) without prognostic significance, and therefore, are Integration of diagnostic LAIP that distinguish AML cells from called negative operationally if the MRD values are below the normal hematopoietic cells in an individual patient and the threshold linked to prognosis.67 For instance, in CBF-AML and more generally defined “different from normal” aberrant immu- NPM1-mutant AML, the transcripts may show persistent low- nophenotype (DfN) allow both for tracking of diagnostic and level expression after treatment, but this is not prognostic of Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 emerging clones and should include core MRD markers (Table relapse.68,70,94-96 The presence of detectable MRD before trans- 5).67 MFC-MRD assessment should be performed with a quali- plant is an independent unfavorable predictor of posttransplant fied assay based on guidelines for rare event detection.78 Evalu- outcome.97-100 However, there is currently no evidence showing ation of residual leukemic stem cells (LSC) by MFC-MRD is still benefit of additional courses of intensive chemotherapy prior to investigational but is recommended for evaluation in clinical transplant in CR1 patients who are MRD positive. If fit enough, studies. The prognostic value of LSC-MRD has been associated such patients should be considered candidates for a myeloabla- with a higher sensitivity and lower false negativity.79,80 LSC can tive conditioning (MAC) regimen or an early taper of posttrans- be immunophenotypically defined as CD341/CD38low cells plant immunosuppression.98 combined with an aberrant marker not present on normal HSCs (eg, CD45RA [PTPRC], CLL-1 [CLEC12A], or CD123 [IL3RA]).81 Definitions of MRD response categories and molecular relapse are listed in Table 8. In Figure 2, the recommended Molecular MRD time points for MRD evaluation and clinical decision making The technique used, including qPCR and dPCR, should reach a are depicted for NPM1-mutated, CBF-AML, and AML limit of detection of at least 1023. Either peripheral blood or assessed by MFC. bone marrow may be used, although sensitivity in blood is gener- ally lower by an order of magnitude compared with bone mar- row. Leukemia-related abnormalities suitable for qPCR monitoring Response criteria and include mutated NPM1; CBFB::MYH11, RUNX1::RUNX1T1, KMT2A::MLLT3, DEK::NUP214, and BCR::ABL1 gene fusions; outcome measures and WT1 expression.67 Validation is most robust for NPM1- AML response criteria and outcome measures are summarized mutated, as well as CBFB::MYH11 and RUNX1::RUNX1T1- in Tables 8 and 9. positive AML.82 Response criteria If using NGS, error-corrected targeted panel-based approaches CR, CRi, partial remission (PR), and morphologic leukemia- are preferred.83 Care must be taken to recognize and exclude free state (MLFS) The criterion “absence of blasts with Auer germline mutations. Mutations consistent with premalignant rods” was eliminated. clonal hematopoiesis (eg, DNMT3A, TET2, ASXL1) should not be considered as MRD.84 Further study is required to identify CR with partial hematologic recovery The term CR with and distinguish mutations truly indicative of residual AML from partial hematologic recovery (CRh) has been introduced for clonal hematopoiesis related abnormalities.85,86 It is important patients with morphologic bone marrow blast clearance and par- to note that NGS-based strategies currently lack standardization as a stand-alone technique for MRD assessment. tial recovery of both neutrophils ($0.5 3 109/L [500/mL]) and platelets ($50 3 109/L [50 000/mL]) because those represent Implementation of MRD testing/decision making clinical benefit to the patient; other CR criteria need to be met. in AML Thus far, CRh has only been used in the context of trials evaluat- The prognostic value of MRD detection in complete remission ing less-intensive therapies. It is recommended that future stud- (CR) or CR with incomplete hematologic recovery (CRi) has been ies validate the role of CRh as a surrogate measure of survival demonstrated both in patients treated with intensive and more after intensive and less-intensive therapies. recently less-intensive treatment modalities.87-89 Various studies and a systematic meta-analysis of 81 publications have shown Response criteria with MRD assessment The 2017 ELN rec- the prognostic value of MRD for relapse and overall survival ommendations included the term CR without MRD (CRMRD2) to (OS).68,87,90-93 Although MRD estimates furnish critical prognos- recognize the increasing role of MRD technologies in stratifying tic insights, they are imperfect, because relapse still occurs in a prognosis of patients in CR.1 The current response criteria minority of MRD-negative patients. Thus, a negative MRD test expand MRD classification to include patients achieving CRh or result may not indicate complete disease eradication but refers CRi without MRD (CRhMRD2 or CRiMRD2). 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1357 Table 5. Expression of cell-surface and cytoplasmic patients yet to have a response assessment, suffering early markers for the diagnosis of AML and MPAL death, exiting the study early, or those with a technically sub- optimal bone marrow sample precluding assessment. Patients Diagnosis of AML previously categorized as having death in aplasia or from indeterminate causes are now designated as nonevaluable Diagnosis of AML for response. Precursor marker CD34, CD117, HLA-DR Myeloid markers Cytoplasmic MPO, CD33, CD13 Treatment failure Myeloid maturation markers CD11b, CD15, CD64, CD65 Relapsed disease is defined as $5% leukemic blasts in the bone Monocytic markers CD14, CD36, CD64, CD4, CD38, marrow, reappearance of leukemic blasts in peripheral blood CD11c (PB) in at least 2 PB samples at least 1 week apart, or develop- Megakaryocytic markers CD41 (glycoprotein IIb/IIIa), CD61 ment of new extramedullary disease. (glycoprotein IIIa), CD36 Erythroid markers CD235a (glycophorin A), CD71, Refractory disease If a specified response has not been CD36 achieved by a defined landmark (ie, failure to achieve response Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 after 2 cycles of intensive chemotherapy or a predetermined Diagnosis of MPAL landmark, eg, 180 days after commencing less-intensive ther- Myeloid lineage MPO (flow cytometry, apy), the patient will be designated as having refractory disease. immunohistochemistry or cytochemistry), or monocytic differentiation (at least CR, CRh, or CRi with MRD relapse For patients initially 2 of the following: non-specific achieving CR, CRh, or CRi without MRD, the term CR, CRh, or esterase cytochemistry, CD11c, CRi with MRD relapse may be applied if there is evidence of CD14, CD64, lysozyme), or MRD relapse as defined by ELN criteria (Table 8).67 at least two myeloid markers, ie, CD177, CD33, CD13 Outcome measures T-lineage Strong cytoplasmic CD3 (with antibodies to CD3 « chain) or Systematic reporting of early death (eg, 30 and 60 days) is recom- surface CD3 mended to enable assessment of treatment-related mortality with B-lineageg Strong CD19 with at least one of new therapies being relevant for the therapy under consideration. the following strongly expressed: cytoplasmic CD79a, Although the primary end point for registrational studies in cCD22 or CD10, or AML has historically been OS, the increased availability of post- weak CD19 with at least two of the following strongly study treatment options with potential to confound OS interpre- expressed: CD79a, cCD22 or tation may encourage adoption of alternative end points, such CD10 as event-free survival (EFS; or relapse-free survival [RFS] for postremission studies) as comparative outcome measures in Core MRD markers registrational studies (see also “Clinical trials”). In a retrospective CD34, CD117, CD45, CD33, patient-level analysis of 8 randomized trials evaluating intensive CD13, CD56, CD7, HLA-DR If monocytic: CD64, CD11b, CD4 chemotherapy conducted by the US Food and Drug Administra- (in addition) tion (FDA), EFS had the best correlation with OS when response was limited to a strict CR (R2 5 0.87; 95% confidence interval [CI], 0.47-0.98); EFS with the definition of response broadened to include CRi and CR with incomplete platelet recovery was also shown to correlate, albeit less strongly, with OS (R2 5 0.59; Time window for response assessment To recognize the 95% CI, 0.13-0.93).101 Limitations of the analysis included rela- potential for continuing improvements in blood counts after tively small sample sizes, heterogeneity among trials, and lack of myelosuppressive therapy, response definitions for patients with multivariate analyses. marrow blast clearance (,5%) may be adjusted to reflect the best hematologic response achieved prior to commencement of For drugs that add myelosuppression (eg, venetoclax, CPX-351, the next treatment cycle. Aspirate reports that include MLFS, gemtuzumab ozogamycin), the sole use of a strict CR in the defi- CRh, or CRi should note the potential for post-marrow blood nition of EFS is increasingly challenged. We recommend broad- counts to alter the final response designation. ening the definition of EFS to include CRh or CRi in response. Patients not achieving response by the predetermined landmark No response Patients evaluable for response but not meeting (refractory disease) should have the event recorded on day 1 of the criteria for CR, CRh, CRi, MLFS, or PR will be categorized as registration in nonrandomized trials (or day 1 of random assign- having “no response.” ment in randomized trials). Patients who die before reaching the response landmark and prior to/without response assessments Nonevaluable for response For accurate reporting of are considered treatment failures and should have the event response, it is necessary to include all registered/randomized recorded at day 1 of registration/randomization. Patients alive patients on an intention to treat principle. Therefore, patients but nonevaluable for response are censored at day 1 of registra- nonevaluable for response should be included in the denomina- tion/randomization. To enable consistency in trial reporting, a tor of response assessment analyses. This category may include response landmark for failure to achieve response should be 1358 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Table 6. 2022 ELN risk classification by genetics at Therapy for AML initial diagnosis* The goal of treatment is control and, whenever possible, eradica- tion of disease. This outcome is accomplished ideally by inducing Risk category† Genetic abnormality a CR with initial therapy, followed by consolidation and/or mainte- Favorable  t(8;21)(q22;q22.1)/RUNX1::RUNX1T1†,‡ nance efforts to deepen the remission and maximize response  inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/ duration. The role of HCT and post-HCT therapies is discussed in CBFB::MYH11†,‡ the section on allogeneic HCT. Results of genetic analyses should  Mutated NPM1†,§ without FLT3-ITD  bZIP in-frame mutated CEBPAk be available as rapidly as possible, preferably within 3 to 5 days, to identify therapeutically actionable targets (Table 4). A short Intermediate  Mutated NPM1†,§ with FLT3-ITD delay in starting treatment to stabilize patients and identify the  Wild-type NPM1 with FLT3-ITD (without adverse-risk genetic lesions) best treatment option is recommended to optimize clinical out-  t(9;11)(p21.3;q23.3)/MLLT3::KMT2A†,¶ come.102 If hyperleukocytosis is present, immediate cytoreduction  Cytogenetic and/or molecular is advised (see Management of special situations). If a patient can- abnormalities not classified as not tolerate an active intensive or nonintensive treatment option, favorable or adverse the purpose of therapy is to optimize quality of life and decrease Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Adverse  t(6;9)(p23.3;q34.1)/DEK::NUP214 the incidence of cytopenia-related complications with transfusion  t(v;11q23.3)/KMT2A-rearranged# and other supportive care measures and early involvement of pal-  t(9;22)(q34.1;q11.2)/BCR::ABL1 liative care services as appropriate.  t(8;16)(p11.2;p13.3)/KAT6A::CREBBP  inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/ GATA2, MECOM(EVI1) The survival of patients with AML that are related to previous  t(3q26.2;v)/MECOM(EVI1)-rearranged therapy overall remains poor, which is mainly due to the high  25 or del(5q); 27; 217/abn(17p) frequency of adverse (cyto)genetic features,103,104 but also to  Complex karyotype,** monosomal karyotype†† the sequelae of prior therapy and sometimes persistent primary  Mutated ASXL1, BCOR, EZH2, RUNX1, disease. In general, patients should be managed according to SF3B1, SRSF2, STAG2, U2AF1, and/or the same general therapeutic principles depending on whether ZRSR2‡‡ they are candidates for intensive or nonintensive therapy and  Mutated TP53a allogeneic HCT.104,105 CPX-351 offers a new option for the treat- *Frequencies, response rates and outcome measures should be reported by risk ment of these patients (see below). category, and, if sufficient numbers are available, by specific genetic lesions indicated. †Mainly based on results observed in intensively treated patients. Initial risk assignment Patients considered fit for intensive therapy may change during the treatment course based on the results from analyses of measurable residual disease. Induction therapy Anthracyclines and cytarabine remain the ‡Concurrent KIT and/or FLT3 gene mutation does not alter risk categorization. backbone of intensive chemotherapy. Alternative options are flu- §AML with NPM1 mutation and adverse-risk cytogenetic abnormalities are categorized darabine, cytarabine, granulocyte colony-stimulating factor, and as adverse-risk. kOnly in-frame mutations affecting the basic leucine zipper (bZIP) region of CEBPA, idarubicin (FLAG-IDA) and mitoxantrone-based cytarabine regi- irrespective whether they occur as monoallelic or biallelic mutations, have been mens (Table 10). It has become standard to incorporate the associated with favorable outcome. kinase inhibitor midostaurin into first-line therapy for patients ¶The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse- risk gene mutations. with FLT3-mutant AML. Midostaurin improved 4-year OS by #Excluding KMT2A partial tandem duplication (PTD). 7.1%, from 44.3 to 51.4% when used as an adjunct to **Complex karyotype: $3 unrelated chromosome abnormalities in the absence of daunorubicin-cytarabine induction and high-dose cytarabine other class-defining recurring genetic abnormalities; excludes hyperdiploid karyotypes with three or more trisomies (or polysomies) without structural abnormalities. consolidation in patients 18 to 59 years of age.106 Although ††Monosomal karyotype: presence of two or more distinct monosomies (excluding loss study treatment incorporated single-agent maintenance for of X or Y), or one single autosomal monosomy in combination with at least one structural chromosome abnormality (excluding core-binding factor AML). 12 monthly cycles, the value of adding maintenance therapy ‡‡For the time being, these markers should not be used as an adverse prognostic remains uncertain.107 In a prospective nonrandomized study, marker if they co-occur with favorable-risk AML subtypes. a midostaurin also showed a beneficial effect in patients up to TP53 mutation at a variant allele fraction of at least 10%, irrespective of the TP53 allelic status (mono- or biallelic mutation); TP53 mutations are significantly associated 70 years of age in comparison with a historical control group.108 with AML with complex and monosomal karyotype. Newer and potentially more potent FLT3 inhibitors are currently under randomized evaluation as therapeutic alternatives to mid- ostaurin.109,110 A placebo-controlled phase 3 trial enrolled 539 prespecified. Furthermore, the response landmark should be rel- patients to either quizartinib or placebo in combination with evant for the treatment received; for example, after completion intensive induction and consolidation chemotherapy followed by of 2 cycles of intensive therapy or 180 days after commencing single agent quizartinib maintenance for up to 36 cycles in less-intensive approaches. patients 18 to 75 years of age with FLT3-ITD–positive AML. Post-HCT maintenance was permitted. Although peer-reviewed The incorporation of MRD outcomes as a measure of treatment results are not yet available, a preliminary meeting abstract failure necessitates the inclusion of new terms incorporating reported prolonged OS for quizartinib compared with placebo. molecular MRD relapse into time to event definitions for EFSMRD, Grade $3 treatment-emergent neutropenia was more frequent RFSMRD, and cumulative incidence of relapse (CIRMRD; Table 9). in the quizartinib arm; early death (#30 days) was 5.7% and For each study, clear definitions regarding how MRD relapse is 3.1% in the quizartinib compared with placebo arms, determined should be specified in the statistical analysis plan. respectively.111 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1359 Table 7. Methods for detection of MRD in AML Applicable Turn-around Limitations/ Method Target Sensitivity in % of AML time (days) problems Established Multi-parameter Leukemia-associated 1023 to 1024 85-90 2 Less sensitive, more flow cytometry immunophenotype subjective analysis (MFC) (LAIP) or different from normal (DfN) Established Real-time Robust data: NPM1, 1024 to 1025 40-50* 3-5 Limited applicability quantitative CBFB::MYH11, PCR (RT-qPCR) RUNX1::RUNX1T1 Less validated: KMT2A::MLLT3, DEK::NUP214, BCR::ABL1, WT1 Exploratory Next-generation Potentially any 1022 to 1024 100 5-10 Less sensitive, costly, Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 sequencing somatic mutation† technically (NGS)†,‡ challenging Exploratory Digital PCR Specific targeted 1023 to 1024 70 3-5 Specific assay (dPCR) mutations necessary for every mutation, limited sensitivity *Less frequent in elderly patients with AML. †The NGS-MRD threshold has not been defined for individual mutations; NGS-MRD positivity is provisionally defined as $ 0.1% variant allele frequency, excluding mutations related to clonal hematopoiesis and germline mutations. ‡Common gene mutations consistent with pre-malignant clonal hematopoiesis such as DNMT3A, TET2, and AXSL1 excluded; further study is required to determine which mutations are truly indicative of residual AML and not clonal hematopoiesis. Gemtuzumab-ozogamicin (GO) is a humanized anti-CD33 IgG4 by approximately 7 days and increased the risk of bleeding. antibody chemically linked to a calicheamicin-based cytotoxic Early 30-day mortality, however, was not increased by warhead. Following a history of initial FDA approval followed by CPX-351 (5.9%) compared with “7 1 3” (10.6%), and less retraction based on questionable clinical benefit, a subsequent mucositis was noted. Randomized data are lacking for randomized study demonstrated an EFS advantage among patients under 60 years and for AML following prior MPN. patients 50 to 70 years with de novo AML, with benefit limited to favorable or intermediate cytogenetic risk disease.112,113 Consolidation therapy After attainment of CR (or CRh/CRi), Although 4 other open-label randomized studies individually patients are consolidated ideally with regimens that include failed to demonstrate improved survival for GO added to front intermediate-dose cytarabine.121 Consecutive administration on line therapy in AML, a meta-analysis of all 5 studies indicated a days 1 to 3, rather than on alternate days (days 1, 3, and 5) may benefit, particularly in patients with CBF-AML.114 In another ran- hasten blood count recovery.122,123 Although high-dose cytara- domized study, a reduction of the relapse probability and bine (3000 mg/m2) is still used in some centers, its greater toxic- greater mutant NPM1 molecular clearance was shown in ity and failure to improve survival argues against its patients with NPM1-mutated AML, but with no EFS differ- continued use.124-126 ence.70,115 GO dosed at 3 mg/m2 (capped at 5 mg) D1, 4, and 7 of induction and day 1 of consolidation has been approved In addition to baseline risk factors, assessment of MRD in CR (or for patients with previously untreated CD33 antigen positive CRh/CRi) is recommended for patients with nonadverse risk in AML in combination with daunorubicin and cytarabine, but a sin- first remission to inform consolidation treatment choice. For gle dose of GO delivered on day 1 of induction may also be patients with an estimated relapse risk exceeding 35% to 40%, efficacious.114,116,117 consolidation with allogeneic HCT remains the preferred postre- mission option.127 These include patients with adverse-risk AML CPX-351 is a dual-drug liposomal formulation that encapsu- or nonadverse-risk disease with MRD persistence. Autologous lates cytarabine/daunorubicin in a 5:1 fixed molar ratio.118 HCT, although not widely used, offers an alternative postremis- In an open label phase 3 randomized study in newly diag- sion option for patients with favorable- or intermediate-risk dis- nosed patients aged 60 to 75 years with disease subtypes ease with an adequate MRD response or for whom allogeneic including therapy-related AML, a history of MDS or CMML, HCT is not available.128 In the subset of patients receiving induc- or de novo AML with myelodysplasia-related cytogenetic tion with a FLT3 inhibitor, GO or CPX-351, these agents may be abnormalities CPX-351 improved the clinical response rate incorporated into consolidation (Table 10). and OS compared with induction with cytarabine- daunorubicin, followed by “5 1 2” consolidation.119 Five- Maintenance therapy There is no generally accepted defini- year OS in the CPX-351 arm was improved from 10% to tion of “maintenance therapy.” In most previous trials, mainte- 18% compared with patients receiving “7 1 3.”120 CPX-351 nance therapy has been administered for a defined period of delayed the median time to neutrophil and platelet recovery time in patients who achieved remission after intensive 1360 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Table 8. Response criteria in AML Category Definition Comment Response CR*,†,‡ Bone marrow blasts , 5%; absence of circulating blasts; absence of extramedullary disease; ANC $ 1.0 3 109/L (1,000/mL); platelet count $ 100 3 109/L (100 000/mL) CRh*,†,‡ ANC $ 0.5 3 109/L (500/mL) and platelet count $ 50 3 If CRh used, CRi should only include patients not 109/L (50 000/mL), otherwise all other CR criteria met meeting the definition of CRh CRi*,†,‡ All CR criteria except for residual neutropenia , 1.0 3 109/L (1,000/mL) or thrombocytopenia , 100 3 109/L (100 000/mL) MLFS Bone marrow blasts , 5%; absence of circulating Marrow should not merely be “aplastic”; bone marrow blasts; absence of extramedullary disease; no spicules should be present; at least 200 cells should hematologic recovery required be enumerated in the aspirate or cellularity should Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 be at least 10% in the biopsy. Mainly used in the context of phase 1-2 clinical trials PR All hematologic criteria of CR; decrease of bone Mainly used in the context of phase 1-2 clinical trials marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50% No response Patients evaluable for response but not meeting the criteria for CR, CRh, CRi, MLFS or PR are categorized as having no response prior to the response landmark. Patients failing to achieve response by the designated landmark are designated as having refractory disease Nonevaluable Non-evaluable for response will include patients for response lacking an adequate bone marrow response evaluation. This category will include patients with early death, withdrawal prior to response assessment, or a technically suboptimal bone marrow sample precluding assessment Response (if including assessment of MRD)§ CR, CRh, or CRi CR, CRh or CRi with MRD below a defined threshold for Sensitivities vary by marker tested, and by method without MRD‡ a genetic marker by qPCR, or by MFC. Response used; therefore, test used, tissue source and (CRMRD-, CRhMRD- without MRD should be confirmed with a subsequent minimum assay sensitivity for evaluability should be or CRiMRD-) assessment at least 4 wk apart. The date of response reported; analyses should be done in experienced without MRD is the first date in which the MRD was laboratories (centralized diagnostics) below the defined threshold Response with MRD detection at low-level (CRMRD-LL) is included in this category of CR, CRh or CRi without MRD. CRMRD-LL is currently only defined for NPM1- mutant and CBF-AML Treatment failure Refractory disease No CR, CRh or CRi at the response landmark, ie, after Patients not responding to a first cycle of 7 1 3 should 2 courses of intensive induction treatment or a be considered for a regimen containing higher doses defined landmark, eg, 180 d after commencing less- of cytarabine intensive therapy Relapsed disease Bone marrow blasts $ 5%; or reappearance of blasts in (after CR, CRh or CRi) the blood in at least 2 peripheral blood samples at least one week apart; or development of extramedullary disease ANC, absolute neutrophil count; CBF, core-binding factor; VAF, variant allele frequency. *To recognize the potential for continuing improvements in blood counts after myelosuppressive therapy, response definitions for patients with marrow blast clearance (, 5%) may be adjusted to reflect the best hematologic response achieved prior to commencement of the next treatment cycle. Aspirate reports that include MLFS, CRh, or CRi should note the potential for post-marrow blood counts to alter the final response designation. Patients should not have received G-CSF, nor platelet transfusions within 7 d prior to hematologic response determination. †For patients with CR, CRh, or CRi, the presence of a low percentage of circulating blasts in the blood may represent a regenerating marrow and should not be interpreted as per- sistent disease. In such cases the blasts generally disappear within a week. ‡A response landmark for CR, CRh, or CRi should be stated, eg, after 2 cycles of intensive therapy; this landmark may be longer for nonintensive based treatment options, eg, 180 days. §MFC-MRD positivity is defined as $ 0.1% of CD45 expressing cells with the target immunophenotype. MRD test positivity by qPCR is defined as cycling threshold (Ct) , 40 and is negative if Ct $ 40 in $ 2 of 3 replicates. In NPM1-mutated and CBF-AML, CR with molecular MRD detectable at low-level (CRMRD-LL) defined as , 2% is designated as negative for MRD, because when measured at the end of consolidation treatment, is associated with a very low relapse rate. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1361 Table 8. (continued) Category Definition Comment Treatment failure (if including assessment of MRD)§ MRD relapse 1. Conversion from MRD negativity to MRD Test methodology, sensitivity of the assay, and cutoff (after CR, CRh or positivity, independent of method, or values used must be reported; analyses should be CRi without MRD) done in experienced laboratories (centralized 2. Increase of MRD copy numbers $ 1 log10 diagnostics) between any two positive samples in patients with CRMRD-LL, CRhMRD-LL or CRiMRD-LL by qPCR The result of 1. or 2. should be rapidly confirmed in a second consecutive sample from the same tissue source Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 ANC, absolute neutrophil count; CBF, core-binding factor; VAF, variant allele frequency. *To recognize the potential for continuing improvements in blood counts after myelosuppressive therapy, response definitions for patients with marrow blast clearance (, 5%) may be adjusted to reflect the best hematologic response achieved prior to commencement of the next treatment cycle. Aspirate reports that include MLFS, CRh, or CRi should note the potential for post-marrow blood counts to alter the final response designation. Patients should not have received G-CSF, nor platelet transfusions within 7 d prior to hematologic response determination. †For patients with CR, CRh, or CRi, the presence of a low percentage of circulating blasts in the blood may represent a regenerating marrow and should not be interpreted as persistent disease. In such cases the blasts generally disappear within a week. ‡A response landmark for CR, CRh, or CRi should be stated, eg, after 2 cycles of intensive therapy; this landmark may be longer for nonintensive based treatment options, eg, 180 days. §MFC-MRD positivity is defined as $ 0.1% of CD45 expressing cells with the target immunophenotype. MRD test positivity by qPCR is defined as cycling threshold (Ct) , 40 and is negative if Ct $ 40 in $ 2 of 3 replicates. In NPM1-mutated and CBF-AML, CR with molecular MRD detectable at low-level (CRMRD-LL) defined as , 2% is designated as negative for MRD, because when measured at the end of consolidation treatment, is associated with a very low relapse rate. chemotherapy. The FDA defines maintenance therapy for AML maintenance (ie, 45% of patients had received 1 consolidation as an extended but time-limited course of treatment, that is usu- cycle, 31% had 2 cycles, and 20% had no consolidation). ally less toxic, given after achievement of CR with the objective of reducing the risk of relapse. Thus, a trial designed to dem- Patients who received midostaurin during induction and consoli- onstrate the efficacy of maintenance therapy would need to dation may continue these agents in maintenance in line with include a specified induction and consolidation treatment fol- the reported phase 3 experience.106 lowed by randomization to a predefined duration of treatment.129 Patients not considered candidates for intensive therapy There are no generally accepted or validated criteria to consider The main objective of maintenance therapy is to deliver a mini- a patient ineligible for intensive chemotherapy. In the context of mally toxic therapy capable of reducing the risk of leukemic clinical trials, criteria have been used that consider a patient not relapse. In a randomized study in newly diagnosed older eligible for intensive chemotherapy (for instance as defined in patients in first remission after 2 cycles of intensive induction, Table 11) that may also offer guidance in routine practice. azacitidine maintenance therapy, administered subcutaneously Substantial progress has been made in the management of for up to 12 cycles, improved disease-free survival compared patients considered unfit for intensive chemotherapy (Table 11). with no maintenance.130 An orally administered version of azaci- Compared with azacitidine alone, addition of the BCL2 inhibitor tidine, CC-486, given over 14 days in 28-day cycles as continu- venetoclax improved clinical response (CR/CRi, 66.4% vs 28.3%) ous postremission therapy, was shown subsequently in a and median OS (14.7 vs 9.6 months), establishing a new stan- randomized placebo-controlled trial to reduce relapse risk and dard of care for older or unfit patients with AML.134 To limit pro- improve median OS (from 14.8 to 24.7 months) among patients longed myelosuppression and the risk of tumor lysis syndrome $ 55 years not considered candidates for allogeneic HCT.131 associated with this regimen, management recommendations Oral azacitidine prolonged OS independently of the MRD status are outlined in Table 12.135 Although not evaluated in random- as assessed by MFC (47% of patients were MRD positive and ized clinical trials, phase 1b/2 studies suggest that clinical out- 53% were MRD negative at study entry).132 Oral azacitidine is comes with decitabine plus venetoclax are similar to the approved for continued treatment of patients with AML in first azacitidine plus venetoclax combination.136 For patients failing CR/CRi following intensive induction chemotherapy who are not frontline venetoclax-based therapy, prognosis appears very able to complete intensive curative therapy, including allogeneic poor.137 For patients unable to receive a hypomethylating agent HCT. However, there are limitations to the trial design that pro- (HMA), low-dose cytarabine (LDC) in combination with veneto- hibit generalizability of the data.133 First, data regarding the role clax represents an alternative treatment option.138 Although an of oral azacitidine in younger populations or patients with CBF- open-label randomized study showed improved survival for the AML are lacking; furthermore, only few patients had AML with hedgehog inhibitor glasdegib in combination with LDC, com- adverse-risk cytogenetics (14%). Second, because the trial did pared with LDC alone, the relatively low response rate (CR/CRi not specify prior induction and consolidation therapy, there was 24%) with this regimen does not favor its use as an alternative considerable variability in therapy prior to selection for nonintensive option.139 1362 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Method Diagnosis After 2 cycles End of treatment Follow-up (24 mo) Analysis qPCR BM every 3 mo, or dPCR BM or PB PB BM PB every 4–6 weeks NGS NPM1 MRD relapse: MRD t2%, or qPCR Conversion MRDneg to log-red. 3–4 Clinical MRDpos or t1 log10 increase biomarker Analysis qPCR BM or PB PB BM PB every 4–6 weeks dPCR CBF-AML MRD relapse: MRD t2%, or qPCR Conversion MRDneg to Clinical log-red. 3–4 MRDpos or t1 log10 increase Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 biomarker Analysis Exploratory: MFCa BM BM BM BM every 3 mo All AML MFCa MRD positive MRD positive MRD positive (exploratory) Clinical biomarker Figure 2. Algorithm of MRD assessment and time points at which MRD is considered a clinically relevant biomarker. Blue squares indicate timepoints of assessment and source of material; pink squares indicate timepoints for treatment modification based on a clinical relevant biomarker: for example, if the level of molecular MRD as assessed by qPCR is $2% or if there is failure to reduce mutant transcript levels by 3 to 4 log after completion of consolidation chemotherapy, treatment modifications (eg, allogeneic hematopoietic cell transplantation) may be considered; similarly, if patients are still MRD positive by MFC after 2 cycles of intensive chemotherapy or at end of treatment. For patients receiving less intensive therapy, timepoints for assessment and clinical decision making are not yet established. Modified from 2021 ELN MRD recommendations67 BM, bone marrow; CBF, core-binding factor. aMFC as assessed by LAIP or the DfN method. For newly diagnosed patients with IDH1 mutation, results from a Table 10. At clinical progression, it is important to highlight the randomized study indicate that the IDH1 inhibitor ivosidenib potential for clonal evolution and emergence of actionable tar- plus azacitidine improves EFS (hazard ratio, 0.33; 95% CI, 0.16- gets not detected at diagnosis. Currently, these include emer- 0.69), clinical response (CR/CRh, 52.8 vs 17.6%), and median OS gence of IDH1/IDH2 mutations or new or expanded FLT3-ITD (24.0 vs 7.9 months) compared with azacitidine plus placebo.140 or FLT3 tyrosine kinase domain clones.142-146 Therefore, molecu- To identify patients suitable for ivosidenib at initial diagnosis, lar re-evaluation at relapse is important to identify patients who rapid IDH1 mutation screening in older patients with AML is rec- may be suitable for targeted salvage options. In the interest of ommended. Patients with IDH1/2-mutated AML who are consid- therapeutic progress, it is recommended to enter these patients ered too frail to tolerate HMA-based treatment may be offered into clinical trials whenever possible. Patients failing to achieve best supportive care or monotherapy with targeted IDH1/IDH2 remission after 2 cycles of induction (including at least 1 cycle of inhibitors.141 intermediate-dose cytarabine) are defined as having primary refractory AML. Patients are unlikely to benefit from further In patients receiving HMA-based combination therapy (with cycles of conventional chemotherapy and instead should be venetoclax, ivosidenib, other investigational agents), response referred for consideration of allogeneic HCT or participation in should be assessed early during the first cycle (eg, on day 14-21) clinical trials.147 due to high rates of early responses seen with HMA combina- tions and the need to delay or modify dosing in the setting of Factors associated with reduced survival at AML relapse include persistent cytopenias in a leukemia-free marrow (Table 12). shorter RFS (,6-12 months), nonfavorable risk karyotype at diag- A second assessment is commonly performed after 3 cycles nosis, older age (.45-55 years), or prior history of HCT.148,149 In and then repeated every 3 cycles for patients in remission or general, after cytoreduction has been achieved, allogeneic HCT at the discretion of the physician outside of a clinical trial. In is recommended. If HCT is not a realistic option (eg, in the older the absence of treatment intolerance, nonintensive treatment patient), disease control using a nonintensive option, such as approaches have commonly been continued until disease pro- HMA with or without venetoclax, may be appropriate. For gression, but for the time being, there are no data supporting patients with relapsed/refractory FLT3-mutated disease, the the advantage of an open-ended duration approach over kinase inhibitor gilteritinib has been approved based on a ran- therapy for a confined period. domized trial showing improved response rates (CR, 21.1% vs 10.5%) and median OS (9.3 vs 5.6 months) in the gilteritinib arm Relapsed and refractory disease Common salvage regimens compared with physician’s choice of salvage therapy.109,150 for patients with refractory or relapsed disease are given in Although more patients receiving gilteritinib were bridged to 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1363 Table 9. Outcome measures for clinical trials in acute myeloid leukemia Category Definition Early death Death from any cause within a timeframe relevant for the therapy being investigated (eg, 30 and 60 d from commencing therapy) Overall survival Defined for all patients in a trial; measured from day 1 of randomization or day 1 of registration in non- randomized trials (or from the date of diagnosis, eg, for correlative science studies) to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive Event-free survival (EFS) Defined for all patients in a trial; measured from day 1 of randomization or day 1 of registration in non- randomized trials to the date of treatment failure, hematologic relapse from CR/CRh/CRi or death from any cause, whichever occurs first; treatment failure is defined as not achieving either CR, CRh or CRi by a pre-defined landmark (eg, after two cycles of intensive chemotherapy or 180 d for non-intensive therapy); patients evaluable for response but not achieving either CR, CRh or CRi by the defined landmark and patients who die before the defined landmark without response assessments are considered an event at day 1 of randomization; patients alive who are non-evaluable for response Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 should be censored at day 1 of the randomization; patients achieving either CR, CRh or CRi by the defined landmark but do not relapse or die should be censored on the date they were last assessed for response Relapse-free survival (RFS)* Defined only for patients achieving CR, CRh, or CRi; measured from the date of achievement of remission until the date of hematologic relapse or death from any cause; patients not known to have relapsed or died at last follow-up are censored on the date they were last known to be alive Cumulative incidence of relapse Defined for all patients achieving CR, CRh, CRi; measured from the date of achievement of a remission (CIR) until the date of hematologic relapse; patients not known to have relapsed are censored on the date they were last assessed for response; patients who died without relapse are counted as a competing cause of failure Cumulative incidence of death Defined for all patients achieving CR, CRh, CRi; measured from the date of achievement of a remission to (CID) death without prior relapse; relapse is considered as competing risk If including assessment of MRD relapse EFSMRD† Measured from day 1 of randomization or day 1 of registration in non-randomized trials to the date of failure to achieve CR, CRh or CRi by a defined landmark (eg, after two cycles of intensive chemotherapy or 180 d for non-intensive therapy), hematologic relapse, MRD relapse (for patients achieving CR, CRh or CRi without MRD) or death from any cause RFSMRD† Measured from the date of achievement of a remission (CR, CRh, or CRi) until the date of hematologic relapse, MRD relapse, or death from any cause CIRMRD† Measured from the date of achievement of a remission (CR, CRh or CRi) until the date of hematologic relapse, or molecular MRD relapse; patients who died without relapse are counted as a competing cause of failure CIDMRD Measured from the date of achievement of a remission (CR, CRh, or CRi) to death without prior relapse; morphologic or molecular MRD relapse is considered as competing risk *Relapse-free and disease-free survival have been used with the same definition. †Molecular MRD relapse should only consider data for mutated NPM1, RUNX1::RUNX1T1 or CBFB::MYH11 fusion transcripts as assessed by real-time quantitative PCR. HCT (25.5% vs 15.3%) and these patients were permitted to these IDH inhibitors induce CR rates in the range of 20% and restart gilteritinib 30 to 90 days after HCT, the clinical benefit of overall response, including hematologic improvement in approx- post-HCT gilteritinib remains uncertain. In addition, only 5.7% of imately 40%.151-153 Median time required to attain CR is 3 to patients received prior midostaurin as first-line therapy in this 4 months, with 80% of cumulative responses attained after com- study, making generalization of treatment outcomes after this pletion of 6 cycles of therapy.151,152 Among responders, molec- and other FLT3 inhibitors difficult. In a randomized trial evaluat- ular clearance with ivosidenib was observed in 21% and was ing the FLT3 inhibitor quizartinib in patients with relapsed/refrac- associated with longer remission duration and prolonged tory FLT3-ITD–positive AML, quizartinib also showed improved survival.151 Although responders to enasidenib may also achieve OS compared with conventional care regimens.110 However, molecular clearance, targeting IDH2 in a nonblinded random- after evaluation of the trial data, neither FDA nor the European ized trial did not show improvement in OS compared with con- Medicines Agency granted approval. ventional care options among patients $60 years failing 2 or 3 prior lines of therapy.154 For management of adverse events For patients with relapsed/refractory IDH1/IDH2-mutant AML, associated with novel agents, see the section on supportive care salvage with ivosidenib or enasidenib is a possibility because below and Table 12. 1364 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Allogeneic hematopoietic cell Preparative regimen intensity Transplant preparative regimens run the gamut from nonmye- transplantation loablative, which would result in only mild, temporary depres- AML is the most frequent indication for allogeneic HCT.155,156 sion of blood counts without transplant, to RIC regimens of Advances allowing for the use of partially matched unrelated varying intensity, to high-dose true MAC. Prospective random- donors, cord blood, and haplo-identical family members mean ized trials yield inconsistent results, but in general, NRM is that an allogeneic donor can be found for most patients in increased, and relapse rates are diminished with higher-dose need. Nonmyeloablative and reduced intensity conditioning regimens. The best evidence supporting the use of MAC regi- (RIC) regimens make allogeneic HCT possible in patients up to mens in patients aged 18 to 65 years comes from the random- age 80 at experienced centers.157,158 With newly approved ized phase 3 BMT CTN 0901 study, which showed improved methods to prevent and treat both infections and graft-versus- survival with MAC compared with RIC because of a marked host disease (GVHD), outcomes following transplant continue to reduction in disease recurrence.172,173 In a retrospective analysis, improve, leaving disease recurrence as the major cause of treat- the benefit of MAC was greatest in patients with genomic evi- ment failure.159 Despite its central role in the management of dence of residual disease before transplant, as determined by adult AML, only a minority of patients for whom transplantation NGS at the time of transplant.98,100 Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 is indicated undergo the procedure.156 Reasons for underutiliza- tion include biologic factors, personal and physician choice, and Donor selection/GVHD prophylaxis lack of access.160 Registry analyses show approximate equivalence in outcomes for patients transplanted using a well-matched unrelated donor Indications for allogeneic HCT compared with those using a matched sibling donor.174,175 However, many patients lack a suitable sibling or volunteer unre- The decision to perform allogeneic HCT during first remission lated donor. The recent demonstration that posttransplant cyclo- depends on the risk-benefit ratio (ie, nonrelapse mortality [NRM] phosphamide GVHD prophylaxis is tolerable and results in and disability/reduction in relapse risk) based on cytogenetic encouraging outcomes using mismatched unrelated and haplo- and molecular genetic features of disease at presentation and identical donors substantially widens the donor pool.176-179 The response to initial therapy, as well as patient, donor, and trans- use of single or double cord blood units with a high nucleated plant factors. Allogeneic HCT should be considered when the cell dose also results in excellent outcomes, particularly in relapse probability without the procedure is predicted to be patients with evidence of pretransplant MRD.179,180 Current data .35% to 40%.127 For patients with favorable-risk disease, allo- support the utilization of a matched sibling donor or well- geneic HCT in CR1 is generally not recommended except for matched unrelated donor as the preferred donor option in those with inadequate clearance of MRD.69,161-163 In contrast, adults with AML.177 Recognition of germline predisposition in allogeneic HCT is recommended for patients with adverse-risk the patient with AML and family members influences donor AML and for the majority of those with intermediate-risk disease, selection, and the use of relatives with deleterious germline var- although quite a few centers rely on the presence of MRD to iants should be avoided (see Germline predisposition). Random- guide their decision based on the predicted risk of relapse. For ized trials comparing outcome after transplantation using a patients who are age 60 or older, mostly based on retrospective matched unrelated donor vs a haplo-identical donor are comparisons, allogeneic HCT in first remission is recommended underway. for those with intermediate-risk or adverse-risk disease willing and able to undergo remission-inducing therapy.164,165 Judi- cious patient selection is important in patients over 60 especially Pre- and posttransplant strategies to prevent regarding the presence of comorbidities and support at home. posttransplant relapse Allogeneic HCT is the only curative therapy for patients with pri- Disease relapse is the major cause of treatment failure in adults mary refractory disease and offers the best chance for cure in allografted for AML.181 For patients who are in CR1 following 2 those who relapse after initial chemotherapy.166 Other factors cycles of intensive therapy, there is no evidence that additional including comorbidities, donor source, and individual patient chemotherapy prior to transplantation reduces the risk of relapse goals must be considered. regardless of pretransplant MRD status. There is increasing inter- est in the use of pharmacological or cellular therapy posttrans- plant to prevent disease recurrence. In patients allografted for Comorbidities and risk scores FLT3-mutated AML, randomized studies show that maintenance Several transplant-related models address the impact of comor- with the FLT3 inhibitor sorafenib, although sometimes challeng- bidities and disease risk.167 The HCT comorbidity index (which ing to deliver, reduces the risk of relapse, suggesting that the has been modified to include age) sums a patient’s comorbid- use of a FLT3 inhibitor is a reasonable option.182,183 A random- ities into a single score that predicts the likelihood of NRM fol- ized trial examining the benefit of posttransplant maintenance lowing transplantation independent of the disease being with the second-generation FLT3 inhibitor gilteritinib in this treated.168,169 A disease-risk index based on disease-stage and patient population is in progress. There is less evidence support- cytogenetics predicts the likelihood of disease recurrence follow- ing the use of other agents as posttransplant maintenance in ing transplantation independent of patient comorbidities.170 The AML. A randomized study of maintenance using subcutaneous modified European Society of Blood and Marrow Transplanta- azacitidine showed no benefit and is not recommended based tion risk score combines both patient and disease risk factors on available evidence184; oral azacitidine (CC-486) is currently thus predicting OS rather than NRM or relapse risk.171 under study. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1365 Table 10. Selected treatment options for patients fit for intensive chemotherapy Fit for intensive chemotherapy Induction Consolidation* Maintenance 2 AML with FLT3 mutation Daunorubicin 60 mg/m IV d1-3; 3-4 cycles of IDAC 1000-1500 Midostaurin 50 mg q12h PO or idarubicin 12 mg/m2 IV mg/m2 IV (500-1000 mg/m2 if d1-28, q4 wk, over 12 cycles‡ d1-3; and cytarabine 100-200 $60 y old) over 3h q12h d1-3; mg/m2/d CIV d1-7; plus plus midostaurin 50 mg q12h midostaurin 50 mg q12h PO PO d8-21 (in all cycles)† d8-21 Re-induction: either 2nd cycle “7 1 3” or regimen containing higher dose of cytarabine, each plus midostaurin, preferable the latter in patients with no response to 1st cycle Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Non-FLT3 mutant§ Daunorubicin 60 mg/m2 IV d1-3, 3-4 cycles of IDAC 1000-1500 Oral azacitidine 300 mg PO daily idarubicin 12 mg/m2 IV d1-3, mg/m2 IV (500-1000 mg/m2 if d1-14, q4 wk, until disease or mitoxantrone 12 mg/m2 IV $60 y old) over 3h q12h d1-3 progressionk d1-3; and cytarabine 100-200 mg/m2/d CIV d1-7 Re-induction: either 2nd cycle “7 1 3” or regimen containing higher dose of cytarabine, preferable the latter in patients with no response Other options Gemtuzumab ozogamicin (GO) Daunorubicin 60 mg/m2 IV d1-3 2-4 cycles of IDAC 1000-1500 for CD33-positive AML, and cytarabine 100-200 mg/m2 IV (500-1000 mg/m2 if favorable (or intermediate) mg/m2/d CIV d1-7; plus GO $60 y old) over 3h q12h d1-3. cytogenetic risk 3 mg/m2 (maximum dose 5 GO 3 mg/m2 may be added mg) IV, d1, 4, 7. GO is also on d1 (in up to 2 cycles). widely administered on day Consider omitting GO if 1 of induction only. allogeneic HCT is planned to Re-induction (if not in CR/CRh/ reduce the risk of veno- CRi) may be with daunorubicin occlusive disease. 60 mg/m2 IV d1-2 and cytarabine 1000 mg/m2 IV (500-1000 mg/m2 if $60 y old) over 3h q12h d1-3 without GO CPX-351 for AML with CPX-351 100 U/m2 (daunorubicin 1-2 cycles of CPX-351 65 U/m2 myelodysplasia-related 44 mg/cytarabine 100 mg) IV (daunorubicin 29 mg/ changes or therapy-related d1, 3, 5 cytarabine 65 mg) IV d1, 3 AML¶ Re-induction (if not in CR/CRh/ CRi): CPX-351 100 U/m2 IV d1, 3 only CIV, continuous IV; IDAC; intermediate-dose cytarabine; PO, per os; QD, once daily; SC, subcutaneously. *Results from assessment of MRD should be taken into account for selecting the appropriate consolidation therapy. †In the trial that led to the regulatory approval of midostaurin for FLT3-mutated AML, consolidation cycles included high-dose cytarabine at 3000 mg/m2, whereas intermediate dose levels of cytarabine (1000-1500 mg/m2) are nowadays more commonly applied in AML therapeutics. ‡The value of maintenance treatment with midostaurin remains uncertain. §Alternative active frontline induction regimens that are sometimes used include FLAG-IDA (defined below under common salvage regimens). kData regarding the role of oral azacitidine maintenance therapy in younger patients (, 55 y) or patients with core-binding factor AML are lacking; in addition, data are lacking for oral azacitidine after GO-based or CPX-351 induction/consolidation therapy. ¶Data in younger adult patients (, 60 y) and for AML post myeloproliferative neoplasm are lacking. No benefit compared with “7 1 3” induction was shown in patients with anteced- ent MDS with prior hypomethylating agent exposure. #Regimens containing higher doses of cytarabine are generally considered as the best option for patients not responding to a first cycle of “7 1 3.” Single-agent IDAC should not be used in patients relapsing within 6 mo following consolidation with higher doses of cytarabine. **Idarubicin may be replaced by mitoxantrone 10 mg/m2 IV d2-4 (FLAG-MITO); or by amsacrine 100 mg/m2 IV d2-4 (FLAG-AMSA). ††Gilteritinib as a salvage option has only been validated in a randomized trial after prior intensive chemotherapy. ‡‡Based on single-arm data. a Although enasidenib did not show improved overall survival in a randomized study in comparison with conventional therapy in late-stage IDH2-mutant AML, clinically useful single- agent anti-leukemic activity has been demonstrated. 1366 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Table 10. (continued) Common salvage regimens in patients not responding to initial induction or with relapsed disease who are candidates for intensive therapy Gilteritinib (AML with FLT3 Gilteritinib 120 mg PO QD d1-28, q4 wk, until disease progression mutation) Intermediate-dose cytarabine# Cytarabine 1000-1500 mg/m2 IV over 3h q12h d1-3 (500-1000 mg/m2 in patients $ 60y); with or without (with or without daunorubicin 60 mg/m2 IV d1-3; idarubicin 8-10 mg/m2 IV d3-5; or mitoxantrone 8-10 mg/m2 IV d1-3 anthracycline) FLAG-IDA** Fludarabine 30 mg/m2 IV d2-6; cytarabine 1500-2000 mg/m2 IV over 3h, starting 4h after fludarabine infusion, d2-6; idarubicin 10 mg/m2 IV d2-4; G-CSF 5 mg/kg SC d1-5; additional G-CSF may be administered starting 7 d after end of chemotherapy until WBC count . 0.5 3 109/L Consider dose reduction in patients $60 y: fludarabine 20 mg/m2; cytarabine 500-1000 mg/m2; idarubicin 8 mg/m2 MEC Mitoxantrone 8 mg/m2 IV d1-5; etoposide 100 mg/m2 IV d1-5; cytarabine 1000 mg/m2 IV d1-5 CLAG-M Cladribine 5 mg/m2 IV d1–5; cytarabine 2000 mg/m2 IV d1–5 (starting 2h after cladribine infusion); Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 mitoxantrone 10 mg/m2 IV d1–3; G-CSF 300 mg SC d0–5 Allogeneic HCT Consider transplantation for patients with primary refractory disease, for patients in second CR (or CRh, CRi) or with major cytoreduction but still active disease following salvage therapy. Consider second transplantation under certain conditions. Perform early HLA typing. Salvage options if not a candidate for intensive chemotherapy Gilteritinib (AML with FLT3 120 mg PO QD d1-28, q4 wk, until disease progression mutation)†† Ivosidenib (AML with IDH1 500 mg PO QD d1-28, q4 wk, until disease progression mutation)‡‡ Enasidenib (AML with IDH2 100 mg PO QD d1-28, q4 wk, until disease progression mutation)a CIV, continuous IV; IDAC; intermediate-dose cytarabine; PO, per os; QD, once daily; SC, subcutaneously. *Results from assessment of MRD should be taken into account for selecting the appropriate consolidation therapy. †In the trial that led to the regulatory approval of midostaurin for FLT3-mutated AML, consolidation cycles included high-dose cytarabine at 3000 mg/m2, whereas intermediate dose levels of cytarabine (1000-1500 mg/m2) are nowadays more commonly applied in AML therapeutics. ‡The value of maintenance treatment with midostaurin remains uncertain. §Alternative active frontline induction regimens that are sometimes used include FLAG-IDA (defined below under common salvage regimens). kData regarding the role of oral azacitidine maintenance therapy in younger patients (, 55 y) or patients with core-binding factor AML are lacking; in addition, data are lacking for oral azacitidine after GO-based or CPX-351 induction/consolidation therapy. ¶Data in younger adult patients (, 60 y) and for AML post myeloproliferative neoplasm are lacking. No benefit compared with “7 1 3” induction was shown in patients with antecedent MDS with prior hypomethylating agent exposure. #Regimens containing higher doses of cytarabine are generally considered as the best option for patients not responding to a first cycle of “7 1 3.” Single-agent IDAC should not be used in patients relapsing within 6 mo following consolidation with higher doses of cytarabine. **Idarubicin may be replaced by mitoxantrone 10 mg/m2 IV d2-4 (FLAG-MITO); or by amsacrine 100 mg/m2 IV d2-4 (FLAG-AMSA). ††Gilteritinib as a salvage option has only been validated in a randomized trial after prior intensive chemotherapy. ‡‡Based on single-arm data. a Although enasidenib did not show improved overall survival in a randomized study in comparison with conventional therapy in late-stage IDH2-mutant AML, clinically useful single- agent anti-leukemic activity has been demonstrated. Relapse after transplant Clinical trials Ninety percent of those who relapse after an allogeneic HCT for It is recommended to enroll patients with AML onto clinical trials AML do so by 2 years. The outcome of patients with morpho- whenever a suitable trial opportunity is available. Real-time avail- logic relapse within the first 12 months is very poor, although a ability of rapid biomarker screening has become a basic require- rapid taper of immunosuppression or donor lymphocyte infusion ment to enable timely enrollment of patients to clinical trials may salvage a proportion of patients with early molecular or targeting defined AML subpopulations. Routine biobanking of cytogenetic relapse.185,186 For patients relapsing after an alloge- patient samples should be standard practice to maximize clinical neic HCT for FLT3-mutated AML, giltertinib is the preferred research. treatment option with evidence of an emergent FLT3 mutant clone. In the pivotal study, giltertinib improved survival in patients with early relapses and was at least equivalent com- Trial design pared with intensive chemotherapy in relapses occurring beyond The execution of clinical trials for drug development in AML has 6 months.109,150 Azacitidine, with or without donor lymphocyte become progressively challenging. There is an increasing num- infusion, and venetoclax-based salvage regimens may produce ber of novel AML therapeutics that warrant evaluation of safety remissions in a small proportion of patients with less toxicity and efficacy, in single agent and combination format, with many than intensive chemotherapy.187 Those who achieve a second requiring prospective allocation to biologically defined geno- CR can sometimes still be cured with either donor lymphocyte types. As AML is already a relatively rare disease, timely comple- infusion or a second allograft.188 tion of adequately powered phase 3 clinical trials within smaller 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1367 Table 11. Selected treatment options for patients not suitable for intensive chemotherapy* Regimen Recommended dosing Azacitidine or decitabine 1 Azacitidine 75 mg/m2 SC/IV d1-7 (alternatively d1-5 1 d8-9) or decitabine 20 mg/m2 IV d1-5; venetoclax venetoclax†,‡ dose ramp up: 100 mg d1, 200 mg d2, 400 mg PO QD d3-28  Adjust venetoclax dose if concurrent strong CYP3A4 inhibitors: 10 mg on d1, 20 mg on d2, 50 mg on d3, 100 mg (or less‡) PO QD from d4  For venetoclax dose modifications and management of myelosuppression see Table 12 Low-dose cytarabine 1 Cytarabine 20 mg/m2 SC daily, d1-10; venetoclax dose ramp up: 100 mg d1, 200 mg d2, 400 mg d3, venetoclax†,‡ 600 mg d4-28 PO  Adjust venetoclax dose if concurrent strong CYP3A4 inhibitors: 10 mg d1, 20 mg d2, 50 mg d3, 100 mg (or less‡) PO QD d4-28  For venetoclax dose modifications and management of myelosuppression see Table 12 Azacitidine 1 ivosidenib Azacitidine 75 mg/m2 SC/IV d1-7 (alternatively d1-5 1 d8-9); ivosidenib 500 mg PO QD d1-28; (AML with IDH1 mutation) both q4 wk, until progression Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Ivosidenib (AML with IDH1 For very frail patients, ivosidenib 500 mg PO QD d1-28 as monotherapy, until progression may be mutation) considered Best supportive care Including hydroxyurea; for patients who cannot tolerate any anti-leukemic therapy, or who do not wish any therapy *For instance, criteria that have been used in clinical trials to select patients not suitable for intensive chemotherapy have been as follows: (1) age $75 y (however, this cannot be an absolute criterion; for instance, patients with more favorable disease and without relevant comorbidities may derive benefit from intensive chemotherapy) or (2) ECOG performance status . 2 and/or age-related comorbidities, such as severe cardiac disorder (eg, congestive heart failure requiring treatment, ejection fraction # 50%, or chronic stable angina), severe pulmonary disorder (eg, DLCO # 65% or FEV1 # 65%), creatinine clearance , 45 mL/min, hepatic disorder with total bilirubin . 1.5 times the upper limit of normal, or any other comorbidity that the physician assesses to be incompatible with intensive chemotherapy. †To reduce the risk of tumor lysis syndrome, the prophylactic use of uric acid lowering drugs, close electrolyte monitoring and cytoreduction of the WBC to , 25 x 109/L or even lower, for patients with high bone marrow blast burden, elevated LDH is recommended. ‡In the VIALE-A and VIALE-C trials, an adjusted venetoclax dose of 50 mg was used in the presence of a strong CYP3A4 inhibitor. This venetoclax dose is supported by a pharmacokinetic study examining venetoclax in the presence of posaconazole.207 disease subsets has become more challenging, highlighting the crossover of patients from the control arm to novel agents has growing need for intercontinental trials. confounded the interpretation of OS increasingly in compara- tive studies (see “Outcome measures”). EFS as a primary study Early-phase clinical development end point will not only eliminate the confounding effect of Innovation in clinical trial design is needed. Phase 1 exploration poststudy therapies, but as an additional advantage, it will of new AML drugs in the relapsed/refractory setting remains a shorten study completion timelines. In this regard, the use of formidable task, with high levels of drug resistance, rapid dis- the restricted “traditional” CR as one of the key events in EFS ease progression, and complications related to severe cytope- has become subject of debate. Because of frequent myelosup- nias representing key hurdles to success. In such settings, a pression with novel drug combinations, and in addition, the pharmacodynamic primary end point verifying the drug’s pro- need to proceed with therapy before full hematologic recov- posed mechanism of action may represent an appropriate ery, from a therapeutic point, it has become increasingly unre- objective during the single agent dose-finding stage, followed alistic to consider failure to attain CRh/CRi as events in EFS by rapid transition to combination testing to demonstrate clinical estimates even though the level of survival after CRh/CRi may efficacy. In phase 2, multiarm biomarker-stratified studies permit- be below that following CR.101 Another way of expediting ear- ting parallel investigation of several drugs simultaneously will lier assessment of drug efficacy is to base outcomes on stan- facilitate more efficient screening of new drugs and combina- dardized MRD measurements.67 To facilitate incorporation of tions for clinical activity.189 MRD as an efficacy end point, CR (or CRh/CRi) with MRD response and EFS with molecular MRD relapse as an event rep- Phase 3 trials resent promising new study end points. This will allow for direct Randomized trials are the cornerstone of drug approval, espe- comparisons between the quantitative depth of response of cially in newly diagnosed patients. Accelerated recruitment to investigational and reference therapies as indicators of relative such trials is of central importance to improvements in outcome therapeutic value. for patients with AML and yet paradoxically this remains a noto- riously slow process. For example, the regulatory approval of Acceleration of drug development could also benefit from using midostaurin in 2017 for FLT3-mutant AML using OS as the pri- a validated control population, thus omitting the concurrent stan- mary study end point took almost a decade. The increasing dard control arm so that all patients recruited to the trial receive number of new therapies in AML coupled with genomic stratifi- investigational therapy. To realize such an approach, a well anno- cation is creating significant challenges to the timely recruitment tated and contemporary external reference cohort is required of patients to practice informing trials. As more effective sal- and efforts to establish real-world databases for this purpose are vage therapies are now available, the OS end point is compli- being explored. Finally, it remains of utmost importance to over- cated further by subsequent lines of AML-directed therapy; ride geographic and interstudy group barriers and continue 1368 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al Table 12. Novel agents: management of selected adverse events AE requiring special attention Agent (incidence all grades) Management Midostaurin QT prolongation (10%) Dose interruption/reduction, substitution of QT prolonging co-medication if possible, otherwise additional ECG controls Gilteritinib Transaminase elevation (81%) Dose interruption/reduction (if grade $ 3) QT prolongation (9%) Dose interruption/reduction, substitution of QT prolonging co-medication if possible PRES (1%) Discontinuation Ivosidenib Differentiation syndrome (25% single Dexamethasone, hydroxyurea for co-occurring leukocytosis, agent, 17% in combination with Dose interruption/reduction azacitidine) QT prolongation (21% single agent, Dose interruption/reduction, substitution of QT prolonging Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 26% combination with azacitidine) co-medication if possible Enasidenib Differentiation syndrome (14% single Dexamethasone, hydroxyurea for co-occurring leukocytosis, agent, 10% in combination with Dose interruption/reduction azacitidine) Bilirubin elevation (81%) Dose interruption/reduction Gemtuzumab Transaminase elevation (24.5%)* Dose interruption/reduction ozogamicin Bilirubin elevation (13%)* VOD/SOS (2.9-4.6%) Dose interruption, supportive care, fluid management, possibly defibrotide Venetoclax Neutropenia Early response assessment, eg, on day 14-21 of cycle 1, if bone Thrombocytopenia marrow blasts , 5%, cease venetoclax for up to 14 d to allow count recovery to $ CRh. If neutropenia does not recover with 7 d of ceasing venetoclax, addition of G-CSF may augment recovery. Subsequent cycles: azacitidine 75 mg/m2 SC/IV d1-7 (or d1-5 1 d8-9) or decitabine 20 mg/m2 IV d1-5 plus venetoclax 400 mg QD, or LDC 20 mg/m2 SC d1-10 plus venetoclax 600 mg QD q4 wk until progression. Delayed count recovery or recurrent treatment-emergent grade 4 neutropenia/thrombocytopenia lasting $ 7 d require reductions in the duration of administered venetoclax (from 28 to 21 or 14 d, or even less) and/or reductions in the dose of azacitidine, decitabine, or LDC if severe bone marrow hypoplasia. Tumor lysis syndrome Dose ramp up in cycle 1; hydration, the prophylactic use of uric acid lowering drugs, close electrolyte monitoring and reduction of WBC to , 25 3 109/L (, 25 000/mL) is recommended.  Moderate CYP3A inhibitors (eg, ciprofloxacin): reduce the Interaction with CYP3A inhibitors venetoclax dose by at least 50%; ramp-up phase: 50 mg on d1, 100 mg on d2, 200 mg PO QD from d3  Strong CYP3A inhibitors (eg, posaconazole): ramp-up phase: 10 mg on d1, 20 mg on d2, 50 mg on d3, 100 mg (or less‡)207 QD PO from d4. Glasdegib Muscle spams (15%) Dose interruption/reduction QT prolongation (8.3%) Dose interruption/reduction, substitution of QT prolonging co-medication if possible CPX-351 Prolonged myelosuppression† Consequent anti-infectious prophylaxis CC-486/oral azacitidine Neutropenia (44%) Dose interruption/reduction, myeloid growth factors Thrombocytopenia (33%) Nausea (65%), vomiting (60%), Prophylactic anti-emetics diarrhea (50%) AE, adverse event; LDC, low-dose cytarabine; PRES, posterior reversible encephalopathy syndrome; SmPC, Summary of Product Characteristics; SOS, sinusoidal obstructive syndrome, VOD, veno-occlusive disease. *Single agent. †Median times to absolute neutrophil count $ 0.5 3 109/L ($500/mL) were 35 and 29 days; and median times to platelet count $ 50 3 109/L ($50 000/mL) were 36.5 and 29 days after CPX-351 vs “7 1 3,” respectively, in patients who achieved CR/CRi after initial induction chemotherapy. ‡In the VIALE-A and VIALE-C trials, an adjusted venetoclax dose of 50 mg was used in the presence of a strong CYP3A4 inhibitor. This venetoclax dose is supported by a pharmacokinetic study examining venetoclax in the presence of posaconazole.207 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1369 efforts to stimulate the formation of “global” alliances and net- the WBC to be promptly lowered without delay by either works to expedite completion of registration-enabling clinical hydroxyurea or planned induction therapy and a restrictive trans- studies within a markedly condensed time window. fusion policy for red blood cells. Retrospective studies suggest a beneficial effect of dexamethasone, which may counteract effects of leukostasis.197 Although leukapheresis may be performed in New therapies parallel with chemotherapy in patients with leukostasis syn- Clinical investigation of new therapies and new combinations is drome,198 current evidence does not support the use of leuka- of critical importance in continuing to improve AML patient out- pheresis in asymptomatic patients with hyperleukocytosis.199,200 comes.190 Drug development strategies have focused until now primarily on single-agent dose finding studies in the relapsed Other special situations requiring therapeutic intervention are the setting, which have led to successful approvals of targeted ther- presence of disseminated intravascular coagulation (DIC), tumor apies, such as FLT3, IDH1, and IDH2 inhibitors, and is the pat- lysis syndrome, and differentiation syndrome. DIC can be tern for the current evaluation of menin inhibitors for patients screened for using a scoring system and is present in 8.5% to with KMT2A rearrangements or NPM1 mutations.109,151,152,191 25% of patients with non–APL, with another 15% also developing DIC soon after the initiation of chemotherapy.201 Other agents (ie, epigenetically targeted therapies) and immu- Special attention to tumor lysis syndrome is required in patients Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 notherapy approaches including bi-specific T-cell engaging anti- with hyperleukocytosis or with venetoclax-based treatments bodies, checkpoint inhibitors, and chimeric antigen receptor (Table 12). Close monitoring for signs of differentiation syndrome T cells or natural killer cells are likely to be most effective in the such as unexplained fever, lung edema, weight gain, pulmonary setting of MRD, in frontline, or early salvage combination infiltrates, hypoxia, and dyspnea is necessary, particularly in approaches.190,192,193 Although of limited single agent activity, patients on treatment with IDH inhibitors.202 the CD47 inhibitor magrolimab has demonstrated preliminary activity in combination with azacitidine in patients with newly diagnosed MDS and AML, even in the setting of TP53-mutated Supportive care disease. Trials of various inhibitors of the CD47-SIRP-a macro- Anti-infectious prophylaxis phage checkpoint are currently under various stages of early For prophylaxis and treatment of infections, prevailing institu- clinical evaluation.194 tional infectious organisms and their drug resistance pattern should be considered primarily. There is good evidence to rec- Due to the changing therapeutic environment, which now ommend antifungal prophylaxis with posaconazole during remis- includes HMAs in combination with small molecule inhibitors like sion induction therapy,203 whereas there is not enough evidence venetoclax or targeted therapies, future development of frontline from randomized trials on antiviral prophylaxis for herpes sim- combinations is now more complex. The evaluation of so-called plex virus in patients with acute leukemia,204 and no evidence “triplet” therapies is an increasingly common clinical trial design for a beneficial effect of Pneumocystis jirovecii pneumonia pro- for “chemotherapy-ineligible” patients, which involves the evalu- phylaxis. For prophylaxis of infectious disease in the setting of ation of a third agent (either approved or investigational) to the allogeneic HCT, we refer to respective guidelines.205 HMA and venetoclax “backbone.” New combination trials in intensive chemotherapy eligible patients typically involve the Vaccination for influenza206 and COVID-19 viral infections is incorporation of a new target or agent in combination with recommended for all patients to reduce the risk of severe infections. standard chemotherapy, such as the ongoing clinical trials of the FLT3 inhibitor gilteritinib with standard “7 1 3” vs “7 1 3” The use of growth factors is not routinely recommended unless and midostaurin or the spleen tyrosine kinase (SYK) inhibitor in individual patients (eg, in case of severe infections) or particu- with “7 1 3” vs “7 1 3” alone for NPM1-mutant AML. lar treatment settings (eg, to reduce the hematologic recovery times in consolidation cycles).1,122,123 In addition, oral formulations of the HMAs are now approved for AML maintenance (oral azacitidine)131 and high-risk MDS (oral Transfusions decitabine/cedazuridine),195 respectively, and given the The availability of several effective novel agents may lead to a increased patient convenience of oral formulations, it is likely higher proportion of patients treated on an outpatient basis. If that these agents will be increasingly used in future HMA-based blood count checks are not possible at regular intervals in the combination trials. outpatient setting, platelet and hemoglobin transfusion triggers should be elevated to ensure adequate support until the next outpatient visit. Besides the platelet count, mucosal bleeding, Management of special situations infection, severe mucositis, and fever should be considered in and supportive care the assessment of bleeding risk and should increase the platelet level transfusion threshold. Otherwise, it is generally accepted to A white blood cell count (WBC) . 100 3 109/L is generally keep the hemoglobin level above 8 g/dL, and a platelet count of defined as hyperleukocytosis and associated with increased ,10 3 109/L remains the trigger for prophylactic platelet induction mortality mainly due to hemorrhagic events, tumor lysis transfusions. syndrome, and the risk for clinical leukostasis syndrome.196 Hydroxyurea (up to 50-60 mg/kg per day) is most commonly used to lower the WBC below 25 3 109/L, particularly before Acknowledgments the commencement of HMA- or venetoclax-based treatments. The authors gratefully acknowledge R€ udiger Hehlmann for his contin- Clinical leukostasis syndrome is a medical emergency requiring uous generous support of these recommendations on behalf of the 1370 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al European LeukemiaNet and Partrycja Gradowska, Axel Benner, Maral Novartis, and Servier and has received clinical research support to his Saadati, and Julia Krzykalla for reviewing the sections “Response institution from Astellas, Celgene, Cellectis, Daiichi Sankyo, Forty Seven/ criteria” and “Outcome measures.” Gilead, Novartis, Rafael Pharmaceuticals and royalties from UpToDate. R.L.L. was on the supervisory board of Qiagen and an scientific advisor H. D€ohner is supported by SFB 1074 “Experimental models and clini- to Imago, Mission Bio, Zentalis, Ajax, Auron, Prelude, C4 Therapeutics, cal translation in leukemia” funded by the Deutsche Forschungsge- and Isoplexis, for which he receives equity; received research support meinschaft. A.H.W. is supported by the Australian National Health from Calico, Constellation, Zentalis, and Ajax; consulted for Incyte, Jans- and Medical Research Council, Victorian Cancer Agency, Metcalf sen, Morphosys, and Novartis; and received honoraria from Roche, Lilly, Family Fellowship, and the Medical Research Future Fund. C.D.D. is and Amgen for invited lectures and from Gilead for grant reviews. Y.M. supported by the LLS Scholar in Clinical Research award. received honoraria from Nippon-Shinyaku, Bristol-Myers Squib, Novartis, Sumitomo Pharma, Kyowa-Kirin, AbbVie, Daiichi-Sankyo, Takeda, Jans- Clara Bloomfield, Elihu Estey and Francesco Lo-Coco have died since sen Pharmaceutical, Astellas, Pfizer, Eizai, and Otsuka Pharmaceutical the publication of the 2017 ELN AML Recommendation edition. The and research funding from Sumitomo-Dainippon. G.O. had an advisory authors acknowledge the impressive seminal contributions that Clara role with honoraria for AbbVie, Astellas, Bristol Myers Squibb, Celgene, Bloomfield, Elihu Estey, and Francesco Lo-Coco made throughout Gilead, Servier, JAZZ, and Novartis. C.R. had an advisory role with hono- many years to improve the treatment of AML and advance our under- raria for AbbVie, Amgen, Astellas, BMS, Celgene, Jazz, Novartis, Pfizer, standing of the pathobiology of the disease. They were founding and Servier and received clinical research funding from AbbVie, Novartis, coauthors of the ELN AML Recommendation editions that first and Pfizer. J.S. had an advisory role with honoraria for AbbVie, Astellas, appeared in 2010 and (pro)actively participated with a high level of AstraZeneca, Berlin-Chemie, Celgene, AvenCell-GEMoaB, Janssen, Jazz Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 commitment in this endeavor. Each one in their own unique way con- Pharmaceuticals, Novartis, and Bristol Myers Squibb and received clinical tributed their invaluable clinical expertise, knowledge, and scientific research funding from AbbVie, Astellas, Jazz Pharmaceuticals, and Jose rigor and were instrumental in establishing these recommendations Carreras International Leukemia Foundation. E.M.S. was on the advisory as a widely accepted standard of reference. board for Novartis, PinotBio, Janssen, Bristol Myers Squibb, Agios, Jazz, Menarini, Genentech, Genesis, AbbVie, Neoleukin, Gilead, Syndax, OnCusp, CTI Biopharma, Foghorn, Servier, Calithera, Daiichi, Aptose, Syros, Astellas, Ono Pharma, and Blueprint; received honoraria from Authorship Kura; performed safety monitoring for Epizyme and Cellectis; and Contribution: All authors reviewed the literature and wrote first drafts of received research funding for Eisai and Bristol Myers Squibb and equity specific sections. H. D€ohner and B.L. assembled the sections and wrote from Auron. M.S.T. was on the advisory boards for AbbVie, Daiichi- the final version of the manuscript. All authors reviewed and approved Sankyo, Orsenix, KAHR, Oncolyze, Jazz Pharma, Roche, Biosight, Novar- the final version of the manuscript. tis, Innate Pharmaceuticals, Kura, Syros Pharmaceuticals, Ipsen Biophar- maceuticals, and Cellularity and received research funding from AbbVie, Conflict-of-interest disclosure: H. D€ohner had an advisory role with hono- Orsenix, Biosight, Gylcomimetics, Rafael Pharmaceuticals, and Amgen raria for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, and royalties from UpToDate. H.-F.T. had an advisory role with honoraria BMS, Celgene, GEMoaB, Gilead, Janssen, Jazz, Novartis, Servier, and for AbbVie, Alexion, Celgene, Daiichi Sankyo, Novartis, and Roche and Syndax and received clinical research funding (to institution) from Abb- received research funding from Celgene. J.W. had an advisory role with Vie, Agios, Amgen, Astellas, Bristol Myers Squibb, Celgene, Jazz Phar- honoraria for AbbVie. A.W. had an advisory role with honoraria for Abb- maceuticals, Kronos Bio, and Novartis. A.H.W. had an advisory role with Vie, Astellas, BMS, Celgene, Gilead, Janssen, Jazz Pharmaceuticals, honoraria for AbbVie, Agios, Amgen, Astellas, AstraZeneca, Roche, BMS, Novartis, and Servier and received clinical research funding from Jazz Celgene, Gilead, Pfizer, Janssen, Jazz, Novartis, and Servier; received Pharmaceuticals. B.L. had an advisory role with honoraria for AbbVie, clinical research funding (to institution) from AbbVie, Servier, Celgene- Astellas, Bristol Myers Squibb/Celgene, Catamaran Bio, AvenCell/GEM- BMS, Astra Zeneca, Amgen, and Novartis; and receives a fraction of roy- oaB, Frame Pharmaceuticals, Gilead, Kronos Bio, Oxford Biomedica, and alty payments from the Walter and Eliza Hall Institute of Medical Servier/Agios and received royalties from UpToDate and equity from Research related to venetoclax. F.R.A. has consulted for Jasper Biote. Frame Pharmaceuticals. All remaining authors declare no competing C.C. had an advisory role with honoraria for AbbVie, Amgen, Astellas, financial interests. AstraZeneca, Berlin-Chemie, BMS, Celgene, Daiichi-Sankyo, Eurocept, Gilead, Janssen, Jazz, and Novartis and received clinical research funding ORCID profiles: H. D€ ohner, 0000-0003-2116-5536; A.H.W., 0000- from AbbVie, Bristol Myers Squibb, Celgene, and Jazz Pharmaceuticals. 0002-7514-3298; C.D.D., 0000-0001-9003-0390; B.L.E., 0000-0003- C.D.D. received honoraria/consulting fees from AbbVie, Agios/Servier, 0197-5451; R.P.H., 0000-0002-7753-0697; R.A.L., 0000-0001-9168- Astellas, Celgene/BMS, Cleave, Foghorn, Genentech, GenMab, GSK, 3203; J.S., 0000-0002-7966-0356; J.W., 0000-0001-9437-9151; A.W., Novartis, Notable Labs, Takeda and research grants (to institution) from 0000-0001-7909-457X; B.L., 0000-0001-8982-5217. AbbVie, Agios/Servier, Astex, Calithera, Celgene/BMS, Cleave, Foghorn, ImmuneOnc, and Loxo. H. Dombret received honoraria/consulting fees from AbbVie, Amgen, Astellas, Celgene-BMS, Daiichi Sankyo, Incyte, Correspondence: Hartmut D€ ohner, Department of Internal Medicine III, Jazz Pharmaceuticals, Pfizer, and Servier and research funding from Ulm University Hospital, Albert-Einstein-Allee 23, 89081 Ulm, Germany; Amgen, Astellas, Celgene-BMS, Incyte, Jazz Pharmaceuticals, and Pfizer. e-mail: hartmut doehner@uniklinik-ulm.de. B.L.E. received consulting fees from GRAIL and research funding from Celgene, Deerfield, Novartis, and Calico and is a member of the scien- tific advisory board and shareholder for Neomorph Therapeutics, TenSix- teen Bio, Skyhawk Therapeutics, and Exo Therapeutics. P.F. received Footnotes honoraria and, as French MDS group chairperson, research support from Submitted 29 April 2022; accepted 29 June 2022; prepublished online Celgene/BMS, Novartis, AbbVie, Jazz, Janssen, and Agios. R.A.L. has on Blood First Edition 7 July 2022. DOI 10.1182/blood.2022016867. been a consultant or advisor to Amgen, Ariad/Takeda, Astellas, Cel- gene/BMS, CVS/Caremark, Epizyme, Immunogen, MedPace, MorphoSys, There is a Blood Commentary on this article in this issue. REFERENCES of Myeloid Neoplasms and Acute expert panel, on behalf of the European 1. D€ohner H, Estey E, Grimwade D, et al. Leukemias: integrating morphologic, LeukemiaNet. Blood. 2010; Diagnosis and management of acute clinical, and genomic data. Blood. 115(3):453-474. myeloid leukemia in adults: 2017 ELN 2022;140(11):1200-1228. 4. Sanz MA, Fenaux P, Tallman MS, et al. recommendations from an international 3. D€ohner H, Estey EH, Amadori S, et al. Management of acute promyelocytic expert panel. Blood. 2017;129(4):424-447. Diagnosis and management of acute leukemia: updated recommendations from an 2. Arber DA, Orazi, A, Hasserjian RP, et al. myeloid leukemia in adults: expert panel of the European LeukemiaNet. The International Consensus Classification recommendations from an international Blood. 2019;133(15):1630-1643. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1371 5. Ley TJ, Miller C, Ding L, et al; Cancer 17. Patel SS, Ho C, Ptashkin RN, et al. abnormalities. Haematologica. 2018;103(4): Genome Atlas Research Network. Genomic Clinicopathologic and genetic 626-633. and epigenomic landscapes of adult de characterization of nonacute NPM1- novo acute myeloid leukemia. N Engl mutated myeloid neoplasms. Blood Adv. 29. Montalban-Bravo G, Kanagal-Shamanna R, J Med. 2013;368(22):2059-2074. 2019;3(9):1540-1545. Class CA, et al. Outcomes of acute myeloid leukemia with myelodysplasia related 6. Papaemmanuil E, Gerstung M, Bullinger L, 18. Forghieri F, Nasillo V, Paolini A, et al. changes depend on diagnostic criteria and et al. Genomic classification and prognosis NPM1-mutated myeloid neoplasms with therapy. Am J Hematol. 2020;95(6): in acute myeloid leukemia. N Engl J Med. ,20% blasts: a really distinct clinico- 612-622. 2016;374(23):2209-2221. pathologic entity? Int J Mol Sci. 2020; 30. Duhoux FP, Ameye G, Montano-Almendras 21(23):8975. 7. Jaiswal S, Ebert BL. Clonal hematopoiesis CP, et al; Belgian Cytogenetic Group for in human aging and disease. Science. 19. Foucar K, Anastasi J. Acute myeloid Haematology and Oncology (BCG-HO). 2019;366(6465):eaan4673. leukemia with recurrent cytogenetic PRDM16 (1p36) translocations define a abnormalities. Am J Clin Pathol. 2015; distinct entity of myeloid malignancies with 8. Arber DA, Hasserjian RP, Orazi A, et al. poor prognosis but may also occur in 144(1):6-18. Classification of myeloid neoplasms/acute lymphoid malignancies. Br J Haematol. leukemia: Global perspectives and the 20. Estey E, Thall P, Beran M, Kantarjian H, 2012;156(1):76-88. international consensus classification Pierce S, Keating M. Effect of diagnosis 31. Ottema S, Mulet-Lazaro R, Beverloo HB, approach. Am J Hematol. 2022;97(5): (refractory anemia with excess blasts, et al. Atypical 3q26/MECOM Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 514-518. refractory anemia with excess blasts in rearrangements genocopy inv(3)/t(3;3) in transformation, or acute myeloid leukemia 9. Arber DA, Orazi A, Hasserjian R, et al. The acute myeloid leukemia. Blood. 2020; [AML]) on outcome of AML-type chemo- 2016 revision to the World Health 136(2):224-234. therapy. Blood. 1997;90(8):2969-2977. Organization classification of myeloid 32. Tarlock K, Lamble AJ, Wang YC, et al. neoplasms and acute leukemia. Blood. 21. DiNardo CD, Garcia-Manero G, Pierce S, CEBPA-bZip mutations are associated with 2016;127(20):2391-2405. et al. Interactions and relevance of blast favorable prognosis in de novo AML: a percentage and treatment strategy among report from the Children’s Oncology Group 10. Cui W, Sun J, Cotta CV, Medeiros LJ, Lin P. younger and older patients with acute [published correction appears in Blood. Myelodysplastic syndrome with myeloid leukemia (AML) and 2022;139(10):1601]. Blood. 2021;138(13): inv(3)(q21q26.2) or t(3;3)(q21;q26.2) has a myelodysplastic syndrome (MDS). Am 1137-1147. high risk for progression to acute myeloid J Hematol. 2016;91(2):227-232. leukemia. Am J Clin Pathol. 2011;136(2): 33. Sierra J, Nomdedeu JF. CEBPA bZip 282-288. 22. Toth LN, Green D, Peterson J, Deharvengt mutations: just a single shot. Blood. 2021; SJ, de Abreu FB, Loo EY. Variant allele 138(13):1091-1092. 11. Haferlach C, Bacher U, Haferlach T, et al. frequencies do not correlate well with The inv(3)(q21q26)/t(3;3)(q21;q26) is myeloblast counts in a clinically validated 34. Taube F, Georgi JA, Kramer M, et al; Study frequently accompanied by alterations of gene sequencing panel for routine acute Alliance Leukemia (SAL). CEBPA mutations the RUNX1, KRAS and NRAS and NF1 myeloid leukemia workup. Leuk in 4708 patients with acute myeloid genes and mediates adverse prognosis Lymphoma. 2019;60(10):2415-2422. leukemia: differential impact of bZIP and both in MDS and in AML: a study in 39 TAD mutations on outcome. Blood. 2022; cases of MDS or AML. Leukemia. 2011; 23. Chen X, Othus M, Wood BL, et al. 139(1):87-103. 25(5):874-877. Comparison of myeloid blast counts and variant allele frequencies of gene mutations 35. Wakita S, Sakaguchi M, Oh I, et al. 12. Ok CY, Hasserjian RP, Fox PS, et al. in myelodysplastic syndrome with excess Prognostic impact of CEBPA bZIP domain Application of the international prognostic blasts and secondary acute myeloid mutation in acute myeloid leukemia. Blood scoring system-revised in therapy-related leukemia. Leuk Lymphoma. 2021;62(5): Adv. 2022;6(1):238-247. myelodysplastic syndromes and oligoblastic 1226-1233. acute myeloid leukemia. Leukemia. 2014; 36. R€ ucker FG, Schlenk RF, Bullinger L, et al. 28(1):185-189. 24. Estey E, Hasserjian RP, D€ ohner H. TP53 alterations in acute myeloid leukemia Distinguishing AML from MDS: a fixed blast with complex karyotype correlate with 13. Rogers HJ, Vardiman JW, Anastasi J, et al. percentage may no longer be optimal. specific copy number alterations, Complex or monosomal karyotype and not Blood. 2022;139(3):323-332. monosomal karyotype, and dismal blast percentage is associated with poor outcome. Blood. 2012;119(9):2114-2121. survival in acute myeloid leukemia and 25. DiNardo CD, Garcia-Manero G, Kantarjian myelodysplastic syndrome patients with HM. Time to blur the blast boundaries. 37. Middeke JM, Herold S, R€ ucker-Braun E, inv(3)(q21q26.2)/t(3;3)(q21;q26.2): a Bone Cancer. 2022;128(8):1568-1570. et al; Study Alliance Leukaemia (SAL). TP53 Marrow Pathology Group study. mutation in patients with high-risk acute 26. Lindsley RC, Mar BG, Mazzola E, et al. myeloid leukaemia treated with allogeneic Haematologica. 2014;99(5):821-829. Acute myeloid leukemia ontogeny is haematopoietic stem cell transplantation. 14. Kayser S, Hills RK, Langova R, et al. defined by distinct somatic mutations. Br J Haematol. 2016;172(6):914-922. Characteristics and outcome of patients Blood. 2015;125(9):1367-1376. 38. Montalban-Bravo G, Benton CB, Wang SA, with acute myeloid leukaemia and 27. Miesner M, Haferlach C, Bacher U, et al. et al. More than 1 TP53 abnormality is a t(8;16)(p11;p13): results from an Multilineage dysplasia (MLD) in acute dominant characteristic of pure erythroid International Collaborative Study. myeloid leukemia (AML) correlates with leukemia. Blood. 2017;129(18):2584-2587. Br J Haematol. 2021;192(5):832-842. MDS-related cytogenetic abnormalities and 39. Short NJ, Montalban-Bravo G, Hwang H, 15. Fang H, Yabe M, Zhang X, et al. a prior history of MDS or MDS/MPN but et al. Prognostic and therapeutic impacts of Myelodysplastic syndrome with has no independent prognostic relevance: mutant TP53 variant allelic frequency in t(6;9)(p22;q34.1)/DEK-NUP214 better a comparison of 408 cases classified as newly diagnosed acute myeloid leukemia. classified as acute myeloid leukemia? “AML not otherwise specified” (AML-NOS) Blood Adv. 2020;4(22):5681-5689. A multicenter study of 107 cases. Mod or “AML with myelodysplasia-related Pathol. 2021;34(6):1143-1152. changes” (AML-MRC). Blood. 2010;116(15): 40. Grob T, Al Hinai ASA, Sanders MA, et al. 2742-2751. Molecular characterization of mutant TP53 16. Montalban-Bravo G, Kanagal-Shamanna R, acute myeloid leukemia and high-risk Sasaki K, et al. NPM1 mutations define a 28. Weinberg OK, Gibson CJ, Blonquist TM, myelodysplastic syndrome. Blood. 2022; specific subgroup of MDS and MDS/MPN et al. Association of mutations with 139(15):2347-2354. patients with favorable outcomes with morphological dysplasia in de novo acute intensive chemotherapy. Blood Adv. 2019; myeloid leukemia without 2016 WHO 41. Weinberg OK, Siddon A, Madanat YF, 3(6):922-933. Classification-defined cytogenetic et al. TP53 mutation defines a unique 1372 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al subgroup within complex karyotype 55. Coombs CC, Zehir A, Devlin SM, et al. Working Group. Assessment of minimal de novo and therapy-related MDS/AML. Therapy-related clonal hematopoiesis in residual disease in standard-risk AML. Blood Adv. 2022;6(9):2847-2853. patients with non-hematologic cancers is N Engl J Med. 2016;374(5):422-433. common and associated with adverse 42. Gardin C, Pautas C, Fournier E, et al. clinical outcomes. Cell Stem Cell. 2017; 69. Balsat M, Renneville A, Thomas X, et al. Added prognostic value of secondary 21(3):374-382.e4. Postinduction minimal residual disease AML-like gene mutations in ELN predicts outcome and benefit from intermediate-risk older AML: ALFA-1200 56. Swisher EM, Harrell MI, Norquist BM, et al. allogeneic stem cell transplantation in study results. Blood Adv. 2020;4(9): Somatic mosaic mutations in PPM1D and acute myeloid leukemia with NPM1 1942-1949. TP53 in the blood of women with ovarian mutation: a study by the Acute Leukemia carcinoma. JAMA Oncol. 2016;2(3): French Association Group. J Clin Oncol. 43. Richardson DR, Swoboda DM, Moore DT, 370-372. 2017;35(2):185-193. et al. Genomic characteristics and prognostic significance of co-mutated 57. Pharoah PDP, Song H, Dicks E, et al; 70. Kapp-Schwoerer S, Weber D, Corbacioglu ASXL1/SRSF2 acute myeloid leukemia. Ovarian Cancer Association Consortium. A, et al. Impact of gemtuzumab Am J Hematol. 2021;96(4):462-470. PPM1D mosaic truncating variants in ozogamicin on MRD and relapse risk in ovarian cancer cases may be treatment- patients with NPM1-mutated AML: results 44. van der Werf I, Wojtuszkiewicz A, related somatic mutations. J Natl Cancer from the AMLSG 09-09 trial. Blood. 2020; Meggendorfer M, et al. Splicing factor Inst. 2016;108(3):djv347. 136(26):3041-3050. gene mutations in acute myeloid leukemia offer additive value if incorporated in 58. Churpek J, Marquez R, Neistadt B, et al. 71. D€ohner K, Thiede C, Jahn N, et al. Impact Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 current risk classification. Blood Adv. 2021; Inherited mutations in cancer susceptibility of NPM1/FLT3-ITD genotypes defined by 5(17):3254-3265. genes are common among breast cancer the 2017 European LeukemiaNet in survivors who develop therapy-related patients with acute myeloid leukemia. 45. Awada H, Durmaz A, Gurnari C, et al. leukemia. Cancer. 2016;122(2):304-311. Blood. 2020;135(5):371-380. Machine learning integrates genomic signatures for subclassification beyond 59. Schulz E, Valentin A, Ulz P, et al. Germline 72. Angenendt L, R€ ollig C, Montesinos P, et al. primary and secondary acute myeloid mutations in the DNA damage response Chromosomal abnormalities and prognosis leukemia [published correction appears in genes BRCA1, BRCA2, BARD1 and TP53 in in NPM1-mutated acute myeloid leukemia: Blood. 2022;139(9):1424-1425]. Blood. patients with therapy related myeloid a pooled analysis of individual patient data 2021;138(19):1885-1895. neoplasms. J Med Genet. 2012;49(7): from nine international cohorts. J Clin 422-428. Oncol. 2019;37(29):2632-2642. 46. Fang H, He R, Chiu A, et al. Genetic factors in acute myeloid leukemia with 60. Qin N, Wang Z, Liu Q, et al. Pathogenic 73. Lugthart S, Gr€ oschel S, Beverloo HB, et al. myelodysplasia-related changes. Am J Clin germline mutations in DNA repair genes in Clinical, molecular, and prognostic Pathol. 2020;153(5):656-663. combination with cancer treatment significance of WHO type inv(3)(q21q26.2)/ exposures and risk of subsequent t(3;3)(q21;q26.2) and various other 3q 47. Morton LM, Dores GM, Schonfeld SJ, et al. neoplasms among long-term survivors of abnormalities in acute myeloid leukemia. Association of chemotherapy for solid childhood cancers. J Clin Oncol. 2020; J Clin Oncol. 2010;28(24):3890-3898. tumors with development of therapy- 38(24):2728-2740. related myelodysplastic syndrome or acute 74. Chilton L, Hills RK, Harrison CJ, Burnett AK, myeloid leukemia in the modern era. JAMA 61. Weinberg OK, Kuo F, Calvo KR. Germline Grimwade D, Moorman AV. Hyperdiploidy Oncol. 2019;5(3):318-325. predisposition to hematolymphoid with 49-65 chromosomes represents a het- neoplasia. Am J Clin Pathol. 2019;152(3): erogeneous cytogenetic subgroup of acute 48. Voso MT, Falconi G, Fabiani E. What’s new 258-276. myeloid leukemia with differential out- in the pathogenesis and treatment of come. Leukemia. 2014;28(2):321-328. therapy-related myeloid neoplasms. Blood. 62. Trottier AM, Godley LA. Inherited 2021;138(9):749-757. predisposition to haematopoietic 75. Walter RB, Ofran Y, Wierzbowska A, et al. malignancies: overcoming barriers and Measurable residual disease as a biomarker 49. McNerney ME, Godley LA, Le Beau MM. exploring opportunities. Br J Haematol. in acute myeloid leukemia: theoretical and Therapy-related myeloid neoplasms: when 2021;194(4):663-676. practical considerations. Leukemia. 2021; genetics and environment collide. Nat Rev 35(6):1529-1538. Cancer. 2017;17(9):513-527. 63. Roloff GW, Drazer MW, Godley LA. Inherited susceptibility to hematopoietic 76. Dillon R, Potter N, Freeman S, Russell N. 50. Schwartz JR, Ma J, Kamens J, et al. The malignancies in the era of precision How we use molecular minimal residual acquisition of molecular drivers in pediatric oncology. JCO Precis Oncol. 2021;5(5): disease (MRD) testing in acute myeloid therapy-related myeloid neoplasms. Nat 107-122. leukaemia (AML). Br J Haematol. 2021; Commun. 2021;12(1):985. 193(2):231-244. 64. Rafei H, DiNardo CD. Hereditary myeloid 51. Ok CY, Patel KP, Garcia-Manero G, et al. malignancies. Best Pract Res Clin 77. Vonk CM, Al Hinai ASA, Hanekamp D, Valk Mutational profiling of therapy-related Haematol. 2019;32(2):163-176. PJM. Molecular minimal residual disease myelodysplastic syndromes and acute detection in acute myeloid leukemia. myeloid leukemia by next generation 65. Yang F, Long N, Anekpuritanang T, et al. Cancers (Basel). 2021;13(21):5431. sequencing, a comparison with de novo Identification and prioritization of myeloid diseases. Leuk Res. 2015;39(3):348-354. malignancy germline variants in a large 78. Wood B, Jevremovic D, B en e MC, Yan M, cohort of adult patients with AML. Blood. Jacobs P, Litwin V; ICSH/ICCS Working 52. Wong TN, Ramsingh G, Young AL, et al. 2022;139(8):1208-1221. Group. Validation of cell-based fluores- Role of TP53 mutations in the origin and cence assays: practice guidelines from the evolution of therapy-related acute myeloid 66. Gibson CJ, Kim HT, Zhao L, et al. Donor ICSH and ICCS - part V - assay perfor- leukaemia. Nature. 2015;518(7540): clonal hematopoiesis and recipient mance criteria. Cytometry B Clin Cytom. 552-555. outcomes after transplantation. J Clin 2013; Oncol. 2022;40(2):189-201. 84(5):315-323. 53. Patel AA, Rojek AE, Drazer MW, et al. Therapy-related myeloid neoplasms in 109 67. Heuser M, Freeman SD, Ossenkoppele GJ, 79. Zeijlemaker W, Kelder A, Cloos J, patients after radiation monotherapy. et al. 2021 Update on MRD in acute Schuurhuis GJ. Immunophenotypic Blood Adv. 2021;5(20):4140-4148. myeloid leukemia: a consensus document detection of measurable residual (stem cell) from the European LeukemiaNet MRD disease using LAIP approach in acute 54. Soerensen JF, Aggerholm A, Kerndrup GB, Working Party. Blood. 2021;138(26): myeloid leukemia. Curr Protoc Cytom. et al. Clonal hematopoiesis predicts 2753-2767. 2019;91(1):e66. development of therapy-related myeloid neoplasms post-autologous stem cell trans- 68. Ivey A, Hills RK, Simpson MA, et al; UK 80. Zeijlemaker W, Grob T, Meijer R, et al. plantation. Blood Adv. 2020;4(5):885-892. National Cancer Research Institute AML CD341CD38- leukemic stem cell frequency 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1373 to predict outcome in acute myeloid 94. Willekens C, Blanchet O, Renneville A, consolidated with allogeneic stem cell leukemia. Leukemia. 2019;33(5):1102-1112. et al; French AML Intergroup. Prospective transplantation. Bone Marrow Transplant. long-term minimal residual disease moni- 2021;56(4):936-945. 81. Hanekamp D, Cloos J, Schuurhuis GJ. toring using RQ-PCR in RUNX1-RUNX1T1- Leukemic stem cells: identification and positive acute myeloid leukemia: results of 106. Stone RM, Mandrekar SJ, Sanford BL, et al. clinical application. Int J Hematol. 2017; the French CBF-2006 trial. Haematologica. Midostaurin plus chemotherapy for acute 105(5):549-557. 2016;101(3):328-335. myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. 82. Ommen HB. Monitoring minimal residual 95. R€ucker FG, Agrawal M, Corbacioglu A, disease in acute myeloid leukaemia: a et al. Measurable residual disease 107. Larson RA, Mandrekar SJ, Huebner LJ, review of the current evolving strategies. monitoring in acute myeloid leukemia with et al. Midostaurin reduces relapse in FLT3- Ther Adv Hematol. 2016;7(1):3-16. mutant acute myeloid leukemia: the Alli- t(8;21)(q22;q22.1): results from the AML ance CALGB 10603/RATIFY trial. Leukemia. Study Group. Blood. 2019;134(19): 83. Ghannam J, Dillon LW, Hourigan CS. Next- 2021;35(9):2539-2551. 1608-1618. generation sequencing for measurable residual disease detection in acute myeloid 108. D€ohner H, Weber D, Krzykalla J, et al. 96. Tiong IS, Dillon R, Ivey A, et al. Clinical leukaemia. Br J Haematol. 2020;188(1): Midostaurin plus intensive chemotherapy impact of NPM1-mutant molecular 77-85. for younger and older patients with AML persistence after chemotherapy for acute and FLT3 internal tandem duplications myeloid leukemia [published correction 84. Heuser M, Heida B, B€uttner K, et al. [published online ahead of print 29 June appears in Blood Adv. 2022;6(5):1489]. Posttransplantation MRD monitoring in 2022]. Blood Adv. doi:10.1182/ Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 Blood Adv. 2021;5(23):5107-5111. patients with AML by next-generation bloodadvances.2022007223. sequencing using DTA and non-DTA muta- 97. Walter RB, Gyurkocza B, Storer BE, et al. tions. Blood Adv. 2021;5(9):2294-2304. 109. Perl AE, Martinelli G, Cortes JE, et al. Comparison of minimal residual disease Gilteritinib or chemotherapy for relapsed or as outcome predictor for AML patients in 85. Cappelli LV, Meggendorfer M, Baer C, refractory FLT3-mutated AML. N Engl first complete remission undergoing et al. Indeterminate and oncogenic J Med. 2019;381(18):1728-1740. myeloablative or nonmyeloablative potential: CHIP vs CHOP mutations in AML allogeneic hematopoietic cell transplantation. with NPM1 alteration. Leukemia. 2022; 110. Cortes JE, Khaled S, Martinelli G, et al. Leukemia. 2015;29(1):137-144. Quizartinib vs salvage chemotherapy in 36(2):394-402. relapsed or refractory FLT3-ITD acute mye- 98. Hourigan CS, Dillon LW, Gui G, et al. 86. Hasserjian RP, Steensma DP, Graubert TA, loid leukaemia (QuANTUM-R): a multicentre, Impact of conditioning intensity of Ebert BL. Clonal hematopoiesis and randomised, controlled, open-label, phase 3 allogeneic transplantation for acute measurable residual disease assessment in trial. Lancet Oncol. 2019;20(7):984-997. myeloid leukemia with genomic evidence acute myeloid leukemia. Blood. 2020; of residual disease. J Clin Oncol. 2020; 111. Erba H, Montesinos P, Vrhovac R, et al. 135(20):1729-1738. 38(12):1273-1283. Quizartinib prolonged survival vs placebo plus 87. Short NJ, Zhou S, Fu C, et al. Association intensive induction and consolidation therapy 99. Craddock C, Jackson A, Loke J, et al. followed by single-agent continuation in of measurable residual disease with survival Augmented reduced-intensity regimen outcomes in patients with acute myeloid patients aged 18-75 years with newly diag- does not improve postallogeneic transplant nosed FLT3-ITD1 AML. HemaSphere. leukemia: a systematic review and meta- outcomes in acute myeloid leukemia. J Clin analysis. JAMA Oncol. 2020;6(12): 2022;6:S100. Oncol. 2021;39(7):768-778. 1890-1899. 112. Castaigne S, Pautas C, Terr e C, et al; Acute 100. Paras G, Morsink LM, Othus M, et al. Leukemia French Association. Effect of 88. Maiti A, DiNardo CD, Wang SA, et al. Conditioning intensity and peritransplant gemtuzumab ozogamicin on survival of Prognostic value of measurable residual flow cytometric MRD dynamics in adult adult patients with de-novo acute myeloid disease after venetoclax and decitabine in AML. Blood. 2022;139(11):1694-1706. leukaemia (ALFA-0701): a randomised, acute myeloid leukemia. Blood Adv. 2021; open-label, phase 3 study. Lancet. 2012; 5(7):1876-1883. 101. Norsworthy KJ, Gao X, Ko C-W, et al. 379(9825):1508-1516. Response rate, event-free survival, and 89. Pratz KW, Jonas BA, Pullarkat V, et al. overall survival in newly diagnosed acute 113. Lambert J, Pautas C, Terr e C, et al. Measurable residual disease response and myeloid leukemia: US Food and Drug Gemtuzumab ozogamicin for de novo prognosis in treatment-naïve acute myeloid Administration trial-level and patient-level acute myeloid leukemia: final efficacy and leukemia with venetoclax and azacitidine. analyses. J Clin Oncol. 2022;40(8):847-854. safety updates from the open-label, phase J Clin Oncol. 2022;40(8):855-865. III ALFA-0701 trial. Haematologica. 2019; 102. R€ ollig C, Kramer M, Schliemann C, et al. 104(1):113-119. 90. Terwijn M, van Putten WL, Kelder A, et al. Does time from diagnosis to treatment High prognostic impact of flow cytometric affect the prognosis of patients with newly 114. Hills RK, Castaigne S, Appelbaum FR, et al. minimal residual disease detection in acute diagnosed acute myeloid leukemia? Blood. Addition of gemtuzumab ozogamicin to myeloid leukemia: data from the HOVON/ 2020;136(7):823-830. induction chemotherapy in adult patients SAKK AML 42A study. J Clin Oncol. 2013; with acute myeloid leukaemia: a meta- 31(31):3889-3897. 103. Kayser S, D€ohner K, Krauter J, et al; analysis of individual patient data from German-Austrian AMLSG. The impact of randomised controlled trials. Lancet Oncol. 91. Jongen-Lavrencic M, Grob T, Hanekamp D, therapy-related acute myeloid leukemia 2014;15(9):986-996. et al. Molecular minimal residual disease in (AML) on outcome in 2853 adult patients acute myeloid leukemia. N Engl J Med. with newly diagnosed AML. Blood. 2011; 115. Schlenk RF, Paschka P, Krzykalla J, et al. 2018;378(13):1189-1199. 117(7):2137-2145. Gemtuzumab ozogamicin in NPM1- mutated AML: Results from the prospective 92. Freeman SD, Hills RK, Virgo P, et al. 104. Kr€oger N, Brand R, van Biezen A, et al; randomized AMLSG 09-09 phase-III study. Measurable residual disease at induction Myelodysplastic Syndromes Subcommittee J Clin Oncol. 2020;38(6):623-632. redefines partial response in acute myeloid of The Chronic Leukaemia Working Party of leukemia and stratifies outcomes in European Group for Blood and Marrow 116. Burnett AK, Hills RK, Milligan D, et al. patients at standard risk without NPM1 Transplantation (EBMT). Risk factors for Identification of patients with acute mutations. J Clin Oncol. 2018;36(15): therapy-related myelodysplastic syndrome myeloblastic leukemia who benefit from 1486-1497. and acute myeloid leukemia treated with the addition of gemtuzumab ozogamicin: allogeneic stem cell transplantation. Hae- results of the MRC AML15 trial. J Clin 93. Venditti A, Piciocchi A, Candoni A, et al. matologica. 2009;94(4):542-549. Oncol. 2011;29(4):369-377. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults 105. Jentzsch M, Grimm J, Bill M, et al. ELN risk 117. Burnett AK, Russell NH, Hills RK, et al. with newly diagnosed acute myeloid stratification and outcomes in secondary Addition of gemtuzumab ozogamicin to leukemia. Blood. 2019;134(12):935-945. and therapy-related AML patients induction chemotherapy improves survival 1374 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al in older patients with acute myeloid 130. Huls G, Chitu DA, Havelange V, et al; through trans or cis dimer-interface muta- leukemia. J Clin Oncol. 2012;30(32): Dutch-Belgian Hemato-Oncology Coopera- tions. Nature. 2018;559(7712):125-129. 3924-3931. tive Group (HOVON). Azacitidine mainte- nance after intensive chemotherapy 144. Harding JJ, Lowery MA, Shih AH, et al. 118. Lim W-S, Tardi PG, Dos Santos N, et al. improves DFS in older AML patients. Isoform switching as a mechanism of Leukemia-selective uptake and cytotoxicity Blood. 2019;133(13):1457-1464. acquired resistance to mutant isocitrate of CPX-351, a synergistic fixed-ratio cytara- dehydrogenase inhibition. Cancer Discov. bine:daunorubicin formulation, in bone 131. Wei AH, D€ ohner H, Pocock C, et al; 2018;8(12):1540-1547. marrow xenografts. Leuk Res. 2010;34(9): QUAZAR AML-001 Trial Investigators. Oral 1214-1223. azacitidine maintenance therapy for acute 145. McMahon CM, Ferng T, Canaani J, et al. myeloid leukemia in first remission. N Engl Clonal selection with RAS pathway 119. Lancet JE, Uy GL, Cortes JE, et al. CPX-351 J Med. 2020;383(26):2526-2537. activation mediates secondary clinical (cytarabine and daunorubicin) liposome for resistance to selective FLT3 inhibition in injection vs conventional cytarabine plus 132. Roboz GJ, Ravandi F, Wei AH, et al. Oral acute myeloid leukemia. Cancer Discov. daunorubicin in older patients with newly azacitidine prolongs survival of patients 2019;9(8):1050-1063. diagnosed secondary acute myeloid with AML in remission independently of leukemia. J Clin Oncol. 2018;36(26): measurable residual disease status. Blood. 146. Schmalbrock LK, Dolnik A, Cocciardi S, 2684-2692. 2022;139(14):2145-2155. et al. Clonal evolution of acute myeloid leukemia with FLT3-ITD mutation under 120. Lancet JE, Uy GL, Newell LF, et al. CPX- 133. Jen EY, Wang X, Li M, et al. FDA approval treatment with midostaurin. Blood. 2021; 351 vs 7 1 3 cytarabine and daunorubicin summary: oral azacitidine for continued Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 137(22):3093-3104. chemotherapy in older adults with newly treatment of adults with acute myeloid diagnosed high-risk or secondary acute leukemia unable to complete intensive 147. Ferguson P, Hills RK, Grech A, et al; UK myeloid leukaemia: 5-year results of a rand- curative therapy. Clin Cancer Res. NCRI AML Working Group. An operational omised, open-label, multicentre, phase 3 2022;28(14):2989-2993. definition of primary refractory acute trial. Lancet Haematol. 2021;8(7): myeloid leukemia allowing early e481-e491. 134. DiNardo CD, Jonas BA, Pullarkat V, et al. identification of patients who may benefit Azacitidine and venetoclax in previously 121. L€ owenberg B. Sense and nonsense of from allogeneic stem cell transplantation. untreated acute myeloid leukemia. N Engl high-dose cytarabine for acute myeloid Haematologica. 2016;101(11):1351-1358. J Med. 2020;383(7):617-629. leukemia. Blood. 2013;121(1):26-28. 148. Breems DA, Van Putten WL, Huijgens PC, 135. DiNardo CD, Wei AH. How I treat acute 122. Jaramillo S, Benner A, Krauter J, et al. myeloid leukemia in the era of new drugs. et al. Prognostic index for adult patients Condensed vs standard schedule of high- Blood. 2020;135(2):85-96. with acute myeloid leukemia in first dose cytarabine consolidation therapy with relapse. J Clin Oncol. 2005;23(9):1969- pegfilgrastim growth factor support in 136. DiNardo CD, Pratz K, Pullarkat V, et al. 1978. acute myeloid leukemia. Blood Cancer J. Venetoclax combined with decitabine or 2017;7(5):e564-e564. azacitidine in treatment-naive, elderly 149. Ganzel C, Sun Z, Cripe LD, et al. Very poor patients with acute myeloid leukemia. long-term survival in past and more recent 123. Dumas PY, Bertoli S, B erard E, et al. Blood. 2019;133(1):7-17. studies for relapsed AML patients: the Delivering HDAC over 3 or 5 days as ECOG-ACRIN experience. Am J Hematol. consolidation in AML impacts health care 137. Maiti A, Rausch CR, Cortes JE, et al. 2018;93(8):1074-1081. resource consumption but not outcome. Outcomes of relapsed or refractory acute Blood Adv. 2020;4(16):3840-3849. myeloid leukemia after frontline 150. Perl AE, Larson RA, Podoltsev NA, et al. hypomethylating agent and venetoclax Follow-up of patients with R/R FLT3- 124. Schaich M, R€ ollig C, Soucek S, et al. regimens. Haematologica. 2021;106(3):894- mutation-positive AML treated with Cytarabine dose of 36 g/m2 compared with 898. gilteritinib in the phase 3 ADMIRAL trial. 12 g/m2 within first consolidation in acute Blood. 2022;139(23):3366-3375. myeloid leukemia: results of patients enrolled 138. Wei AH, Montesinos P, Ivanov V, et al. onto the prospective randomized AML96 Venetoclax plus LDAC for newly diagnosed 151. DiNardo CD, Stein EM, de Botton S, et al. study. J Clin Oncol. 2011;29(19):2696-2702. AML ineligible for intensive chemotherapy: Durable remissions with ivosidenib in IDH1- a phase 3 randomized placebo-controlled mutated relapsed or refractory AML. N 125. L€ owenberg B, Pabst T, Vellenga E, et al; trial. Blood. 2020;135(24):2137-2145. Engl J Med. 2018;378(25):2386-2398. Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and Swiss 139. Cortes JE, Heidel FH, Hellmann A, et al. 152. Stein EM, DiNardo CD, Pollyea DA, et al. Group for Clinical Cancer Research (SAKK) Randomized comparison of low dose Enasidenib in mutant IDH2 relapsed or Collaborative Group. Cytarabine dose for cytarabine with or without glasdegib in refractory acute myeloid leukemia. Blood. acute myeloid leukemia. N Engl J Med. patients with newly diagnosed acute 2017;130(6):722-731. 2011;364(11):1027-1036. myeloid leukemia or high-risk myelodys- plastic syndrome. Leukemia. 2019;33(2): 153. Stein EM, DiNardo CD, Fathi AT, et al. 126. Burnett AK, Russell NH, Hills RK, et al. 379-389. Molecular remission and response patterns Optimization of chemotherapy for younger in patients with mutant-IDH2 acute myeloid patients with acute myeloid leukemia: results 140. Montesinos P, Recher C, Vives S, et al. leukemia treated with enasidenib. Blood. of the medical research council AML15 trial. Ivosidenib and azacitidine in previously 2019;133(7):676-687. J Clin Oncol. 2013;31(27):3360-3368. untreated IDH1-mutated acute myeloid leu- kemia. N Engl J Med. 2022;386(16): 154. de Botton S, Montesinos P, Schuh AC, 127. Cornelissen JJ, Blaise D. Hematopoietic 1519-1531. et al. Enasidenib vs conventional care stem cell transplantation for patients with regimens in older patients with late-stage AML in first complete remission. Blood. 141. Roboz GJ, DiNardo CD, Stein EM, et al. mutant-IDH2 relapsed/refractory acute 2016;127(1):62-70. Ivosidenib induces deep durable myeloid leukemia: a randomized phase 3 remissions in patients with newly 128. Ferrara F, Picardi A. Is there still a role for trial [published online ahead of print 17 diagnosed IDH1-mutant acute myeloid autologous stem cell transplantation for the June 2022]. Blood. doi:10.1182/blood. leukemia. Blood. 2020;135(7):463-471. treatment of acute myeloid leukemia? 2021014901. Cancers (Basel). 2019;12(1):59. 142. DiNardo CD, Tiong IS, Quaglieri A, et al. Molecular patterns of response and 155. Niederwieser D, Baldomero H, Bazuaye N, 129. US Food and Drug Administration. 2020, treatment failure after frontline venetoclax et al. One and a half million hematopoietic Guidance for industry. Acute myeloid combinations in older patients with AML. stem cell transplants: continuous and leukemia: developing drugs and biological Blood. 2020;135(11):791-803. differential improvement in worldwide products for treatment. Available at: access with the use of non-identical family https://www.fda.gov/media/140821/. 143. Intlekofer AM, Shih AH, Wang B, et al. donors. Haematologica. 2022;107(5): Accessed 30 June 2022. Acquired resistance to IDH inhibition 1045-1053. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1375 156. D’Souza A, Fretham C, Lee SJ, et al. cell transplantation: where do we stand? minimal residual disease. N Engl J Med. Current use of and trends in hematopoietic Biol Blood Marrow Transplant. 2017;23(11): 2016;375(10):944-953. cell transplantation in the United States. 1839-1846. Biol Blood Marrow Transplant. 2020;26(8): 180. Barker JN, Devlin SM, Naputo KA, et al. e177-e182. 168. Sorror ML, Maris MB, Storb R, et al. High progression-free survival after inter- Hematopoietic cell transplantation (HCT)- mediate intensity double unit cord blood 157. Appelbaum FR. Effectiveness of allogeneic specific comorbidity index: a new tool for transplantation in adults. Blood Adv. 2020; hematopoietic cell transplantation for older risk assessment before allogeneic HCT. 4(23):6064-6076. patients with acute myeloid leukemia. Best Blood. 2005;106(8):2912-2919. Pract Res Clin Haematol. 2021;34(4): 181. Loke J, Malladi R, Moss P, Craddock C. 101320. 169. Sorror ML, Storb RF, Sandmaier BM, et al. The role of allogeneic stem cell Comorbidity-age index: a clinical measure transplantation in the management of 158. Ringd en O, Boumendil A, Labopin M, et al. of biologic age before allogeneic acute myeloid leukaemia: a triumph of Outcome of allogeneic hematopoietic stem hematopoietic cell transplantation. J Clin hope and experience. Br J Haematol. 2020; cell transplantation in patients age .69 Oncol. 2014;32(29):3249-3256. 188(1):129-146. years with acute myelogenous leukemia: on behalf of the Acute Leukemia Working 170. Armand P, Gibson CJ, Cutler C, et al. A 182. Burchert A, Bug G, Fritz LV, et al. Sorafenib Party of the European Society for Blood disease risk index for patients undergoing maintenance after allogeneic and Marrow Transplantation. Biol Blood allogeneic stem cell transplantation. Blood. hematopoietic stem cell transplantation for Marrow Transplant. 2019;25(10):1975-1983. 2012;120(4):905-913. acute myeloid leukemia with FLT3-internal tandem duplication mutation (SORMAIN). Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 159. McDonald GB, Sandmaier BM, Mielcarek 171. Shouval R, Bondi O, Mishan H, Shimoni A, J Clin Oncol. 2020;38(26):2993-3002. M, et al. Survival, nonrelapse mortality, and Unger R, Nagler A. Application of machine relapse-related mortality after allogeneic learning algorithms for clinical predictive 183. Xuan L, Wang Y, Huang F, et al. Sorafenib hematopoietic cell transplantation: compar- modeling: a data-mining approach in SCT. maintenance in patients with FLT3-ITD ing 2003-2007 vs 2013-2017 cohorts. Ann Bone Marrow Transplant. 2014;49(3): acute myeloid leukaemia undergoing allo- Intern Med. 2020;172(4):229-239. 332-337. geneic haematopoietic stem-cell transplan- tation: an open-label, multicentre, 160. Eapen M. Since everyone has a donor, why 172. Scott BL, Pasquini MC, Logan BR, et al. randomised phase 3 trial. Lancet Oncol. are some eligible patients still not Myeloablative vs reduced-intensity hemato- 2020;21(9):1201-1212. transplanted? Best Pract Res Clin poietic cell transplantation for acute mye- Haematol. 2021;34(4):101321. loid leukemia and myelodysplastic 184. Oran B, de Lima M, Garcia-Manero G, syndromes. J Clin Oncol. 2017;35(11):1154- et al. A phase 3 randomized study of 161. Dholaria B, Savani BN, Hamilton BK, et al. 1161. 5-azacitidine maintenance vs observation Hematopoietic cell transplantation in the after transplant in high-risk AML and MDS treatment of newly diagnosed adult acute 173. Scott BL, Pasquini MC, Fei M, et al. patients [published correction appears in myeloid leukemia: an evidence-based Myeloablative vs reduced-intensity condi- Blood Adv. 2021;5(6):1755-1756]. Blood review from the American Society of Trans- tioning for hematopoietic cell transplanta- Adv. 2020;4(21):5580-5588. plantation and Cellular Therapy. Transplant tion in acute myelogenous leukemia and Cell Ther. 2021;27(1):6-20. myelodysplastic syndromes - long-term fol- 185. Kekre N, Kim HT, Thanarajasingam G, et al. low-up of the BMT CTN 0901 clinical trial. Efficacy of immune suppression tapering in 162. Pollyea DA, Bixby D, Perl A, et al. NCCN Transplant Cell Ther. 2021;27(6): treating relapse after reduced intensity Guidelines Insights: Acute Myeloid 483.e1-483.e6. allogeneic stem cell transplantation. Leukemia, Version 2.2021. J Natl Compr Haematologica. 2015;100(9):1222-1227. Canc Netw. 2021;19(1):16-27. 174. Dehn J, Spellman S, Hurley CK, et al. Selection of unrelated donors and cord 186. Schmid C, Labopin M, Schaap N, et al. 163. Loke J, Buka R, Craddock C. Allogeneic blood units for hematopoietic cell Long-term results and GvHD after stem cell transplantation for acute myeloid transplantation: guidelines from the NMDP/ prophylactic and preemptive donor leukemia: who, when, and how? Front CIBMTR. Blood. 2019;134(12): lymphocyte infusion after allogeneic stem Immunol. 2021;12:659595. 924-934. cell transplantation for acute leukemia. Bone Marrow Transplant. 2022;57(2): 164. Ustun C, Le-Rademacher J, Wang HL, et al. 175. Woolfrey A, Lee SJ, Gooley TA, et al. HLA- 215-223. Allogeneic hematopoietic cell allele matched unrelated donors compared transplantation compared to chemotherapy to HLA-matched sibling donors: role of cell 187. Craddock C, Labopin M, Robin M, et al. consolidation in older acute myeloid source and disease risk category. Biol Clinical activity of azacitidine in patients leukemia (AML) patients 60-75 years in first Blood Marrow Transplant. 2010;16(10): who relapse after allogeneic stem cell complete remission (CR1): an alliance 1382-1387. transplantation for acute myeloid leukemia. (A151509), SWOG, ECOG-ACRIN, and Haematologica. 2016;101(7):879-883. CIBMTR study. Leukemia. 2019;33(11): 176. Kasamon YL, Bola~ nos-Meade J, Prince GT, 2599-2609. et al. Outcomes of nonmyeloablative HLA- 188. Kharfan-Dabaja MA, Labopin M, Polge E, haploidentical blood or marrow transplan- et al. Association of second allogeneic 165. Russell NH, Hills RK, Thomas A, et al. tation with high-dose post-transplantation hematopoietic cell transplant vs donor Outcomes of older patients aged 60 to 70 cyclophosphamide in older adults. J Clin lymphocyte infusion with overall survival in years undergoing reduced intensity Oncol. 2015;33(28):3152-3161. patients with acute myeloid leukemia transplant for acute myeloblastic leukemia: relapse. JAMA Oncol. 2018;4(9):1245-1253. results of the NCRI acute myeloid leukemia 177. Gooptu M, Romee R, St Martin A, et al. 16 trial. Haematologica. 2021; HLA-haploidentical vs matched unrelated 189. Burd A, Levine RL, Ruppert AS, et al. 107(7):1518–1527. donor transplants with posttransplant Precision medicine treatment in acute cyclophosphamide-based prophylaxis. myeloid leukemia using prospective genomic 166. Heinicke T, Krahl R, Kahl C, et al. Blood. 2021;138(3):273-282. profiling: feasibility and preliminary efficacy of Allogeneic hematopoietic stem cell the Beat AML Master Trial. Nat Med. 2020; transplantation improves long-term out- 178. Shaw BE, Jimenez-Jimenez AM, Burns LJ, 26(12):1852-1858. come for relapsed AML patients across all et al. National Marrow Donor Program- ages: results from two East German Study sponsored multicenter, phase II trial of 190. D€ ohner H, Wei AH, L€ owenberg B. Towards Group Hematology and Oncology (OSHO) HLA-mismatched unrelated donor bone precision medicine for AML. Nat Rev Clin trials. Ann Hematol. 2021;100(9): marrow transplantation using post- Oncol. 2021;18(9):577-590. 2387-2398. transplant cyclophosphamide. J Clin Oncol. 2021;39(18):1971-1982. 191. Stein EM, Aldoss J, DiPersio JF, et al. 167. Potdar R, Varadi G, Fein J, Labopin M, Safety and efficacy of menin inhibition in Nagler A, Shouval R. Prognostic scoring 179. Milano F, Gooley T, Wood B, et al. Cord- patients with MLL-rearranged and NPM1 systems in allogeneic hematopoietic stem blood transplantation in patients with mutant acute leukemia: a phase 1, first-in- 1376 blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 € DOHNER et al human study of SNDX-5613. Blood. 2021; the eighth special issue. J Clin Apher. Infections in Leukaemia. J Antimicrob 138(suppl 1):699. 2019;34(3):171-354. Chemother. 2018;73(12):3221-3230. 192. Uy GL, Aldoss I, Foster MC, et al. 199. Bewersdorf JP, Giri S, Tallman MS, Zeidan 204. Styczynski J, Reusser P, Einsele H, et al. Flotetuzumab as salvage immunotherapy AM, Stahl M. Leukapheresis for the Management of HSV, VZV and EBV for refractory acute myeloid leukemia. management of hyperleukocytosis in acute infections in patients with hematological Blood. 2021;137(6):751-762. myeloid leukemia: a systematic review and malignancies and after SCT: guidelines from meta-analysis. Transfusion. 2020;60(10): the Second European Conference on 193. Wermke M, Kraus S, Ehninger A, et al. 2360-2369. Infections in Leukemia. Bone Marrow Proof of concept for a rapidly switchable Transplant. 2009;43(10):757-770. universal CAR-T platform with UniCAR-T- 200. Stahl M, Shallis RM, Wei W, et al. CD123 in relapsed/refractory AML. Blood. Management of hyperleukocytosis and impact 205. Ullmann AJ, Schmidt-Hieber M, Bertz H, 2021;137(22):3145-3148. of leukapheresis among patients with acute et al; Infectious Diseases Working Party of myeloid leukemia (AML) on short- and long- the German Society for Hematology and 194. Zeidan AM, DeAngelo DJ, Palmer J, et al. term clinical outcomes: a large, retrospective, Medical Oncology (AGIHO/DGHO) and the Phase 1 study of anti-CD47 monoclonal DAG-KBT (German Working Group for multicenter, international study. Leukemia. antibody CC-90002 in patients with Blood and Marrow Transplantation). Infec- 2020;34(12):3149-3160. relapsed/refractory acute myeloid leukemia tious diseases in allogeneic haematopoietic and high-risk myelodysplastic syndromes. 201. Ten Cate H, Leader A. Management of stem cell transplantation: prevention and Ann Hematol. 2022;101(3):557-569. disseminated intravascular coagulation in prophylaxis strategy guidelines 2016. Ann Hematol. 2016;95(9):1435-1455. Downloaded from http://ashpublications.org/blood/article-pdf/140/12/1345/1921355/bloodbld2022016867.pdf by guest on 26 July 2023 acute leukemias. Hamostaseologie. 2021; 195. Garcia-Manero G, Griffiths EA, Steensma 41(2):120-126. DP, et al. Oral cedazuridine/decitabine 206. Engelhard D, Mohty B, de la Camara R, for MDS and CMML: a phase 2 202. Fathi AT, DiNardo CD, Kline I, et al; AG221- Cordonnier C, Ljungman P. European pharmacokinetic/pharmacodynamic C-001 Study Investigators. Differentiation guidelines for prevention and management randomized crossover study. Blood. 2020; syndrome associated with enasidenib, a of influenza in hematopoietic stem cell 136(6):674-683. selective inhibitor of mutant isocitrate transplantation and leukemia patients: dehydrogenase 2 analysis of a phase 1/2 summary of ECIL-4 (2011), on behalf of 196. Bewersdorf JP, Zeidan AM. ECIL, a joint venture of EBMT, EORTC, study. JAMA Oncol. 2018;4(8):1106-1110. Hyperleukocytosis and leukostasis in acute ICHS, and ELN. Transpl Infect Dis. 2013; myeloid leukemia: can a better 203. Maertens JA, Girmenia C, Br€ uggemann RJ, 15(3):219-232. understanding of the underlying molecular et al; European Conference on Infections in pathophysiology lead to novel treatments? Leukaemia (ECIL), a joint venture of the 207. Agarwal SK, DiNardo CD, Potluri J, et al. Cells. 2020;9(10):2310. Management of venetoclax-posaconazole European Group for Blood and Marrow interaction in acute myeloid leukemia 197. Recher C. Clinical implications of Transplantation (EBMT), the European patients: evaluation of dose adjustments. inflammation in acute myeloid leukemia. Organization for Research and Treatment Clin Ther. 2017;39(2):359-367. Front Oncol. 2021;11:623952. of Cancer (EORTC), the Immunocompromised Host Society (ICHS) 198. Padmanabhan A, Connelly-Smith L, Aqui N, and the European LeukemiaNet (ELN). © 2022 by The American Society of Hematology. Licensed et al. Guidelines on the use of therapeutic European guidelines for primary antifungal under Creative Commons Attribution-NonCommercial- apheresis in clinical practice: evidence- prophylaxis in adult haematology patients: NoDerivatives 4.0 International (CC BY-NC-ND 4.0), based approach from the Writing Commit- summary of the updated recommendations permitting only noncommercial, nonderivative use with tee of the American Society for Apheresis: from the European Conference on attribution. All other rights reserved. 2022 ELN AML RECOMMENDATIONS blood® 22 SEPTEMBER 2022 | VOLUME 140, NUMBER 12 1377