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Acute myeloid leukemia: Risk factors and prognosis

Acute myeloid leukemia: Risk factors and prognosis
Authors:
Charles A Schiffer, MD
Geoffrey Uy, MD
Section Editor:
Richard A Larson, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: Jan 2024.
This topic last updated: Jan 19, 2024.

INTRODUCTION — Acute myeloid leukemia (AML) refers to a large and diverse category of hematopoietic neoplasms involving cells committed to the myeloid lineage of cellular development.

Leukemia arises from the serial acquisition of somatic mutations in hematopoietic stem and progenitor cells that have the capacity to self-renew and propagate the malignant clone. Acquired cytogenetic abnormalities and gene mutations are the primary drivers of the development of AML, and they affect the natural history and treatment response of these diseases. However, patient age, comorbid conditions, and prior history also contribute to clinical manifestations and treatment.

Treatment of AML is primarily informed by age, fitness, and comorbid conditions and, as a result, outcomes are heterogeneous. Prognosis for an individual patient is influenced by both clinical features and the immunophenotypic and cytogenetic/molecular characteristics of the leukemic blasts.

This topic reviews prognostic factors in AML.

Adverse risk factors that are more common in older adults (eg, patients over age 60 years) with AML are discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Prognosis'.)

Related topics include:

●(See "Clinical manifestations, pathologic features, and diagnosis of acute myeloid leukemia".)

●(See "Acute myeloid leukemia: Classification".)

●(See "Acute myeloid leukemia: Cytogenetic abnormalities".)

●(See "Acute myeloid leukemia in adults: Overview".)

RISK FACTORS — Outcomes with AML are associated with both the individual's clinical attributes and cytogenetic/molecular features of the malignant blasts.

Clinical — The strongest clinical predictors of survival and response to therapy in patients with AML are age, performance status, prior exposure to cytotoxic agents or radiation therapy, and antecedent hematologic disorders.

Age — Compared with younger patients, older individuals with AML generally have lower rates of achieving a complete remission (CR) and shorter disease-free survival (DFS). However, various age thresholds (eg, 55, 60, 65, or 70 years) have been used for clinical trials, but there is no consensus definition of "older" adults.

Higher age appears to be an adverse prognostic marker even in younger patients.

●In a population-based study of 11,303 patients with AML (2001 to 2006), the estimated five-year overall survival (OS) rate was 15 percent [1]. OS varied with age at diagnosis:

•15 to 24 years (289 patients) – 53 percent

•25 to 39 years (702 patients) – 49 percent

•40 to 59 years (2170 patients) – 33 percent

•60 to 69 years (2208 patients) – 13 percent

•70 to 79 years (3258 patients) – 3 percent

•≥80 years (2676 patients) – 0 percent

●A retrospective analysis of 891 patients (children 2 to <13 years), adolescents (13 to <21 years), and young adults (21 to <30 years) reported that rates of five-year event-free survival (EFS) declined with patient age at diagnosis (54, 46, and 28 percent, respectively) [2]. With favorable karyotypes excluded, five-year EFS was superior in children (44 percent) compared with adolescents (35 percent) and young adults (23 percent).

●A randomized trial using intensive induction therapy in patients >60 years reported 11 percent 30-day mortality [3].

The effect of age on outcomes in older patients with AML is discussed in more detail separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Prognosis'.)

Performance status — Aside from age, most clinical risk factors in AML are related to comorbid conditions (eg, heart failure, renal insufficiency, concurrent infection) that are, at least partially, reflected by the patient's performance status (PS) [4,5].

The most commonly used tools for assessing PS are the Karnofsky PS and the Eastern Cooperative Oncology Group (ECOG) PS (table 1A-B). When estimating PS, greater emphasis is placed on chronic comorbidities than on intercurrent illnesses. As an example, a significant infection may cause a well-functioning individual (eg, ECOG PS 0 or 1) to quickly decline (eg, to ECOG 3 or 4); however, prompt treatment and resolution of the infection may restore the individual's PS.

Most reports of treatment outcomes with AML are from clinical studies that used intensive induction therapy. It is important to recognize that such studies generally excluded individuals with impaired PS or significant organ dysfunction. PS appears to have greater prognostic value in older adults than in younger patients; early outcomes of AML therapy (eg, mortality, intensive care unit admission, treatment response) are not closely linked with PS in younger patients [6].

●In a study of 3365 adults with AML, PS and age were the most important predictors of treatment-related mortality (TRM; ie, death within four weeks of initiating therapy) [7]. Combining age and PS was a more accurate predictor of TRM than either factor alone.

●Retrospective analysis of 968 adults enrolled in clinical trials of induction therapy for newly diagnosed AML reported that TRM increased with worsening PS and increased age at diagnosis [8]. For younger patients (≤65 years), ECOG PS scores of 0, 1, 2, or 3 were associated with 5, 4, 9, and 21 percent 30-day mortality, respectively; by contrast, the corresponding 30-day mortality rates in older patients were 13, 16, 35, and 60 percent, respectively. Older patients with a worse PS were also less likely to obtain a CR.

Studies that used lower-intensity regimens reported lower rates of short-term mortality in older patients than those described above. Treatment with such regimens and the relation of PS with outcomes in older adults with AML are discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults", section on 'Physical functioning'.)

Therapy-related myeloid neoplasms — Therapy-related myeloid neoplasms (t-MNs) refers to a continuum of disorders that includes AML, myelodysplastic syndromes/neoplasms (MDS), and MDS/myeloproliferative neoplasms (MPN) that arise in persons who were previously exposed to cytotoxic chemotherapy or radiation therapy.

t-MNs account for 5 to 20 percent of all cases of AML [9-11]. The incidence of t-MNs varies with the cytotoxic agent, preceding condition, time since initial exposure, and other factors. Prognosis for patients with a t-MN is generally worse than that for the corresponding de novo myeloid neoplasm [12]. t-MNs are associated with adverse cytogenetic lesions, with >90 percent having an abnormal karyotype [13,14].

Labels, diagnostic criteria, and categorization of t-MNs differ between the two contemporary classification schemes: the International Consensus Classification (ICC) [15] and the World Health Organization 5th edition [16], as discussed separately. (See "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis".)

Antecedent hematologic disorders — Antecedent hematologic disorders are present in up to one-quarter of older patients with AML. Some younger patients (especially children, adolescents, and a smaller fraction of adults with AML) have an inherited or germline condition that may be associated with other hematologic conditions and/or other somatic manifestations.

●A population-based registry in Sweden reported that 19.8 percent of 3055 patients with AML (2000 to 2013) previously had MDS or MDS/MPN; compared with de novo AML, patients with secondary AML had inferior rates of survival and CR [17].

●In a study that compared mutations in patients with secondary AML (arising after a prior myeloid malignancy), therapy-related AML, and unspecified AML, identification of a gene mutation in one of eight genes (SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2) was highly specific for a diagnosis of secondary AML and a poor clinical outcome [18].

Inferior outcomes with antecedent hematologic conditions may be more closely related to the genetic characteristics of the AML than to the prior history. As an example, dysplasia of residual hematopoietic cells lacks independent prognostic significance in patients with AML [19,20]. Aside from adverse biologic features of secondary AML, clinical presentation and outcomes may also be affected by platelet and neutrophil dysfunction, transfusion dependence, recurrent bleeding, and prior infections.

Germline conditions that may contribute to the development of AML are discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes".)

Others — It is uncertain if race and/or ethnicity affect patient outcomes in AML. Both socioeconomic factors and differences in disease biology may contribute to any such effects.

●Black patients had shorter survival than White patients in an analysis of non-Hispanic Black and White adults with AML [21]. Black race was independently associated with inferior survival in an analysis of data from 25,523 patients in the United States SEER (Surveillance Epidemiology and End Results) database and findings from 1339 patients with AML who were treated on Alliance clinical trials. After adjustment for socioeconomic and molecular factors, the disparity was especially pronounced in Black patients <60 years, who had fewer NPM1 mutations and more IDH2 mutations. OS in younger Black patients was adversely affected by IDH2 and FLT3-ITD (internal tandem duplication) mutations, but mutated NPM1 (which was associated with better outcomes in White patients) was not associated with better outcomes in the younger Black patients.

●Cytogenetic risk groups and age differed significantly between African American patients and White American patients in an analysis of data from seven research studies [22]. African American males had significantly lower rates of CR (54 versus 64 percent) and five-year OS (16 versus 24 percent) compared with White males.

Cytogenetic and molecular features — Cytogenetic and molecular features of the leukemic blasts are important for classification of AML subtypes, certain aspects of treatment, and for assessing prognosis.

●Classification of AML subtypes is discussed separately. (See "Acute myeloid leukemia: Classification".)

●Use of cytogenetic and molecular features for selecting treatment is discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Risk stratification' and "Treatment of relapsed or refractory acute myeloid leukemia".)

●Application of these features for estimating prognosis is discussed below. (See 'European LeukemiaNet 2022 classification' below.)

Cytogenetics — Leukemic blasts should undergo metaphase chromosome banding (karyotyping), with or without FISH (fluorescence in situ hybridization).

Chromosomal banding is required in all patients with AML because some clinically relevant structural abnormalities (eg, inv(16) or KMT2A rearrangement) may not be detected by FISH. Next generation sequencing (NGS) can also detect some structural abnormalities and may be useful in patients in which cytogenetics fail or are suboptimal [23].  

Approximately 45 percent of adults who present with AML have a normal karyotype [24,25]. Monosomal karyotype (defined as ≥2 autosomal monosomies or a single monosomy with an additional structural abnormality) and complex karyotype (≥3 clonal cytogenetic abnormalities) are adverse prognostic features in AML [26-28]. (See 'Adverse prognosis' below.)

Cytogenetic techniques and specific abnormalities associated with AML are discussed in greater detail separately. (See "Acute myeloid leukemia: Cytogenetic abnormalities".)

Mutations — Mutation status in AML is primarily assessed using NGS myeloid gene panels, which are available from commercial reference laboratories and referral centers.

Mutations of key myeloid genes are found in >95 percent of cases of AML (table 2), whether the leukemic blasts are cytogenetically normal or abnormal [29]. Some mutations are associated with favorable prognosis, while others are associated with adverse prognosis; however, the molecular context (eg, concurrent mutations, mutation allele ratio, and/or rearrangement partners) may influence the effect of some mutations (table 3). Mutation status is especially important for assessing prognosis in patients with cytogenetically normal AML.

The following sections describe the impact of selected genes on outcomes in patients with AML.

NPM1 — NPM1 encodes a ubiquitously expressed phosphoprotein that shuttles between the nucleus and cytoplasm and is involved in ribosome protein assembly and transport. AML-associated mutations of NPM1 eliminate the C-terminus amino acids that are responsible for nucleolar localization; as a result, mutant NPM1 is retained in the cytoplasm.

NPM1 mutations occur in approximately 30 percent of all cases of AML and in approximately one-half of cases of cytogenetically normal AML [30-38].

AML with mutated NPM1 is generally associated with more favorable outcomes (eg, higher rates of OS, EFS, and CR), but this effect may be diminished by concurrent adverse cytogenetic abnormalities, other gene mutations (eg, FLT3), and the NPM1 mutant allele burden [31,39-46].

The impact of concurrent cytogenetic abnormalities is considered when assigning risk stratification in a patient with mutated NPM1. (See 'New features in European LeukemiaNet 2022' below.)

The impact of NPM1 status on selection of post-remission therapy for AML is discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Favorable-risk disease'.)

FLT3 — FLT3 encodes a tyrosine kinase (TK) receptor that, when activated, stimulates cell proliferation.

There are two major classes of FLT3 mutations in AML, both of which lead to constitutive activation [47-52]:

●FLT3-ITD

●Point mutations in the tyrosine kinase domain (TKD; eg, FLT3 D835)

FLT3-ITD mutations are seen in one-third of cases of AML, while FLT3-TKD mutations are found in approximately 10 percent [30,53,54]. FLT3 mutations are most common in patients with cytogenetically normal AML, and they are less common in children than in adults.

Compared with wild-type FLT3, FLT3-ITD is associated with inferior OS and decreased DFS [48,51,53-57]. However, the mutational context can influence the impact of the FLT3 mutation [58]; examples include concurrent mutation of NPM1, the FLT3 mutant/wild-type allelic ratio, and the absence of the wild-type FLT3 allele (ie, homozygous or hemizygous FLT3-ITD) [30,47,59-62]. FLT3-ITD mutational status is an especially important predictor of outcomes in patients with intermediate-risk AML [31].

Both FLT3-ITD and FLT3-TKD mutations can be targeted with TK inhibitors (TKIs; eg, midostaurin, quizartinib), as discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'AML with mutated FLT3'.)

The impact of FLT3-ITD on post-remission treatment decisions is discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Stratification by genetic risk'.)

All cases of AML with FLT3-ITD are now categorized as intermediate risk (irrespective of the allelic ratio or concurrent NPM1 mutation) because of their sensitivity to FLT3 inhibitors. (See 'New features in European LeukemiaNet 2022' below.)

CEBPA — CEBPA encodes CCAAT/enhancer binding protein alpha, which is a key transcription factor for granulocytic differentiation.

Mutations in CEBPA are reported in 7 to 11 percent of cases of AML and in 13 to 15 percent of cytogenetically normal AML [31,53,63-69]. AML-associated mutations can occur in the basic leucine zipper (bZIP) region or the transcription activation domain (TAD) of this intronless gene. Rare cases of AML are associated with germline pathogenic gene variants of AML [70].

In-frame mutations of the CEBPA bZIP (either as one or two copies) are associated with a favorable prognosis [37,63,66,71,72]. Mutations in the CEBPA TAD are not associated with a more favorable prognosis [73].

The effect of mono- and bi-allelic mutations of CEBPA bZIP domain on prognosis in AML is discussed below. (See 'New features in European LeukemiaNet 2022' below.)

The impact of CEBPA mutations on post-remission management of AML is discussed separately. (See "Acute myeloid leukemia in younger adults: Post-remission therapy", section on 'Stratification by genetic risk'.)

AML associated with germline/inherited CEBPA variants is discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial AML with mutated CEBPA'.)

IDH1 — IDH1 encodes isocitrate dehydrogenase 1, a metabolic enzyme that catalyzes conversion of alpha ketoglutarate to the oncometabolite, 2-hydroxyglutarate, which can block normal myeloid differentiation [74,75].

IDH1 mutations have been reported in 6 to 9 percent of AML cases and in 8 to 16 percent of normal karyotype AML [31,76-81]. IDH1 mutations are more common in AML with mutations of NPM1 or DNMT3A and in AML with wild-type CEBPA or wild-type FLT3 [31,76].

The impact of IDH1 mutation on AML prognosis has been inconsistent in various studies [78-81]. As a result, IDH1 mutation does not influence the prognostic category of AML. (See 'European LeukemiaNet 2022 classification' below.)

IDH1 mutations can be targeted with ivosidenib and olutasidenib, as discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'HMA plus IDH1 inhibitor' and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Targeted agents'.)

IDH2 — Mutant IDH2, like its counterpart mutant IDH1, converts alpha ketoglutarate to 2-hydroxyglutarate.

Mutations in IDH2 have been reported in 8 to 12 percent of cases of AML and in 19 percent of cases of normal karyotype AML [31,76-79,82]. IDH1 mutations and IDH2 mutations are nearly always mutually exclusive [76,78,79].

The prognostic impact of IDH2 mutations has been inconsistent [31,77-79,82]. As a result, mutant IDH2 does not influence the prognostic category of AML. (See 'European LeukemiaNet 2022 classification' below.)

IDH2 mutations can be targeted with enasidenib, as discussed separately. (See "Acute myeloid leukemia: Management of medically unfit adults", section on 'IDH inhibitors' and "Treatment of relapsed or refractory acute myeloid leukemia", section on 'Targeted agents'.)

DNMT3A — DNMT3A encodes deoxyribonucleic acid (DNA) methyltransferase 3A, an enzyme involved in DNA methylation.

DNMT3A mutations have been reported in approximately 20 percent of cases of AML and in approximately one-third of cases of cytogenetically normal AML [27,31,83-87]. Concurrent mutations of DNMT3A and NPM1 are commonly seen.

The prognostic significance of DNMT3A mutations is uncertain, and its impact may depend on patient age and type of mutation [31,83-87].

DNMT3A mutation does not determine the prognostic category of AML. (See 'European LeukemiaNet 2022 classification' below.)

It should be recognized that mutations of DNMT3A (or other genes, such as TET or ASXL1) are common in patients with clonal hematopoiesis of indeterminate potential (CHIP), which increases with age and often precedes development of myeloid neoplasms [88-90], as discussed separately. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)

KIT — KIT encodes CD117, a TK receptor that binds stem cell factor on immature hematopoietic cells.

KIT mutations have been reported in 6 percent of AML and in one-fifth of patients with core binding factor (CBF) AML (ie, t[8;21] or inv[16]) [31,91-93]. Concurrent mutations in KIT and RAS were much less likely [94].

KIT mutations are associated with decreased OS and decreased relapse-free survival in the setting of t(8;21) [91,92,95,96].

KIT mutation does not determine a prognostic category of AML. (See 'European LeukemiaNet 2022 classification' below.)

Mutated KIT can be targeted by dasatinib and other TKIs in selected cases of AML [97]. Treatment with KIT inhibitors is discussed separately. (See "Advanced systemic mastocytosis: Management and prognosis".)

TP53 — TP53 encodes the tumor suppressor, p53, which plays a key role in regulating cell division and proliferation. TP53 mutation is associated with adverse outcomes in AML.

TP53 mutations are present in approximately 12 percent of AML cases [18,29,98] and are more common in patients ≥60 years of age than in younger patients [99]. TP53 mutations are overrepresented in several subtypes of AML; they are most common in AML with a complex karyotype and are found in nearly one-quarter of cases of therapy-related AML (where they are frequently associated with monosomal karyotype and/or abnormalities in chromosomes 5 and/or 7) [100].

TP53 mutations are associated with unfavorable risk and poor outcomes [29,99,100]. Compared with TP53 deletions, TP53 mutations were associated with a worse prognosis [99]. The negative prognostic impact of TP53 mutation and complex karyotype appears to be additive.

Mutated TP53 with a variant allele frequency ≥10 percent categorizes AML as having an adverse prognosis. (See 'Prognostic categories' below.)

Because of distinctive biologic features, resistance to treatment, and adverse prognostic impact, AML and MDS with mutant TP53 are considered a continuum of disorders that constitute a distinct category in the ICC, as discussed separately. (See "Acute myeloid leukemia: Classification", section on 'Mutated TP53'.)

KMT2A/MLL — Rearrangements involving KMT2A (lysine [K]-specific methyltransferase 2A; previously called mixed-lineage leukemia [MLL]) on chromosome 11q23 can be detected in a variety of acute leukemias, most commonly in younger patients and in infants with acute lymphoblastic leukemia, but also in patients with therapy-induced AML, de novo AML, and mixed-phenotype acute leukemia (MPAL). KMT2A has been found in rearrangements with >100 translocation partners, with most conferring an adverse prognosis; an exception is the KMT2A::AF9 fusion found in t(9;11) de novo AML, which has an intermediate prognosis.

RUNX1 — RUNX1 encodes RUNX1 (runt-related transcription factor 1), which is a component of the heterodimeric CBF transcription factor complex.

RUNX1 mutations are found in approximately 10 percent of de novo AML [18,101,102]. Mutated RUNX1 is associated with age ≥60 years, male sex, secondary AML evolving from MDS, and mutations of epigenetic modifiers (eg, ASXL1, IDH2, KMT2A, EZH2). Inherited mutations in RUNX1 are associated with an increased incidence of hematologic disorders that can evolve into AML, as discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

RUNX1 mutations are associated with adverse prognosis in AML [18,101,102]. RUNX1 mutation does not determine a prognostic category of AML. (See 'European LeukemiaNet 2022 classification' below.)

ASXL1 — ASXL1 (additional sex combs 1) encodes a protein that binds the polycomb complex transcriptional repressor complex, but its biologic function is not well understood.

Mutations in ASXL1 are present in 6 to 30 percent of normal karyotype AML; the incidence increases with age and is higher in secondary AML [18,103-108]. ASXL1 mutations and NPM1 mutations are mutually exclusive, whereas ASXL1 mutations are strongly associated with alterations in regulators of ribonucleic acid (RNA) splicing (eg, SRSF2) [29,104,109].

ASXL1 mutations are associated with poor prognosis [29,103-107]. The prognostic impact of mutations in ASXL1 and SRSF2 appears to be additive; while the presence of either portends a poor prognosis, patients with both abnormalities have an even worse prognosis.

The presence of mutated ASXL1 confers adverse prognosis. (See 'Adverse prognosis' below.)

Germline pathologic variants of RUNX1 are associated with a predisposition to AML and other hematologic disorders, as discussed separately. (See "Familial disorders of acute leukemia and myelodysplastic syndromes", section on 'Familial platelet disorder with propensity to myeloid malignancies (FPD)'.)

Spliceosome components — Mutations of genes that encode regulators of RNA splicing (eg, SRSF2, SF3B1, U2AF1, ZRSR2) are common in AML, especially in older patients and in those with antecedent myeloid disorders.

Mutations of regulators of RNA splicing are frequently associated with alterations of chromatin-modifying genes (ASXL1, STAG2, BCOR, MLL, EZH2, PHF6); together, mutations in RNA splicing regulators and chromatin modifiers constitute 18 percent of newly diagnosed AML [29]. Patients with these mutations are generally older and more frequently have antecedent myeloid disorders (eg, MDS).

Mutations of splicing regulators are associated with inferior outcomes [18,29,110-112]. The presence of these mutations confers an adverse prognosis. (See 'New features in European LeukemiaNet 2022' below.)

Other features — Other features of AML blasts have been associated with outcomes in patients with AML, but they are generally not used in clinical practice. Examples include gene expression profiling, microRNA expression, multidrug resistance/drug efflux pumps (eg, P-glycoprotein), and expression of CD25 (interleukin 2 [IL-2] receptor alpha) [113-119].

Measurable residual disease — Measurable residual disease (MRD) refers to the detection of malignant cells, even in the setting of apparent hematologic complete remission. MRD can be used for prognostic purposes, disease monitoring, and response assessment in AML.

The two most widely applied technologies for detecting MRD are multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (RT-qPCR). European LeukemiaNet has published standardized methods for MFC-MRD and RT-qPCR MRD thresholds, MRD response definitions, and application of MRD for clinical decision making [120]. Other techniques that have been developed for assessing MRD include NGS and digital droplet PCR [121,122]. A positive MRD test result refers to the detection of leukemic cells above a specific threshold, which may vary by assay and laboratory.

The prognostic value of MRD has been validated for patients treated with both intensive chemotherapy and lower-intensity therapies.

●A meta-analysis that included 11,151 patients reported that OS and DFS were superior for patients who achieved MRD negativity compared with patients with detectable MRD [123]. MRD-negative patients had a better five-year OS (68 versus 34 percent; hazard ratio [HR] 0.36 [95% CI 0.33-0.39]) and five-year DFS (64 versus 25 percent; HR 0.37 [95% CI 0.34-0.40]). The value of MRD negativity was consistent across age groups, AML subtypes, time of MRD assessment, specimen source, and method for MRD detection.

●MRD measured by RT-qPCR after two cycles of intensive chemotherapy was an independent prognostic factor in 346 patients with NPM1-mutated AML (HR for death 4.38 [95% CI 2.57-7.47]) [124]. MRD measured by an NGS panel after two cycles of intensive therapy was also associated with better outcomes in a study of 482 patients; those with persistent MRD had an inferior four-year OS (42 versus 66 percent; HR for death 2.06) and higher rates of relapse at four years (55 versus 32 percent) [125].

●MRD also has prognostic value for patients treated with less intensive therapy, but it is less well documented is these settings. In a trial that used azacitidine plus venetoclax (VIALE-A), patients with CR and MRD negativity had a longer OS (HR 0.29 [95% CI 0.16-0.51]), longer EFS, and greater duration of response [126]. Other studies have also demonstrated the prognostic value of MRD in patients treated for AML with lower-intensity therapy [127-129].

The application of MRD for treatment decisions in patients with AML is discussed separately. (See "Acute myeloid leukemia: Induction therapy in medically fit adults", section on 'Measurable residual disease'.)

EUROPEAN LEUKEMIANET 2022 CLASSIFICATION — We assess the prognosis of patients with AML using European LeukemiaNet (ELN) 2022 guidelines, which integrates cytogenetic and molecular features of the leukemic blasts and incorporates response assessment, such as measurable residual disease (MRD) [130].

New features in European LeukemiaNet 2022 — Compared with the previous ELN risk-stratification model (2017) [131], ELN 2022 differs in the following ways [130]:

●FLT3 – All cases of AML with FLT3-ITD (internal tandem duplication) are categorized as intermediate risk; this classification is irrespective of the allelic ratio or concurrent NPM1 mutation.

●Myelodysplasia-related gene mutations – ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 are now included as adverse prognostic features, whether they are associated with antecedent hematologic disease (eg, myelodysplastic syndromes [MDS]/neoplasia) or found in de novo AML.

●NPM1 – Mutated NPM1 in association with adverse cytogenetic features is considered adverse risk.

●CEBPA – Only in-frame mutations of the CEBPA basic leucine zipper (bZIP) region confer a favorable prognosis; this mutation can be mono- or bi-allelic.

●Additional disease-defining cytogenetic abnormalities – Examples of new abnormalities that now confer adverse risk are t(3q26.2;v) involving MECOM and t(8;16)(p11;p13) associated with KAT6A::CREBBP gene fusion.

●Hyperdiploid karyotypes – Hyperdiploid karyotypes with multiple trisomies or polysomies are no longer considered complex karyotypes.

Prognostic categories — ELN 2022 divides cases of AML into three prognostic risk groups that differ based on rates of complete remission, disease-free survival, and/or overall survival [130].

Numerous prospective clinical trials and retrospective studies have reported associations of cytogenetic and molecular features with outcomes in patients with AML [29,130]. However, it is important to recognize that ELN 2022 is largely based on data from patients who receive intensive treatments. (See "Acute myeloid leukemia: Induction therapy in medically fit adults".)

ELN 2022 is less applicable to patients who are treated with less intensive regimens, such as hypomethylating agent-based therapies. Prognosis in older patients, who are more likely to receive lower-intensity treatments, is discussed separately. (See "Pretreatment evaluation and prognosis of acute myeloid leukemia in older adults".)

Cytogenetic and molecular features that confer a prognostic category are listed in the following sections.

Favorable prognosis

•t(8;21)(q22;q22.1); RUNX1::RUNX1T1 (presence of KIT or FLT3 mutations does not alter the risk category)

•inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB::MYH11

•Mutated NPM1 without FLT3-ITD or adverse-risk cytogenetic abnormalities

•In-frame bZIP mutated CEBPA (mono- or bi-allelic)

Intermediate prognosis

•FLT3-ITD (irrespective of allelic ratio or NPM1 mutation)

•t(9;11)(p21.3;q23.3)/MLLT3::KMT2A (this mutation takes precedence over rare, concurrent adverse-risk gene mutations)

•Cytogenetic and/or molecular abnormalities not classified as favorable or adverse

Adverse prognosis

•t(6;9)(p23;q34.1)/DEK::NUP214

•t(v;11q23.3)/KMT2A rearranged (excluding KMT2A-PTD [partial tandem duplication])

•t(9;22)(q34.1;q11.2)/BCR::ABL1

•(8;16)(p11;p13)/KAT6A::CREBBP

•inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM (EVI1)

•t(3q26.2;v)/MECOM (EVI1)-rearranged

•-5 or del(5q); -7; 17/abn(17p)

•Monosomal karyotype or complex karyotype (ie, ≥3 unrelated chromosome abnormalities in the absence of other class-defining recurring genetic abnormalities; this excludes hyperdiploid karyotypes with ≥3 trisomies or polysomies without structural abnormalities)

•Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2 (mutated NPM1 plus one of these adverse findings remains in the adverse-risk category)

•Mutated TP53 (variant allele frequency ≥10 percent), irrespective of TP53 allelic status (ie, mono- or bi-allelic mutation)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Acute myeloid leukemia (AML) treatment in adults (Beyond the Basics)")

SUMMARY

●Description – Acute myeloid leukemia (AML) refers to a diverse category of myeloid neoplasms.

Individual subtypes of AML are defined by cytogenetic (ie, chromosomal) abnormalities and molecular features (ie, mutations), as discussed separately. (See "Acute myeloid leukemia: Classification".)

●Risk factors – Outcomes in patients treated for AML are affected by clinical aspects of the individual patient and by cytogenetic and molecular features of the leukemic blasts.

●Clinical risk factors – The major clinical features that are associated with outcomes in patients with AML:

•Age – Older age is generally associated with inferior outcomes. (See 'Age' above.)

•Performance status – Performance status (PS) generally reflects comorbid conditions and overall fitness. The most common tools to assess PS are Karnofsky PS (table 1A) and Eastern Cooperative Oncology Group (ECOG) (table 1B).

•Prior cytotoxic treatments – AML that arises in a person who was previously treated with cytotoxic chemotherapy or radiation therapy is described as a therapy-related myeloid neoplasm and is associated with an adverse prognosis. (See 'Therapy-related myeloid neoplasms' above.)

•Antecedent hematologic disorders – AML that arises in a patient with an underlying hematologic disorder (eg, myelodysplastic syndrome/neoplasm [MDS]) is associated with worse outcomes than the corresponding de novo subtype. (See 'Antecedent hematologic disorders' above.)

●Cytogenetic/molecular features – Cytogenetic and molecular features of leukemic blasts are important for prognosis, aspects of treatment selection, and classification of AML subtypes.

•Cytogenetics – Metaphase chromosome banding (karyotyping), with or without FISH (fluorescence in situ hybridization), is used to define cytogenetic abnormalities in AML. More than one-half of cases of AML have cytogenetic abnormalities. (See 'Cytogenetics' above.)

•Mutations – Mutation status in AML is primarily assessed using next generation sequencing (NGS) myeloid gene panels. The frequency and impact on the prognosis of individual mutations associated with AML are discussed above. (See 'Mutations' above.)

●European LeukemiaNet 2022 – European LeukemiaNet (ELN) 2022 is the preferred model for assessing a prognosis in patients with AML. Changes from the previous ELN model are discussed above. (See 'New features in European LeukemiaNet 2022' above.)

●Prognostic categories – Note that important details of qualifying cytogenetic features are described above.

•Favorable (see 'Favorable prognosis' above)

-t(8;21)(q22;q22.1); RUNX1::RUNX1T1

-inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB::MYH11

-Mutated NPM1 without FLT3-ITD

-In-frame bZIP mutated CEBPA

•Intermediate (see 'Intermediate prognosis' above)

-FLT3-ITD (internal tandem duplication)

-t(9;11)(p21.3;q23.3)/MLLT3::KMT2A

-Cytogenetic and/or molecular abnormalities not classified as favorable or adverse

•Adverse (see 'Adverse prognosis' above)

-t(6;9)(p23;q34.1)/DEK::NUP214

-t(v;11q23.3)/KMT2A rearranged

-t(9;22)(q34.1;q11.2)/BCR::ABL1

-(8;16)(p11;p13)/KAT6A::CREBBP

-inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2, MECOM (EVI1)

-t(3q26.2;v)/MECOM (EVI1)-rearranged

--5 or del(5q); -7; 17/abn(17p)

-Monosomal karyotype or complex karyotype

-Mutated splicing factors (ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2)

-Mutated TP53

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  125. Jongen-Lavrencic M, Grob T, Hanekamp D, et al. Molecular Minimal Residual Disease in Acute Myeloid Leukemia. N Engl J Med 2018; 378:1189.
  126. Pratz KW, Jonas BA, Pullarkat V, et al. Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine. J Clin Oncol 2022; 40:855.
  127. Maiti A, DiNardo CD, Wang SA, et al. Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia. Blood Adv 2021; 5:1876.
  128. Simoes C, Paiva B, Martínez-Cuadrón D, et al. Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical trial. Blood Adv 2021; 5:760.
  129. Santaliestra M, Garrido A, Carricondo M, et al. Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5-azacytidine: Identification of responding patients. Eur J Haematol 2019; 103:208.
  130. Döhner H, Wei AH, Appelbaum FR, et al. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN. Blood 2022; 140:1345.
  131. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017; 129:424.
Topic 4516 Version 75.0

References

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2 : Significance of age in acute myeloid leukemia patients younger than 30 years: a common analysis of the pediatric trials AML-BFM 93/98 and the adult trials AMLCG 92/99 and AMLSG HD93/98A.

3 : High-dose daunorubicin in older patients with acute myeloid leukemia.

4 : Therapeutic options for acute myelogenous leukemia.

5 : Morphologic dysplasia in de novo acute myeloid leukemia (AML) is related to unfavorable cytogenetics but has no independent prognostic relevance under the conditions of intensive induction therapy: results of a multiparameter analysis from the German AML Cooperative Group studies.

6 : Do quality of life or physical function at diagnosis predict short-term outcomes during intensive chemotherapy in AML?

7 : Prediction of early death after induction therapy for newly diagnosed acute myeloid leukemia with pretreatment risk scores: a novel paradigm for treatment assignment.

8 : Age and acute myeloid leukemia.

9 : Therapy-related leukemia and myelodysplasia: susceptibility and incidence.

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11 : Clinicobiological features and outcome of acute promyelocytic leukemia occurring as a second tumor: the GIMEMA experience.

12 : Etiology and management of therapy-related myeloid leukemia.

13 : Mutational profiling of therapy-related myelodysplastic syndromes and acute myeloid leukemia by next generation sequencing, a comparison with de novo diseases.

14 : Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia.

15 : International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.

16 : The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms.

17 : Epidemiology and Clinical Significance of Secondary and Therapy-Related Acute Myeloid Leukemia: A National Population-Based Cohort Study.

18 : Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

19 : Multilineage dysplasia (MLD) in acute myeloid leukemia (AML) correlates with MDS-related cytogenetic abnormalities and a prior history of MDS or MDS/MPN but has no independent prognostic relevance: a comparison of 408 cases classified as "AML not otherwise specified" (AML-NOS) or "AML with myelodysplasia-related changes" (AML-MRC).

20 : Outcomes of acute myeloid leukemia with myelodysplasia related changes depend on diagnostic criteria and therapy.

21 : Poor Survival and Differential Impact of Genetic Features of Black Patients with Acute Myeloid Leukemia.

22 : Differences in prognostic factors and outcomes in African Americans and whites with acute myeloid leukemia.

23 : Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.

24 : Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461).

25 : The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties.

26 : Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype.

27 : Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience.

28 : Dismal prognostic value of monosomal karyotype in elderly patients with acute myeloid leukemia: a GOELAMS study of 186 patients with unfavorable cytogenetic abnormalities.

29 : Genomic Classification and Prognosis in Acute Myeloid Leukemia.

30 : Mutations and treatment outcome in cytogenetically normal acute myeloid leukemia.

31 : Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.

32 : Acute myeloid leukemia carrying cytoplasmic/mutated nucleophosmin (NPMc+ AML): biologic and clinical features.

33 : Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations.

34 : Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML).

35 : Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype.

36 : Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype.

37 : Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers.

38 : Favorable prognostic impact of NPM1 gene mutations in childhood acute myeloid leukemia, with emphasis on cytogenetically normal AML.

39 : Favorable prognostic impact of NPM1 mutations in older patients with cytogenetically normal de novo acute myeloid leukemia and associated gene- and microRNA-expression signatures: a Cancer and Leukemia Group B study.

40 : AML with mutated NPM1 carrying a normal or aberrant karyotype show overlapping biologic, pathologic, immunophenotypic, and prognostic features.

41 : High NPM1-mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML.

42 : Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

43 : Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials.

44 : Mutations in nucleophosmin (NPM1) in acute myeloid leukemia (AML): association with other gene abnormalities and previously established gene expression signatures and their favorable prognostic significance.

45 : Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia.

46 : Prognostic significance of FLT3 internal tandem duplication, nucleophosmin 1, and CEBPA gene mutations for acute myeloid leukemia patients with normal karyotype and younger than 60 years: a systematic review and meta-analysis.

47 : Absence of the wild-type allele predicts poor prognosis in adult de novo acute myeloid leukemia with normal cytogenetics and the internal tandem duplication of FLT3: a cancer and leukemia group B study.

48 : The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials.

49 : Activating mutation of D835 within the activation loop of FLT3 in human hematologic malignancies.

50 : Identification of novel FLT-3 Asp835 mutations in adult acute myeloid leukaemia.

51 : Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia.

52 : Internal tandem duplication of the flt3 gene found in acute myeloid leukemia.

53 : Risk assessment in patients with acute myeloid leukemia and a normal karyotype.

54 : Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm.

55 : FLT3 internal tandem duplication associates with adverse outcome and gene- and microRNA-expression signatures in patients 60 years of age or older with primary cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

56 : Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16).

57 : Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia.

58 : The FLT3ITD mRNA level has a high prognostic impact in NPM1 mutated, but not in NPM1 unmutated, AML with a normal karyotype.

59 : Impact of numerical variation in FMS-like tyrosine kinase receptor 3 internal tandem duplications on clinical outcome in normal karyotype acute myelogenous leukemia.

60 : Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis.

61 : The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia.

62 : Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.

63 : CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations.

64 : Prognostic significance of CEBPA mutations in a large cohort of younger adult patients with acute myeloid leukemia: impact of double CEBPA mutations and the interaction with FLT3 and NPM1 mutations.

65 : Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA).

66 : Prognostic significance of, and gene and microRNA expression signatures associated with, CEBPA mutations in cytogenetically normal acute myeloid leukemia with high-risk molecular features: a Cancer and Leukemia Group B Study.

67 : Prevalence, clinical profile, and prognosis of NPM mutations in AML with normal karyotype.

68 : Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group.

69 : Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity.

70 : Somatic CEBPA mutations are a frequent second event in families with germline CEBPA mutations and familial acute myeloid leukemia.

71 : The favorable impact of CEBPA mutations in patients with acute myeloid leukemia is only observed in the absence of associated cytogenetic abnormalities and FLT3 internal duplication.

72 : Multilineage dysplasia does not influence prognosis in CEBPA-mutated AML, supporting the WHO proposal to classify these patients as a unique entity.

73 : CEBPA mutations in 4708 patients with acute myeloid leukemia: differential impact of bZIP and TAD mutations on outcome.

74 : Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.

75 : Oncometabolite 2-hydroxyglutarate is a competitive inhibitor ofα-ketoglutarate-dependent dioxygenases.

76 : IDH1 and IDH2 gene mutations identify novel molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study.

77 : IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication.

78 : Acquired mutations in the genes encoding IDH1 and IDH2 both are recurrent aberrations in acute myeloid leukemia: prevalence and prognostic value.

79 : Molecular alterations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) metabolic genes and additional genetic mutations in newly diagnosed acute myeloid leukemia patients.

80 : Distinct clinical and biologic characteristics in adult acute myeloid leukemia bearing the isocitrate dehydrogenase 1 mutation.

81 : Recurring mutations found by sequencing an acute myeloid leukemia genome.

82 : The prognostic impact and stability of Isocitrate dehydrogenase 2 mutation in adult patients with acute myeloid leukemia.

83 : Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia.

84 : Age-related prognostic impact of different types of DNMT3A mutations in adults with primary cytogenetically normal acute myeloid leukemia.

85 : DNMT3A mutations in acute myeloid leukemia.

86 : Prognostic impact of DNMT3A mutations in patients with intermediate cytogenetic risk profile acute myeloid leukemia.

87 : Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association.

88 : Age-related mutations associated with clonal hematopoietic expansion and malignancies.

89 : Age-related clonal hematopoiesis associated with adverse outcomes.

90 : Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.

91 : Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): a Cancer and Leukemia Group B Study.

92 : Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML).

93 : KIT mutations confer a distinct gene expression signature in core binding factor leukaemia.

94 : Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG).

95 : Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study.

96 : KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival.

97 : Avapritinib is effective for treatment of minimal residual disease in acute myeloid leukemia with t (8;21) and kit mutation failing to immunotherapy after allogeneic hematopoietic stem cell transplantation.

98 : Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.

99 : The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases.

100 : TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome.

101 : RUNX1 mutations in acute myeloid leukemia: results from a comprehensive genetic and clinical analysis from the AML study group.

102 : RUNX1 mutations in acute myeloid leukemia are associated with distinct clinico-pathologic and genetic features.

103 : Genetic analysis of transforming events that convert chronic myeloproliferative neoplasms to leukemias.

104 : Mutual exclusion of ASXL1 and NPM1 mutations in a series of acute myeloid leukemias.

105 : Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia.

106 : Distinct clinical and biological features of de novo acute myeloid leukemia with additional sex comb-like 1 (ASXL1) mutations.

107 : ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome.

108 : ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category.

109 : Frequent ASXL2 mutations in acute myeloid leukemia patients with t(8;21)/RUNX1-RUNX1T1 chromosomal translocations.

110 : Added prognostic value of secondary AML-like gene mutations in ELN intermediate-risk older AML: ALFA-1200 study results.

111 : Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification.

112 : Machine learning integrates genomic signatures for subclassification beyond primary and secondary acute myeloid leukemia.

113 : Prognostically useful gene-expression profiles in acute myeloid leukemia.

114 : An 86-probe-set gene-expression signature predicts survival in cytogenetically normal acute myeloid leukemia.

115 : Identification of a 24-gene prognostic signature that improves the European LeukemiaNet risk classification of acute myeloid leukemia: an international collaborative study.

116 : Independent confirmation of a prognostic gene-expression signature in adult acute myeloid leukemia with a normal karyotype: a Cancer and Leukemia Group B study.

117 : The prognostic and functional role of microRNAs in acute myeloid leukemia.

118 : MDR1 and MRP1 gene expression are independent predictors for treatment outcome in adult acute myeloid leukaemia.

119 : CD25 expression status improves prognostic risk classification in AML independent of established biomarkers: ECOG phase 3 trial, E1900.

120 : 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party.

121 : Sequencing-Based Measurable Residual Disease Testing in Acute Myeloid Leukemia.

122 : Quantification of rare NPM1 mutation subtypes by digital PCR.

123 : Association of Measurable Residual Disease With Survival Outcomes in Patients With Acute Myeloid Leukemia: A Systematic Review and Meta-analysis.

124 : Assessment of Minimal Residual Disease in Standard-Risk AML.

125 : Molecular Minimal Residual Disease in Acute Myeloid Leukemia.

126 : Measurable Residual Disease Response and Prognosis in Treatment-Naïve Acute Myeloid Leukemia With Venetoclax and Azacitidine.

127 : Prognostic value of measurable residual disease after venetoclax and decitabine in acute myeloid leukemia.

128 : Measurable residual disease in elderly acute myeloid leukemia: results from the PETHEMA-FLUGAZA phase 3 clinical trial.

129 : Bone marrow WT1 levels in patients with myeloid neoplasms treated with 5-azacytidine: Identification of responding patients.

130 : Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.

131 : Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.

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