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BACKGROUND: Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent. METHODS: This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete. FINDINGS: Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified. INTERPRETATION: An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes. FUNDING: Bristol Myers Squibb.
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The evaluation of measurable residual disease (MRD) in acute myeloid leukemia (AML) using comprehensive mutation analysis by next-generation sequencing (NGS) has been investigated in several studies. However controversial results exist regarding the detection of persisting mutations in DNMT3A, TET2, and ASXL1 (DTA). Benchmarking of NGS-MRD taking into account other molecular MRD strategies has to be done. Here, we performed error-corrected-NGS-MRD in 189 patients homogeneously treated in the ALFA-0702 study (NCT00932412). Persistence of non-DTA mutations (HR = 2.23 for RFS and 2.26 for OS), and DTA mutations (HR = 2.16 for OS) were associated with poorer prognosis in multivariate analysis. Persistence of at least two mutations in complete remission (CR) was associated with a higher cumulative incidence of relapse (CIR) (HR = 3.71, p < 0.0001), lower RFS (HR = 3.36, p < 0.0001) and OS (HR = 3.81, p = 0.00023) whereas persistence of only one mutation was not. In 100 analyzable patients, WT1-MRD, but not NGS-MRD, was an independent factor for RFS and OS. In the subset of 67 NPM1 mutated patients, both NPM1 mutation detection (p = 0.0059) and NGS-MRD (p = 0.035) status were associated with CIR. We conclude that detectable NGS-MRD including DTA mutations correlates with unfavorable prognosis in AML. Its integration with alternative MRD strategies in AML management warrants further investigations.
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Secuenciación de Nucleótidos de Alto Rendimiento , Leucemia Mieloide Aguda , Mutación , Neoplasia Residual , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Femenino , Masculino , Persona de Mediana Edad , Adulto , Anciano , Adulto Joven , Pronóstico , ADN Metiltransferasa 3A , Anciano de 80 o más Años , ADN (Citosina-5-)-Metiltransferasas/genética , Adolescente , Proteínas Represoras/genética , Análisis Mutacional de ADNRESUMEN
We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.
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Síndrome Hipereosinofílico , Mutación , Factor de Transcripción STAT5 , Humanos , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Factor de Transcripción STAT5/genética , Janus Quinasa 2/genética , Transducción de Señal , Janus Quinasa 1/genética , Anciano de 80 o más Años , Pirimidinas/uso terapéutico , Adulto JovenRESUMEN
BACKGROUND OF THE STUDY: AML classification tools have been developed to stratify the risk at AML diagnosis. There is a need to evaluate these tools in the current therapeutic era. COHORT CHARACTERISTICS: In this retrospective study, we compared five classifiers: ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil et al. classifier, and Lindsley et al. classifier, in a real-life cohort of 281 patients newly diagnosed for AML in Nice University Hospital. In our cohort median age was 68 years old, sex ratio was M/F 56%/44%, performance status was lower than 2 in 73.1% of patients, AML subtype was "De novo" in 71.5%, "secondary" in 22.4%, and "therapy-related" in 6.0% of patients. Intensive chemotherapy was used in 53.0% of patients, and non-intensive chemotherapy in 40.6% of patients. Molecular analysis was available in a large majority of patients and the main mutations found were NPM1 (22.7%), DNMT3A (17.4%), TP53 (13.1%), TET2 (12.4%), and FLT3-ITD (12.4%). RESULTS: In our findings, the comparison of overall survival between the three prognostic groups in the global cohort was statistically significant in all classifiers: ELN 2017 p < 0.0001, ELN 2022 p < 0.0001, ALFA classifier p < 0.0001, Papaemmanuil classifier p < 0.0001, Lindsley classifier p = 0.001. ELN 2017, ELN 2022, ALFA classifier, Papaemmanuil classifier, and Lindsley classifier were calculated respectively in 99%, 99%, 89%, 90%, and 89% of patients. CONCLUSIONS: Using Akaike's information criteria (AIC) to compare all five classifiers, ELN 2022 is the best classifier into younger and older patients and for prognosis.
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Leucemia Mieloide Aguda , Humanos , Anciano , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Nucleofosmina , Estudios Retrospectivos , Pronóstico , Mutación , Medición de RiesgoRESUMEN
The spectrum of childhood leukemia predisposition syndromes has grown significantly over last decades. These predisposition syndromes mainly involve CEBPA, ETV6, GATA2, IKZF1, PAX5, RUNX1, SAMD9/SAMD9L, TP53, RAS-MAPK pathway, DNA mismatch repair system genes, genes associated with Fanconi anemia, and trisomy 21. The clinico-biological features leading to the suspicion of a leukemia predisposition are highly heterogeneous and require varied exploration strategies. The study of the initial characteristics of childhood leukemias includes high-throughput sequencing techniques, which have increased the frequency of situations where a leukemia predisposing syndrome is suspected. Identification of a leukemia predisposition syndrome can have a major impact on the choice of chemotherapy, the indication for hematopoietic stem cell transplantation, and screening for associated malformations and pathologies. The diagnosis of a predisposition syndrome can also lead to the exploration of family members and genetic counseling. Diagnosis and management should be based on dedicated and multidisciplinary care networks.
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Síndrome de Down , Leucemia , Neoplasias , Niño , Humanos , Leucemia/diagnóstico , Leucemia/genética , Leucemia/terapia , Familia , Predisposición Genética a la Enfermedad , Péptidos y Proteínas de Señalización IntracelularRESUMEN
Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms).
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Leucemia Mieloide Aguda , Adulto , Humanos , Proteínas Potenciadoras de Unión a CCAAT/genética , Mutación del Sistema de Lectura , Mutación , PronósticoRESUMEN
Whether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing-based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.
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Leucemia Mieloide Aguda , Nucleofosmina , Adulto , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Inducción de Remisión , Supervivencia sin Enfermedad , Factores de Riesgo , Neoplasia Residual/genéticaRESUMEN
Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.
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Leucemia Mieloide Aguda , Adulto , Niño , Humanos , Supervivencia sin Enfermedad , Tirosina Quinasa 3 Similar a fms/genética , Leucemia Mieloide Aguda/genética , Mutación , Pronóstico , Inducción de RemisiónRESUMEN
The advent of new technologies has made it possible to identify genetic predispositions to myelodysplastic syndromes (MDS) and acute leukemias (AL) more frequently. The most frequent and best characterized at present are mutations in CEBPA, RUNX1, GATA2, ETV6 and DDX41 and, either in the presence of one of these mutations with a high allelic frequency, or in the case of a personal or family history suggestive of blood abnormalities such as non-immune thrombocytopenia, it is recommended to look for the possibility of a hereditary hematological malignancy (HHM). Indeed, early recognition of these HHMs allows better adaptation of the management of patients and their relatives, as allogeneic hematopoietic stem cell transplantation (HSCT) is very often proposed for these pathologies. According to current data, with the exception of the GATA2 mutation, the constitutional or somatic nature of the mutations does not seem to influence the prognosis of hematological diseases. Therefore, the indication for an allograft will be determined according to the usual criteria. However, when searching for a family donor, it is important to ensure that there is no hereditary disease in the donor. In order to guarantee the possibility of performing the HSC allograft within a short period of time, it may be necessary to initiate a parallel procedure to find an unrelated donor. Given the limited information on the modalities of HSC transplantation in this setting, it is important to assess the benefit/risk of the disease and the procedure to decide on the type of conditioning (myeloablative or reduced intensity). In view of the limited experience with the risk of secondary cancers in the medium and long-term, it may be appropriate to recommend reduced intensity conditioning, as in the case of better characterized syndromic hematological diseases such as Fanconi anemia or telomere diseases. In summary, it seems important to evoke HHM more frequently, particularly in the presence of a family history, certain mutations or persistent blood abnormalities, in order to discuss the specific modalities of HSC allografting, particularly with regard to the search for a donor and the evaluation of certain modalities of the procedure, such as conditioning. It should be noted that the discovery of HHM, especially if the indication of an allogeneic HSC transplant is retained, will raise ethical and psychological considerations not only for the patient, but also for his family. A multidisciplinary approach involving molecular biologists, geneticists, hematologists and psychologists is essential.
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Enfermedades Hematológicas , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Leucemia , Humanos , Predisposición Genética a la Enfermedad , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia/genética , Leucemia/terapia , Acondicionamiento Pretrasplante/métodosRESUMEN
BACKGROUND: Internal tandem duplications in the FLT3 gene, termed FLT3-ITDs, are useful molecular markers in acute myeloid leukemia (AML) for patient risk stratification and follow-up. FLT3-ITDs are increasingly screened through high-throughput sequencing (HTS) raising the need for robust and efficient algorithms. We developed a new algorithm, which performs no alignment and uses little resources, to identify and quantify FLT3-ITDs in HTS data. RESULTS: Our algorithm (FiLT3r) focuses on the k-mers from reads covering FLT3 exons 14 and 15. We show that those k-mers bring enough information to accurately detect, determine the length and quantify FLT3-ITD duplications. We compare the performances of FiLT3r to state-of-the-art alternatives and to fragment analysis, the gold standard method, on a cohort of 185 AML patients sequenced with capture-based HTS. On this dataset FiLT3r is more precise (no false positive nor false negative) than the other software evaluated. We also assess the software on public RNA-Seq data, which confirms the previous results and shows that FiLT3r requires little resources compared to other software. CONCLUSION: FiLT3r is a free software available at https://gitlab.univ-lille.fr/filt3r/filt3r . The repository also contains a Snakefile to reproduce our experiments. We show that FiLT3r detects FLT3-ITDs better than other software while using less memory and time.
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Leucemia Mieloide Aguda , Secuencias Repetidas en Tándem , Humanos , Secuencias Repetidas en Tándem/genética , Leucemia Mieloide Aguda/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Exones , Secuencia de Bases , Tirosina Quinasa 3 Similar a fms/genética , MutaciónRESUMEN
DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We describe here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of these patients, treated with intensive chemotherapy in 5 prospective Acute Leukemia French Association/French Innovative Leukemia Organization trials, were compared with those of 1604 patients with DDX41 wild-type (DDX41WT) AML, representing a prevalence of 5%. Patients with DDX41MutGL AML were mostly male (75%), in their seventh decade, and with low leukocyte count (median, 2 × 109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%), and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients, and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission rates (94% vs 69%; P < .0001) and longer restricted mean overall survival censored at hematopoietic stem cell transplantation (HSCT) than 2017 European LeukemiaNet intermediate/adverse (Int/Adv) DDX41WT patients (5-year difference in restricted mean survival times, 13.6 months; P < .001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs 44%) but later increased to be similar to Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first complete remission was associated with prolonged relapse-free survival (hazard ratio, 0.43; 95% confidence interval, 0.21-0.88; P = .02) but not with longer overall survival (hazard ratio, 0.77; 95% confidence interval, 0.35-1.68; P = .5).
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , ARN Helicasas DEAD-box/genética , Femenino , Mutación de Línea Germinal , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/terapia , Masculino , Pronóstico , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
OBJECTIVE: The detection of somatic mutations among the genes of myeloid cells in asymptomatic patients-defining clonal haematopoiesis of indeterminate potential (CHIP)-is associated with a predisposition to cardiovascular events (CVEs) in the general population. We aimed to determine whether CHIP was associated with CVEs in SLE patients. METHODS: The study is an ancillary study of the randomized, double-blind, placebo-controlled, multicentre PLUS trial conducted from June 2007 through August 2010 at 37 centres in France, involving 573 SLE patients. The search for somatic mutations by high-throughput sequencing of 53 genes involved in clonal haematopoiesis was performed on genomic DNA collected at PLUS inclusion. CHIP prevalence was assessed in SLE and in a retrospective cohort of 479 patients free of haematological malignancy. The primary outcome was an incident CVE in SLE. RESULTS: Screening for CHIP was performed in 438 SLE patients [38 (29-47) years, 91.8% female]. Overall, 63 somatic mutations were identified in 47 patients, defining a CHIP prevalence of 10.7% in SLE. Most SLE patients (78.7%) carried a single mutation. Most variants (62.5%) were located in the DNMT3A gene. CHIP frequency was related to age and to age at SLE diagnosis, and was associated with a lower frequency of aPLs. CHIP occurred >20 years earlier (P < 0.00001) in SLE than in controls. The detection of CHIP at inclusion was not found to be associated with occurrence of CVEs during follow-up [HR = 0.42 (0.06-3.21), P = 0.406]. CONCLUSION: The prevalence of CHIP is relatively high in SLE for a given age, but was not found to be associated with incident CVEs. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT05146414.
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Enfermedades Cardiovasculares , Lupus Eritematoso Sistémico , Humanos , Femenino , Masculino , Hematopoyesis Clonal , Hematopoyesis/genética , Estudios Retrospectivos , Lupus Eritematoso Sistémico/complicaciones , Enfermedades Cardiovasculares/complicacionesAsunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucocitosis/diagnóstico , Monocitos/citología , Anciano de 80 o más Años , Recuento de Células Sanguíneas , Análisis Citogenético , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Inmunofenotipificación , Leucemia Mielógena Crónica BCR-ABL Positiva/etiología , Leucocitosis/etiología , Masculino , Evaluación de SíntomasRESUMEN
The independent prognostic impact of specific dysplastic features in acute myeloid leukemia (AML) remains controversial and may vary between genomic subtypes. We apply a machine learning framework to dissect the relative contribution of centrally reviewed dysplastic features and oncogenetics in 190 patients with de novo AML treated in ALFA clinical trials. One hundred and thirty-five (71%) patients achieved complete response after the first induction course (CR). Dysgranulopoiesis, dyserythropoiesis and dysmegakaryopoiesis were assessable in 84%, 83% and 63% patients, respectively. Multi-lineage dysplasia was present in 27% of assessable patients. Micromegakaryocytes (q = 0.01), hypolobulated megakaryocytes (q = 0.08) and hyposegmented granulocytes (q = 0.08) were associated with higher ELN-2017 risk. Using a supervised learning algorithm, the relative importance of morphological variables (34%) for the prediction of CR was higher than demographic (5%), clinical (2%), cytogenetic (25%), molecular (29%), and treatment (5%) variables. Though dysplasias had limited predictive impact on survival, a multivariate logistic regression identified the presence of hypolobulated megakaryocytes (p = 0.014) and micromegakaryocytes (p = 0.035) as predicting lower CR rates, independently of monosomy 7 (p = 0.013), TP53 (p = 0.004), and NPM1 mutations (p = 0.025). Assessment of these specific dysmegakarypoiesis traits, for which we identify a transcriptomic signature, may thus guide treatment allocation in AML.
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Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Análisis Citogenético , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Aprendizaje Automático , Masculino , Megacariocitos/patología , Persona de Mediana Edad , Pronóstico , Resultado del TratamientoRESUMEN
Introduction: RUNX1 is an essential transcription factor for normal and malignant hematopoiesis. RUNX1 forms a heterodimeric complex with CBFB. Germline mutations and somatic alterations (i.e. translocations, mutations and abnormal expression) are frequently associated with acute myeloid leukemia (AML) with RUNX1 mutations conferring unfavorable prognosis. Therefore, RUNX1 constitutes a potential innovative and interesting therapeutic target. In this review, we discuss recent therapeutic advances of RUNX1 targeting in AML.Areas covered: Firstly, we cover the clinical basis for RUNX1 targeting. We have subdivided recent therapeutic approaches either by common biochemical pathways or by similar pharmacological targets. Genome editing of RUNX1 induces anti-leukemic effects; however, off-target events prohibit clinical use. Several molecules inhibit the interaction between RUNX1/CBFB and control AML development and progression. BET protein antagonists target RUNX1 (i.e. specific BET inhibitors, BRD4 shRNRA, proteolysis targeting chimeras (PROTAC) or expression-mimickers). All these molecules improve survival in mutant RUNX1 AML preclinical models.Expert opinion: Some of these novel molecules have shown encouraging anti-leukemic potency at the preclinical stage. A better understanding of RUNX1 function in AML development and progression and its key downstream pathways, may result in more precise and more efficient RUNX1 targeting therapies.