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INTRODUCTION: Elderly acute myeloid leukemia (AML) patients with poor-risk cytogenetics have a poor outcome with intensive chemotherapy (IC). While Venetoclax (VEN) has changed the outcomes of elderly unfit patients treatment, it is unknown whether it could be effective in poor-risk cytogenetics 60-75 years old patients. MATERIALS AND METHODS: We included 60-75-year-old AML patients eligible to allogenic stem cell transplantation (allo-SCT) treated with VEN (combined with azacitidine or with Cladribin and Aracytine) at Institut Paoli Calmettes, between 2020 and 2023 and compared this cohort with patients treated by IC between 2010 and 2019. RESULTS: Twenty six patients were treated with VEN (17 in combination with azacitidine and 9 with Cladribin and Aracytine) and 90 were treated with IC. Thirteen patients (50%) had a TP53 mutation. The median time for leucocyte and platelet counts recovery was 26 days (range 0-103) and 26 days (range, 0-63). The median duration of the first hospitalization was 32 days (ranges, 7-79). The composite response rate was 69% (CR = 50%, CRi = 4%, MLFS = 15%). Allo-SCT could be performed in 42% of cases. Median overall survival (OS) was 7.9 months (20.9 months in the group of patients who transitioned to allo-SCT). We found no difference with the historical cohort of patients treated with IC except a trend toward less lower and upper tract gastro-intestinal (GI) tract infections in the VEN group (respectively 8% vs 26%, p = .06; and 0% vs. 13% p = .06). CONCLUSION: VEN-based treatment was found to be effective in high risk AML can be considered as an alternative to IC in patients aged 60-75 with adverse cytogenetics.
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Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) can be monitored by quantitative PCR after having achieved first complete remission (CR) to detect morphologic relapse and drive preemptive therapy. How to best manage these patients is unknown. We retrospectively analyzed 303 patients with CBF and NPM1-mutated AML, aged 18-60 years, without allogeneic hematopoietic cell transplantation (HCT) in first CR, with molecular monitoring after first-line intensive therapy. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse (53 received preemptive therapy and 42 progressed to morphologic relapse at salvage therapy), and 55 (18%) had upfront morphologic relapse. Patients who received preemptive therapy had higher OS than those who received salvage therapy after having progressed from molecular to morphologic relapse and those with upfront morphologic relapse (three-year OS: 78% vs. 51% vs. 51%, respectively, P = 0.01). Preemptive therapy included upfront allogeneic HCT (n = 19), intensive chemotherapy (n = 21), and non-intensive therapy (n = 13; three-year OS: 92% vs. 79% vs. 58%, respectively, P = 0.09). Although not definitive due to the non-randomized allocation of patients to different treatment strategies at relapse, our study suggests that molecular monitoring should be considered during follow-up to start preemptive therapy before overt morphologic relapse.
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Leucemia Mieloide Aguda , Mutación , Proteínas Nucleares , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Adulto , Persona de Mediana Edad , Femenino , Masculino , Proteínas Nucleares/genética , Adolescente , Adulto Joven , Estudios Retrospectivos , Recurrencia , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Unión al Sitio Principal/genética , Pronóstico , Terapia Recuperativa , Inducción de Remisión , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patologíaAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Proteínas Nucleares , Nucleofosmina , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas Nucleares/genética , Persona de Mediana Edad , Masculino , Femenino , Anciano , Resultado del Tratamiento , Mutación , Adulto , PronósticoRESUMEN
Acute erythroid leukemia (AEL) is a rare (2%-5%) form of acute myeloid leukemia (AML). Molecular alterations found in AEL resemble those of other AMLs. We report a classification of AELs in three major classes, with different prognosis and some specific features such as a tendency to mutual exclusion of mutations in epigenetic regulators and signaling genes.
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Venetoclax (VEN) belongs the BH3-mimetic class that selectively targets BCL-2, activating apoptosis. The combination of VEN and azacitidine (AZA) has changed the paradigm of treatment of newly diagnosed (ND) acute myeloid leukemia (AML) patients ineligible for intensive chemotherapy. There is scarce evidence for the use of VEN-AZA for relapsed or refractory (R/R) AML. We compared the outcome of 39 R/R AML and 38 ND AML patients treated between 01/20 and 12/21. The median age was 69 (22-86) and 73 (61-81) in the R/R and ND groups, respectively. Adverse cytogenetics were found in 36% of patients in the R/R group and 59% of patients in the ND group. Overall response rate was 37% in R/R AML, including 13% CR, 8% CRi, 3% PR and 13% MLFS, and 58% in the ND AML, including 32% CR, 13% CRi and 13% MLFS. Adverse cytogenetics was associated with treatment failure in the R/R group (Relative Risk = 0.13, p = 0.005). Median overall survival (OS) was 5.9 months in the R/R group and 9.4 months in the ND group. Median OS was 2.2 months in the adverse cytogenetics group versus 8.7 months in the intermediate cytogenetics group in the R/R group (p = 0.02). Median leukemia-free survival was not different between the two groups (9.4 months and 10.3 months), indicating that VEN-AZA can be an efficient salvage treatment for selected R/R AML patients. In conclusion, VEN-AZA is a promising treatment for ND AML and for selected R/R AML patients.
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Translocation t(4;12)(q11-13;p13) is a recurrent but very rare chromosomal aberration in acute myeloid leukaemia (AML) resulting in the non-constant expression of a CHIC2/ETV6 fusion transcript. We report clinico-biological features, molecular characteristics and outcomes of 21 cases of t(4;12) including 19 AML and two myelodysplastic syndromes (MDS). Median age at the time of t(4;12) was 78 years (range, 56-88). Multilineage dysplasia was described in 10 of 19 (53%) AML cases and CD7 and/or CD56 expression in 90%. FISH analyses identified ETV6 and CHIC2 region rearrangements in respectively 18 of 18 and 15 of 17 studied cases. The t(4;12) was the sole cytogenetic abnormality in 48% of cases. The most frequent associated mutated genes were ASXL1 (n = 8/16, 50%), IDH1/2 (n = 7/16, 44%), SRSF2 (n = 5/16, 31%) and RUNX1 (n = 4/16, 25%). Interestingly, concurrent FISH and molecular analyses showed that t(4;12) can be, but not always, a founding oncogenic event. Median OS was 7.8 months for the entire cohort. In the 16 of 21 patients (76%) who received antitumoral treatment, overall response and first complete remission rates were 37% and 31%, respectively. Median progression-free survival in responders was 13.7 months. Finally, t(4;12) cases harboured many characteristics of AML with myelodysplasia-related changes (multilineage dysplasia, MDS-related cytogenetic abnormalities, frequent ASXL1 mutations) and a poor prognosis.
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Cromosomas Humanos Par 12 , Cromosomas Humanos Par 4 , Predisposición Genética a la Enfermedad , Trastornos Mieloproliferativos/diagnóstico , Trastornos Mieloproliferativos/genética , Translocación Genética , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Aberraciones Cromosómicas , Análisis Citogenético , Femenino , Estudios de Asociación Genética , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/etiología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/etiología , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Trastornos Mieloproliferativos/mortalidad , Trastornos Mieloproliferativos/terapia , PronósticoAsunto(s)
Leucemia Mieloide Aguda , Enfermedad Aguda , Niño , Humanos , Leucemia Mieloide Aguda/genéticaAsunto(s)
Cromosomas Humanos X/genética , Isocromosomas , Leucemia Mieloide/genética , Síndromes Mielodisplásicos/genética , Distribución por Edad , Anciano , Médula Ósea/patología , Cromosomas Humanos X/ultraestructura , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Estudios de Seguimiento , Genes Relacionados con las Neoplasias , Humanos , Leucemia Mieloide/epidemiología , Leucemia Mieloide/patología , Masculino , Persona de Mediana Edad , Mutación , Síndromes Mielodisplásicos/epidemiología , Síndromes Mielodisplásicos/patología , Proteínas de Neoplasias/genética , Neoplasias Primarias Secundarias/genética , Neoplasias Primarias Secundarias/patología , Proteínas Proto-Oncogénicas/genética , Distribución por SexoAsunto(s)
Predisposición Genética a la Enfermedad , Mutación , Policitemia Vera/genética , Mielofibrosis Primaria/genética , Trombocitemia Esencial/genética , Biomarcadores , Estudios de Asociación Genética , Humanos , Estimación de Kaplan-Meier , Policitemia Vera/diagnóstico , Policitemia Vera/mortalidad , Mielofibrosis Primaria/diagnóstico , Mielofibrosis Primaria/mortalidad , Pronóstico , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/mortalidadRESUMEN
Retinoic acid (RA) and arsenic target the t(15;17)(q24;q21) PML/RARA driver of acute promyelocytic leukemia (APL), their combination now curing over 95% patients. We report exome sequencing of 64 matched samples collected from patients at initial diagnosis, during remission, and following relapse after historical combined RA-chemotherapy treatments. A first subgroup presents a high incidence of additional oncogenic mutations disrupting key epigenetic or transcriptional regulators (primarily WT1) or activating MAPK signaling at diagnosis. Relapses retain these cooperating oncogenes and exhibit additional oncogenic alterations and/or mutations impeding therapy response (RARA, NT5C2). The second group primarily exhibits FLT3 activation at diagnosis, which is lost upon relapse together with most other passenger mutations, implying that these relapses derive from ancestral pre-leukemic PML/RARA-expressing cells that survived RA/chemotherapy. Accordingly, clonogenic activity of PML/RARA-immortalized progenitors ex vivo is only transiently affected by RA, but selectively abrogated by arsenic. Our studies stress the role of cooperating oncogenes in direct relapses and suggest that targeting pre-leukemic cells by arsenic contributes to its clinical efficacy.
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Antineoplásicos/administración & dosificación , Trióxido de Arsénico/administración & dosificación , Resistencia a Antineoplásicos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Tretinoina/administración & dosificación , 5'-Nucleotidasa/genética , 5'-Nucleotidasa/metabolismo , Animales , Humanos , Leucemia Promielocítica Aguda/metabolismo , Masculino , Ratones , Mutación , Proteína de la Leucemia Promielocítica/genética , Proteína de la Leucemia Promielocítica/metabolismo , Recurrencia , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Tirosina Quinasa 3 Similar a fms/genética , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Acute myeloid leukemias secondary (sAML) to myeloproliferative neoplasms (MPN) have variable clinical courses and outcomes, but remain almost always fatal. Large cohorts of sAML to MPN are difficult to obtain and there is very little scientific literature or prospective trials for determining robust prognostic markers and efficient treatments. We analyzed event-free survival (EFS) and overall survival (OS) of 73 patients with MPN who progressed to sAML, based on their epidemiological characteristics, the preexisting MPN, the different treatments received, the different prognostic groups and the responses achieved according to the ELN, and their mutational status determined by next-generation DNA sequencing (NGS). For 24 patients, we were able to do a comparative NGS analysis at both MPN and sAML phase. After acute transformation EFS and OS were respectively of 2.9 months (range: 0-48.1) and 4.7 months (range: 0.1-58.8). No difference in EFS or OS regarding the previous MPN, the ELN2017 prognostic classification, the first-line therapy or the response was found. After univariate analysis, three genes, TP53, SRSF2 and TET2, impacted pejoratively sAML prognosis at sAML time. In multivariate analysis, TP53 (P = .0001), TET2 (P = .011) and SRSF2 (P = .018) remained independent prognostic factors. Time to sAML transformation was shorter in SRSF2-mutated patients (51.2 months, range: 14.7-98) than in SRSF2-unmutated patients (133.8 months, range: 12.6-411.2) (P < .001). Conventional clinical factors (age, karyotype, ELN2017 prognostic classification, treatments received, treatments response, Allo-SCT ) failed to predict the patients' outcome. Only the mutational status appeared relevant to predict patients' prognosis at sAML phase.
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Genes Relacionados con las Neoplasias , Leucemia Mieloide Aguda/genética , Trastornos Mieloproliferativos/patología , Lesiones Precancerosas/patología , Adulto , Anciano , Anciano de 80 o más Años , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Terapia Combinada , ADN de Neoplasias/genética , Proteínas de Unión al ADN/genética , Dioxigenasas , Femenino , Genes p53 , Trasplante de Células Madre Hematopoyéticas , Humanos , Cariotipificación , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/genética , Cuidados Paliativos , Lesiones Precancerosas/genética , Pronóstico , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas/genética , Análisis de Secuencia de ADN , Factores de Empalme Serina-Arginina/genética , Análisis de SupervivenciaRESUMEN
Acute myeloid leukemia (AML) originates from hematopoietic stem and progenitor cells that acquire somatic mutations, leading to disease and clonogenic evolution. AML is characterized by accumulation of immature myeloid cells in the bone marrow and phenotypic cellular heterogeneity reflective of normal hematopoietic differentiation. Here, we show that JAM-C expression defines a subset of leukemic cells endowed with leukemia-initiating cell activity (LIC). Stratification of de novo AML patients at diagnosis based on JAM-C-expressing cells frequencies in the blood served as an independent prognostic marker for disease outcome. Using publicly available leukemic stem cell (LSC) gene expression profiles and gene expression data generated from JAM-C-expressing leukemic cells, we defined a single cell core gene expression signature correlated to JAM-C expression that reveals LSC heterogeneity. Finally, we demonstrated that JAM-C controls Src family kinase (SFK) activation in LSC and that LIC with exacerbated SFK activation was uniquely found within the JAM-C-expressing LSC compartment. Cancer Res; 77(23); 6627-40. ©2017 AACR.
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Biomarcadores de Tumor/metabolismo , Moléculas de Adhesión Celular/metabolismo , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Familia-src Quinasas/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Animales , Antígenos CD34/metabolismo , Biomarcadores de Tumor/genética , Moléculas de Adhesión Celular/genética , Línea Celular Tumoral , Activación Enzimática , Femenino , Perfilación de la Expresión Génica , Humanos , Subunidad alfa del Receptor de Interleucina-3/metabolismo , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Trasplante de Neoplasias , Células Madre Neoplásicas/citología , Trasplante HeterólogoRESUMEN
Multiple cytogenetic subgroups have been described in adult Philadelphia chromosome (Ph)-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL), often comprising small numbers of patients. In this study, we aimed to reassess the prognostic value of cytogenetic abnormalities in a large series of 617 adult patients with Ph-negative BCP-ALL (median age, 38 years), treated in the intensified Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-2003/2005 trials. Combined data from karyotype, DNA index, fluorescence in situ hybridization, and polymerase chain reaction screening for relevant abnormalities were centrally reviewed and were informative in 542 cases (88%), allowing classification in 10 exclusive primary cytogenetic subgroups and in secondary subgroups, including complex and monosomal karyotypes. Prognostic analyses focused on cumulative incidence of failure (including primary refractoriness and relapse), event-free survival, and overall survival. Only 2 subgroups, namely t(4;11)/KMT2A-AFF1 and 14q32/IGH translocations, displayed a significantly worse outcome in this context, still observed after adjustment for age and after censoring patients who received allogeneic stem cell transplantation (SCT) in first remission at SCT time. A worse outcome was also observed in patients with low hypodiploidy/near triploidy, but this was likely related to their higher age and worse tolerance to therapy. The other cytogenetic abnormalities, including complex and monosomal karyotypes, had no prognostic value in these intensive protocols designed for adult patients up to the age of 60 years.
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Aberraciones Cromosómicas , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Adolescente , Adulto , Aberraciones Cromosómicas/estadística & datos numéricos , Ensayos Clínicos como Asunto/estadística & datos numéricos , Análisis Citogenético , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Adulto JovenAsunto(s)
Transformación Celular Neoplásica/genética , Genómica , Neoplasias Hematológicas/genética , Mutación , Trastornos Mieloproliferativos/genética , Proteínas de Neoplasias/genética , Enfermedad Aguda , Transformación Celular Neoplásica/metabolismo , Transformación Celular Neoplásica/patología , Enfermedad Crónica , Femenino , Neoplasias Hematológicas/metabolismo , Neoplasias Hematológicas/patología , Humanos , Masculino , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , Proteínas de Neoplasias/metabolismoRESUMEN
Cytogenetic evaluation is one the most important criteria for diagnosis and response to treatment in chronic myeloid leukemia, and recent baseline prognostic factors including particular additional clonal cytogenetic abnormalities have been established. The French cytogenetic group in hematology GFCH proposes here an updating of recommendations for cytogenetic assessment of CML in the era of tyrosine kinase inhibitors.
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Análisis Citogenético/normas , Hematología/normas , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Aberraciones Cromosómicas , Análisis Citogenético/métodos , Análisis Citogenético/tendencias , Francia , Hematología/organización & administración , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Monitoreo Fisiológico/métodos , Monitoreo Fisiológico/normas , Sociedades Médicas , Translocación GenéticaRESUMEN
The recent years have witnessed tremendous progress in the molecular characterization of Philadelphia-negative myeloproliferative neoplasms (MPN). Beside a better understanding of pathophysiology, these abnormalities often constitute very useful diagnostic markers in diseases where exclusion of reactive states used to be the strongest argument. However, conventional and molecular cytogenetics keep a major interest in MPN, either as a second line exploration, in cases where no molecular marker is available, for differential diagnosis or as a proof of clonality or in first line for cases with hyperleukocytosis, for differential diagnosis (CML), to evidence druggable targets (ABL1, RET, PDGFR ) or as a prognosis marker. In this article, we will review the interest of cytogenetic techniques in myeloproliferative neoplasms.