RESUMO
OBJECTIVES: To compare the efficacy of venetoclax-azacitidine (VEN-AZA) with AZA in the real-life for patients with first relapsed or refractory acute myeloid leukaemia (R/R AML). METHODS: We retrospectively analysed R/R AML patients treated with VEN-AZA at the Institut Paoli Calmettes between September 2020 and February 2022. We compared them to a historical cohort of patients treated with AZA between 2010 and 2021. RESULTS: Thirty-five patients treated with VEN-AZA were compared with 140 patients treated with AZA. There were more favourable cytogenetics (25.7% vs. 8.6%; p = 0.01) and less FLT3-ITD mutated AML (8.8% vs. 25.5%; p = .049) in the VEN-AZA group. The overall 30-day mortality rate was 7.4% and the overall 90-day mortality was 20%, with no difference between the groups. The complete remission rate was 48.6% in the VEN-AZA group versus 15% (p < .0001). The composite complete response rate was 65.7% in the VEN-AZA group versus 23.6% (p < .0001). OS was 12.8 months in the VEN-AZA group versus 7.3 months (p = 0.059). Patients with primary refractory AML, poor-risk cytogenetics, prior hematopoietic stem-cell transplantation (HSCT) and FLT3-ITD mutated AML had lower response and survival rates. CONCLUSION: VEN-AZA was associated with a better response rate and a longer survival than AZA monotherapy in AML patients who relapsed after or were refractory to intensive chemotherapy.
Assuntos
Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Terapia de Salvação , Estudos Retrospectivos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Targeted next-generation sequencing (tNGS) and ex vivo drug sensitivity/resistance profiling (DSRP) have laid foundations defining the functional genomic landscape of acute myeloid leukemia (AML) and premises of personalized medicine to guide treatment options for patients with aggressive and/or chemorefractory hematological malignancies. Here, we have assessed the feasibility of a tailored treatment strategy (TTS) guided by systematic parallel ex vivo DSRP and tNGS for patients with relapsed/refractory AML (number NCT02619071). A TTS issued by an institutional personalized committee could be achieved for 47/55 included patients (85%), 5 based on tNGS only, 6 on DSRP only, while 36 could be proposed on the basis of both, yielding more options and a better rationale. The TSS was available in <21 days for 28 patients (58.3%). On average, 3 to 4 potentially active drugs were selected per patient with only five patient samples being resistant to the entire drug panel. Seventeen patients received a TTS-guided treatment, resulting in four complete remissions, one partial remission, and five decreased peripheral blast counts. Our results show that chemogenomic combining tNGS with DSRP to determine a TTS is a promising approach to propose patient-specific treatment options within 21 days.
Assuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Medicina de Precisão , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Estudos de Viabilidade , Feminino , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular/métodos , Mutação/efeitos dos fármacos , Recidiva Local de Neoplasia/genética , Medicina de Precisão/métodos , Estudos Prospectivos , Adulto JovemRESUMO
Although complete remission (CR) is achieved in 50 to 70% of older fit patients with acute myeloid leukemia (AML), consolidation therapy in this age group remains challenging. In this retrospective study, we aimed to compare outcome in elderly patients treated with different post-remission modalities, including allogenic and autologous hematopoietic stem cell transplantation (HSCT), intensive chemotherapy, and standard-dose chemotherapy (repeated 1 + 5 regimen). We collected data of 441 patients ≥ 60 years in first CR from a single institution. Median age was 67 years. Sixty-one (14%) patients received allo-HSCT, 51 (12%) auto-HSCT, 70 (16%) intensive chemotherapy with intermediate- or high-dose cytarabine (I/HDAC), and 190 (43%) 1 + 5 regimen. Median follow-up was 6.5 years. In multivariate analysis, allo-HSCT, cytogenetics, and PS had a significant impact on OS and LFS. In spite of a more favorable-risk profile, the patients who received I/HDAC had no significantly better LFS as compared with patients treated with 1 + 5 (median LFS 8.8 months vs 10.6 months, p = 0.96). In transplanted patients, median LFS was 13.3 months for auto-HSCT and 25.8 months for allo-HSCT. Pre-transplant chemotherapy with I/HDAC had no effect on the outcome. Toxicity was significantly increased for both transplanted and non-transplanted patients treated with I/HDAC, with more units of blood and platelet transfusion and more time spent in hospitalization, but no higher non-relapse mortality. This study shows that post-remission chemotherapy intensification is not associated with significantly better outcome as compared with standard-dose chemotherapy in elderly patients for whom, overall results remain disappointing.
Assuntos
Quimioterapia de Consolidação , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transfusão de Componentes Sanguíneos , Terapia Combinada , Citarabina/administração & dosagem , Citarabina/efeitos adversos , Daunorrubicina/administração & dosagem , Daunorrubicina/efeitos adversos , Intervalo Livre de Doença , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Transplante Autólogo , Resultado do TratamentoAssuntos
Leucemia Eritroblástica Aguda , Mutação , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Eritroblástica Aguda/sangue , Leucemia Eritroblástica Aguda/classificação , Leucemia Eritroblástica Aguda/genética , Leucemia Eritroblástica Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Organização Mundial da SaúdeRESUMO
Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.
Assuntos
Proteínas de Fusão bcr-abl/análise , Calibragem , Proteínas de Fusão bcr-abl/normas , Genes abl , Humanos , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-bcr/genética , Padrões de Referência , Organização Mundial da SaúdeAssuntos
Biomarcadores Tumorais/genética , Aberrações Cromossômicas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Leucemia Eritroblástica Aguda/genética , Mutação/genética , Feminino , Humanos , Leucemia Eritroblástica Aguda/mortalidade , Leucemia Eritroblástica Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Taxa de SobrevidaAssuntos
Biomarcadores Tumorais/genética , Transtornos Plaquetários/complicações , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Leucemia Mieloide Aguda/etiologia , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Adolescente , Adulto , Transtornos Plaquetários/genética , Plaquetas/patologia , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Linhagem , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patologia , PrognósticoAssuntos
Biomarcadores Farmacológicos , Imidazóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Piridazinas/administração & dosagem , Adulto , Cromossomos Humanos Par 1/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Translocação Genética/genéticaAssuntos
Metilação de DNA , Epigênese Genética , Histonas/genética , Leucemia Mieloide Aguda/genética , Família Multigênica , Idoso , Biomarcadores/metabolismo , Cromatina/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , NucleofosminaAssuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Mutação/genética , Proteínas Nucleares/genética , Proteínas Repressoras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Hibridização Genômica Comparativa , Feminino , Humanos , Cariotipagem , Masculino , Pessoa de Meia-Idade , Nucleofosmina , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo Genético , Prognóstico , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética , Proteínas ras/genéticaAssuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Mutação de Sentido Incorreto , Fatores de Transcrição NFI/genética , Proteínas de Neoplasias/genética , Mutação Puntual , Policitemia Vera/genética , Deleção de Sequência , Substituição de Aminoácidos , Sequência de Bases , Cromossomos Humanos Par 1/genética , Erros de Diagnóstico , Progressão da Doença , Feminino , Genes Supressores de Tumor , Humanos , Janus Quinase 2/genética , Leucemia Monocítica Aguda/genética , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Fatores de Transcrição NFI/química , Proteínas de Neoplasias/química , Policitemia Vera/diagnóstico , Estrutura Terciária de Proteína/genética , Trombocitemia Essencial/diagnósticoRESUMO
The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.