RESUMEN
Asciminib is a myristoyl site BCR::ABL1 inhibitor approved for chronic phase chronic myeloid leukaemia (CP-CML) patients failing ≥2 prior lines of therapy. The Australasian Leukaemia & Lymphoma Group (ALLG) conducted the ASCEND study to assess efficacy of asciminib for newly-diagnosed CP-CML. Patients commenced asciminib 40 mg twice daily (BID) and thereafter were managed according to molecular milestones. Patients with treatment failure, defined as BCR::ABL1 >10% (IS) at 3 or 6 months, or >1% at 12 or 18 months, received either imatinib, nilotinib or dasatinib in addition to asciminib. In patients with suboptimal response, defined as levels of 1-10% at 6 months, >0.1-1% at 12 months, or >0.01%-1% at 18 months, the asciminib dose was increased to 80 mg BID. With a median follow-up of 21 months (range 0-36), 82/101 patients continue asciminib. The most frequent reasons for treatment discontinuation were adverse events (6%), loss of response (4%) and withdrawn consent (5%). There were no deaths; one patient developed lymphoid blast crisis at 6 months. The co-primary endpoints were early molecular response (BCR::ABL1 ≤10% at 3 months), achieved in 93% (96% CI 86-97%), and major molecular response by 12 months achieved in 79%; (95% CI 69.7-86.8%), respectively. The cumulative incidence of MR4.5 was 53% by 24 months. One patient had 2 cerebrovascular events; no other arterial occlusive events were reported. Asciminib as frontline therapy in CP-CML produces high rates of molecular response with excellent tolerance and a low rate of discontinuation for toxicity. (ANZ Clinical Trials Registry ACTRN12620000851965).
RESUMEN
All-trans retinoic acid (ATRA) and arsenic trioxide (ATO) are effective induction therapy for acute promyelocytic leukaemia (APL). However, early thrombo-haemorrhagic complications and mortality remain high. We aimed to investigate how the timing of ATRA initiation and the inclusion of ATO influence patient outcomes. Clinical records were retrospectively reviewed for all patients treated for APL in a single, tertiary centre during 2000-2017. Among 70 patients with APL, 36 (51.4%) presented with thrombo-haemorrhagic complications, and four (5.8%) died within 30 days. The median time to ATRA initiation was 11.2 (range 0-104) h from the time of admission. Patients requiring more transfusions started on ATRA sooner (Pâ¯=â¯0.04). Patients with adverse early events did not start ATRA later (Pâ¯=â¯0.99). Nevertheless, patients that required additional tests for diagnosis (PML immunofluorescence or molecular) started on ATRA later (28.5 versus 5.3â¯h; Pâ¯<â¯0.0001), and had more thrombo-haemorrhagic complications (Pâ¯=â¯0.04). Long-term survival was actually better in patients who started ATRA later (Pâ¯=â¯0.03), which is likely explained by higher proportion of low risk patients in this group. Patients treated with ATO (nâ¯=â¯23) maintained higher fibrinogen levels and required less transfusions during induction (Pâ¯<â¯0.05), with no disease-related deaths in this group over a median follow-up time of 37.8 months (interquartile range 44.9 months). In summary, fast ATRA initiation reduces early but not late adverse events in APL patients, and the inclusion of ATO helps further improve both early and late outcomes in APL.
RESUMEN
Current guidelines recommend that a rapid test be used to assist diagnosis of acute promyelocytic leukaemia (APL), but the choice of an assay is discretionary. PML immunofluorescence (PML IF) identifies the microparticulate pattern of the PML protein localisation, highly specific for APL. The aim of this study was to evaluate clinical utility of PML IF in a real-life setting based on a retrospective records review for all patients who had PML IF performed in our centre between 2000 and 2017. Final analysis included 151 patients, 70 of whom had APL. PML IF was reported on average 3 days faster than cytogenetics. Compared with genetic results, PML IF showed sensitivity of 96% and specificity of 100%. PML IF accurately predicted APL in four APL cases with cryptic karyotype/FISH and excluded APL in 98% cases tested based on the suspicious immunophenotype alone, 21/28 of whom had mutated NPM1. Results of PML IF influenced decision to start ATRA in 25 (36%) APL patients and led to its termination in six non-APL patients. In conclusion, PML IF is a fast and reliable test that facilitates accurate treatment decisions when APL is suspected. This performance of PML IF remains hard to match in a real-life setting.
Asunto(s)
Leucemia Promielocítica Aguda/diagnóstico , Proteínas Nucleares/genética , Proteína de la Leucemia Promielocítica/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Inmunofenotipificación , Cariotipo , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/patología , Leucemia Promielocítica Aguda/terapia , Nueva Zelanda , Nucleofosmina , Proteína de la Leucemia Promielocítica/genética , Estudios Retrospectivos , Sensibilidad y Especificidad , Centros de Atención TerciariaRESUMEN
Recent advances in next-generation sequencing have made it possible to perform genome wide identification of somatic mutation in cancers. Most studies focus on identifying somatic mutations in the protein coding portion of the genome using whole exome sequencing (WES). Every human genome has around 4 million single nucleotide polymorphisms (SNPs). A sizeable fraction of these germline SNPs is very rare and will not be found in the databases. Thus, in order to unambiguously identify somatic mutation, it is absolutely necessary to know the germline SNPs of the patient. While a blood sample can serve as source of germline DNA from patients with solid tumours, obtaining germline DNA from patients with haematological malignancies is very difficult. Tumor cells often infiltrate the skin, and their DNA can be found in saliva and buccal swab samples. The DNA in the tips of nails stems from keratinocytes that have undergone keratinization several months ago. DNA was successfully extracted from nail clippings of 5 probands for WES. We were able to identify somatic mutations in one tumor exome by using the nail exome as germline reference. Our results demonstrate that nail DNA is a reliable source of germline DNA in the setting of hematological malignancies.
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ADN de Neoplasias/genética , Secuenciación del Exoma , Leucemia Mieloide Aguda/genética , Uñas/química , Células Madre Germinales Adultas/metabolismo , Células Madre Germinales Adultas/patología , ADN de Neoplasias/química , Bases de Datos Genéticas , Exoma/genética , Genoma Humano/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mieloide Aguda/sangre , Leucemia Mieloide Aguda/patología , Mucosa Bucal , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Saliva/metabolismoAsunto(s)
Modelos Animales de Enfermedad , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Células Madre Neoplásicas/patología , Proteínas de Fusión Oncogénica/genética , Animales , Heterogeneidad Genética , Ratones , Proteínas de Ensamble de Clatrina Monoméricas/genética , Factores de Transcripción/genética , Transducción GenéticaRESUMEN
Human megakaryocytes release glutamate and express glutamate-gated Ca(2+)-permeable N-methyl-D-aspartate receptors (NMDARs) that support megakaryocytic maturation. While deregulated glutamate pathways impact oncogenicity in some cancers, the role of glutamate and NMDARs in megakaryocytic malignancies remains unknown. The aim of this study was to determine if NMDARs participate in Ca(2+) responses in leukemic megakaryoblasts and if so, whether modulating NMDAR activity could influence cell growth. Three human cell lines, Meg-01, Set-2 and K-562 were used as models of leukemic megakaryoblasts. NMDAR components were examined in leukemic cells and human bone marrow, including in megakaryocytic disease. Well-established NMDAR modulators (agonists and antagonists) were employed to determine NMDAR effects on Ca(2+) flux, cell viability, proliferation and differentiation. Leukemic megakaryoblasts contained combinations of NMDAR subunits that differed from normal bone marrow and the brain. NMDAR agonists facilitated Ca(2+) entry into Meg-01 cells, amplified Ca(2+) responses to adenosine diphosphate (ADP) and promoted growth of Meg-01, Set-2 and K-562 cells. Low concentrations of NMDAR inhibitors (riluzole, memantine, MK-801 and AP5; 5-100µM) were weakly cytotoxic but mainly reduced cell numbers by suppressing proliferation. The use-dependent NMDAR inhibitor, memantine (100µM), reduced numbers and proliferation of Meg-01 cells to less than 20% of controls (IC50 20µM and 36µM, respectively). In the presence of NMDAR inhibitors cells acquired morphologic and immunophenotypic features of megakaryocytic differentiation. In conclusion, NMDARs provide a novel pathway for Ca(2+) entry into leukemic megakaryoblasts that supports cell proliferation but not differentiation. NMDAR inhibitors counteract these effects, suggesting a novel opportunity to modulate growth of leukemic megakaryoblasts.
Asunto(s)
Señalización del Calcio , Calcio/metabolismo , Diferenciación Celular , Proliferación Celular , Ácido Glutámico/metabolismo , Leucemia Megacarioblástica Aguda/metabolismo , Femenino , Humanos , Células K562 , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patología , Masculino , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
BACKGROUND: Although inherited thrombophilias are more common in patients with venous thromboembolism, their influence on the development of myocardial infarction (MI) requires clarification. METHODS AND RESULTS: To determine whether there are increased frequencies of mutations/polymorphisms in 14 genes potentially causing thrombophilia in patients with no flow-limiting stenoses after MI compared with patients with > or =1 flow-limiting stenosis of >50%, we studied 395 patients (60 with no flow-limiting stenosis) who underwent angiography at approximately 1 month. The mutations/polymorphisms studied included Factor V Leiden, prothrombin variant G20210A, beta-fibrinogen 448 (G/A), endothelial protein C receptor (23-base pair insertion), methyl tetrahydrofolate reductase 677 (C/T), platelet glycoprotein IIIa PlA1/A2, plasminogen activator inhibitor-1 4G/5G, angiotensin II type 1 receptor (A/C), hemochromatosis gene 282 (G/A), nitric oxide synthase (NOS) (3 forms: eNOS, eNOS3, eNOS4), p22 phox of NADPH oxidase C242T, and angiotensin-converting enzyme insertion/deletion polymorphism. The frequencies of Factor V Leiden and the beta-fibrinogen 448 A allele were higher in patients with no flow-limiting stenosis than in patients with > or =1 stenosis (11.7% vs 3.6%, odds ratio [OR] 3.6, 95% CI 1.3-9.4, P =.015; and 42% vs 27%, OR 2.0, 95% CI 1.1-3.5, P =.018, respectively), and there was a trend toward an increased frequency of prothrombin variant G20210A (6.7% vs 2.1%, OR 3.4, 95% CI 0.95-11.8, P =.069). However, in patients with no flow-limiting stenosis after MI the frequencies of the other gene mutations/polymorphisms were not increased. Also, there were no significant interactions between any of these 14 mutation/polymorphisms, major cardiovascular risk factors, and the absence of any flow-limiting stenosis, except for Factor V Leiden and hypertension (OR 6.34, 95% CI 2.67-100, P =.004). CONCLUSIONS: Patients with no flow-limiting stenosis after MI had increased frequencies of 2 inherited thrombophilias (Factor V Leiden and beta-fibrinogen 448 A allele), and there was a trend toward an increased frequency of prothrombin variant G20210A compared with patients with > or =1 stenosis. These data suggest that polymorphisms/mutations in some gene products influencing coagulation may influence the pathogenesis of MI.
Asunto(s)
Factor V/genética , Fibrinógeno/genética , Mutación , Infarto del Miocardio/genética , Adulto , Estenosis Coronaria/complicaciones , Estenosis Coronaria/genética , Femenino , Frecuencia de los Genes , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Polimorfismo Genético , Factores de Riesgo , Trombofilia/complicaciones , Trombofilia/genéticaAsunto(s)
Antioxidantes/uso terapéutico , Ácido Ascórbico/uso terapéutico , Proteínas de Unión al ADN/genética , Leucemia Mieloide Aguda/tratamiento farmacológico , Proteínas Proto-Oncogénicas/genética , Proteínas WT1/genética , Dioxigenasas , Humanos , Leucemia Mieloide Aguda/genética , Inducción de Remisión , Resultado del TratamientoAsunto(s)
Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/inducido químicamente , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Neoplasias Primarias Secundarias/inducido químicamente , Piperazinas/efectos adversos , Piperazinas/uso terapéutico , Pirimidinas/efectos adversos , Pirimidinas/uso terapéutico , Enfermedad Aguda , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Benzamidas , Resultado Fatal , Femenino , Humanos , Mesilato de Imatinib , Leucemia Mieloide de Fase Crónica/patología , Persona de Mediana EdadRESUMEN
Protein Z-dependent protease inhibitor (ZPI) is a plasma inhibitor of factor (F)Xa and FXIa. In an earlier study, five mutations were identified within the ZPI gene of venous thrombosis patients and healthy controls. Two of these were nonsense mutations and three were missense mutations in important regions of the protein. Here we report that two of these latter three mutations, F145L and Q384R, impair the inhibitory function of ZPI in vitro. Recombinant wild-type and mutant proteins were prepared; stability in response to thermal challenge was similar. Inhibition of FXa in the presence of the cofactor protein Z was reduced 68-fold by the Q384R mutant; inhibition of FXIa by the F145L mutant was reduced two- to three-fold compared to the wild-type ZPI. An analysis of all five ZPI mutations was undertaken in a cohort of venous thrombosis patients (n=550) compared to healthy controls (n=600). Overall, there was a modest increase in incidence of these mutations in the thrombosis group (odds ratio 2.0, 1.05-3.7, p=0.044). However, in contrast to W324X (nonsense mutation), the Q384R missense mutation and R88X nonsense mutation were evenly distributed in patients and controls; F145L was rare. The final mutation (S143Y) was also rare and did not significantly alter ZPI function in laboratory studies. The F145L and particularly the Q384R mutation impaired the function of the coagulation inhibitor ZPI; however, there was no convincing association between these mutations and venous thrombosis risk. The functional role for ZPI in vivo has yet to be clarified.