RESUMEN
The introduction of all-trans retinoic acid (ATRA) combined with anthracyclines has significantly improved the outcomes for patients with acute promyelocytic leukemia (APL), and this strategy remains the standard of care in countries where arsenic trioxide is not affordable. However, data from national registries and real-world databases indicate that low- and middle-income countries (LMIC) still face disappointing results, mainly due to high induction mortality and suboptimal management of complications. The American Society of Hematology established the International Consortium on Acute Leukemias (ICAL) to address this challenge through international clinical networking. Here, we present the findings from the ICAPL study involving 806 patients with APL recruited in Brazil, Chile, Paraguay, Peru, and Uruguay. The induction mortality rate has decreased to 14.6% compared to the pre-ICAL rate of 32%. Multivariable logistic regression analysis revealed as factors associated with induction death: age ≥ 40 years, ECOG = 3, high-risk status based on the PETHEMA/GIMEMA classification, albumin level ≤ 3.5 g/dL, bcr3 PML/RARA isoform, the interval between presenting symptoms to diagnosis exceeding 48 hours, and the occurrence of central nervous system and pulmonary bleeding. With a median follow-up of 53 months, the estimated 4-year overall survival (OS) rate is 81%, the 4-year disease-free survival (DFS) rate is 80%, and the 4-year cumulative incidence of relapse (CIR) rate is 15%. These results parallel those observed in studies conducted in high-income countries, highlighting the long-term effectiveness of developing clinical networks to improve clinical care and infrastructure in LMIC.
RESUMEN
The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of p53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematologic malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid and anthracycline-based chemotherapy, according to the International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio, 4.47; 95% confidence interval, 1.64-12.2; P = .0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
Asunto(s)
Empalme Alternativo , Proteínas de Unión al ADN/biosíntesis , Regulación Leucémica de la Expresión Génica , Leucemia Promielocítica Aguda/metabolismo , Leucemia Promielocítica Aguda/mortalidad , Modelos Biológicos , Proteínas Nucleares/biosíntesis , Proteínas Supresoras de Tumor/biosíntesis , Adolescente , Adulto , Anciano , Niño , Proteínas de Unión al ADN/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Promielocítica Aguda/genética , Leucemia Promielocítica Aguda/patología , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Modelos de Riesgos Proporcionales , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/genética , Tasa de Supervivencia , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/genéticaAsunto(s)
COVID-19 , Leucemia Mieloide Aguda , Adulto , Brasil/epidemiología , Humanos , SARS-CoV-2 , Encuestas y CuestionariosRESUMEN
Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Leucemia Promielocítica Aguda/patología , Proteínas Adaptadoras Transductoras de Señales/genética , Adolescente , Adulto , Anciano , Animales , Antraciclinas/farmacología , Antraciclinas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Médula Ósea/patología , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia sin Enfermedad , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Leucemia Promielocítica Aguda/sangre , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/mortalidad , Recuento de Leucocitos , Masculino , Microdominios de Membrana/metabolismo , Ratones , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Tretinoina/farmacología , Tretinoina/uso terapéutico , Ensayos Antitumor por Modelo de Xenoinjerto , Adulto JovenRESUMEN
We retrospectively studied the outcomes of adults with de novo acute myeloid leukemia treated in a reference center in Brazil and analyzed the association with the human development index (HDI) of the United Nations used as a socioeconomic factor. Among 123 patients, 46 (37%) died during induction, 65 (53%) reached complete remission and 45 (37%) received high-dose cytarabine (Hidac) consolidation. The 5-year overall survival and leukemia-free survival (LFS) were 17 and 26%, respectively, for all patients and 36 and 30%, respectively, for those receiving Hidac. In multivariate analysis, an HDI <0.660 was associated with a lower probability to receive Hidac (P = 0.001), a trend for higher mortality in remission induction (P = 0.062) and a decreased LFS (P < 0.0001). However, it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is satisfactory; however, socioeconomic factors may have selected patients to receive intensive Hidac consolidation.