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BACKGROUND: There are no studies assessing the evolution and patterns of genetic studies performed at diagnosis in acute myeloid leukemia (AML) patients. Such studies could help to identify potential gaps in our present diagnostic practices, especially in the context of increasingly complex procedures and classifications. METHODS: The REALMOL study (NCT05541224) evaluated the evolution, patterns, and clinical impact of performing main genetic and molecular studies performed at diagnosis in 7285 adult AML patients included in the PETHEMA AML registry (NCT02607059) between 2000 and 2021. RESULTS: Screening rates increased for all tests across different time periods (2000-2007, 2008-2016, and 2017-2021) and was the most influential factor for NPM1, FLT3-ITD, and next-generation sequencing (NGS) determinations: NPM1 testing increased from 28.9% to 72.8% and 95.2% (p < .001), whereas FLT3-ITD testing increased from 38.1% to 74.1% and 95.9% (p < .0001). NGS testing was not performed between 2000-2007 and only reached 3.5% in 2008-2016, but significantly increased to 72% in 2017-2021 (p < .001). Treatment decision was the most influential factor to perform karyotype (odds ratio [OR], 6.057; 95% confidence interval [CI], 4.702-7.802), and fluorescence in situ hybridation (OR, 2.273; 95% CI, 1.901-2.719) studies. Patients ≥70 years old or with an Eastern Cooperative Oncology Group ≥2 were less likely to undergo these diagnostic procedures. Performing genetic studies were associated with a favorable impact on overall survival, especially in patients who received intensive chemotherapy. CONCLUSIONS: This unique study provides relevant information about the evolving landscape of genetic and molecular diagnosis for adult AML patients in real-world setting, highlighting the increased complexity of genetic diagnosis over the past 2 decades.
RESUMEN
Despite the absence of mutations in the DNA repair machinery in myeloid malignancies, the advent of high-throughput sequencing and discovery of splicing and epigenetics defects in chronic myelomonocytic leukaemia (CMML) prompted us to revisit a pathogenic role for genes involved in DNA damage response. We screened for misregulated DNA repair genes by enhanced RNA-sequencing on bone marrow from a discovery cohort of 27 CMML patients and 9 controls. We validated 4 differentially expressed candidates in CMML CD34+ bone marrow selected cells and in an independent cohort of 74 CMML patients, mutationally contextualized by targeted sequencing, and assessed their transcriptional behavior in 70 myelodysplastic syndrome, 66 acute myeloid leukaemia and 25 chronic myeloid leukaemia cases. We found BAP1 and PARP1 down-regulation to be specific to CMML compared with other related disorders. Chromatin-regulator mutated cases showed decreased BAP1 dosage. We validated a significant over-expression of the double strand break-fidelity genes CDKN1A and ERCC1, independent of promoter methylation and associated with chemorefractoriness. In addition, patients bearing mutations in the splicing component SRSF2 displayed numerous aberrant splicing events in DNA repair genes, with a quantitative predominance in the single strand break pathway. Our results highlight potential targets in this disease, which currently has few therapeutic options.
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Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Reparación del ADN/genética , Proteínas de Unión al ADN/metabolismo , Endonucleasas/metabolismo , Leucemia Mielomonocítica Crónica/genética , Anciano , Médula Ósea/patología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/genética , Poli(ADP-Ribosa) Polimerasa-1/genética , Factores de Empalme Serina-Arginina/genética , Transcripción Genética , Proteínas Supresoras de Tumor/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
This retrospective study investigated outcomes of 404 patients with relapsed/refractory (R/R) FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) acute myeloid leukemia (AML) enrolled in the PETHEMA registry, pre-approval of tyrosine kinase inhibitors. Most patients (63%) had received first-line intensive therapy with 3 + 7. Subsequently, patients received salvage with intensive therapy (n = 261), non-intensive therapy (n = 63) or supportive care only (n = 80). Active salvage therapy (i.e., intensive or non-intensive therapy) resulted in a complete remission (CR) or CR without hematological recovery (CRi) rate of 42%. More patients achieved a CR/CRi with intensive (48%) compared with non-intensive (19%) salvage therapy (p < 0.001). In the overall population, median overall survival (OS) was 5.5 months; 1- and 5-year OS rates were 25% and 7%. OS was significantly (p < 0.001) prolonged with intensive or non-intensive salvage therapy compared with supportive therapy, and in those achieving CR/CRi versus no responders. Of 280 evaluable patients, 61 (22%) had an allogeneic stem-cell transplant after they had achieved CR/CRi. In conclusion, in this large cohort study, salvage treatment approaches for patients with FLT3-ITD mutated R/R AML were heterogeneous. Median OS was poor with both non-intensive and intensive salvage therapy, with best long-term outcomes obtained in patients who achieved CR/CRi and subsequently underwent allogeneic stem-cell transplant.
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We have analyzed treatment patterns and outcomes of relapsed/refractory(R/R) FLT3mut AML adult patients registered in our institutional data base between 1998 and 2018. Overall, 147 patients were evaluable: 34 from 1998 to 2009, 113 from 2010 to 2018. Salvage treatments were intensive chemotherapy (n = 25, 74%), and supportive care (n = 9, 26%) in the 1998-2009 period, and intensive chemotherapy (n = 63, 56%), hypomethylating agent (n = 7, 6%), low-dose cytarabine-based (n = 8, 7%), clinical trial (n = 16, 14%) and supportive care (n = 19, 17%) in the 2010-2018 period. Complete remission (CR) or with incomplete recovery (CRi) rate was 44%, 49% among patients treated intensively (vs 30% with non-intensive p = 0.005). Median overall survival since first R/R was 5.8 months, and 16.3 months in subjects receiving an allo-HSCT in CR/CRi after first salvage (vs 3.8 in the remaining patients p < 0.0001). Clinical outcomes of R/R FLT3mut AML remain unsatisfactory. Inclusion in clinical trials and expanding options could lead to improved outcomes.
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Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Citarabina/uso terapéutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Inducción de Remisión , Terapia Recuperativa , Resultado del Tratamiento , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
There are no studies analyzing how therapeutic changes impact on outcomes of older AML patients. This study analyzes patient´s and disease characteristics, treatment patterns, and outcomes of 3637 AML patients aged ≥60 years reported to the PETHEMA registry. Study periods were 1999-2006 (before hypomethylating agents-HMAs availability) vs 2007-2013, and treatments were intensive chemotherapy (IC), non-intensive, clinical trial (CT), and supportive care only (SC). Median age was 72 (range, 60-99), 57% male, median ECOG 1 (range, 0-4), secondary AML 914 (30%), with adverse-risk genetic in 720 (32%). Treatment differed between study periods (1999-2006 vs 2007-2013): IC 58% vs 32%, non-intensive 1 vs 23%, CT 0 vs 2%, SC 27 vs 28% (p < 0.001). Median OS was 4.7 months (1-year OS 29% and 5-years 7%, without differences between periods), 1.2 for SC, 7.8 for non-intensive, 8.6 for IC, and 10.4 for CT (p < 0.001). OS improved in the 2007-2013 period for IC patients (10.3 vs 7.5 months, p = 0.004), but worsened for SC patients (1.2 vs 1.6 months, p = 0.03). Our real-life study shows that, despite evolving treatment for elderly patients during the last decade, OS has remained unchanged. Epidemiologic registries will critically assess whether novel therapies lead to noteworthy advances in the near future (#NCT02606825).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/mortalidad , Anciano , Anciano de 80 o más Años , Terapia Combinada , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Transfusion of washed platelet concentrates (W-PC) is recommended for some patients, such as those who have had previous severe allergic transfusion reactions. However, we still lack a standardised method for preparing these products. Here, we assessed the effect of a manual washing procedure on in vitro platelet quality and on the transfusion efficacy of W-PCs. MATERIALS AND METHODS: Buffy coat-derived W-PC in Composol solution were prepared by one-step centrifugation. Platelet activation and function were evaluated before and after washing by means of: (i) CD62 expression by flow cytometry; (ii) platelet aggregation (LTA); and (iii) the VerifyNow® P2Y12 test. A pilot prospective transfusion study was carried out in 11 onco-hematology patients receiving, in a short time, two consecutive transfusions: one with standard PC (S-PC) and one with W-PC. The post-transfusion platelet increment, the 1 h and 24 h corrected count increment (CCI) and occurrence of bleeding events were used as indices of transfusion efficacy. RESULTS: Platelet recovery in W-PC was 84.8±5.4%. Washing slightly increased platelet activation in W-PC vs pre-washed samples (% CD62+ platelets 23.6±7 vs 14.8±1; p=0.03). As compared to prewash samples, platelet reactivity of W-PC as measured by VerifyNow® P2Y12 was significantly lower with ADP (PRU 32.2±37.7 vs 4.2±2.4, p=0.027), but similar using TRAP. Platelet aggregation responses to TRAP, collagen, ristocetin and arachidonic acid were maintained in W-PC. The pilot transfusion trial showed similar 1 h (13.5±5.6 vs 11.5±7.3, p=0.49) and 24 h (11±7.2 vs 9±6.5, p=0.48) CCI for S-PC and W-PC. Transfusion of W-PC was not associated with an increased number of bleeding events. DISCUSSION: We have set up a simple method to obtain buffy-coat-derived W-PC, which has minor effects on in vitro platelet quality and transfusion effectiveness. This procedure can be easily implemented in transfusion centres for on-demand preparation of washed platelets.
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Capa Leucocitaria de la Sangre , Transfusión de Plaquetas/métodos , Plaquetoferesis/métodos , Garantía de la Calidad de Atención de Salud , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proyectos PilotoAsunto(s)
Inversión Cromosómica , Cromosomas Humanos Par 16/genética , Leucemia Mieloide Aguda/patología , Neoplasias Primarias Secundarias/patología , Neutrófilos/patología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Gránulos Citoplasmáticos/patología , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Leucemia Mieloide Aguda/inducido químicamente , Leucemia Mieloide Aguda/genética , Linfoma Relacionado con SIDA/tratamiento farmacológico , Masculino , Neoplasias Primarias Secundarias/inducido químicamente , Neoplasias Primarias Secundarias/genéticaRESUMEN
PURPOSE: We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). PATIENTS AND METHODS: From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. RESULTS: Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. CONCLUSION: t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.
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Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Médula Ósea/inducido químicamente , Leucemia Promielocítica Aguda/tratamiento farmacológico , Neoplasias Primarias Secundarias/inducido químicamente , Tretinoina/efectos adversos , Adulto , Anciano , Antraciclinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Médula Ósea/epidemiología , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/epidemiología , Pronóstico , Estudios Prospectivos , Factores de Riesgo , Resultado del Tratamiento , Tretinoina/administración & dosificaciónRESUMEN
PURPOSE:We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR).PATIENTS AND METHODS:From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy.RESULTS:Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months.CONCLUSION:t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted(AU)
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Humanos , Antraciclinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Médula Ósea/inducido químicamente , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/efectos adversos , Bibliografía Nacional , UruguayRESUMEN
PURPOSE:We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR).PATIENTS AND METHODS:From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy.RESULTS:Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with > or = 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months.CONCLUSION:t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted(AU)