RESUMEN

Four afatinib derivatives were designed and modeled. These derivatives were compared to the known tyrosine-kinase inhibitors in treating Chronic Myeloid Leukemia, i.e., imatinib and ponatinib. The molecules were evaluated through computational methods, including docking studies, the non-covalent interaction index, Electron Localization and Fukui Functions, in silico ADMET analysis, QTAIM, and Heat Map analysis. The AFA(IV) candidate significantly increases the score value compared to afatinib. Furthermore, AFA(IV) was shown to be relatively similar to the ponatinib profile when evaluating a range of molecular descriptors. The addition of a methylpiperazine ring seems to be well distributed in the structure of afatinib when targeting the BCR-ABL enzyme, providing an important hydrogen bond interaction with the Asp381 residue of the DFG-switch of BCR-ABL active site residue and the AFA(IV) new chemical entities. Finally, in silico toxicity predictions show a favorable index, with some molecules presenting the loss of the irritant properties associated with afatinib in theoretical predictions.

Asunto(s)

Afatinib , Proteínas de Fusión bcr-abl , Simulación del Acoplamiento Molecular , Inhibidores de Proteínas Quinasas , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/química , Afatinib/química , Afatinib/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Humanos , Modelos Moleculares , Simulación por Computador , Mutación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Enlace de Hidrógeno , Antineoplásicos/química , Antineoplásicos/farmacología , Imidazoles/química , Imidazoles/farmacología , Piridazinas

RESUMEN

Chronic Myeloid Leukemia is a blood cancer for which standard therapy with Tyrosine-Kinase Inhibitors is successful in the majority of patients. After discontinuation of treatment half of the well-responding patients either present undetectable levels of tumor cells for a long time or exhibit sustained fluctuations of tumor load oscillating at very low levels. Motivated by the consequent question of whether the observed kinetics reflect periodic oscillations emerging from tumor-immune interactions, in this work, we analyze a system of ordinary differential equations describing the immune response to CML where both the functional response against leukemia and the immune recruitment exhibit optimal activation windows. Besides investigating the stability of the equilibrium points, we provide rigorous proofs that the model exhibits at least two types of bifurcations: a transcritical bifurcation around the tumor-free equilibrium point and a Hopf bifurcation around a biologically plausible equilibrium point, providing an affirmative answer to our initial question. Focusing our attention on the Hopf bifurcation, we examine the emergence of limit cycles and analyze their stability through the calculation of Lyapunov coefficients. Then we illustrate our theoretical results with numerical simulations based on clinically relevant parameters. Besides the mathematical interest, our results suggest that the fluctuating levels of low tumor load observed in CML patients may be a consequence of periodic orbits arising from predator-prey-like interactions.

Asunto(s)

Simulación por Computador , Leucemia Mielógena Crónica BCR-ABL Positiva , Conceptos Matemáticos , Leucemia Mielógena Crónica BCR-ABL Positiva/inmunología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Humanos , Modelos Inmunológicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Modelos Biológicos , Carga Tumoral/inmunología

RESUMEN

Imatinib is the tyrosine kinase inhibitor used as the gold standard for the treatment of Chronic Myeloid Leukemia. However, about 30% of patients do not respond well to this therapy. Variants in drug administration, distribution, metabolism and excretion (ADME) genes play an important role in drug resistance especially in admixed populations. We investigated 129 patients diagnosed with Chronic Myeloid Leukemia treated with imatinib as first choice therapy. The participants of the study are highly admixed, populations that exhibit genetic diversity and complexity due to the contributions of multiple ancestral groups. Thus, the aim of this work was to investigate the association of 30 SNVs in genes related to response to treatment with Imatinibe in CML. Our results indicated that for the rs2290573 of the ULK3 gene, patients with the recessive AA genotype are three times more likely to develop resistance over time (secondary resistance) (p = 0.019, OR = 3.19, IC 95%= 1.21-8.36). Finally, we performed interaction analysis between the investigated variants and found several associations between SNVs and secondary resistance. We concluded that the variant rs2290573 of the ULK3 gene may be relevant for predicting treatment response of CML with imatinib, as well as possible treatment resistance. The use of predictive biomarkers is an important tool for therapeutic choice of patients, improving their quality of life and treatment efficacy.

Asunto(s)

Antineoplásicos , Resistencia a Antineoplásicos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas , Humanos , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Resistencia a Antineoplásicos/genética , Masculino , Femenino , Persona de Mediana Edad , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Antineoplásicos/uso terapéutico , Anciano , Farmacogenética , Genotipo , Adulto Joven

RESUMEN

Background: Chronic myelogenous leukemia is a neoplastic proliferation of the granulocytic series. In Mexico, chronic myelogenous leukemia accounts for approximately 10% of all leukemias. Tyrosine-kinase inhibitors are considered front-line therapy in high-income countries, whereas allogeneic hematopoietic stem cell transplantation is a recognized therapeutic approach, mainly in low- and middle-income countries. Objective: To analyze the overall survival of persons with chronic myelogenous leukemia who have received tyrosine-kinase inhibitors or allogeneic hematopoietic stem cell transplantation in a medical center, since 1994, and briefly discuss the current indications of these treatments in the tyrosine-kinase inhibitors era. Methods: We retrospectively analyzed all patients with a diagnosis of chronic myelogenous leukemia treated in a medical center between 1994 and 2023; subsets of individuals who received an allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors therapy as first-line treatment were analyzed. Results: 60 persons with chronic myelogenous leukemia were treated with allogeneic hematopoietic stem cell transplantation or tyrosine-kinase inhibitors: 35 received an allogeneic hematopoietic stem cell transplantation, whereas 25 were given tyrosine-kinase inhibitors. All patients who underwent an allogeneic hematopoietic stem cell transplantation engrafted successfully, and the procedure was completed on an outpatient basis in most cases (29/35). The median survival in allogeneic hematopoietic stem cell transplantation was 78.3 months (CI 95%: 0-205.6) and in persons given tyrosine-kinase inhibitors the median was not reached. Conclusion: Tyrosine-kinase inhibitors were significantly superior to allogeneic hematopoietic stem cell transplantation in prolonging the overall survival of persons with chronic myelogenous leukemia in our single institution experience.

Asunto(s)

Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , México , Inhibidores de Proteínas Quinasas/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Adulto Joven , Anciano , Adolescente , Tasa de Supervivencia , Trasplante Homólogo

RESUMEN

Imatinib mesylate was the first representative BCR-ABL1 tyrosine kinase inhibitor (TKI) class for the treatment of chronic myeloid leukemia. Despite the revolution promoted by TKIs in the treatment of this pathology, a resistance mechanism occurs against all BCR-ABL1 inhibitors, necessitating a constant search for new therapeutic options. To develop new antimyeloproliferative substances, we applied a medicinal chemistry tool known as molecular hybridization to design 25 new substances. These compounds were synthesized and biologically evaluated against K562 cells, which express BCR-ABL1, a constitutively active tyrosine kinase enzyme, as well as in WSS-1 cells (healthy cells). The new compounds are conjugated hybrids that contain phenylamino-pyrimidine-pyridine (PAPP) and an isatin backbone, which are the main pharmacophoric fragments of imatinib and sunitinib, respectively. A spiro-oxindole nucleus was used as a linker because it occurs in many compounds with antimyeloproliferative activity. Compounds 2a, 2b, 3c, 4c, and 4e showed promise, as they inhibited cell viability by between 45% and 61% at a concentration of 10 µM. The CC50 of the most active substances was determined to be within 0.8-9.8 µM.

Asunto(s)

Antineoplásicos , Supervivencia Celular , Mesilato de Imatinib , Oxindoles , Humanos , Células K562 , Mesilato de Imatinib/farmacología , Oxindoles/farmacología , Oxindoles/síntesis química , Oxindoles/química , Antineoplásicos/farmacología , Antineoplásicos/síntesis química , Antineoplásicos/química , Supervivencia Celular/efectos de los fármacos , Relación Estructura-Actividad , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proliferación Celular/efectos de los fármacos , Estructura Molecular , Relación Dosis-Respuesta a Droga , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Proteínas de Fusión bcr-abl/metabolismo , Compuestos de Espiro/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/síntesis química , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Ensayos de Selección de Medicamentos Antitumorales

RESUMEN

Abstract Bulbine natalensis and Chorophytum comosum are potential medicinal source for the treatment of cancers. Chronic myeloid leukaemia is a hematopoietic stem cells disorder treated by tyrosine kinase inhibitors but often cause recurrence of the leukaemia after cessation of therapy, hence require alternative treatment. This study determines the anti-cancer effect of leaf, root and bulb methanolic and aqueous extracts of B. natalensis and C. comosum in chronic human myelogenous leukaemia (K562) cell line by MTT, Hoechst bis-benzimide nuclear and annexin V stain assays. The root methanolic extract of B. natalensis and C. comosum showed a high cytotoxicity of 8.6% and 16.7% respectively on the K562 cell line at 1,000 μg/ml concentration. Morphological loss of cell membrane integrity causing degradation of the cell and fragmentation were observed in the root methanolic extract of both plants. A high apoptosis (p < 0.0001) was induced in the K562 cells by both leaf and root extracts of the C. comosum compared to the B. natalensis. This study shows both plants possess apoptotic effect against in vitro myelogenous leukaemia which contributes to the overall anti-cancer properties of B. natalensis and C. comosum to justify future therapeutic applications against chronic myelogenous leukaemia blood cancer.

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Resumo Bulbine natalensis Baker e Chorophytum comosum (Thunb.) Jacques são potenciais fontes medicinais para o tratamento de cânceres. A Leucemia Mieloide Crônica (LMC) é um distúrbio das células-tronco hematopoiéticas que é tratado com inibidores da tirosina quinase, mas frequentemente, causa recorrência da leucemia após a interrupção da terapia, portanto, requer um tratamento alternativo. Este estudo determinou o efeito anticancerígeno de extratos metanólicos e aquosos de folha, raiz e bulbo de B. natalensis e C. comosum na linhagem celular de leucemia mieloide humana crônica (K562) por ensaios de MTT, Hoechst bis-benzimida nuclear e anexina V. O extrato metanólico da raiz de B. natalensis e C. comosum apresentou alta citotoxidade de 8,6% e 16,7% respectivamente, na linhagem celular K562 com a concentração de 1,000 μg / ml. Perda morfológica da integridade da membrana celular causando degradação dos núcleos, citoplasma e encolhimento celular foi observada no extrato metanólico da raiz de ambas as plantas. Uma alta apoptose (p <0,0001) foi induzida nas células K562 por extratos de folhas e raízes de C. comosum em comparação com B. natalensis. Este estudo mostrou que ambas as plantas possuem efeito apoptótico contra leucemia mieloide in vitro que contribui para as propriedades anticâncer gerais de B. natalensis e C. comosum para justificar futuras aplicações terapêuticas contra câncer de sangue de LMC.

Asunto(s)

Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Asphodelaceae , Apoptosis , Células K562

RESUMEN

The aim of this work is to estimate the effect of Imatinib, exosomes, and Imatinib-exosomes mixture in chronic myeloid leukemia (CML). For this purpose, mathematical models based on Gompertzian and logistic growth differential equations were proposed. The models contained parameters representing the effects of the three components on CML proliferation. Parameters estimation was performed under the Bayesian statistical approach. Experimental data reported in the literature were used, corresponding to four trials of a human leukemia xenograft in BALB/c female rats over a period of forty days. The models were fitted to the following growth dynamics: normal tumor growth, growth with exosomes, growth with Imatinib, and growth with exosomes-Imatinib mixture. For the proposed logistic growth model, it was determined that when using Imatinib treatment the growth rate is 0.93 (95% CrI: 84.33-99.64) slower and reduces the tumor volume to approximately 10% (95% CrI : 8.67-10.81). In the presence of exosome treatment, the growth rate is 0.83 (95% CrI: 1.52-16.59) faster and the tumor volume is expanded by 40% (95% CrI: 25.36-57.28). Finally, in the presence of Imatinib-exosomes mixture treatment, the growth rate is 0.82 (95% CrI: 76.87-88.51) slower and the tumor volume is reduced by 95% (95% CrI: 86.76-99.85). It is concluded that the presence of exosomes partially inactivates the effect of the Imatinib drug on tumor growth in a mouse xenograft model.

Asunto(s)

Antineoplásicos , Exosomas , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Femenino , Ratones , Ratas , Animales , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Teorema de Bayes , Xenoinjertos , Exosomas/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico

RESUMEN

The discovery and development of effective novel compounds is paramount in oncology for improving cancer therapy. In this study, we developed a new derivative of spiroindolone (7',8'-Dimethoxy-1',3'-dimethyl-1,2,3',4'-tetrahydrospiro[indole-3,5'- pyrazolo[3,4-c]isoquinolin]-2-one) and evaluated its anticancer- and immunomodulatory potential in a vitro model of chronic leukemia. We utilized the chronic leukemia cell line K562, as well as non-cancerous peripheral blood mononuclear cells (PBMC) and Vero cells (kidney epithelium of Cercopithecus aethiops). We assessed the cytotoxicity of the compound using the MTT assay, and performed cell cycle assays to determine its impact on different stages of the cell cycle. To evaluate its antineoplastic activity, we conducted a colony formation test to measure the effect of the compound on the clonal growth of cancer cells. Furthermore, we evaluated the immunomodulatory activity of the compound by measuring the levels of pro and anti-inflammatory cytokines. The study findings demonstrate that the spiroindolone-derived compound exerted noteworthy cytotoxic effects against K562 cells, with an IC50 value of 25.27 µg/mL. Additionally, it was observed that the compound inhibited the clonal proliferation of K562 cells while displaying minimal toxicity to normal cells. The compound exhibited its antiproliferative activity by inducing G2/M cell cycle arrest, preventing the entry of K562 cells into mitosis. Notably, the compound demonstrated an immunomodulatory effect by upregulating the production of cytokines IL-6 and IL-12/23p40. In conclusion, the spiroindolone-derived compound evaluated in this study has demonstrated significant potential as a therapeutic agent for the treatment of chronic myeloid leukemia. Further investigations are warranted to explore its clinical applications.

Asunto(s)

Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Animales , Chlorocebus aethiops , Leucocitos Mononucleares , Células Vero , Proliferación Celular , Apoptosis , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Células K562 , Citocinas/farmacología , Indoles/farmacología

RESUMEN

Chronic myeloid leukemia (CML) is a well-characterized oncological disease in which virtually all patients possess a translocation (9;22) that generates the tyrosine kinase BCR::ABL1 protein. This translocation represents one of the milestones in molecular oncology in terms of both diagnostic and prognostic evaluations. The molecular detection of the BCR::ABL1 transcription is a required factor for CML diagnosis, and its molecular quantification is essential for assessing treatment options and clinical approaches. In the CML molecular context, point mutations on the ABL1 gene are also a challenge for clinical guidelines because several mutations are responsible for tyrosine kinase inhibitor resistance, indicating that a change may be necessary in the treatment protocol. So far, the European LeukemiaNet and the National Comprehensive Cancer Network (NCCN) have presented international guidelines on CML molecular approaches, especially those related to BCR::ABL1 expression. In this study, we show almost three years' worth of data regarding the clinical treatment of CML patients at the Erasto Gaertner Hospital, Curitiba, Brazil. These data primarily comprise 155 patients and 532 clinical samples. BCR::ABL1 quantification by a duplex-one-step RT-qPCR and ABL1 mutations detection were conducted. Furthermore, digital PCR for both BCR::ABL1 expression and ABL1 mutations were conducted in a sub-cohort. This manuscript describes and discusses the clinical importance and relevance of molecular biology testing in Brazilian CML patients, demonstrating its cost-effectiveness.

Asunto(s)

Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Brasil , Proteínas de Fusión bcr-abl/genética , Resistencia a Antineoplásicos/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Translocación Genética

RESUMEN

Use of the potent tyrosine kinase inhibitor imatinib as the first-line treatment in chronic myeloid leukemia (CML) has decreased mortality from 20% to 2%. Approximately 30% of CML patients experience imatinib resistance, however, largely because of point mutations in the kinase domain of the BCR-ABL1 fusion gene. The aim of this study was to use next-generation sequencing (NGS) to identify mutations related to imatinib resistance. The study included 22 patients diagnosed with CML and experiencing no clinical response to imatinib. Total RNA was used for cDNA synthesis, with amplification of a fragment encompassing the BCR-ABL1 kinase domain using a nested-PCR approach. Sanger and NGS were applied to detect genetic alterations. HaplotypeCaller was used for variant calling, and STAR-Fusion software was applied for fusion breakpoint identification. After sequencing analysis, F311I, F317L, and E450K mutations were detected respectively in three different participants, and in another two patients, single nucleotide variants in BCR (rs9608100, rs140506, rs16802) and ABL1 (rs35011138) were detected. Eleven patients carried e14a2 transcripts, nine had e13a2 transcripts, and both transcripts were identified in one patient. One patient had co-expression of e14a2 and e14a8 transcripts. The results identify candidate single nucleotide variants and co-expressed BCR-ABL1 transcripts in cellular resistance to imatinib.

Asunto(s)

Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapéutico , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Nucleótidos/uso terapéutico , Resistencia a Antineoplásicos/genética

RESUMEN

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021 y ampliada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 97-IETSI-ESSALUD2022, se ha elaborado el presente dictamen, el que expone la actualización del Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 20-SDEPFyOTS-DETSIETSI-2018 "Eficacia y seguridad de ponatinib para el tratamiento de pacientes con diagnóstico de leucemia mieloide crónica, mutación T3151 positiva, en fase crónica, acelerada o blástica" (IETSI-EsSalud 2018), publicado en junio de 2018. ASPECTOS GENERALES: La leucemia mieloide crónica (LMC) es una neoplasia mieloproliferativa que produce la expansión clonal de células diferenciadas de la línea mieloide, provocada por la producción incontrolada de una proteína cinasa única BCR-ABL1 (Steegman JL et al., 2020; Van Etten R, 2022). La LMC representa del 15 al 20 % del total de las leucemias en adultos, con una incidencia mundial entre 1 y 2 casos por 100 000 habitantes por año. (Romero, 2020; ACS, 2019). En el Perú, de acuerdo con el Registro de Cáncer de Lima Metropolitana en el año 2004, la LMC representó la sexta causa de muerte por cáncer, representando el 4.5 % del total de defunciones (Navarro Cabrera et al, 2010). METODOLOGIA: Se llevó a cabo una búsqueda sistemática de la literatura con el objetivo de actualizar el Dictamen Preliminar de Evaluación de Tecnología Sanitaria N° 020-SDEPFyOTSDETS-IETS1-2018 "Eficacia y seguridad de Ponatinib para el tratamiento de pacientes con diagnóstico de leucemia mieloide crónica, mutación T3151 positiva, en fase crónica, acelerada o blástica" (I ETS I-EsSalud 2018). La búsqueda bibliográfica se realizó en las bases de datos: PubMed, The Cochrane Library, Web of Science y LILACS. Adicionalmente, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo la National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC). Asimismo, se realizó una búsqueda manual en el portal de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), del repositorio institucional de la DIGEMID, del Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI), de la National Comprehensive Cancer Network (NCCN), de la British Society for Haematology (BSH) y de la European Society for Medical Oncology (ESMO). Finalmente, se realizó una búsqueda manual en la página web del registro de ensayos clínicos (EC) del ClinicalTrials.govpara identificar ensayos clínicos en curso o con resultados que no hayan sido publicados. RESULTADOS: Luego de la búsqueda bibliográfica desde junio de 2018 a diciembre de 2022, se incluyeron dos GPC, una elaborada por la National Comprehensive Cancer Network (NCCN-2022) y una por la British Society for Haematology (BSH-2022), y dos publicaciones correspondientes a dos EC de fase II que incluye a los resultados finales del EC PACE (Cortes et al., 2018) y a los resultados primarios del EC OPTIC (Cortes et al., 2021), los cuales responden a la pregunta PICO. CONCLUSIONES: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de ponatinib para el tratamiento de pacientes con diagnóstico de leucemia mieloide crónica, mutación T3151 positiva, en fase crónica, acelerada o blástica, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud.

Asunto(s)

Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Eficacia , Análisis Costo-Beneficio/economía

RESUMEN

INTRODUCTION: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome. After the introduction of imatinib mesylate (IM) in 2000, the natural history of the disease changed. Data on the treatment of CML with IM are from randomized clinical trials. Establishing whether these results can be reproduced or if caution is needed when extrapolating data to the general population with CML is essential. OBJECTIVES: To evaluate the molecular response (MR) in patients with chronic-phase CML (CML-CP) not included in clinical studies and correlate them with the responses obtained in clinical trials. METHODS: Between January 2007 and January 2017, 227 patients newly diagnosed with CML-CP treated with IM as first-line treatment were included. This study is an observational, retrospective, and single-center study. RESULTS: At a median follow-up time of 7.3 years, 60.3% of the 227 patients who started IM were still on IM. Early molecular response (EMR) at 3 and 6 months was achieved by 74.2% and 65%, respectively. The median time to a MMR was nine months. The MR4.0 and MR4.5 were 67.2% and 51.1%, respectively. The overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of the patients who exclusively used IM were 91%, 91%, and 85.1%, respectively. CONCLUSION: The results presented are similar to those described in prospective and randomized trials, demonstrating that the outcomes are reproducible in the real world. EMR at 3 and 6 months reflects better long-term responses, including higher rates of deeper molecular responses. Considering treatment costs, the absence of literature evidence of an impact on overall survival demonstrated by first-line second-generation tyrosine kinase inhibitors (TKIs), and the global OS of 85.8%, imatinib mesylate (IM) is still an excellent therapeutic option.

Asunto(s)

Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapéutico , Estudios Retrospectivos , Estudios Prospectivos , Resultado del Tratamiento , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Cromosoma Filadelfia , Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/genética

RESUMEN

Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is safe under adequate molecular monitoring, but questions remain regarding which factors may be considered predictive for TFR. Argentina Stop Trial (AST) is a multicenter TFR trial showing that 65% of patients sustain molecular remission, and the prior time in deep molecular response (DMR) was associated with successful TFR. Luminex technology was used to characterize cytokines in plasma samples. Using machine learning algorithms, MCP-1 and IL-6 were identified as novel biomarkers and MCP-1low/IL-6low patients showed eightfold higher risk of relapse. These findings support the feasibility of TFR for patients in DMR and MCP-1/IL-6 plasma levels are strong predictive biomarkers.

Asunto(s)

Interleucina-6 , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Inhibidores de Proteínas Quinasas , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Biomarcadores , Inducción de Remisión , Resultado del Tratamiento

RESUMEN

Imidazo[1,2-a]pyridines (IPs) have been studied regarding drug development. The objective of this work was to evaluate the antileukemic capacity of IP derivatives by screening their ability as a pro-oxidant. IP derivatives were synthesized and oral bioavailability and toxicity were analyzed in silico. Redox screening was performed on human Kasumi, KG-1, K562, and Jurkat leukemia cells. The IP derivative and the most responsive leukemic cell were selected for cytotoxicity, cell proliferation, cell senescence, and oxidative stress assays. The predictive toxicity analysis showed a possible effect on the reproductive system, but without mutagenic, carcinogenic, or irritability effects. MRK-107 against K562 cells was the compound that showed the best redox profile. MRK-107 did not induce cell death in K562 and monocyte cells. However, this compound was able to decrease cell proliferation and increase cell senescence after 48 and 72 h. Furthermore, MRK-107 induced oxidative stress in K562 cells after 72 h, increasing lipid peroxidation and decreasing reduced glutathione (GSH) contents. This study demonstrated that MRK-107-induced senescence with the involvement of oxidative stress is a possible mechanism of action, addressing this compound as a potential antitumor drug against chronic myeloid leukemia.

Asunto(s)

Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia Mieloide , Humanos , Apoptosis , Estrés Oxidativo , Antineoplásicos/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Proliferación Celular , Senescencia Celular , Piridinas/farmacología , Células K562

RESUMEN

BACKGROUND: Salidroside is a phenolic natural product, which is a kind of Rhodiola rosea. It has been confirmed that it has inhibitory effects on chronic myeloid leukemia, but the specific performance of its molecular effects is still unclear. OBJECTIVE: To systematically study the pharmacological mechanism of salidroside on chronic myeloid leukemia by means of network pharmacology. METHODS: First, the possible target genes of salidroside were predicted through the Traditional Chinese Medicine Pharmacology Database and Analysis Platform, the target gene names were converted into standardized gene names using the Uniprot website. At the same time, the related target genes of chronic myeloid leukemia were collected from GeneCards and DisGenet; Collect summary data and screen for commonly targeted genes. Then, the above-mentioned intersected genes were imported into the String website to construct the protein-protein interaction (PPI) network, and the Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were further analyzed. To investigate the overall pharmacological effects of salidroside on chronic myeloid leukemia, we constructed a drug component-target gene-disease (CTD) network. Finally, molecular docking was performed to verify the possible binding conformation between salidroside and the candidate target. RESULTS: A total of 126 salidroside target genes were retrieved, and 106 of them had interactions with chronic myeloid leukemia. The pharmacological effects of salidroside on chronic myeloid leukemia are related to some important oncogenes and signaling pathways. Molecular docking studies confirmed that the main role of salidroside binding to the target genes is hydrogen bonding. CONCLUSIONS: We revealed the potential mechanism of action of salidroside against chronic myeloid leukemia, verified by network pharmacology combined with molecular docking. However, salidroside is a promising drug for the prevention and treatment of chronic myeloid leukemia, and further research is needed to prove it.

Asunto(s)

Medicamentos Herbarios Chinos , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Simulación del Acoplamiento Molecular , Farmacología en Red , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Glucósidos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico

RESUMEN

BACKGROUND: Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. OBJECTIVE: To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. METHODS: Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. RESULTS: Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. CONCLUSION: Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence.

Asunto(s)

Antineoplásicos , Leucemia Mielógena Crónica BCR-ABL Positiva , Femenino , Humanos , Persona de Mediana Edad , Mesilato de Imatinib/uso terapéutico , Antineoplásicos/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico

RESUMEN

Chronic Myeloid Leukemia (CML) is a hematologic neoplasia, characterized as a proliferative disease of the hematopoietic system. Imatinib mesylate (IM), a selective tyrosine kinase inhibitor, is considered a first-line therapy for CML, indicated for both adult and pediatric patients presenting the Philadelphia chromosome (Ph+). However, patients in treatment with IM may show different responses due to interindividual pharmacokinetic variability. Therapeutic drug monitoring should be routinely performed to identify treatment response profile, adherence to treatment, or possible drug interactions, thus supporting better treatment management. Volumetric absorptive microsampling (VAMS) are innovative devices for blood collection whose advantages include the possibility of home collection by the patient or at the physician's office. The assay was fully validated according to bioanalytical validation guidelines. Estimated plasma concentrations of IM were not statistically different between groups according to adherence (p = 0.15), with median of 789 ng ml-1 in the group with some level of non-adherence versus 1141.9 ng ml-1 in the group with adherence, classified with the Morisky-Green questionnaire. This study included 33 patients with CML in treatment with IM. These patients answered socioeconomic, sociodemographic, and adherence profile (Morisky-Green) questionnaires. Patients also received instructions for home blood collection with VAMS devices. Afterwards, the samples were analyzed by LC-MS/MS. The mean age of the patients was 52 years, 84.8% were ingesting doses of 400 mg/day and the majority were male (69.7%). IM and its metabolite NIM were extracted from VAMS with an aqueous solution with 0.1% formic acid, followed by protein precipitation with acetonitrile. The methodology developed in this study was satisfactory for the determination of IM and NIM in VAMS and can be used in hospital and office routines for the therapeutic monitoring of patients with CML.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Espectrometría de Masas en Tándem , Adulto , Humanos , Masculino , Niño , Femenino , Persona de Mediana Edad , Mesilato de Imatinib/uso terapéutico , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Enfermedad Crónica

RESUMEN

INTRODUÇÃO: A leucemia mieloide crônica (LMC) é uma neoplasia mieloproliferativa com incidência de 1-2 casos por 100.000 adultos, e responsável por aproximadamente 15% dos casos recém diagnosticados de leucemia em adultos. A patogênese da LMC origina-se da fusão do gene Abelson da leucemia murina (ABL), no cromossomo 9, com o ponto de interrupção do gene da região de agrupamento (BCR) no cromossomo 22, o que resulta na expressão de uma oncoproteína denominada BCR-ABL. Esta é uma tirosina quinase que promove o crescimento e a replicação celular, o que influencia a leucemogênese. De acordo com o PCDT da LMC do Adulto publicado pelo Ministério da Saúde, o imatinibe é indicado como o tratamento de 1ª linha na LMC. Na falha ou intolerância a esse tratamento, o nilotinibe e o dasatinibe são recomendados para 2ª linha. Quando o tratamento em 2ª linha falha, a terapia subsequente fica a critério de cada CACON ou UNACON. Para estes pacientes, o ponatinibe se constitui como uma opção de tratamento. PERGUNTA: O uso do ponatinibe no tratamento de pacientes adultos com L

Asunto(s)

Humanos , Proteínas Tirosina Quinasas/efectos adversos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidor de la Tirosina Quinasa/uso terapéutico , Sistema Único de Salud , Brasil , Análisis Costo-Beneficio/economía

RESUMEN

Acute lymphoblastic leukemia (ALL) is hematological neoplasia that affects human beings from early life to adulthood. Although ALL treatment has been effective, an important percentage of ALL patients are resilient to treatment. Therefore, there is an urgent need for testing a new combination of compounds for the treatment of this disease. Recently, combined TPEN and TPGS (T2 combo) have shown selective cytotoxic effects in vitro leukemia cells such as Jurkat, K562, and Ba/F3 cells. In this study, we aimed to test the effect of combined TPEN and TPGS agents (T2 combo) at a fixed dose (TPEN 5 mg/kg: TPGS 100 mg/kg) on leukemic Ba/F3-BCR-ABL P210 BALB-c mice model. We found that 4 successive 2-day apart intravenous injections of T2 combo showed a statistically significant reduction of Ba/F3 BCR-ABL leukemia cells (- 69%) in leukemia BALB/c mice (n = 6) compared to untreated leukemia group (n = 6). Moreover, the T2 combo was innocuous to non-leukemia BALB/c mice (n = 3) compared to untreated non-leukemia mice (control, n = 3). After treatments (day 42), all mice were left to rest until day 50. Outstandingly, the leukemia BALB/c mice treated with the T2 combo showed a lower percentage of Ba/F3-BCR-ABL P210 cells (- 84%) than untreated leukemia BALB/c mice. Furthermore, treatment of leukemia and non-leukemia mice with T2 combo showed no significant tissue alteration/damage according to the histopathological analysis of brain, heart, liver, kidney, and spleen samples; however, T2 combo significantly reduced the number of leukocytes in the bone marrow of treated leukemia mice. We conclude that the T2 combo specifically affects leukemia cells but no other tissue/organs. Therefore, we anticipate that the T2 combo might be a potential pro-oxidant combination for the treatment of leukemia patients.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Leucemia-Linfoma Linfoblástico de Células Precursoras , Humanos , Ratones , Animales , Adulto , Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Cromosoma Filadelfia , Ratones Endogámicos BALB C

RESUMEN

Despite decades of research, standard therapies remain ineffective for most leukemias, pushing toward an essential unmet need for targeted drug screens. Moreover, preclinical drug testing is an important consideration for success of clinical trials without affecting non-transformed stem cells. Using the transgenic chronic myeloid leukemia (CML) mouse model, we determine that leukemic stem cells (LSCs) are transcriptionally heterogenous with a preexistent drug-insensitive signature. To test targeting of potentially important pathways, we establish ex vivo expanded LSCs that have long-term engraftment and give rise to multilineage hematopoiesis. Expanded LSCs share transcriptomic signatures with primary LSCs including enrichment in Wnt, JAK-STAT, MAPK, mTOR and transforming growth factor ß signaling pathways. Drug testing on expanded LSCs show that transforming growth factor ß and Wnt inhibitors had significant effects on the viability of LSCs, but not leukemia-exposed healthy HSCs. This platform allows testing of multiple drugs at the same time to identify vulnerabilities of LSCs.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Transcriptoma , Ratones , Animales , Células Madre Neoplásicas/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Factor de Crecimiento Transformador beta/metabolismo