RESUMEN

PURPOSE: This work aimed to evaluate the impact of a guaranteed access program to imatinib on the survival of patients with Chronic Myeloid Leukemia. METHODS: We carried out a retrospective, observational, and analytical study of the database of patients diagnosed with Chronic Myeloid Leukemia of the Instituto Nacional de Cancerología and the Hospital General de México Dr. Eduardo to assess overall survival based on guaranteed access or not to imatinib. RESULTS: With an average follow-up of 99 months, all patients' estimated 20-year overall survival was 72% (95% CI, 76-67). A significant difference was found in the 20-year survival probability in favor of patients with guaranteed access 76% (95% CI, 81-71) vs. 61% (95% CI, 69-52) (p < 0.001), in addition to those in which they had better attachment 81.2% (95% CI, 85-76) vs. 44.9% (95% CI, 52-37) (p < 0.001). CONCLUSION: CML is the most frequent chronic leukemia in Mexico. It mainly affects the economically active population (mean age 40), and the prognosis in our country has improved, emulating developed countries; however, the results depend on access to treatment and proper monitoring.

RESUMEN

Current therapy in chronic myeloid leukemia (CML) has improved patient life expectancy close to that of healthy individuals. However, molecular alterations other than BCR::ABL1 fusion gene in CML are barely known. MicroRNAs are important regulators of gene expression, and variants in some of the components of microRNA biosynthesis pathways have been associated with genetic susceptibility to different types of cancer. Thus, the aim of this study was to evaluate the association of variants located in genes involved in the biogenesis of microRNAs with susceptibility to CML. Fifteen variants in eight genes involved in the biogenesis of miRNAs were genotyped in 296 individuals with CML and 485 healthy participants using TaqMan probes. The association of gene variants with CML and clinical variables was evaluated by a Chi-square test, and odds ratios and 95% confidence intervals were estimated by logistic regression. The variant rs13078 in DICER1 was significantly higher among CML individuals than in healthy participants. In addition, the variants rs7813 and rs2740349 were significantly associated with worse prognosis, according to their Hasford scores, whereas the rs2740349 variant was also associated with a later age at diagnosis. These findings suggest that variants in components of the microRNA biogenesis pathway could be involved in CML genetic risk.

Asunto(s)

ARN Helicasas DEAD-box , Leucemia Mielógena Crónica BCR-ABL Positiva , MicroARNs , Polimorfismo de Nucleótido Simple , Ribonucleasa III , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , MicroARNs/genética , Femenino , Masculino , Persona de Mediana Edad , Ribonucleasa III/genética , Adulto , ARN Helicasas DEAD-box/genética , Anciano , Predisposición Genética a la Enfermedad , Estudios de Casos y Controles , Pronóstico

RESUMEN

Purpose: This report highlights a rare case of delayed manifestation of proliferative retinopathy associated with chronic myeloid leukemia (CML) during remission. Observations: Case report and review of the literature; In this case report, we outline the delayed manifestation and clinical progression of proliferative retinopathy in a 52-year-old male patient with a history of CML diagnosed in 2001. Initially, the patient presented with a white blood cell count (WBC) of 402,200/µl, and the leukocytosis persisted until 2005. Thereafter, the patient remained in remission for over 15 years without any visual complaints until 2022. At that time, the patient sought medical attention due to a ten-day history of left eye visual impairment, leading to the discovery of peripheral neovascularization in both eyes and vitreous hemorrhage in the left eye during fundus examination. The WBC count at the time of presentation to the Emergency Department was 10,460/µl. The patient was treated with fluorescein angiography guided panretinal photocoagulation to the areas of ischemic retina. Subsequent follow-up after eight months demonstrated regression of neovascularization. Conclusions and Importance: Our findings highlight the occurrence of proliferative retinopathy in the context of CML, uniquely manifesting during remission. This case emphasizes the importance of ophthalmological assessments not only at the time of CML diagnosis but also during subsequent follow-ups, recognizing the potential for delayed presentation of ocular complications.

RESUMEN

This study investigates COVID-19 outcomes and immune response in chronic myeloid leukemia (CML) patients post-SARS-CoV-2 vaccination, comparing effectiveness of various vaccine options. Data from 118 CML patients (85 in Brazil, 33 in the US) showed similar infection rates prior (14% Brazil, 9.1% US) and post-vaccination (24.7% vs. 27.3%, respectively). In Brazil, AstraZeneca and CoronaVac were the most commonly used vaccine brands, while in the US, Moderna and Pfizer-BioNTech vaccines dominated. Despite lower seroconversion in the Brazilian cohort, all five vaccine brands analyzed prevented severe COVID-19. Patients who received mRNA and recombinant viral vector vaccines (HR: 2.20; 95%CI 1.07-4.51; p < .031) and those that had achieved at least major molecular response (HR: 1.51; 95% CI 1.01-3.31; p < .0001) showed higher seroconversion rates. Our findings suggest that CML patients can generate antibody responses regardless of the vaccine brand, thereby mitigating severe COVID-19. This effect is more pronounced in patients with well-controlled disease.

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

Three-dimensional structured illumination microscopy (3D-SIM) and fluorescence in situ hybridization on three-dimensional preserved cells (3D-FISH) have proven to be robust and efficient methodologies for analyzing nuclear architecture and profiling the genome's topological features. These methods have allowed the simultaneous visualization and evaluation of several target structures at super-resolution. In this chapter, we focus on the application of 3D-SIM for the visualization of 3D-FISH preparations of chromosomes in interphase, known as Chromosome Territories (CTs). We provide a workflow and detailed guidelines for sample preparation, image acquisition, and image analysis to obtain quantitative measurements for profiling chromosome topological features. In parallel, we address a practical example of these protocols in the profiling of CTs 9 and 22 involved in the translocation t(9;22) in Chronic Myeloid Leukemia (CML). The profiling of chromosome topological features described in this chapter allowed us to characterize a large-scale topological disruption of CTs 9 and 22 that correlates directly with patients' response to treatment and as a possible potential change in the inheritance systems. These findings open new insights into how the genome structure is associated with the response to cancer treatments, highlighting the importance of microscopy in analyzing the topological features of the genome.

Asunto(s)

Imagenología Tridimensional , Hibridación Fluorescente in Situ , Humanos , Hibridación Fluorescente in Situ/métodos , Imagenología Tridimensional/métodos , Translocación Genética , Cromosomas/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Interfase/genética , Cromosomas Humanos/genética , Procesamiento de Imagen Asistido por Computador/métodos

RESUMEN

INTRODUCTION: Imatinib mesylate (IM) is the drug of choice for the treatment of chronic myeloid leukemia (CML). However, despite most of the results obtained with this therapy being positive, some patients still present a suboptimal therapeutic response or still develop some type of resistance. Therefore, the aim of this study was to evaluate IM plasma levels in CML patients treated at a referral unit in Manaus and correlate them with variables that might interfere with these levels. METHODS: Data from 52 patients were obtained through a standardized questionnaire containing clinical, sociodemographic, lifestyle, and use of other medication information, as well as an estimate of therapeutic adherence. Additionally, blood collection was performed to measure the plasma concentration of the drug using the HPLC-UV technique. Molecular studies were done to identify the presence of polymorphism in the ABCG2 C421A membrane transporter. RESULTS: Most patients were male with a mean age of 52 ± 12.3 years (95% CI 49.0-55.9). There was a high variation in drug concentrations in the range from 0 to 4694 ng/mL, with a mean of 1558.59 ± 989.79 ng/mL (95% CI 1283.0-1834.1). CONCLUSION: Approximately two-thirds of patients were classified in the drug-level range considered therapeutic, and there was a correlation between plasma concentration and higher molecular response. Additionally, most individuals had the normal genotype for the ABCG2 C421A polymorphism but further studies should be performed to reveal the role of this variable in the outcome of the disease in this population.

RESUMEN

Bcr-Abl is an oncoprotein with aberrant tyrosine kinase activity involved in the progression of chronic myeloid leukemia (CML) and has been targeted by inhibitors such as imatinib and nilotinib. However, despite their efficacy in the treatment of CML, a mechanism of resistance to these drugs associated with mutations in the kinase region has emerged. Therefore, in this work, we report the synthesis of 14 new 2,6,9-trisubstituted purines designed from our previous Bcr-Abl inhibitors. Here, we highlight 11b, which showed higher potency against Bcr-Abl (IC50 = 0.015 µM) than imatinib and nilotinib and exerted the most potent antiproliferative properties on three CML cells harboring the Bcr-Abl rearrangement (GI50 = 0.7-1.3 µM). In addition, these purines were able to inhibit the growth of KCL22 cell lines expressing Bcr-AblT315I, Bcr-AblE255K, and Bcr-AblY253H point mutants in micromolar concentrations. Imatinib and nilotinib were ineffective in inhibiting the growth of KCL22 cells expressing Bcr-AblT315I (GI50 > 20 µM) compared to 11b-f (GI50 = 6.4-11.5 µM). Molecular docking studies explained the structure-activity relationship of these purines in Bcr-AblWT and Bcr-AblT315I. Finally, cell cycle cytometry assays and immunodetection showed that 11b arrested the cells in G1 phase, and that 11b downregulated the protein levels downstream of Bcr-Abl in these cells.

RESUMEN

Tyrosine kinase inhibitors (TKI) have revolutionized the treatment of patients with chronic myeloid leukemia. Patients who achieve sustained deep molecular response are eligible for treatment discontinuation. DES-CML is an ongoing, phase 2 multicentric discontinuation trial. Adult patients with CML in chronic phase with typical BCR::ABL1 transcripts, stable deep molecular response (MR4.5 IS) for two years, and no previous resistance were eligible. Patients underwent a phase of TKI dose de-escalation for six months before discontinuation. TKI was reintroduced at the previous dose if the patient lost major molecular response (MMR) at any time. This study aimed to assess the impact of BCR-ABL transcript kinetics during TKI de-escalation and discontinuation phases on treatment-free survival. So far, the study recruited 41 patients, and 38 patients discontinued therapy (4 were in the second discontinuation attempt). Eleven patients lost MMR, one during the de-escalation phase and ten after discontinuation. 24-month treatment-free survival was 66% (95% CI: 48-84%) in a median follow-up of 7 (1-30) months. No patient lost hematological response or had disease progression. A higher rate of molecular relapses occurred in patients with fluctuating BCR::ABL1 levels after the discontinuation phase (with loss of MR4.5, but no loss of MMR) (P=0.04, HR-4.86 (1.03-22.9) but not confirmed in the multivariate analysis. The longer duration of TKI treatment (P=0.03, HR-1.02, 95%CI - 1.00-1.04) and MMR (P=0.004, HR-0.95, 95%CI - 0.92-098) were independent factors of a lower relapse rate.

RESUMEN

Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal translocation t(9;22)(q34;q11), in the BCR and ABL genes. These rearrangements in both genes lead to the formation of various fusion mRNA products, with preferential expression of b2a2, b3a2, and other BCR::ABL1 mRNA variants, combined with additional chromosomal abnormalities. Notably, the distribution and frequency of different mRNA variants vary in different populations. However, studies concerning this in Mexico are limited, and the results have been inconclusive. This study therefore aimed to determine the distribution of BCR::ABL1 mRNA variants in different clinical phases of CML and their effect on hematological parameters and patient survival. This study included 33 patients, whose demographic, clinical, and molecular data on BCR::ABL1 mRNA variants and hematological parameters were collected to identify potential associations. A total of 84.8% (n = 28) of patients had BCR::ABL1 translocation and increased platelet and basophil counts. The most frequent mRNA variant was b3a2 (64.3%), followed by b2a2 (28.6%) and e1a2 (3.6%). Concerning the clinical phases of CML, 75.8% (n = 25), 21.2% (n = 7), and 3% (n = 1) of patients were in the chronic, blast, and accelerated phases, respectively. Moreover, the b3a2 mRNA variant was more commonly identified in patients in the chronic phase. No correlation was observed between mRNA variant expression and patient survival. However, b2a2 was indicative of patients with longer survival as well as those treated with imatinib or nilotinib. Additionally, platelet count could be a marker of BCR::ABL1 translocation.

Asunto(s)

Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/sangre , Femenino , Masculino , Persona de Mediana Edad , Proteínas de Fusión bcr-abl/genética , Adulto , Anciano , ARN Mensajero/genética , ARN Mensajero/metabolismo , Mesilato de Imatinib/uso terapéutico , Translocación Genética , Adulto Joven

RESUMEN

El priapismo es una erección dolorosa y persistente acompañada o no de estímulo sexual. Una causa poco frecuente de esta anormalidad es la leucemia mieloide crónica. Se han reportado pocos casos de priapismo como manifestación inicial de una leucemia de este tipo en pacientes adolescentes. A continuación, se informa el caso de un paciente de 16 años de edad que presentó priapismo como manifestación inicial de una leucemia mieloide crónica. Durante su evolución, no se realizó aspiración de los cuerpos cavernosos. Se inició tratamiento hematológico específico y, ante la persistencia del priapismo, fue necesario realizar un shunt de cuerpos cavernosos en dos ocasiones, tratamiento a pesar del cual existen altas probabilidades de secuelas.

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Priapism is a painful and persistent erection, with or without sexual stimulation. A rare cause of such abnormality is chronic myeloid leukemia. Few cases of priapism as an initial manifestation of this type of leukemia have been reported in adolescent patients. Here we describe the case of a 16-year-old patient who presented with priapism as the initial manifestation of chronic myeloid leukemia. No cavernosal aspiration was performed. A specific hematological treatment was started and, given the persistence of priapism, the patient required 2 corpora cavernosa shunt procedures; despite this treatment, there is a high probability of sequelae.

Asunto(s)

Humanos , Masculino , Adolescente , Priapismo/complicaciones , Priapismo/etiología , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Enfermedad Crónica

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

Chronic myeloid leukemia (CML) is a type of leukemia whose main genetic marker is the reciprocal translocation that leads to the production of the BCR::ABL1 oncoprotein. The expression of some genes may interfere with the progression and development of leukemias. MicroRNAs are small non-coding RNAs that have the potential to alter the expression of some genes and may be correlated with some types of leukemia and could be used as biomarkers in the diagnosis and prognosis of patients. Therefore, this project carried out an analysis of microRNA-type plasma biomarkers in patients with chronic myeloid leukemia at unique points, including follow-up analysis of patients from the Erasto Gaertner Hospital. 35 microRNAs were analyzed in different cohorts. Inside those groups, 70 samples were analyzed at unique points and 11 patients in a follow-up analysis. Statistically different results were found for microRNA-7-5p, which was found to be upregulated in patients with high expression of the BCR::ABL1 transcript when compared to healthy controls. This microRNA also had evidence of behavior related to BCR::ABL1 when analyzed in follow-up, but strong evidence was not found. In this way, this work obtained results that may lead to manifestations of a relationship between miR-7-5p and chronic myeloid leukemia, and evaluations of possible microRNAs that are not related to this pathology.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , MicroARNs , Humanos , MicroARNs/genética , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Translocación Genética , Biomarcadores

RESUMEN

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by leukocytosis and left shift. The primary molecular alteration is the BCR::ABL1, chimeric oncoprotein with tyrosine kinase activity, responsible for the initial oncogenesis of the disease. Therapy of CML was revolutionized with the advent of tyrosine kinase inhibitors, but it is still not considered curative and may present resistance and serious adverse effects. Discoveries in CML inaugurated a new era in cancer treatment and despite all the advances, a new biomarker is needed to detect resistance and adverse effects. Circular RNAs (circRNAs) are a special type of non-coding RNA formed through a process called backsplicing. The majority of circRNAs are derived from protein-coding genes. CircHIPK3 is formed from the second exon of the HIPK3 gene and has been found in various pathologies, including different types of cancer. New approaches have demonstrated the potential of circular RNAs in cancer research, and circHIPK3 has shown promising results. It is often associated with cellular regulatory pathways, suggesting an important role in the molecular dynamics of tumors. The identification of biomarkers is an important tool for therapeutic improvement; thus we review the role of circHIPK3 and its potential as a biomarker in CML.

RESUMEN

Chronic myeloid leukemia (CML) is associated with the Philadelphia chromosome and distinct BCR::ABL1 gene transcripts. We assessed the frequencies of these transcripts in Mexico, Latin America, and worldwide. We determined the prevalence of BCR::ABL1 transcripts in CML patients and intercontinental or regional variations using specialized databases and keywords. We analyzed 34 studies from 20 countries, encompassing 5795 patients. Keyword-based searches in specialized databases guided data collection. ANOVA was employed for transcript distribution analysis. The b3a2 transcript was most prevalent globally, followed by b2a2, with e1a2 being the least frequent. Interestingly, Mexico City exhibited a higher incidence of b2a2, while b3a2 predominated in the remaining country. Overall, no significant intercontinental or regional variations were observed. b3a2 was the most common BCR::ABL1 transcript worldwide, with b2a2 following closely; e1a2 was infrequent. Notably, this trend remained consistent in Mexico. Evaluating transcript frequencies holds clinical relevance for CML management. Understanding the frequency of transcript informs personalized CML treatments.

Asunto(s)

Proteínas de Fusión bcr-abl , Leucemia Mielógena Crónica BCR-ABL Positiva , Humanos , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Cromosoma Filadelfia , México/epidemiología

RESUMEN

Priapism is a painful and persistent erection, with or without sexual stimulation. A rare cause of such abnormality is chronic myeloid leukemia. Few cases of priapism as an initial manifestation of this type of leukemia have been reported in adolescent patients. Here we describe the case of a 16-year-old patient who presented with priapism as the initial manifestation of chronic myeloid leukemia. No cavernosal aspiration was performed. A specific hematological treatment was started and, given the persistence of priapism, the patient required 2 corpora cavernosa shunt procedures; despite this treatment, there is a high probability of sequelae.

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El priapismo es una erección dolorosa y persistente acompañada o no de estímulo sexual. Una causa poco frecuente de esta anormalidad es la leucemia mieloide crónica. Se han reportado pocos casos de priapismo como manifestación inicial de una leucemia de este tipo en pacientes adolescentes. A continuación, se informa el caso de un paciente de 16 años de edad que presentó priapismo como manifestación inicial de una leucemia mieloide crónica. Durante su evolución, no se realizó aspiración de los cuerpos cavernosos. Se inició tratamiento hematológico específico y, ante la persistencia del priapismo, fue necesario realizar un shunt de cuerpos cavernosos en dos ocasiones, tratamiento a pesar del cual existen altas probabilidades de secuelas.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Priapismo , Masculino , Humanos , Adolescente , Priapismo/etiología , Priapismo/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Enfermedad Crónica

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

Introduction: Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase is considered a safe option if suitable molecular monitoring is available. However, the question arises as to which factors can contribute to the maintenance of TFR, and immunologic surveillance of the remaining leukemic cells is believed to be one of them. Argentina Stop Trial is an open-label, single-arm, multicenter trial assessing TFR after tyrosine kinase inhibitors interruption, that after more than 4 years showed a successful TFR rate of 63%. Methods: In this context, we set up an immunological study by flow cytometry in order to analyze specific NK cell subsets from peripheral blood patient samples both at the time of discontinuation as well as during the subsequent months. Results: At the time of discontinuation, patients show a mature NK cell phenotype, probably associated to TKI treatment. However, 3 months after discontinuation, significant changes in several NK cell receptors occurred. Patients with a higher proportion of CD56dim NK and PD-1+ NK cells showed better chances of survival. More interestingly, non-relapsing patients also presented a subpopulation of NK cells with features associated with the expansion after cytomegalovirus infection (expression of CD57+NKG2C+), and higher proportion of NKp30 and NKp46 natural cytotoxicity receptors, which resulted in greater degranulation and associated with better survival (p<0.0001). Discussion: This NK cell subset could have a protective role in patients who do not relapse, thus further characterization could be useful for patients in sustained deep molecular response.

Asunto(s)

Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Células Asesinas Naturales , Inhibidores de Proteínas Quinasas/uso terapéutico , Inducción de Remisión

RESUMEN

INTRODUCTION: Treatment-free remission (TFR) is successful in half of the patients with chronic myeloid leukemia who discontinue Imatinib (IM) after sustained molecular response. METHODS: In a prospective trial, we used pioglitazone for 3 months before stopping IM in 30 patients. Percentages of peripheral blood lymphocyte subsets were assessed before and after treatment. The relation of these data with duration of IM treatment and TRF were examined. RESULTS: The median time of IM treatment was 117.6 months. After discontinuation, 11 patients had molecular recurrence after 5.2 months (2.4 - 30). The observation time for those remaining in TFR was 46 (26 - 56) months. The independent factors for the maintenance of TFR were the duration of IM treatment and the percentage of double-positive T cells at IM stop. CONCLUSION: A longer treatment with imatinib was associated with a longer TFR after discontinuation. Pioglitazone could act as an immunomodulator, increasing DP T cells which may contribute to prevent relapse.