Therapeutic Choices in Patients with Ph-Positive Chronic Myelogenous Leukemia In Mexico in the Era of Tyrosine Kinase Inhibitors: Stem Cell Transplantation or Tyrosine Kinase Inhibitors? Fifteen Years Later.

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.

Therapeutic Choices in Patients with Ph-Positive Chronic Myelogenous Leukemia In Mexico in the Era of Tyrosine Kinase Inhibitors: Stem Cell Transplantation or Tyrosine Kinase Inhibitors? Fifteen Years Later

ABSTRACT 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. (Rev Invest Clin. 2024;76(2):91-6)

Detachment of Hexokinase II From Mitochondria Promotes Collateral Sensitivity in Multidrug Resistant Chronic Myeloid Leukemia Cells.

Chronic Myeloid Leukemia is a neoplastic disease characterized by the abnormal expansion of hematopoietic cells with compromised functions. Leukemic cells often display a multidrug resistance phenotype, enabling them to evade a number of structurally unrelated cytotoxic compounds. One of those mechanisms relies on the high expression of efflux transporters, such as the ABC proteins, whose activity depends on the hydrolysis of ATP to reduce intracellular drug accumulation. In the present work, we employed a well-known erythroleukemia cell line, K562, and a multidrug resistant derivative cell, FEPS, to evaluate how hexokinase II, a key regulator for the rate-limiting step glycolysis, contributes to the establishment of the multidrug resistance phenotype. We found that multidrug resistant cells primarily resort to glycolysis to generate ATP. Clotrimazole reduced the expression of mitochondrial hexokinase II, which destabilized bioenergetic parameters such as reactive oxygen species production, ATP, and glutathione levels on multidrug resistant cells. This impaired the activity of ABCC1, leading to increased drug accumulation and cell death. In summary, we propose that decoupling of hexokinase II from the mitochondria emerges as a promising strategy to generate collateral sensitivity and aid in the management of chronic myeloid leukemia in chemotherapy-refractory patients.

Respuesta molecular profunda con ponatinib en leucemia mieloide crónica en fase crónica con resistencia a imatinib y dasatinib: Reporte de caso y revisión de la literatura / Profound molecular response with ponatinib in chronic phase of chronic myeloid leukemia with resistance to imatinib and dasatinib: Case report and review of the literature

RESUMEN Se reporta el caso de una mujer quien a la edad de 54 años fue diagnosticada de leucemia mieloide crónica en fase crónica; inició tratamiento con inhibidor de tirosina cinasa de primera generación, y evidenció falla por ausencia de respuesta hematológica y citogenética. A pesar del cambio de tratamiento a un inhibidor de tirosina cinasa de segunda generación (dasatinib), no fue posible alcanzar niveles óptimos de respuesta, documentándose la positividad para la mutación T315I en dominio ABL de la tirosina cinasa desregulada BCR/ABL, frente a la cual el único medicamento que muestra actividad es ponatinib. Luego de iniciar tratamiento con ponatinib, se evidenciaron niveles óptimos de respuesta citogenética y molecular, así como una adecuada calidad de vida de la paciente.

SUMMARY We report the case of a woman who at the age of 54 years was diagnosed with chronic myeloid leukemia in chronic phase; she began treatment with a first-generation tyrosine kinase inhibitor, and evidenced failure due to the absence of a hematological and cytogenetic response. Despite changing treatment to a second-generation tyrosine kinase inhibitor (dasatinib), it was not possible to achieve optimal levels of response, documenting positivity for the T315I mutation in the ABL domain of the deregulated BCR/ABL tyrosine kinase, compared to ponatinib, the only drug that shows activity. After starting treatment with ponatinib, optimal levels of cytogenetic and molecular response were evidenced, as well as an adequate quality of life for the patient.

Impacto econômico da interrupção do tratamento com inibidor de tirosina quinase em pacientes com leucemia mieloide crônica em um hospital federal referência em oncologia / Economic impact of discontinuing treatment with tyrosine kinase inhibitor in patients with chronic myeloid leukemia at a federal hospital reference in oncology

Objetivo: Avaliar o impacto econômico da descontinuação do tratamento da leucemia mieloide crônica (LMC) com inibidores da tirosina quinase (ITQs) em primeira ou segunda linha. Métodos: O modelo incluiu pacientes com diagnóstico de LMC em tratamento com ITQs que iniciaram o tratamento até 2012, em condições elegíveis no ano de 2015. Foi considerado um horizonte temporal de cinco anos sob a perspectiva do sistema público de saúde. Custos associados ao tratamento, como medicamento, monitoramento e manejo de eventos adversos, foram analisados. A avaliação foi composta por dois cenários: o cenário referência, com uso contínuo do medicamento, e o cenário comparador, com a interrupção do tratamento medicamentoso. Ambos os cenários consideraram as tecnologias disponíveis no período de 2015 a 2019. A análise de sensibilidade propôs variações nos cenários com a finalidade de avaliar a robustez do modelo. Além disso, uma extrapolação para nível nacional foi realizada, utilizando dados epidemiológicos para a obtenção do número de pacientes. Resultados: Foram selecionados 268 pacientes que iniciaram o tratamento até 2012. Desses, 65 foram elegíveis à descontinuação. A análise econômica mostrou uma economia de R$ 670.558,10 no primeiro ano, uma economia acumulada em cinco anos de R$ 3.665.355,98 e de R$ 66.517.232,80 no contexto institucional e nacional, respectivamente. A análise de sensibilidade foi favorável em todos os cenários propostos. Conclusões: A descontinuidade do tratamento da LMC mostrou-se, economicamente, uma importante oportunidade sob a perspectiva do sistema de saúde em flexibilizar novos investimentos tecnológicos e/ou ampliação de cesso, além da melhoria na qualidade de vida do paciente.

Objective: To assess the economic impact of discontinuing treatment of chronic myeloid leukemia (CML) with first or second line tyrosine kinase inhibitors (ITQs). Methods: The model included patients diagnosed with CML undergoing treatment with ITQs who started treatment until 2012, under eligible conditions in the year 2015. A 5-year time horizon was considered from the perspective of the public health system. Costs associated with treatment, such as medication, monitoring and handling adverse events were analyzed. The evaluation consisted of two scenarios, the reference scenario with continuous use of the drug and the comparator scenario with the interruption of drug treatment. Both scenarios considered the technologies available in the period from 2015 to 2019. The sensitivity analysis proposed variations in the scenarios in order to assess the robustness of the model. In addition, an extrapolation to the national level was performed, using epidemiological data to obtain the number of patients. Results: 268 patients who started treatment until 2012 were selected. Of these, 65 were eligible for discontinuation. The economic analysis showed savings of R$ 670,558.10 in the first year, accumulated savings in five years of R$ 3,665,355.98 and R$ 66,517,232.80 in the institutional and national context, respectively. The sensitivity analysis was favorable in all the proposed scenarios. Conclusions: The discontinuity of CML treatment proved to be, economically, an important opportunity from the perspective of the health system in making new technological investments and / or expanding access more flexible, in addition to improving the patient's quality of life

Dual anticancer and antibacterial activities of bismuth compounds based on asymmetric [NN'O] ligands.

Two new bismuth(III) complexes, [BiL1Cl2] (1) and [BiL2Cl2] (2), in which L1 is (2-hydroxy-4-6-di-tert-butylbenzyl-2-pyridylmethyl)amine and L2 is 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol, were synthesized and characterized by elemental and conductivity analyses, atomic absorption spectrometry, infrared and 1H NMR spectroscopies. The molecular structure of 1 reveals that the NN'O ligand forms a 1:1 complex with bismuth through coordination via the nitrogen of the aliphatic amine, the nitrogen of the pyridine ring and the oxygen of the phenolate. The coordination sphere is completed with two chloride anions in a distorted square pyramidal geometry. Bismuth exhibits the same coordination mode in compound 2. The cytotoxic activity of 1 and 2 was investigated in a chronic myelogenous leukemia cell line. The complexes are approximately three times more potent than the corresponding free ligands, with the IC50 values 0.30 and 0.38 µM for complex 1 and 2, respectively. To address the cellular mechanisms underlying cell demise, apoptosis was quantified by flow cytometry analysis. From 0.1 µM, both complexes induce apoptosis and there is a remarkable concentration-dependent increase in the population of cells in apoptosis. The complexes were also evaluated against Gram-positive and Gram-negative bacteria. Both inhibited the bacterial growth in a concentration-dependent way, with remarkable activity in some of the tested strains, for example, complex 2 was more active than its free ligand against all bacterial strains and approximately fourteen times more potent against S. dysenteriae and S. typhimurium.

Inhibition of glycosphingolipid biosynthesis reverts multidrug resistance by differentially modulating ABC transporters in chronic myeloid leukemias.

Multidrug resistance (MDR) in cancer arises from cross-resistance to structurally- and functionally-divergent chemotherapeutic drugs. In particular, MDR is characterized by increased expression and activity of ATP-binding cassette (ABC) superfamily transporters. Sphingolipids are substrates of ABC proteins in cell signaling, membrane biosynthesis, and inflammation, for example, and their products can favor cancer progression. Glucosylceramide (GlcCer) is a ubiquitous glycosphingolipid (GSL) generated by glucosylceramide synthase, a key regulatory enzyme encoded by the UDP-glucose ceramide glucosyltransferase (UGCG) gene. Stressed cells increase de novo biosynthesis of ceramides, which return to sub-toxic levels after UGCG mediates incorporation into GlcCer. Given that cancer cells seem to mobilize UGCG and have increased GSL content for ceramide clearance, which ultimately contributes to chemotherapy failure, here we investigated how inhibition of GSL biosynthesis affects the MDR phenotype of chronic myeloid leukemias. We found that MDR is associated with higher UGCG expression and with a complex GSL profile. UGCG inhibition with the ceramide analog d-threo-1-(3,4,-ethylenedioxy)phenyl-2-palmitoylamino-3-pyrrolidino-1-propanol (EtDO-P4) greatly reduced GSL and monosialotetrahexosylganglioside levels, and co-treatment with standard chemotherapeutics sensitized cells to mitochondrial membrane potential loss and apoptosis. ABC subfamily B member 1 (ABCB1) expression was reduced, and ABCC-mediated efflux activity was modulated by competition with nonglycosylated ceramides. Consistently, inhibition of ABCC-mediated transport reduced the efflux of exogenous C6-ceramide. Overall, UGCG inhibition impaired the malignant glycophenotype of MDR leukemias, which typically overcomes drug resistance through distinct mechanisms. This work sheds light on the involvement of GSL in chemotherapy failure, and its findings suggest that targeted GSL modulation could help manage MDR leukemias.

Impact of Additional Cytogenetic Abnormalities on the Clinical Behavior of Patients With Chronic Myeloid Leukemia: Report on a Latin American Population.

INTRODUCTION: Additional cytogenetic abnormalities (ACA) in patients with chronic myeloid leukemia (CML) are related to an increased risk of treatment failure, leukemic progression, and decreased survival. Currently, there are scarce data available for the Latin American population. The aim of this study was to outline the impact of ACA emergence in Mexican patients with CML. METHODS: We retrospectively analyzed clinical data from adult patients with CML treated with upfront imatinib between January 2001 and December 2016. Two groups were defined for comparison according to the presence or absence of ACA. RESULTS: Ninety-seven patients were included. ACAs were found in 30 patients, 20% at diagnosis and 80% during follow-up. In 90% of the patients, ACA emergence was detected in the CML-chronic phase. Regarding clinical outcomes, the complete cytogenetic response rate (16.5% vs. 59.8%; P < .001), progression-free survival (PFS) at 10 years (76% vs. 95%; P = .009), and failure-free survival (FFS) at 10 years (16% vs. 73%; P < .001) were significantly inferior in the ACA group. Multivariate analysis confirmed that ACA emergence was a deleterious independent prognostic factor for PFS (hazard ratio [HR] 8.9; 95% confidence interval [CI] 1.35-58.4; P = .023) and FFS (HR 3.7; 95% CI 1.54-8.58; P = .003). CONCLUSIONS: This study confirms previously reported data regarding the adverse impact of ACA over clinical outcomes in a Latin American population.

[Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib]. / Leucemia mieloide crónica. Monitoreo y factores predictivos de una respuesta favorable en el tratamiento con imatinib.

The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.

Leucemia mieloide crónica: Monitoreo y factores predictivos de una respuesta favorable en el tratamiento con imatinib / Chronic myelogenous leukemia: monitoring and predictors of a favorable response to treatment with imatinib

La supervivencia a cinco años de los pacientes con leucemia mieloide crónica en fase crónica tratados con inhibidores de tirosina quinasa es superior al 90%. Existen escasos datos a nivel local. Esta información puede ser de interés, ya que el imatinib genérico se encuentra disponible en la región. El objetivo del presente estudio es proporcionar información del monitoreo y los resultados a largo plazo del tratamiento con imatinib fuera de un ensayo clínico controlado, así como analizar el valor predictivo de respuestas tempranas para el logro de respuesta molecular 4.0 y la detección de variables que puedan condicionar falla al tratamiento. Se incluyeron 106 pacientes tratados con imatinib 400 mg diarios como inhibidor de primera línea durante una mediana de 8.9 años IQR (5.8-11.7) entre junio del 2000 y diciembre del 2015. La supervivencia global fue de 93%. En la última evaluación, 74% de los pacientes continuaba recibiendo el imatinib inicial. La obtención de respuesta en los objetivos temporales específicos (6, 12 meses) se asoció con mayor supervivencia libre de falla: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 y mayor adquisición de respuesta molecular 4.0: OR 5.6 (IC 95% 1.6-19.0) p = 0.003; OR 5.3 (IC 95% 1.4-21.0) p = 0.006. Luego del prolongado seguimiento, el imatinib proporcionó altas tasas de respuesta y supervivencia. Se confirmó el valor pronóstico de la respuesta en momentos temporales específicos. Este estudio refuerza la importancia del monitoreo estandarizado en los puntos temporales conocidos, que debe continuar siendo un objetivo en Argentina.

The expected five-year survival of chronic-phase chronic myeloid leukemia patients treated with tyrosine kinase inhibitors is over 90%. Little data is available regarding the results in the Argentinian population. This information might be of interest as generic imatinib is now available in the region. The aim of this study is to provide information on monitoring and the long-term treatment with imatinib outside of a controlled clinical trial, as well as to analyze the predictive effect of early responses to achieve molecular remission 4.0 (RM 4.0) and the detection of variables that may condition treatment failure. We included 106 patients, who received imatinib 400 mg daily as first-line inhibitor for a median of 8.9 years (IQR 5.8-11.7) between June 2000 and December, 2015. Overall survival was 93%. At latest follow-up 74% of patients continues on initial imatinib. The achievement of response at targeted milestones (6, 12 months) was associated with increased failure-free survival: 87% vs. 56%, p = 0.007; 90% vs. 69% p = 0.01 and was independently associated to RM 4.0: OR 5.6 (95% CI: 1.6-19.0); OR 5.3 (95% CI: 1.4-21.0) p = 0.006. After long-term follow-up, imatinib provided high-rates of response and survival. The prognostic value of response at targeted milestones was confirmed. This study reinforces the importance of molecular monitoring under IS standardization at known timepoints and this must continue to be a target in Argentina.

Opening the door to the development of novel Abl kinase inhibitors.

The discovery of the importance of kinase activity and its relationship to the emergence and proliferation of cancer cells, due to changes in normal physiology, opened a remarkable pathway for the treatment of chronic myelogenous leukemia through intense search of drug candidates. Six Abl kinase inhibitors have received the US FDA approval as chronic myelogenous leukemia treatment, and continuous efforts in obtaining new, more effective and selective molecules are being carried out. Herein we discuss the mechanisms of Abl inhibition, structural features and ligand/protein interactions that are important for the design of new Abl kinase inhibitors. This review provides a broad overview of binding mode predictions, through molecular docking, which can be an approach to discover novel Abl kinase inhibitors.

[HLA DRB1*, DQB1*, DPA1*, and DPB1* and their association with the pathogenesis of leukemia in the population of Venezuela]. / HLA DRB1*, DQB1*, DPA1* y DPB1* y su asociación con la patogénesis de las leucemias en población venezolana.

BACKGROUND: The HLA complex involved is a factor in the pathogenesis of leukemia. OBJECTIVES: The presence of class II HLA alleles DRB1 *, DQB1 *, DPA1 *, and DPB1 * was evaluated in 47 patients with acute lymphoblastic leukemia (ALL) and 48 with chronic myeloid leukemia (CML) for comparison with 48 healthy volunteers in Zulia, Venezuela, and to evaluate potential associations of HLA with leukemia. METHODS: Low- and high-resolution PCR-SSP was used for class II HLA regions DRB1 *, DQB1 *, DPA1 *, and DPB1 * following the instructions of KIT Olerup SSP Genovision. RESULTS: Alleles HLA-DRB1*14, especially DRB1*14:21, -DPA1*1:06, -DPA1*01:03,-DPA1*02:01, and the haplotypes HLA-DPA1*01:03-DPB1*04:01, DPA1*01:03-DPB1*02:01, DPA1*01:03-DPB1*99:01, -DRB1*14-DPA1*01:03, -DRB1*15-DPA1*01:03 were associated with CML (RR > 3); alleles HLA-DRB1*13, -DQB1*02, -DPA1*01:05, -DPA1*01:09 and the haplotypes HLA-DPA1*01:09-DPB1*02:01, DPA1*01:09-DPB1*04:01 were protective (RR < 1). Alleles HLA-DQB1*04, -DQB1*05, -DPA1*1:06, -DPA1*01:07, -DPA1*1:08 had a positive association with ALL. Alleles HLA-DPA1*01:09, -DPA1*02:01, -DPB1*02:01, -DPB1*03:01 and the haplotypes HLA-DPA1*01:03-DPB1*04:02, -DPA1*01:09-DPB1*02:01, -DPA1*01:09-DPB1*04:01, -DPA1*02:01-DPB1*04:02 were negatively associated. CONCLUSIONS: The other association patterns identified suggest marked differences in the pathogenesis of leukemia, which suggests possible deficiencies in antigen presentation for ALL or potential effects of molecular mimicry in CML.

Antecedentes: La presencia de HLA es un factor que influye en la patogénesis de las leucemias. Objetivos: Se evaluó la presencia de alelos HLA clase II DRB1*, DQB1*, DPA1* y DPB1* en 47 pacientes con leucemia linfoide aguda (LLA) y 48 con leucemia mieloide crónica (LMC), para compararlos con 48 voluntarios sanos de Zulia, Venezuela, y determinar las posibles asociaciones de HLA con las leucemias. Métodos: Se utilizó la técnica de PCR-SSP de baja y alta resolución para las regiones HLA clase II DRB1*, DQB1*, DPA1* y DPB1* conforme las instrucciones del KIT Olerup SSP Genovision. Resultados: Los alelos HLA-DRB1*14, especialmente DRB1*14:21, -DPA1*1:06, -DPA1*01:03,-DPA1*02:01, y los haplotipos HLA-DPA1*01:03-DPB1*04:01, DPA1*01:03-DPB1*02:01, DPA1*01:03-DPB1*99:01, -DRB1*14-DPA1*01:03, -DRB1*15-DPA1*01:03 tuvieron asociación con LMC (RR > 3); los alelos HLA-DRB1*13, -DQB1*02, -DPA1*01:05, -DPA1*01:09 y los haplotipos HLA-DPA1*01:09-DPB1*02:01, DPA1*01:09-DPB1*04:01 resultaron protectores (RR < 1). Los alelos HLA-DQB1*04, -DQB1*05, -DPA1*1:06, -DPA1*01:07, -DPA1*1:08 tuvieron asociación positiva con LLA. Los alelos HLA-DPA1*01:09, -DPA1*02:01, -DPB1*02:01, -DPB1*03:01 y los haplotipos HLA-DPA1*01:03-DPB1*04:02, -DPA1*01:09-DPB1*02:01, -DPA1*01:09-DPB1*04:01, -DPA1*02:01-DPB1*04:02 resultaron asociados negativamente. Conclusiones: La fuerte asociación de HLA DRB1*14 con la LMC y la ausencia de asociaciones DRB1* con LLA y los otros patrones de asociación identificados sugieren marcadas diferencias en las patogénesis de las leucemias, lo que orienta hacia posibles deficiencias en la presentación antigénica para LLA o posibles efectos de mimetismo molecular en LMC.

Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison.

Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons.

Leucemia mieloide crónica en niño de 2 años. Reporte de caso / Chronic myelogenous leukemia in a 2 year-old boy. Case report

La leucemia mieloide crónica (LMC) representa el 3% de las leucemias pediátricas diagnosticadas y su incidencia es de 0,7 millones por año, extremadamente rara entre las edades de 1 a 14 años y debido a esta inusual presentación existen pocos casos descritos. La patogénesis molecular de la LMC implica la fusión quimérica de la proteína BCR-ABL, cuyo aumento constitutivo de la actividad tirosina quinasa, contribuido por el componente ABL, parece ser el causante de la alteración molecular en la LMC. La identificación de esta proteína quimérica resultó en el desarrollo exitoso del mesilato de imatinib, fármaco que ha revolucionado el tratamiento de esta enfermedad. El tratamiento con imatinib en niños ha logrado alcanzar un 90% de remisión completa a los 5 años, sustituyendo de esta manera al trasplante alogénico como primera línea de terapia. A continuación reportamos el caso de un niño de 2 años cuyo hemograma reportó: anemia microcítica moderada (hemoglobina de 11,7 g%), hiperleucocitosis (leucocitos 80,8 x10(9)/L), y trombocitosis (721x10(9)/L). Los estudios de citogenética, FISH y RT-PCR para BCR-ABL1 dieron positivos, confirmando el diagnóstico de LMC en fase crónica. Se inició inmediatamente el tratamiento con imatinib y a 3 años del diagnóstico el paciente se encuentra en remisión completa a nivel molecular, con ausencia del clon neoplásico y sin haber presentado efectos colaterales adversos de importancia.

Chronic myeloid leukemia (CML) accounts for 3% of all diagnosed pediatric leukemias. It has an incidence of 0.7 million per year, rarely diagnosed between the ages of 1 to 14 years, so few cases have been reported. The CML molecular pathogenesis involves a chimeric fusion of the BCR-ABL protein which increased constitutive tyrosine kinase activity contributed by ABL component seems to be the cause of the molecular alteration in CML. The identification of this chimeric protein resulted in the successful development of imatinib mesylate, a drug that has revolutionized the treatment of this disease. The use of imatinib in children has reached 90% of complete remission at 5 years, replacing in this way the allogeneic transplant as first-line therapy. This report presents the case of a 2 year old child whose CBC reported: moderate microcytic anemia (hemoglobin 11.7 g%), hyperleukocytosis (leukocytes 80.8 x10(9)/L) and thrombocytosis (721x10(9)/ L). Cytogenetic, FISH and RT-PCR Studies for BCR-ABL1 were positive, confirming the diagnosis of CML in chronic phase. Treatment with imatinib was initiated immediately and 3 years after diagnosis the patient is in complete molecular remission with the absence of neoplastic clone and without having presented significant side effects.

Trends in mortality of adult patients diagnosed with myeloid leukemia from 1994 to 2011 in southeastern Brazil.

OBJECTIVE: To evaluate trends in mortality among adults with myeloid leukemia in the Vale do Paraíba, State of São Paulo. METHODS: Data from the Brazilian National Health Service database DATASUS provided the number of deaths caused by myeloid leukemia and the number of inhabitants per year in the Regional Health Division XVII from 1994 to 2011. Registries were categorized according to gender into four age ranges (over 20 years, 20-49, 50-69 and over 70 years) for an estimation of the annual percent change for age-adjusted mortality rates. The percent changes were calculated using the Joinpoint regression analysis model. RESULTS: Overall, a significant decline per year was demonstrated for the entire sample (over 20 years) across the 18-year period studied (annual percent change: -5.59%; 95% CI: -8.5 to -2.5% for males; p-value<0.05 and -7.02%; 95% CI -11.2 to -2.8% for females; p-value<0.05) with no significant difference between genders. In an analysis using two Joinpoints, significant drops were observed from 1994 to 2001 (annual percent change: -21.22%; 95% confidence interval: -27.9 to -13.9%; p-value<0.05) and from 1994 to 2003 (annual percent change: -12.86%; 95% confidence interval -22.2 to -2.5%; p-value<0.05) for men and women, respectively. The declining trends were greatest for patients aged over 70 years with the age-adjusted mortality rates in younger groups declining non-significantly except for males aged 50-69 years old. CONCLUSION: Our data suggest a significant decline per year in age-adjusted mortality rates of adult patients diagnosed with myeloid leukemia from 1994 to 2011 in the Vale do Paraíba, State of São Paulo.

Trends in mortality of adult patients diagnosed with myeloid leukemia from 1994 to 2011 in southeastern Brazil

Objective: To evaluate trends in mortality among adults with myeloid leukemia in the Vale do Paraíba, State of São Paulo. Methods: Data from the Brazilian National Health Service database DATASUS provided the number of deaths caused by myeloid leukemia and the number of inhabitants per year in the Regional Health Division XVII from 1994 to 2011. Registries were categorized according to gender into four age ranges (over 20 years, 20-49, 50-69 and over 70 years) for an estimation of the annual percent change for age-adjusted mortality rates. The percent changes were calculated using the Joinpoint regression analysis model. Results: Overall, a significant decline per year was demonstrated for the entire sample (over 20 years) across the 18-year period studied (annual percent change: −5.59%; 95% CI: −8.5 to −2.5% for males; p-value < 0.05 and −7.02%; 95% CI −11.2 to −2.8% for females; p-value < 0.05) with no significant difference between genders. In an analysis using two Joinpoints, significant drops were observed from 1994 to 2001 (annual percent change: −21.22%; 95% confidence interval: −27.9 to −13.9%; p-value < 0.05) and from 1994 to 2003 (annual percent change: −12.86%; 95% confidence interval −22.2 to −2.5%; p-value < 0.05) for men and women, respectively. The declining trends were greatest for patients aged over 70 years with the age-adjusted mortality rates in younger groups declining non-significantly except for males aged 50-69 years old. Conclusion: Our data suggest a significant decline per year in age-adjusted mortality rates of adult patients diagnosed with myeloid leukemia from 1994 to 2011 in the Vale do Paraíba, State of São Paulo. .

[Molecular response with triple therapy in patients with chronic myeloid leukemia]. / Respuesta molecular con terapia triple en pacientes con leucemia mieloide crónica.

BACKGROUND: Chronic myeloid leukemia is a myeloproliferative disorder which results from the translocation t(9;22)(q34;q11). Imatinib mesylate is an inhibitor of kinase tyrosine that has proved to be useful in patients with chronic myeloid leukemia. Our aim was to evaluate the major molecular response to 12 months with triple therapy, analyze the evolution of these patients, and the hematological and non-hematological toxicity. METHODS: It was performed a longitudinal study in patients with diagnosis of chronic myeloid leukemia who were treated with sequential triple therapy: Pegylated interferon alpha 2a (90 µg/week for four weeks) + imatinib (800 mg a day for 30 days) + cytarabine (20 mg/m2 from day 1 to 10). Molecular and hematologic responses at 12 months of treatment were analyzed. RESULTS: Thirty eight patients with chronic myeloid leukemia were eligible; the mean age was 43.4 years and the medians of hemoglobin levels, leukocyte and platelet counts at diagnosis were 10 g/dL (5.1 to 16.0 g/dL), 208 000/µL3 (10 600 to 529 000/µL3) and 573 500/µL3 (130 000 to 4 272 000/µL3), respectively. According to the Sokal score, 68.4 % had low risk, 26.3 % intermediate and 5.3 % high risk. CONCLUSIONS: The hematologic response was similar to that reported in the IRIS study, but the molecular response was greater in more cases. The adverse hematological effects grades 3-4 and non-hematological were significative: 45 % and 87 %, which forces to continous monitoring. The combination of interferon alpha 2a, cytarabine and a high-dose of imatinib induced the major molecular response, of 68.4 %, at 12 months.

INTRODUCCIÓN: la leucemia mieloide crónica es un trastorno mieloproliferativo provocado por la translocación t (9;22)(q34;q11). El mesilato de imatinib es un inhibidor de la tirosina cinasa útil en el tratamiento de la leucemia mieloide crónica. El objetivo de este estudio fue evaluar la respuesta molecular mayor a los 12 meses con esquema terapéutico triple, analizar la evolución de los pacientes, así como la toxicidad general y la hematológica. MÉTODOS: estudio observacional longitudinal en pacientes con leucemia mieloide crónica, tratados con interferón pegilado alfa 2a subcutáneo (90 µg/semana por cuatro semanas) + imatinib oral (800 mg/día por 30 días) + citarabina subcutánea (20 mg/m2 de superficie corporal del día 1 al 10). Se analizaron las respuestas hematológica y molecular a los 12 meses. RESULTADOS: se trataron 38 pacientes con leucemia mieloide crónica con edad media de 43.4 años. Los niveles de hemoglobina, leucocitos y plaquetas al diagnóstico fueron de 10 g/dL (5.1 a 16 g/dL), 208 000/µL3 (10 600 a 529 000/µL3) y 573 500/µL3 (130 000 a 4 272 000/µL3), respectivamente. Según la escala Sokal, 68.4 % tuvo bajo riesgo, 26.3 % intermedio y 5.3 % riesgo alto. CONCLUSIONES: la respuesta hematológica fue semejante a la del estudio IRIS. Se obtuvo una respuesta molecular mayor en mayor proporción de casos. Los efectos secundarios hematológicos grados 3 y 4 y no hematológicos fueron significativos: 45 y 87 %, lo que obliga al monitoreo continuo. La combinación de interferón alfa 2a, citarabina e imatinib a dosis altas indujo la remisión molecular mayor a los 12 meses en 68.4 % de los casos.

[Response to treatment with tyrosine kinase inhibitors in chronic myeloid leukemia]. / Respuesta a inhibidores de tirosina cinasa en pacientes con leucemia mieloide crónica.

BACKGROUND: Chronic myeloid leukemia represents 15 % of all the leukemias in adults. With the introduction of tyrosine kinase inhibitors, overall survival at 10 years is 80-90 %. The objective was to describe the epidemiology, complete cytogenetic response and major molecular response with tyrosine kinase inhibitors in patients with chronic myeloid leukemia. METHODS: It was performed a descriptive cross-sectional study of patients with chronic myeloid leukemia and Philadelphia chromosome-positive in treatment with tyrosine kinase inhibitors. RESULTS: The sample included 54 patients with a mean age of 41 years; 78 % of patients were in chronic phase, and in 8 % of patients were identified complex karyotype at diagnosis. All patients received imatinib as first-line treatment. We identified mutations in 8 %. The patients with primary or secondary resistance (30%) received second-generation tyrosine kinase inhibitors as a second-line therapy. Of 35 patients treated with imatinib, 23 had complete cytogenetic response, 23 had major molecular response, and 16 had loss of response to treatment. Of nine patients treated with nilotinib, two presented complete cytogenetic response, two major molecular response, and five loss of response to treatment. Of seven patients treated with dasatinib, two had complete cytogenetic response, two major molecular response, and four loss of response to treatment. CONCLUSIONS: Of patients studied, 30 % was resistant to imatinib, 52 % achieved a complete cytogenetic response, and 42 % major molecular response. The use of second generation tyrosine kinase inhibitors led to obtain a complete cytogenetic and major molecular response in fewer time.

INTRODUCCIÓN: la leucemia mieloide crónica representa 15 % de las leucemias en los adultos. Con los inhibidores de la tirosina cinasa, la sobrevida a 10 años es de 80 a 90 %. El objetivo de esta investigación fue describir las características epidemiológicas, respuesta citogenética completa y respuesta molecular mayor con inhibidores de tirosina cinasa en pacientes con leucemia mieloide crónica. MÉTODOS: se realizó un estudio transversal descriptivo de los expedientes clínicos de pacientes con leucemia mieloide crónica positivos a cromosoma Filadelfia que fueron sometidos a tratamiento con inhibidores de tirosina cinasa. RESULTADOS: se incluyeron 54 pacientes; la edad media fue de 41 años, 78 % estaba en fase crónica y en 8 % se detectaron cariotipos complejos al diagnóstico. Todos recibieron imatinib como tratamiento de primera línea. Se identificaron mutaciones en 8 % de los pacientes. Los pacientes con resistencia primaria o secundaria (30 %) recibieron inhibidores de tirosina cinasa de segunda generación como tratamiento de segunda línea. De 35 pacientes tratados con imatinib, 23 presentaron respuesta citogenética completa, 23 respuesta molecular mayor y 16, pérdida de respuesta. De nueve pacientes tratados con nilotinib, dos presentaron respuesta citogenética completa, dos respuesta molecular mayor y cinco, pérdida de respuesta. De siete pacientes tratados con dasatinib, dos presentaron respuesta citogenética completa, dos respuesta molecular mayor y cuatro, pérdida de respuesta. CONCLUSIONES: 30 % de los pacientes presentó resistencia, 52 % alcanzó una respuesta citogenética completa con imatinib y 42 % una respuesta molecular mayor. El uso de inhibidores de tirosina cinasa de segunda generación permite alcanzar respuestas citogenética completa y molecular mayor en menor tiempo.

[Nilotinib in patients with chronic myeloid leukemia without response to imatinib]. / Nilotinib en pacientes con leucemia mieloide crónica con falla a imatinib.

BACKGROUND: Resistance and intolerance to imatinib in patients with chronic myeloid leukemia requires alternative therapies. Nilotinib provides a choice as a second-line treatment. The objective of this report was to show the results of a group of patients with chronic myeloid leukemia who received nilotinib as a second-line treatment. METHODS: The medical records of 16 patients of both sexes, of any age, diagnosed with chronic myeloid leukemia, who received nilotinib as a second-line treatment, were reviewed. All of them had received imatinib prior as first-line treatment; the causes to switch to nilotinib were intolerance, resistance and clinical progression of leukemia. RESULTS: The sample was of 16 patients, who achieved at least a hematologic response; 10 were males (62.5%). The age range was 24 to 75 years. Two patients received nilotinib due to intolerance to imatinib; seven due to resistance to imatinib and seven due to lack of response. There was response in the two patients who received nilotinib due to intolerance. One patient died five months after starting nilotinib due to progression of leukemia; four patients achieved major molecular response, two patients had reduced expression of BCR-ABL gene. Six patients continued with high expression of BCR-ABL gene; two of them carrying M244V mutation, and one with a complex karyotype with numerical and structural alterations. CONCLUSIONS: Nilotinib is an option for patients with intolerance or resistance to imatinib.

INTRODUCCIÓN: la resistencia e intolerancia al imatinib en pacientes con leucemia mieloide crónica requiere el uso de otros fármacos, como el nilotinib. El objetivo de este informe es presentar los resultados obtenidos en un grupo de pacientes con leucemia mieloide crónica que recibió tratamiento de segunda línea con nilotinib. MÉTODOS: se incluyeron 16 pacientes con diagnóstico de leucemia mieloide crónica que recibieron tratamiento de segunda línea con nilotinib, después de que no respondieron adecuadamente al imatinib. El cambio de fármaco se debió a intolerancia, resistencia o progresión de la leucemia. RESULTADOS: los 16 pacientes consiguieron al menos respuesta hematológica. Hubo respuesta molecular mayor en dos pacientes en los que el cambio se debió a intolerancia a imatinib. Un paciente falleció a los cinco meses de haber iniciado nilotinib, debido a progresión de la leucemia y hemorragia cerebral. En cinco, el cambio se debió a resistencia a imatinib y progresión de la leucemia; en ellos se logró respuesta molecular mayor. Dos pacientes presentaron reducción de la expresión del gen BCR-ABL. En seis pacientes persistió la elevada expresión del gen BCR-ABL. De estos últimos, dos portaban mutación M244V y uno, cariotipo muy complejo con alteraciones numéricas y estructurales. CONCLUSIONES: nilotinib es una opción viable para tratar a los pacientes con intolerancia o resistencia a imatinib.

[Pregnancy and myeloid leukemia treated with imatinib. Development and monitoring of a patient]. / Embarazo y leucemia mieloide crónica tratada con imatinib. Evolución y monitoreo de una paciente.

BACKGROUND: Imatinib has changed the natural history of chronic myeloid leukemia. There are women with chronic myeloid leukemia in reproductive age with pregnancy desires. The aim of this case was to report the course and outcome of pregnancy in a patient with chronic myeloid leukemia diagnosis treated with imatinib. CLINICAL CASE: A 32 year old female with diagnosis of chronic myeloid leukemia with follow-up of 11 years. She received standard treatment, but she reported poor adherence; therefore, she received imatinib therapy two years after the diagnosis. The patient stopped the treatment herself because she was looking to be pregnant. She presented amenorrhea, which lasted for six weeks; pregnancy was confirmed. During a period of 10 months, she remained untreated and there were no symptoms of leukemia progression. The pregnancy was terminated by cesarean section at 35.5 weeks of gestation. The product was born healthy. In the post-cesarean visit, the lab showed a cell blood count which reported: hemoglobin 8.7 g/dL, hematocrit 25 %, white blood cell 22,000/mL, platelets 170,000/mL. Since October the patient resumed imatinib 600 mg/day. CONCLUSIONS: The prolonged period of treatment with imatinib had no effect on the pregnancy and the product. The molecular monitoring showed the need to reinstall the treatment once the pregnancy finished. The efficacy and safety of treatment allows patients to fulfill life projects that seemed distant in other time.

INTRODUCCIÓN: el tratamiento con imatinib ha modificado la historia natural de la leucemia mieloide crónica, y ha permitido que las mujeres con este padecimiento puedan embarazarse. El objetivo de este reporte es describir el curso y desenlace de un embarazo en una paciente con diagnóstico previo de leucemia mieloide crónica, que recibía tratamiento con imatinib. CASO CLÍNICO: mujer de 32 años con leucemia mieloide crónica de 11 años de evolución. Al diagnóstico se inició tratamiento estándar, pero debido a poca adherencia terapéutica, a los dos años se le prescribió imatinib. Debido al deseo de procrear, la paciente decidió suspender el medicamento. Un mes después acudió a la consulta con amenorrea de seis semanas de evolución; se confirmó embarazo. Durante 10 meses que permaneció sin tratamiento, no tuvo síntomas de progresión de la leucemia. El embarazo se interrumpió por cesárea a las 35.5 semanas de gestación. El neonato aparentemente se encontraba sano. En el transcurso del puerperio quirúrgico, la paciente acudió a consulta; los resultados de la biometría hemática indicaron hemoglobina de 8.7 g/dL, hematócrito de 25 %, leucocitos de 22 000/mL y plaquetas de 170 000/mL. Ese día se reinició tratamiento con 600 mg/día de imatinib. CONCLUSIONES: el tratamiento prolongado con imatinib no tuvo repercusión sobre el embarazo ni el neonato. El monitoreo molecular evidenció la necesidad de re-iniciarlo una vez concluido el embarazo. La eficacia y seguridad de los tratamientos actuales permiten cumplir proyectos de vida que en otro tiempo eran impensables.