RESUMEN
Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.
Asunto(s)
Interferón alfa-2 , Interferón-alfa , Polietilenglicoles , Proteínas Recombinantes , Trombocitemia Esencial , Humanos , Trombocitemia Esencial/tratamiento farmacológico , Polietilenglicoles/uso terapéutico , Polietilenglicoles/efectos adversos , Polietilenglicoles/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Proteínas Recombinantes/efectos adversos , Proteínas Recombinantes/administración & dosificación , Interferón alfa-2/uso terapéutico , Interferón alfa-2/efectos adversos , Interferón-alfa/uso terapéutico , Interferón-alfa/efectos adversos , Estudios Prospectivos , Masculino , Femenino , Resultado del Tratamiento , Adulto , Persona de Mediana Edad , AncianoRESUMEN
In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.
Asunto(s)
Antineoplásicos/uso terapéutico , Imidazoles/uso terapéutico , Leucemia Mieloide de Fase Crónica/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Piridazinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Proteínas de Fusión bcr-abl/genética , Humanos , Imidazoles/administración & dosificación , Imidazoles/efectos adversos , Leucemia Mieloide de Fase Crónica/genética , Masculino , Persona de Mediana Edad , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Piridazinas/administración & dosificación , Piridazinas/efectos adversos , Resultado del Tratamiento , Adulto JovenRESUMEN
Packed red blood cells (pRBCs), the most commonly transfused blood product, are exposed to environmental disruptions during storage in blood banks. In this study, temporal sequence of changes in the ion exchange in pRBCs was analyzed. Standard techniques commonly used in electrolyte measurements were implemented. The relationship between ion exchange and red blood cells (RBCs) morphology was assessed with use of atomic force microscopy with reference to morphological parameters. Variations observed in the Na+, K+, Cl-, H+, HCO3-, and lactate ions concentration show a complete picture of singly-charged ion changes in pRBCs during storage. Correlation between the rate of ion changes and blood group type, regarding the limitations of our research, suggested, that group 0 is the most sensitive to the time-dependent ionic changes. Additionally, the impact of irreversible changes in ion exchange on the RBCs membrane was observed in nanoscale. Results demonstrate that the level of ion leakage that leads to destructive alterations in biochemical and morphological properties of pRBCs depend on the storage timepoint.
Asunto(s)
Conservación de la Sangre/métodos , Eritrocitos/metabolismo , Intercambio Iónico , Manejo de Especímenes/métodos , Carbonatos/metabolismo , Membrana Eritrocítica , Humanos , Iones/metabolismo , Ácido Láctico/metabolismo , Microscopía de Fuerza Atómica , Potasio/metabolismo , Sodio/metabolismoRESUMEN
Ruxolitinib is a potent Janus kinase (JAK) 1/JAK2 inhibitor approved for the treatment of myelofibrosis (MF). Ruxolitinib was assessed in JUMP, a large (N = 2233), phase 3b, expanded-access study in MF in countries without access to ruxolitinib outside a clinical trial, which included patients with low platelet counts (<100 × 109 /l) and patients without splenomegaly - populations that have not been extensively studied. The most common adverse events (AEs) were anaemia and thrombocytopenia, but they rarely led to discontinuation (overall, 5·4%; low-platelet cohort, 12·3%). As expected, rates of worsening thrombocytopenia were higher in the low-platelet cohort (all grades, 73·2% vs. 53·5% overall); rates of anaemia were similar (all grades, 52·9% vs. 59·5%). Non-haematologic AEs, including infections, were mainly grade 1/2. Overall, ruxolitinib led to meaningful reductions in spleen length and symptoms, including in patients with low platelet counts, and symptom improvements in patients without splenomegaly. In this trial, the largest study of ruxolitinib in patients with MF to date, the safety profile was consistent with previous reports, with no new safety concerns identified. This study confirms findings from the COMFORT studies and supports the use of ruxolitinib in patients with platelet counts of 50-100 × 109 /l. (ClinicalTrials.gov identifier NCT01493414).
Asunto(s)
Mielofibrosis Primaria/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazoles/uso terapéutico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anemia/inducido químicamente , Femenino , Humanos , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/antagonistas & inhibidores , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/etiología , Masculino , Persona de Mediana Edad , Neoplasias/etiología , Nitrilos , Recuento de Plaquetas , Mielofibrosis Primaria/sangre , Mielofibrosis Primaria/complicaciones , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/efectos adversos , Pirazoles/efectos adversos , Pirimidinas , Bazo/patología , Esplenomegalia/etiología , Trombocitopenia/inducido químicamente , Adulto JovenRESUMEN
Based on the multimodal characterization of human red blood cells (RBCs), the link between the storage-related sequence of the nanoscale changes in RBC membranes in the relation to their biochemical profile as well as mechanical and functional properties was presented. On the background of the accumulation of RBCs waste products, programmed cell death and impaired rheological properties, progressive alterations in the RBC membranes including changes in their height and diameter as well as the in situ characterization of RBC-derived microparticles (RMPs) on the RBCs surface were presented. The advantage of atomic force microscopy (AFM) in RMPs visualization, even at the very early stage of vesiculation, was shown based on the results revealed by other reference techniques. The nanoscale characterization of RMPs was correlated with a decrease in cholesterol and triglycerides levels in the RBC membranes, proving the link between the lipids leakage from RBCs and the process of vesiculation.
Asunto(s)
Eritrocitos/metabolismo , Microscopía de Fuerza Atómica/métodos , Micropartículas Derivadas de Células/metabolismo , Recuento de Eritrocitos , Citometría de Flujo , HumanosRESUMEN
Chronic myeloid leukemia (CML) is usually diagnosed in chronic phase, yet there is a small percentage of patients that is diagnosed in accelerated phase or blast crisis. Due to this rarity, little is known about the prognosis of these patients. Our aim was to identify prognostic factors for this cohort. We identified 283 patients in the EUTOS population-based and out-study registries that were diagnosed in advanced phase. Nearly all patients were treated with tyrosine kinase inhibitors. Median survival in this heterogeneous cohort was 8.2 years. When comparing patients with more than 30% blasts to those with 20-29% blasts, the hazard ratio (HR) was 1.32 (95%-confidence interval (CI): [0.7-2.6]). Patients with 20-29% blasts had a significantly higher risk than patients with less than 20% blasts (HR: 2.24, 95%-CI: [1.2-4.0], P = .008). We found that the blast count was the most important prognostic factor; however, age, hemoglobin, basophils and other chromosomal aberrations should be considered as well. The ELTS score was able to define two groups (high risk vs non-high risk) with an HR of 3.01 (95%-CI: [1.81-5.00], P < .001). Regarding the contrasting definitions of blast crisis, our data clearly supported the 20% cut-off over the 30% cut-off in this cohort. Based on our results, we conclude that a one-phase rather than a two-phase categorization of de novo advanced phase CML patients is appropriate.
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Crisis Blástica/mortalidad , Leucemia Mieloide de Fase Acelerada/mortalidad , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Crisis Blástica/sangre , Crisis Blástica/diagnóstico , Crisis Blástica/genética , Médula Ósea/patología , Recuento de Células , Aberraciones Cromosómicas , Europa (Continente)/epidemiología , Femenino , Estudios de Seguimiento , Hemoglobinas/análisis , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide de Fase Acelerada/sangre , Leucemia Mieloide de Fase Acelerada/diagnóstico , Leucemia Mieloide de Fase Acelerada/genética , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias/métodos , Células Madre Neoplásicas , Pronóstico , Modelos de Riesgos Proporcionales , Sistema de Registros , Adulto JovenRESUMEN
Nilotinib, a second-generation tyrosine kinase inhibitor, was designed to overcome resistance of a wide range of BCR-ABL mutants to imatinib. When used in the first-line treatment in newly diagnosed chronic myeloid leukemia (CML), it induces faster and deeper molecular responses in higher than imatinib percentage of patients. Treatment-free remission after achievement of sustained deep molecular response represents an emerging treatment goal for a proportion of patients with CML in chronic phase. The pharmacologic properties, and the role of nilotinib in the current treatment of CML in the context of considered optimal end point of therapy including the discontinuation trial and durable treatment-free remission achievement is discussed in the article.
Asunto(s)
Antineoplásicos/uso terapéutico , Proteínas de Fusión bcr-abl/antagonistas & inhibidores , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Antineoplásicos/farmacología , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos/genética , Proteínas de Fusión bcr-abl/genética , Humanos , Mesilato de Imatinib/farmacología , Mesilato de Imatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inducción de Remisión/métodos , Resultado del TratamientoRESUMEN
Background: Treatment-free remission (TFR)-that is, stopping tyrosine kinase inhibitor (TKI) therapy without loss of response-is an emerging treatment goal in chronic myeloid leukemia (CML). Objective: To evaluate TFR after discontinuation of second-line nilotinib therapy. Design: Single-group, phase 2, open-label study. (ClinicalTrials.gov: NCT01698905). Setting: 63 centers in 18 countries. Patients: Adults with CML in chronic phase who received TKI therapy for at least 3 years (>4 weeks with imatinib, then ≥2 years with nilotinib) and achieved MR4.5 (BCR-ABL1 ≤0.0032% on the International Scale [BCR-ABL1IS]) while receiving nilotinib entered a 1-year consolidation phase. Those with sustained MR4.5 during consolidation were eligible to enter TFR. Interventions: Patients received nilotinib during consolidation; those who entered TFR stopped treatment. Patients with loss of major molecular response (MMR) (BCR-ABL1IS ≤0.1%) or confirmed loss of MR4 (BCR-ABL1IS ≤0.01%) during TFR reinitiated nilotinib treatment. Measurements: Proportion of patients without loss of MMR, confirmed loss of MR4, or treatment reinitiation within 48 weeks of stopping treatment (primary end point). Results: 163 patients who had switched from imatinib to nilotinib (for reasons including resistance, intolerance, and physician preference) enrolled in the study and entered the consolidation phase. Of these patients, 126 met the criteria for entering the TFR phase, and 73 (58% [95% CI, 49% to 67%]) and 67 (53% [CI, 44% to 62%]) maintained TFR at 48 weeks (primary end point) and 96 weeks, respectively. Of the 56 patients who reinitiated nilotinib therapy, 55 regained MMR or better and 52 regained MR4.5. None had CML progression to accelerated phase or blast crisis. Musculoskeletal pain was more frequent during the first 48 weeks after nilotinib discontinuation. Limitation: The study included a heterogeneous patient population and was not designed to compare outcomes between patients continuing and those stopping treatment. Conclusion: TFR seems achievable in patients with sustained MR4.5 after switching to nilotinib. Primary Funding Source: Novartis Pharmaceuticals Corporation.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Esquema de Medicación , Femenino , Humanos , Mesilato de Imatinib/uso terapéutico , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Inducción de Remisión , Resultado del TratamientoRESUMEN
AIM OF THE STUDY: The aim of the study was to investigate whether there are differences in the various dimensions of the health locus of control between oncological and non-oncological patients and to determine whether there is a relationship between the level of health locus of control and the type, duration of disease and gender. MATERIAL AND METHODS: The study was conducted at the Department of Hematology and the 1st Department of Cardiology of the University Hospital in Krakow. 204 patients were enrolled. Our own questionnaire developed for this purpose and the Multidimensional Health Locus of Control scale were used. The US normalization group and the Polish standardization groups of the chronically ill patients were used for comparative analysis. RESULTS: Analysis showed significant differences between women and men in the Internal control scale (p < 0.02). The respondents from both groups showed lower scores in the Internal locus of control and much higher scores in the dimension Powerful Others. In the group of oncological patients, a negative correlation was found between the Internal scale of health locus of control and the duration of the disease (p = 0.007). There was a significant difference between oncological and non-oncological patients in the Powerful Others scale (p < 0.004). CONCLUSIONS: The results suggest that oncologically ill patients could be more convinced that others are responsible for their health when compared to non-oncological patients. The longer the disease persists in oncological patients, the weaker is their internal motivation to achieve good treatment results.
RESUMEN
Philadelphia-negative myeloproliferative neoplasms (MPNs) are a diverse group of diseases whose common feature is the presence of V617F mutation of the JAK2 gene. In the era of novel therapeutic strategies in MPNs, such as JAK-inhibitor therapy, there is a growing need for establishing high sensitive quantitative methods, which can be useful not only at diagnosis but also for monitoring therapeutic outcomes, such as minimal residual disease (MRD). In this study, we compared the qPCR and ddPCR methods and their clinical utility for diagnosis, prognostication, and treatment monitoring of MPNs with JAK2 V617F mutation in 63 MPN patients of which 6 were subjected to ruxolitinib treatment. We show a high conformance between the two methods (correlation coefficient r = 0.998 (p < 0.0001)). Our experiments revealed high analytical sensitivity for both tests, suggesting that they are capable of detecting the JAK2 V617F mutation at diagnosis of MPN with a limit of detection (LoD) of 0.12% for qPCR and 0.01% for ddPCR. The alterations of JAK2 V617F allele burden in patients treated with ruxolitinib were measured by both methods with equal accuracy. The results suggest an advantage of ddPCR in monitoring MRD because of allele burdens below the LoD of qPCR. Overall, the clinical utility of qPCR and ddPCR is very high, and both methods could be recommended for the routine detection of the V617F mutation at diagnosis, though ddPCR will probably supersede qPCR in the future due to cost-effectiveness.
Asunto(s)
Alelos , Neoplasias Hematológicas/genética , Janus Quinasa 2/genética , Mutación Missense , Trastornos Mieloproliferativos/genética , Cromosoma Filadelfia , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Adulto , Anciano , Sustitución de Aminoácidos , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/tratamiento farmacológico , Humanos , Janus Quinasa 2/sangre , Masculino , Persona de Mediana Edad , Trastornos Mieloproliferativos/sangre , Trastornos Mieloproliferativos/tratamiento farmacológico , Rituximab/administración & dosificaciónRESUMEN
Identification and quantitative monitoring of mutant BCR-ABL1 subclones displaying resistance to tyrosine kinase inhibitors (TKIs) have become important tasks in patients with Ph-positive leukemias. Different technologies have been established for patient screening. Various next-generation sequencing (NGS) platforms facilitating sensitive detection and quantitative monitoring of mutations in the ABL1-kinase domain (KD) have been introduced recently, and are expected to become the preferred technology in the future. However, broad clinical implementation of NGS methods has been hampered by the limited accessibility at different centers and the current costs of analysis which may not be regarded as readily affordable for routine diagnostic monitoring. It is therefore of interest to determine whether NGS platforms can be adequately substituted by other methodological approaches. We have tested three different techniques including pyrosequencing, LD (ligation-dependent)-PCR and NGS in a series of peripheral blood specimens from chronic myeloid leukemia (CML) patients carrying single or multiple mutations in the BCR-ABL1 KD. The proliferation kinetics of mutant subclones in serial specimens obtained during the course of TKI-treatment revealed similar profiles via all technical approaches, but individual specimens showed statistically significant differences between NGS and the other methods tested. The observations indicate that different approaches to detection and quantification of mutant subclones may be applicable for the monitoring of clonal kinetics, but careful calibration of each method is required for accurate size assessment of mutant subclones at individual time points.
Asunto(s)
ADN/análisis , Proteínas de Fusión bcr-abl/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Reacción en Cadena de la Polimerasa , Análisis de Secuencia de ADN , Hibridación Genómica Comparativa , ADN/genética , ADN/metabolismo , Proteínas de Fusión bcr-abl/química , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patologíaRESUMEN
More than 95% of patients with detected translocation t(9;22), is characterized by the fusion between exons e13 or e14 of BCR gene, which are located in major breakpoint cluster region (M-bcr) and exon a2 of ABL gene. These fusions are described as b2a2 (e13a2) and b3a2 (e14a2). Other fusions of exons e1, e6, e8, e12, e19, e20 of BCR gene with exons a2 or a3 of ABL gene occur very rarely and lead to formation of so called unusual fusion BCR-ABL genes. The aim of this study is to describe long-term observations of the occurrence and routine procedure in the diagnosis of atypical variants of the fusion gene BCR-ABL in a population of patients with chronic myeloid leukemia (CML). It was found that the vast majority of patients with detected BCR-ABL transcripts were b3a2 and b2a2. Other detected variants, which are described as rare were: e1a2, b2a3, b3a3, c3a2, e6a2, e6a3. At the stage of diagnosis as well as during monitoring of the effects of treatment, molecular methods which are based on polymerase chain reaction were used (multiplex RT-PCR, nested RT-PCR, RQ-PCR). Multiplex RT-PCR reaction gave possibility to detect variants of the fusion BCR-ABL gene in one reaction and was crucial in the selection of appropriate test used for further monitoring of the disease and the effectiveness of treatment. This paper proposes a scheme for dealing with the diagnosis and monitoring of minimal residual disease (MRD) in patients with CML treated with tyrosine kinase inhibitors (TKIs) in the presence of rare fusion of the BCR and ABL genes.
Asunto(s)
Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Humanos , Lactante , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neoplasia Residual , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto JovenRESUMEN
INTRODUCTION: Tyrosine kinase inhibitors (TKIs) revolutionized treatment of chronic myeloid leukemia (CML), but are endowed with negative effects on endothelial function. OBJECTIVES: We aimed to characterize endothelial function in patients with CML treated with various TKIs. PATIENTS AND METHODS: A total of 48 patients diagnosed with chronicphase CML treated with TKIs, such as imatinib, bosutinib, nilotinib, ponatinib, and asciminib were included. Endothelial function was assessed in the brachial artery and microcirculation based on flowmediated dilation (FMD), reactive hyperemia peripheral arterial tonometry (RHPAT) and flowmediated skin fluorescence (FMSF). RESULTS: Reactive hyperemia index, FMD, reactive hyperemia response (RHR), normoxia oscillatory index, and hyperemic response index did not differentiate between the group of patients with low / moderate risk in the Systematic Coronary Risk Estimation 2 (SCORE2), SCORE2Older Persons (SCORE2OP), and those with high / very high risk scores. Among the patients with low / intermediate risk based on the SCORE2 algorithm, some had lower (below the first quartile) values of the endothelial parameters, reflecting impaired endothelial function, as compared with the high / very high risk patient population. Lower values of the endothelial function parameters were associated with overall longterm treatment with TKIs or ponatinib. Importantly, endothelial function assessed by FMSF (RHR) negatively correlated with total duration of TKI treatment, also after adjustment for age. CONCLUSIONS: Endothelial function in CML patients treated with TKIs was not related to cardiovascular risk based on SCORE2/SCORE2OP algorithms but correlated with CMLspecific factors, including duration of TKI treatment. FMSFbased assessment of skin microcirculation was a sensitive method for detecting the vascular effects of TKIs.
Asunto(s)
Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Adulto , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiopatología , Algoritmos , Enfermedades Cardiovasculares/inducido químicamente , Piridazinas/uso terapéutico , Medición de RiesgoRESUMEN
A key hallmark of myelofibrosis is anemia, which ranges from mild to severe based on hemoglobin levels. To more clearly define outcomes with the Janus kinase (JAK) 1/JAK2/activin A receptor type 1 inhibitor momelotinib by anemia severity, we performed a descriptive post hoc exploratory analysis of the double-blind, randomized, phase 3 SIMPLIFY-1 study (NCT01969838; N = 432, JAK inhibitor naive, momelotinib vs. ruxolitinib); subgroups were defined by baseline hemoglobin: <10 (moderate/severe), ≥10 to <12 (mild), or ≥12 g/dL (nonanemic). Spleen and symptom results were generally consistent with those previously reported for the intent-to-treat population. In anemic subgroups, momelotinib was associated with higher rates of transfusion independence and reduced/stable transfusion intensity vs. ruxolitinib. No new or unexpected safety signals were identified. Overall, momelotinib provides spleen, symptom, and anemia benefits to JAK inhibitor-naive patients with myelofibrosis regardless of baseline hemoglobin level, and greater anemia-related benefits vs. ruxolitinib in patients with hemoglobin <12 g/dL.
Asunto(s)
Hemoglobinas , Nitrilos , Mielofibrosis Primaria , Pirazoles , Pirimidinas , Humanos , Pirimidinas/uso terapéutico , Pirazoles/uso terapéutico , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Hemoglobinas/análisis , Hemoglobinas/metabolismo , Anciano , Resultado del Tratamiento , Benzamidas/uso terapéutico , Método Doble Ciego , Anemia/etiología , Anemia/diagnóstico , Adulto , Inhibidores de Proteínas Quinasas/uso terapéutico , Anciano de 80 o más Años , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 2/genética , Janus Quinasa 2/antagonistas & inhibidoresRESUMEN
Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8+PD-1+ cells in patients losing TFR. The level of CD8+PD-1+ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8+PD-1+ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8+PD-1+ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib.
Asunto(s)
Linfocitos T CD8-positivos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva , Receptor de Muerte Celular Programada 1 , Humanos , Mesilato de Imatinib/uso terapéutico , Mesilato de Imatinib/farmacología , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Receptor de Muerte Celular Programada 1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anciano , Proteínas de Fusión bcr-abl/genética , Proteínas de Fusión bcr-abl/metabolismo , Adulto JovenRESUMEN
BACKGROUND: The treatment of patients with polycythemia vera (PV) and essential thrombocythemia (ET) is conducted according to well-defined risk stratification systems. We hypothesized that adherence to the guidelines, namely the decision to refrain from introducing cytoreduction in non-high-risk patients, is particularly difficult in patients diagnosed when they are between 40 and 59 years of age (intermediate-age group). OBJECTIVES: To evaluate the group of intermediate-age PV and ET patients, focusing on a first-line treatment approach adapted at diagnosis. MATERIAL AND METHODS: The study group consisted of 308 PV and ET patients recruited from 6 Polish Adult Leukemia Group (PALG) Centers. Patients were analyzed with respect to disease phenotype, risk group, treatment approach, cardiovascular (CV) risk factors, and occurrence of bleeding or thrombosis. RESULTS: Overall, 74% of patients in the study group were started on cytoreduction at diagnosis, including 70% of the low-risk PV patients and 85-89% of the non-high-risk ET patients. Factors influencing the decision to start the treatment included higher hemoglobin (Hb) concentration (in PV) as well as higher platelet (PLT) count, and the presence of CV risk factors (in ET). Introducing cytoreduction at diagnosis had no impact on thrombotic events. Patients harboring CV risk factors experienced a higher incidence of complications both at diagnosis and follow-up, independently of the treatment strategy. CONCLUSIONS: We underline the low adherence to recommendations in the treatment of intermediate-age PV and ET patients. Moreover, we emphasize the importance of CV risk factors and stress their impact on disease phenotype in this patient population.
RESUMEN
Bone marrow fibrosis (BMF) is a pathological feature of myelofibrosis, with higher grades associated with poor prognosis. Limited data exist on the association between outcomes and BMF changes. We present BMF data from Janus kinase (JAK) inhibitor-naive patients from SIMPLIFY-1 (NCT01969838), a double-blind, randomized, phase 3 study of momelotinib vs ruxolitinib. Baseline and week 24 bone marrow biopsies were graded from 0 to 3 as per World Health Organization criteria. Other assessments included Total Symptom Score, spleen volume, transfusion independence status, and hemoglobin levels. Paired samples were available from 144 and 160 patients randomized to momelotinib and ruxolitinib. With momelotinib and ruxolitinib, transfusion independence was achieved by 87% and 44% of patients with BMF improvement of ≥1 grade and 76% and 56% of those with stable/worsening BMF; there was no association between BMF changes and transfusion independence for either arm (momelotinib, p = .350; ruxolitinib, p = .096). Regardless of BMF changes, hemoglobin levels also generally increased on momelotinib but decreased on ruxolitinib. In addition, no associations between BMF changes and spleen (momelotinib, p = .126; ruxolitinib, p = .407)/symptom (momelotinib, p = .617; ruxolitinib, p = .833) outcomes were noted, and no improvement in overall survival was observed with ≥1-grade BMF improvement (momelotinib, p = .395; ruxolitinib, p = .407). These data suggest that the anemia benefit of momelotinib is not linked to BMF changes, and question the use of BMF assessment as a surrogate marker for clinical benefit with JAK inhibitors.
RESUMEN
Blast phase (BP) of chronic myeloid leukemia (CML) still represents an unmet clinical need with a dismal prognosis. Due to the rarity of the condition and the heterogeneity of the biology and clinical presentation, prospective trials and concise treatment recommendations are lacking. Here we present the analysis of the European LeukemiaNet Blast Phase Registry, an international collection of the clinical presentation, treatment and outcome of blast phases which had been diagnosed in CML patients after 2015. Data reveal the expected heterogeneity of the entity, lacking a clear treatment standard. Outcomes remain dismal, with a median overall survival of 23.8 months (median follow up 27.8 months). Allogeneic stem cell transplantation (alloSCT) increases the rate of deep molecular responses. De novo BP and BP evolving from a previous CML do show slightly different features, suggesting a different biology between the two entities. Data show that outside clinical trials and in a real-world setting treatment of blast phase is individualized according to disease- and patient-related characteristics, with the aim of blast clearance prior to allogeneic stem cell transplantation. AlloSCT should be offered to all patients eligible for this procedure.
Asunto(s)
Crisis Blástica , Leucemia Mielógena Crónica BCR-ABL Positiva , Sistema de Registros , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto Joven , Crisis Blástica/patología , Manejo de la Enfermedad , Europa (Continente) , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Pronóstico , Tasa de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Anciano de 80 o más AñosRESUMEN
Membrane transporters are important determinants of drug bioavailability. Their expression and activity affect the intracellular drug concentration in leukemic cells impacting response to therapy. Pharmacogenomics represents genetic markers that reflect allele arrangement of genes encoding drug transporters associated with treatment response. In previous work, we identified SNP rs460089 located in the promotor of SLC22A4 gene encoding imatinib transporter OCTN1 as influential on response of patients with chronic myeloid leukemia treated with imatinib. Patients with rs460089-GC pharmacogenotype had significantly superior response to first-line imatinib treatment compared to patients with rs460089-GG. This study investigated whether pharmacogenotypes of rs460089 are associated with sustainability of treatment-free remission (TFR) in patients from the EUROpean Stop Kinase Inhibitor (EURO-SKI) trial. In the learning sample, 176 patients showed a significantly higher 6-month probability of molecular relapse free survival (MRFS) in patients with GC genotype (73%, 95% CI: 60-82%) compared to patients with GG (51%, 95% CI: 41-61%). Also over time, patients with GC genotype had significantly higher MRFS probabilities compared with patients with GG (HR: 0.474, 95% CI: 0.280-0.802, p = 0.0054). Both results were validated with data on 93 patients from the Polish STOP imatinib study. In multiple regression models, in addition to the investigated genotype, duration of TKI therapy (EURO-SKI trial) and duration of deep molecular response (Polish study) were identified as independent prognostic factors. The SNP rs460089 was found as an independent predictor of TFR.