Influència de l'haplotip 46/1 del gen JAK2 en la variació de la càrrega al·lèlica de la mutació JAK2V617F en pacients amb policitèmia vera i trombocitèmia esencial

La presència de l'haplotip 46/1 del gen JAK2 predisposa a neoplàsies mieloproliferatives associades a la mutació de JAK2V617F, però la seva rellevància clínica és desconeguda. En aquest treball determinem, de forma retrospectiva, la càrrega al·lèlica de JAK2V617F de 62 pacients amb NMP JAK2V617+, en el moment del diagnòstic i en l'últim control. Posteriorment, analizem l'augment de la càrrega al·lèlica de JAK2V617F amb l'objectiu de determinar si aquesta es manté estable o presenta un augment progressiu durant el curs natural de la malaltia. Finalment, analitzem la relació entre els resultats obtinguts i l'evolució clínica dels pacients

Impact of Individual Comorbidities on Survival of Patients with Myelofibrosis

Comorbidities; Myelofibrosis; SurvivalComorbilidades; Mielofibrosis; SupervivenciaComorbiditats; Melofibrosi; SupervivènciaThe comorbidity burden is an important risk factor for overall survival (OS) in several hematological malignancies. This observational prospective study was conducted to evaluate the impact of individual comorbidities on survival in a multicenter series of 668 patients with primary myelofibrosis (PMF) or MF secondary to polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Hypertension (hazard ratio (HR) = 4.96, p < 0.001), smoking (HR = 5.08, p < 0.001), dyslipidemia (HR = 4.65, p < 0.001) and hepatitis C virus (HCV) (HR = 4.26, p = 0.015) were most adversely associated with OS. Diabetes (HR = 3.01, p < 0.001), pulmonary disease (HR = 3.13, p < 0.001) and renal dysfunction (HR = 1.82, p = 0.037) were also associated with an increased risk of death. Multivariate analysis showed that pulmonary disease (HR = 2.69, p = 0.001), smoking (HR = 3.34, p < 0.001), renal dysfunction (HR = 2.08, p = 0.043) and HCV (HR = 11.49, p = 0.001) had a negative impact on OS. When ruxolitinib exposure was included in the model, the effect of each comorbidity on survival was modified. Therefore, individual comorbidities should be taken into account in determining the survival prognosis for patients with MF.This research was supported by an unrestricted grant from Novartis Pharmaceutical. The opinions expressed in this article are those of the authors and do not necessarily reflect those of Novartis

Design and Synthesis of Multi-Functional Ligands through Hantzsch Reaction: Targeting Ca2+ Channels, Activating Nrf2 and Possessing Cathepsin S Inhibitory, and Antioxidant Properties

This work relates to the design and synthesis of a series of novel multi-target directed ligands (MTDLs), i.e., compounds 4a–l, via a convenient one-pot three-component Hantzsch reaction. This approach targeted calcium channel antagonism, antioxidant capacity, cathepsin S inhibition, and interference with Nrf2 transcriptional activation. Of these MTDLs, 4i emerged as a promising compound, demonstrating robust antioxidant activity, the ability to activate Nrf2-ARE pathways, as well as calcium channel blockade and cathepsin S inhibition. Dihydropyridine 4i represents the first example of an MTDL that combines these biological activities.This work was supported by the Regional Council of Franche-Comté (2022Y-13659 and 13660 ACCURATE PROJECT).Peer reviewe

Inhaled Loxapine as a Rapid Treatment for Agitation in Patients with Personality Disorder : A Prospective Study on the Effects of Time

Agitation in patients diagnosed with personality disorders (PD) is one of the most frequent crises in emergency departments (ED). Although many medications have been tested, their effectiveness has been small or non-significant, and no specific drugs are supported by the available evidence. This study aimed to evaluate the efficacy of Inhaled loxapine (IL) as a therapeutic option for agitated patients with PD. A naturalistic, unicentric, prospective study was carried out. Thirty subjects diagnosed with PD and attending the ED with episodes of agitation were recruited most of whom were women diagnosed with Borderline Personality Disorder. Subjects were treated with a single dose of IL (9.1 mg). Efficacy was assessed with the Clinical Global Impression scale, the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) and the Agitation-Calmness Evaluation Scale (ACES). Patients were followed 60 minutes after administration to measure IL effect and its duration. IL exhibited an overall efficacy in managing mild to severe agitation, with a quick onset of effect and persistence. 'Effect of time', where IL efficacy is maintained over time, is more marked in higher-severity agitation. No additional treatments were needed to improve agitation during the follow-up time. Results suggest that IL could be a safe and effective option to manage agitation in PD

Impact of BCR-ABL1 Transcript Type on Response, Treatment-Free Remission Rate and Survival in Chronic Myeloid Leukemia Patients Treated with Imatinib

The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine-kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript

Machine Learning Improves Risk Stratification in Myelofibrosis: An Analysis of the Spanish Registry of Myelofibrosis

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) with heterogeneous clinical course. Allogeneic hematopoietic cell transplantation remains the only curative therapy, but its morbidity and mortality require careful candidate selection. Therefore, accurate disease risk prognostication is critical for treatment decision-making. We obtained registry data from patients diagnosed with MF in 60 Spanish institutions (N = 1386). These were randomly divided into a training set (80%) and a test set (20%). A machine learning (ML) technique (random forest) was used to model overall survival (OS) and leukemia-free survival (LFS) in the training set, and the results were validated in the test set. We derived the AIPSS-MF (Artificial Intelligence Prognostic Scoring System for Myelofibrosis) model, which was based on 8 clinical variables at diagnosis and achieved high accuracy in predicting OS (training set c-index, 0.750; test set c-index, 0.744) and LFS (training set c-index, 0.697; test set c-index, 0.703). No improvement was obtained with the inclusion of MPN driver mutations in the model. We were unable to adequately assess the potential benefit of including adverse cytogenetics or high-risk mutations due to the lack of these data in many patients. AIPSS-MF was superior to the IPSS regardless of MF subtype and age range and outperformed the MYSEC-PM in patients with secondary MF. In conclusion, we have developed a prediction model based exclusively on clinical variables that provides individualized prognostic estimates in patients with primary and secondary MF. The use of AIPSS-MF in combination with predictive models that incorporate genetic information may improve disease risk stratification

Caracterización de los progenitores hematopoyéticos CD34+ en las neoplasias mieloproliferativas y su papel en la evolución de la carga mutacional

Las neoplasias mieloproliferativas (NMP) son enfermedades clonales de la célula madre hematopoyética que se caracterizan por la proliferación de una o más de las líneas mieloides. Se acuerdo con la clasificación actual de la OMS, las NMP cromosoma Filadelfia negativas clásicas incluyen la policitemia vera (PV), la trombocitemia esencial (TE) y la mielofibrosis primaria (MFP). En el año 2005 se describió la mutación p.V617F del gen JAK2 presente en el 95% de los pacientes con PV y en la mitad de los casos de TE y MFP. Más recientemente, se han descrito mutaciones que afectan al gen MPL y mutaciones en el gen de la CALR en los pacientes con TE y MFP JAK2 no mutadas. Todas estas mutaciones se consideran mutaciones driver o conductoras de las NMP. Adicionalmente, se han descrito otras mutaciones somáticas que no actúan primariamente en la proliferación celular, pero que pueden modificar el efecto de las mutaciones driver. Las NMP JAK2V617F mutadas se caracterizan por la coexistencia de progenitores clonales JAK2V617F mutados y no mutados. El conocimiento de la carga mutacional de JAK2V617F y de las mutaciones non-driver a nivel de los progenitores hematopoyéticos podría proporcionar información sobre la base biológica de los cambios clínicos evolutivos, especialmente, la transformación a mielofibrosis y leucemia aguda. Asimismo, la carga mutacional a nivel progenitor también podría influir en la respuesta al tratamiento. Algunos autores postulan que las NMP CALR mutadas son una entidad distinta de las JAK2 mutadas, tanto desde el punto de vista biológico, como clínico y pronóstico. Estas observaciones podrían ser la consecuencia de un comportamiento diferente a nivel de los progenitores hematopoyéticos. En este contexto, el presente trabajo de investigación ha caracterizado las subpoblaciones de progenitores hematopoyéticos (CD34+CD38- y CD34+CD38+) de pacientes con NMP JAK2 y CALR mutadas y se ha correlacionado la carga mutacional con la fase evolutiva de la enfermedad, la presencia de mutaciones adicionales y con la presencia de dominancia clonal. Asimismo, se han evaluado las diferencias en el tamaño del clon mutado de los progenitores mutados de acuerdo con el genotipo JAK2 o CALR. Finalmente, se ha investigado el efecto del tratamiento con inhibidores de JAK2 en la evolución de la carga mutacional a nivel progenitor. Los resultados del primer trabajo mostraron que el porcentaje de células CD34+ con mutación V617F del gen JAK2 en los pacientes con PV aumenta durante la evolución de la enfermedad y que en la MF post-PV existe un predominio de progenitores hematopoyéticos mutados probablemente como consecuencia de la expansión de los clones homocigotos. Finalmente, se observó que en el momento del diagnóstico de la PV puede existir hematopoyesis clonal debido a la expansión de clones con mutaciones adicionales. En el segundo trabajo pudimos demostrar que la proporción de progenitores hematopoyéticos mutados es diferente de acuerdo con el genotipo de las NMP. Los pacientes con mutación de CALR se caracterizan por una expansión de los progenitores mutados, mientras que los pacientes con TE y PV JAK2V617F presentan un pequeño porcentaje de progenitores mutados con una alta capacidad de diferenciación. Por último, analizamos la evolución de la carga mutacional de JAK2V617F en una serie de 7 pacientes con NMP durante los primeros 12 meses de tratamiento con un inhibidor de JAK2 (Ruxolitinib). Los resultados obtenidos sugieren que dicho fármaco tiene una escasa capacidad de modificar la carga mutacional de JAK2V617F en las células CD34+ en los pacientes con PV y MF.Myeloproliferative neoplasms (MPN) are clonal diseases that origin from hematopoietic stem cell and are characterized by a proliferation of one or more of the myeloid cell types. According to the current WHO Classification, classic Philadelphia negative MPN include polycythemia vera (PV), essential thrombocythemia (TE) and primary mielofibrosis (PMF). In 2005, JAK2V617F mutation was described in 95% of PV patients and in half of ET and PMF patients. More recently, mutations affecting MPL or CALR gene have been reported in patients with JAK2V617F negative TE and PMF. All these mutations are considered driver mutations. In addition, other somatic mutations that do not act primarily on cell proliferation, but can modify the effect of the driver mutations, have been described. JAK2V617F MPN are characterized by the coexistence of normal and JAK2V617F-mutated progenitors. Knowledge of the mutational allele burden of JAK2V617F at the progenitor level could provide information on the biological basis of evolutionary clinical changes, especially myelofibrotic and acute leukemia transformation. Moreover, the mutational load at the progenitor level may also influence treatment response. Finally, some authors postulate that CALR mutated MPN are a distinct entity from a biological, clinical and prognostic point of view from JAK2V617F MPN. These observations could be the consequence of a different behaviour at the level of hematopoietic progenitors. In this sense, this work has characterized different subpopulations of hematopoietic progenitor cells (CD34+CD38- and CD34+CD38+) from patients with JAK2V617F and CALR-mutated MPN and their mutational allele burden has been correlated with disease status, presence of additional mutations and presence of clonal dominance. Also, we compared the mutational allele burden at the progenitor level according to the genotype (JAK2 or CALR). Finally, we evaluated the effect of the treatment with JAK2 inhibitors on the JAK2V617F mutant allele burden of the progenitor cells. In our first study, we showed that the percentage of CD34+ cells carrying JAK2V617F mutation increases during the evolution of the disease in PV patients. Moreover, we could demonstrate that the transformation to myelofibrosis is characterized by a predominance of JAK2V617F progenitor cells probably due to the expansion of homozygous clones. Finally, we observed that at the time of PV diagnosis there may be clonal hematopoiesis due to the expansion of clones with additional mutations. In the second study, we could show that the proportion of mutated hematopoietic progenitors is different according to the genotype. Patients with CALR-mutated MPN are characterized by an expansion of mutated progenitors, whereas patients with JAK2V617F ET and PV present a low percentage of mutated progenitors with a high differentiation capacity. Finally, we analysed the evolution of the mutational allele burden of JAK2V617F in 7 patients with MPN during the first 12 months of treatment with JAK2 inhibitor (Ruxolitinib). The results suggest that ruxolitinib has a minimal effect on the JAK2V617F mutant allele burden variation in CD34+ cells