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INTRODUCCIÓN: Cuadro clínico: La Enfermedad de Injerto Contra Huésped (EICH) es una complicación multisistémica frecuente y potencialmente mortal del Trasplante Alogénico de Células Progenitoras Hematopoyéticas (TACPH). Las complicaciones están influenciadas por factores relacionados con el paciente como la edad, el estado funcional, comorbilidades, y pueden afectar la piel, boca, ojos, pulmón, hígado e intestinos. La EICH crónica se presenta entre el 30% a 70% de pacientes post TACPH. En estos pacientes, la mortalidad por EICH crónica puede alcanzar hasta un 10%, siendo una de las principales causas de muerte, superada únicamente por la recaída de la enfermedad primaria. La mortalidad por EICH crónica puede atribuirse tanto a complicaciones propias de la enfermedad como a la terapia inmunosupresora, y está fuertemente correlacionada con la respuesta al tratamiento de primera línea. Por otro lado, la EICH crónica contribuye de manera sustancial a la morbilidad, deterioro funcional y disminución de la calidad de vida. Los pacientes que viven con EICH crónica tienen el doble de probabilidad de desarrollar otra enfermedad grave o potencialmente mortal, con un mayor riesgo de segundas neoplasias, enfermedad cardiovascular, infecciones y complicaciones pulmonares. Estos pacientes suelen experimentar ansiedad, angustia, menor resiliencia, deterioro de la calidad de vida, estado funcional deficiente y pobre funcionalidad social. Entre los factores de riesgo se ha descrito el aumento de la edad del huésped, el estado del citomegalovirus (CMV) del donante y del huésped, la seropositividad del virus de Epstein-Barr (VEB) del donante, el trasplante de células madre de sangre periférica versus trasplante de médula ósea, EICH aguda previa, la presencia de un ambiente estéri
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Humanos , Transplante Homólogo/métodos , Corticosteroides/farmacologia , Transplante de Células-Tronco Hematopoéticas/instrumentação , Janus Quinase 1/uso terapêutico , Janus Quinase 2/uso terapêutico , Síndrome de Bronquiolite Obliterante/etiologia , Imunossupressores/administração & dosagem , Avaliação em Saúde/economia , EficáciaRESUMO
El uso compasivo de ruxolitinib en la covid-19 demostró una mejoría en las imágenes de tórax y mayor número de altas en el grupo que lo usó vs. el grupo 1 (cloroquinas y azitromicina), con descenso de los marcadores inflamatorios. Existe un artículo que señaló que un caso que fue refractario a la terapia anti-IL6, pero respondió a la inhibición de Jak-Stat con ruxolitinib.1 La comorbilidad más frecuente en ambos grupos fue la hipertensión arterial, seguida por la diabetes tipo 2; el grupo 1 presentó un mayor número de pacientes que no presentaban comorbilidades (18 pacientes). El número de hombres con enfermedad por SARS-CoV2 fue mayor en el grupo 1, con 31 hombres (62,0%) frente un total de 19 mujeres (38,0%), mientras que, en el grupo 2, el 25,0% eran hombres y mujeres, el 25,0%. La gravedad de la covid-19 fue definida como moderada: adolescente o adulto con signos clínicos de neumonía (fiebre, tos, disnea, taquipnea), en particular SpO2 ≥ 90% con aire ambiente; y grave: adolescente o adulto con signos clínicos de neumonía (fiebre, tos, disnea, taquipnea) más alguno de los siguientes: frecuencia respiratoria > 30 inspiraciones/min, dificultad respiratoria grave o SpO2 < 90% con aire ambiente.2 El síndrome de dificultad respiratoria aguda (SDRA) en ambos grupos fue de un pro medio de relación entre la presión arterial de oxígeno y la fracción inspirada de oxígeno (PaFi) en el grupo ruxolitinib 135,3 mmHg vs. Grupo control PaFi 138,9 mmHg. Se definió la eficacia por descenso de los marcadores inflamatorios, mejoría gasométrica de la PaFi, menor requerimiento de oxígeno, disminución del ingreso a unidad de cuidados intensivos de los pacientes con sintomatología grave, demostración de la seguridad del fármaco en los 10 días posteriores a su uso y detallado del número de casos con alta médica.
The group with compassionate use of ruxolitinib for Covid-19 showed improved chest images and a larger number of discharged patients, compared to group 1 (chloro quines and azithromycin), with a decrease in inflammatory markers. There is one arti cle that described a case which refractory to anti-IL6 therapy but responded to Jak-Stat inhibition with ruxolitinib.1 The most common comorbidity in both groups was arterial hypertension, followed by diabetes type 2; group 1 showed a larger number of patients without comorbidities (18 patients). The number of male patients with the disease caused by SARS-CoV2 was larger in group 1, with 31 males (62.0%), compared to a total of 19 females (38.0%), whereas in group 2, 25.0% were males, and 25.0% females. The severity of Covid-19 was defined as moderate: adolescent or adult with clinical signs of pneumonia (fever, cough, dys pnea, tachypnea), particularly SpO2 ≥ 90% on ambient air; and severe: adolescent or adult with clinical signs of pneumonia (fever, cough, dyspnea, tachypnea) plus some of the following: respiratory rate > 30 breaths/min, severe respiratory distress or SpO2 < 90% on ambient air.2 The acute respiratory distress syndrome (ARDS) in both groups had an average ratio of pressure arterial oxygen and fraction of inspired oxygen (PaFi) of 135.3 mmHg in the ruxolitinib group versus 138.9 mmHg in the control group. Efficacy was defined as: decrease in inflammatory markers, gasometric improvement in the PaFi, lower oxygen requirement, lower number of patients with severe symptoms admitted to the Intensive Care Unit, proof of the drug's safety 10 days after use, and detailed number of discharged patients.
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Síndrome do Desconforto Respiratório do Recém-Nascido , Cloroquina , Citocinas , Infecções por Coronavirus , SARS-CoV-2RESUMO
INTRODUCTION: Severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) infection is characterised by a viral phase and a severe pro-inflammatory phase. The inhibition of the JAK/STAT pathway limits the pro-inflammatory state in moderate to severe COVID-19. METHODOLOGY: We analysed the data obtained by an observational cohort of patients with SARS-CoV-2 pneumonia treated with ruxolitinib in 22 hospitals of Mexico. The applied dose was determined based on physician's criteria. The benefit of ruxolitinib was evaluated using the 8-points ordinal scale developed by the NIH in the ACTT1 trial. Duration of hospital stay, changes in pro-inflammatory laboratory values, mortality, and toxicity were also measured. RESULTS: A total of 287 patients were reported at 22 sites in Mexico from March to June 2020; 80.8% received ruxolitinib 5 mg BID and 19.16% received ruxolitinib 10 mg BID plus standard of care. At beginning of treatment, 223 patients were on oxygen support and 59 on invasive ventilation. The percentage of patients on invasive ventilation was 53% in the 10 mg and 13% in the 5 mg cohort. A statistically significant improvement measured as a reduction by 2 points on the 8-point ordinal scale was described (baseline 5.39 ± 0.93, final 3.67± 2.98, p = 0.0001). There were 74 deaths. Serious adverse events were presented in 6.9% of the patients. CONCLUSIONS: Ruxolitinib appears to be safe in COVID-19 patients, with clinical benefits observed in terms of decrease in the 8-point ordinal scale and pro-inflammatory state. Further studies must be done to ensure efficacy against mortality.
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Tratamento Farmacológico da COVID-19 , Pirazóis , Pirimidinas , Estudos de Coortes , Humanos , Nitrilas , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , SARS-CoV-2 , Resultado do TratamentoRESUMO
Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK) 2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. Although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.
La mielofibrosis (MF) es una neoplasia mieloproliferativa negativa para BCR-ABL1 caracterizada por mieloproliferación clonal, señalización de cinasa desregulada y liberación de citocinas anormales. En los últimos años se han realizado importantes avances en el conocimiento de la biología molecular y la valoración pronóstica de la MF. El tratamiento convencional tiene un impacto limitado en la supervivencia de los pacientes; incluye un enfoque de espera para pacientes asintomáticos, agentes estimulantes de la eritropoyesis, andrógenos o agentes inmunomoduladores para la anemia, fármacos citorreductores como la hidroxiurea para la esplenomegalia y los síntomas constitucionales, y esplenectomía o radioterapia en pacientes seleccionados. El descubrimiento de la mutación Janus cinasa (JAK) 2 desencadenó el desarrollo de la terapia dirigida molecular de la MF. Los inhibidores de JAK son efectivos tanto en MF con JAK2 positivo como con JAK2 negativo; uno de ellos, el ruxolitinib, es la mejor terapia disponible actualmente para la esplenomegalia y los síntomas constitucionales de la MF. Sin embargo, aunque el ruxolitinib ha cambiado el escenario terapéutico de la MF, no hay indicios claros de un efecto modificador de la enfermedad. El alotrasplante de células madre sigue siendo la única terapia curativa de la MF, pero debido a su morbilidad y mortalidad asociadas, generalmente se restringe a pacientes elegibles con MF de riesgo alto e intermedio 2. Para mejorar los resultados terapéuticos actuales, actualmente se está probando la combinación de inhibidores de JAK con otros agentes y se están investigando fármacos más nuevos.
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ABSTRACT Background: In Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) models, reactive oxygen species (ROS) are elevated and have been implicated in genomic instability, JAK2/STAT signaling amplification, and disease progression. Although the potential effects of ROS on the MPN phenotype, the effects of ruxolitinib treatment on ROS regulation have been poorly explored. Herein, we have reported the impact of ruxolitinib on redox signaling transcriptional network, and the effects of diphenyleneiodonium (DPI), a pan NOX inhibitor, in JAK2V617F-driven cellular models. Method: Redox signaling-related genes were investigated in SET2 cells upon ruxolitinib treatment by RNA-seq (GEO accession GSE69827). SET2 and HEL cells, which represent JAK2V617F-positive MPN cellular models with distinct sensitivity to apoptosis induced by ruxolitinib, were used. Cell viability was evaluated by MTT, apoptosis by annexin V/PI and flow cytometry, and cell signaling by quantitative PCR and Western blot. Main results: Ruxolitinib impacted on a network composed of redox signaling-related genes, and DUOX1 and DUOX2 were identified as potential modulators of ruxolitinib response. In SET2 and HEL cells, DPI reduced cell viability and, at low doses, it significantly potentiated ruxolitinib-induced apoptosis. In the molecular scenario, DPI inhibited STAT3, STAT5 and S6 ribosomal protein phosphorylation and induced PARP1 cleavage in JAK2V617F-positive cells. DPI combined with ruxolitinib increased PARP1 cleavage in SET2 cells and potentiated ruxolitinib-reduced STAT3, STAT5 and S6 ribosomal protein in HEL cells. Conclusion: Our study reveals a potential adaptation mechanism for resistance against ruxolitinib by transcriptionally reprogramming redox signaling in JAK2V617F cells and exposes redox vulnerabilities with therapeutic value in MPN cellular models.
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Janus Quinase 2 , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Oxirredução , NADPH Oxidases , Oxidases Duais , Transtornos MieloproliferativosRESUMO
BACKGROUND: The cause of end-organ damage and acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients is postulated to be connected to the uncontrolled increase of pro-inflammatory cytokines. The upregulation of many cytokines is dependent on signaling through the Janus kinase 1 (JAK-1) and JAK-2 pathways. Ruxolitinib, a JAK-1 and JAK-2 inhibitor, is documented to have potent anti-inflammatory activity by targeting several cytokines and growth factors with proposed efficacy in the cytokine storm observed in severe COVID-19 patients; therefore, this study examines the efficacy and tolerability of ruxolitinib for adult COVID-19 patients. MATERIALS AND METHODS: This review was conducted using preferred reporting items for aystematic reviews and meta-analyses (PRISMA) methodology. Six reviewers analyzed 1,120 results. Seven studies were selected and validated. A quantitative meta-analysis was further performed to evaluate clinical improvement at day 28, mortality at day 28, and oxygen requirements comparing treatment and standard of care groups. RESULTS: 168 individuals were involved in the studies selected: 122 in cohort studies, 4 in case reports, and 41 in randomized controlled studies. The ruxolitinib group had a higher likelihood of clinical improvement by the 28th day of treatment when assessed with the standard of care (SOC) group (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 0.53 - 4.16; P = 0.45; I² = 0%). The SOC group was at a higher risk of experiencing serious adverse events (OR: 0.17; 95% CI: 0.03 - 1.13; P = 0.07). Notably the SOC group had a higher likelihood of death (OR: 0.51; 95% CI: 0.11-2.29; P = 0.07; I² = 0%). CONCLUSION: Prior studies on ruxolitinib have demonstrated it is able to decrease inflammatory markers. In recent studies on COVID-19, treatment with ruxolitinib decreased the time on mechanical ventilation, hospitalization time, and the need for vasopressor support. Additionally, ruxolitinib showed decreased mortality and demonstrated improvement in lung congestion as evidenced by computerized tomography imaging. These findings warrant further clinical investigation into Ruxolitinib as a potential treatment approach for severe COVID-19.
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Abstract Introduction: Graft-versus-host disease (GVHD) is a serious complication in allogeneic transplantation. The first-line treatment is high doses of corticosteroids. In the absence of response to corticosteroids, several immunosuppressive drugs can be used, but they entail an elevated risk of severe infections. Added to this, there are patients who do not improve on any immunosuppressive treatment, with subsequent deteriorated quality of life and high mortality. Ruxolitinib has been shown to induce responses in refractory patients. In this study we have presented our real-life experience. Methods: A retrospective analysis was performed on patients with severe GVHD refractory to corticosteroids. Demographic, previous treatment, response and mortality data were collected. Results: Since 2014, seventeen patients with GVHD were treated with ruxolitinib due to refractoriness to corticosteroids and immunosuppressants and a few to extracorporeal photopheresis, 8 with acute GVHD (1 pulmonary, 4 cutaneous grade IV and 3 digestive grade IV) and 9 with chronic GHVD (5 cutaneous sclerodermiform, 2 pulmonary and 1 multisystemic). The overall response to ruxolitinib treatment for acute GVHD was 80%, 40% with partial response and 40% with complete remission. Global response in chronic GVHD was 79%. The GVHD mortality was only seen in acute disease and was 40%. Causes of mortality in those patients were severe viral pneumonia, post-transplantation hemophagocytic syndrome and meningeal GVHD refractory to ruxolitinib. Conclusions: In our series, the use of ruxolitinib as a rescue strategy in acute or chronic GVHD was satisfactory. Ruxolitinib treatment in patients with a very poor prognosis showed encouraging results. However, the GVHD mortality remains high in refractory patients, showing that better therapeutic strategies are needed.
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Humanos , Masculino , Feminino , Transplante Homólogo , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/prevenção & controle , Corticosteroides , Reação Transfusional , Doença Enxerto-Hospedeiro/tratamento farmacológicoRESUMO
Alopecia areata (AA) is a chronic, immune-mediated form of nonscarring alopecia that is multifactorial and results in localized patches. It is often described as a self-limiting condition that results in the spontaneous regrowth of hair in most cases. However, this regrowth may take several months or years to occur in some patients, leading to the development of psychoemotional trauma in those that are affected. Although several therapies for AA have been developed and tested, there is no specific treatment that has been approved, leading to the availability of many off-label conventional treatment options, with very limited responses. More recently, with the advancement of pre-clinical and genetic studies, a greater understanding of the pathomechanisms involved in the development of AA has been uncovered. This has resulted in the introduction of targeted therapies that use small molecules to block specific pathways involved in AA pathophysiology. As such, the use of janus kinase (JAK) inhibitors for treatment of AA has emerged. JAK inhibitors block the T-cell mediated inflammatory response thought to be the driving factor behind AA pathogenesis, by inhibiting the janus kinase (JAK) signal transducer and activator of transcription (STAT) signaling pathway, leading to a reversal of hair loss in AA patients. Thus, in an effort to demonstrate the efficacy of JAK inhibitors in the treatment of AA, several studies have been published within recent years. However, the question remains, "Are JAK inhibitors effective and safe in the management of Alopecia Areata?". This review aims to provide a comprehensive report on the role, efficacy, and outcomes of using JAK inhibitors in the treatment of AA. To competently answer the research question highlighted, the most recent, quality articles published over a 10-15-year period were sourced using PubMed, NCBI, Research gate, Medline, Cochrane Central Register of Controlled Trials, EMBASE and Google scholar. The literature search was primarily focused on randomized controlled trials (RCTs); however, in the absence of such, only the most recently published case reports, case series, clinical trials and open-label studies published to date were included.
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INTRODUCTION: Currently, severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is a major public health problem worldwide. Although most patients present a mild infection, effective strategies are required for patients who develop the severe disease. Anti-inflammatory treatment with JAK inhibitors has been considered in SARS-CoV-2. METHODS: In this study, we presented our experience in a group of severe SARS-CoV-2 Chilean patients. This prospective study was performed on consecutive patients presenting severe respiratory failure owing to COVID-19 or high-risk clinical condition associated with SARS-CoV-2, and who were treated with ruxolitinib for management of associated inflammation. Overall, 18 patients presenting SARS-CoV-2 viral-induced hyperinflammation were treated with ruxolitinib, with 16 patients previously treated with steroids, 4 with tocilizumab, and 3 with both treatments. RESULTS: Ten patients evolved with favorable response, including 7 patients admitted with severe respiratory failure (PaFi less than 200 mm Hg in high-flow nasal cannula), presenting complete regression of hyperinflammation, regression of the lung lesions, and subsequent discharge. In the remaining 8 patients, 25% showed reduced inflammation, but early discharge was not achieved owing to the slow evolution of respiratory failure. Unfortunately, 3 patients demonstrated a severe respiratory failure. The early initiation of ruxolitinib was found to be associated with better clinical evolution (p < 0.005). CONCLUSION: In this study, ruxolitinib resolved hyperinflammatory state in 55% of the patients, regardless of the previous steroid or tocilizumab therapy. Unfortunately, few patients demonstrated severe evolution despite ruxolitinib therapy. Notably, the treatment starting time appears to play an important role in achieving good outcomes. Further validation in randomized controlled trials is crucial.
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COVID-19/complicações , Inflamação/tratamento farmacológico , Nitrilas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Pirimidinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/patologia , COVID-19/virologia , Chile , Feminino , Humanos , Inflamação/etiologia , Masculino , Pessoa de Meia-Idade , Nitrilas/efeitos adversos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Pirimidinas/efeitos adversos , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/etiologia , SARS-CoV-2/isolamento & purificação , Esteroides/uso terapêutico , Trombocitopenia/etiologia , Resultado do TratamentoRESUMO
INTRODUCTION: Graft-versus-host disease (GVHD) is a serious complication in allogeneic transplantation. The first-line treatment is high doses of corticosteroids. In the absence of response to corticosteroids, several immunosuppressive drugs can be used, but they entail an elevated risk of severe infections. Added to this, there are patients who do not improve on any immunosuppressive treatment, with subsequent deteriorated quality of life and high mortality. Ruxolitinib has been shown to induce responses in refractory patients. In this study we have presented our real-life experience. METHODS: A retrospective analysis was performed on patients with severe GVHD refractory to corticosteroids. Demographic, previous treatment, response and mortality data were collected. RESULTS: Since 2014, seventeen patients with GVHD were treated with ruxolitinib due to refractoriness to corticosteroids and immunosuppressants and a few to extracorporeal photopheresis, 8 with acute GVHD (1 pulmonary, 4 cutaneous grade IV and 3 digestive grade IV) and 9 with chronic GHVD (5 cutaneous sclerodermiform, 2 pulmonary and 1 multisystemic). The overall response to ruxolitinib treatment for acute GVHD was 80%, 40% with partial response and 40% with complete remission. Global response in chronic GVHD was 79%. The GVHD mortality was only seen in acute disease and was 40%. Causes of mortality in those patients were severe viral pneumonia, post-transplantation hemophagocytic syndrome and meningeal GVHD refractory to ruxolitinib. CONCLUSIONS: In our series, the use of ruxolitinib as a rescue strategy in acute or chronic GVHD was satisfactory. Ruxolitinib treatment in patients with a very poor prognosis showed encouraging results. However, the GVHD mortality remains high in refractory patients, showing that better therapeutic strategies are needed.
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COVID-19 has rapidly become a major concern for the health systems worldwide. Its high contagiousness and associated mortality demand the discovery of helpful interventions with promising safety profile. Here, we report 3 severe COVID-19 cases, which achieved rapid and sustained improvement in outcome with the use of ruxolitinib, a JAK/STAT pathway inhibitor.
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COVID-19/patologia , Doenças Hematológicas/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Adulto , Proteína C-Reativa/análise , COVID-19/complicações , COVID-19/virologia , Ferritinas/análise , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Doenças Hematológicas/etiologia , Humanos , Inibidores de Janus Quinases/farmacologia , Masculino , Pessoa de Meia-Idade , Nitrilas , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Pirimidinas , SARS-CoV-2/isolamento & purificação , Transdução de Sinais/efeitos dos fármacos , Tórax/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: In Philadelphia chromosome-negative myeloproliferative neoplasm (MPN) models, reactive oxygen species (ROS) are elevated and have been implicated in genomic instability, JAK2/STAT signaling amplification, and disease progression. Although the potential effects of ROS on the MPN phenotype, the effects of ruxolitinib treatment on ROS regulation have been poorly explored. Herein, we have reported the impact of ruxolitinib on redox signaling transcriptional network, and the effects of diphenyleneiodonium (DPI), a pan NOX inhibitor, in JAK2V617F-driven cellular models. METHOD: Redox signaling-related genes were investigated in SET2 cells upon ruxolitinib treatment by RNA-seq (GEO accession GSE69827). SET2 and HEL cells, which represent JAK2V617F-positive MPN cellular models with distinct sensitivity to apoptosis induced by ruxolitinib, were used. Cell viability was evaluated by MTT, apoptosis by annexin V/PI and flow cytometry, and cell signaling by quantitative PCR and Western blot. MAIN RESULTS: Ruxolitinib impacted on a network composed of redox signaling-related genes, and DUOX1 and DUOX2 were identified as potential modulators of ruxolitinib response. In SET2 and HEL cells, DPI reduced cell viability and, at low doses, it significantly potentiated ruxolitinib-induced apoptosis. In the molecular scenario, DPI inhibited STAT3, STAT5 and S6 ribosomal protein phosphorylation and induced PARP1 cleavage in JAK2V617F-positive cells. DPI combined with ruxolitinib increased PARP1 cleavage in SET2 cells and potentiated ruxolitinib-reduced STAT3, STAT5 and S6 ribosomal protein in HEL cells. CONCLUSION: Our study reveals a potential adaptation mechanism for resistance against ruxolitinib by transcriptionally reprogramming redox signaling in JAK2V617F cells and exposes redox vulnerabilities with therapeutic value in MPN cellular models.
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Resumen En la actual pandemia de enfermedad por coronavirus 2019 (COVID-19) se ha observado que las principales complicaciones se presentan como resultado de la liberación de múltiples citocinas como interleucina (IL) 1, IL-6, factor de necrosis tumoral alfa e interferones de tipo 1 que generan un estado proinflamatorio caracterizado por lesión tisular pulmonar y subsecuentemente falla orgánica múltiple. En el campo de la hematología se cuenta con experiencia en el uso de diversos fármacos diseñados para limitar estas citocinas los cuales se han utilizado ya en pacientes con COVID-19 entre los que se encuentran los inhibidores de la IL-6 como el tocilizumab, el sarilumab y el siltuximab, el inhibidor de IL-1 anakinra y los inhibidores de la janus cinasa ruxolitinib y baricitinib. Al conocer la base fisiopatológica de la COVID-19, la utilidad de este tipo de fármacos muestra resultados alentadores para los cuadros moderados a graves de la enfermedad y extender su uso en ensayos clínicos mayores.
Abstract In the current SARS-CoV-2 pandemic, it has been observed that the main complications arise as a result of the release of multiple cytokines such as IL-1, IL-6, TNF-α and type 1 interferons that generate a proinflammatory state characterized by lung tissue injury and subsequently multiple organ failure. In the hematology field, there is experience in the use of various drugs designed to limit these cytokines which have already been used in patients with COVID-19 including IL-6 inhibitors such as tocilizumab, sarilumab, and siltuximab; the IL-1 inhibitor anakinra; and the janus kinase inhibitors ruxolitinib and baricitinib. Knowing the pathophysiological basis of COVID-19, the usefulness of this type of drugs show encouraging results for moderate to severe symptoms of the disease and encourages its use in larger clinical trials.
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Secondary lymphohistiocytosis is a severe inflammatory condition characterized by uncontrolled inflammatory response hyperactivation of antigen-presenting cells, hemophagocytosis, cytopenias, and multiorgan failure, and is secondary to subjacent pathologies such as cancer, infection, or immune disease. Standard treatment includes chemotherapy; however, this is not always possible or safe. Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor can reduce inflammation and cytokine activity and has been used in refractory cases and first-line treatment. Here, we present a 35-year-old patient with HIV infection and secondary lymphohistiocytosis due to CMV/EBV infection who was successfully treated with ruxolitinib as first-line therapy. He rapidly showed clinical and biochemical improvement and transfusion independence without complications.
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Infecções por HIV/complicações , Inibidores de Janus Quinases/uso terapêutico , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Pirazóis/uso terapêutico , Adulto , Citocinas/metabolismo , Infecções por Citomegalovirus/complicações , Infecções por Vírus Epstein-Barr/complicações , Humanos , Inflamação , Mediadores da Inflamação/metabolismo , Linfo-Histiocitose Hemofagocítica/etiologia , Linfo-Histiocitose Hemofagocítica/metabolismo , Masculino , Nitrilas , Pirimidinas , Resultado do TratamentoRESUMO
Abstract Introduction Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. Methods JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. Results All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n = 20). Serious AEs were reported in 62.5% of patients (n = 65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. Conclusion Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414
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Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Tratamento Farmacológico , Mielofibrose Primária/terapia , Policitemia , Esplenomegalia , Trombocitose , BrasilRESUMO
JAK2V617F can mimic growth factor signaling, leading to PI3K/AKT/mTOR activation and inhibition of autophagy. We hypothesized that selective inhibition of JAK1/2 by ruxolitinib could induce autophagy and limit drug efficacy in myeloproliferative neoplasms (MPN). Therefore, we investigated the effects of ruxolitinib treatment on autophagy-related genes and cellular processes, to determine the potential benefit of autophagy inhibitors plus ruxolitinib in JAK2V617F cells, and to verify the frequency and clinical impact of autophagy-related gene mutations in patients with MPNs. In SET2 JAK2V617F cells, ruxolitinib treatment induced autophagy and modulated 26 out of 79 autophagy-related genes. Ruxolitinib treatment reduced the expressions of important autophagy regulators, including mTOR/p70S6K/4EBP1 and the STAT/BCL2 axis, in a dose- and time-dependent manner. Pharmacological inhibition of autophagy was able to significantly suppress ruxolitinib-induced autophagy and increased ruxolitinib-induced apoptosis. Mutations in autophagy-related genes were found in 15.5% of MPN patients and were associated with increased age and a trend towards worse survival. In conclusion, ruxolitinib induces autophagy in JAK2V617F cells, potentially by modulation of mTOR-, STAT- and BCL2-mediated signaling. This may lead to inhibition of apoptosis. Our results suggest that the combination of ruxolitinib with pharmacological inhibitors of autophagy, such as chloroquine, may be a promising strategy to treat patients with JAK2V617F-mutated MPNs.
Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Janus Quinase 2/metabolismo , Pirazóis/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/metabolismo , Nitrilas , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Adulto JovemRESUMO
INTRODUCTION: Ruxolitinib has been approved for the treatment of myelofibrosis (MF). In this study, we present safety and efficacy findings from an analysis of 104 patients with intermediate- and high-risk MF in a Brazilian cohort of the JUMP study who received treatment with ruxolitinib. METHODS: JUMP is a single-arm, open-label, phase IIIb, expanded-access study. The primary endpoint was to evaluate the safety and tolerability (frequency, duration, and severity of adverse events [AEs]) of ruxolitinib. RESULTS: All of the 104 patients received the treatment. Median duration of exposure was 35.8 months. The most common hematologic AEs were anemia (57.7), thrombocytopenia (38.5%), neutropenia (11.5%), and leukopenia (9.6%). Second malignancies (all grades) occurred in 19.2% of patients (n=20). Serious AEs were reported in 62.5% of patients (n=65). The proportions of patients with ≥50% reduction from baseline in palpable spleen length at weeks 24 and 48 were 62.7% and 69.2%, respectively. The mean change from the baseline in the Functional Assessment of Cancer Therapy (FACT)-Lymphoma total score was 10.8 [15.6%] at week 4, 12.6 [14.1%] at week 24, and 12.2 [14.3%] at week 48. The mean change from the baseline for the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale was 3.9 [42.8%] at week 4, 4.9 [29.9%] at week 24, and 4.7 [28%] at week 48. At week 48, the estimated progression-free survival, leukemia-free survival, and overall survival probabilities were 91%, 91% and 93%, respectively Overall, 21 deaths were observed in the present study. CONCLUSION: Findings from this study suggest that ruxolitinib could be evaluated as a standard-of-care treatment for the MF population in need of a viable treatment option. NCT01493414.
RESUMO
JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JAK2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubG0 phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bortezomib/farmacologia , Janus Quinase 1/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , Mieloma Múltiplo/tratamento farmacológico , Pirazóis/farmacologia , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/efeitos dos fármacos , Talidomida/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Lenalidomida , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/enzimologia , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Nitrilas , Pirimidinas , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Talidomida/farmacologia , Fatores de TempoRESUMO
The JAK/STAT pathway is constitutively activated in myeloproliferative neoplasms and can be inhibited by ruxolitinib, a selective JAK1/2 inhibitor. The JAK2(V617F) mutation leads to constitutive STAT3 phosphorylation and potentially leads to inhibition of Stathmin 1 activity via STAT3. In support of this hypothesis, we found that, in HEL JAK2(V617F) cells, ruxolitinib treatment decreased STAT3 and Stathmin 1 association, induced Stathmin 1 activation and microtubule instability. Silencing of Stathmin 1 significantly reduced cell proliferation and clonal growth, and increased apoptosis induced by ruxolitinib. Stathmin 1 silencing also prevented ruxolitinib-induced microtubule instability. To phenocopy the effect of Stathmin 1 inhibition, cells were treated with paclitaxel, a microtubule-stabilizing drug, in association or not with ruxolitinib; combined treatment significantly increased apoptosis, when compared to monotherapy. Notably, Stathmin 1 mRNA levels were highly expressed in CD34(+) cells from primary myelofibrosis patients. We then proposed that an undesired effect of ruxolitinib treatment may constitute Stathmin 1 activation and microtubule instability in JAK2(V617F) cells. Induction of microtubule stability, through Stathmin 1 silencing or paclitaxel treatment, combined with ruxolitinib could be an effective strategy for promoting apoptosis in JAK2(V617F) cells.