Danazol for the Treatment of Myelodysplastic Syndromes: A Systematic Review.

Purpose To study the potential utility of danazol for treating patients with myelodysplastic syndromes, with a focus on efficacy and adverse effects (AEs). Methods MEDLINE In-Process & Other Non-Indexed Citations, MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus were searched for relevant publications from inception June 1, 1950, until June 28, 2022. The studies were screened by title and abstract, followed by full-text screening. The quality of the included studies was assessed via a prespecified set of questionnaires. Data on the efficacy measures and adverse outcomes were extracted and included in a descriptive summary. Results Nine studies consisting of 246 participants were included in our review. The overall quality of the included studies was fair. The age of the participants ranged from 61 to 78 years. In all 9 studies, more male patients had been enrolled than female patients. Overall, a proportion of patients in all the studies reported a desired major response to a danazol dose of 400 to 800 mg/day. Few studies did not observe any improvement in the platelet count. Elevated liver enzyme levels, weight gain, headache, dermatitis, and weakness were the most common AEs observed. One study reported a fatal intracerebral hemorrhage in 1 participant. Conclusions Danazol has been effective in increasing platelet count and hemoglobin level. Despite a few AEs, danazol is a safe drug for the treatment of patients with myelodysplastic syndromes.

Modification of oestrogen signalling pathways influences cough induced by citric acid but not capsaicin in the animal model of both sexes.

To clarify the role of oestrogen signalling and the role of oestrogen receptor alpha (ERα) in the cough pathways we performed a study in which coughing was observed in both sexes animal models after the treatment by selective ERα degrader fulvestrant (ICI 182-780) and inhibitor of oestrogen synthesis danazol. Degradation of ERα with the normal plasma oestrogen levels induced by fulvestrant, significantly augments the cough response of female but not male guinea pigs. These changes were observed in citric acid-induced cough. Female guinea pigs responded with an increased count of cough expulsions per challenge time and we also detected shorter cough latency. The capsaicin-induced cough did not change. A similar response was observed after danazol treatment, which decreased the plasma oestrogen level. Our results indicate that the transient receptor potential vanilloid-1 (TRPV1) channel-mediated cough is resistant to the hypoestrous state, while the citric acid-mediated cough is oestrogen-dependent and hypersensitive during the hypoestrous state.

Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.

BACKGROUND: Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. METHODS: MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. FINDINGS: 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). INTERPRETATION: Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. FUNDING: Sierra Oncology.

MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.

Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.

Lay abstract The most important features of myelofibrosis (MF) are low blood cell counts and symptoms including tiredness, night sweats and itching, along with increased size of the spleen, which may cause a feeling of fullness and pain. Low red blood cell counts (anemia) may mean regular blood transfusions are needed and this is one of the signs MF is getting worse. Drugs called JAK inhibitors (JAKi) are available to treat MF, but can have a side effect of making blood cell counts lower. Momelotinib (MMB) is a different type of JAKi to the ones currently available, and is an experimental drug for MF. MMB is designed to treat symptoms and spleen like other JAKi, but also to improve blood cell counts. MMB has already been given to more than 820 patients with MF in other clinical studies. Some of the patients in these studies had been treated with different JAKi before, and others got MMB as their first JAKi treatment. The MOMENTUM Phase III study is designed to collect more information on the safety and effectiveness of MMB in MF.

Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

Uso de testosterona en mujeres: un comentario sobre el consenso global sobre el uso de la terapia de testosterona para mujeres / Global consensus position statement on the use of testosterone therapy for women

Las mujeres han sido tratadas por décadas con testosterona intentando aliviar una gran variedad de síntomas con riesgos y beneficios inciertos. En la mayoría de los países, la testosterona se prescribe "off-label", de modo que las mujeres están utilizando compuestos y dosis ideadas para tratamientos en hombres. En este sentido, varias sociedades médicas de distintos continentes adoptaron recientemente por consenso una toma de posición sobre los beneficios y potenciales riesgos de la terapia con testosterona en la mujer, explorar las áreas de incertidumbre e identificar prácticas de prescripción con potencial de causar daño. Las recomendaciones con respecto a los beneficios y riesgos de la terapia con testosterona se basan en los resultados de ensayos clínicos controlados con placebo de al menos 12 semanas de duración. A continuación se comentan las recomendaciones. (AU)

There are currently no clear established indications for testosterone replacement therapy for women. Nonetheless, clinicians have been treating women with testosterone to alleviate a variety of symptoms for decades with uncertainty regarding its benefits and risks. In most countries, testosterone therapy is prescribed off-label, which means that women are using testosterone formulations or compounds approved for men with a modified dose for women. Due to these issues, there was a need for a global Consensus Position Statement on testosterone therapy for women based on the available evidence from placebo randomized controlled trials (RCTs). This Position Statement was developed to inform health care professionals about the benefits and potential risks of testosterone therapy intended for women. The aim of the Consensus was to provide clear guidance as to which women might benefit from testosterone therapy; to identify symptoms, signs, and certain conditions for which the evidence does not support the prescription of testosterone; to explore areas of uncertainty, and to identify any prescribing practices that have the potential to cause harm. (AU)

5-Aminolevulinic acid photodynamic therapy and isotretinoin for treatment of drug-induced acne fulminans in a patient with idiopathic thrombocytopenic purpura.

In this work, we present a case of deteriorative acne that occurred during methylprednisolone and danazol treatment of idiopathic thrombocytopenic purpura (ITP). Treatment of the patient with a combination of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and isotretinoin was satisfactory, though the patient had platelets as low as 4-10 × 109/L during treatment. We consider that the combination of oral isotretinoin and ALA-PDT was effective in this patient may be due to the synergetic effect of these treatments. To the best of our knowledge, no such cases have been reported.

Flow-mediated vasodilation assay indicates no endothelial dysfunction in hereditary angioedema patients with C1-inhibitor deficiency.

BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare, potentially life-threatening disorder characterized by recurrent edematous attacks. The edema formation is the consequence of interaction of bradykinin and various vasoactive peptides with endothelium. Besides these agents, danazol, a modified testosterone derivative used in these patients to prevent edematous attacks, can also affect the function of the endothelium, because it shifts the blood lipid profile to a pro-atherogenic phenotype. OBJECTIVE: To assess the endothelial function in C1-INH-HAE patients and in healthy matched controls. METHODS: To evaluate the endothelial function, we used the flow-mediated dilation method measured in the region of the brachial artery in 33 C1-INH-HAE patients and in 30 healthy matched controls. Laboratory measurements of standard biochemical parameters were performed on computerized laboratory analyzers. RESULTS: No difference was found in endothelial function (reactive hyperemia, RH) between patients (median, 9.0; 25%-75% percentile, 6.3-12.9) and controls (median, 7.37; 25%-75% percentile, 4.52-9.93). Although we found elevated cardiovascular risk (high body mass index and low-density lipoprotein/high-density lipoprotein ratio) in danazol-treated C1-INH-HAE patients, RH values did not differ between danazol-treated and nontreated patients. Furthermore, risk factors correlated with the endothelial function only in healthy controls and patients not treated with danazol. CONCLUSION: In summary, our results did not indicate any signs of endothelial dysfunction in C1-INH-HAE patients. Moreover, the normal endothelial function in danazol-treated patients with pro-atherogenic lipid profile suggests that elevated bradykinin level or other factor(s) involved in the pathogenesis of edematous attacks may have a protective role against endothelial dysfunction and atherosclerosis.

Effect of laparoscopy combined with mifepristone in the treatment of endometriosis and drug reaction analysis.

Endometriosis is a common benign disease of Gynecology, which often causes symptoms of dysmenorrhea, pelvic pain and infertility. In this paper, we analyzed the effect of laparoscopy combined with mifepristone in the treatment of endometriosis. By observing the clinical efficacy and side effects of small dose mifepristone, we explored the feasibility of small dose mifepristone in the treatment of recurrent endometriosis. The results showed that the clinical symptoms of small dose mifepristone group and danazol group were improved to varying degrees. The improvement rate of mifepristone group was 96.7% for dysmenorrhea and 61.1% for non menstrual lower abdominal pain, respectively. In conclusion, small dose mifepristone is an effective treatment for recurrent endometriosis with high remission and good curative effect.

Danazol as First-Line Therapy for Myelodysplastic Syndrome.

BACKGROUND: Allogeneic stem cell transplantation (ASCT) represents the only option with a potential cure rate of 30% to 50% in myelodysplastic syndrome (MDS); however, < 5% of patients are optimal candidates for this management. Therapeutic options are limited in patients unsuitable for ASCT. Evidence that androgens might be beneficial in MDS is controversial. We aimed to document the clinical outcomes of patients diagnosed with MDS treated with danazol as first-line therapy. PATIENTS AND METHODS: We retrospectively reviewed patients diagnosed in our center with MDS according to the World Health Organization 2008 criteria and treated with danazol between 2005 and 2015. Response was defined according to international working group criteria. RESULTS: We included 42 patients treated exclusively with danazol. Median dose was 400 mg/d (range, 100-600 mg/d). Median follow-up was 12 (range, 3-76) months. Twenty-four of these patients (60%) achieved clinical response. Median overall survival was 24 months (95% confidence interval, 5.1-42). Responders were older than nonresponders (P = .025) and had higher baseline hemoglobin concentration (P = .009). No patients discontinued danazol because of toxicity. Fifteen patients died (35.7%) and 5 progressed to acute myeloid leukemia. CONCLUSION: Danazol as first-line therapy is an acceptable treatment option with low side effects for patients with MDS who cannot receive ASCT.

Treatment of inherited bone marrow failure syndromes beyond transplantation.

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.

Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. METHODS: We did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 × 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 × 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 × 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263. FINDINGS: From June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4·94, 95% CI 2·03-12·02, p=0·00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group. INTERPRETATION: Patients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. FUNDING: National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China.

[Effect of danazol treatment on growth in pediatric patients with hereditary angioedema due to C1-inhibitor deficiency]. / A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére.

INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.

Management of Children With Hereditary Angioedema Due to C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) is a potentially life-threatening inherited disease characterized by attacks of skin swelling, severe abdominal pain, and upper airway swelling. Attacks typically begin in childhood, but the appropriate diagnosis is often missed. Attacks do not respond to epinephrine, antihistamines, or glucocorticoids. Recently, many effective drugs have been approved for treatment of adults with HAE, and the Medical Advisory Board of the HAE Patient's Association has developed and reported treatment recommendations for adults. Only 1 medication is approved for treatment of children <12 years of age, and there are no reported consensus recommendations for treatment of young children in the United States. The 11-member Medical Advisory Board, with extensive experience in the treatment of children, in concert with the leaders of the HAE Patient's Association, has developed these consensus recommendations to help in recognition, diagnosis, treatment of attacks, and prophylaxis of children with HAE.

Danazol-induced peliosis hepatis accompanied by disseminated intravascular coagulation in a patient with myelodysplastic syndrome transformed from aplastic anemia.

Peliosis hepatis (PH) is a condition involving benign tumors pathologically characterized by multiple blood-filled cavities, mostly affecting the liver and spleen. Androgenic-steroids are widely used in patients with bone marrow failure syndromes (e.g.: aplastic anemia) and these patients are at increased risk of developing PH. Although patients with PH are generally asymptomatic, PH can progress to liver failure and even fatal spontaneous intraabdominal hemorrhage. Therefore, early diagnosis is critical in order to prevent life-threatening complications of PH. We herein report a patient with PH which had been treated with danazol, who presented with liver dysfunction and multiple hepatic lesions on imaging studies at the time of diagnosis. Although the patient presented with disseminated intravascular coagulation (DIC), a bone marrow biopsy revealed no evidence of leukemic transformation. The patient was diagnosed as having danazol-induced PH, and these abnormalities spontaneously resolved after the discontinuation of danazol. PH is one of the most important complications of long-term administration of androgenic-steroids. Although the mechanisms remain unclear, the multiple blood-filled cavities characteristic of PH may be responsible for the development of DIC. Therefore, monitoring of coagulation markers might also be a key strategy for early diagnosis of PH.

Eficacia y seguridad de eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de medula ósea / Efficacy and safety of eltrombopag in patients with severe medullary aplasia, non-tributary to immunosuppressive triple therapy and bone marrow transplantation

INTRODUCCIÓN: Antecedentes: El presente dictamen responde a la solicitud de evaluación de tecnología sanitaria del uso fuera del petitorio de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Aspectos Generales: La trombopeyetina es un factor humoral o citoquina, el cual estimula la producción de trombocitos (plaquetas), proliferación de megacariocitos de la médula ósea y por ende liberación de plaquetas en un mecanismo llamado trombopoyesis. El rol principal de las plaquetas es proveer la interacción y activación de factores de coagulación en la cascada de coagulación. Los pacientes con anemia aplásica exhiben altos niveles de trombopoyetina y pero aún así presentan trombocitopenia debido a una supresión o falla por parte de la producción de plaquetas en la médula ósea. Tecnología Sanitaria de Interés: Eltrombopag (ETP), Revolade o Promacta (GlaxoSmithKline lnc) es un medicamento agonista del receptor de la trombopoyetina (TPOr) que promueve la diferenciación megacariocítica, la proliferación y la producción de plaquetas. Es un agente hematopoyético que actúa como agonista no peptídico del receptor de la trombopoyetina. Interacciona con el dominio transmembrana e induce a la proliferación y diferenciación de los megacariocitos produciendo, a consecuencia de ello, un incremento en el recuento plaquetario. METODOLOGÍA: Estrategia de Búsqueda: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Para la búsqueda primaria se revisó en primer lugar la información disponible por entes reguladoras y normativas de autorización comercial como la Administración de Drogas y Alimentos (FDA) de Estados Unidos, la Agencia de Medicamentos Europea (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID) en el Perú. Seguidamente, se emplearon los motores de búsqueda de los metabuscadores Translating Research into Practice (TRIPDATABASE), Epistemonikos y Health Systems Evidence (HSE). Asimismo, se buscó información generada por grupos internacionales que realizan revisiones sistemáticas, evaluaciones de tecnologías sanitarias y guías de práctica clínica, tales como el National Institute for Health and Care Excellence (NICE) del Reino Unido, National Guideline Clearinghouse (NGC) de Estados Unidos, Canadian Agency for Drugs and Technologies in Health (CADTH) de Canadá, Scottish Medicines Consortium (SMC) de Escocia, Haute Authorité de Santé (HAS) de Francia, el Instituto de Evaluación de Tecnologías Sanitarias (IETS) de Colombia, el Instituto de efectividad clínica y sanitaria (IECS) de Argentina. Finalmente, se realizó una búsqueda dentro de las bases de datos Pubmed, EMBASE, y The Web of Science que a su vez fue complementada con una búsqueda en www.clinicaltrials.gov y www.clinicaltrialsregister.eu. RESULTADOS: Sinopsis de la Evidencia: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de eficacia y seguridad de eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. En la presente sinopsis se describe la evidencia encontrada a la fecha. Guías de práctica clínica: No se encontraron guías de práctica clínica de buena calidad que recomienden eltrombopag en AAS. Evaluaciones de tecnologías sanitarias: El grupo evaluador de NICE revisó este año (2016) la evidencia disponible para AAS con eltrombopag. Sin embargo es observable que tanto la CADTH de Canada, la SMC de Escocia, el IECS Argentina, IETS Colombia, y la HAS de Francia los cuales son referentes internacionales de evaluaciones de tecnologías sanitarias, no han realizado aún evaluaciones ni han emitido recomendaciones para el uso de eltrombopag en AAS. Ensayos clínicos: Se encontraron los ensayos clínicos fase II de Olnes et al., 2012 y Desmond et al., 2014. Ensayos clínicos no-publicados: Se encontraron tres estudios en progreso en la página de clinicaltrials.gov que corresponden a NCT01891994, NCT 01703169, y NCT 02148133. Otros documentos adicionales: Documento de recomendación como Guía de la BCSH. CONCLUSIONES: El presente dictamen responde a la solicitud de evaluación de tecnología sanitaria del uso fuera del petitorio de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. Se encontraron dos ensayos clínicos fase II, no-aleatorizados, abiertos y de un solo brazo y tres ensayos clínicos en proceso no-publicados, los cuales evaluaron la respuesta hematológica a eltrombopag en la población de interés. La evidencia generada por éstos contiene limitaciones severas para la interpretación y generalización de los resultados para la población de interés. El Instituto de Evaluación de Tecnologías en Salud e Investigación ­IETSI, aprueba el uso de Eltrombopag en pacientes con aplasia medular severa, no tributarios a terapia triple inmunosupresora ni trasplante de médula ósea. La vigencia del presente dictamen preliminar es de un año. En los subsiguientes meses a la publicación del presente dictamen, se evaluará la nueva evidencia publicada en la literatura internacional, y se analizarán los datos clínicos de todos aquellos pacientes que hayan recibido eltrombopag en el contexto del presente dictamen, con el fin de establecer el impacto del mismo. Esta información será tomada en cuenta para actualizar el presente dictamen al culminar su vigencia.

Development of hepatocellular carcinoma after long-term immunosuppressive therapy including danazol in a dog.

A 2-year-old female beagle was referred to our hospital for evaluation of anemia. Laboratory tests, including bone marrow cytology, revealed non-regenerative immune-mediated anemia (NRIMA). Although initial immunosuppressive multi-drug therapy was not effective, additional administration of danazol was successful in treating the anemia. However, hepatocellular carcinoma (HCC) developed about 20 months after the administration of danazol. In humans, several cases of development of HCC after the administration of danazol have been reported. The present report describes a case of HCC development in a dog after chronic administration of danazol in addition to other immunosuppressive drugs.