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Moving forward from spleen response as an endpoint in randomized controlled trials in myelofibrosis.

Anticancer drugs should make patients live longer and/or feel better. Ideally, endpoints of cancer randomized controlled trials (RCT) should demonstrate that a drug leads to an increase in overall survival and/or improvement in quality of life. With the aim of including smaller numbers of patients, running shorter trials and thus getting new drugs to patients faster, cancer RCT are increasingly using (putative) surrogate endpoints. However, changes in surrogate endpoints often do not reliably predict improvements in overall survival and/or quality of life. Furthermore, especially in later line

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… Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-280. Erratum in: Lancet. 2023;401(10386): 1426,. … Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): an updated analysis of an international, double-blind, randomised phase 3 study. Lancet Haematol. 2023;10(9):e735-e746. 53. Mesa R, Harrison C, Oh ST, et al. …

Daratumumab-based treatment of monoclonal gammopathy-associated angioedema due to acquired C1-inhibitor deficiency.

Daratumumab-based treatment could control severe, treatment-refractory, life-threatening angioedema due to acquired C1-inhibitor deficiency associated with monoclonal gammopathy.

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… Prophylaxis with danazol (200 mg orally once daily) reduced the attack frequency; however, severe psychological side effects required discontinuation of this treatment. Tranexamic acid (1000 mg orally 3 times daily) was not effective. …

Telomerase-targeted therapies in myeloid malignancies.

Human telomeres are tandem arrays that are predominantly composed of 5'-TTAGGG-3' nucleotide sequences at the terminal ends of chromosomes. These sequences serve 2 primary functions: they preserve genomic integrity by protecting the ends of chromosomes, preventing inappropriate degradation by DNA repair mechanisms, and they prevent loss of genetic information during cellular division. When telomeres shorten to reach a critical length, termed the Hayflick limit, cell senescence or death is triggered. Telomerase is a key enzyme involved in synthesizing and maintaining the length of telomeres wit

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… end point IMpactMF (NCT045761) 9.4 mg/kg IV every 3 weeks vs BAT ∗ DIPSS intermediate-2 + MF, refractory to JAKi OS IMerge ( NCT02598661 ) 7.5 mg/kg IV every 4 weeks vs placebo IPSS low- to intermediate-risk MDS, transfusion dependence refractory to ESA TI ∗ Hydroxyurea, thalidomide or analog, IFN, danazol … Ongoing phase 3 trials ∗ Hydroxyurea, thalidomide or analog, IFN, danazol, HMA, or chemotherapy; excludes JAKi. …

Safety and efficacy of daratumumab in immune thrombocytopenia.

AbstractResistance to B-cell-targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38+ long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase 2 study evaluated safety and efficacy of daratumumab in 21 patients with previously treated ITP. Following a safety run-in, 2 dosing cohorts received 8 and 10 subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary end points were safety and response (2 consecutive platelet counts ≥50 × 109/L at w

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… 3 (100) 9 (100) 9 (100) IVIG 14 (67) 2 (67) 5 (56) 7 (78) Rituximab 16 (76) 3 (100) 6 (67) 7 (78) TPO-RA † 18 (86) 3 (100) 8 (67) 7 (78) Fostamatinib 1 (5) 0 0 1 (11) Rilzabrutinib 1 (5) 1 (33) 0 0 Azathioprine 2 (10) 0 1 (11) 1 (11) Mycophenolate mofetil 2 (10) 0 0 2 (22) Dapsone 1 (5) 0 0 1 (11) Danazol … 78) Rituximab | 16 (76) | 3 (100) | 6 (67) | 7 (78) TPO-RA † | 18 (86) | 3 (100) | 8 (67) | 7 (78) Fostamatinib | 1 (5) | 0 | 0 | 1 (11) Rilzabrutinib | 1 (5) | 1 (33) | 0 | 0 Azathioprine | 2 (10) | 0 | 1 (11) | 1 (11) Mycophenolate mofetil | 2 (10) | 0 | 0 | 2 (22) Dapsone | 1 (5) | 0 | 0 | 1 (11) Danazol …

Targeted treatment of autoimmune cytopenias in primary immunodeficiencies.

Primary Immunodeficiencies (PID) are a group of rare congenital disorders of the immune system. Autoimmune cytopenia (AIC) represents the most common autoimmune manifestation in PID patients. Treatment of AIC in PID patients can be really challenging, since they are often chronic, relapsing and refractory to first line therapies, thus requiring a broad variety of alternative therapeutic options. Moreover, immunosuppression should be fine balanced considering the increased susceptibility to infections in these patients. Specific therapeutic guidelines for AIC in PID patients are lacking. Treatm

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… kg <6y) orally Romiplostin (>18yrs or eltr. non responders) 100-250 ug/m (2 )week If signs of CID: consider targeted therapy, HSCT Rituximab (discussed as 2 nd or 3 rd line therapy) 375 mg/m2 once per week, 4 times especially in case of: chronic EBV infection, high CD19+ frequency THIRD LINE OPTIONS Danazol … AZT, VCR, CY, CSA targeted treatments: Bortezomib, Daratumumab, Belimumab, Ibrutinib, Epratuzumab, Abatacept, PI3Kδ inhibitors, JAK Inhibitors, Anakinra, TNF inhibitors, Eculizumab, Plerixafor HSCT, GT adults: splenectomy (vaccinate before; consider OPSI prophylaxis) | THIRD LINE OPTIONS Rituximab, Danazol …

Single agent selinexor is active in patients with myelofibrosis refractory or intolerant to JAK inhibitors.

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… Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401:269–80. 13. Mascarenhas J, Komrokji RS, Palandri F, Martino B, Niederwieser D, Reiter A, et al. …

Prospects of Chimeric Antigen Receptor T-Cell Therapy in Myelofibrosis: From Immunopathogenesis to Therapeutic Strategies.

Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by clonal hematopoietic dysregulation, amplification of chronic inflammation, and progressive remodeling of the bone marrow fibrotic niche, clinically manifesting as bone marrow failure, splenomegaly, and systemic inflammatory symptoms. Although Janus kinase (JAK) inhibitors can alleviate symptom burden and reduce spleen size, they have limited capacity to eradicate malignant clones or reverse fibrosis. Allogeneic hematopoietic stem cell transplantation remains the only potentially curative option; however, its application is co

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… Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): Results from an international, double-blind, randomised, controlled, phase 3 study Lancet 2023 401 269 280 10.1016/S0140-6736(22)02036-0 36709073 10. Gerds A.T. Verstovsek S. Vannucchi A.M. Al-Ali H.K. … Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis previously treated with a JAK inhibitor (MOMENTUM): An updated analysis of an international, double-blind, randomised phase 3 study Lancet Haematol. 2023 10 e735 e746 10.1016/S2352-3026(23)00174-6 37517413 11. …

The management of uterine leiomyomas.

OBJECTIVES: The aim of this guideline is to provide clinicians with an understanding of the pathophysiology, prevalence, and clinical signif … selective progesterone receptor modulators, (I) oral contraceptives, (II-2) progestins, (II-2) and danazol. (II-2) 6. Effective medical treatments for women with bulk symptoms associated with fibroids include selective progesterone receptor modulators and gonadotropin-releasing hormone analogues. (I) 7. Hysterectomy is the most effective treatment for sy …

Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis.

Myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF) is characterized by cytopenias, marrow fibrosis, constitutional symptoms, extramedullary hematopoiesis, splenomegaly, and shortened survival. Constitutive activation of the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway in MF leads to cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative malignant cells. Fedratinib is a selective oral JAK2 inhibitor recently approved in the United States for treatment of adult patients with intermediate-2 or high-risk M

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… managed with Peg-IFN-α-2a, hydroxyurea, immunomodulatory drugs (e.g., lenalidomide) [ 15 , 16 ], or ruxolitinib (approved in Europe but not in the USA for symptomatic low-risk MF) [ 17 ], and a variety of agents are used to address MF-related anemia (e.g., erythropoiesis stimulating agents [ 18 ], danazol … Cervantes F Isola IM Alvarez-Larran A Hernandez-Boluda JC Correa JG Pereira A Danazol therapy for the anemia of myelofibrosis: assessment of efficacy with current criteria of response and long-term results Ann Hematol 2015 94 1791 6 26122869 10.1007/s00277-015-2435-7 20. …

Evans syndrome: clinical perspectives, biological insights and treatment modalities.

Evans syndrome (ES) is a rare and chronic autoimmune disease characterized by autoimmune hemolytic anemia and immune thrombocytopenic purpura with a positive direct anti-human globulin test. It is classified as primary and secondary, with the frequency in patients with autoimmune hemolytic anemia being 37%-73%. It predominates in children, mainly due to primary immunodeficiencies or autoimmune lymphoproliferative syndrome. ES during pregnancy is associated with high fetal morbidity, including severe hemolysis and intracranial bleeding with neurological sequelae and death. The clinical presenta

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… These patients received 1–12 modalities of treatment, mostly steroids plus IVIG, whereas others underwent splenectomy and/or received cyclosporine, vincristine, danazol, azathioprine, cyclophosphamide and plasmapheresis, with no optimal response. … Value of the corticoids–danazol combination Rev Rhum Mal Osteoartic 1991 58 7 519 522 French 1925397 34 Quinn JP Gilligan OM Horgan M Evan’s syndrome complicating multicentric Castleman’s disease – dramatic response to rituximab Eur J Haematol 2004 73 5 384 385 15458520 10.1111/j.1600-0609.2004.00302 …

Therapeutic approaches in myelofibrosis and myelodysplastic/myeloproliferative overlap syndromes.

The discovery of JAK2 (V617F) a decade ago led to optimism for a rapidly developing treatment revolution in Ph(-) myeloproliferative neoplasms. Unlike BCR-ABL, however, JAK2 was found to have a more heterogeneous role in carcinogenesis. Therefore, for years, development of new therapies was slow, despite standard treatment options that did not address the overwhelming symptom burden in patients with primary myelofibrosis (MF), post-essential thrombocythemia MF, post-polycythemia vera MF, and myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) syndromes. JAK-STAT inhibitors have ch

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… This is reviewed in detail elsewhere. 30 Androgens, IFNα, and thalidomide Though wrought with toxicities, such androgens as oxymetholone, methandrostenolone, nandrolone, and fluoxymesterone have displayed improvement in anemia for some MF patients compared to transfusions alone. 31 Danazol, an attenuated … PMC4800699 31 Brubaker LH Brière J Laszlo J Treatment of anemia in myeloproliferative disorders: a randomized study of fluoxymesterone v transfusions only Arch Intern Med 1982 142 8 1533 1537 7103635 32 Cervantes F Alvarez-Larrán A Domingo A Arellano-Rodrigo E Montserrat E Efficacy and tolerability of danazol …

Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies.

Treatment of myelofibrosis (MF), a BCR-ABL-negative myeloproliferative neoplasm, is challenging. The only current potentially curative option, allogeneic hematopoietic stem cell transplant, is recommended for few patients. The remaining patients are treated with palliative therapies to manage MF-related anemia and splenomegaly. Identification of a mutation in the Janus kinase 2 (JAK2) gene (JAK2 V617F) in more than half of all patients with MF has prompted the discovery and clinical development of inhibitors that target JAK2. Although treatment with JAK2 inhibitors has been shown to improve sy

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… Therapies intended to treat MF-associated anemia include growth factors (eg, erythropoietin), androgens (eg, danazol), and the immunomodulatory drugs (IMiDs) thalidomide (± prednisone), lenalidomide (± prednisone), and pomalidomide (± prednisone) [ 20 - 26 ]. … Lasho TL Hogan WJ Litzow MR Allred JB Jones D Byrne C Zeldis JB Ketterling RP McClure RF Giles F Kantarjian HM Lenalidomide therapy in myelofibrosis with myeloid metaplasia Blood 2006 108 1158 1164 10.1182/blood-2006-02-004572 16609064 Cervantes F Hernández-Boluda JC Alvarez A Nadal E Montserrat E Danazol …

Polypharmacology: new drugs in 2023-2024.

Polypharmacology is an emerging approach to drug design and development that involves the use of multi-target-directed ligands (MTDLs), agents capable of interacting with multiple biological targets simultaneously. The effective treatment of chronic and multifactorial conditions, driven by the dysregulation of multiple interconnected pathways, such as cancer, autoimmune and metabolic disorders, cardiovascular and neurodegenerative diseases, is one of the most substantial challenges in contemporary pharmacology. 'Traditional' single-target-based treatment frequently shows limited effectiveness,

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… Momelotinib is a useful treatment option across all levels of anemia severity, including cases with concurrent thrombocytopenia [ 64 ], which, in two head-to-head clinical trials was superior to danazol (parameter: total symptom score [ 69 ]) and noninferior to ruxolitinib (spleen volume [ 70 ]). … Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269–80. 10.1016/S0140-6736(22)02036-0. 70. …

Interventions for heavy menstrual bleeding; overview of Cochrane reviews and network meta-analysis.

BACKGROUND: Heavy menstrual bleeding (HMB) is excessive menstrual blood loss that interferes with women's quality of life, regardless of the … OC), combined vaginal ring (CVR), long-cycle and luteal oral progestogens, LNG-IUS, ethamsylate and danazol (included to provide indirect evidence), which were compared to placebo. Surgical interventions were: open (abdominal), minimally invasive (vaginal or laparoscopic) and unspecified (or surgeon's choice of route of) hysterectomy, REA, NREA, unspecifi …

Hematology and Hemostasis

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… Immunosuppressive therapy using antithymocyte globulin, cyclosporin, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood. 2000;96:2049–54. 7. …

Real-world patient characteristics and clinical outcomes in patients with myelofibrosis in Japan.

Anemia is associated with increased morbidity, mortality, healthcare resource utilization, and costs in myelofibrosis. This longitudinal, retrospective, and descriptive cohort study used a Japanese health administrative database (Medical Data Vision) to examine treatment patterns, transfusion burden, healthcare resource utilization, and costs in patients with myelofibrosis and a subset treated with a Janus kinase inhibitor. Ruxolitinib (a Janus kinase inhibitor) was the first targeted therapy for myelofibrosis in Japan (2014). Patients were identified from April 1, 2015 to June 30, 2022. In th

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… Anemia was defined as a hemoglobin value ≤10 g/dL (in patients with available hemoglobin data), an anemia diagnosis, or an anemia treatment of interest (erythropoietin or epoetin alfa, danazol [androgen], blood transfusion). …

Profile of pomalidomide and its potential in the treatment of myelofibrosis.

Myelofibrosis, a Philadelphia-negative myeloproliferative neoplasm, is in a new treatment era after the discovery of the JAK2V617F mutation in 2005. JAK inhibitors boast improvements in disease-related symptoms, splenomegaly, and overall survival; however, treatment of myelofibrosis remains a challenge, given the lack of improvement in cytopenias with these agents. Second-generation immunomodulatory agents, such as pomalidomide, have shown efficacy in myelofibrosis-associated anemia within multiple clinical trials. Five major pomalido-mide clinical trials have been completed to date, and demon

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… Combination therapy with the androgenic agent danazol is a therapeutic strategy that is currently under active clinical investigation ( ClinicalTrials.gov NCT01732445 ). …

Haematological Diseases in the Tropics

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Indian Society of Hematology and Blood Transfusion (ISHBT) Consensus Document on Hematological Practice During COVID-19 Pandemic.

The SARS-CoV-2 (COVID-19) pandemic is a worldwide public health emergency with widespread impact on health care delivery. Unforeseen challenges have been noted during administration of usual haematology care in these unusual COVID-19 times. Medical services have been overstretched and frontline health workers have borne the brunt of COVID-19 pandemic. Movement restrictions during lockdown prevented large sections of population from accessing health care, blood banks from holding blood drives, and disrupted delivery of diagnostic hematology services. The disruption in hematology care due to COV

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… Alternative agents in combination like eltrombopag, low dose cyclosporine (2–3 mg/kg/day), danazol/stanazolol can be considered for patients who can stay at home [ 27 , 28 ]. …

Proceedings of the Canadian Society of Allergy and Clinical Immunology Annual Scientific Meeting 2018

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