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1.
EJHaem ; 5(3): 494-504, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38895059

RESUMO

Understanding the impact of induction and maintenance therapy on patients' quality of life (QoL) is important for treatment selection. This study aims to compare patient-reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL-C 30 and QOL-MY20 questionnaires in the AGMT-02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health-related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross-sectional comparisons indicated a "slight" superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross-sectional comparisons revealed a "slight" improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with "slight" or "moderate" impairments in several QoL scales compared with the observation group.

3.
Thromb Res ; 223: 102-110, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36738663

RESUMO

BACKGROUND: The bleeding phenotype in immune thrombocytopenia (ITP) is heterogeneous, but usually mild and only partly dependent on the severity of thrombocytopenia. Platelet reactivity has previously been suggested to underly the mild phenotype. METHODS: Platelet function was assessed as basal and agonist-induced surface expression of P-selectin and activation of GPIIb/IIIa via flow cytometry, and soluble (s)P-selectin levels were assessed in plasma of 77 patients with primary ITP, 19 hemato-oncologic thrombocytopenic controls (TC) and 20 healthy controls (HC). The association of platelet function with laboratory and clinical parameters such as bleeding manifestations at inclusion and previous thrombosis was analyzed. RESULTS: ITP patients showed tendency towards increased surface P-selectin and elevated levels of activated GPIIb/IIIa. Platelet activation after stimulation with all agonists including TRAP-6, ADP, arachidonic acid and CRP was decreased compared to HC. Compared to TC, only GPIIb/IIIa activation but not surface P-selectin was higher in ITP. Levels of soluble (s)P-selectin were significantly higher in ITP patients compared to TC, but similar to HC. Higher sP-selectin levels were associated with blood group O and current therapy, with highest levels in TPO-RA treated patients. Platelet reactivity was not associated with platelet count or size, platelet antibodies, treatment regime, or blood group. No correlation between platelet activation with the bleeding phenotype or previous thrombotic events could be observed. CONCLUSION: ITP patients did not have hyper-reactive platelets compared to HC, but partly higher reactivity compared to TC. Further studies are needed to understand the underlying mechanism behind the bleeding and pro-thrombotic phenotype in ITP. 250/250.


Assuntos
Púrpura Trombocitopênica Idiopática , Trombocitopenia , Humanos , Selectina-P , Plaquetas/metabolismo , Contagem de Plaquetas , Hemorragia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo
4.
Am J Hematol ; 98(5): 770-783, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36814396

RESUMO

Myeloproliferative neoplasms (MPN) are characterized by uncontrolled expansion of myeloid cells, disease-related mutations in certain driver-genes including JAK2, CALR, and MPL, and a substantial risk to progress to secondary acute myeloid leukemia (sAML). Although behaving as stem cell neoplasms, little is known about disease-initiating stem cells in MPN. We established the phenotype of putative CD34+ /CD38- stem cells and CD34+ /CD38+ progenitor cells in MPN. A total of 111 patients with MPN suffering from polycythemia vera, essential thrombocythemia, or primary myelofibrosis (PMF) were examined. In almost all patients tested, CD34+ /CD38- stem cells expressed CD33, CD44, CD47, CD52, CD97, CD99, CD105, CD117, CD123, CD133, CD184, CD243, and CD274 (PD-L1). In patients with PMF, MPN stem cells often expressed CD25 and sometimes also CD26 in an aberrant manner. MPN stem cells did not exhibit substantial amounts of CD90, CD273 (PD-L2), CD279 (PD-1), CD366 (TIM-3), CD371 (CLL-1), or IL-1RAP. The phenotype of CD34+ /CD38- stem cells did not change profoundly during progression to sAML. The disease-initiating capacity of putative MPN stem cells was confirmed in NSGS mice. Whereas CD34+ /CD38- MPN cells engrafted in NSGS mice, no substantial engraftment was produced by CD34+ /CD38+ or CD34- cells. The JAK2-targeting drug fedratinib and the BRD4 degrader dBET6 induced apoptosis and suppressed proliferation in MPN stem cells. Together, MPN stem cells display a unique phenotype, including cytokine receptors, immune checkpoint molecules, and other clinically relevant target antigens. Phenotypic characterization of neoplastic stem cells in MPN and sAML should facilitate their enrichment and the development of stem cell-eradicating (curative) therapies.


Assuntos
Leucemia Mieloide Aguda , Transtornos Mieloproliferativos , Policitemia Vera , Animais , Camundongos , Calreticulina/genética , Janus Quinase 2/genética , Mutação , Transtornos Mieloproliferativos/genética , Células-Tronco Neoplásicas , Proteínas Nucleares/genética , Fenótipo , Policitemia Vera/genética , Fatores de Transcrição/genética , Humanos
7.
Memo ; 14(4): 350-354, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691269

RESUMO

Immune thrombocytopenic purpura (ITP) is a rare hematological disorder with an autoimmune-mediated, often dramatic reduction of platelets in peripheral blood. Thrombocytopenia results from a reduced life span of thrombocytes and an additionally decreased production in bone marrow. For decades, the first-line therapy for ITP has been corticosteroids. As significant thrombocytopenic bleedings occur, the use of additional medication may be needed. Recent updates on therapy guidelines recommend the shortest possible use of corticosteroids. Thrombopoietin-receptor agonists are often used second line. Today splenectomy, which was previously recommended after unsuccessful first-line therapy, is usually considered much later. Patients who do not respond even after multiple lines of therapy continue to pose a major challenge. New drugs for ITP treatment are now available after steroid failure and will be discussed. This review gives a short summary on actual therapy guidelines taking into account newly available therapy options. In addition, comparisons between selected published data and experience at our department are made.

8.
Blood Adv ; 4(6): 997-1005, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32176765

RESUMO

Cold agglutinin disease (CAD) causes predominantly extravascular hemolysis and anemia via complement activation. Sutimlimab is a novel humanized monoclonal antibody directed against classical pathway complement factor C1s. We aimed to evaluate the safety and efficacy of long-term maintenance treatment with sutimlimab in patients with CAD. Seven CAD patients treated with sutimlimab as part of a phase 1B study were transitioned to a named patient program. After a loading dose, patients received biweekly (once every 2 weeks) infusions of sutimlimab at various doses. When a patient's laboratory data showed signs of breakthrough hemolysis, the dose of sutimlimab was increased. Three patients started with a dose of 45 mg/kg, another 3 with 60 mg/kg, and 1 with a fixed dose of 5.5 g every other week. All CAD patients responded to re-treatment, and sutimlimab increased hemoglobin from a median initial level of 7.7 g/dL to a median peak of 12.5 g/dL (P = .016). Patients maintained near normal hemoglobin levels except for a few breakthrough events that were related to underdosing and which resolved after the appropriate dose increase. Four of the patients included were eventually treated with a biweekly 5.5 g fixed-dose regimen of sutimlimab. None of them had any breakthrough hemolysis. All patients remained transfusion free while receiving sutimlimab. There were no treatment-related serious adverse events. Overlapping treatment with erythropoietin, rituximab, or ibrutinib in individual patients was safe and did not cause untoward drug interactions. Long-term maintenance treatment with sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels in re-exposed, previously transfusion-dependent CAD patients.


Assuntos
Anemia Hemolítica Autoimune , Complemento C1s , Anemia Hemolítica Autoimune/tratamento farmacológico , Ativação do Complemento , Hemólise , Humanos , Rituximab
9.
Blood ; 133(9): 893-901, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30559259

RESUMO

Cold agglutinin disease is a difficult-to-treat autoimmune hemolytic anemia in which immunoglobulin M antibodies bind to erythrocytes and fix complement, resulting in predominantly extravascular hemolysis. This trial tested the hypothesis that the anti-C1s antibody sutimlimab would ameliorate hemolytic anemia. Ten patients with cold agglutinin disease participated in the phase 1b component of a first-in-human trial. Patients received a test dose of 10-mg/kg sutimlimab followed by a full dose of 60 mg/kg 1 to 4 days later and 3 additional weekly doses of 60 mg/kg. All infusions were well tolerated without premedication. No drug-related serious adverse events were observed. Seven of 10 patients with cold agglutinin disease responded with a hemoglobin increase >2 g/dL. Sutimlimab rapidly increased hemoglobin levels by a median of 1.6 g/dL within the first week, and by a median of 3.9 g/dL (interquartile range, 1.3-4.5 g/dL; 95% confidence interval, 2.1-4.5) within 6 weeks (P = .005). Sutimlimab rapidly abrogated extravascular hemolysis, normalizing bilirubin levels within 24 hours in most patients and normalizing haptoglobin levels in 4 patients within 1 week. Hemolytic anemia recurred when drug levels were cleared from the circulation 3 to 4 weeks after the last dose of sutimlimab. Reexposure to sutimlimab in a named patient program recapitulated the control of hemolytic anemia. All 6 previously transfused patients became transfusion-free during treatment. Sutimlimab was safe, well tolerated, and rapidly stopped C1s complement-mediated hemolysis in patients with cold agglutinin disease, significantly increasing hemoglobin levels and precluding the need for transfusions. This trial was registered at www.clinicaltrials.gov as #NCT02502903.


Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Anemia Hemolítica/prevenção & controle , Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C1s/antagonistas & inibidores , Hemólise/efeitos dos fármacos , Índice de Gravidade de Doença , Idoso , Anemia Hemolítica/etiologia , Anemia Hemolítica Autoimune/complicações , Complemento C1s/imunologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
10.
Curr Rheumatol Rep ; 19(5): 29, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28401384

RESUMO

PURPOSE OF REVIEW: Rosai-Dorfman disease (RDD) is a rare histiocytic disorder typically presenting as painless cervical lymphadenopathy. Extranodal involvement is common and may also affect bones. Here, we present a patient with typical nodal disease and multifocal bone manifestations. Further, a systematic literature review was performed to better understand the phenotype, clinical course and treatment options of such patients. RECENT FINDINGS: RDD is a nonmalignant, classically sporadic histiocytosis. Nevertheless, increasing evidence also suggests familial forms of the disease. According to our literature review, bone involvement is exceedingly rare and heterogeneous. Clinical outcome in terms of mortality seems to be favorable in most cases. Currently, therapy strategies include surgical and immunosuppressive treatments, but the optimal treatment of osseous RDD remains to be defined. Patients with osseous RDD may present to rheumatologists with arthralgia or arthritis. Due to the rarity of the disease, diagnosis and treatment remain challenging.


Assuntos
Doenças Ósseas/diagnóstico , Histiocitose Sinusal/diagnóstico , Adulto , Artralgia/etiologia , Doenças Ósseas/complicações , Doenças Ósseas/tratamento farmacológico , Diagnóstico Diferencial , Quimioterapia Combinada , Feminino , Glucocorticoides/uso terapêutico , Mãos/diagnóstico por imagem , Histiocitose Sinusal/complicações , Histiocitose Sinusal/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Imageamento por Ressonância Magnética , Radiografia
11.
Wien Klin Wochenschr ; 124(3-4): 111-23, 2012 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-22382553

RESUMO

Immune Thrombocytopenia (ITP) is a rare and - in most patients - mild disease, but might be associated with severe or even life-threatening bleeding complications. The treatment of ITP has partly changed in recent years, due to new therapeutic options. International guidelines changed accordingly. This consensus statement by the Austrian Society of Hematology and Oncology (OEGHO) is not a new evaluation of the current evidence, but rather tries to discuss the available international guidelines and adapt them to the situation in Austria. The subject is primary ITP in adults only. Classification, epidemiology, clinical presentation and diagnostics of ITP, and especially the management of this disease, are discussed in detail. This includes current aspects of first, second, and third line therapies, splenectomy with its indications and contraindications, and the use of new therapeutic options like thrombopoetin receptor agonists (TRA).


Assuntos
Hematologia/normas , Oncologia/normas , Guias de Prática Clínica como Assunto , Púrpura Trombocitopênica Idiopática/diagnóstico , Púrpura Trombocitopênica Idiopática/terapia , Adulto , Áustria , Conferências de Consenso como Assunto , Humanos
12.
Ann Hematol ; 85(6): 386-93, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16557380

RESUMO

Transplantation of autologous hematopoietic stem cells is a well established therapeutic procedure. Despite advances in efficacy of the stem cell mobilization and apheresis process until now a predictive factor for the expected stem cell yield before initiation of mobilization therapy could not be identified. The main objective of our study was to evaluate alterations in enzymes involved in fatty acid metabolism on the level of gene expression in mononuclear cells, as changes in relative mRNA levels of these enzymes could represent the hematopoietic regenerative potential. Data of 23 consecutive patients with different lymphoid malignancies undergoing stem cell mobilization were analyzed. Our results show that mRNA levels of microsomal carnitine palmitoyltransferase in peripheral blood mononuclear cells quantified before application of mobilization therapy correlate positively with the amount of CD34 positive cells in peripheral blood before first apheresis, in the first apheresis product and in the total harvest outcome. The association of enzymes involved in fatty acid metabolism with hematoopoiesis was further confirmed in healthy subjects on altitude-adaptation training and in proliferating or differentiating HL60 cells. This gives evidence for a possible predictive value of such analyzes though further data of a larger sample are to be collected to confirm our observations.


Assuntos
Remoção de Componentes Sanguíneos , Carnitina O-Palmitoiltransferase/genética , Células-Tronco Hematopoéticas/citologia , RNA Mensageiro/sangue , Adolescente , Adulto , Altitude , Antígenos CD34/sangue , Ensaio de Unidades Formadoras de Colônias , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/análise , Proteínas de Ligação ao GTP/análise , Células HL-60 , Neoplasias Hematológicas/sangue , Neoplasias Hematológicas/patologia , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Proteínas Heterotriméricas de Ligação ao GTP/análise , Humanos , Leucócitos Mononucleares/enzimologia , Microssomos/enzimologia , Pessoa de Meia-Idade , Proteínas de Transporte de Cátions Orgânicos/análise , Transplante de Células-Tronco de Sangue Periférico , RNA Mensageiro/genética , Membro 5 da Família 22 de Carreadores de Soluto , Transplante Autólogo
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