Hasil untuk "Diseases of the blood and blood-forming organs"

Margareth C. Ozelo, Anthony K.C. Chan, Luciani Matteo et al.

Shirong Li, Josefine Krüger, Guifen Liu et al.

Abstract: Our recent study identifies germinal center kinase (GCK) as a novel therapeutic target in RAS-mutated multiple myeloma (MM). Inhibiting GCK downregulates critical transcriptional factors, notably IKZF1/3, BCL-6, and c-MYC proteins, leading to MM cell growth inhibition and cell death. Distinct from immunomodulatory drug (IMiD)–induced IKZF1/3 degradation, GCK inhibition triggers IKZF1/3 proteolysis through a cereblon (CRBN) E3 ligase–independent mechanism. Here, we demonstrated that GCK inhibition overcomes IMiD resistance in MM. An isogenic subline of MM.1S cells with acquired lenalidomide resistance remains sensitive to GCK inhibition–induced IKZF1/3 downregulation and cell growth inhibition. Consistently, the CRBN-resistant IKZF1 Q146H mutant maintains sensitivity to GCK inhibitor–induced degradation, similar to the IKZF1 wild-type protein, suggesting a CRBN-independent protein degradation. In accordance with the distinct IKZF1/3 degradation mechanisms, GCK silencing enhances iberdomide-induced IKZF1/3 and c-MYC downregulation and MM growth inhibition. More importantly, the combination of a GCK inhibitor with iberdomide exhibited synergistic anti-MM effects in a panel of MM cell lines and primary plasma cells. The synergistic effects were confirmed in an MM xenograft mouse model, in which combining GCK silencing and iberdomide resulted in significantly enhanced tumor inhibition and prolonged mice survival compared to single treatments. These findings underscore GCK as a promising therapeutic target for bypassing IMiD resistance in MM. Combining GCK inhibition with iberdomide could provide a novel strategy to manage relapsed or refractory patients with multidrug resistance, especially after the exhaustion of immunotherapy.

Kazimieras Maneikis, Evelien Krumb, Cedric Hermans

Hemophilia is an inherited bleeding disorder characterized by a deficiency in clotting factor, leading to impaired thrombin generation, bleeding complications, and long-term morbidity that severely impacts patients’ quality of life. Recent advancements in treatment have significantly empowered the hemophilia community, improving disease control, reducing treatment burden, expanding access to care, and lowering the risks of lifelong complications. These advancements have continually elevated the goals of hemophilia care. The latest innovations have introduced a new ambition: the “normalization” of life for persons with hemophilia. This aspiration is both desirable and promising, with the potential to greatly enhance patients’ quality of life and achieve equitable health outcomes. However, it is crucial for the entire community to first determine and define what constitutes an optimal and realistically achievable level of hemostasis normalization using current and emerging therapies. The significant psychosocial impact of hemophilia underscores the importance of targeting not only hemostasis normalization but also life normalization. This approach prioritizes reducing treatment burden and restoring mental well-being. Novel standardized tools are urgently needed to appropriately complement novel therapies, as traditional bleeding rate-based outcome metrics are becoming inadequate for assessing treatment superiority objectively. The potential risks of striving for normalized hemostasis must also be carefully considered. Moreover, specific needs and challenges associated with normalization must be addressed, particularly for carriers and women and girls with hemophilia.

Robert Winkler, Dirk Heckl, Michelle Ng et al.

NM Bernardes, WSV Júnior, LMB Batista et al.

Introdução: A neoplasia de células dendríticas plasmocitárias blásticas (NCDPB) é uma neoplasia hematológica rara e agressiva, que se manifesta como lesões cutâneas com ou sem envolvimento da medula óssea e disseminação leucêmica. Relato de caso: Paciente de 60 anos, masculino, casado, trabalhador rural, sem comorbidades, iniciou quadro de astenia, perda ponderal, febre, odinofagia e disfagia progressiva com 60 dias de evolução. Associado, exantema difuso em membros superiores, tórax, abdome e dorso, e nódulos cutâneos hipercrômicos, violáceos, endurecidos e indolores em dorso, mamilo e cervical. Amigdalas aumentadas, com áreas de necrose. Exames de imagem demonstravam linfonodomegalias cervicais, toracoabdominais, hepatoesplenomegalia. Hemograma: hb 6,4, plaquetas 10.000, Leucocitose (30.000) com 49% células atípicas. Realizada biópsia de amigdalas, que mostrou células neoplásicas com núcleos pleomórficos, hipercromáticos, cromatina grumosa e nucléolos evidentes e eosinofílicos. Aventada a hipótese de doença linfoproliferativa ou leucose aguda: mielograma mostrava medula óssea hipercelular, 87% de blastos pleomórficos e 6% de monócitos, não visualizados bastonetes de Auer, demais séries hipocelulares. Imunofenotipagem de medula óssea compatível com leucemia aguda com duas populações distintas: 12% de blastos mieloides e 45% de blastos com características de células dentríticas plasmocitoides. Realizada biópsia de lesão de pele, que corroborou com diagnóstico: anatomopatológico demonstrou neoplasia hemolinfopoiética de padrão blástico, imuno-histoquímica com positividade para CD56, CD34, CD43, CD5, CD3, CD117 e HLA-DR, confirmando NCDPB com causa de infiltração da pele. Apresentava cariótipo normal (46, XY) e biologia molecular com BCR-ABL, CBFβ, RUNX1, FLT3 e NPM1 negativos. Paciente apresentava lise tumoral espontânea, iniciadas medidas, além de citorredução com Hidroxiureia. No entanto, evoluiu com choque séptico de foco pulmonar, com disfunção de múltiplos órgãos (renal, hepático e respiratório), evoluindo para óbito 8 dias após a admissão, sem tempo hábil para tratamento específico. Discussão: A NCDPB é uma doença rara, agressiva, que acomete sobretudo adultos, com média de idade de 60 anos, e predominância masculina (2,5:1). As principais manifestações clínicas são lesões cutâneas com ou sem envolvimento da medula óssea e disseminação leucêmica. As lesões cutâneas podem ser castanhas a violáceas, formam placas ou tumores, podendo ser únicas ou disseminadas. Citopenias, linfadenopatia e hepatoesplenomegalia estão presentes na maioria dos casos. Envolvimento das amígdalas, cavidades paranasais, olhos, sistema nervoso central (SNC) têm sido relatados. Nosso paciente apresentava a maioria dessas manifestações, como descrito acima, conduzindo ao diagnóstico, confirmado por exames anatomopatológicos e imunofenotípicos. Apresentava positividade para CD4 e CD56, além de CD123, necessário para o diagnóstico definitivo de NCDPB. Devido à gravidade do quadro clínico e óbito precoce, não iniciado tratamento quimioterápico. Na literatura, indicado uso de Tagraxofusp (anti CD123), não disponível no Brasil. Opta-se por esquemas para leucemia linfoblástica aguda, com consolidação com transplante de medula óssea alogênico. O prognóstico é reservado. Conclusão: A NCDPB é uma doença cujo diagnóstico é desafiador devido a sua raridade, o qual deve ser cogitado em quadros leucêmicos com infiltração de pele, acometimento linfonodal e visceromegalias.

CEL Rolim, ASB Costa, GKL Rolim et al.

Objetivo: A eficácia da farmacoterapia está intrinsecamente ligada ao entendimento do indivíduo acerca da terapêutica aplicada à sua patologia, tal conhecimento culmina na adesão ao tratamento e na minimização de eventos adversos, fatores esses que compõem os objetivos previstos na Política Nacional de Assistência Farmacêutica. Outrossim, a realização de consultas farmacêuticas periódicas, principalmente em condições crônicas, detém uma significativa contribuição no monitoramento do perfil de adesão medicamentosa, desde os primeiros meses de vida, tal como ocorre nos casos de hemoglobinopatia do tipo S identificados na triagem neonatal, popularmente conhecido como “teste do pezinho”. Dito isso, o trabalho em questão visa mensurar o impacto do serviço de assistência farmacêutica na farmacoterapia de pacientes em tratamento de hemoglobinopatias, coagulopatias e outras morbidades que interferem na hematopoiese e hemostasia. Materiais e métodos: Trata-se de um relato de experiência da rotina do serviço em um consultório farmacêutico no ambulatório de hematologia do centro de hemoterapia e hematologia do estado do Pará no período de janeiro a junho de 2023, embasado na literatura atual e vivência em residência multiprofissional. Resultados e discussão: No total foram atendidos 400 pacientes, sendo destes 56% (224) do sexo feminino e 44% (176) do masculino, em uma faixa etária entre 0 a 86 anos, sendo alguns pacientes de repetição em consultas farmacêutica. Além disso, do número total 35,75% realizam terapia para coagulopatias, 46,25% para hemoglobinopatias e 18% para outros distúrbios hematopoiéticos ou condições autoimunes, sendo 172 pacientes advindos da região metropolitana de Belém e 228 do interior do estado. Pode-se perceber com o decorrer dos atendimentos que diversos pacientes mesmo aqueles com diagnóstico há muitos anos não possuem total conhecimento acerca do processo de cuidados que envolvem sua patologia e ao final dos atendimentos terminavam não só por estabelecer um vínculo de confiança com o farmacêutico como também se apropriaram do conhecimento necessário para se tornarem agentes do seu próprio cuidado, partindo com a capacidade de realizarem questionamentos a equipe multiprofissional de forma mais concisa e confiante. Tendo como exemplo os pacientes coagulopatas, que realizam infusão de pró-coagulantes periodicamente para evitar sangramentos espontâneos, os quais após os atendimentos terminaram fomentando o compromisso com sua terapêutica e melhorando a adesão ao tratamento. Dessa forma, se pode perceber que avaliação do paciente por um farmacêutico clínico auxilia não somente na conduta dos prescritores, propiciando uma maior segurança, como também serve como barreira para circunstâncias geradoras de problemas relacionados a medicamentos, possibilitando atuação preventiva à ocorrência de resultados desfavoráveis da terapia medicamentosa, e contribuindo para a segurança do paciente e a racionalidade da farmacoterapia. Conclusão: Assim, a incorporação de consultas farmacêuticas servem como estratégias de grande valia não somente para pacientes em condições crônicas, que necessitam desse atendimento mais próximo, mas também para dar mais confiabilidade do desenvolvimento assistencial para toda equipe multidisciplinar visando proporcionar o melhor atendimento, a promoção a saúde e a qualidade de vida desses usuários.

Z Yuan, A King, B Inusa

Man FANG, Yan ZHOU, Jing WANG et al.

Objective To explore the effect of autologous platelet-rich plasma (PRP) in the treatment of refractory wounds after radical breast cancer resection. Methods The clinical data of 8 patients with refractory wound healing after radical resection of breast cancer, who received autologous PRP treatment at the South District Wound Treatment Center from November 2020 to May 2021, were collected, including age, sex, wound location, wound area/depth, TNM staging, surgical method, postoperative pathology, chemotherapy conditions, PRP treatment, etc. Wound healing time and scar hyperplasia (vascular distribution, color, softness, thickness, itching, pain, etc.) were observed after PRP treatment. The efficacy of autologous PRP was analyzed and evaluated retrospectively based on the above data. Results The wounds of 8 patients healed smoothly, and the granulation tissue of the wound was relatively matured and completely covered by the crawling epidermis. The wound healing time was 14 to 26 (20.6±3.6) days, and all patients had not developed scar hyperplasia. Conclusion The efficacy of autologous PRP treatment of refractory wounds after radical breast cancer resection is fast and effective, and can eliminate scar hyperplasia, which is worthy of clinical promotion.

Felicitas Thol, Michael Heuser

Patients with relapsed or refractory (r/r) acute myeloid leukemia (AML) have a poor prognosis and treatment remains challenging. For the majority of r/r patients, allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment approach. Salvage therapy is given in order to reduce the leukemia load prior to transplantation. Patients achieving complete remission prior to allogeneic HSCT have a more favorable outcome. Intensive salvage regimens commonly consist of an anthracycline and high-dose cytarabine backbone. Donor lymphocyte infusions have shown efficacy in patients relapsing after allogeneic HSCT. For patients who cannot be intensively treated (eg, elderly AML patients), outcome is generally very poor and combinations with novel agents are currently under investigation. Mutational analysis should be repeated at the time of relapse to identify aberrations that can be targeted with new agents. For r/r AML patients with mutated fms-related tyrosine kinase 3 (FLT3), gilteritinib has shown superior results to intensive salvage regimens. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved gilteritinib for FLT3 mutated r/r AML patients. Ivosidenib and enasidenib, inhibitors for mutated isocitrate dehydrogenase (IDH) 1 and 2, respectively, have received approval for IDH1/IDH2 mutated r/r AML by the FDA (not EMA). APR-246 restores the function of mutated TP53 and early study results are promising. Other agents targeting CD47, menin, neural-precursor-cell-expressed developmentally down-regulated 8, as well as bispecific antibodies or chimeric antigen receptor T cells are under investigation. Further trials are needed to understand how to best combine novel agents with each other or with chemotherapy.

Mary-Elizabeth M. Percival, Megan Othus, Sarah Mirahsani et al.

Few patients with cancer, including those with acute myeloid leukemia and high-grade myeloid neoplasms, participate in clinical trials. Broadening standard eligibility criteria may increase clinical trial participation. In this retrospective single-center analysis, we identified 442 consecutive newly diagnosed patients from 2014 to 2016. Patients were considered eligible if they had performance status 0-2, normal renal and hepatic function, no recent solid tumor, left ventricular ejection fraction (EF) ≥ 50%, and no history of congestive heart failure (CHF) or myocardial infarction (MI); ineligible patients failed to meet one or more of these criteria. We included 372 patients who received chemotherapy. Ineligible patients represented 40% of the population and had a 1-79-fold greater risk of death (95% CI 1.37, 2.33) than eligible patients. Very few patients had cardiac co-morbidities, including 2% with low EF, 4% with prior CHF, and 5% with prior MI. In multivariable analysis, ineligibility was associated with decreased survival [HR 1-44 (95% CI 1-07, 1-93)]. Allogeneic transplantation, performed in 150 patients (40%), was associated with improved survival [HR 0-66, 95% CI (0-48, 0-91)]. Therefore, standard eligibility characteristics identify a patient population with improved survival. Further treatment options are needed for patients considered ineligible for clinical trials.

Richard T. Silver, Spencer Krichevsky

Distinguishing essential thrombocythemia JAK2V617F from polycythemia vera is difficult because of shared mutation and phenotypic characteristics. The World Health Organization suggested hemoglobin and hematocrit values to diagnose polycythemia vera (PV), but their sensitivity and specificity were not tested. Moreover, red cell values do not accurately predict red cell mass, which we use to discriminate essential thrombocythemia JAK2V617F from PV. Eighty-three PV and 39 essential thrombocythemia JAK2V617F patients were diagnosed based on JAK2V617F positivity, chromium-51 red cell mass, and marrow biopsy findings. Red cell values used to construct a receiver operating characteristic analysis determined optimal thresholds for distinguishing essential thrombocythemia JAK2V617F from PV. Red cell value frequencies were plotted determining if overlap existed. Chromium-51 red cell mass separated PV from essential thrombocythemia JAK2V617F, but red cell values overlapped in 25.0-54.7%. Our data indicate that a significant proportion of PV patients may be underdiagnosed by using only red cell values. A bone marrow biopsy was performed in 199 of 410 (48.5%) and a serum erythropoietin value was measured in 225 of 410 (54.9%) of potential PV patients at our institution. Without isotope studies, marrow biopsies and serum erythropoietin values should improve diagnostic accuracy and become mandatory, but clinical data suggest these tests have not been routinely performed. Therefore, the clinical hematologist must be aware of imperfect accuracy when using only red cell values for distinguishing essential thrombocythemia JAK2V617F from PV.

Hanny Al-Samkari, Athena Kritharis, David J. Kuter

Boris E. Shmukler, Nicholas C. Huston, Jonathan N. Thon et al.

Shahla Ansari, Miri Aliabad Ghasem, Saeed Yousefian

Shoumariyeh K, von Bubnoff N

Khalid Shoumariyeh, Nikolas von BubnoffDepartment of Hematology, Oncology and Stem Cell Transplantation, University Hospital Freiburg, Freiburg, Germany Abstract: Treatment of chronic myeloid leukemia (CML) has undergone dramatic changes in the last decade. Dissecting the molecular pathways that lead to the development of this disease resulted in the development of targeted therapy against the molecular driver of CML, namely the aberrantly activated tyrosine kinase BCR-ABL1. By introducing the tyrosine kinase inhibitor imatinib to the treatment repertoire, the natural course of the disease has been dramatically altered and overall survival of patients with CML prolonged substantially. Nevertheless, a significant number of patients are primarily resistant, acquire resistance during the course of their disease, or do not tolerate the intake of imatinib due to adverse effects. Second-generation tyrosine kinase inhibitors were developed in an attempt to overcome these problems. Dasatinib is a potent oral kinase inhibitor that was originally developed as an Src-kinase inhibitor but exhibited promising potency against BCR-ABL1 as well. Phase I and II trials demonstrated efficacy in patients failing imatinib, and thus dasatanib was approved in 2006 for the treatment of imatinib-resistant or -intolerant patients with chronic-phase CML harboring the BCR-ABL1 fusion protein. It has since shown promising efficacy and good overall tolerability in subsequent clinical trials, including the Phase III first-line DASISION trial that led to the extension of its approval for first-line treatment of chronic-phase CML. The following review summarizes the available data on the long-term efficacy and safety of dasatinib as a second-line therapy in chronic-phase CML. Keywords: BCR-ABL1, TKI, CML-CP, second-line treatment

Diamantina Vasilatou, Sotirios Papageorgiou, Efthymia Bazani et al.

Central nervous system (CNS) involvement in acute myeloid leukemia (AML) is a rare complication of the disease and is associated with poor prognosis. Sometimes the clinical presentation can be unspecific and the diagnosis can be very challenging. Here we report a case of CNS infiltration in a patient suffering from AML who presented with normal complete blood count and altered mental status.

Pinelopi Argyriou, Panagiota Economopoulou, Sotirios Papageorgiou

Despite the fact that the majority of lymphomas initially respond to treatment, many patients relapse and die from disease that is refractory to current regimens. The need for new treatment strategies in lymphomas has led to the investigation and evaluation of novel agents that target cellular pathways. The mammalian target of rapamycin (mTOR) is a representative pathway that may be implicated in lymphomagenesis. Rapamycin and especially its derivatives (temsirolimus, everolimus, and deforolimus) represent the first described mTOR inhibitors. These agents have shown promising results in the treatment of lymphoid malignancies. On the other hand, new ATP-competitive mTOR inhibitors that provoke a broader inhibition of mTOR activity are in early stages of clinical development. The purpose of this paper is to summarize the existing knowledge about mTOR inhibitors and their use in the treatment of B-cell lymphomas. Relevant issues regarding mTOR biology in general as well as in B-cell lymphoid neoplasms are also discussed in short.

Lars Fischer, Nicola Gökbuget, Stefan Schwartz et al.

Background Expression of CD56 has been associated with poor prognosis in acute myeloid leukemia and aggressive lymphoma.Design and Methods We analyzed the impact of CD56 expression in a cohort of 452 newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients; clinical data were available for 306 patients. Treatment was according to the GMALL study protocols 06/99 and 07/03 stipulating stratification into standard (thymic T-ALL) and high risk (pre- and mature T-ALL) groups.Results CD56 expression was detected in 63/452 (13.9%) patients. CD56+ T-ALL were predominantly of non-thymic (pre-T 35%, mature 41%) immunophenotypic subtypes, whereas 53% of the CD56− cases were thymic T-ALL (p=0.00002). CD13, CD33, CD34 and HLA-DR were significantly more frequently expressed. A clonal T-cell receptor rearrangement was detected in 22/23 CD56+ ALL. No major clinical differences were observed at presentation. Treatment of CD56+ ALL resulted in a lower rate of complete remissions (70% vs. 88%) (p=0.001) and a higher rate of resistant disease (21% vs. 8%) (p=0.004). CD56 expression had no significant influence on overall (48% vs. 59%) and disease free survival (67% vs. 57%) at three years.Conclusions CD56 is expressed on a subset of adult T-ALL with distinct immunophenotypical features and higher resistance to therapy. Most CD56+ ALL were treated in the high-risk arm of the GMALL study protocols owing to their non-thymic phenotype. Thus after risk adapted treatment a prognostic impact of CD56 expression was not detectable.

Marije Booman, Jenny Douwes, Marie-Cecile Legdeur et al.

We describe a patient with a primary diffuse large B-cell lymphoma of the central nervous system who developed a localized testicular relapse after 8 years. Both tumours lacked HLA-DR expression, the relapse additionally lost HLA class I expression. Immunoglobulin heavy chain gene rearrangements were identical in both lymphomas with extensive and ongoing somatic hypermutations resulting in extensive idiotype modulation. We hypothesize that these immune sanctuaries initially provided a safe haven for the tumour cells. When the environment becomes more permissive for an anti-tumour response, the continuous idiotype modulation and progressive loss of HLA expression on the tumour cells facilitates further immune escape.

<abstract language="eng">The study of chimerism in the allogeneic transplantation of hematopoietic cells allows to know if the the lymphohematopoietic system of the donor has been able to implant itself in the recipient and if it does it by totally displacing the lymphohematopoietic system of the recepient or coexisting with it. Polymerase chain reaction is used to amplify the highly polymorphic DNA zones. The first results of the mollecular study of chimerism in 12 patients with different malignant and nonmalignant pathologies are shown. This study made possible to determine if the transplant was successful and to evaluate the graft ' s evolution