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Blood Rev ; : 101072, 2023 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-36934059


Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients.

Mayo Clin Proc ; 97(11): 2170-2173, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36333023

Livros , Médicos , Humanos
BMC Cancer ; 22(1): 1013, 2022 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-36153475


BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with on August 19, 2019 (Registration No. NCT04061421).

Doenças Mieloproliferativas-Mielodisplásicas , Qualidade de Vida , Acetonitrilas , Citidina Desaminase , DNA/uso terapêutico , Decitabina/uso terapêutico , Humanos , Metiltransferases , Estudos Prospectivos , Pirazóis , Pirimidinas , Pirróis , Síndrome
Mayo Clin Proc ; 97(7): 1409-1410, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35787874

COVID-19 , Etnicidade , Humanos
Blood Adv ; 6(9): 2854-2866, 2022 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-35143613


DNA methyltransferase inhibitors (DNMTIs) for patients with higher risk myelodysplastic syndromes (HR-MDS) have low complete remission rates and are not curative. Early DNMTI combination clinical trials in HR-MDS are often termed "promising," but many randomized trials subsequently failed to show benefit. Clearer understanding of when a combination is likely to improve upon DNMTI monotherapy would inform randomized studies. We reviewed MDS azacitidine or decitabine monotherapy studies. We collected baseline demographics including International Prognostic Scoring System (IPSS) risk, DNMTI, disease characteristics; and response variables including survival and marrow and hematologic responses. Aggregate estimates across studies were calculated using meta-analyses techniques. Using a binomial design, we estimated the necessary operating characteristics to design a phase 2 study showing improved efficacy of a combination over monotherapy. Among 1908 patients, the overall response rate (ORR) was 24% (n = 464; 95% confidence interval [CI], 0.22-0.26): 267 complete response (CR, 14%), 68 partial response (4%), and 129 marrow complete remission (7%). Among 1604 patients for whom a hematologic response was reported, 476 (30%; 95% CI, 0.27-0.32) reported hematologic improvement (HI). More patients treated with azacitidine achieved HI (38%; 95% CI, 0.35-0.41) compared with decitabine (15%; 95% CI, 0.13-0.19), whereas the marrow ORR rate was higher with decitabine (29%; 95% CI, 0.26-0.33) compared with azacitidine (21%; 95% CI, 0.19-0.23). CR rates were similar between DNMTIs: 13% with azacitidine and 16% with decitabine. Variables that influence MDS response include the specific DNMTI backbone and the distribution of IPSS risk of patients enrolled on a trial. Considering these factors can help identify which early combination approaches are worth assessing in larger randomized trials.

Síndromes Mielodisplásicas , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , DNA/uso terapêutico , Decitabina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Metiltransferases/uso terapêutico , Motivação , Síndromes Mielodisplásicas/tratamento farmacológico , Resultado do Tratamento
Leuk Lymphoma ; 63(1): 199-204, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34448437


Myelodysplastic syndrome/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is characterized by anemia, ring sideroblast erythroid precursors, and persistent thrombocytosis. Case reports suggest lenalidomide may be effective in treating MDS/MPN-RS-T. We evaluated a large series of patients with MDS/MPN-RS-T to compare hematological improvement (HI) response rates among different drug therapies including lenalidomide. We identified 167 patients with MDS/MPN-RS-T. Among the patients tested, 84% had SF3B1 mutations and 43% had JAK2 V617F mutations. The median OS for the cohort was 81 months. Overall, 76 patients (46%) received erythropoiesis-stimulating agents (ESAs), 47 patients (28%) received lenalidomide, and 45 patients (27%) received hypomethylating agents (HMAs). The HI rates were 58%, 53%, and 24%, respectively. The median duration of treatment was 11 months for lenalidomide compared to 6 months for HMAs. Rates of HI improvement were higher in patients with MDS/MPN-RS-T treated with ESAs or lenalidomide, in comparison to those treated with HMAs.

Anemia Sideroblástica , Doenças Mieloproliferativas-Mielodisplásicas , Neoplasias , Trombocitose , Anemia Sideroblástica/diagnóstico , Anemia Sideroblástica/tratamento farmacológico , Anemia Sideroblástica/etiologia , Humanos , Mutação , Doenças Mieloproliferativas-Mielodisplásicas/complicações , Doenças Mieloproliferativas-Mielodisplásicas/diagnóstico , Doenças Mieloproliferativas-Mielodisplásicas/tratamento farmacológico , Trombocitose/tratamento farmacológico , Trombocitose/genética , Resultado do Tratamento
Blood Adv ; 6(7): 2230-2235, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-34847227


Clonal hematopoiesis (CH) is associated with adverse outcomes in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma undergoing autologous stem cell transplantation. Still, its implications for patients with indolent NHL have not been well studied. We report the prevalence of CH in patients with Waldenström macroglobulinemia (WM) and its association with clinical outcomes. To unambiguously differentiate CH mutations from those in the WM clone, CH was defined by the presence of somatic mutations in DNMT3A, TET2, or ASXL1 (DTA) and was detected in 14% of 587 patients with IgM monoclonal gammopathy of undetermined significance (MGUS), smoldering WM (SWM) or WM. The presence and size of DTA clones were associated with older age. Patients with CH had an increased risk of progression from MGUS or SWM to WM, but not worse overall survival in this cohort. These findings further illuminate the clinical effects of CH in patients with indolent NHL such as WM.

Transplante de Células-Tronco Hematopoéticas , Macroglobulinemia de Waldenstrom , Hematopoiese Clonal , Humanos , Imunoglobulina M , Transplante Autólogo , Macroglobulinemia de Waldenstrom/genética , Macroglobulinemia de Waldenstrom/patologia
Best Pract Res Clin Haematol ; 34(4): 101327, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34865699


Clonal hematopoiesis (CH) - a biological state in which one or a small number of hematopoietic stem or progenitor cells contribute disproportionately to blood cell production, usually as a result of somatic gene mutations in the stem cells - is often considered to be a precursor to myeloid neoplasia, especially myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, the majority of people with CH never develop an overt myeloid neoplasm, and CH can be a precursor to lymphoid cancers as well as myeloid neoplasms. In addition, CH increases all-cause mortality and augments the risk of several non-neoplastic medical conditions, including atherosclerotic cardiovascular disease. CH can arise during aging, or in the context of an inherited marrow failure syndrome, aplastic anemia, or hematopoietic cell transplantation. Risk factors for progression of CH to myeloid neoplasia include larger clone size; the presence of a TP53, IDH1/2, or splicing mutation; multiple mutations; and associated cytopenias or abnormal red blood cell indices. The receipt of genotoxic chemotherapy or radiation, which can promote clonal expansion of mutant clones at the expense of healthy progenitor cells, may result in therapy-related MDS/AML.

Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Transtornos Mieloproliferativos , Hematopoiese Clonal , Hematopoese , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapia
Cancer ; 127(23): 4339-4347, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34375439


LAY SUMMARY: People who have advanced myelodysplastic syndromes (MDS) may live longer if they get a bone marrow transplant (BMT) instead of other therapies. However, only 15% of people with MDS actually get BMT. Experts say community physicians and transplant physicians should team up with insurance companies and patient advocacy groups to 1) spread this news about lifesaving advances in BMT, 2) ensure that everyone can afford health care, 3) provide emotional support for patients and families, 4) help patients and families get transportation and housing if they need to travel for transplant, and 5) improve care for people of under-represented racial and ethnic backgrounds.

Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Medula Óssea , Humanos , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante , Transplante Homólogo
J Clin Oncol ; 39(33): 3737-3746, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34406850


PURPOSE: Patients with myelodysplastic syndromes (MDS) have a survival that can range from months to decades. Prognostic systems that incorporate advanced analytics of clinical, pathologic, and molecular data have the potential to more accurately and dynamically predict survival in patients receiving various therapies. METHODS: A total of 1,471 MDS patients with comprehensively annotated clinical and molecular data were included in a training cohort and analyzed using machine learning techniques. A random survival algorithm was used to build a prognostic model, which was then validated in external cohorts. The accuracy of the proposed model, compared with other established models, was assessed using a concordance (c)index. RESULTS: The median age for the training cohort was 71 years. Commonly mutated genes included SF3B1, TET2, and ASXL1. The algorithm identified chromosomal karyotype, platelet, hemoglobin levels, bone marrow blast percentage, age, other clinical variables, seven discrete gene mutations, and mutation number as having prognostic impact on overall and leukemia-free survivals. The model was validated in an independent external cohort of 465 patients, a cohort of patients with MDS treated in a prospective clinical trial, a cohort of patients with paired samples at different time points during the disease course, and a cohort of patients who underwent hematopoietic stem-cell transplantation. CONCLUSION: A personalized prediction model on the basis of clinical and genomic data outperformed established prognostic models in MDS. The new model was dynamic, predicting survival and leukemia transformation probabilities at different time points that are unique for a given patient, and can upstage and downstage patients into more appropriate risk categories.

Algoritmos , Biomarcadores Tumorais/genética , Transformação Celular Neoplásica/patologia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Modelos Estatísticos , Mutação , Síndromes Mielodisplásicas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Transformação Celular Neoplásica/genética , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Feminino , Seguimentos , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto Jovem
Mayo Clin Proc ; 96(7): 2012-2013, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34218874


Stamp Vignettes focus on biographical details and accomplishments related to science and medicine, and not individual views and prejudices except when they had a major impact on the subject's life. The authors of Stamp Vignettes do not intend to imply any endorsement of such views when discussing a Stamp Vignette on Medical Science.

Fixação Interna de Fraturas , Fixadores Internos/história , Ortopedia/história , Bélgica , Fixação Interna de Fraturas/história , Fixação Interna de Fraturas/instrumentação , Fixação Interna de Fraturas/métodos , História do Século XIX , História do Século XX , Humanos , Procedimentos Ortopédicos