RESUMO
The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute for more than 2 decades, is focused on improving the outcomes of hematopoietic cell transplantation (HCT) and other cellular therapies. It answered critical questions about conditioning intensity, donor choice, graft-versus-host disease prevention and treatment, and relapse mitigation strategies in a manner made possible by an extensive network of centers that have enrolled more than 16,000 patients to more than 55 trials. Although the BMT CTN has engaged patients in a variety of ways since its establishment, there is a growing realization that increasing that engagement and including caregivers offers many additional benefits to patients and investigators alike. Bringing the voice of patients and caregivers to clinical trial design is likely to enhance trial participation and reduce barriers to recruitment/retention. Unless clinical trials are designed with unique considerations of patients who have socioeconomic and access challenges, these populations will remain under-represented in HCT trials with limited generalizability of results. The next main frontier in our field is patient and caregiver access to high-quality HCT facilities coupled with the opportunity to participate in relevant, meaningful clinical research. In 2021, the BMT CTN Executive Committee convened a Patient and Caregiver Advocacy Task Force with a diverse membership representing a variety of stakeholders. The charge to the Task Force was to provide achievable recommendations for incorporating patient input at all steps of clinical trial development from initial concept to dissemination of results. Four focus areas were identified: (1) patient and caregiver input in research portfolio; (2) patient engagement in informed consent, protocol development and trial conduct; (3) communication to patients about trial progress, primary outcomes and secondary analyses; and (4) increased awareness among patients who may be considering BMT or cell therapy about BMT CTN trials. Three specific initiatives were considered as high priority by the Task Force: Fostering patient and caregiver engagement in development of the research portfolio and protocols; Developing communication plans for ongoing studies; and Simplifying the process for informed consent to make it more patient friendly. The BMT CTN has established a patient and caregiver advocacy committee that is tasked with developing concrete steps to incorporate recommendations of the BMT CTN Task Force in its current and future work. The BMT CTN recognizes patient and caregivers are valuable partners whose voice will enhance the conduct of impactful trials in BMT and cell therapy.
Assuntos
Cuidadores , Transplante de Células-Tronco Hematopoéticas , Humanos , Medula Óssea , Transplante de Medula Óssea/métodos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Consentimento Livre e Esclarecido , Ensaios Clínicos como AssuntoRESUMO
BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P<0.001); median progression-free survival was 46.2 months and 67.5 months. The percentage of patients with a partial response or better was 95.0% in the RVD-alone group and 97.5% in the transplantation group (P = 0.55); 42.0% and 46.8%, respectively, had a complete response or better (P = 0.99). Treatment-related adverse events of grade 3 or higher occurred in 78.2% and 94.2%, respectively; 5-year survival was 79.2% and 80.7% (hazard ratio for death, 1.10; 95% CI, 0.73 to 1.65). CONCLUSIONS: Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed. (Funded by the National Heart, Lung, and Blood Institute and others; DETERMINATION ClinicalTrials.gov number, NCT01208662.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Quimioterapia de Manutenção , Mieloma Múltiplo , Transplante de Células-Tronco , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bortezomib/administração & dosagem , Bortezomib/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Progressão da Doença , Intervalo Livre de Doença , Humanos , Lenalidomida/administração & dosagem , Lenalidomida/efeitos adversos , Quimioterapia de Manutenção/métodos , Melfalan/administração & dosagem , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/cirurgia , Transplante AutólogoRESUMO
In 2021 the BMT CTN held the 4th State of the Science Symposium where the deliberations of 11 committees concerning major topics pertinent to a particular disease, modality, or complication of transplant, as well as two committees to consider clinical trial design and inclusion, diversity, and access as cross-cutting themes were reviewed. This article summarizes the individual committee reports and their recommendations on the highest priority questions in hematopoietic stem cell transplant and cell therapy to address in multicenter trials.
Assuntos
Transplante de Medula Óssea , Transplantes , Ensaios Clínicos como Assunto , Transplante de Células-Tronco Hematopoéticas , HumanosRESUMO
Mutations in SET-binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.
Assuntos
Medula Óssea/metabolismo , Proteínas de Transporte/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Leucemia Mielomonocítica Juvenil/patologia , Sistema de Sinalização das MAP Quinases , Proteínas de Membrana/metabolismo , Proteínas Nucleares/metabolismo , Piridonas/farmacologia , Pirimidinonas/farmacologia , Animais , Medula Óssea/efeitos dos fármacos , Proteínas de Transporte/genética , Células Cultivadas , Modelos Animais de Doenças , GTP Fosfo-Hidrolases/genética , Humanos , Leucemia Mielomonocítica Juvenil/genética , Leucemia Mielomonocítica Juvenil/metabolismo , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutação , Proteínas Nucleares/genética , Inibidores de Proteínas Quinases/farmacologia , Transdução de SinaisRESUMO
Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. The interaction between these distinct classes of mutations occurs at the level of myeloid lineage enhancers where mutant CEBPA prevents activation of a subset of differentiation associated enhancers. To confirm this enhancer-dependent mechanism, we demonstrate that CEBPA mutations must occur as the initial event in AML initiation. This improved mechanistic understanding will facilitate therapeutic development targeting the intersection of oncogene cooperativity.
Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/genética , Leucemia Mieloide Aguda/genética , Receptores de Fator Estimulador de Colônias/genética , Animais , Diferenciação Celular/genética , Linhagem da Célula/genética , Humanos , Células K562 , Mutação com Perda de Função , Camundongos , MutaçãoRESUMO
: Mutations in the colony-stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as acute myeloid leukemia. Here, we studied the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions were potently oncogenic and activated the receptor independently of its ligand GCSF. These mutations activated the JAK-STAT signaling pathway and conferred sensitivity to JAK inhibitors. Mass spectrometry revealed that the N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans. N610 was also the primary site of sialylation of the receptor. Membrane-proximal N-linked glycosylation was critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevented membrane-proximal N-glycosylation of CSF3R, which then drove ligand-independent cellular expansion. Kinase inhibitors blocked growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation. SIGNIFICANCE: This study reveals the critical importance of membrane-proximal N-linked glycosylation of CSF3R for the maintenance of ligand dependency in leukemia.
Assuntos
Carcinogênese , Mutação em Linhagem Germinativa , Leucemia/genética , Mutação , Receptores de Fator Estimulador de Colônias/genética , Motivos de Aminoácidos , Animais , Sítios de Ligação , Membrana Celular/metabolismo , Progressão da Doença , Feminino , Regulação Leucêmica da Expressão Gênica , Glicosilação , Células HEK293 , Humanos , Janus Quinases/metabolismo , Leucemia/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Neutrofílica Crônica/genética , Ligantes , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Proteômica , Receptores de Fator Estimulador de Colônias/metabolismo , Fatores de Transcrição STAT/metabolismo , Análise de Sequência de DNA , Transdução de Sinais , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por MatrizRESUMO
Because of the complexity of hematopoietic cell transplant trial treatments, informed consent forms are often long and difficult to read. We evaluated a 2-column easy-to-read informed consent (ETRIC) form that incorporates elements of health literacy and readability in participants and centers participating in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) clinical trials. In a randomized study 198 adult patients from 25 centers potentially eligible to participate in 4 BMT CTN interventional trials were randomized to the ETRIC form or a standard consent form for that trial. Both forms were written at no more than an eighth-grade reading level. The primary endpoint was objective comprehension score on the Quality of Informed Consent, part A (QuIC-A) instrument. In a parallel evaluation study, 2 moderators conducted semistructured interviews of 49 investigators, research staff, and institutional review board (IRB) members at 9 BMT CTN trial sites. The mean QuIC-A scores were comparable in 152 patients (77%) assessable for the primary endpoint (ETRIC form, 80.5; standard form, 81.8; P = .37). In regression analysis there was no significant association between the consent type and QuIC-A score. In the evaluation study dominant themes identified on qualitative analyses included general comfort and willingness to use the ETRIC template and that its formatting and layout enhancements would offer additional value to research participants, investigators, and IRBs. IRB language preferences and requirements, length, and prior experience with alternative consent formats were perceived as barriers. Among patients considering participation in BMT CTN clinical trials, the formatting enhancements of the ETRIC form did not alter comprehension of the trial. Despite local challenges to implementation, trial sites generally viewed the ETRIC form favorably and expressed willingness to use it over standard consent form.
Assuntos
Compreensão , Termos de Consentimento , Consentimento Livre e Esclarecido , Competência Mental , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Human diseases are often caused by loss of somatic cells that are incapable of re-entering the cell cycle for regenerative repair. Here, we report a combination of cell-cycle regulators that induce stable cytokinesis in adult post-mitotic cells. We screened cell-cycle regulators expressed in proliferating fetal cardiomyocytes and found that overexpression of cyclin-dependent kinase 1 (CDK1), CDK4, cyclin B1, and cyclin D1 efficiently induced cell division in post-mitotic mouse, rat, and human cardiomyocytes. Overexpression of the cell-cycle regulators was self-limiting through proteasome-mediated degradation of the protein products. In vivo lineage tracing revealed that 15%-20% of adult cardiomyocytes expressing the four factors underwent stable cell division, with significant improvement in cardiac function after acute or subacute myocardial infarction. Chemical inhibition of Tgf-ß and Wee1 made CDK1 and cyclin B dispensable. These findings reveal a discrete combination of genes that can efficiently unlock the proliferative potential in cells that have terminally exited the cell cycle.
Assuntos
Coração/fisiologia , Miócitos Cardíacos/metabolismo , Animais , Proteína Quinase CDC2/genética , Proteína Quinase CDC2/metabolismo , Proteínas de Ciclo Celular/antagonistas & inibidores , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Ciclina B1/genética , Ciclina B1/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Citocinese , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/veterinária , Miócitos Cardíacos/citologia , Cadeias Pesadas de Miosina/genética , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/metabolismo , Proteínas Tirosina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/metabolismo , Ratos , Regeneração , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismoRESUMO
Hematopoietic stem cells can be procured from unrelated donors via either the bone marrow (BM) aspiration or peripheral blood stem cell (PBSC) collection methods. There is no evidence from prospective randomized trials in the unrelated donor setting about the relative health-related quality-of-life (HRQoL) benefits/costs to donors. The goals of this prospective longitudinal investigation were to describe and compare the donation-related HRQoL experiences of 332 BM and PBSC donors. Donors were interviewed before donation, 48 hours after donation, weekly until fully recovered, and at 6 and 12 months after donation. Before donation, BM donors had lower confusion, fewer concerns, and were more prepared for donation. Shortly after donation, BM donors reported more physical side effects. BM donors also reported more donation-related impact on their social activities. However, BM donors reported somewhat better psychological status and were more likely to indicate that the donation made their lives more meaningful. There were virtually no longer term differences in the experiences of the 2 donor groups, including no recovery time difference beginning 3 weeks after donation. Although BM donors may experience the process as more physically stressful and more psychologically beneficial in the short term, the longer term HRQoL consequences of BM and PBSC donors are similar.
Assuntos
Transplante de Medula Óssea , Doadores Vivos/psicologia , Transplante de Células-Tronco de Sangue Periférico , Qualidade de Vida/psicologia , Doadores não Relacionados/psicologia , Adulto , Medula Óssea/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Classe Social , Coleta de Tecidos e ÓrgãosRESUMO
Informed consent is essential to ethical research and is requisite to participation in clinical research. Yet most hematopoietic cell transplantation (HCT) informed consent forms (ICFs) are written at reading levels that are above the ability of the average person in the United States (U.S.). The recent development of ICF templates by the National Cancer Institute, National Institutes of Health, and the National Heart Blood and Lung Institute have not resulted in increased patient comprehension of information. Barriers to creating Easy-to-Read ICFs that meet U.S. federal requirements and pass institutional review board (IRB) review are the result of multiple interconnected factors. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) formed an ad hoc review team to address concerns regarding the overall readability and length of ICFs used for BMT CTN trials. This paper summarizes recommendations of the review team for the development and formatting of Easy-to-Read ICFs for HCT multicenter clinical trials, the most novel of which is the use of a 2-column format. These recommendations intend to guide the ICF writing process, simplify local IRB review of the ICF, enhance patient comprehension, and improve patient satisfaction. The BMT CTN plans to evaluate the impact of the Easy-to-Read format compared with the traditional format on the informed consent process.