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1.
Transplant Cell Ther ; 2022 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-35872304

RESUMO

Young adults (YA), age 18 to 39 years, are at a stage of life that may make them more vulnerable than older adults to impairments in health-related quality of life (HRQOL) during and after hematopoietic cell transplantation (HCT). Health self-efficacy (HSE), the belief that one can implement strategies to produce a desired health outcome, has been associated with health outcomes in oncology research. Little is known about HRQOL or HSE in YA HCT survivors compared with older HCT survivors. Given the age-specific psychosocial challenges facing YA HCT recipients and research on non-transplant YA cancer survivors, we hypothesized that YA survivors would have worse post-HCT HRQOL compared with older adults, and that among YA HCT survivors, higher levels of HSE would be associated with higher levels of HRQOL and lower levels of cancer-related distress. This was a cross-sectional secondary analysis of 2 combined baseline datasets from multicenter studies of HCT survivors approached for participation in clinical trials of survivorship interventions. Participants from 20 transplantation centers in the United States were at 1 to 10 years post-HCT and age ≥18 years at the time of study enrollment, had no evidence of disease relapse/progression or subsequent malignancies, and could read English adequately to consent for and complete assessments. Medical record and patient-reported data were obtained for demographics and HCT-related clinical factors and complications (eg, total body irradiation, chronic graft-versus-host disease [cGVHD]). Participants completed surveys on HRQOL, including the Short-Form [SF]-12, HSE, and Cancer and Treatment Distress (CTXD), which includes 6 subscales and reports an overall mean score. On the SF-12, both the Mental Component Score (MCS) and Physical Component Score (PCS) were calculated. Two cohorts were compared: YAs (age 18 to 39 years at transplantation) and older adults (age ≥40 years at transplantation). Multiple linear regression analyses identified factors associated with HSE, PCS, MCS, and CTXD in YAs. In this analysis of 979 survivors, compared with the older adults, the YA participants had lower median mental health scores (SF-12 MCS: 48.40 versus 50.23; P = .04) and higher cancer-related distress (CTXD: .96 versus .85; P = .04), but better physical health (SF-12 PCS: 48.99 versus 47.18; P = .049). Greater overall cancer-related distress was driven by higher levels of uncertainty, financial concern, and medical demand subscales for YAs compared with older adults. Young adults also had lower HSE (2.93 versus 3.08; P = .0004). In a multivariate model, HSE was strongly associated with age group (P = .0005) after adjusting for multiple other transplantation-related factors. Among YAs, HSE was associated with the SF-12 MCS and PCS and the CTXD, and HSE remained significant after adjusting for other transplantation-related factors. Overall, the YA HCT survivors had lower mental health, increased cancer-related distress, and lower levels of HSE compared with the older adults. Although the direction of these effects cannot be determined with these data, the strong association between HSE and HRQOL among YAs suggests that targeting interventions to improve HSE may have broad impact on health outcomes.

2.
Blood Cancer J ; 12(2): 27, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145071

RESUMO

Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses are associated with better progression free survival (PFS) and overall survival (OS). To test the hypothesis that Mass-Fix, a mass spectrometry-based means to detect monoclonal proteins, is superior to existing methodologies to predict for survival outcomes, samples from the STAMINA trial (NCT01109004), a trial comparing three transplant approaches, were employed. Samples from 575 patients from as many as three time points (post-induction [post-I; pre-maintenance [pre-M]; 1 year post enrollment [1YR]) were tested when available. Four response parameters were assessed: Mass-Fix, serum immunofixation, complete response, and measurable residual disease (MRD) by next generation flow cytometry. Of the four response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses. Although MRD drove Mass-Fix from the model for PFS at post-I and pre-M, 1YR Mass-Fix was independent of 1YR MRD. For OS, the only prognostic pre-I measure was Mass-Fix, and the only 1YR measures that were prognostic on multivariate analysis were 1YR MRD and 1YR Mass-Fix. SIFE and CR were not. Mass-Fix is a powerful means to track response.


Assuntos
Mieloma Múltiplo , Diterpenos , Citometria de Fluxo/métodos , Humanos , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/tratamento farmacológico , Neoplasia Residual/diagnóstico , Prognóstico , Intervalo Livre de Progressão , Resultado do Tratamento
3.
Nat Commun ; 13(1): 807, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145077

RESUMO

Osteolytic lesions (OL) characterize symptomatic multiple myeloma. The mechanisms of how malignant plasma cells (PC) cause OL in one region while others show no signs of bone destruction despite subtotal infiltration remain unknown. We report on a single-cell RNA sequencing (scRNA-seq) study of PC obtained prospectively from random bone marrow aspirates (BM) and paired imaging-guided biopsies of OL. We analyze 148,630 PC from 24 different locations in 10 patients and observe vast inter- and intra-patient heterogeneity based on scRNA-seq analyses. Beyond the limited evidence for spatial heterogeneity from whole-exome sequencing, we find an additional layer of complexity by integrated analysis of anchored scRNA-seq datasets from the BM and OL. PC from OL are characterized by differentially expressed genes compared to PC from BM, including upregulation of genes associated with myeloma bone disease like DKK1, HGF and TIMP-1 as well as recurrent downregulation of JUN/FOS, DUSP1 and HBB. Assessment of PC from longitudinally collected samples reveals transcriptional changes after induction therapy. Our study contributes to the understanding of destructive myeloma bone disease.


Assuntos
Heterogeneidade Genética , Genômica , Mieloma Múltiplo/genética , Mieloma Múltiplo/metabolismo , Doenças Ósseas/genética , Medula Óssea/metabolismo , Análise por Conglomerados , Regulação Neoplásica da Expressão Gênica , Humanos , Mieloma Múltiplo/patologia , Plasmócitos , Sequenciamento Completo do Exoma
5.
Sci Rep ; 11(1): 23284, 2021 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-34857802

RESUMO

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma de Células Renais/terapia , Hematopoiese Clonal , Imunoterapia/efeitos adversos , Neoplasias Renais/terapia , Leucemia Mieloide Aguda/etiologia , Neoplasias Pulmonares/terapia , Melanoma/terapia , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/etiologia , Segunda Neoplasia Primária/etiologia , Feminino , Humanos , Leucemia Mieloide Aguda/epidemiologia , Masculino , Síndromes Mielodisplásicas/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Fatores de Risco , Estados Unidos/epidemiologia
6.
EClinicalMedicine ; 40: 101093, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34746714

RESUMO

BACKGROUND: Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT. METHODS: We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011. FINDINGS: Using meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse. INTERPRETATION: These data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies. FUNDING: This project was funded by grants from the National Institutes of Health, USA.

7.
Nat Commun ; 12(1): 6233, 2021 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-34716350

RESUMO

Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10-8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).


Assuntos
Antígenos HLA/genética , Leucemia Mieloide Aguda/genética , Polimorfismo de Nucleotídeo Único , Aldeído Redutase/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , /genética
8.
Transplant Cell Ther ; 27(3): 245.e1-245.e8, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-34706824

RESUMO

Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Intervalo Livre de Doença , Humanos , Melfalan , Mieloma Múltiplo/terapia , Transplante Autólogo , Vacinação
9.
JAMA Netw Open ; 4(10): e2128373, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34673965

RESUMO

Importance: Hodgkin lymphoma is an aggressive blood cancer that is highly curable in younger patients who receive multiagent chemotherapy. Worse survival in older patients may reflect less-aggressive treatment, competing risks of death, or different disease biological factors. Objective: To examine the association between treatment intensity and cause-specific mortality among older adults with Hodgkin lymphoma. Design, Setting, and Participants: This was a population-based cohort study of patients aged 65 years or older with Medicare Part A and B fee-for-service coverage who received a diagnosis of Hodgkin lymphoma from 2000 to 2013. The association between treatment intensity and cause-specific mortality was estimated separately for early-stage and advanced-stage disease with Cox proportional hazards models. Multivariable adjustment and propensity score weighting helped control for confounding. Data are from the 1999 to 2016 Surveillance, Epidemiology, and End Results Medicare database. Data analysis was performed from April 2020 to June 2021. Exposures: First-line treatment categorized as (1) full chemotherapy regimen, (2) partial chemotherapy regimen, (3) single chemotherapy agent or radiotherapy, or (4) no treatment. Main Outcomes and Measures: The main outcome was 3-year Hodgkin lymphoma-specific and other-cause mortality. Results: Among 2686 patients (mean [SD] age, 75.7 [6.9] years; 1333 men [50%]), 1307 had early-stage disease and 1379 had advanced-stage disease. For Hodgkin lymphoma-specific mortality in patients with early-stage disease, hazard ratios (HRs) were higher for partial regimens (HR, 1.77; 95% CI, 1.22-2.57) or no treatment (HR, 1.91; 95% CI, 1.31-2.79) than for full regimens; there was no difference between single-agent chemotherapy or radiotherapy and full regimens. For other-cause mortality in patients with early-stage disease, HRs were higher for partial regimens (HR, 1.69; 95% CI, 1.18-2.44), single-agent chemotherapy or radiotherapy (HR, 1.62; 95% CI, 1.13-2.33), or no treatment (HR, 2.71; 95% CI, 1.95-3.78) than for full regimens. For Hodgkin lymphoma-specific mortality in patients with advanced-stage disease, HRs were higher for partial regimens (HR, 3.26; 95% CI, 2.44-4.35), single-agent chemotherapy or radiotherapy (HR, 2.85; 95% CI, 1.98-4.11), or no treatment (HR, 4.06; 95% CI, 3.06-5.37) than for full regimens. For other-cause mortality in patients with advanced-stage disease, HRs were higher for partial regimens (HR, 1.76; 95% CI, 1.32-2.33), single-agent chemotherapy or radiotherapy (HR, 1.65; 95% CI, 1.15-2.37), or no treatment (HR, 2.24; 95% CI, 1.71-2.94) than for full regimens. Conclusions and Relevance: This cohort study found variability in the magnitude of the association between treatment intensity and mortality by stage and cause-specific mortality, possibly reflecting competing risks of death. However, full chemotherapy regimens were associated with lower mortality and could be considered for older adults who can tolerate them.


Assuntos
Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Resultado do Tratamento , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Modelos de Riscos Proporcionais
10.
Blood Adv ; 5(18): 3528-3539, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34496026

RESUMO

Richter syndrome (RS) represents a transformation from chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), which is associated with a dismal prognosis. Patients with DLBCL-RS have poor outcomes with DLBCL-directed therapy; thus, consolidation with hematopoietic cell transplantation (HCT) has been used, with durable remissions observed. Studies reporting HCT outcomes in patients with DLBCL-RS have been small, have not evaluated the prognostic impact of cytogenetic risk factors, and were conducted prior to the era of novel targeted therapy of CLL/SLL. We performed a Center for International Blood and Transplant Research registry study evaluating outcomes after autologous HCT (auto-HCT; n = 53) and allogeneic HCT (allo-HCT; n = 118) in patients with DLBCL-RS treated in the modern era. More auto-HCT recipients were in complete response (CR) at HCT relative to allo-HCT recipients (66% vs 34%), whereas a higher proportion of allo-HCT recipients had 17p deletion (33% vs 7%) and had previously received novel agents (39% vs 10%). In the auto-HCT cohort, the 3-year relapse incidence, progression-free survival (PFS), and overall survival (OS) were 37%, 48%, and 57%, respectively. Among allo-HCT recipients, the 3-year relapse incidence, PFS, and OS were 30%, 43%, and 52%, respectively. In the allo-HCT cohort, deeper response at HCT was associated with outcomes (3-year PFS/OS, 66%/77% CR vs 43%/57% partial response vs 5%/15% resistant; P < .0001 for both), whereas cytogenetic abnormalities and prior novel therapy did not impact outcomes. In our study, HCT resulted in durable remissions in therapy-sensitive patients with DLBCL-RS treated in the era of targeted CLL/SLL therapy, including patients with high-risk features.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/terapia , Prognóstico , Transplante Autólogo
11.
Transplant Cell Ther ; 27(10): 875.e1-875.e9, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34216792

RESUMO

Poor physical functioning is associated with adverse outcomes after allogeneic hematopoietic cell transplantation (alloHCT). Analytic tools to predict mortality in alloHCT recipients include the HCT Comorbidity Index (HCT-CI) based on comorbidities and the Disease Risk Index (DRI) based on disease and disease status. We developed and replicated a risk model for overall survival (OS), early mortality (ie, death from any cause at or before day +100), initial hospital length of stay (LOS), and percentage of inpatient days within the first year post-alloHCT. In this study, we incorporated a physical therapy (PT) assessment with the HCT-CI and DRI to improve outcome predictions. The well-defined and feasible measure of functional status for assessing risk includes (1) the number of sit-to-stands performed in 30 seconds, (2) performance of 25 step-ups on the right/left side with (3) oxygen saturation recovery and (4) heart rate recovery, (5) weight-bearing ability, (6) assistance with ambulation, (7) motor and grip strength, (8) sensory and coordination impairment (eg, self-reported peripheral neuropathy, imbalance), (9) self-reported pain, and (10) limited endurance (ie, inability to complete step-ups and/or sit-to-stands). Our training cohort (TC) included 349 consecutive alloHCT recipients at Roswell Park treated between 2010 and 2016 and a subsequent replication cohort (RC; n = 163) treated between 2016 and 2019. Four of the 10 metrics-self-reported pain, limited endurance, self-reported neuropathy, and <10 sit-to-stands in 30 seconds-were identified as significant predictors and were included in the multivariable models with the HCT-CI and DRI to create a new risk index (HCT-PCDRI: HCT-physical, comorbidity, and DRI) for outcomes. Models were tested in the RC. Shorter OS was associated with self-reported pain, limited endurance, higher HCT-CI, and higher DRI. At a median follow-up of 34 months, the 3-year OS based on the HCT-PCDRI was 30% for the very-high-risk group, 54% for the high-risk group, 49% for the intermediate-risk group, and 80% for the low-risk group. The number of patients identified as very high risk increased from 55 using HCT-CI alone to 120 with the new HCT-PCDRI, whereas the number in the low-risk group decreased from 91 to 45. Early mortality and a higher percentage of inpatient days within the first year post-alloHCT (a proxy for poor quality of life and high healthcare utilization) were associated with self-reported pain, higher HCT-CI, and higher DRI. A shorter initial LOS (ie, initial low healthcare utilization) was associated with performance of >10 sit-to-stands in 30 seconds, no self-reported neuropathy, and lower HCT-CI. These PT metrics combined with the HCT-CI and DRI created the HCT-PCDRI, which resulted in more patients being categorized accurately as high risk versus low risk. The HCT-PCDRI results were replicated in an independent cohort. Pre-alloHCT PT metrics with self-reported symptoms (pain and neuropathy) were associated with survival post-alloHCT and prolonged hospital LOS. The HCT-PCDRI scoring system for risk stratification of alloHCT recipients more accurately identifies patients at potential risk of poor outcomes. The HCT-PCDRI can be tested in <15 minutes to identify patients for intervention before or during treatment to potentially improve outcomes.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Qualidade de Vida , Estado Funcional , Humanos , Aceitação pelo Paciente de Cuidados de Saúde , Prognóstico
12.
Sci Rep ; 11(1): 15004, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294836

RESUMO

To improve risk stratification and treatment decisions for patients with acute myeloid leukemia (AML) undergoing hematopoietic cell transplantation (HCT). We used SNP-array data from the DISCOVeRY-BMT study to detect chromosomal aberrations in pre-HCT peripheral blood (collected 2-4 weeks before the administration of conditioning regimen) from 1974 AML patients who received HCT between 2000 and 2011. All aberrations detected in ≥ 10 patients were tested for their association with overall survival (OS), separately by remission status, using the Kaplan-Meier estimator. Cox regression models were used for multivariable analyses. Follow-up was through January 2019. We identified 701 unique chromosomal aberrations in 285 patients (7% of 1438 in complete remission (CR) and 36% of 536 not in CR). Copy-neutral loss-of-heterozygosity (CNLOH) in chr17p in CR patients (3-year OS = 20% vs. 50%, with and without chr17p CNLOH, p = 0.0002), and chr13q in patients not in CR (3-year OS = 4% vs. 26%, with and without chr13q CNLOH, p < 0.0001) are risk factors for poor survival. Models adjusted for clinical factors showed approximately three-fold excess risk of post-HCT mortality with chr17p CNLOH in CR patients (hazard ratio, HR = 3.39, 95% confidence interval CI 1.74-6.60, p = 0.0003), or chr13q CNLOH in patients not in CR (HR = 2.68, 95% CI 1.75-4.09, p < 0.0001). The observed mortality was mostly driven by post-HCT relapse (HR = 2.47, 95% CI 1.01-6.02, p = 0.047 for chr17p CNLOH in CR patients, and HR = 2.58, 95% CI 1.63-4.08, p < 0.0001 for chr13q CNLOH in patients not in CR. Pre-transplant CNLOH in chr13q or chr17p predicts risk of poor outcomes after unrelated donor HCT in AML patients. A large prospective study is warranted to validate the results and evaluate novel strategies to improve survival in those patients.


Assuntos
Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Leucemia Mieloide Aguda/terapia , Doadores de Tecidos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Prognóstico , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
13.
Front Genet ; 12: 554948, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34220922

RESUMO

The role of common genetic variation in susceptibility to acute myeloid leukemia (AML), and myelodysplastic syndrome (MDS), a group of rare clonal hematologic disorders characterized by dysplastic hematopoiesis and high mortality, remains unclear. We performed AML and MDS genome-wide association studies (GWAS) in the DISCOVeRY-BMT cohorts (2,309 cases and 2,814 controls). Association analysis based on subsets (ASSET) was used to conduct a summary statistics SNP-based analysis of MDS and AML subtypes. For each AML and MDS case and control we used PrediXcan to estimate the component of gene expression determined by their genetic profile and correlate this imputed gene expression level with risk of developing disease in a transcriptome-wide association study (TWAS). ASSET identified an increased risk for de novo AML and MDS (OR = 1.38, 95% CI, 1.26-1.51, Pmeta = 2.8 × 10-12) in patients carrying the T allele at s12203592 in Interferon Regulatory Factor 4 (IRF4), a transcription factor which regulates myeloid and lymphoid hematopoietic differentiation. Our TWAS analyses showed increased IRF4 gene expression is associated with increased risk of de novo AML and MDS (OR = 3.90, 95% CI, 2.36-6.44, Pmeta = 1.0 × 10-7). The identification of IRF4 by both GWAS and TWAS contributes valuable insight on the role of genetic variation in AML and MDS susceptibility.

14.
Transplant Cell Ther ; 27(10): 836.e1-836.e7, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34174468

RESUMO

Graft-versus-host-disease (GVHD) is a multistep process that involves T-cell recognition and priming toward alloantigen, expansion, acquisition of effector function, and repeated tissue injury, resulting in clinical manifestations of the disease. All of these processes have considerable metabolic demands and understanding the key role of mitochondria in cellular metabolism as it relates to GVHD has increased significantly. Mitochondrial DNA (mtDNA) haplotypes have been linked to functional differences in vitro, suggesting they have functional differences at an organismal level. We previously used mtDNA typing to assess the impact of mtDNA haplotypes on outcomes of ~400 allo-HCT patients. This pilot study identified uncommon mtDNA haplotypes potentially associated with inferior outcomes. We sought to validate pilot findings of associations between donor and recipient mitochondrial haplotypes and transplant outcome. We examined a cohort of 4143 donor-recipient pairs obtained from the Center for International Blood and Marrow Transplant Research. MtDNA was extracted from whole blood or peripheral blood mononuclear cells from donors and recipients and sequenced to discern haplotype. We used multiple regression analysis to examine the independent association of mtDNA haplotype with overall survival and grade III-IV acute GVHD (aGVHD) adjusting for known risk factors for poor transplant outcome. Neither recipient nor donor mtDNA haplotype reached groupwise significance for overall survival (P =.26 and .39, respectively) or grade III-IV aGVHD (P = .68 and.57, respectively). Adjustment for genomically determined ancestry in the subset of donor-recipient pairs for which this was available did not materially change results. We conclude that our original finding was due to chance in a small sample size and that there is essentially no evidence that mtDNA haplotype or haplotype mismatch contributes to risk of serious outcomes after allogeneic transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doadores não Relacionados , Haplótipos , Humanos , Leucócitos Mononucleares , Mitocôndrias , Projetos Piloto
15.
Transplant Cell Ther ; 27(3): 271.e1-271.e8, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33781538

RESUMO

Chronic graft-versus-host disease (cGVHD) is the most common cause of nonrelapse mortality after allogeneic hematopoietic cell transplantation (alloHCT). Cutaneous cGVHD is characterized by thickening of the skin and connective tissues, causing discomfort and limited mobility. Current assessment of these skin lesions is based on physical examination of their thickening, pinchability, and movability. Optical coherence tomography (OCT) is a noninvasive, high-resolution technique using near-infrared light to interrogate tissues and image the microstructure without the use of contrast agents. We determined the applicability of OCT to human cutaneous cGVHD. Seven patients with varying degrees of cutaneous cGVHD, including 3 controls who underwent autologous HCT were prospectively examined using the cGVHD Skin (Vienna) Scale and imaged with OCT. Analysis of OCT images and clinical exams revealed that stratum corneum thickness, epidermal thickness, and depth of light transmission were correlated with cutaneous cGVHD severity in the hands, forearms, upper arms, legs, thighs, and upper back (P ≤ .03). Longitudinal OCT changes during cGVHD treatment paralleled clinical changes in the arm and upper back. OCT changes were observed in the absence of clinical changes. OCT imaging reflects the severity of cutaneous cGVHD and can be used to follow these lesions. OCT may facilitate the design of therapeutic trials in cGVHD by providing a quantitative measurement of cGVHD severity. Additional studies are needed.


Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Dermatopatias , Doença Crônica , Doença Enxerto-Hospedeiro/diagnóstico por imagem , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Tomografia de Coerência Óptica
17.
Cancer ; 127(4): 609-618, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33085090

RESUMO

BACKGROUND: The association of community factors and outcomes after hematopoietic cell transplantation (HCT) has not been comprehensively described. Using the County Health Rankings and Roadmaps (CHRR) and the Center for International Blood and Marrow Transplant Research (CIBMTR), this study evaluated the impact of community health status on allogeneic HCT outcomes. METHODS: This study included 18,544 adult allogeneic HCT recipients reported to the CIBMTR by 170 US centers in 2014-2016. Sociodemographic, environmental, and community indicators were derived from the CHRR, an aggregate community risk score was created, and scores were assigned to each patient (patient community risk score [PCS]) and transplant center (center community risk score [CCS]). Higher scores indicated less healthy communities. The impact of PCS and CCS on patient outcomes after allogeneic HCT was studied. RESULTS: The median age was 55 years (range, 18-83 years). The median PCS was -0.21 (range, -1.37 to 2.10; standard deviation [SD], 0.42), and the median CCS was -0.13 (range, -1.04 to 0.96; SD, 0.40). In multivariable analyses, a higher PCS was associated with inferior survival (hazard ratio [HR] per 1 SD increase, 1.04; 99% CI, 1.00-1.08; P = .0089). Among hematologic malignancies, a tendency toward inferior survival was observed with a higher PCS (HR, 1.04; 99% CI, 1.00-1.08; P = .0102); a higher PCS was associated with higher nonrelapse mortality (NRM; HR, 1.08; 99% CI, 1.02-1.15; P = .0004). CCS was not significantly associated with survival, relapse, or NRM. CONCLUSIONS: Patients residing in counties with a worse community health status have inferior survival as a result of an increased risk of NRM after allogeneic HCT. There was no association between the community health status of the transplant center location and allogeneic HCT outcomes.


Assuntos
Planejamento em Saúde Comunitária , Neoplasias Hematológicas/epidemiologia , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Transplante Homólogo/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Neoplasias Hematológicas/patologia , Neoplasias Hematológicas/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/terapia , Saúde Pública/estatística & dados numéricos , Fatores de Risco , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
18.
Cytometry B Clin Cytom ; 100(4): 497-508, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33017079

RESUMO

BACKGROUND: Daratumumab is an anti-CD38 immunotherapeutic drug that has increasingly been used to treat patients with heavily pre-treated and relapsed/refractory multiple myeloma. In so doing, the detection of CD38 antigen on plasma cells by flow cytometry is impeded. We hypothesized that alternative markers can be used in place or in addition to CD38 when detecting plasma cells post-treated with daratumumab. METHODS: A total of 16 alternative markers were tested using 22 bone marrow aspirates from patients with plasma cell neoplasm. The ability of selected markers to discern plasma cells from other hematopoietic cells were evaluated. The stability of tested markers when stored at 4 or 25°C after T = 0, 24, 48, and 72 h was also established. Finally, selected markers were incorporated into a panel used for monitoring multiple myeloma measurable residual disease to test their utility to identify plasma cells in the presence of daratumumab and/or elotuzumab (anti-CD319) drugs. RESULTS: Out of the 16 tested markers, CD319, CD54, CD229, CD317, and p63 were expressed by >90% of the plasma cells. Only CD319, CD54, and CD229 achieved 100% detection sensitivity. Further analysis showed that CD319 was better than CD229 and CD54 at resolving plasma cells from background hematopoietic cells, with CD54 being the worst (resolution metric, mean ± SD: CD319 [2.04 ± 0.86]; CD229 [1.47 ± 0.45]; and CD54 [1.22 ± 0.60]). CD229 was expressed by >90% of T lymphocytes, whereas CD319 was expressed preferentially by the CD8+ T cells and less frequently in CD4+ T cells. Additionally, CD229 was found on >60% of B and NK cells, as well as minor subsets of monocytes and granulocytes. CD319 was expressed on most NK cells and a minor subset of B cells, granulocytes, and monocytes. Even though CD229 and CD319 were expressed by different leukocyte subsets, their expression levels were highest on plasma cells. The expression of CD138 on plasma cells was significantly lower after storage at 4°C, while the expression levels of CD38, CD229, and CD319 remained stable at 4 or 25°C. Using limiting dilution experiments, the treatment of cells with daratumumab severely impeded the detection of CD38 antigen on plasma cells, whereas elotuzumab treatment did not block detection of CD319 on plasma cells. CONCLUSIONS: CD319 is a suitable alternative to CD38 for identifying plasma cells. Our results showed that a panel used for monitoring multiple myeloma measurable residual disease could be modified by using CD319 alone or in combination with CD38 to detect PCs in daratumumab or elotuzumab treated patients.


Assuntos
Biomarcadores Tumorais/sangue , Mieloma Múltiplo/tratamento farmacológico , Neoplasias de Plasmócitos/sangue , Família de Moléculas de Sinalização da Ativação Linfocitária/sangue , ADP-Ribosil Ciclase 1/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/sangue , Feminino , Citometria de Fluxo/métodos , Regulação Neoplásica da Expressão Gênica/genética , Granulócitos/metabolismo , Granulócitos/patologia , Humanos , Imunofenotipagem/métodos , Molécula 1 de Adesão Intercelular/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Mieloma Múltiplo/sangue , Mieloma Múltiplo/patologia , Neoplasias de Plasmócitos/patologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/patologia , Adulto Jovem
19.
Blood ; 137(4): 556-568, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33104215

RESUMO

Social determinants of health, including poverty, contribute significantly to health outcomes in the United States; however, their impact on pediatric hematopoietic cell transplantation (HCT) outcomes is poorly understood. We aimed to identify the association between neighborhood poverty and HCT outcomes for pediatric allogeneic HCT recipients in the Center for International Blood and Marrow Transplant Research database. We assembled 2 pediatric cohorts undergoing first allogeneic HCT from 2006 to 2015 at age ≤18 years, including 2053 children with malignant disease and 1696 children with nonmalignant disease. Neighborhood poverty exposure was defined a priori per the US Census definition as living in a high-poverty ZIP code (≥20% of persons below 100% federal poverty level) and used as the primary predictor in all analyses. Our primary outcome was overall survival (OS), defined as the time from HCT until death resulting from any cause. Secondary outcomes included relapse and transplantation-related mortality (TRM) in malignant disease, acute and chronic graft-versus-host disease, and infection in the first 100 days post-HCT. Among children undergoing transplantation for nonmalignant disease, neighborhood poverty was not associated with any HCT outcome. Among children undergoing transplantation for malignant disease, neighborhood poverty conferred an increased risk of TRM but was not associated with inferior OS or any other transplantation outcome. Among children with malignant disease, a key secondary finding was that children with Medicaid insurance experienced inferior OS and increased TRM compared with those with private insurance. These data suggest opportunities for future investigation of the effects of household-level poverty exposure on HCT outcomes in pediatric malignant disease to inform care delivery interventions.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Pobreza , Determinantes Sociais da Saúde , Adolescente , Causas de Morte , Criança , Pré-Escolar , Doença Crônica/mortalidade , Doença Crônica/terapia , Bases de Dados Factuais , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/economia , Transplante de Células-Tronco Hematopoéticas/mortalidade , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Humanos , Lactente , Infecções/epidemiologia , Cobertura do Seguro/estatística & dados numéricos , Masculino , Medicaid , Neoplasias/mortalidade , Neoplasias/terapia , Recidiva , Análise de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Estados Unidos
20.
Lancet Haematol ; 7(10): e715-e723, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32976751

RESUMO

BACKGROUND: The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. METHODS: We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. FINDINGS: We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. INTERPRETATION: Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. FUNDING: The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Interleucinas/genética , Leucemia Mieloide Aguda/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Adulto , Feminino , Genótipo , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Resultado do Tratamento , Doadores não Relacionados , Adulto Jovem
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