RESUMO
Venetoclax with azacitidine (ven/aza) is a lower-intensity therapeutic regimen that has been shown to improve outcomes in elderly patients with acute myeloid leukemia (AML). Measurable residual disease (MRD) using flow cytometry is a valuable tool for the prediction of relapse in AML using conventional therapies and ven/aza; however, the prognostic value for broadscale molecular MRD after ven/aza treatment is less clear. We aimed to determine the utility of retrospective assessment using multi-gene molecular MRD by droplet digital polymerase chain reaction (ddPCR). We found this approach correlates with outcomes in a cohort of patients receiving frontline ven/aza for AML. The predictive value of ddPCR MRD persisted when NPM1 mutations were removed from analysis, as well as after adjustment for the impact of stem cell transplant on outcomes. Late achievement of MRD negativity, including after SCT, was still associated with superior outcomes compared to persistently detectable MRD. We further explored the impact of ven/aza on the burden of different classes of mutations, and identified the persistence of splicing factor mutations, commonly associated with MDS, as a consistent finding after ven/aza treatment. These data add to our understanding of the effects of ven/aza on AML disease biology and provide details on molecular depth of remission that can guide prospective trials in the future.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Mutação , Neoplasia Residual , Nucleofosmina , Sulfonamidas , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Neoplasia Residual/diagnóstico , Sulfonamidas/uso terapêutico , Sulfonamidas/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Idoso , Masculino , Feminino , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Reação em Cadeia da Polimerase/métodos , Prognóstico , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Adulto , Resultado do TratamentoRESUMO
Venetoclax+azacitidine is the standard of care for newly-diagnosed patients with acute myeloid leukemia (AML) for whom intensive chemotherapy is inappropriate. Efforts to optimize this regimen are necessary. We designed a clinical trial to investigate two hypotheses: i) higher doses of venetoclax are tolerable and more effective, and ii) azacitidine can be discontinued after deep remissions. Forty-two newly diagnosed AML patients were enrolled in the investigator-initiated High Dose Discontinuation Azacitidine+Venetoclax (HiDDAV) Study (clinicaltrials gov. Identifier: NCT03466294). Patients received one to three "induction" cycles of venetoclax 600 mg daily with azacitidine. Responders received MRD-positive or MRDnegative "maintenance" arms: azacitidine with 400 mg venetoclax or 400 mg venetoclax alone, respectively. The toxicity profile of HiDDAV was similar to 400 mg venetoclax. The overall response rate was 66.7%; the duration of response (DOR), event-free survival (EFS) and overall survival were 12.9, 7.8 and 9.8 months, respectively. The MRD negativity rate was 64.3% by flow cytometry and 25.0% when also measured by droplet digital polymerase chain recation. MRD-negative patients by flow cytometry had improved DOR and EFS; more stringent measures of MRD negativity were not associated with improved OS, DOR or EFS. Using MRD to guide azacitidine discontinuation did not lead to improved DOR, EFS or OS compared to patients who discontinued azacitidine without MRD guidance. Within the context of this study design, venetoclax doses >400 mg with azacitidine were well tolerated but not associated with discernible clinical improvement, and MRD may not assist in recommendations to discontinue azacitidine. Other strategies to optimize, and for some patients, de-intensify, venetoclax+azacitidine regimens are needed.
Assuntos
Azacitidina , Leucemia Mieloide Aguda , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Neoplasia Residual/tratamento farmacológicoRESUMO
Background: Little is known about the relative harms of edible and inhalable cannabis products. Objective: To describe and compare adult emergency department (ED) visits related to edible and inhaled cannabis exposure. Design: Chart review of ED visits between 1 January 2012 and 31 December 2016. Setting: A large urban academic hospital in Colorado. Participants: Adults with ED visits with a cannabis-related International Classification of Diseases, Ninth or 10th Revision, Clinical Modification (ICD-9-CM or ICD-10-CM), code. Measurements: Patient demographic characteristics, route of exposure, dose, symptoms, length of stay, disposition, discharge diagnoses, and attribution of visit to cannabis. Results: There were 9973 visits with an ICD-9-CM or ICD-10-CM code for cannabis use. Of these, 2567 (25.7%) visits were at least partially attributable to cannabis, and 238 of those (9.3%) were related to edible cannabis. Visits attributable to inhaled cannabis were more likely to be for cannabinoid hyperemesis syndrome (18.0% vs. 8.4%), and visits attributable to edible cannabis were more likely to be due to acute psychiatric symptoms (18.0% vs. 10.9%), intoxication (48% vs. 28%), and cardiovascular symptoms (8.0% vs. 3.1%). Edible products accounted for 10.7% of cannabis-attributable visits between 2014 and 2016 but represented only 0.32% of total cannabis sales in Colorado (in kilograms of tetrahydrocannabinol) during that period. Limitation: Retrospective study design, single academic center, self-reported exposure data, and limited availability of dose data. Conclusion: Visits attributable to inhaled cannabis are more frequent than those attributable to edible cannabis, although the latter is associated with more acute psychiatric visits and more ED visits than expected. Primary Funding Source: Colorado Department of Public Health and Environment.
Assuntos
Cannabis/efeitos adversos , Fumar Maconha/efeitos adversos , Plantas Comestíveis/efeitos adversos , Doença Aguda , Adulto , Cannabis/intoxicação , Doenças Cardiovasculares/induzido quimicamente , Colorado , Serviço Hospitalar de Emergência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicoses Induzidas por Substâncias/etiologia , Estudos Retrospectivos , Vômito/induzido quimicamenteRESUMO
Given the limited treatment options for relapsed lymphoma post-allogeneic hematopoietic cell transplantation (post-allo-HCT) and the success of programmed death 1 (PD-1) blockade in classical Hodgkin lymphoma (cHL) patients, anti-PD-1 monoclonal antibodies (mAbs) are increasingly being used off-label after allo-HCT. To characterize the safety and efficacy of PD-1 blockade in this setting, we conducted a multicenter retrospective analysis of 31 lymphoma patients receiving anti-PD-1 mAbs for relapse post-allo-HCT. Twenty-nine (94%) patients had cHL and 27 had ≥1 salvage therapy post-allo-HCT and prior to anti-PD-1 treatment. Median follow-up was 428 days (range, 133-833) after the first dose of anti-PD-1. Overall response rate was 77% (15 complete responses and 8 partial responses) in 30 evaluable patients. At last follow-up, 11 of 31 patients progressed and 21 of 31 (68%) remain alive, with 8 (26%) deaths related to new-onset graft-versus-host disease (GVHD) after anti-PD-1. Seventeen (55%) patients developed treatment-emergent GVHD after initiation of anti-PD-1 (6 acute, 4 overlap, and 7 chronic), with onset after a median of 1, 2, and 2 doses, respectively. GVHD severity was grade III-IV acute or severe chronic in 9 patients. Only 2 of these 17 patients achieved complete response to GVHD treatment, and 14 of 17 required ≥2 systemic therapies. In conclusion, PD-1 blockade in relapsed cHL allo-HCT patients appears to be highly efficacious but frequently complicated by rapid onset of severe and treatment-refractory GVHD. PD-1 blockade post-allo-HCT should be studied further but cannot be recommended for routine use outside of a clinical trial.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Doença Enxerto-Hospedeiro/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/uso terapêutico , Feminino , Expressão Gênica , Doença Enxerto-Hospedeiro/imunologia , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Doença de Hodgkin/imunologia , Doença de Hodgkin/mortalidade , Doença de Hodgkin/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Nivolumabe , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Indução de Remissão , Estudos Retrospectivos , Terapia de Salvação/métodos , Análise de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
BACKGROUND: IDH1/2 mutated glioma has been associated with a germline risk variant, the rs55705857 G allele. The Utah Population Database (UPDB), a computerized genealogy of people in Utah, is a unique resource to evaluate cancer risk in related individuals. METHODS: One hundred and two individuals with IDH1/2 mutant or 1p/19q co-deleted glioma were genotyped and linked to the UPDB. DNA came from blood (21), tumor tissue (43), or both (38). We determined congruence between somatic and germline samples and estimated the relative risk for developing cancer to first and second-degree relatives of G and A allele carriers at rs55705857. RESULTS: Somatic (glioma) DNA had 85.7% sensitivity (CI 57.2-98.2%) and 95.8% specificity (CI 78.9-99.89%) for germline rs55705857 G allele. Forty-one patients were linked to pedigrees in the UPDB with at least three generations of data. First-degree relatives of rs55705857 G allele carriers were at significantly increased risk for developing cancer (RR = 1.72, p = 0.045, CI 1.02-2.94), and specifically for oligodendroglioma (RR = 57.61, p = 0.017, CI 2.96-320.98) or prostate cancer (RR = 4.10, p = 0.008, CI 1.62-9.58); relatives of individuals without the G allele were not at increased risk. Second-degree relatives of G allele carriers also had significantly increased risk for developing cancer (RR = 1.50, p = 0.007, CI 1.15-2.01). CONCLUSIONS: Tumor DNA may approximate genotype at the rs55705857 locus. We confirmed this locus confers an increased risk of all cancers and especially of oligodendroglioma. No increased cancer or brain tumor risk is seen in family members of individuals without the high-risk G allele.
Assuntos
Neoplasias Encefálicas/genética , Cromossomos Humanos Par 8/genética , Neoplasias Colorretais/genética , Mutação em Linhagem Germinativa/genética , Glioma/genética , Neoplasias da Próstata/genética , Neoplasias da Glândula Tireoide/genética , Alelos , Astrocitoma/genética , Bases de Dados Factuais , Família , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Armazenamento e Recuperação da Informação , Isocitrato Desidrogenase/genética , Masculino , Mutação , Neoplasias/genética , Oligodendroglioma/genética , UtahRESUMO
BACKGROUND: Sinonasal malignancies are a rare and heterogeneous group of tumors for which there is a paucity of robust data with which to guide management decisions. The authors used the National Cancer Data Base to better understand the presenting characteristics of these tumors and to compare outcomes by treatment modality. METHODS: The National Cancer Data Base was queried for sinonasal malignancies diagnosed between 2004 and 2012. Overall survival was assessed using multivariate analyses and propensity score matching. RESULTS: A total of 11,160 patients were identified for the initial analysis. The majority were male, aged 40 to 69 years, with tumors of the nasal cavity or maxillary sinus. Squamous cell histology was most common. The majority of patients presented with advanced tumor stage but without locoregional lymph node or distant metastases. Treatment modalities were compared for squamous cell carcinomas. In multivariate analysis, compared with surgery alone, patients who received adjuvant radiotherapy (hazard ratio [HR], 0.658 [P<.001]), adjuvant chemoradiotherapy (HR, 0.696 [P = .002]), or neoadjuvant therapy (HR, 0.656 [P = .007]) had improved overall survival. Patients who received radiotherapy alone (HR, 1.294 [P = .001]) or chemotherapy alone (HR, 1.834 [P<.001]) had worse outcomes. These findings were validated in propensity score matching. It is important to note that neoadjuvant chemoradiotherapy was associated with achieving a negative surgical margin (odds ratio, 2.641 [P = .045]). CONCLUSIONS: Surgery is the mainstay of therapy for patients with sinonasal malignancies, but multimodality therapy is associated with improved overall survival. Cancer 2017;123:3040-49. © 2017 American Cancer Society.
Assuntos
Carcinoma Adenoide Cístico/terapia , Carcinoma Adenoescamoso/terapia , Carcinoma Mucoepidermoide/terapia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Melanoma/terapia , Neoplasias Nasais/terapia , Neoplasias dos Seios Paranasais/terapia , Adolescente , Adulto , Idoso , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoescamoso/patologia , Carcinoma Mucoepidermoide/patologia , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia Adjuvante , Quimioterapia Adjuvante , Criança , Pré-Escolar , Bases de Dados Factuais , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Lactente , Recém-Nascido , Linfonodos/patologia , Masculino , Margens de Excisão , Melanoma/patologia , Pessoa de Meia-Idade , Análise Multivariada , Terapia Neoadjuvante , Neoplasias Nasais/patologia , Procedimentos Cirúrgicos Otorrinolaringológicos , Neoplasias dos Seios Paranasais/patologia , Prognóstico , Pontuação de Propensão , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: Squamous cell carcinoma of the head and neck (HNSCC) represents an array of disease processes with a generally unfavorable prognosis. Inflammation plays an important role in tumor development and response to therapy. We performed a retrospective analysis of HNSCC patients to explore the relationship of the lymphocyte and neutrophil counts, the neutrophil-to-lymphocyte ratio (NLR) overall survival (OS), cancer-specific survival (CSS), local control (LC) and distant control (DC). MATERIALS/METHODS: All patients received definitive treatment for cancers of the oropharynx or larynx between 2006-2015. Neutrophil and lymphocyte counts were collected pre-, during-, and post-treatment. The correlations of patient, tumor, and biological factors to OS, CSS, LC and DC were assessed. RESULTS: 196 patients met our inclusion criteria; 171 patients were Stage III or IV. Median follow-up was 2.7 years. A higher neutrophil count at all treatment time points was predictive of poor OS with the pre-treatment neutrophil count and overall neutrophil nadir additionally predictive of DC. Higher pre-treatment and overall NLR correlated to worse OS and DC, respectively. CONCLUSION: A higher pre-treatment neutrophil count correlates to poor OS, CSS and DC. Lymphocyte counts were not found to impact survival or tumor control. Higher pre-treatment NLR is prognostic of poor OS.
Assuntos
Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Neutrófilos/patologia , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/sangue , Contagem de Linfócitos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias Orofaríngeas/sangue , Prognóstico , Análise de SobrevidaRESUMO
INTRODUCTION: The risk of cancer in patients diagnosed with myotonic dystrophy (DM) is reported for the homogeneous Utah population. METHODS: Clinical data accessed from the largest Utah healthcare providers have been record-linked to the Utah Population Database, a population-based resource also linked to the Utah Cancer Registry. Relative risks were estimated for 36 cancers of different types in 281 DM patients. RESULTS: Testicular cancer (relative risk [RR] = 10.74; 95% confidence interval [CI], 1.91-38.79), endometrial cancer (RR = 6.98; 95% CI, 1.24-25.22), and non-Hodgkin lymphoma (RR = 4.25; 95% CI, 1.16-12.43) were all observed at significant excess in DM patients. CONCLUSIONS: This study confirms an overall increased risk of cancer in DM. Individuals diagnosed with DM might benefit from risk counseling. Muscle Nerve 54: 783-785, 2016.
Assuntos
Distrofia Miotônica/diagnóstico , Distrofia Miotônica/epidemiologia , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Vigilância da População , Inquéritos e Questionários , Neoplasias do Endométrio/diagnóstico , Neoplasias do Endométrio/epidemiologia , Feminino , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/epidemiologia , Masculino , Vigilância da População/métodos , Fatores de Risco , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/epidemiologia , Utah/epidemiologiaRESUMO
INTRODUCTION: A population-level relative risk assessment for comorbidities associated with myotonic dystrophy has not been performed. METHODS: In this study we utilized the Utah Population Database to identify patients with myotonic dystrophy in Utah according to ICD-9 coding. Comorbidity cases listed in the medical record were compared with those of the Utah population. RESULTS: Individuals with myotonic dystrophy were found to possess an increased risk of central and obstructive sleep apnea, hypothyroidism, and intellectual disability. The risk of cardiac conduction disorder is 60 times the population risk. CONCLUSIONS: This study provides a population-level relative risk assessment of comorbidities in myotonic dystrophy. This allows for improved counseling of patients regarding these increased risks.
Assuntos
Arritmias Cardíacas/epidemiologia , Catarata/epidemiologia , Sistema de Condução Cardíaco/anormalidades , Deficiência Intelectual/epidemiologia , Distrofia Miotônica/epidemiologia , Transtornos do Sono-Vigília/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome de Brugada , Doença do Sistema de Condução Cardíaco , Criança , Pré-Escolar , Planejamento em Saúde Comunitária , Comorbidade , Bases de Dados Bibliográficas/estatística & dados numéricos , Feminino , Humanos , Lactente , Recém-Nascido , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Utah/epidemiologia , Adulto JovemAssuntos
Administração por Inalação , Abuso de Maconha/complicações , Doenças Cardiovasculares/etiologia , Colorado/epidemiologia , Serviço Hospitalar de Emergência/organização & administração , Humanos , Abuso de Maconha/epidemiologia , Abuso de Maconha/fisiopatologia , Transtornos Mentais/etiologia , Estudos Retrospectivos , Vômito/etiologiaRESUMO
BACKGROUND: Despite the concurrent use of haploidentical-cord (HCT) and dual cord (DCT) stem cell transplant approaches for over a decade, there have been few comparisons of their outcomes. OBJECTIVES: Our objective in this study is to assess for differences in the outcomes and adverse effects associated with HCTs vs DCTs. STUDY DESIGN: Here we report a retrospective analysis of HCTs and DCTs at our institution. From October 2012 to October 2022, 70 HCT and 133 DCT transplants were performed following 50 mg/kg of IV cyclophosphamide, 150 mg/m2 of IV fludarabine, 10 mg/kg of IV thiotepa, and 4 Gy total body irradiation conditioning. RESULTS: With a median follow-up of 3.6 years among survivors, there was no difference in overall survival (3 year OS 65% DCT vs 63% HCT, p=1) or relapse free survival (3 year RFS 62% DCT vs 64% HCT, p=0.97) for all patients. Time to neutrophil recovery was faster in HCT recipients (median 17 vs 22 days, p=0.021), with no difference in platelet recovery to 20,000/µL (p=0.12). Median hospitalization for HCT recipients was 20 days versus 24 days for DCT recipients (p<0.0001). Engraftment syndrome treated with steroids occurred in 47/133 (35%) DCT recipients vs 42/70 (60%) HCT recipients (OR 0.37, p-value=0.001). There was a significant increase in grade 3-4 acute graft-versus-host-disease (aGVHD) in haplo-cord recipients (p=0.007), but no difference in grade 2-4 aGVHD (p=0.11), all chronic GVHD (cGVHD) (p=0.9), or moderate-severe cGVHD (p=0.3). CONCLUSIONS: Our outcomes demonstrate faster engraftment and shorter hospitalization in HCTs relative to DCTs, but more engraftment syndrome and higher grade 3-4 aGVHD. When both are options, these factors should guide the choice between HCTs and DCTs.
RESUMO
Predictors for response to intensive therapy in AML have focused on baseline factors: percent leukemic blasts in marrow, cytogenetic/molecular genetic abnormalities, and presence of secondary AML. Non-baseline dynamic factors, occurring after induction but before response, may be useful for decisions related to salvage chemotherapy. We hypothesized white blood cell (WBC) count nadir after induction may be a real time indicator of treatment efficacy. We also examined whether time to stem cell transplant (SCT) or baseline molecular genetic abnormalities are associated with a low nadir. Data showed WBC nadir = 0 was a negative predictor for response to intensive induction and was correlated with reduced overall survival and progression free survival. Patients with WBC nadir = 0 did not have a significantly longer time to SCT, and none of the mutations increased the likelihood of reaching WBC nadir = 0. WBC nadir may be a useful real-time monitor in AML patients receiving intensive induction chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/genética , Contagem de Leucócitos , Pessoa de Meia-Idade , Masculino , Feminino , Prognóstico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Quimioterapia de Indução/métodos , Resultado do Tratamento , Adulto Jovem , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
INTRODUCTION: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory (R/R) B-cell lymphomas, though certain patients do not respond to treatment or relapse afterwards. The purpose of this study is to determine patient variables that are predictive of response to CAR-T therapy. METHODS: We conducted a retrospective review of 59 R/R B-cell non-Hodgkin lymphoma patients who received anti-CD19 CAR T-cell therapy. Risk factors for progression free survival (PFS) and overall survival (OS) were identified and multivariate logistic regression models for PFS and OS at 1 year were created using stepwise selection. The final multivariate logistic regression models were used to estimate the area under the receiver operating curve (AUROC). RESULTS: At median follow up of 25.6 months, median overall survival was not reached, and median progression free survival was 5.7 months. Stage IV disease (odds ratio (OR) 9.335, P = .025) was identified as a predictive variable for progression at day 365 with an AUC of 0.7922 (P < .001). IPI (OR 2.828, P = .014), ALC ≥ 0.50 at collection (OR 0.183, P = .043), CRP ≥ 11 (OR 6.177, P = .019), and tocilizumab administration (OR 0.062, P = .005) as predictors for death at day 365 with an AUC 0.8626 (P < .001). CONCLUSION: Clinical variables identify R/R lymphoma patients who are at risk for progression and poor overall survival after CAR T-cell therapy. IPI, CRP, ALC, and tocilizumab administration may be predictors of survival.
Assuntos
Linfoma de Células B , Linfoma , Humanos , Imunoterapia Adotiva/efeitos adversos , Recidiva Local de Neoplasia/terapia , Antígenos CD19RESUMO
Monoclonal antibodies targeting CD38 are important for treatment of both newly diagnosed and relapsed multiple myeloma (MM). Daratumumab and isatuximab are anti-CD38 antibodies with the US Food and Drugs Administration approval in multiple different combinations. Despite good initial efficacy, patients inevitably develop drug resistance. Whether patients can be effectively re-treated with these antibodies in subsequent lines of therapy is unclear. Thus far, studies have mostly been limited to clinical retrospectives with short washout periods. To answer whether patients regain sensitivity after longer washouts, we used ex vivo sensitivity testing to isolate the anti-CD38 antibody-specific cytotoxicity in samples obtained from patients who had been exposed to and then off daratumumab for up to 53 months. MM cells from patients who had been off daratumumab for >1 year showed greater sensitivity than those with <1 year, although they still were less sensitive than those who were daratumumab naïve. CD38 expression on MM cells gradually recovered, although, again, not to the level of anti-CD38 antibody-naïve patients. Interestingly, low MM CD38 explained only 45% of cases identified to have daratumumab resistance. With clinical follow-up, we found ex vivo sensitivity predicted subsequent clinical response but CD38 overexpression did not. Patients clinically re-treated with anti-CD38 antibodies had <6 months of clinical benefit, but 1 patient who was daratumumab exposed but not refractory achieved complete response lasting 13 months. We conclude that transient efficacy can be achieved by waiting 1 year before CD38 antibody rechallenge, but this approach may be best used as a bridge to, or after, chimeric antigen receptor T-cell therapy.
Assuntos
Mieloma Múltiplo , Humanos , Mieloma Múltiplo/metabolismo , ADP-Ribosil Ciclase 1 , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Estudos RetrospectivosRESUMO
PURPOSE: To investigate quantitative trait loci linked to refractive error, we performed a genome-wide quantitative trait linkage analysis using single nucleotide polymorphism markers and family data from five international sites. METHODS: Genomic DNA samples from 254 families were genotyped by the Center for Inherited Disease Research using the Illumina Linkage Panel IVb. Quantitative trait linkage analysis was performed on 225 Caucasian families and 4,656 markers after accounting for linkage disequilibrium and quality control exclusions. Two refractive quantitative phenotypes, sphere (SPH) and spherical equivalent (SE), were analyzed. The SOLAR program was used to estimate identity by descent probabilities and to conduct two-point and multipoint quantitative trait linkage analyses. RESULTS: We found 29 markers and 11 linkage regions reaching peak two-point and multipoint logarithms of the odds (LODs)>1.5. Four linkage regions revealed at least one LOD score greater than 2: chromosome 6q13-6q16.1 (LOD=1.96 for SPH, 2.18 for SE), chromosome 5q35.1-35.2 (LOD=2.05 for SPH, 1.80 for SE), chromosome 7q11.23-7q21.2 (LOD=1.19 for SPH, 2.03 for SE), and chromosome 3q29 (LOD=1.07 for SPH, 2.05 for SE). Among these, the chromosome 6 and chromosome 5 regions showed the most consistent results between SPH and SEM. Four linkage regions with multipoint scores above 1.5 are near or within the known myopia (MYP) loci of MYP3, MYP12, MYP14, and MYP16. Overall, we observed consistent linkage signals across the SPH and SEM phenotypes, although scores were generally higher for the SEM phenotype. CONCLUSIONS: Our quantitative trait linkage analyses of a large myopia family cohort provided additional evidence for several known MYP loci, and identified two additional potential loci at chromosome 6q13-16.1 and chromosome 5q35.1-35.2 for myopia. These results will benefit the efforts toward determining genes for myopic refractive error.
Assuntos
Biomarcadores/metabolismo , Miopia/genética , Locos de Características Quantitativas/genética , Erros de Refração/genética , População Branca/genética , Adulto , Austrália , Cromossomos Humanos/genética , Estudos de Coortes , Europa (Continente) , Feminino , Ligação Genética , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Cooperação Internacional , Escore Lod , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estados UnidosRESUMO
OBJECTIVES: To determine if blood type is a risk factor for coronavirus disease 2019 (COVID-19) disease incidence and severity after correcting for ethnicity differences between novel infections and known ABO blood type frequency differences. METHODS: We performed a retrospective analysis on all severe acute respiratory system coronavirus 2 (SARS-CoV-2) infections and disease severity across two major testing sites in Colorado. We evaluated all individuals with a SARS-CoV-2 nucleic acid test (NAT) and a known blood type between March 1, 2020, and June 1, 2020. We then created a prediction algorithm based on the corrected blood types by ethnicity using data from the Colorado Department of Health and established blood types by ethnicity. We applied this prediction algorithm to all patients in our sample. RESULTS: Of 8,676 patients, 485 (5.6%) had a positive SARS-CoV-2 NAT test and 8,191 (94.4%) had a negative test. All patients had ABO blood types that mirrored the expected blood type distribution within the state of Colorado (Pâ =â .15, χâ2 statisticâ =â 5.31). No differences in expected blood groups were present between ethnicity-adjusted SARS-CoV-2-negative and SARS-CoV-2-positive patients (χâ2â =â 3.416313, Pâ =â .332). CONCLUSIONS: Blood type is not associated with COVID-19 disease incidence or severity after correcting for ethnicity differences in expected blood type frequencies.
Assuntos
COVID-19 , Sistema ABO de Grupos Sanguíneos , Etnicidade , Humanos , Incidência , Estudos Retrospectivos , SARS-CoV-2RESUMO
Background: Acute myeloid leukemia (AML) is associated with poor prognosis, particularly in elderly patients with comorbidities. Combining azacitidine (AZA) with BCL-2 inhibitor venetoclax (VEN) demonstrated significant improvement in outcomes for newly-diagnosed AML patients compared to AZA alone. However, this regimen is myelosuppressive, and the incidence of invasive fungal infections (IFIs) and impact of antifungal prophylaxis are not well defined. Methods: This retrospective cohort study evaluated newly-diagnosed AML patients treated with VEN/AZA at the University of Colorado Hospital from January 2014 to August 2020. Patients with history of prior IFI were excluded. Primary outcome was IFI incidence during VEN/AZA therapy. χ2 and Fisher exact tests assessed the impact of patient demographics, AML-specific risk factors, and receipt of antifungal prophylaxis on IFI incidence. Results: 144 VEN/AZA-treated AML patients were included in the study. 25 (17%) patients developed IFI: 8% (n = 2) "proven," 24% (n = 6) "probable," and 68% (n = 17) "possible" per European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium criteria. There was no statistically significant association between IFI incidence with age, sex, or European LeukemiaNet classification. 10 patients received antifungal prophylaxis; none developed IFI. IFI incidence rate per 1000 patient-days was greatest 0-9 days after starting VEN/AZA, at 8.39. Conclusions: Incidence of "proven" and "probable" IFI in our VEN/AZA-treated AML cohort was 5.6%, in-line with incidence rates reported by recent similar studies. Furthermore, IFI incidence decreased as days from starting VEN/AZA therapy increased.
RESUMO
BACKGROUND: The time-limited combination of venetoclax and obinutuzumab (VenG) was established by the German CLL Study Group in the CLL14 trial for the upfront management of newly diagnosed chronic lymphocytic leukemia (CLL), showing a superior progression free survival benefit. The incidence of grade 3-4 neutropenia was reported in the range of 52.8%-57.7%. However, patients who develop neutropenia with this combination have yet to be formally characterized in the literature as it has impact on the clinical practice setting. AIM: To determine the incidence of grade 3 and 4 neutropenia and identify risk factors for neutropenia among CLL patients treated with the VenG regimen. METHODS: We conducted a retrospective, single-center study of all adult patients with a diagnosis of CLL treated with VenG at the University of Colorado Hospital. Demographic information, laboratory data, clinical data, and medication prescriptions were collected from the patients' electronic medical record. RESULTS: A total of 14 patients (73%) developed neutropenia during the course of therapy. The mean time to neutropenia from the start of treatment was 42 days (range 1-131). Our cohort harbored more high risk disease features and more comorbidities (CIRS score of 12). Four patients (28.6%) in the neutropenic group developed infectious complications during therapy and 6 (31%) patients were unable to be dose escalated to the final FDA approved dose of 400 mg. CONCLUSION: Our study cohort had higher incidence of grade 3 and 4 neutropenia occurring in 73% of patients. This could be attributed to a higher rate of comorbidities, high risk features, concomitant interacting medications, and prior chemotherapy. Further studies are warranted to determine if growth factor support is efficacious to achieve dose escalation with this therapy.
Assuntos
Leucemia Linfocítica Crônica de Células B , Neutropenia , Adulto , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Compostos Bicíclicos Heterocíclicos com Pontes , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Leucemia Linfocítica Crônica de Células B/etiologia , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , SulfonamidasRESUMO
Allogeneic hematopoietic stem cell transplantation (SCT) after a patient with acute myeloid leukemia (AML) achieves a remission from intensive chemotherapy (IC) is given with curative intent. Recently, venetoclax-based regimens have become the standard of care for patients with newly diagnosed AML who are unfit for IC. If these patients achieve remission, they may also be considered for potentially curative consolidation with SCT. There are limited data comparing outcomes after SCT with these different induction strategies. The purpose of the current study was to evaluate depth of remission before SCT and outcomes after SCT in adults with nonrelapsed/refractory AML receiving pre-SCT therapy with either venetoclax/azacitidine (ven/aza) or IC. This was a retrospective, single-institution analysis of 169 patients receiving SCT in first remission after IC or ven/aza. Patient demographics and AML risk features were collected, as well as pre-SCT measurable residual disease (MRD) assessed by flow cytometry and molecular methods. Relapse, transplantation-related mortality, incidence of acute and chronic graft-versus-host-disease (GVHD), and death from any cause were also recorded. Descriptive and survival statistics were applied to these data to compare IC and ven/aza groups. Cox proportional hazard models were used for univariate and multivariate analyses. We demonstrate that despite differences in baseline factors between these groups, outcomes were similar. Relapse-free and overall survival, as well as cumulative incidences of transplantation-related mortality, relapse, and acute and chronic GVHD were comparable between groups. Exploring survival in younger (<65 years) versus older (≥65 years) patients by treatment group did not alter these results. Finally, although pre-SCT MRD by flow cytometry was significantly predictive of post-SCT relapse and survival in the IC + SCT patients, it was not significantly predictive of relapse and survival in the ven/aza + SCT patients. Although these findings require prospective validation in a larger cohort of patients, they suggest that ven/aza followed by SCT is a reasonable management strategy for transplantation candidates at any age.