Gene expression-based outcome prediction in advanced stage classical Hodgkin lymphoma treated with BEACOPP.
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ABSTRACT:
SUBMITTER: Jachimowicz RD
PROVIDER: S-EPMC8632672 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC8807388 | biostudies-literature
Project description:Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.
| S-EPMC7955404 | biostudies-literature
Project description:PurposeOur aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET).MethodsExpression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.ResultsA 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.ConclusionA gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.
| S-EPMC3574267 | biostudies-literature
Project description: Not available
| S-EPMC6481581 | biostudies-literature
Project description:The glycoprotein CD47 regulates antiphagocytic activity via signal regulatory protein alpha (SIRPa). This study investigated CD47 expression on Hodgkin and Reed-Sternberg (HRS) cells in the classical Hodgkin lymphoma (cHL) tumour microenvironment and its correlation with prognosis, programmed-death (PD) immune markers, and SIRPa+ leukocytes. We conducted immunohistochemistry with CD47 and SIRPa antibodies on diagnostic biopsies (tissue microarrays) from cHL patients from two cohorts (n = 178). In cohort I (n = 136) patients with high expression of CD47 on HRS cells (n = 48) had a significantly inferior event-free survival [hazard ratio (HR) = 5.57; 95% confidence interval (CI), 2.78-11.20; p < 0.001] and overall survival (OS) (HR = 8.54; 95% CI, 3.19-22.90; p < 0.001) compared with patients with low expression (n = 88). The survival results remained statistically significant in multivariable Cox regression adjusted for known prognostic factors. In cohort II (n = 42) high HRS cell CD47 expression also carried shorter event-free survival (EFS) (HR = 5.96; 95% CI, 1.20-29.59; p = 0.029) and OS (HR = 5.61; 95% CI, 0.58-54.15; p = 0.136), although it did not retain statistical significance in the multivariable analysis. Further, high CD47 expression did not correlate with SIRPa+ leukocytes or PD-1, PD-L1 and PD-L2 expression. This study provides a deeper understanding of the role of CD47 in cHL during an era of emerging CD47 therapies.
| S-EPMC9310712 | biostudies-literature
Project description:More than 80% of patients with advanced-stage Hodgkin lymphoma are now cured with contemporary treatment approaches. The ongoing challenge is how to further improve outcomes by identifying both high-risk patients who may benefit from more intensive frontline therapy to reduce the risk of relapse as well as lower-risk patients who may do just as well with less intensive therapy. Numerous trials have used an interim positron emission tomography (PET) response-adapted approach to evaluate early escalation or deescalation of therapy for patients with a positive or negative interim PET scan, respectively. Recent trials have incorporated novel agents, including brentuximab vedotin (BV) and the immune checkpoint inhibitors, in the frontline setting. Based on results of the ECHELON-1 trial, the Food and Drug Administration approved BV in combination with adriamycin, vinblastine, and dacarbazine chemotherapy for stage III to IV Hodgkin lymphoma. Improved methods to assess higher risk at diagnosis using quantitative PET metrics, such as metabolic tumor volume and total lesion glycolysis, and incorporation of emerging biomarkers may further refine patient selection for more intensive upfront therapy. The ultimate goal is to achieve the highest level of efficacy for an individual patient while minimizing the short- and long-term toxicities.
| S-EPMC6245987 | biostudies-literature
Project description:Classical Hodgkin lymphoma (cHL) is a common malignancy in children and adolescents. Although cHL is highly curable, treatment with chemotherapy and radiation often come at the cost of long-term toxicity and morbidity. Effective risk-stratification tools are needed to tailor therapy. Here, we used gene expression profiling (GEP) to investigate tumor microenvironment (TME) biology, to determine molecular correlates of treatment failure, and to develop an outcome model prognostic for pediatric cHL. A total of 246 formalin-fixed, paraffin-embedded tissue biopsies from patients enrolled in the Children's Oncology Group trial AHOD0031 were used for GEP and compared with adult cHL data. Eosinophil, B-cell, and mast cell signatures were enriched in children, whereas macrophage and stromal signatures were more prominent in adults. Concordantly, a previously published model for overall survival prediction in adult cHL did not validate in pediatric cHL. Therefore, we developed a 9-cellular component model reflecting TME composition to predict event-free survival (EFS). In an independent validation cohort, we observed a significant difference in weighted 5-year EFS between high-risk and low-risk groups (75.2% vs 90.3%; log-rank P = .0138) independent of interim response, stage, fever, and albumin. We demonstrate unique disease biology in children and adolescents that can be harnessed for risk-stratification at diagnosis. This trial was registered at www.clinicaltrials.gov as #NCT00025259.
| S-EPMC8832480 | biostudies-literature
Project description:Commonly attributed to the prevalence of M2 macrophages, tumor-associated macrophages (TAM) are linked to poor outcome in Hodgkin lymphoma (HL). MYC is supposed to control the expression of M2-specific genes in macrophages, and deficiency in MYC-positive macrophages inhibits tumor growth in mouse models. To verify this hypothesis for HL, seventy-six samples were subjected to immunohistochemical double staining using CD68 or CD163 macrophage-specific antibodies and a reagent detecting MYC. For each cell population, labelled cells were grouped according to low, intermediate and high numbers and related to disease-free survival (DFS) and overall survival (OS). MYC+ cells accounted for 21% and 18% of CD68+ and CD163+ cells, respectively. Numbers of MYC- macrophages were significantly higher in EBV+ cases while no differences were observed for MYC+ macrophages between EBV+ and EBV- cases. Cases with highest numbers of macrophages usually showed worst DFS and OS. In most scenarios, intermediate numbers of macrophages were associated with better outcome than very low or very high numbers. Our observations are reminiscent of the "hormesis hypothesis" and suggest that a relative lack of TAM may allow HL growth while macrophages display an inhibitory effect with increasing numbers. Above a certain threshold, TAM may again support tumor growth.
| S-EPMC7287068 | biostudies-literature
Project description:ObjectivesRelapse occurs in ~20% of patients with classical Hodgkin lymphoma (cHL) despite treatment adaption based on 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography response. The objective was to evaluate pre-treatment FDG PET/CT-derived machine learning (ML) models for predicting outcome in patients with cHL.MethodsAll cHL patients undergoing pre-treatment PET/CT at our institution between 2008 and 2018 were retrospectively identified. A 1.5 × mean liver standardised uptake value (SUV) and a fixed 4.0 SUV threshold were used to segment PET/CT data. Feature extraction was performed using PyRadiomics with ComBat harmonisation. Training (80%) and test (20%) cohorts stratified around 2-year event-free survival (EFS), age, sex, ethnicity and disease stage were defined. Seven ML models were trained and hyperparameters tuned using stratified 5-fold cross-validation. Area under the curve (AUC) from receiver operator characteristic analysis was used to assess performance.ResultsA total of 289 patients (153 males), median age 36 (range 16-88 years), were included. There was no significant difference between training (n = 231) and test cohorts (n = 58) (p value > 0.05). A ridge regression model using a 1.5 × mean liver SUV segmentation had the highest performance, with mean training, validation and test AUCs of 0.82 ± 0.002, 0.79 ± 0.01 and 0.81 ± 0.12. However, there was no significant difference between a logistic model derived from metabolic tumour volume and clinical features or the highest performing radiomic model.ConclusionsOutcome prediction using pre-treatment FDG PET/CT-derived ML models is feasible in cHL patients. Further work is needed to determine optimum predictive thresholds for clinical use.Key points• A fixed threshold segmentation method led to more robust radiomic features. • A radiomic-based model for predicting 2-year event-free survival in classical Hodgkin lymphoma patients is feasible. • A predictive model based on ridge regression was the best performing model on our dataset.
| S-EPMC9403224 | biostudies-literature
Project description:Although specific microRNA (miRNA) signatures in classical Hodgkin lymphoma (cHL) have been proposed, their relationship with clinical outcome remains unclear. Despite treatment advances, a substantial subset of patients with advanced cHL are refractory to standard therapies based on adriamycin and its variants. Global miRNA expression data of 29 advanced cHL patients and five cHL-derived cell lines were used to identify profiles from Hodgkin-Reed-Sternberg (HRS) cells and their non-tumoural microenvironment. A cHL-miRNA signature was identified with 234 miRNAs differentially expressed. A subset of these miRNAs was associated with outcome and selected for study in an independent set of 168 cHL samples using quantitative reverse transcription polymerase chain reaction. Multivariate Cox regression analyses including cross-validation with failure-free survival (FFS) as clinical endpoint revealed a miRNA signature with MIR21, MIR30E, MIR30D and MIR92B* that identified two risk-groups with significant differences in 5-year FFS (81% vs. 35.7%; P < 0.001). Additionally, functional silencing of MIR21 and MIR30D in L428 cells showed increased sensitivity to doxorubicin-induced apoptosis, pointing towards abnormalities of mitochondrial intrinsic and TP53-CDKN1A pathways as related to miRNA deregulation in cHL. These results suggest that clinical outcome in cHL is associated with a specific miRNA signature. Moreover, functional analyses suggest a role for MIR21 and MIR30D in cHL pathogenesis and therapeutic resistance.
| S-EPMC5291117 | biostudies-literature