Cost-Effectiveness of Molecularly Guided Treatment in Diffuse Large B-Cell Lymphoma (DLBCL) in Patients under 60.

BACKGROUND: Classifying diffuse large B-cell lymphoma (DLBCL) into cell-of-origin (COO) subtypes could allow for personalized cancer control. Evidence suggests that subtype-guided treatment may be beneficial in the activated B-cell (ABC) subtype of DLBCL, among patients under the age of 60. METHODS: We estimated the cost-effectiveness of age- and subtype-specific treatment guided by gene expression profiling (GEP). A probabilistic Markov model examined costs and quality-adjusted life-years gained (QALY) accrued to patients under GEP-classified COO treatment over a 10-year time horizon. The model was calibrated to evaluate the adoption of ibrutinib as a first line treatment among patients under 60 years with ABC subtype DLBCL. The primary data source for efficacy was derived from published estimates of the PHOENIX trial. These inputs were supplemented with patient-level, real-world data from BC Cancer, which provides comprehensive cancer services to the population of British Columbia. RESULTS: We found the cost-effectiveness of GEP-guided treatment vs. standard care was $77,806 per QALY (24.3% probability of cost-effectiveness at a willingness-to-pay (WTP) of $50,000/QALY; 53.7% probability at a WTP of $100,000/QALY) for first-line treatment. Cost-effectiveness was dependent on assumptions around decision-makers' WTP and the cost of the assay. CONCLUSIONS: We encourage further clinical trials to reduce uncertainty around the implementation of GEP-classified COO personalized treatment in this patient population.

Assessment of Capture and Amplicon-Based Approaches for the Development of a Targeted Next-Generation Sequencing Pipeline to Personalize Lymphoma Management.

Targeted next-generation sequencing panels are increasingly used to assess the value of gene mutations for clinical diagnostic purposes. For assay development, amplicon-based methods have been preferentially used on the basis of short preparation time and small DNA input amounts. However, capture sequencing has emerged as an alternative approach because of high testing accuracy. We compared capture hybridization and amplicon sequencing approaches using fresh-frozen and formalin-fixed, paraffin-embedded tumor samples from eight lymphoma patients. Next, we developed a targeted sequencing pipeline using a 32-gene panel for accurate detection of actionable mutations in formalin-fixed, paraffin-embedded tumor samples of the most common lymphocytic malignancies: chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and follicular lymphoma. We show that hybrid capture is superior to amplicon sequencing by providing deep more uniform coverage and yielding higher sensitivity for variant calling. Sanger sequencing of 588 variants identified specificity limits of thresholds for mutation calling, and orthogonal validation on 66 cases indicated 93% concordance with whole-genome sequencing. The developed pipeline and assay identified at least one actionable mutation in 91% of tumors from 219 lymphoma patients and revealed subtype-specific mutation patterns and frequencies consistent with the literature. This pipeline is an accurate and sensitive method for identifying actionable gene mutations in routinely acquired biopsy materials, suggesting further assessment of capture-based assays in the context of personalized lymphoma management.

Treatment patterns and costs of care for patients with relapsed and refractory Hodgkin lymphoma treated with brentuximab vedotin in the United States: A retrospective cohort study.

OBJECTIVES: Although brentuximab vedotin (BV) has changed the management of patients with relapsed or refractory Hodgkin lymphoma (RRHL), little information is available on routine clinical practice. We identified treatment patterns and costs of care among RRHL patients in the United States (US) treated with BV. METHODS: A retrospective observational study of adults initiating BV for RRHL from 2011-2015, with ≥6 months of data prior to and following BV initiation, was conducted. Treatments were classified based on dispensations and chemotherapy administration. Median total and monthly costs were estimated based on all-cause healthcare resource use in 2015 US dollars (USD). RESULTS: The cohort comprised 289 patients (59% male; mean age at diagnosis, 42 years) with a mean follow-up of 250 weeks. Eleven percent had BV salvage therapy prior to ASCT, and 32% had BV for a relapse post-ASCT. 43% received treatment post-BV, most commonly allogeneic stem cell transplant (SCT) and bendamustine (both 10.2%). Median (IQR) total costs from BV initiation to censoring were 294,790 (142,110-483,360) USD; and were highest among those treated with BV prior to ASCT (up to 421,900 [300,940-778,970] USD). Median monthly costs were almost 20,000 USD per month, and up to 25,000 USD per month among those with BV and ASCT. Medications were the greatest driver of median monthly costs. CONCLUSIONS: Median total all-cause costs were almost 300,000 USD, and median monthly costs approximately 20,000 USD, per patient treated. Patients requiring treatment following BV continue to incur high costs, highlighting the economic burden associated with managing patients in the RRHL setting.

International Assessment of Event-Free Survival at 24 Months and Subsequent Survival in Peripheral T-Cell Lymphoma.

Purpose Peripheral T-cell lymphomas (PTCLs) have aggressive clinical behavior. We have previously shown that event-free survival (EFS) at 24 months (EFS24) is a clinically useful end point in diffuse large B-cell lymphoma. Here, we assess EFS24 and subsequent overall survival (OS) in large, multinational PTCL cohorts. Patients and Methods Patients with systemic PTCL newly diagnosed from 2000 to 2012 and treated with curative intent were included from the United States and Sweden (initial cohorts) and from Canada (replication cohort). EFS was defined as time from date of diagnosis to progression after primary treatment, retreatment, or death. Subsequent OS was measured after achieving EFS24 or from the time of progression if it occurred within 24 months. OS rates were compared with the age-, sex-, and country-matched general population. Results Seven hundred seventy-five patients were included in the study (the median age at diagnosis was 64 years; 63% were men). Results were similar in the initial and replication cohorts, and a combined analysis was undertaken. Sixty-four percent of patients progressed within the first 24 months and had a median OS of only 4.9 months (5-year OS, 11%). In contrast, median OS after achieving EFS24 was not reached (5-year OS, 78%), although relapses within 5 years of achieving EFS24 occurred in 23% of patients. Superior outcomes after achieving EFS24 were observed in younger patients (≤ 60 years of age: 5-year OS, 91%). Conclusion EFS24 stratifies subsequent outcome in PTCL. Patients with PTCL with primary refractory disease or early relapse have extremely poor survival. However, more than one third of patients with PTCL remain in remission 2 years after diagnosis with encouraging subsequent OS, especially in younger patients. These marked differences in outcome suggest that EFS24 has utility for patient counseling, study design, and risk stratification in PTCL.

Response assessment in lymphoma: Concordance between independent central review and local evaluation in a clinical trial setting.

BACKGROUND: Independent central review of clinical imaging remains the standard for oncology clinical trials with registration potential. A limited independent central review strategy has been proposed for solid tumor trials based on concordance between central and local evaluation of response. Concordance between independent central review and local evaluation of response in hematological malignancies is not known. METHODS: We retrospectively evaluated concordance between prospectively performed central and local assessments of response using the Revised Response Criteria for Malignant Lymphoma across two international, open-label, single-arm, registration studies of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma (N = 102) or systemic anaplastic large-cell lymphoma (N = 58). RESULTS: Overall objective response rates were similar between assessors for both the trial in Hodgkin lymphoma (75% independent central review, 72% local evaluation) and the trial in anaplastic large-cell lymphoma (86% independent central review, 83% local evaluation). Patient-specific objective response concordance was also substantial (Hodgkin lymphoma: kappa = 0.68; anaplastic large-cell lymphoma: kappa = 0.74). Median progression-free survival was similar between assessors for patients with anaplastic large-cell lymphoma (14.3 months by independent central review (95% confidence interval: 6.9, -); 14.5 months by local evaluation (95% confidence interval: 9.4, -)), but longer by local evaluation in patients with Hodgkin lymphoma (5.8 months by independent central review (95% confidence interval: 5.0, 9.0); 9.0 months by local evaluation (95% confidence interval: 7.1, 12.0)). Median duration of response was longer by local evaluation in both malignancies, which was primarily attributable to earlier computed tomography and positron emission tomography-based scoring of progression by independent central review. CONCLUSION: A limited independent review audit strategy for clinical trials of some lymphomas appears feasible and practical based on substantial concordance in assessments of overall objective response by central and local evaluation in two international, prospective, registration trials in lymphoma. Some variability between assessors in the time-to-event endpoints was observed, which appeared attributable to earlier assignments of progression by independent central review compared with local evaluation.

Risk assessment in the management of newly diagnosed classical Hodgkin lymphoma.

Treatment of Hodgkin lymphoma is associated with 2 major types of risk: that the treatment may fail to cure the disease or that the treatment will prove unacceptably toxic. Careful assessment of the amount of the lymphoma (tumor burden), its behavior (extent of invasion or specific organ compromise), and host related factors (age; coincident systemic infection; and organ dysfunction, especially hematopoietic, cardiac, or pulmonary) is essential to optimize outcome. Elaborately assembled prognostic scoring systems, such as the International Prognostic Factors Project score, have lost their accuracy and value as increasingly effective chemotherapy and supportive care have been developed. Identification of specific biomarkers derived from sophisticated exploration of Hodgkin lymphoma biology is bringing promise of further improvement in targeted therapy in which effectiveness is increased at the same time off-target toxicity is diminished. Parallel developments in functional imaging are providing additional potential to evaluate the efficacy of treatment while it is being delivered, allowing dynamic assessment of risk during chemotherapy and adaptation of the therapy in real time. Risk assessment in Hodgkin lymphoma is continuously evolving, promising ever greater precision and clinical relevance. This article explores the past usefulness and the emerging potential of risk assessment for this imminently curable malignancy.

Cost-effectiveness of the addition of rituximab to CHOP chemotherapy in first-line treatment for diffuse large B-cell lymphoma in a population-based observational cohort in British Columbia, Canada.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) has primarily been treated with cyclophosphamide, doxorubicin, vincristine, and predisone (CHOP) chemotherapy since the 1970s. Recently, the addition of rituximab to CHOP (CHOP-R) has been found to improve survival and trial-based results have suggested that it is a cost-effective alternative to CHOP. OBJECTIVES: The objective in this study was to evaluate the cost-effectiveness of CHOP-R relative to CHOP in first-line treatment of DLBCL in a population-based setting in British Columbia, Canada. METHODS: We created a patient-level simulation model describing potential pathways for DLBCL patients initiating treatment with either CHOP or CHOP-R. Model parameters were populated with statistical analyses of individual-level treatment and effectiveness data and published cost estimates. All results were stratified by age at treatment initiation (<60 years vs. ≥60 years). The base-case scenario was based on a 15-year time horizon and a 3% discount rate. Probabilistic sensitivity analysis was performed. All costs are reported as 2006 $CDN. RESULTS: For the base-case scenario, incremental cost-effectiveness ratios (ICERs) for younger individuals ranged from $11,965 per disease-free life-year gained to $19,144 per quality-adjusted life-year gained. For older individuals, estimated ICERs for all health outcomes were below $10,000 per unit outcome gained for a 15-year time horizon. CONCLUSIONS: Using population-based data, CHOP-R was found to be a cost-effective alternative to CHOP, particularly for individuals aged 60 years and older. Results from this Canadian observational data source were consistent with international clinical trial-based studies. The use of CHOP-R as a first-line treatment for DLBCL is recommended, with respect to both clinical and cost-effectiveness.

Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances.

The secondary genetic events associated with follicular lymphoma (FL) progression are not well defined. We applied genome-wide BAC array comparative genomic hybridization to 106 diagnostic biopsies of FL to characterize regional genomic imbalances. Using an analytical approach that defined regions of copy number change as intersections between visual annotations and a Hidden Markov model-based algorithm, we identified 71 regional alterations that were recurrent in at least 10% of cases. These ranged in size from approximately 200 kb to 44 Mb, affecting chromosomes 1, 5, 6, 7, 8, 10, 12, 17, 18, 19, and 22. We also demonstrated by cluster analysis that 46.2% of the 106 cases could be sub-grouped based on the presence of +1q, +6p/6q-, +7, or +18. Survival analysis showed that 21 of the 71 regions correlated significantly with inferior overall survival (OS). Of these 21 regions, 16 were independent predictors of OS using a multivariate Cox model that included the international prognostic index (IPI) score. Two of these 16 regions (1p36.22-p36.33 and 6q21-q24.3) were also predictors of transformation risk and independent of IPI. These prognostic features may be useful to identify high-risk patients as candidates for risk-adapted therapies.