Clinical outcomes in patients relapsed/refractory after ≥2 prior lines of therapy for follicular lymphoma: a systematic literature review and meta-analysis.

BACKGROUND: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapy (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT identified through systematic literature review. METHODS: Eligible studies included comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT published prior to 31st May 2021. Prior LOT must have included an anti-CD20 monoclonal antibody and an alkylating agent, in combination or separately. Overall response rate (ORR) and complete response (CR) were estimated using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) curves for progression-free survival (PFS) and overall survival (OS) estimated by reconstructing digitized curves using the Guyot algorithm, and survival analyses were conducted, stratified by ≥2 prior LOT and ≥ 3 prior LOT groups (as defined in the source material). Restricting the analyses to the observational cohorts was investigated as a sensitivity analysis. RESULTS: The analysis-set included 20 studies published between 2014 and 2021. Studies were primarily US and/or European based, with the few exceptions using treatments approved in US/Europe. The estimated ORR was 58.47% (95% confidence interval [CI]: 51.13-65.62) and proportion of patients with CR was 19.63% (95% CI: 15.02-24.68). The median OS among those ≥2 prior LOT was 56.57 months (95% CI: 47.8-68.78) and median PFS was 9.78 months (95% CI: 9.01-10.63). The 24-month OS decreased from 66.50% in the ≥2 prior LOT group to 59.51% in the ≥3 prior LOT group, with a similar trend in PFS at 24-month (28.42% vs 24.13%). CONCLUSIONS: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of treated patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by treatments currently available in the US and Europe.

Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma.

The quality-adjusted time without symptoms or toxicity (Q-TWiST) methodology provides a comprehensive framework for treatment comparison that partitions survival time into distinct health states reflecting both treatment toxicity and disease progression. ZUMA-7 (ClinicalTrials.gov identifier NCT03391466), a phase 3 randomized open-label multicenter study, was conducted to evaluate the efficacy of axicabtagene ciloleucel (axi-cel), a chimeric antigen receptor T cell therapy, compared with standard of care (SOC) involving platinum-based salvage chemotherapy with autologous stem cell transplantation (ASCT) consolidation as a second-line treatment for relapsed/refractory (R/R) large B cell lymphoma (LBCL), and met its primary endpoint of improved event-free survival (EFS). We aimed to use the Q-TWiST method to compare the quality-adjusted survival of R/R LBCL patients treated with axi-cel and those treated with SOC who were enrolled in ZUMA-7. The preplanned analysis of overall survival (OS) was partitioned into 3 mutually exclusive health states: time with grade ≥3 adverse events before the event as defined in the EFS analysis (TOX), time without severe toxicity before the event (TWiST), and time after the event (REL). Q-TWiST was computed as a weighted sum of mean TOX, TWiST, and REL values multiplied by state-specific quality of life (QoL) utility scores. Q-TWiST was evaluated in the intention-to-treat cohort at median follow-up. A relative Q-TWiST gain of 10% was deemed "clinically important" and a gain of ≥15% was deemed "clearly clinically important" based on established categorization. Sensitivity analyses with follow-up ranging from 3 months to the maximum follow-up and subgroup analyses by age and R/R status were explored. At a median follow-up of 23.5 months, the axi-cel cohort showed a significantly longer time without severe toxicity compared with the SOC cohort, with a mean TWiST duration of 11.18 months versus 5.39 months, respectively. The mean TOX was 1.16 months versus .74 months, and mean REL was 6.02 months versus 10.66 months. Quality-adjusted survival was significantly longer with axi-cel by 3.7 months (95% CI, 2.3 to 5.2 months), representing a relative gain of 21.9%. This was reflected across all subgroups, with estimated Q-TWiST gains of 3.1 months (95% CI, 1.5 to 4.9 months) for patients age <65 years, 5.2 months (95% CI, 2.4 to 7.9 months) for those age ≥65 years, 3.2 months (95% CI, 1.4 to 4.9 months) for those with primary refractory disease, 9.1 months (95% CI, 3.9 to months 13.5) for those who relapsed within 6 months, and 4.1 months (95% CI, 1.1 to 7.1 months) for those who relapsed between 6 and 12 months. The Q-TWiST gain for axi-cel also was statistically significant across follow-up durations, increasing from .2 month (95% CI, .1 to .3 month) at a 3-month follow-up to 4.9 months (95% CI, 2.4 to 7.8 months) at the maximum follow-up of 37.7 months. Axi-cel was associated with a statistically significant and "clearly clinically important" gain in quality-adjusted survival, regardless of the relative decline in QoL associated with treatment toxicity, disease progression, or additional cancer treatment. This finding adds to the existing evidence supporting a benefit for axi-cel as a second-line treatment for patients with R/R LBCL.

Treatment patterns and outcomes in relapsed/refractory follicular lymphoma: results from the international SCHOLAR-5 study.

The SCHOLAR-5 study examines treatment patterns and outcomes of real-world follicular lymphoma (FL) patients on 3rd line of treatment (LoT) or higher, for whom existing data are limited. SCHOLAR-5 is a retrospective cohort study using data from adults (≥ 18 years) with grade 1-3a FL, initiating ≥3rd LoT after June 2014 at major lymphoma centers in the US and Europe. Objective response rate (ORR), complete response (CR), progression-free survival (PFS) and overall survival (OS) were analyzed by LoT. Time-to-event outcomes were assessed using Kaplan-Meier methods. Of 128 patients, 87 initiated 3rd LoT, 63 initiated 4th LoT, and 47 initiated 5th LoT. At 1st eligible LoT, 31% progressed within 24-months of 1st LoT anti-CD20 combination therapy, 28% had prior autologous stem cell transplantation, and 31% were refractory to the previous LoT. The most common regimen in each LoT was chemoimmunotherapy; however, experimental drugs were increasingly used at later LoT. In the US, anti-CD20 monotherapy was more common at ≥3rd LoT compared to Europe, where stem cell transplants were more common. ORR at 3rd LoT was 68% (CR 44%), but decreased after each LoT to 37% (CR 22%) in ≥5 LoT. Median OS and PFS at 3rd LoT were 68 and 11 months, respectively, and reduced to 43 and 4 months at ≥5 LoT. Treatments were heterogenous at each LoT in both the US and Europe. Few FL patients achieved CR in later LoT, and duration of response and survival diminished with each subsequent line.

The Cost-Effectiveness of Axicabtagene Ciloleucel as Second-Line Therapy in Patients with Large B-Cell Lymphoma in the United States: An Economic Evaluation of the ZUMA-7 Trial.

Axicabtagene ciloleucel (axi-cel) was found to have superior clinical outcomes compared to standard of care (SOC; salvage chemoimmunotherapy, followed by high-dose therapy with autologous stem cell rescue for responders) for second-line large B-cell lymphoma (2L LBCL) in the pivotal ZUMA-7 trial. The aim of this analysis was to evaluate the cost effectiveness of using axi-cel compared to the current standard 2L LBCL therapy. A 3-state partitioned-survival model estimated the cost effectiveness and budget impact from a payer perspective in the United States. Clinical outcomes were extrapolated based on the pivotal trial. The model calculated expected quality-adjusted life years (QALYs), total costs (in United States dollars [USD], and the incremental cost-effectiveness ratio (ICER), along with the budget impact. Sensitivity and scenario analyses were performed. The proportion alive at 10 years was estimated as 48% for axi-cel and 38% for SOC; median overall survival was estimated at 59 and 24 months for axi-cel and SOC, respectively. Over a lifetime horizon, the model estimated a total of 5.56 and 7.08 QALYs for SOC and axi-cel, respectively, of which 41% and 74% were in the event-free state, respectively. Incremental QALYs and costs were 1.51 and $100,366 USD, resulting in an ICER of $66,381 USD per QALY for axi-cel versus SOC. Despite crossover to subsequent CAR T in the SOC arm, second-line CAR T use was found to improve the quality and length of life compared to SOC. Cost offsets due to subsequent CAR T use led to a limited incremental cost difference. Treatment with axi-cel is a cost-effective option that addresses an important unmet clinical need for patients with LBCL who relapse or are refractory to front-line therapy.

Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

Comparative effectiveness of ZUMA-5 (axi-cel) vs SCHOLAR-5 external control in relapsed/refractory follicular lymphoma.

In the pivotal ZUMA-5 trial, axicabtagene ciloleucel (axi-cel; an autologous anti-CD19 chimeric antigen receptor T-cell therapy) demonstrated high rates of durable response in relapsed/refractory (r/r) follicular lymphoma (FL) patients. Here, outcomes from ZUMA-5 are compared with the international SCHOLAR-5 cohort, which applied key ZUMA-5 trial eligibility criteria simulating randomized controlled trial conditions. SCHOLAR-5 data were extracted from institutions in 5 countries, and from 1 historical clinical trial, for r/r FL patients who initiated a third or higher line of therapy after July 2014. Patient characteristics were balanced through propensity scoring on prespecified prognostic factors using standardized mortality ratio (SMR) weighting. Time-to-event outcomes were evaluated using weighted Kaplan-Meier analysis. Overall response rate (ORR) and complete response (CR) rate were compared using weighted odds ratios. The 143 ScHOLAR-5 patients reduced to an effective sample of 85 patients after SMR weighting vs 86 patients in ZUMA-5. Median follow-up time was 25.4 and 23.3 months for SCHOLAR-5 and ZUMA-5. Median overall survival (OS) and progression-free survival (PFS) in SCHOLAR-5 were 59.8 months and 12.7 months and not reached in ZUMA-5. Hazard ratios for OS and PFS were 0.42 (95% confidence interval [CI], 0.21-0.83) and 0.30 (95% CI, 0.18-0.49). The ORR and CR rate were 49.9% and 29.9% in SCHOLAR-5 and 94.2% and 79.1% in ZUMA-5, for odds ratios of 16.2 (95% CI, 5.6-46.9) and 8.9 (95% CI, 4.3-18.3). Compared with available therapies, axi-cel demonstrated an improvement in meaningful clinical endpoints, suggesting axi-cel addresses an important unmet need for r/r FL patients. This trial was registered at www.clinicaltrials.gov as #NCT03105336.

Cost-Effectiveness of Chimeric Antigen Receptor T Cell Therapy in Patients with Relapsed or Refractory Large B Cell Lymphoma: No Impact of Site of Care.

INTRODUCTION: Cost-effectiveness data on chimeric antigen receptor (CAR) T cell therapies for relapsed/refractory large B cell lymphoma (R/R LBCL), accounting for inpatient/outpatient site of care (site), are sparse. METHODS: This payer model compares lifetime costs/benefits for CAR T cell-treated (axicabtagene ciloleucel [axi-cel], lisocabtagene maraleucel [liso-cel], tisagenlecleucel [tisa-cel]) patients with R/R LBCL in the USA. Three-month post-infusion costs were derived from unit costs and real-world all-payer (RW) site-specific utilization data for 1175 patients with diffuse R/R LBCL (CAR T cell therapy October 2017-September 2020). Therapy- and site-specific grade 3+ cytokine release syndrome (CRS) and neurologic event (NE) incidences were imputed from published trials. Lifetime quality-adjusted life-years (QALYs) and long-term costs were calculated from therapy-specific overall and progression-free survival data, adjusted for differences in trial populations. The base case used 17% outpatient site (RW) for all therapies. ZUMA-1 trial cohorts 1/2 informed other axi-cel base case inputs; ZUMA-1 cohorts 4/6 data (updated safety management) supported scenario analyses. RESULTS: Base case total costs for axi-cel exceeded liso-cel ($637 K versus $621 K) and tisa-cel ($631 K versus $577 K) costs. Three-month post-infusion costs were $57 K to $59 K across all therapies. Total QALYs for axi-cel also exceeded those for liso-cel (7.7 versus 5.9) and tisa-cel (7.2 versus 5.0) with incremental costs per QALY gained of $9 K versus liso-cel and $25 K versus tisa-cel. Base case incremental net monetary benefit was $255 K (95% confidence interval (CI) $181-326 K) for axi-cel versus liso-cel, and $280 K (95% CI $200-353 K) versus tisa-cel. Longer survival with axi-cel conferred higher lifetime costs. In all scenarios (e.g., varied outpatient proportions, CRS/NE incidence), axi-cel was cost-effective versus both comparators at a maximum willingness-to-pay of under $26 K/QALY as a result of axi-cel's higher incremental survival gains and quality-of-life. CONCLUSIONS: Axi-cel is a cost-effective CAR T cell therapy for patients with R/R LBCL compared to tisa-cel and liso-cel. Site of care does not impact the cost-effectiveness of CAR T cell therapy.

Approaches to Selecting "Time Zero" in External Control Arms with Multiple Potential Entry Points: A Simulation Study of 8 Approaches.

BACKGROUND: When including data from an external control arm to estimate comparative effectiveness, there is a methodological choice of when to set "time zero," the point at which a patient would be eligible/enrolled in a contemporary study. Where patients receive multiple lines of eligible therapy and thus alternative points could be selected, this issue is complex. METHODS: A simulation study was conducted in which patients received multiple prior lines of therapy before entering either cohort. The results from the control and intervention data sets are compared using 8 methods for selecting time zero. The base-case comparison was set up to be biased against the intervention (which is generally received later), with methods compared in their ability to estimate the true intervention effectiveness. We further investigate the impact of key study attributes (such as sample size) and degree of overlap in time-varying covariates (such as prior lines of therapy) on study results. RESULTS: Of the 8 methods, 5 (all lines, random line, systematically selecting groups based on mean absolute error, root mean square error, or propensity scores) showed good performance in accounting for differences between the line at which patients were included. The first eligible line can be statistically inefficient in some situations. All lines (with censoring) cannot be used for survival outcomes. The last eligible line cannot be recommended. CONCLUSIONS: Multiple methods are available for selecting the most appropriate time zero from an external control arm. Based on the simulation, we demonstrate that some methods frequently perform poorly, with several viable methods remaining. In selecting between the viable methods, analysts should consider the context of their analysis and justify the approach selected. HIGHLIGHTS: There are multiple methods available from which an analyst may select "time zero" in an external control cohort.This simulation study demonstrates that some methods perform poorly but most are viable options, depending on context and the degree of overlap in time zero across cohorts.Careful thought and clear justification should be used when selecting the strategy for a study.

Cost-effectiveness of axicabtagene ciloleucel versus lisocabtagene maraleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the US.

AIMS: This study evaluated from a US payer perspective the cost-effectiveness of two chimeric antigen receptor T (CAR T) cell therapies, axicabtagene ciloleucel (axi-cel) versus lisocabtagene maraleucel (liso-cel), for the treatment of adult patients with relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following two or more systemic therapy lines. METHODS: We developed a 3-state (i.e., pre-progression, post-progression, death) partitioned survival model to estimate patients' lifetime outcomes. Mixture cure models were used for survival extrapolation to account for long-term remission. Survival inputs were based on a matching-adjusted indirect comparison (MAIC) that reweighted the ZUMA-1 population (receiving axi-cel) to match patient characteristics in TRANSCEND-NHL-001 (assessing liso-cel). Costs included apheresis, drug acquisition, and administration for conditioning chemotherapy and CAR T therapies, monitoring, transplant, hospitalization, adverse events, routine care, and terminal care, per published literature and databases. Utilities were derived from ZUMA-1 and literature. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: In the base case, axi-cel was associated with more QALYs (7.76 vs. 5.94) and greater costs overall ($611,440 vs. $597,174) than liso-cel, at $7,843/QALY gained. The incremental costs (+$14,266) were largely driven by higher routine care costs (+$18,596) due to longer survival and hospitalization (+$10,993) but partially offset by reduced costs of CAR T acquisition (‒$11,300) and terminal care (‒$4,025). Sensitivity analyses consistently suggested robustness of base-case results. LIMITATIONS: This study relied on an MAIC in which trial design differences and unobserved confounders could not be accounted for. Future real-world studies for recently approved CAR T are warranted to validate our results. Due to a lack of data, we assumed equivalent use of transplants and treatment for B-cell aplasia between the two therapies based on clinicians' opinions. CONCLUSIONS: In the US, axi-cel is a potentially cost-effective treatment option compared with liso-cel for adult patients with r/r LBCL after two or more systemic therapy lines.

Burden of Illness and Treatment Patterns in Second-line Large B-cell Lymphoma.

PURPOSE: This study examined real-world treatment patterns with curative intent, adverse events, and health care resource utilization and costs in patients with relapsed or refractory large B-cell lymphoma (LBCL) to understand the unmet medical need in the United States. METHODS: Adult patients with ≥2 LBCL diagnoses between January 1, 2012, and March 31, 2019, were identified (index date was the date of the earliest LBCL diagnosis) from MarketScan® Commercial and Medicare Supplemental Databases. Patients had ≥1 claim for any LBCL treatment, ≥6 months of data before (baseline) and ≥12 months of data after (follow-up period) the index date, and no baseline LBCL diagnosis. Treatment patterns, adverse events, and all-cause and LBCL-related health care resource utilization and costs were examined. All patients had received first-line therapy of cyclophosphamide, doxorubicin, vincristine, and prednisone with or without rituximab; etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride with or without rituximab; or regimens with anthracycline and second-line therapy with stem cell transplant (SCT)-intended intensive therapy or platinum-based chemotherapy. Patients who received an SCT-intended second-line regimen or received an SCT regardless of second-line regimen were considered SCT eligible. FINDINGS: A total of 188 patients met the criteria of eligibility for SCT. Among the 119 patients who received a second-line regimen intended for SCT, only 22.7% received an SCT. Patients eligible for SCT started first-line therapy within 1 month of their LBCL index date, and the mean duration of first-line therapy was 4.1 months. The mean gap in therapy between first- and second-line therapy was 6.6 months, and the mean duration of second-line therapy was 3.0 months. During the second-line therapy treatment window (mean duration with SCT, 12.4 months; mean duration without SCT, 4.8 months), the most common regimens for patients eligible for SCT were ifosfamide, carboplatin, and etoposide with or without rituximab and gemcitabine and oxaliplatin with or without rituximab; the top 4 most common treatment-related adverse events were febrile neutropenia (56.4%), anemia (49.5%), thrombocytopenia (42.6%), and nausea and vomiting (36.2%), which were similar regardless of receipt of SCT; mean (SD) per-patient-per-month all-cause costs were $46,174 ($49,057) for patients with SCT and $45,780 ($52,813) for patients without SCT. IMPLICATIONS: Treatment patterns among patients with relapsed or refractory LBCL eligible for SCT were highly varied. Only 22.7% of patients who received an SCT-preparative regimen ultimately received SCT, which highlights the magnitude of unmet needs in this population. The occurrence of treatment-related adverse events was similar regardless of SCT status. Per-patient-per-month all-cause costs were also similar with upfront SCT costs averaged during a longer follow-up.

Patient Perspectives on Health-Related Quality of Life in Diffuse Large B-Cell Lymphoma Treated with Car T-Cell Therapy: A Qualitative Study.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR T) therapy offers a potentially curative option for patients with relapsed and refractory hematologic malignancies, including diffuse large B-cell lymphoma (DLBCL). Patient-reported experiences with CAR T therapy are limited and have not been well characterized. The purpose of this qualitative study was to explore patient descriptions of key domains of health-related quality of life (HRQoL) in DLBCL patients treated with CAR T therapy. METHODS: A targeted literature review was initially conducted to inform the development of the interview guide comprising predetermined open-ended questions. Two focus groups were conducted with a total of 18 patients with DLBCL identified from patient advisory boards. Focus group sessions were recorded and transcribed verbatim. MAXQDA 18.2.0 qualitative data analysis software was utilized to facilitate a constant-comparative coding process to identify key concepts. RESULTS: Eight domain impairments (social functioning, emotional functioning, fatigue, physical functioning, cognitive functioning, role functioning, sleep, and pain/discomfort) were identified from the qualitative analysis and endorsed by DLBCL patients treated with CAR T. Compared with before CAR T therapy, patients reported increased impairment in every domain during or immediately after CAR T therapy. This impairment improved for each domain 6 months after CAR T therapy except for pain/discomfort. Compared with before CAR T therapy, improvement in impairment for each domain was observed 6 months after CAR T therapy except for fatigue, sleep, and pain/discomfort. CONCLUSION: This study provides meaningful information regarding the impact of CAR T therapy on HRQoL in patients with DLBCL throughout their treatment journey. Health care professionals and investigators can utilize these data in examining existing patient-reported outcome (PRO) measures that are used in DLBCL clinical trials and to better understand the needs of DLBCL survivors.

Cost effectiveness of axicabtagene ciloleucel versus tisagenlecleucel for adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy in the United States.

AIMS: To assess from a US payer perspective the cost-effectiveness of the chimeric antigen receptor T (CAR T)-cell therapies axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) to treat relapsed or refractory (r/r) large B-cell lymphoma (LBCL) following ≥2 systemic therapy lines. METHODS: A three-state (i.e. pre-progression, post-progression, and death) partitioned survival model was used to estimate the quality-adjusted life-years (QALYs) and costs for patients on each treatment over a lifetime horizon. Progression-free survival (PFS) and overall survival (OS) were based on a matching-adjusted indirect treatment comparison (MAIC) that accounted for differences in trial population baseline characteristics. Mixture cure models (MCMs) were used to account for long-term survivors. Costs included drug acquisition and administration for the CAR T-cell therapies and conditioning chemotherapy, apheresis, CAR T-specific monitoring, transplant, hospitalization, adverse events, routine care, and terminal care. Health state utilities were derived from trial and published data. Sensitivity analyses included probabilistic sensitivity analyses (PSAs) and an analysis of extremes that assessed the results across a vast array of combinations of parametric OS and PFS curves across the two therapies. RESULTS: Compared to tisa-cel, axi-cel resulted in 2.31 QALYs gained and a cost reduction of $1,407 in the base case. In the PSA, the cost per QALY gained was ≤$31,500 in 95% of the 1,000 simulations. In the analysis of extremes, the cost per QALY gained was ≤$7,500 in 99% of the 1,296 combinations of MCMs and ≤$40,000 in 95% of the 1,296 combinations of standard models. LIMITATIONS: In absence of head-to-head comparative data, we relied on a MAIC, which cannot account for all possible confounders. Moreover, some outcomes (i.e. transplantations, hospitalizations, adverse events (AEs)) were not adjusted in the MAIC. CONCLUSIONS: In this simulation, axi-cel was a superior treatment option as it is predicted to achieve better outcomes at lower or minimal incremental costs versus tisa-cel.

Assessing the prior event rate ratio method via probabilistic bias analysis on a Bayesian network.

BACKGROUND: Unmeasured confounders are commonplace in observational studies conducted using real-world data. Prior event rate ratio (PERR) adjustment is a technique shown to perform well in addressing such confounding. However, it has been demonstrated that, in some circumstances, the PERR method actually increases rather than decreases bias. In this work, we seek to better understand the robustness of PERR adjustment. METHODS: We begin with a Bayesian network representation of a generalized observational study, which is subject to unmeasured confounding. Previous work evaluating PERR performance used Monte Carlo simulation to calculate joint probabilities of interest within the study population. Here, we instead use a Bayesian networks framework. RESULTS: Using this streamlined analytic approach, we are able to conduct probabilistic bias analysis (PBA) using large numbers of combinations of parameters and thus obtain a comprehensive picture of PERR performance. We apply our methodology to a recent study that used the PERR in evaluating elderly-specific high-dose (HD) influenza vaccine in the US Veterans Affairs population. That study obtained an HD relative effectiveness of 25% (95% CI: 2%-43%) against influenza- and pneumonia-associated hospitalization, relative to standard-dose influenza vaccine. In this instance, we find that the PERR-adjusted result is more like to underestimate rather than to overestimate the relative effectiveness of the intervention. CONCLUSIONS: Although the PERR is a powerful tool for mitigating the effects of unmeasured confounders, it is not infallible. Here, we develop some general guidance for when a PERR approach is appropriate and when PBA is a safer option.

How Does Treating Chronic Hepatitis C Affect Individuals in Need of Organ Transplants in the United Kingdom?

OBJECTIVES: To estimate the impact of cures for chronic hepatitis C (CHC) infection on organ donation in the United Kingdom. Curing CHC infection reduces the need for liver transplants and enables cured individuals to donate organs of all types. METHODS: We adapted a double-queuing model of organ allocation to estimate the effects of CHC infection cures on liver, lung, heart, and kidney transplants in the United Kingdom. We assumed that cured individuals would donate organs at similar rates as the general population and no longer require liver transplants because of CHC infection. We estimated how curing CHC infection influences waitlist lengths for each organ and the annual net present value to society on the basis of quality-adjusted life-years gained through additional transplants under opt-in and opt-out organ donation policies. RESULTS: Curing CHC generates the most value for patients on the liver waitlist, because it increases the number of transplantable livers and reduces the need for transplants. Under the current opt-in policy, liver waitlist length falls by 24%, generating £34.3 million of annual net present value. Growth in the number of uninfected lungs, hearts, and kidneys generates an additional £19.2 million annually, with £18.7 million from kidneys. Implementing the opt-out policy, liver waitlist length would decrease by 75%, implying that treating CHC eliminates one-third of the excess liver waitlist due to an opt-in policy. CONCLUSIONS: Treating CHC has large positive spillovers to uninfected individuals by reducing the need for liver transplants and allowing cured individuals to donate organs. These spillovers have not been included in traditional value assessments of CHC treatment.

Association Between State Medicaid Eligibility Thresholds and Deaths Due to Substance Use Disorders.

Importance: The United States is currently facing an epidemic of deaths related to substance use disorder (SUD), with totals exceeding those due to motor vehicle crashes and gun violence. The epidemic has led to decreased life expectancy in some populations. In recent years, Medicaid eligibility has expanded in some states, and the association of this expansion with SUD-related deaths is yet to be examined. Objective: To examine the association between eligibility thresholds for state Medicaid coverage and SUD-related deaths. Design, Setting, and Participants: Economic evaluation study using a retrospective analysis of state-level data between 2002 and 2015 to determine the association between the Medicaid eligibility threshold and SUD-related deaths, controlling for other relevant policies, state socioeconomic characteristics, fixed effects, and a time trend. Policy variables were lagged by 1 year to allow time for associations to materialize. Data were collected and analyzed from 2016 to 2017. Exposures: The policy of interest was the state Medicaid eligibility threshold, ie, the highest allowed income that qualifies a person for Medicaid, expressed as a percentage of the federal poverty level. State policies related to mental health, overdose treatment, and law enforcement of drug crimes were included as controls. Main Outcomes and Measures: The primary outcome was number of SUD-related deaths, obtained from data provided by the Centers for Disease Control and Prevention. Results: Across 700 state-year observations, the mean (SD) number of SUD-related deaths was 21.15 (6.05) per 100 000 population. Between 2002 and 2015, the national SUD-related death rate increased from 16.0 to 27.5 per 100 000, while the average Medicaid eligibility threshold increased from 87.2% to 97.1% of the federal poverty level. Over this period, every 100-percentage point increase in the Medicaid eligibility threshold (eg, from 50% to 150% of the federal poverty level) was associated with 1.373 (95% CI, -2.732 to -0.014) fewer SUD-related deaths per 100 000 residents, a reduction of 6.50%. In the 22 states with net contractions in eligibility thresholds between 2005 and 2015, an estimated increase of 570 SUD-related deaths (95% CI, -143 to 1283) occurred. In the 28 states that increased eligibility thresholds, an estimated 1045 SUD-related deaths (95% CI, -209 to 2299) may have been prevented. Conclusions and Relevance: These findings suggest that the overall increase in SUD-related deaths between 2002 and 2015 may have been greater had the average eligibility threshold for Medicaid not increased over this period. Broader eligibility for Medicaid coverage may be one tool to help reduce SUD-related deaths.

Challenges with Forecasting Budget Impact: A Case Study of Six ICER Reports.

BACKGROUND: Payers frequently rely on budget impact model (BIM) results to help determine drug coverage policy and its effect on their bottom line. It is unclear whether BIMs typically overestimate or underestimate real-world budget impact. OBJECTIVE: We examined how different modeling assumptions influenced the results of 6 BIMs from the Institute for Clinical and Economic Review (ICER). STUDY DESIGN: Retrospective analysis of pharmaceutical sales data. METHODS: From ICER reports issued before 2016, we collected estimates of 3 BIM outputs: aggregate therapy cost (ie, cost to treat the patient population with a particular therapy), therapy uptake, and price. We compared these against real-world estimates that we generated using drug sales data. We considered 2 classes of BIM estimates: those forecasting future uptake of new agents, which assumed "unmanaged uptake," and those describing the contemporaneous market state (ie, estimates of current, managed uptake and budget impact for compounds already on the market). RESULTS: Differences between ICER's estimates and our own were largest for forecasted studies. Here, ICER's uptake estimates exceeded real-world estimates by factors ranging from 7.4 (sacubitril/valsartan) to 54 (hepatitis C treatments). The "unmanaged uptake" assumption (removed from ICER's approach in 2017) yields large deviations between BIM estimates and real-world consumption. Nevertheless, in some cases, ICER's BIMs that relied on current market estimates also deviated substantially from real-world sales data. CONCLUSIONS: This study highlights challenges with forecasting budget impact. In particular, assumptions about uptake and data source selection can greatly influence the accuracy of results.

Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an instrumental variable method.

BACKGROUND: Observational studies of the relative effectiveness of influenza vaccines are essential for public health decision making. Their estimates, however, are subject to bias due to unmeasured confounders. Instrumental variable (IV) methods can control for observed and unobserved confounders. METHODS: We used linked electronic medical record databases in the Veterans Health Administration (VHA) as well as Medicare administrative files to examine the relative vaccine effectiveness (rVE) of high-dose influenza vaccine (HD) versus standard-dose influenza vaccines (SD) in preventing hospitalizations among VHA-enrolled Veterans ≥65 years of age during 5 influenza seasons (2010-2011 through 2014-2015). Using multivariable IV Poisson regression modeling to address unmeasured confounding and bias, we analyzed the data by each season and through longitudinal analysis of all five seasons. FINDINGS: We included 3,638,924 person-influenza seasons of observation where 158,636 (4%) were among HD vaccine recipients and 3,480,288 (96%) were among SD vaccine recipients. Of the 1,728,562 Veterans, 1,702,824 (98.5%) were male and 1,299,412 (75%) were non-Hispanic white. Based on the longitudinal analysis of all five seasons, the IV-adjusted rVE estimate of HD vs. SD was 10% (95% CI, 8-12%) against all-cause hospitalization; 18% (95% CI, 15-21%) against cardiorespiratory-associated hospitalization; and 14% (95% CI, 6-22%) against influenza/pneumonia-associated hospitalization. The findings by season were similar. INTERPRETATION: Our analysis of VHA clinical data collected from approximately 1.7 million Veterans 65 years and older during five seasons demonstrates that high-dose influenza vaccine is more effective than standard-dose influenza vaccines in preventing influenza- or pneumonia-associated hospitalizations, cardiorespiratory hospitalizations, and all-cause hospitalizations.

Examination of universal purchase programs as a driver of vaccine uptake among US States, 1995-2014.

BACKGROUND: Immunization against numerous potentially life-threatening illnesses has been a great public health achievement. In the United States, the Vaccines for Children (VFC) program has provided vaccines to uninsured and underinsured children since the early 1990s, increasing vaccination rates. In recent years, some states have adopted Universal Purchase (UP) programs with the stated aim of further increasing vaccination rates. Under UP programs, states also purchase vaccines for privately-insured children at federally-contracted VFC prices and bill private health insurers for the vaccines through assessments. METHODS: In this study, we estimated the effect of UP adoption in a state on children's vaccination rates using state-level and individual-level data from the 1995-2014 National Immunization Survey. For the state-level analysis, we performed ordinary least squares regression to estimate the state's vaccination rate as a function of whether the state had UP in the given year, state demographic characteristics, other vaccination policies, state fixed effects, and a time trend. For the individual analysis, we performed logistic regression to estimate a child's likelihood of being vaccinated as a function of whether the state had UP in the given year, the child's demographic characteristics, state characteristics and vaccine policies, state fixed effects, and a time trend. We performed separate regressions for each of nine recommended vaccines, as well as composite measures on whether a child was up-to-date on all required vaccines. RESULTS: In the both the state-level and individual-level analyses, we found UP had no significant (p < 0.10) effect on any of the vaccines or composite measures in our base case specifications. Results were similar in alternative specifications. CONCLUSIONS: We hypothesize that UP was ineffective in increasing vaccination rates. Policymakers seeking to increase vaccination rates would do well to consider other policies such as addressing provider practice issues and vaccine hesitancy.

Relative Vaccine Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among Veterans Health Administration Patients.

Background: We examined whether a high-dose inactivated influenza vaccine was more efficacious in preventing hospitalizations than a standard-dose vaccine in the Veterans Health Administration (VHA) senior population. Methods: This study estimated the relative vaccine effectiveness (rVE) of high dose versus standard dose using a retrospective cohort of VHA patients 65 years of age or older in the 2015-2016 influenza season. To adjust for measured confounders, we matched each high-dose recipient with up to 4 standard-dose recipients vaccinated at the same location within a 2-week period and having 2 or more pre-existing medical comorbidities. We used the previous event rate ratio method (PERR), a type of difference-in-differences analysis, to adjust for unmeasured confounders. Results: We evaluated 104965 standard-dose and 125776 high-dose recipients; matching decreased the population to 49091 standard-dose and 24682 high-dose recipients. The matched, PERR-adjusted rVE was 25% (95% confidence interval [CI], 2%-43%) against influenza- or pneumonia-associated hospitalization, 7% (95% CI, -2% to 14%) against all-cause hospitalization, 14% (95% CI, -8% to 32%) against influenza- or pneumonia-associated outpatient visit, 5% (95% CI, 2%-8%) against all-cause outpatient visit, and 38% (95% CI, -5% to 65%) against laboratory-confirmed influenza. Conclusions: In protecting senior VHA patients against influenza- or pneumonia-associated hospitalization, a high-dose influenza vaccine is more effective than a standard-dose vaccine.

Association Between Breast Cancer Disease Progression and Workplace Productivity in the United States.

OBJECTIVE: Determine workplace productivity losses attributable to breast cancer progression. METHODS: Longitudinal analysis linking 2005 to 2012 medical and pharmacy claims and workplace absence data in the US patients were commercially insured women aged 18 to 64 diagnosed with breast cancer. Productivity was measured as employment status and total quarterly workplace hours missed, and valued using average US wages. RESULTS: Six thousand four hundred and nine women were included. Breast cancer progression was associated with a lower probability of employment (hazard ratio [HR] = 0.65, P < 0.01) and increased workplace hours missed. The annual value of missed work was $24,166 for non-metastatic and $30,666 for metastatic patients. Thus, progression to metastatic disease is associated with an additional $6500 in lost work time (P < 0.05), or 14% of average US wages. CONCLUSIONS: Breast cancer progression leads to diminished likelihood of employment, increased workplace hours missed, and increased cost burden.