CAR T-cell therapy in relapsed/refractory diffuse large B-cell lymphoma: physician preferences trading off benefits, risks and time to infusion.

Aims: We evaluated physicians' willingness to trade-off benefits, risks and time to infusion for CAR T-cell therapy for relapsed or refractory diffuse large B-cell lymphoma. Materials & methods: In a discrete-choice experiment survey, 150 US oncologists/hematologists chose between two hypothetical CAR T-cell treatments defined by six attributes. Results: Decreasing time to infusion from 113 to 16 days yielded the greatest change in preference weight (1.91). Physicians were willing to accept a >20% increase in risk of severe cytokine release syndrome and 15% increase in risk of severe neurological events in exchange for an increase in the probability of overall survival at 24 months from 40 to 55%. Conclusion: Physicians value reducing time to infusion and will accept incremental increases in serious adverse event risks to gain survival improvements.

Lay abstract CAR-T therapy is a treatment option for patients with diffuse large B-cell lymphoma that has not responded to at least two other kinds of treatments. CAR-T therapies are manufactured from a patient's white blood cells, modified to attack lymphoma cells. A CAR-T therapy takes time to manufacture after these cells are collected. CAR-T therapies can result in the reduction or disappearance of lymphoma tumors and can increase the chances of survival, but also cause serious side effects for a few patients. One of these is cytokine release syndrome (CRS), in which high levels of inflammation throughout the body may cause fever, heart problems or difficulty breathing. Another is the development of temporary but serious neurological problems such as confusion, seizures and memory problems. To understand how important physicians consider certain features of CAR-T therapies to be when deciding whether to recommend them, we asked physicians to choose between two treatment options resembling CAR-T therapies in a series of questions, with the CAR-T features varying in each question. Their answers indicated whether disappearance of tumors, a patient's chances of survival after 1 and 2 years of treatment, manufacturing time, or the risk of CRS or neurological problems was the most important factor. Physicians most wanted to reduce manufacturing time from 113 to 16 days, but also were willing to accept a >20% increase in risk of severe CRS and a 15% increase in risk of severe neurological events to increase a patient's chance of survival from 40 to 55% at 2 years.

Direct Costs Associated with Relapsed Diffuse Large B-Cell Lymphoma Therapies.

BACKGROUND: About one third of patients with diffuse large B-cell lymphoma (DLBCL) relapse after receiving first-line (1L) treatment of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Relapsed patients may then be eligible for second-line (2L) therapy. The study's objective was to examine health care use and costs among treated patients with DLBCL receiving 2L therapy versus those without relapse. MATERIALS AND METHODS: We analyzed Truven Health MarketScan® claims data between 2006 and 2015. Patients (≥18 years of age) had ≥1 DLBCL claim from 1 year before to 90 days after beginning 1L therapy, and comprised those without 2L treatment for ≥2 years (cured controls) versus those who initiated non-R-CHOP chemotherapy after discontinuing 1L therapy (2L cohort). 2L patients were further subgrouped: hematopoietic stem cell transplant (HSCT [yes/no]) and time of relapse (months between 1L and 2L): early (≤3), mid (4-12), and late (>12) relapse. The primary outcome was 1- and 2-year health care costs. Hospitalization rate and length of stay were also measured. RESULTS: A total of 1,374 patients with DLBCL received R-CHOP and fulfilled all criteria: 1,157 cured controls and 217 2L patients (87 early-relapse, 66 mid-relapse, 64 late-relapse). Twenty-eight percent of 2L patients received HSCT. Charlson Comorbidity Index/mortality risk was higher for 2L patients (4.2 [SD: 3.0]) versus controls (3.8 [2.6]; p = .039), as were yearly costs (Year 1: $210,488 [$172,851] vs. $25,044 [$32,441]; p < .001 and Year 2: $267,770 [$266,536] vs. $42,272 [$49,281]; p < .001). HSCT and chemotherapy were each significant contributors of cost among 2L patients. CONCLUSION: DLBCL is resource intensive, particularly for 2L patients. Great need exists for newer, effective therapies for DLBCL that may save lives and reduce costs. IMPLICATIONS FOR PRACTICE: This study identified multiple important drivers of cost in the understudied population of patients with diffuse large B-cell lymphoma (DLBCL) receiving second-line (2L) treatment. Such drivers included hematopoietic stem cell transplant (HSCT) and chemotherapy. Even though HSCT is currently the only curative therapy for DLBCL, less than one third of patients receiving 2L and subsequent treatment underwent transplant, which indicates potential underuse. The variation in chemotherapy regimens suggested a lack of consensus for best practices. Further research focusing on newer and more effective treatment options for DLBCL has the potential to decrease mortality, in addition to reducing the extensive costs related to therapy options such as transplant.

Estimating Long-Term Survival for Patients with Relapsed or Refractory Large B-Cell Lymphoma Treated with Chimeric Antigen Receptor Therapy: A Comparison of Standard and Mixture Cure Models.

Patients treated with anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have shown either sustained remission or rapid progression. Traditional survival modeling may underestimate outcomes in these situations, by assuming the same mortality rate for all patients. To illustrate this issue, we compare standard parametric models to mixture cure models for estimating long-term overall survival in patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel). Compared to standard models without cure proportions, mixture cure models have similar fit, but substantially different extrapolated survival. Standard models (Weibull and generalized gamma) estimate mean survival of 2.0 years (95% CI (1.5, 3.0)) and 3.0 years (95% CI (1.7, 5.6)), respectively, compared to 15.7 years (95% CI (9.3, 21.1)) and 17.5 yrs (12.0, 22.8) from mixture cure models (using Weibull and generalized gamme distributions). For cancer therapies where substantial fractions achieve long term remission, our results suggest that assumptions of the modeling approach should be considered. Given sufficient follow-up, mixture cure models may provide a more accurate estimate of long-term overall survival compared with standard models.

Cost-effectiveness of axicabtagene ciloleucel for adult patients with relapsed or refractory large B-cell lymphoma in the United States.

PURPOSE: Axicabtagene ciloleucel (axi-cel) was recently approved for treatment of relapsed or refractory (R/R) large B-cell lymphoma (LBCL) following two or more prior therapies. As the first CAR T-cell therapy available for adults in the US, there are important questions about clinical and economic value. The objective of this study was to assess the cost-effectiveness of axi-cel compared to salvage chemotherapy using a decision model and a US payer perspective. MATERIALS AND METHODS: A decision model was developed to estimate life years (LYs), quality-adjusted life years (QALYs), and lifetime cost for adult patients with R/R LBCL treated with axi-cel vs salvage chemotherapy (R-DHAP). Patient-level analyses of the ZUMA-1 and SCHOLAR-1 studies were used to inform the model and to estimate the proportion achieving long-term survival. Drug and procedure costs were derived from US average sales prices and Medicare reimbursement schedules. Future healthcare costs in long-term remission was derived from per capita Medicare spending. Utility values were derived from patient-level data from ZUMA-1 and external literature. One-way and probabilistic sensitivity analyses evaluated uncertainty. Outcomes were calculated over a lifetime horizon and were discounted at 3% per year. RESULTS: In the base case, LYs, QALYs, and lifetime costs were 9.5, 7.7, and $552,921 for axi-cel vs 2.6, 1.1, and $172,737 for salvage chemotherapy, respectively. The axi-cel cost per QALY gained was $58,146. Cost-effectiveness was most sensitive to the fraction achieving long-term remission, discount rate, and axi-cel price. The likelihood that axi-cel is cost-effective was 95% at a willingness to pay of $100,000 per QALY. CONCLUSION: Axi-cel is a potentially cost-effective alternative to salvage chemotherapy for adults with R/R LBCL. Long-term follow-up is necessary to reduce uncertainties about health outcomes.

Systematic literature review of health-related quality of life among aggressive non-Hodgkin lymphoma survivors.

OBJECTIVE: Studies have shown that a proportion of patients with aggressive non-Hodgkin lymphoma (NHL) treated with standard chemotherapy will have long-term life expectancy comparable to those in the age-adjusted general population. This systematic literature review summarizes current literature regarding health-related quality of life (HRQoL) of long-term (≥2 years) survivors of aggressive NHL. METHODS: Electronic databases (without restriction on years) and abstracts from four major oncology and HRQoL conferences from 2014 to 2017 were searched. Studies were included if HRQoL or health utility was assessed at least 2 years after NHL diagnosis. Studies focusing on central nervous system lymphoma, or indolent NHL, were excluded. Results were categorized relative to baseline (improvement, deterioration or no change) and compared to the general population (better, comparable or worse). RESULTS: Fourteen studies met the inclusion criteria. Twelve studies included ≥1 HRQoL instrument, and two measured health utilities using EQ-5D. Half of the studies showed improvement (5/10) and half no change (5/10) in overall HRQoL. Compared to the general population, overall HRQoL was more comparable when assessed at ≥3 years from baseline (3/3 better or comparable) versus assessment at <3 years (2/3 better or comparable). Six studies reported on the physical HRQoL domain with improvement in 4/6 studies and no change in 2/6 studies. CONCLUSIONS: HRQoL of NHL survivors may improve from baseline and becomes more comparable to general population HRQoL with longer survival. Overall HRQoL improvement is driven mostly by improvements in the physical domain.

Cost-Effectiveness of Cetuximab as First-line Treatment for Metastatic Colorectal Cancer in the United States.

PURPOSE: We conducted a cost-effectiveness analysis incorporating recent phase III clinical trial (FIRE-3) data to evaluate clinical and economic tradeoffs associated with first-line treatments of KRAS wild-type (WT) metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: A cost-effectiveness model was developed using FIRE-3 data to project survival and lifetime costs of FOLFIRI plus either cetuximab or bevacizumab. Hypothetical KRAS-WT mCRC patients initiated first-line treatment and could experience adverse events, disease progression warranting second-line treatment, or clinical response and hepatic metastasectomy. Model inputs were derived from FIRE-3 and published literature. Incremental cost-effectiveness ratios (ICERs) were reported as US$ per life year (LY) and quality-adjusted life year (QALY). Scenario analyses considered patients with extended RAS mutations and CALGB/SWOG 80405 data; 1-way and probabilistic sensitivity analyses were conducted. RESULTS: Compared with bevacizumab, KRAS-WT patients receiving first-line cetuximab gained 5.7 months of life at a cost of $46,266, for an ICER of $97,223/LY ($122,610/QALY). For extended RAS-WT patients, the ICER was $77,339/LY ($99,584/QALY). Cetuximab treatment was cost-effective 80.3% of the time, given a willingness-to-pay threshold of $150,000/LY. Results were sensitive to changes in survival, treatment duration, and product costs. CONCLUSIONS: Our analysis of FIRE-3 data suggests that first-line treatment with cetuximab and FOLFIRI in KRAS (and extended RAS) WT mCRC patients may improve health outcomes and use financial resources more efficiently than bevacizumab and FOLFIRI. This information, in combination with other studies investigating comparative effectiveness of first-line options, can be useful to clinicians, payers, and policymakers in making treatment and resource allocation decisions for mCRC patients.

Step-up care improves impairment in uncontrolled asthma: an administrative data study.

OBJECTIVE: To determine whether step-up care recommended by national asthma guidelines improves asthma control in a large managed care organization. STUDY DESIGN: Cohort analysis. METHODS: A cohort with uncontrolled asthma, defined as impairment or risk in a 1-year consecutive period, was identified using electronic medical records among continuously enrolled patients with asthma aged 12 to 56 years. Guideline-based step level of care was determined 3 months before and 3 months after the index event of uncontrolled asthma according to an algorithm of asthma medication dispensing using electronic pharmacy data. Impairment based on short-acting ß-agonist canisters dispensed and risk based on asthma emergency or hospital care were compared during the following year in patients with vs without step-up care, adjusting for demographics, prior utilizations, asthma risk, and comorbidities. RESULTS: Uncontrolled asthma was identified in 7694 eligible patients (mean [SD] age, 35.7 [14.4] years; 54.0% female). Step-up care during the 3-month period after the uncontrolled asthma event was seen in 2160 of 7177 patients (30.1%) with classifiable step care. Step-up care was associated with significant reductions in impairment, with adjusted relative risks of 0.78 (95% confidence interval [CI], 0.73-0.85) during the first 6 months and 0.84 (95% CI, 0.78-0.90) during the full 12-month follow-up period. Emergency or hospital care was unaffected by step-up care. Subgroups with uncontrolled asthma defined by impairment only and risk only showed outcomes generally similar to those of the entire cohort. CONCLUSION: Guideline-based step-up care in uncontrolled asthma was determined by administrative data and was shown to be associated with significant and clinically meaningful improvements in asthma impairment but not risk.