Comparing Efficacy, Safety, and Preinfusion Period of Axicabtagene Ciloleucel versus Tisagenlecleucel in Relapsed/Refractory Large B Cell Lymphoma.

Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are autologous anti-CD19 chimeric antigen receptor T (CAR T) cell therapies for the treatment of patients with relapsed/refractory large B cell lymphoma (RR-LBCL). Both can induce durable responses; however, cross-trial comparisons are difficult due to differences in study design. In this study, the registration trials of axi-cel and tisa-cel were compared using a matching adjusted indirect comparison (MAIC). A MAIC was performed to adjust for differences in patient characteristics between trials. The estimates for the ZUMA-1 (axi-cel) trial were adjusted using patient-level data to match the study population in JULIET (tisa-cel) for key variables: International Prognostic Index), Eastern Cooperative Oncology Group score, stage, refractoriness or relapsed disease, double/triple hit status, cell of origin, and number of prior lines of therapy. The endpoints analyzed were response, overall survival (OS), and adverse events. After adjusting for differences in patient characteristics between trials, axi-cel was associated with a greater objective response rate (relative risk [RR]=1.61; 95% confidence interval [CI], 1.29 to 2.01) and complete response (RR = 1.62; 95% CI, 1.16 to 2.27) than tisa-cel among patients who underwent infusion. The OS from infusion onward comparing axi-cel to tisa-cel had a hazard ratio of 0.51 (95% CI, 0.31 to 0.83). The indirect comparison showed a higher rate of grade 1 to 2 cytokine release syndrome (CRS) in ZUMA-1 compared with JULIET (RR = 2.03; 95% CI, 1.55 to 2.65) and similar rates of grade ≥3 CRS and neurologic events. In the absence of a direct head-to-head study, the MAIC statistical technique suggests axi-cel may have superior efficacy but a greater risk of grade 1 to 2 CRS. Future real-world studies can further inform the relative efficacy and safety of CAR T therapies in RR-LBCL.

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.

Estimating Long-Term Survival of Adults with Philadelphia Chromosome-Negative Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia Treated with Blinatumomab Using Historical Data.

INTRODUCTION: Blinatumomab is a bispecific T cell-engaging antibody construct indicated for adult patients with relapsed/refractory (R/R) Ph(-) B-precursor acute lymphoblastic leukemia (ALL), an aggressive disease with poor prognosis. A phase 2 single-arm clinical study showed that 43% of patients achieved CR/CRh within two cycles and approximately 20% of patients receiving blinatumomab were still alive after 2 years. METHODS: The objective of the current analysis was to estimate long-term survival of patients receiving blinatumomab beyond the observed time period in the clinical study using a large historical observational dataset. Conditional survival probabilities of blinatumomab-treated patients beyond month 60 were assumed to be the same as the US general population. RESULTS: At month 60, the estimated proportion of blinatumomab-treated patients alive was more than double that of historical patients (12.6% vs 5.4%). The mean overall survival was 76.1 months for blinatumomab patients and 39.8 months for historical patients. Sensitivity analyses including additional follow-up data from the clinical study showed consistent results. CONCLUSIONS: These findings suggest that blinatumomab provides substantial overall survival benefit to patients with (R/R) Ph(-) B-precursor ALL compared with salvage chemotherapy. FUNDING: Amgen. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01466179 and NCT02003612.

Association between health-related quality of life and body mass after adjustable gastric banding: a nonlinear approach.

OBJECTIVE: To estimate the relationship between health utilities and body mass index (BMI) among a cohort of obese patients who underwent laparoscopic adjustable gastric banding (LAGB). METHODS: We used a cross-sectional survey to ascertain demographic, clinical, and health utility data from patients who had undergone LAGB in Washington State from 2004 to 2010. The EuroQol five-dimensional (EQ-5D) questionnaire was used for health utility estimation. We calculated adjusted EQ-5D questionnaire indices across BMI categories by using a two-part model. We also used logistic regression to examine the relationship between BMI and the likelihood of reporting problems on each of the EQ-5D questionnaire dimension. RESULTS: Data were obtained from 790 subjects. The mean adjusted EQ-5D questionnaire indices for all obese BMI categories were significantly lower than those in the normal weight category. The relationship between BMI and EQ-5D questionnaire indices was nonlinear. Respondents classified as morbidly obese II (BMI > 50 kg/m(2)) had the greatest decrement (-0.15, 95% confidence interval -0.28 to -0.01) in EQ-5D questionnaire indices. The association between EQ-5D questionnaire indices and BMI at the time of the survey was weaker after adjusting for weight loss after LAGB. Respondents with higher BMI were more likely to report having problems in the mobility, usual/activity, pain/discomfort, and anxiety/depression dimensions (trend test, P < 0.05), but not for the self-care dimension (trend test, P = 0.08). CONCLUSIONS: The EQ-5D questionnaire has a negative and nonlinear relationship with BMI for obese patients who had LAGB. The relationship is confounded by weight loss. Within the EQ-5D questionnaire dimensions, patients are more likely to report having problems in the mobility, usual/activity, pain/discomfort, and anxiety/depression dimensions in higher BMI categories, but not in the self-care dimension.

Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding.

BACKGROUND: Studies demonstrate the potential for statins to prevent dementia and Alzheimer's disease (AD), but the evidence is inconclusive. OBJECTIVE: Conduct a meta-analysis to estimate any benefit of statins in preventing dementia and examine the potential effect of study design and confounding on the benefit of statins in dementia. A secondary goal is to explore factors that may elucidate the mechanisms by which statins exert their potentially beneficial effect. METHODS: Performed systematic literature review to identify relevant publications. Relative risk (RR) estimates were pooled using both fixed and random effect models. Studies were stratified by study design and potential confounding factors. RESULTS: The pooled results for all-type dementia suggest that use of statins is associated with a lower RR of dementia when compared to non-statin users (random effects model: RR 0.82 (95%CI [0.69, 0.97]). The pooled results for AD also suggested a lower RR with statin user compared to non-statin users in random effects models (RR: 0.70, 95% CI [0.60, 0.83]). Study design and methods used to address biases may influence the results. CONCLUSION: These pooled results suggest that statins may provide a slight benefit in the prevention of AD and all-type dementia. This benefit observed in both disease states should be interpreted with caution as observational studies are subject to bias, and it is possible that the slight benefit observed may disappear when these biases are addressed in a well-designed randomized controlled trial.

Patients' experience and outcomes after laparoscopic adjustable gastric banding in Washington state.

BACKGROUND: There is very little evidence regarding the real world experience and outcomes after laparoscopic adjustable gastric banding (LAGB). Our objective was to estimate the amount of postoperative weight loss, change in co-morbidity status, and complications after LAGB. The setting was LAGB surgical centers in Washington state. METHODS: A cross-sectional survey was developed to collect primary data from patients who had undergone LAGB in Washington state from 2004 to 2010. The survey contained questions on patient characteristics, weight change, co-morbidities, and complications after LAGB surgery. We used descriptive and other statistical tests to evaluate our key research questions by the period since LAGB. RESULTS: A total of 1556 surveys were sent out, and 790 were returned (response rate 50.8%). Responders were categorized into 4 groups according to the follow-up period: <2, 2-3, 3-4, and >4 years. The corresponding average body mass index reduction in each group was 21.0%, 22.5%, 21.3%, and 20.4%. Of the respondents, 21.7%, 34.8%, 44.6%, and 38.7% indicated they did not have any adjustments in the year preceding the survey. The percentage of respondents who had undergone additional operations related to LAGB was 8.6%. Specifically, 3.6% of the respondents had undergone either band removal or conversion to another type of bariatric operation. CONCLUSION: We found that although LAGB appeared to be beneficial for weight reduction and improving co-morbidities, the underuse of band adjustments and significant rate of treatment failure might limit the long-term effectiveness of LAGB.

Comparison of Ustekinumab With Other Biological Agents for the Treatment of Moderate to Severe Plaque Psoriasis: A Bayesian Network Meta-analysis.

OBJECTIVE To compare the efficacy of ustekinumab with that of other biological agents using the Psoriasis Area and Severity Index (PASI) among adult patients with moderate to severe plaque psoriasis. DATA SOURCES We conducted a systematic search of the period January 31, 1992, to February 1, 2012, using MEDLINE (PubMed), Embase, the Cochrane Library, and clinicaltrials.gov. STUDY SELECTION We included randomized controlled trials of biological agents compared with placebo or other biological agents using the PASI in patients who had moderate to severe plaque psoriasis. DATA EXTRACTION Study data were extracted independently by 2 of us, with disagreement resolved by consensus. Data extracted included the size of the trial, follow-up period, age range of patients, disease duration, body surface area involvement, baseline PASI, PASI response, and previous treatment with biological agents. DATA SYNTHESIS A Bayesian network meta-analysis was performed by fitting 3 regression models: a fixed-effects model, a random-effects model, and a random-effects model with meta-regression coefficients. The random-effects model achieved the best fit for these data. In pairwise comparisons, ustekinumab use was associated with statistically significantly higher odds for achieving a 75% reduction in the PASI compared with adalimumab use (odds ratio [OR], 1.84; 95% credible interval [CrI], 1.01-3.54), alefacept use (OR, 10.38; CrI, 3.44-27.62), and etanercept use (OR, 2.07; 95% CrI, 1.42-3.06) but was associated with lower odds compared with infliximab use (OR, 0.36; 95% CrI, 0.14-0.82) . In the therapeutic class comparison, the interleukin-12/23 inhibitor had the highest odds for achieving a 75% reduction in the PASI compared with placebo (OR, 69.48; 95% CrI, 36.89-136.46), followed by tumor necrosis factor inhibitors (OR, 42.22; 95% CrI, 27.94-69.34) and the T-cell inhibitor (OR, 5.63; 95% CrI, 1.35-24.24). CONCLUSION For the treatment of moderate to severe plaque psoriasis, ustekinumab may be more efficacious than adalimumab, etanercept, and alefacept but not infliximab.