Matching-adjusted indirect comparison from the Lymphoma Epidemiology of Outcomes Consortium for Real World Evidence (LEO CReWE) study to a clinical trial of mosunetuzumab in relapsed or refractory follicular lymphoma.

Mosunetuzumab is a novel bispecific antibody targeting epitopes on CD3 on T cells and CD20 on B cells with the goal of inducing T-cell mediated elimination of malignant B cells. A recent pivotal phase I/II clinical trial (GO29781) demonstrated that mosunetuzumab induced an overall response rate of 80%, complete response rate of 60%, and a median progression-free survival of 17.9 months in patients with relapsed/refractory (r/r) follicular lymphoma (FL) following at least two prior lines of systemic therapy, including alkylator and anti-CD20 antibody-based therapy. Historical data from cohorts receiving therapy for r/r FL can provide some context for interpretation of single-arm trials. We compared the results from the mosunetuzumab trial to outcomes from a cohort of patients with r/r FL from the LEO Consortium for Real World Evidence (LEO CReWE). We applied clinical trial eligibility criteria to the LEO CReWE cohort and utilized matching-adjusted indirect comparison weighting to balance the clinical characteristics of the LEO CReWE cohort with those from the mosunetuzumab trial. Overall response rates (73%, 95% CI:65-80%) and complete response rates (53%, 95% CI:45-61%) observed in the weighted LEO CReWE cohort were lower than those reported on the mosunetuzumab trial (ORR=80%, 95% CI:70-88%; CR=60%, 95% CI:49-70% respectively). Progression-free survival at 12 months was similar in the weighted LEO CReWE (60%, 95% CI:51-69%) and the mosunetuzumab trial (PFS 58%, 95% CI:47-68%). Sensitivity analyses examining the impact of matching variables, selection of line of therapy, and application of eligibility criteria, provide context for best practices in this setting.

Comparative effectiveness between mosunetuzumab monotherapy clinical trial and real-world data in relapsed/refractory follicular lymphoma in third or subsequent lines of systemic therapy.

A comparison of clinical outcomes in the third or subsequent line (3 L+) of systemic therapy between a real-world data (RWD) external control cohort and a mosunetuzumab single-arm clinical trial cohort is presented. Data for 3 L + patients with relapsed/refractory follicular lymphoma (FL) were obtained from the mosunetuzumab single-arm trial (n = 90) and a US electronic health records database (n = 158), with patients meeting key eligibility criteria from the trial, balanced on pre-specified prognostic factors. Overall response and complete response rates were 80% and 60% in the mosunetuzumab cohort and 75% and 33% in the RWD cohort, odds ratios of 1.23 (95% CI, 0.52-2.93) and 3.18 (95% CI, 1.41-7.17), respectively. Hazard ratios for progression-free survival and overall survival were 0.82 (95% CI, 0.53-1.27) and 0.43 (95% CI, 0.19-0.94). These findings support a clinically meaningful benefit of mosunetuzumab monotherapy as a chemotherapy-free option for the 3 L + FL population.

Treatment patterns and outcomes of patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy (LEO CReWE): a multicentre cohort study.

BACKGROUND: Novel therapies for relapsed or refractory follicular lymphoma are commonly evaluated in single-arm studies without formal comparison with other treatments or historical controls. Consequently, rigorously defined treatment outcomes informing expectations for novel therapeutic strategies in this population are sparse. To inform outcome expectations, we aimed to describe treatment patterns, survival outcomes, and duration of response in patients with relapsed or refractory follicular lymphoma receiving three or more lines of systemic therapy. METHODS: In this multicentre cohort study, we developed a database of patients with relapsed or refractory follicular lymphoma from eight academic centres in the USA using data collected in the LEO Cohort study (NCT02736357) and the LEO Consortium. For this analysis, eligible patients were aged at least 18 years, had non-transformed grade 1-3a follicular lymphoma, and were receiving systemic therapy in the third line or later after previous therapy with an anti-CD20 antibody and an alkylating agent. Clinical data and patient outcomes were abstracted from medical records by use of a standard protocol. The index therapy for the primary analysis was defined as the first line of systemic therapy after the patient had received at least two previous systemic therapies that included an alkylating agent and an anti-CD20 therapy. The main endpoints of interest were overall response rate, progression-free survival, and overall survival. Outcomes were also evaluated in subsets of clinical interest (index therapy characteristics, patient and disease characteristics, treatment history, and best response assessment). FINDINGS: We screened 933 patients with follicular lymphoma, of whom 441 were included and diagnosed between March 6, 2002, and July 20, 2018. Index therapies included immunochemotherapy (n=133), anti-CD20 antibody monotherapy (n=53), lenalidomide with or without anti-CD20 (n=37), and phosphoinositide 3-kinase inhibitors with or without anti-CD20 (n=25). 57 (13%) of 441 patients received haematopoietic stem-cell transplantation and 98 (23%) of 421 patients with complete data received therapy on clinical trials. After a median follow-up of 71 months (IQR 64-79) from index therapy, 5-year overall survival was 75% (95% CI 70-79), median progression-free survival was 17 months (15-19), and the overall response rate was 70% (65-74; 280 of 400 patients evaluable for response). Patients who were refractory to therapy with an alkylating agent had a lower overall response rate (170 [68%] of 251 patients vs 107 [77%] of 139 patients) and a significantly lower 5-year overall survival (72%, 95% CI 66-78 vs 81%, 73-89; hazard ratio 1·60, 95% CI 1·04-2·46) than patients who were not refractory to therapy with an alkylating agent. INTERPRETATION: Patients with relapsed or refractory follicular lymphoma receive heterogeneous treatments in the third-line setting or later. We observed high response rates to contemporary therapies that were of short duration. These data identify unmet needs among patients with follicular lymphoma, especially those who are refractory to alkylating agents, and might provide evidence by which clinical trials evaluating novel treatments could be assessed. FUNDING: Genentech and the National Cancer Institute.

Dosing of Intravenous Tocilizumab in a Real-World Setting of Rheumatoid Arthritis: Analyses from the Corrona Registry.

INTRODUCTION: In the United States, the recommended starting dose of intravenous tocilizumab (TCZ) is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response for patients with moderate to severe rheumatoid arthritis; however, data on how TCZ dose is escalated in real life are missing. The objective of this analysis was to describe patterns of early intravenous TCZ dose escalation in a real-world setting using data from the Corrona registry. METHODS: All patients enrolled in the comparative effectiveness substudy (CERTAIN) nested within Corrona who initiated TCZ and completed 3- and 6-month study visits were eligible for inclusion. Patients who initiated TCZ 4 mg/kg were categorized into 1 of 2 groups: those who remained on TCZ 4 mg/kg at 3 months (Group 1) and those who escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Changes in clinical disease activity measures were provided. RESULTS: Of the 213 patients who were eligible for analysis, 86 (40.4%) remained on their initial dose of TCZ 4 mg/kg (Group 1) and 110 (51.6%) were escalated to TCZ 8 mg/kg by or at 3 months (Group 2). Baseline demographic and clinical characteristics were similar between the 2 groups; except in Group 2, patients were older (58.3 vs. 54.0 years) and a lower proportion was female (75.5% vs. 89.4%) than in Group 1. Significant improvements in disease activity measures were observed at 3 and 6 months in both groups, with the majority of patients in both groups achieving moderate or good European League Against Rheumatism response. CONCLUSION: Real-world data demonstrated that physicians escalate TCZ dose at varying frequencies. The ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01625650.

Risk of Infection Associated With Subsequent Biologic Agent Use After Rituximab: Results From a National Rheumatoid Arthritis Patient Registry.

OBJECTIVE: To assess whether the time between the last rituximab infusion and initiation of a different biologic agent influenced infection risk in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who newly initiated rituximab within the Consortium of Rheumatology Researchers of North America registry were included if they switched to a nonrituximab biologic agent and had ≥1 followup visit within 12 months of switching. Patients were categorized by duration of time between their last rituximab infusion and initiation of a subsequent biologic agent (≤5 months, 6-11 months, and ≥12 months). The primary outcome was time to first infectious event. Adjusted Cox regression models estimated the association between time to starting a subsequent biologic agent and infection. RESULTS: A total of 44 overall infections (7 serious, 37 nonserious) were reported during the 12-month followup in the 215 patients included in this analysis (104 switched at ≤5 months, 67 at 6-11 months, and 44 at ≥12 months). Median (interquartile range) time to infection was 4 (2-5) months. Infection rates per patient-year in the ≤5-month, 6-11-month, and ≥12-month groups were 0.34 (95% confidence interval [95% CI] 0.22-0.52), 0.30 (95% CI 0.17-0.52), and 0.41 (95% CI 0.22-0.77), respectively. After adjustment, time to switch to a subsequent biologic agent was not associated with infection, which remained unchanged when number and rate of rituximab retreatments were included in the models. CONCLUSION: In this real-world cohort of patients with RA, infection rates ranged from 0.30 to 0.41 per patient-year, with no significant difference in the rate between patients who initiated a subsequent biologic agent earlier versus later after rituximab treatment.

Comparative effectiveness and safety of rituximab versus subsequent anti-tumor necrosis factor therapy in patients with rheumatoid arthritis with prior exposure to anti-tumor necrosis factor therapies in the United States Corrona registry.

INTRODUCTION: Patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor(anti-TNF)agent treatment can switch to either a subsequent anti-TNF agent or a biologic with an alternative mechanism of action, such as rituximab; however, there are limited data available to help physicians decide between these 2 strategies. The objective of this analysis was to examine the effectiveness and safety of rituximab versus a subsequent anti-TNF agent in anti-TNF-experienced patients with RA using clinical practice data from the Corrona registry. METHODS: Rituximab-naive patients from the Corrona registry with prior exposure to ≥1 anti-TNF agent who initiated rituximab or anti-TNF agents (2/28/2006-10/31/2012) were included. Two cohorts were analyzed: the trimmed population (excluding patients who fell outside the propensity score distribution overlap) and the stratified-matched population (stratified by 1 vs. ≥2 anti-TNF agents, then matched based on propensity score). The primary effectiveness outcome was achievement of low disease activity (LDA)/remission (Clinical Disease Activity Index ≤10) at 1 year. Secondary outcomes included achievement of modified American College of Rheumatology (mACR) 20/50/70 responses and meaningful improvement (≥0.25) in modified Health Assessment Questionnaire (mHAQ) score at 1 year. New cardiovascular, infectious and cancer events were reported. RESULTS: Estimates for LDA/remission, mACR response and mHAQ improvement were consistently better for rituximab than for anti-TNF agent users in adjusted analyses. The odds ratio for likelihood of LDA/remission in rituximab versus anti-TNF patients was 1.35 (95% CI, 0.95-1.91) in the trimmed population and 1.54 (95% CI, 1.01-2.35) in the stratified-matched population. Rituximab patients were significantly more likely than anti-TNF patients to achieve mACR20/50 and mHAQ improvement in the trimmed population and mACR20 and mHAQ in the stratified-matched population. The rate of new adverse events per 100 patient-years was similar between groups. CONCLUSIONS: In anti-TNF-experienced patients with RA, rituximab was associated with an increased likelihood of achieving LDA/remission, mACR response and physical function improvement, with a comparable safety profile, versus subsequent anti-TNF agent users. TRIAL REGISTRATION: ClinicalTrials.gov NCT01402661 . Registered 25 July 2011.

Effectiveness of Rituximab for the Treatment of Rheumatoid Arthritis in Patients with Prior Exposure to Anti-TNF: Results from the CORRONA Registry.

OBJECTIVE: To characterize the real-world effectiveness of rituximab (RTX) in patients with rheumatoid arthritis. METHODS: Clinical effectiveness at 12 months was assessed in patients who were prescribed RTX based on the Clinical Disease Activity Index (CDAI). Change in CDAI was calculated (CDAI at 12 mos minus at initiation). Achievement of remission or low disease activity (LDA; CDAI ≤ 10) among those with moderate/high disease activity at the time of RTX initiation was compared based on prior anti-tumor necrosis factor agent (anti-TNF) use (1 vs ≥ 2) using logistic regression models. RESULTS: Patients (n = 265) were followed for 12 months with a mean change in CDAI of -8.1 (95% CI -9.8 - -6.4). Of the 218 patients with moderate/high disease activity at baseline, patients with 1 prior anti-TNF (baseline CDAI 25.0) demonstrated a mean change in CDAI of -10.1 (95% CI -13.2 - -7.0); patients with ≥ 2 prior anti-TNF (baseline CDAI 30.0) demonstrated a mean change of -10.5 (95% CI -12.9 - -8.0). The unadjusted OR for achieving LDA/remission in patients with moderate/high disease activity at baseline exposed to ≥ 2 versus 1 prior anti-TNF was 0.40 (95% CI 0.22-0.73), which was robust to 4 different adjusted models (OR range 0.38-0.44). CONCLUSION: A good clinical response was observed in all patients; however, patients previously treated with 1 anti-TNF, who had lower baseline CDAI and a greater opportunity for clinical improvement compared with patients previously treated with ≥ 2 anti-TNF, were more likely to achieve LDA/remission.

Characteristics Associated with Biologic Monotherapy Use in Biologic-Naive Patients with Rheumatoid Arthritis in a US Registry Population.

INTRODUCTION: The aim of this study was to describe factors associated with initiating a biologic as monotherapy vs in combination with a conventional disease-modifying antirheumatic drug (DMARD) in biologic-naive patients with rheumatoid arthritis (RA) enrolled in the Corrona registry. METHODS: First biologic initiations were classified as monotherapy (Bio MT) or combination therapy (Bio CMB). Baseline demographic and clinical characteristics were evaluated. Odds ratios (OR) based on mixed effects regression models estimated the association of covariates and use of monotherapy. Median odds ratios (MOR) based on estimated physician random effects quantified variation in individual physician use of monotherapy. RESULTS: Between October 2001 and April 2012, 3,923 previously biologic-naive patients initiated biologic therapy, of which 19.1 % initiated as monotherapy. Baseline characteristics of patients initiating Bio MT and Bio CMB were similar for age, sex, duration of RA, and clinical disease activity index. Significantly higher proportions of Bio CMB initiators had prior conventional DMARD (97.23 vs 85.60 %; P < 0.01) and methotrexate (MTX) use (91.68 vs 71.87 %; P < 0.01) compared with Bio MT initiators. Variation in individual physician use of monotherapy [MOR 1.89; 95 % confidence interval (CI), 1.66-2.23] and use of biologics approved by the United States Food and Drug Administration for monotherapy (OR 1.47; 95 % CI, 1.20-1.81) significantly influenced the odds of initiating Bio MT. Patient history of hepatic disease, neutropenia, and malignancy were associated with increased odds of being prescribed Bio MT. CONCLUSION: In addition to regulatory approval for monotherapy and specific pre-existing comorbidities, significant variation in physician use of monotherapy was associated with increased likelihood of initiating Bio MT, independent of patient factors.

Health Care Coverage Decision Making in Low- and Middle-Income Countries: Experiences from 25 Coverage Schemes.

Lessons learned by countries that have successfully implemented coverage schemes for health services may be valuable for other countries, especially low- and middle-income countries (LMICs), which likewise are seeking to provide/expand coverage. The research team surveyed experts in population health management from LMICs for information on characteristics of health care coverage schemes and factors that influenced decision-making processes. The level of coverage provided by the different schemes varied. Nearly all the health care coverage schemes involved various representatives and stakeholders in their decision-making processes. Maternal and child health, cardiovascular diseases, cancer, and HIV were among the highest priorities guiding coverage development decisions. Evidence used to inform coverage decisions included medical literature, regional and global epidemiology, and coverage policies of other coverage schemes. Funding was the most commonly reported reason for restricting coverage. This exploratory study provides an overview of health care coverage schemes from participating LMICs and contributes to the scarce evidence base on coverage decision making. Sharing knowledge and experiences among LMICs can support efforts to establish systems for accessible, affordable, and equitable health care.

Clinical validity of cytochrome P450 metabolism and serotonin gene variants in psychiatric pharmacotherapy.

Adverse events, response failures and medication non-compliance are common in patients receiving medications for the treatment of mental illnesses. A systematic literature review assessed whether pharmacokinetic (PK) or pharmacodynamic (PD) responses to 26 commonly prescribed antipsychotic and antidepressant medications, including efficacy or side effects, are associated with nucleotide polymorphisms in eight commonly studied genes in psychiatric pharmacotherapy: CYP2D6, CYP2C19, CYP2C9, CYP1A2, CYP3A4, HTR2C, HTR2A, and SLC6A4. Of the 294 publications included in this review, 168 (57%) showed significant associations between gene variants and PK or PD outcomes. Other studies that showed no association often had insufficient control for confounding variables, such as co-medication use, or analysis of medications not substrates of the target gene. The strongest gene-outcome associations were for the PK profiles of CYP2C19 and CYP2D6 (93% and 90%, respectively), for the PD associations between HTR2C and weight gain (57%), and for SLC6A4 and clinical response (54%), with stronger SLC6A4 response associations for specific drug classes (60-83%). The preponderance of evidence supports the validity of analyzing nucleotide polymorphisms in CYP and pharmacodynamic genes to predict the metabolism, safety, or therapeutic efficacy of psychotropic medications commonly used for the treatment of depression, schizophrenia, and bipolar illness.

Cost-effectiveness of gene-expression profiling for tumor-site origin.

OBJECTIVES: Gene-expression profiling (GEP) reliably supplements traditional clinicopathological information on the tissue of origin (TOO) in metastatic or poorly differentiated cancer. A cost-effectiveness analysis of GEP TOO testing versus usual care was conducted from a US third-party payer perspective. METHODS: Data on recommendation changes for chemotherapy, surgery, radiation therapy, blood tests, imaging investigations, and hospice care were obtained from a retrospective, observational study of patients whose physicians received GEP TOO test results. The effects of chemotherapy recommendation changes on survival were based on the results of trials cited in National Comprehensive Cancer Network and UpToDate guidelines. Drug and administration costs were based on average doses reported in National Comprehensive Cancer Network guidelines. Other unit costs came from Centers for Medicare & Medicaid Services fee schedules. Quality-of-life weights were obtained from literature. Bootstrap analysis estimated sample variability; probabilistic sensitivity analysis addressed parameter uncertainty. RESULTS: Chemotherapy regimen recommendations consistent with guidelines for final tumor-site diagnoses increased significantly from 42% to 65% (net difference 23%; P<0.001). Projected overall survival increased from 15.9 to 19.5 months (mean difference 3.6 months; two-sided 95% confidence interval [CI] 3.2-3.9). The average increase in quality-adjusted life-months was 2.7 months (95% CI 1.5-4.3), and average third-party payer costs per patient increased by $10,360 (95% CI $2,982-$19,192). The cost per quality-adjusted life-year gained was $46,858 (95% CI $13,351-$104,269). CONCLUSIONS: GEP TOO testing significantly altered clinical practice patterns and is projected to increase overall survival, quality-adjusted life-years, and costs, resulting in an expected cost per quality-adjusted life-year of less than $50,000.

Cost-effectiveness of rituximab as maintenance therapy in patients with follicular non-Hodgkin lymphoma after responding to first-line rituximab plus chemotherapy.

A recent phase III trial demonstrated that maintenance rituximab® therapy after response to first-line treatment with rituximab plus chemotherapy (R-chemo) increases progression-free survival (PFS) for follicular non-Hodgkin lymphoma (f-NHL). A cost-effectiveness analysis of R-maintenance versus observation was conducted from a US payer perspective to estimate PFS and overall survival (OS) over a representative patient's lifetime. Primary outcomes were cost per life-year gained (LYG) and cost per quality-adjusted life-year (QALY) gained. Compared with observation, R-maintenance increased mean PFS by 1.50 years, OS by 1.21 years and QALYs gained by 1.11 years. The incremental cost of maintenance therapy was $38,545. The costs per LYG and QALY gained were $31,934 and $34,842, respectively. Within the limitations of modeling long-term outcomes, R-maintenance therapy in patients who received R-chemo for previously untreated f-NHL compared with observation alone after R-chemo for first-line treatment for f-NHL is cost-effective from the US payer perspective.

Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for the treatment of previously untreated chronic lymphocytic leukemia.

A recent phase III trial demonstrated improved progression-free survival (PFS) and overall survival (OS) associated with adding rituximab to fludarabine and cyclophosphamide (R-FC) compared to FC in treatment of previously untreated chronic lymphocytic leukemia (CLL). A cost-effectiveness analysis of R-FC over FC was performed from a US third-party payer perspective over a lifetime horizon in the base case. One-way, two-way and probabilistic sensitivity analyses were conducted to assess the robustness of the results. A secondary analysis was performed by also considering a societal perspective. R-FC was associated with an incremental 1.15 quality-adjusted life-years (QALYs) compared to FC and resulted in an incremental cost-effectiveness ratio of $23 530 per QALY in the base case and $31 513 per QALY considering a societal perspective. Results were most sensitive to time horizon, discount rate and unit drug cost for rituximab. Within the limitations of modeling long-term outcomes, R-FC is cost-effective for previously untreated CLL.

Broadening the perspective when assessing evidence on boosted protease inhibitor-based regimens for initial antiretroviral therapy.

Several national and international guidelines recommend the use of antiretroviral therapy containing a protease inhibitor (PI) with ritonavir (RTV) boosting for human immunodeficiency virus (HIV)-infected treatment-naïve patients. RTV-boosted PIs such as lopinavir (LPV/r), atazanavir (ATV + RTV), darunavir (DRV + RTV), fosamprenavir (FPV + RTV), and saquinavir (SQV + RTV) are usually recommended in regimens for initial therapy. The guideline recommendations are generally based on the clinical efficacy of the regimens. A broadened perspective of assessing the evidence related to selection of a PI for optimal first-line therapy might consider additional factors for evaluation, such as effectiveness in actual clinical practice and cost-effectiveness of individual drugs in formulating recommendations. Among the guideline-recommended PIs, LPV/r is one of the earliest PIs approved, has been a well-recognized boosted PI for treatment-naïve patients in all guidelines, and demonstrates the most evidence on long-term clinical and economic effectiveness. Studies have shown its efficacy in various controlled and real-world settings in different populations, the relationship of adherence to virologic efficacy, and the implications of resistance when used in sequence with other PI regimens. In the absence of published evidence for other guideline-recommended PIs that will greatly facilitate a fully transparent, comparative effectiveness evaluation, the cumulative evidence from this broader perspective indicates all PIs should not be viewed as equally safe and effective across all patients for initial therapy, nor should any single PI within the class be considered preferred for all treatment-naïve patients.

Obstacles and proposed solutions to effective antiretroviral therapy in resource-limited settings.

More than 3 million people were receiving antiretroviral therapy (ART) at the end of 2007, but this number represents only 31% of people clinically eligible for ART in resource-limited settings. The primary objective of this study is to summarize the key obstacles that impede the goal of universal access prevention, care, and treatment. We performed a systematic literature search to review studies that reported barriers to diagnosis and access to treatment of HIV/AIDS in resource-limited countries. Persons living with HIV/ AIDS commonly face economic, sociocultural, and behavioral obstacles to access treatment and care for HIV. A variety of programs to overcome these barriers have been implemented, including efforts to destigmatize HIV/AIDS, enhance treatment literacy, provide income-generation skills, decentralize HIV services, promote gender equality, and adopt a multisectoral approach to optimize limited resources. An understanding of these obstacles and suggested methods to overcome them must be addressed by global policy makers before universal ART access can be achieved.