[The clinical features, survival analysis, and geriatric assessment of 85 patients with follicular lymphoma: a single-center study].

Objective: To retrospectively analyze the clinical characteristics and prognosis of 85 newly diagnosed patients with follicular lymphoma (FL), as well as the prognostic value of comprehensive geriatric assessment (CGA) in patients with FL aged ≥ 60 years old. Methods: The clinical data and prognosis of 85 newly diagnosed FL patients admitted from August 2011 to June 2022 were collected. The clinical features, laboratory indicators, therapeutic efficacy, survival and prognostic factors of patients were statistically analyzed, and the prognosis of patients was stratified using various geriatric assessment tools. Results: ① The patients with FL were mostly middle-aged and older, with a median age of 59 (20-87) years, including 41 patients (48.2%) aged ≥60 years. The ratio of male to female was 1∶1.36. Overall, 77.6% of the patients were diagnosed with Ann Arbor stage Ⅲ-Ⅳ, and 17 cases (20.0%) were accompanied by B symptoms. Bone marrow involvement was the most common (34.1%). ②Overall, 71 patients received immunochemotherapy. The overall response rate was 86.6%, and the complete recovery rate was 47.1% of 68 evaluated patients. Disease progression or relapse in the first 2 years was observed in 23.9% of the patient. Overall, 14.1% of the patients died during follow-up. ③Of the 56 patients receiving R-CHOP-like therapies, the 3-year and 5-year progression-free survival (PFS) rates were 85.2% and 72.8%, respectively, and the 3-year and 5-year overall survival (OS) rates were 95.9% and 88.8%, respectively. The univariate analysis showed that age ≥60 years old (HR=3.430, 95% CI 1.256-9.371, P=0.016), B symptoms (HR=5.030, 95% CI 1.903-13.294, P=0.016), Prognostic Nutritional Index (PNI) <45.25 (HR=3.478, 95% CI 1.299-9.310, P=0.013), Follicular Lymphoma International Prognostic Index (FLIPI) high-risk (HR=2.918, 95% CI 1.074-7.928, P=0.036), and PRIMA-prognostic index (PRIMA-PI) high-risk (HR=2.745, 95% CI 1.057-7.129, P=0.038) significantly predicted PFS. Moreover, age ≥60 years old and B symptoms were independent risk factors for PFS. Progression of disease within 24 months (POD24) significantly predicted OS in the univariate analysis. Conclusions: FL is more common among middle-aged and older women. Age, B symptoms, PNI score, FLIPI high-risk, PRIMA-PI high-risk, and POD24 influenced PFS and OS. The CGA can be used for treatment selection and risk prognostication in older patients with FL.

Comparative effectiveness study of chemotherapy in follicular lymphoma patients in the rituximab era: a Japanese claims database study.

Aim: To evaluate comparative effectiveness of rituximub (R)-based versus non-R-based therapies for follicular lymphoma patients in Japan, where limited studies have been reported. Materials & methods: Patients who received R-based index regimens were propensity score matched to those who did not receive R, based on patient baseline attributes and clinical characteristics using Japanese retrospective claims database to assess clinical and economic outcomes. Results & conclusion: A total of 1947 patients remained in the overall follicular lymphoma cohorts: 1294 receiving an R-based and 653 a non-R-based regimen. Patients on R-based therapy underwent fewer hospitalizations and had a shorter length of stay, but had higher costs during the first year of intensive R-based therapy. Improved clinical outcomes were associated with patients who were younger, female and chose R-based regimens in first index line.

High serum levels of IL-2R, IL-6, and TNF-α are associated with higher tumor burden and poorer outcome of follicular lymphoma patients in the rituximab era.

The clinical behavior of FL patients is heterogeneous. The levels of sIL-2R have been correlated with tumor burden and outcome in FL. However, the impact of IL-6 and TNF-α in this disease is unclear. We studied 253 patients diagnosed with grade 1-3a FL between 2002 and 2018, with available information on serum levels of sIL-2R, IL-6, and TNF-α at diagnosis. Patients with cytokine levels above the cutoff had features of a higher tumor burden and higher-risk disease. Levels of any of the studied cytokines above the cutoff and a higher number of cytokines above the cutoff impacted on a shorter PFS and OS. TNF-α levels were an independent predictor of a poorer PFS. No differences were observed in the risk of histological transformation or second malignancies. The determination of cytokine levels in FL patients is feasible in clinical practice, and elevated levels are associated with a higher tumor burden and poorer survival.

Patient-level Factors Associated With the Initial Management of Older Adults Diagnosed With Follicular Lymphoma: A Surveillance, Epidemiology, and End Results-Medicare Analysis.

INTRODUCTION: We evaluated patient-level factors associated with the initial management of older adults diagnosed with follicular lymphoma (FL). MATERIALS AND METHODS: Using linked Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) data; we identified 11,500 beneficiaries aged ≥ 66 years, diagnosed with FL between 2000 and 2013. A logistic regression model was used to estimate adjusted odds ratios (AORs) for factors associated with the receipt of active treatment versus watchful waiting (WW) as an initial management strategy. A multinomial logistic regression model was used to predict factors associated with receipt of specific active treatments, namely chemoimmunotherapy, rituximab monotherapy, chemotherapy, or radiation as compared with WW. RESULTS: Overall, the initial management strategies adopted were WW (49%), chemoimmunotherapy (25%), radiation (10%), rituximab monotherapy (9%), and chemotherapy (7%). In reference to WW, grade III FL (AOR, 2.21; 95% confidence interval [CI], 1.99-2.46), increasing disease stage (Stage IV AOR, 1.80; 95% CI, 1.62-2.00), and use of preventive services (AOR, 1.18; 95% CI, 1.07-1.30) were associated with increased odds of active treatment receipt. Age > 80 years (AOR, 0.79; 95% CI, 0.71-0.87), Non-Hispanic African-American race (AOR, 0.64; 95% CI, 0.50-0.80), and state buy-in coverage (AOR, 0.81; 95% CI, 0.70-0.94) were associated with decreased odds of active treatment receipt. In reference to WW, the multinomial logistic regression model displayed differences in the receipt of rituximab-based therapies by age and comorbidity burden. Non-Hispanic African-American race and state buy-in coverage were associated with decreased odds of receiving rituximab-based therapies. CONCLUSION: The present analysis identifies disparities in the initial management of older adults with FL owing to race and socioeconomic status. Future research should examine implications for subsequent treatment and health outcomes.

Idelalisib for Treatment of Relapsed Follicular Lymphoma and Chronic Lymphocytic Leukemia: A Comparison of Treatment Outcomes in Clinical Trial Participants vs Medicare Beneficiaries.

Importance: Idelalisib (IDEL) is approved as monotherapy in relapsed follicular lymphoma (FL) and with rituximab (IDEL+R) for relapsed chronic lymphocytic leukemia (CLL). Toxic effects can be severe and treatment-limiting. Outcomes in a real-world population are not yet characterized. Objective: We compared IDEL treatment outcomes in the clinical setting with outcomes in clinical trial data. Design, Setting, and Participants: This cohort study compared clinical trial participants treated with IDEL, aged 65 years or older, in studies 101-09 and 312-0116 with Medicare beneficiaries treated with IDEL of the same disease state and treatment regimen. Study 101-09 was a phase 2, single-group, open-label trial supporting accelerated approval of IDEL for relapsed or refractory FL. Study 312-0116 was a phase 3, multicenter, randomized, double-blind trial supporting approval of IDEL+R for relapsed CLL. Analyses were conducted between February and December 2018. Main Outcomes and Measures: Treatment duration, on-treatment and overall mortality, and serious and fatal infections were compared between trial participants and Medicare beneficiaries. Cox proportional hazards models quantified differences by cohort. Results: We identified 26 trial participants (mean [SD] age, 73 [4.9] years; 12 [46.2%] women) and 305 Medicare beneficiaries (mean [SD] age, 76 [6.9] years; 103 [54.8%] women) receiving IDEL for FL and 89 trial participants (mean [SD] age, 74 [6.0] years; 30 [33.7%] women) and 294 Medicare beneficiaries (mean age, 76 [6.3] years; 111 [37.8%] women) receiving IDEL+R for CLL. Medicare beneficiaries were older with higher comorbidity; had a shorter median treatment duration for CLL (173 days vs 473 days, P < .001) but not FL (114, days vs 160 days, P = .38); a numerically higher mortality rate (CLL: HR, 1.40; 95% CI, 0.93-2.11; FL: HR, 1.39; 95% CI, 0.69-2.78); and a significantly higher fatal infection rate per 100 person-years for CLL (18.4 vs 9.8, P = .04) and a numerically higher rate for FL (27.6 vs 18.6, P = .54), compared with trial participants. Trial participants had approximately twice as many dose reductions (CLL: 32.6% vs 18.0%; P = .003; FL: 38.5% vs 16.1%; P = .02). Among Medicare beneficiaries, a hospitalized infection within 6 months prior to IDEL initiation was associated with a 2.11-fold increased risk for on-treatment fatal infections (95% CI, 1.44-3.10). Despite a March 2016 recommendation for Pneumocystis jirovecii pneumonia prophylaxis in patients treated with IDEL, prophylaxis rates were low after March 2016 (FL: 25%, CLL: 37%). Conclusions and Relevance: We observed substantial imbalances in baseline comorbidities and treatment outcomes between Medicare beneficiaries and trial participants aged 65 years or older. Immunosuppression-related toxic effects, including infections, may have been somewhat reduced in trials by more frequent dose reductions and exclusion of patients with ongoing infections. Selective eligibility criteria and closer monitoring of trial patients may be responsible for limited generalizability of trial data to clinical practice.

Assessing the Effectiveness of Treatment Sequences for Older Patients With High-risk Follicular Lymphoma With a Multistate Model.

BACKGROUND: Disease progression within < 2 years of initial chemoimmunotherapy and patient age > 60 years have been associated with poor overall survival (OS) in follicular lymphoma (FL). No standard treatment exists for these high-risk patients, and the effectiveness of sequential therapies remains unclear. PATIENTS AND METHODS: We studied the course of FL with first-, second-, and third-line treatment. Using large population-based data, we identified 5234 patients with FL diagnosed in 2000 to 2009. Of these patients, 71% had received second-line therapy < 2 years, and 29% had received no therapy after first-line therapy, with a median OS of < 3 years. Treatment included rituximab, R-CVP (rituximab, cyclophosphamide, vincristine), R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine), R-Other (other rituximab-containing), and other regimens. The Aalen-Johansen estimator and Cox proportional hazards models were used to quantify the outcomes and assess the effects of the clinical and sociodemographic factors. RESULTS: R-CHOP demonstrated the most favorable 5-year OS among first- (71%), second- (55%), and third-line (61%) therapies. First-line R-CHOP improved OS (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.50-0.64) and reduced the mortality risks after first-line (HR, 0.60; 95% CI, 0.47-0.77), second-line (HR, 0.40; 95% CI, 0.29-0.53), and third-line (HR, 0.63; 95% CI, 0.53-0.76) treatments. B-symptoms, being married, and histologic grade 1/2 were associated with the use of earlier second-line therapy. Early progression from second- to third-line therapy was associated with poor OS. The repeated use of R-CHOP or R-CVP as first- and second-line treatment yielded high 2-year mortality rates (R-CHOP + R-CHOP, 17.3%; R-CVP + R-CVP, 21.1%). CONCLUSION: Our multistate approach assessed the effect of sequential therapy on the immediate and subsequent treatment-line outcomes. We found that R-CHOP in any line improved OS for patients with high-risk FL.

Burden of illness of follicular lymphoma and marginal zone lymphoma.

Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are two subtypes of indolent B cell non-Hodgkin lymphoma (NHL) that account for approximately 20% and 12% of all NHLs, respectively. FL and MZL are rare conditions with orphan disease designations. We conducted a comprehensive review of the burden of FL and MZL that encompasses the epidemiological, real world clinical, economic, and humanistic impact of these diseases globally. A targeted literature search identified 31 eligible studies for review. Epidemiological coverage was poor, with data obtained for studies from only seven countries. The incidences of both subtypes were low: age-standardized incidence rates of FL ranged from 2.1/100,000 in France to 4.3/100,000 in the USA, while for MZL it varied geographically from 0.5/100,000 in Australia to 2.6/100,000 in the UK. The cumulative total direct healthcare costs for FL were higher for patients with progressive disease compared to those without ($30,890 vs. $8704 at 12 months, respectively) and main driver of costs related to the use of chemotherapy. Five-year overall survival was improved in patients with FL compared with MZL (e.g., 76.5% vs 60.7% in one study that reported on both subtypes). Mortality rates were particularly lower in female patients with FL aged < 60 years. However, limited outcome data for MZL patients were identified. FL and MZL contribute significant burden on healthcare systems and on patients globally, with delays in progression potentially leading to cost savings. More rigorous characterization of these two NHL subtypes, new and more effective treatments, and standardization of reporting would lead to a more robust understanding of future data in this disease area.

Cause-specific mortality among Medicare beneficiaries with newly diagnosed non-Hodgkin lymphoma subtypes.

BACKGROUND: As the US population ages and non-Hodgkin lymphoma (NHL)-specific mortality declines, deaths from causes other than NHL will become increasingly important in treatment decision making for older patients with NHL. The objective of the current study was to describe how the 5-year cumulative incidence of NHL-specific and other-cause mortality varies by subtype, age, comorbidity level, and time since diagnosis in older patients. METHODS: Using the Surveillance, Epidemiology, and End Results cancer registry data linked to Medicare claims, patients aged ≥66 years were identified at the time of diagnosis with a first, primary NHL diagnosis from 2004 through 2013. Death certificate data and Fine-Gray competing risks models were used to estimate the 5-year cumulative incidence of NHL-specific and other-cause mortality by NHL subtype, age, and comorbidity level. Estimates were displayed over time using stacked cumulative incidence curves. RESULTS: Among 30,666 patients with NHL, 32% died of NHL and 13% died of other causes within 5 years of diagnosis. The cumulative incidence of other-cause mortality increased with age and comorbidity level for all subtypes. Among patients with aggressive NHL subtypes, NHL-specific mortality exceeded other-cause mortality across all age groups, comorbidity levels, and number of years after diagnosis. For patients with indolent NHL subtypes, other-cause mortality was similar to or exceeded NHL-specific mortality, especially among older patients with severe comorbidity or with the indolent marginal zone, lymphoplasmacytic, and mycosis fungoides subtypes. CONCLUSIONS: The findings of the current study suggest that mortality from causes other than NHL are important for patients of an older age, with a higher comorbidity level, and with indolent disease. Evidence from the current study can guide the development of tools for estimating individual prognosis that inform treatment discussions in patients with NHL.

Congestive heart failure in older adults diagnosed with follicular lymphoma: A population-based study.

BACKGROUND: To the authors' knowledge, there is limited information regarding the long-term risk of congestive heart failure (CHF) among patients with follicular lymphoma, a prevalent non-Hodgkin lymphoma diagnosis among those aged >65 years, especially within the context of therapeutic exposures and preexisting comorbidities. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data from 1999 through 2013, the authors identified 6109 patients with follicular lymphoma who were diagnosed at age ≥66 years between January 1, 2000 and December 31, 2011, and a frequency-matched Medicare noncancer sample. Subdistribution hazards models assessed risks associated with new-onset CHF through December 31, 2013. Propensity score-matched models examined CHF risk in patients receiving anthracyclines when compared with matched noncancer controls. RESULTS: When compared with matched controls, patients with follicular lymphoma receiving anthracyclines at ages 66 to 75 years had a 1.7-fold (95% confidence interval, 1.4-fold to 2.1-fold) higher risk of new-onset CHF; patients diagnosed at age >75 years did not differ from noncancer controls with regard to CHF risk. Preexisting hypertension was associated with a 1.7-fold and 1.35-fold, respectively, increased hazard of CHF for each age group, independent of anthracycline exposure. Preexisting diabetes was associated with 1.5-fold increased hazard of CHF only in those patients aged 66 to 75 years. Patients with new-onset CHF had a 18% lower 10-year survival compared with those without CHF. CONCLUSIONS: Patients with follicular lymphoma who were exposed to anthracyclines between the ages of 66 years and 75 years were found to be at an increased risk of new-onset CHF; preexisting hypertension and diabetes appeared to increase this risk. The findings of the current study support and inform the risk-based follow-up of vulnerable populations.

A Generic Model for Follicular Lymphoma: Predicting Cost, Life Expectancy, and Quality-Adjusted-Life-Year Using UK Population-Based Observational Data.

OBJECTIVES: To use real-world data to develop a flexible generic decision model to predict cost, life expectancy, and quality-adjusted life-years (QALYs) for follicular lymphoma (FL) in the general patient population. METHODS: All patients newly diagnosed with FL in the UK's population-based Haematological Malignancy Research Network (www.hmrn.org) between 2004 and 2011 were followed until 2015 (N = 740). Treatment pathways, QALYs, and costs were incorporated into a discrete event simulation to reflect patient heterogeneity, including age and disease management. Two scenario analyses, based on the latest National Institute for Health and Clinical Excellence (NICE) guidelines (rituximab induction therapy for newly diagnosed asymptomatic patients and rituximab maintenance therapy for patients between treatments), were conducted and their economic impacts were compared to current practice. RESULTS: Incidence-based analysis revealed expected average lifetime costs ranging from £6,165 [US$7,709] to £63,864 [US$79,862] per patient, and average life expectancy from 75 days to 17.56 years. Prevalence-based analysis estimated average annual treatment costs of £60-65 million [US$75-80 million], accounting for approximately 10% of the United Kingdom's annual National Health Service budget for hematological cancers as a whole. Assuming that treatment effects reported in trials are applicable to all patient groups, scenario analyses for two recent NICE guidelines demonstrated potential annual cost savings for the United Kingdom that ranged with uptake frequency from £0.6 million to £11 million [US$0.75-2.75 million]. CONCLUSIONS: Costs, survival, and QALYs associated with FL vary markedly with patient characteristics and disease management. Allowing the production of more realistic outcomes across the patient population as a whole, our model addresses this heterogeneity and is a useful tool with which to evaluate new technologies/treatments to support healthcare decision makers.

Disparities in survival by insurance status in follicular lymphoma.

Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma and most common indolent non-Hodgkin lymphoma. Lower socioeconomic status is associated with poor outcomes in FL, suggesting that access to care is an important prognostic factor; however, the association between insurance status and FL survival has not been sufficiently examined. The National Cancer Database, a nationwide cancer registry, was used to evaluate 43 648 patients with FL diagnosed between 2004 and 2014. All analyses were performed on 2 cohorts segmented at age 65 years to account for changes in insurance status with Medicare eligibility. Cox proportional hazard models calculated hazard ratios (HRs) with confidence intervals (CIs) for the association between insurance status and overall survival (OS) controlling for the available sociodemographic and prognostic factors. Kaplan-Meier curves display outcomes by insurance status for patients covered by private insurance, no insurance, Medicaid, or Medicare. When compared with patients younger than age 65 years with private insurance, patients younger than age 65 years with no insurance (HR, 1.96; 95% CI, 1.69-2.28), with Medicaid (HR, 1.82; 95% CI, 1.57-2.12), and with Medicare (HR, 1.96; 95% CI, 1.71-2.24) had significantly worse OS after adjusting for sociodemographic and prognostic factors. Compared with patients age 65 years or older with private insurance, those with Medicare only (HR, 1.28; 95% CI, 1.17-1.4) had significantly worse OS. For adults with FL, expanding access to care through insurance has the potential to improve outcomes.

Retrospective analysis of first-line treatment for follicular lymphoma based on outcomes and medical economics.

BACKGROUND: Follicular lymphoma (FL) is the most common type of non-Hodgkin lymphoma (NHL), with indolent progression. Several treatment options are selected, based not only on disease status, quality of life (QOL), and age of patient, but also on recent increasing medical costs. We retrospectively analysed the first-line treatment of FL with regard to treatment outcomes and medical economics, and discuss the appropriate strategies for FL. METHODS: Data on a total of 69 newly-diagnosed patients with FL was retrospectively collected from 2001 to 2015. RESULTS: The median age of the patients was 60 years and the median follow-up was 58 months. A total of 25 cases with FL were treated with R monotherapy, and 28 cases were treated with R-CHOP as first-line treatment. The factors affecting the decision of physicians to use R or R-CHOP treatment were serum level of lactate dehydrogenase (LDH) and disease stage. The first-line treatment-associated survival did not show any statistical differences between R and R-CHOP. The average hospitalization and average of all medical costs during the first-line treatment were 4.1 days (R) versus 55.7 days (R-CHOP), and JPY 1,707,693 (USD 15,324) (R) versus JPY 2,136,117 (USD 19,170) (R-CHOP), respectively. CONCLUSION: R monotherapy for patients whose diseases show low tumor burden and who are not candidates for local treatment has benefits as a first-line treatment compared to R-CHOP, based on the patients' QOL and medical economics.

Cost-Effectiveness Analysis of Bendamustine Plus Rituximab as a First-Line Treatment for Patients with Follicular Lymphoma in Spain.

BACKGROUND: Follicular lymphoma (FL) is the second most common type of lymphoid cancer in Western Europe. OBJECTIVE: The aim of this study was to evaluate the cost utility of rituximab-bendamustine treatment compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) treatment as a first-line therapy for patients with advanced FL in Spain. METHODS: A Markov model was developed to estimate the cost effectiveness of rituximab-bendamustine compared with R-CHOP as first-line treatment for patients with advanced FL in the Spanish National Health System (NHS). Transitions between health states (progression-free, including induction and maintenance; first relapse; second relapse; and death) were allowed for the patient cohort in 4-week-long cycles. Clinical data for the extrapolation of progression-free survival curves were obtained from randomized trials. Mortality rates and utilities were obtained from the literature. Outcomes were measured as quality-adjusted life-years (QALYs). The total costs (€, 2013) included drug costs (ex-factory prices with mandatory deductions), disease management costs and adverse event-associated costs. Costs and outcomes were discounted at a 3 % annual rate. Probabilistic sensitivity analysis was performed using 10,000 Monte Carlo simulations to assess the model robustness. RESULTS: Treatment and administration costs during the induction phase were higher for rituximab-bendamustine (€17,671) than for R-CHOP (€11,850). At the end of the 25-year period, the rituximab-bendamustine first-line strategy had a total cost of €68,357 compared with €69,528 for R-CHOP. Health benefits were higher for rituximab-bendamustine treatment (10.31 QALYs) than for R-CHOP treatment (9.82 QALYs). In the probabilistic analysis, rituximab-bendamustine was the dominant strategy over treatment with R-CHOP in 53.4 % of the simulations. CONCLUSION: First-line therapy with rituximab-bendamustine in FL patients was the dominant strategy over treatment with R-CHOP; it showed cost savings and higher health benefits for the Spanish NHS.

Estimating the Population Benefits and Costs of Rituximab Therapy in the United States from 1998 to 2013 Using Real-World Data.

BACKGROUND: Rituximab was approved in 1997 and is regularly one of the largest drug expenditures for Medicare; however, its benefits and costs have not been estimated from a population perspective. OBJECTIVES: To estimate both the clinical and the economic outcomes of rituximab for its approved hematological uses at the population level. RESEARCH DESIGN: Analyses using cancer registry incidence data from the Surveillance, Epidemiology, and End Results (SEER) program, and outcomes data from SEER data linked with Medicare administrative claims (SEER-Medicare data). These results were incorporated into an epidemiological simulation model of the population over time. SUBJECTS: We modeled all United States patients from 1998 to 2013 diagnosed with diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. MEASURES: Using this model, we estimated the life-years saved, as well as their economic benefit, in the United States population. We also estimated the incremental cost of adding rituximab to chemotherapy. All economic inputs were based on Medicare reimbursed amounts inflated to 2013 dollars. RESULTS: There were 279,704 cumulative life-years saved which were valued at $25.44 billion. The incremental direct medical cost of rituximab was estimated to be $8.92 billion, resulting in an incremental economic gain of $16.52 billion. CONCLUSIONS: These analyses, based on real-world evidence, show that the introduction of rituximab into clinical practice has produced a substantial number of incremental life-years. Importantly, the economic benefit of the life-years gained greatly exceeds the added costs of treatment.

Joint modeling approach for semicompeting risks data with missing nonterminal event status.

Semicompeting risks data, where a subject may experience sequential non-terminal and terminal events, and the terminal event may censor the non-terminal event but not vice versa, are widely available in many biomedical studies. We consider the situation when a proportion of subjects' non-terminal events is missing, such that the observed data become a mixture of "true" semicompeting risks data and partially observed terminal event only data. An illness-death multistate model with proportional hazards assumptions is proposed to study the relationship between non-terminal and terminal events, and provide covariate-specific global and local association measures. Maximum likelihood estimation based on semiparametric regression analysis is used for statistical inference, and asymptotic properties of proposed estimators are studied using empirical process and martingale arguments. We illustrate the proposed method with simulation studies and data analysis of a follicular cell lymphoma study.

[Cost-effectiveness analysis of maintenance therapy with rituximab in patients with follicular lymphoma responding to induction therapy at the first line]. / Análisis coste-efectividad del tratamiento de mantenimiento con rituximab en pacientes con linfoma folicular que responden a la terapia de inducción en primera línea.

BACKGROUND: Maintenance therapy with rituximab for follicular lymphoma (FL) responding to induction at the first-line, significantly increases progression-free survival compared with observation. To estimate the efficiency of this therapeutic option, we performed a cost-effectiveness analysis of maintenance therapy of the follicular lymphoma (FL) that responds to induction in first line, with rituximab, compared with the option of "watch and wait" strategy. METHODS: We did a Markov model of the FL, with four health states (progression free survival in first or second line, progression and death). The transition probabilities between states were obtained from clinical trials PRIMA and EORTC 20981. Health state utilities were obtained from literature. The use of health resources, from the perspective of the National Health System was estimated by a panel of Spanish clinical experts. Unit costs (euros in 2011) were obtained from Spanish sources. Deterministic and probabilistic analyses were made. RESULTS: In the deterministic base case analysis, for a time horizon of 30 years, the cost per life year gained (LYG) and quality-adjusted life-years (QALYs) gained, was euros 5,663 and euros 6,253 respectively. The sensitivity analyses confirmed the stability of the base case for time horizons of 10 and 20 years and various statistical distributions (Weibull, exponential, log-logistic, log-normal, Gompertz, and gamma) ranging between euros 4,222 and euros 8,766. Rituximab maintenance is cost-effective from a time horizon of 5.7 years (cost per QALY gained of euros 29,998). CONCLUSION: Compared with observation, rituximab maintenance treatment of the FL that responds to induction therapy in first line, is cost-effective according to the present model.

Clinical trial risk in Non-Hodgkin's lymphoma: endpoint and target selection.

PURPOSE: To quantify the clinical trial risk of new drug development in Non-Hodgkin's lymphoma (NHL). Risk estimates for this disease have not been reported before. METHODS: We undertook a retrospective review of clinical trials in (NHL) in four subtypes to compare the success rate with the industry average. Our inclusion criteria required that a drug must initiate its phase I trial in one of the four NHL subtypes between 1998 and June 2008 in the US. In addition, clinical trials of new drug candidates that pertain to four subtypes of NHL were retrieved from clinicaltrial.gov. Drug candidates that did not meet these criteria were excluded from the study. RESULTS: The overall success rate (8-11%) was significantly lower than the industry standard (17%). Overall survival (OS) as a secondary outcome appeared more predictive than primary endpoints that were surrogate, of overall success. Further, targeted therapies appear more successful in these lymphoma sub-types than broad acting drugs. CONCLUSION: Clinical trial risk in NHL, with an 89% failure rate reported here, may be reduced by basing decisions on OS secondary endpoints and biologic drugs.