Choosing First-Line Therapy for Follicular Lymphoma (FL): A Decision Analysis

Abstract Introduction: There is no standard of care for first-line therapy of low-grade FL. In US practice, the most common strategy is rituximab with combination chemotherapy. However, the optimal choice of regimen remains controversial; options include RCVP, RCHOP and R-Fludarabine-based chemotherapy (RFlu). Because data from randomized clinical trials are not available and unlikely to be generated in the future, we performed a decision analysis comparing RCVP, RCHOP, and RFlu as first-line therapy for FL. Methods: We constructed a Markov model of sequential first- and second-line therapy based on prescribing patterns in the US. The endpoint of the model was quality-adjusted time to tertiary referral for therapy such as RIT or autologous transplant (≥3rd line). A literature review was performed of the Medline database and international meeting abstracts. Clinical trials of both untreated and previously treated patients were systematically evaluated using explicit eligibility criteria. Data were extracted regarding response rates, treatment-related mortality, and progression-free survival (PFS). Weighted estimates were obtained using a fixed effects meta-analysis. The model also incorporated published data on heath state utilities, risk of anthracycline cardiotoxicity and fludarabine-related delayed cytopenias. Primary and sensitivity analyses were performed using TreeAge software. Results: The optimal treatment strategy consisted of RCHOP in first-line followed by RFlu in second-line (9.0 quality-adjusted life years; QALYs). Strategies containing RCVP in either first- or second-line were inferior (6.2–7.7 QALYs). The model was sensitive to first-line PFS of RCHOP and RFlu when these were varied over the range of estimates obtained from individual published trials. The model was robust in sensitivity analysis of most other parameters, including rate of delayed cytopenias after RFlu, anthracycline cardiotoxicity, and quality of life adjustments. Conclusions: Using decision analysis, the optimal first-line therapy for low-grade FL is RCHOP, followed by RFlu in second-line. This strategy maximizes quality-adjusted time to tertiary therapy. Use of RCVP does not improve overall quality-adjusted time relative to more intensive therapies.

Download Full-text

Impact of Treatment Sequencing on Outcomes and Costs in Relapsed Follicular or Other Low Grade B-Cell Non-Hodgkin Lymphoma - Results of an Evidence-Based Budget Impact Model

Blood ◽

10.1182/blood-2020-141748 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 14-15

Author(s):

Ali McBride ◽

Daniel O. Persky

Keyword(s):

Follicular Lymphoma ◽

Low Grade ◽

Second Line ◽

Treatment Sequence ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Duration Of Response ◽

Budget Impact Model

Introduction: The choice of initial therapy in follicular lymphoma can be a key determinant in future therapy, as irreversible toxicities with first line regimens can impact the patient's ability to tolerate future treatment. Minimizing drug exposure will result in less frequent occurrence of significant adverse events and associated treatment costs. In the era of COVID-19 pandemic, there is additional benefit to minimizing the number of patient visits and hospital admissions. Limited information exists related to the outcomes and associated costs of existing treatment sequences. Additionally, treatment administration at different types of clinical sites results in varied reimbursement models, making informed evaluation of clinical and financial evidence challenging. Methods: The current study applies a budget impact model methodology in order to describe the associated impact of treatment selection and sequencing on outcomes and costs in the treatment of relapsed or refractory low-grade follicular lymphoma in first line therapy followed by Consolidation and also in first line therapy to second line therapy. Key model inputs included: Number of treatment cycles, number of days a treatment was received, duration of response (DOR), rate of side effects and associated costs, and total treatment costs, including drugs, medical treatment, laboratory testing and adverse event costs. Treatment outcomes were based on the published literature that summarized the overall response rate, median DOR, and toxicity. Treatment regimen costs were evaluated based on payer pricing, Wholesale Acquisition Cost (WAC), Average Selling Price (ASP) and Average Wholesale Price (AWP) and modified to adjust for weight-based dosing and negotiate payer reimbursement rates. Associated medical costs for medical treatment and supportive care were estimated using current Medicare fee schedule rates. Included were seven options for first line therapy of follicular lymphoma from 2020 NCCN Guidelines - (Bendamustine + rituximab (BR); Bendamustine + Obinutuzumab (OB); CHOP rituximab (RCHOP); CHOP + Obinutuzumab (OCHOP); CVP+ rituximab (RCVP); CVP + Obinutuzumab (OCVP); Lenalidomide + rituximab (R2)), followed by three for Consolidation (Rituximab maintenance (RM); Obinutuzumab maintenance (O); Radioimmunotherapy (RIT with 90 Y-ibritumomab tiuxetan (Y90-IT, Zevalin)) and three Second Line therapy options (RIT; Lenalidomide only; Lenalidomide + Obinutuzumab (LO)). Results: The treatment sequence of first line BR followed by Consolidation with RIT Y90 (Zevalin) had the longest predicted DOR (2586 days). The associated treatment sequence costs were $212,485 for BR followed by Y90-IT, compared with $233, 388 for BR followed by rituximab maintenance, which had a predicted DOR of 2478 days. The predicted DOR for treatment sequences starting with OCHOP, OCVP and RCHOP and followed by RIT with Y90-IT was approximately 1000 days less than BR followed by Y90-IT for a cost difference of $4,421, $12,914 and $25,826, respectively. The treatment sequence of first line BR followed by Second Line RIT Y90-IT had the second longest predicted DOR of 2586 days at costs of $212,485, compared to 2778 days for BR followed by LO, at a total sequence costs of $796,695. Conclusion: The use of Y90-IT in Consolidation or Second Line treatment demonstrated desired patient outcomes at one of the lowest cost profiles. Additionally, Y90-IT administration can be completed in only two clinic visits, reducing patient travel and contact, improving safety in an era of COVID-19 precautionary measures and reducing cost. Figure 1. Duration of Response and Total Sequence Costs for Twelve First Line to Consolidation and First Line to Second Line Treatment Regimens. Disclosures McBride: Merck: Speakers Bureau; Coherus BioSciences: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy.

Download Full-text

Economic evaluation of crizotinib, alectinib, ceritinib, and brigatininb in anaplastic lymphoma kinase positive (ALK+) non-small cell lung cancer (NSCLC) as second-line treatment.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21104 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21104-e21104

Author(s):

Nimer S. Alkhatib ◽

Briana Choi ◽

Hala Halawah ◽

Matthias Calamia ◽

Dexter Gulick ◽

...

Keyword(s):

Cost Effectiveness ◽

Adverse Events ◽

Incremental Cost ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Reference Drug ◽

First Line Therapy ◽

Line Therapy ◽

Life Years

e21104 Background: Crizotinib, alectinib, ceritinib, and brigatinib are approved as second line treatment for ALK+ NSCLC. Crizotinib was the first ALK inhibitor for first line therapy approved by Food and Drug Administration (2011) then ceritinib (2014), alectinib (2015), and brigatinib (2017) were approved as second line drugs. Following more data, these agents were approved as the first line therapy (2017 for ceritinib and alectinib; 2020 for brigatinib). These remain as a treatment option in patients who fail the first line therapy. Cost-effectiveness/utility analyses were conducted to assess clinical efficacy with varying costs of the agents. Methods: A three state Markov model were assumed (progression free, progression and death). Progression free survival (PFS) curves were digitized and fitted with exponential function. US payer perspective, a lifetime horizon, and discount rate of 3% were applied. Drug costs were Redbook wholesale acquisition cost. Other costs included were monitoring, adverse events and disease progression from published data (US$ 2020). Adverse events reported >5% in patients were included. Measured outcomes were PFS life years (PFSLY) and quality adjusted life years (PFSQALY). Crizotinib was the reference drug. Incremental cost-effectiveness and utility ratios (ICER/ICUR) of PFSLY and PFSQALY gained (PFSLYG, PFSQALYG) and lost were estimated. Base case (BCA) and probabilistic sensitivity analyses (PSA) were conducted. Results: Crizotinib was the reference drug for the following outcomes. For alectinib, with the decremental cost of -$14,653 (-$14,712), the incremental PFSLY of 0.16 (0.16) and PFSQALY of 0.05 (0.05) resulted in an ICER / PFSLYG of -$89,337 (-$88,604) and an ICUR / PFSQALYG of -$269,835 (-$266,510). For brigatinib, with the decremental cost of -$14,975 (-$14,954), the incremental PFSLY of 0.01 (0.01) and PFSQALY of ̃0.01 (0.02) yielded an ICER / PFSLYG of -$1,982,962 (-$1,431,631) and an ICUR / PFSQALYG of -$2,140,534 (-$570,538). For ceritinib, with the incremental cost of $7,590 ($7,514), there were decremental PFSLY of -0.01 (-0.01) and PFSQALY of -0.03 (-0.03). Conclusions: As second line treatment, crizotinib, ceritinib, and brigatinib had comparable PFSLYs and PFSQALYs while alectinib had the most PFSLY and PFSQALY and the lowest cost. Therefore, alectinib is the most cost-effective treatment for treating ALK+ NSCLC as the second line therapy.[Table: see text]

Download Full-text

Is Prior Rituximab Exposure Associated with a Difference in Outcomes in Relapsed Low-Grade Lymphomas Retreated with Rituximab in Comparison to Rituximab NaïVe Patients?

Blood ◽

10.1182/blood.v128.22.1795.1795 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1795-1795

Author(s):

Abi Vijenthira ◽

Manjula Mangati ◽

Michael Crump ◽

Vishal Kukreti ◽

John Kuruvilla ◽

...

Keyword(s):

Research Funding ◽

Low Grade ◽

Line Treatment ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Time Period ◽

Group 2 ◽

Indolent Lymphomas

Abstract Introduction: Evidence from several randomized clinical trials demonstrates the survival benefit and superior magnitude of disease control of rituximab use in indolent lymphomas compared to chemotherapy alone in remission induction. However, there is a paucity of evidence regarding retreatment with rituximab in patients who have previously been exposed. Despite this, Canadian agencies fund the use of rituximab retreatment in patients who have previously received rituximab, sustained a response, and been treatment free for over a year. The purpose of this study was to describe the characteristics and outcomes of patients with relapsed indolent lymphomas re-treated with a rituximab-containing regimen at Princess Margaret Cancer Centre (PM). Methods: This was a retrospective chart review of patients treated at a Canadian tertiary care centre (PM) with relapsed low-grade lymphomas (follicular, mantle cell, marginal zone, and lymphoplasmacyticlymphomas) between January 2006 and November 2015. The start date of January 2006 is when provincial rituximab funding became available. Patients were identified from our lymphoma and pharmacy databases. Patients were included if they had sustained a treatment free period ³1 year between first- and second-line therapy, and received rituximab as part of their second-line therapy. They were divided into two groups: Group 1 included patients who received any rituximab exposure as part of their first line therapy; Group 2 included patients na•ve to rituximab, who were treated with a non-rituximab containing first-line regimen. Primary outcome was progression-free survival (PFS) from start of second-line treatment. Secondary outcomes were overall survival (OS), overall response rate (ORR), and number of patients achieving a complete response (CR) at the end of second-line treatment. Results: 687 patients were identified who received rituximab for indolent lymphoma treatment (any line) during this time period. Of the eligible relapsed subset, 41 transformed to aggressive lymphoma, and 39 progressed < 1yr post-first line therapy. 60 patients (55% female) met inclusion criteria, of which 21 (35%) had been retreated with rituximab during this time period. See Table 1 for patient characteristics. From start of second-line treatment, median follow-up was 43 months (range 4 to 132 months). Multivariate cox regression revealed a significant PFS difference between groups, with Group 1 having inferior PFS (2 year PFS 56% vs 77%, OR 2.38 95% CI 1.08-5.26, p=0.03, see Figure 1). Furthermore, patients who were older, had a higherCharlsoncomorbidity score, and those who did not receive maintenance rituximab had a lower PFS. More patients in Group 2 received oral chemotherapy as their first line treatment (such aschlorambuciland prednisone, reflecting an earlier treatment era, p=0.0003). There was no OS difference between groups (2 year OS 87% vs 79%, OR 1.73, 95%CI 0.64-4.64, p=0.28), although male gender and age were associated with lower OS. There was also no difference in groups in terms of ORR (75% vs 72%, p=0.8), or number achieving a CR at the end of second-line treatment (OR 0.38, 95% CI 0.11-1.37, p=0.14). Conclusions: Retreatment with rituximab was associated with an inferior PFS in patients with indolent lymphoma who sustained a one-year or greater response to first-line therapy with a rituximab-containing regimen, compared to rituximab-na•ve patients. This study is limited by small sample size, but our findings are consistent with other studies that evaluated rituximab retreatment in similar patient populations, and in diffuse large B-cell lymphoma. The PFS in patients retreated with rituximab was still superior to prior studies evaluating the use of second-line treatment with non-rituximab containing regimens in patients previously exposed to rituximab. There was no difference between groups in OS, ORR, or number achieving a CR at the end of treatment. Disclosures Crump: Celgene: Consultancy; Janssen-Ortho: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy. Kukreti:Lundbeck: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Kuruvilla:Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Merck: Honoraria; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Amgen: Honoraria; Roche Canada: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Lundbeck: Honoraria. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Chen:Takeda: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Prica:Celgene: Honoraria; Janssen: Honoraria.

Download Full-text

Using Data from a Sickness Fund Claims Database to Assess the Treatment Patterns and Healthcare Resource Utilization among Patients with Metastatic Renal Cell Carcinoma in Germany

Urologia Internationalis ◽

10.1159/000509973 ◽

2020 ◽

Vol 104 (11-12) ◽

pp. 982-993

Author(s):

Martin Bögemann ◽

Aleksandra Zagorska ◽

Divine Akumo ◽

Laila El Hadad ◽

Marc Pignot

Keyword(s):

Renal Cell Carcinoma ◽

Healthcare Resource ◽

Healthcare Resource Utilization ◽

Prescribing Patterns ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

Claims Database ◽

First Line Therapy ◽

Line Therapy

Objectives: To characterize real-world prescribing patterns and their clinical and healthcare resource utilization (HRU) implications in patients with metastatic renal cell carcinoma (mRCC) treated in Germany. Methods: Eligible individuals were enrolled in the “Bundesverband der Betriebskrankenkassen” claims database and received targeted mRCC therapy between 1 January 2008 and 31 December 2016. Prescribing patterns and HRU were characterized by treatment line and summarized by descriptive statistics. Proxy progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier curves. Results: 536 patients receiving mRCC treatment were included. The median treatment duration was 4.2 months (interquartile range [IQR]: 1.7–9.3) for first-line therapy and 3.8 months (IQR: 1.7–9.1) for second-line therapy. Median PFS and OS estimates were similar for the first- and second-line treatments: PFS, 7.4 versus 7.2 months; OS, 14.9 versus 13.6 months. Mean HRU costs were higher for patients receiving first-line therapy (€7,253.2) compared with those receiving second-line therapy (€6,242.9). Exploratory stratification of outcomes by centre expertise suggested a possible trend towards improved OS in the 10 most experienced centres versus all -others: first-line, 18.4 versus 13.2 months; second-line, 16.4 versus 12.4 months. Conclusions: In routine care, German clinicians make rational prescribing decisions; possible variations in outcomes between centres warrant further investigation.

Download Full-text

1338. Analysis of Prescription Guideline Adherence in Pediatric Outpatient Pneumonia Treatment

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1520 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S680-S681

Author(s):

Carly Heck ◽

Judith Martin ◽

Marcia Kurs-Lasky

Keyword(s):

Drug Allergy ◽

Health Concern ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Comparison Results ◽

Significant Difference ◽

Recommended Therapy

Abstract Background Background: Antibiotic resistance is a major public health concern. A modifiable intervention is outpatient antibiotic stewardship. The goal of this study was to review the electronic health records (EHR) of children diagnosed with community acquired pneumonia (CAP) to compare patients who received non-guideline concordant therapy with those prescribed recommended therapy. Methods Methods: This was a retrospective chart review of 300 children (6 months to 6 years old) with an outpatient diagnosis of CAP between July 2017 and June 2019. 45 Children’s Hospital of Pittsburgh (CHP) and UPMC Children’s Community Pediatrics (CCP) practices were included. CHP practices are academic-based with trainees involved in visits, while CCP practices do not include trainees. First-line recommended therapy was defined as amoxicillin, second-line therapy as azithromycin or amoxicillin-clavulanate, and all other prescriptions were defined as other. Patients prescribed first-line therapy were compared to patients with second-line therapy or other. If first-line therapy was not prescribed, the EHR was manually reviewed for justification. If drug allergy was listed, the medication allergy and type of reaction were recorded. Results Results: In this study the minority of children (43%) were prescribed first-line therapy. This group was younger (57 vs. 63 months of age), more likely to be Non-white (80%), and seen at the CHP locations than those prescribed non-guideline concordant therapy. The average symptom duration was shorter, heart rate and respiratory rate were higher and the presence of fever was more common in the first-line therapy group. Justification for non-guideline therapy was most often reported as to provide coverage for atypical organisms. The most common drug allergy recorded was amoxicillin, and urticaria with unknown timing was the most common type of reaction. Demographics Comparison Results Justification for Second-line / Other Therapy and Drug Allergy Results Conclusion This project observed a high proportion of children being prescribed non-guideline concordant therapy for a diagnosis of CAP. Age, race, practice location, and severity of illness measures showed a statistically significant difference between groups. This study highlights the importance of education which reviews the current guidelines and the most likely pathogens for children with CAP. Disclosures All Authors: No reported disclosures

Download Full-text

Retention rate of a second line with a biologic DMARD after failure of a first-line therapy with abatacept, tocilizumab, or rituximab: results from the Italian GISEA registry

Clinical Rheumatology ◽

10.1007/s10067-021-05734-3 ◽

2021 ◽

Author(s):

Marco Sebastiani ◽

◽

Vincenzo Venerito ◽

Serena Bugatti ◽

Chiara Bazzani ◽

...

Keyword(s):

Retention Rate ◽

Second Line ◽

First Line ◽

First Line Therapy ◽

Line Therapy ◽

Biologic Dmard

Download Full-text

Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

Journal of Clinical Oncology ◽

10.1200/jco.2004.11.037 ◽

2004 ◽

Vol 22 (7) ◽

pp. 1209-1214 ◽

Cited By ~ 761

Author(s):

Axel Grothey ◽

Daniel Sargent ◽

Richard M. Goldberg ◽

Hans-Joachim Schmoll

Keyword(s):

Colorectal Cancer ◽

Advanced Colorectal Cancer ◽

Cytotoxic Agents ◽

Phase Iii ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy ◽

Phase Iii Trials

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

Download Full-text

Modeling sequential systemic therapy for unresectable hepatocellular carcinoma in the era of immunotherapy: What comes next?

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.324 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 324-324

Author(s):

Ciro Celsa ◽

Giuseppe Cabibbo ◽

Marco Enea ◽

Salvatore Battaglia ◽

Giacomo Emanuele Maria Rizzo ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Survival Data ◽

Survival Curve ◽

Second Line ◽

First Line ◽

Lifetime Horizon ◽

First Line Therapy ◽

Line Therapy ◽

Unresectable Hepatocellular Carcinoma ◽

Sequential Strategy

324 Background: Atezolizumab plus Bevacizumab represents the new best performing first-line approach for unresectable hepatocellular carcinoma (u-HCC). However, the best sequential strategy after every first-line failure (for progression or intolerance) remains elusive, and options for retreating patients failing Atezolizumab plus Bevacizumab with multi-kinase inhibitors (MKI) or immune checkpoint inhibitor (ICI) are yet undefined. Methods: We developed a Markov model to analyze simulated-Overall Survival (s-OS) of second-line ICIs or MKIs after first-line Atezolizumab plus Bevacizumab over a lifetime horizon. For first-line therapy, PFS of Atezolizumab plus Bevacizumab was extracted from Imbrave 150 trial and it was used as endpoint since it is not influenced by post-progression survival. For second-line retreatment, pooled OS of MKIs (Regorafenib and Cabozantinib), or ICIs (Nivolumab and Pembrolizumab) were adopted. Survival estimates for sequential settings considered the proportion of patients who did not receive second-line therapy due to death during first-line therapy. Individual patient survival data were extracted from PFS and OS Kaplan-Meier curves of RESORCE trial for Regorafenib, CELESTIAL trial for Cabozantinib, CheckMate-040 for Nivolumab and Keynote-240 for Pembrolizumab. Each reconstructed survival curve was inspected for accuracy and was compared with originally published curves. Results: First-line Atezolizumab plus Bevacizumab followed by second-line ICIs turned on from the model as the best sequential strategy (median s-OS 24 months; 95% Confidence Interval (CI) 23-26 months) and extends survival when compared Atezolizumab plus Bevacizumab followed by MKIs (median s-OS 20 months; 95% CI 19-21 months). Conclusions: To our knowledge and given the absence of adequately designed sequential RCTs, this is the first model to date which suggests, with a proper methodological approach, an accurate estimate of outcome of patients with u-HCC treated by sequential systemic therapies. In patients with u-HCC failing first-line treatment, modelling estimates of s-OS for each retreatment strategies may assist in choosing the most promising sequences in order to plan appropriate RCTs.

Download Full-text