Real-world adherence and discontinuation among Medicare beneficiaries initiating venetoclax vs. BTKis in relapsed/refractory chronic lymphocytic leukemia.

The treatment landscape for chronic lymphocytic leukemia (CLL) has been transformed by the availability of Bruton's tyrosine kinase inhibitors (BTKis) and the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax. Despite clinical trial data supporting these novel oral agents, evidence evaluating real-world adherence is limited. This study used 2015-2019 Medicare claims data for elderly patients with relapsed/refractory CLL to assess differences in real-world adherence and discontinuation in the 12 months after treatment initiation. In the final sample of 711 venetoclax patients and 1,566 BTKi patients, we found that those initiating venetoclax tended to be younger (mean age 75.6 [SD 6.0] vs 77.6 [SD 6.9] years, p < .001) but had poorer clinical characteristics. After risk-adjustment, the venetoclax group had higher adherence (61.9% vs. 45.4%, p < .0001) and lower discontinuation when compared to the BTKi group (28.5% vs. 47.4%, p < .001). These favorable real-world findings underscore the importance of developing well-tolerated novel combinations for older adults.

Cost-Effectiveness Analysis of Relmacabtagene Autoleucel for Relapsed or Refractory Large B-Cell Lymphoma in China.

OBJECTIVES: Relmacabtagene autoleucel (relma-cel) was recently approved in China for treating relapsed or refractory large B-cell lymphoma (r/r LBCL). We conducted a cost-effectiveness analysis from the perspective of Chinese healthcare system. METHODS: A mixture-cure model was developed to project life-years (LYs), quality-adjusted LYs (QALYs), and overall direct cost with a lifetime horizon for patients with r/r LBCL treated with relma-cel versus salvage chemotherapy. Patient-level data from RELIANCE trial and published data from Collaborative Trial in Relapsed Aggressive Lymphoma extension study were used to inform the model. The incremental cost-effectiveness ratio (ICER) was estimated and cost-effectiveness was evaluated at the willingness-to-pay threshold of 3 times the national gross domestic product per capita. RESULTS: The model projected that treatment with relma-cel was associated with incremental gains of 5.11 LYs and 5.26 QALYs compared with salvage chemotherapy at an increased cost of ¥1 067 430 (∼$154 152), resulting in an ICER of ¥203 137 (∼$29 435) per QALY. The model was most sensitive to the uncertainty around the estimated cure rate. The ICER of relma-cel was within the willingness-to-pay threshold in the base case and the probability of relma-cel treatment being considered cost-effective was approximately 74%. CONCLUSIONS: Compared with salvage chemotherapy, treatment with relma-cel for r/r LBCL in patients who have failed at least 2 lines of systemic therapy is within the cost-effective range from the perspective of Chinese healthcare system and represents a good use of healthcare resources.

Cost-Effectiveness of KTE-X19 for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in the United States.

INTRODUCTION: Despite currently available treatments for adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), survival outcomes remain poor, highlighting the need for new therapeutic strategies. This study estimates the cost-effectiveness of KTE-X19 to treat adults with R/R ALL from a US payer perspective. METHODS: The model had two components: a decision-tree, where pre-infusion costs for patients who ultimately did not receive KTE-X19 are accounted for, followed by a partitioned survival analysis, where all KTE-X19 infused patients would enter the three-state (pre-progression, progressed disease, death) model. Comparators included current standard of care treatments, i.e., blinatumomab (BLIN), inotuzumab ozogamicin (INO), and salvage chemotherapy (CHEMO). Both standard parametric and mixture cure models were used to model survival. Efficacy, safety, healthcare resource utilization, and health state utility inputs were derived from the ZUMA-3 trial (NCT02614066) and literature. Cost inputs were derived from literature or publicly available sources. Outcomes and costs were discounted 3% annually. Results of KTE-X19 versus comparators are reported as total and incremental life-years (LYs), quality-adjusted life-years (QALYs), costs, and resulting incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses (PSA) and key scenario analyses were also performed. RESULTS: In the base case, incremental QALYs for KTE-X19 were 2.44, 3.26, and 4.61 versus BLIN, INO, and CHEMO, respectively. Incremental costs were $50,913, $251,532, and $432,027, respectively, resulting in ICERs of $20,843/QALY (versus BLIN), $77,271/QALY (versus INO), and $93,768/QALY (versus CHEMO). Deterministic sensitivity analysis results were most sensitive to subsequent allogeneic stem cell transplant rates and post-progression utilities. PSA found that KTE-X19 is 78.4%, 74.0%, and 75.4% likely to be cost-effective versus BLIN, INO, and CHEMO, respectively. Across most scenarios, at a willingness-to-pay (WTP) threshold of $150,000/QALY, KTE-X19 was cost-effective versus all treatments. CONCLUSIONS: Compared to current options for adults with R/R ALL, KTE-X19 is cost-effective, driven primarily by improved survival.

Several treatments for adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) have been approved in the past decade in the US, including blinatumomab (BLIN) and inotuzumab ozogamicin (INO). However, despite the high costs associated with these treatments, survival for patients remains poor. KTE-X19, an autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy, approved by the Food and Drug Administration in October 2021, has potential to improve survival, but its economic value has not yet been determined. This model comprehensively evaluated the long-term clinical and economic value of KTE-X19 versus current treatments, including BLIN, INO, and salvage chemotherapy (CHEMO). Inputs were derived from key clinical trials, the literature, and other publicly available sources. The model used the perspective of a US third party payer over a patient lifetime. Compared to BLIN, INO and CHEMO, KTE-X19 resulted in improved quality of life as measured with incremental quality-adjusted life years (QALYs) of 2.44 (vs BLIN), 3.26 (vs INO), and 4.61 (vs CHEMO). Treatment with KTE-X19 had incremental costs of $50,913 (vs BLIN), $251,532 (vs INO), and $432,027 (vs CHEMO). KTE-X19 was found to provide good value for money based on incremental cost-effectiveness ratios of $20,843/QALY (vs BLIN), $77,271/QALY (vs INO), and $93,768/QALY (vs CHEMO). These values are well below the commonly accepted thresholds to determine economic value. Results were also found to be robust across sensitivity and scenario analyses.

Assessment of therapeutic effect of CD20-targeted immunoliposome in primary central nervous system lymphoma.

Primary central nervous system lymphoma (PCNSL) is a form of extranodal non-Hodgkin's B-cell lymphoma limited to the CNS. The treatment of PCNSL is ineffective partly due to the blood-brain barrier (BBB) restriction of delivery of many drugs including anti-CD20 (Rituximab; RTX) which is a standard treatment for systemic B-cell lymphomas. In this study, liposome with tween-80 surface modification was fabricated and conjugated with RTX for enhancing BBB penetration to target lymphoma cells in the CNS. Physicochemical characterizations of Lip/RTX were performed and spherical shape liposomes with narrow size distribution were demonstrated by TEM. An average diameter of Lip/RTX was 168.57 ± 1.57 nm with the percentage of RTX conjugation at 90.94. Cell internalization monitored by flow cytometry confirmed that conjugation of RTX promoted liposome entry into Raji cells expressing CD20. Antitumor activity of Lip/RTX was comparable to free RTX indicating that RTX moieties on liposome remained their therapeutic function. In addition, Lip/RTX inhibited tumor aggressiveness by limiting cell migration and invasion. Systemic administration of Lip/RTX significantly prolonged survival of mice harboring intracranial lymphoma xenografts. Taken together, Lip/RTX presents a new potential treatment for patients with PCNSL.

Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL.

PURPOSE: CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS: We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS: Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION: With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.

Choroidal lymphoma diagnosed by polymerase chain reaction-based clonality assessment.

PURPOSE: To report a case of primary choroidal lymphoma that was confirmed by polymerase chain reaction-based clonality testing. CASE REPORT: A 50-year-old woman presented with unilateral progressive vision loss. Fundus examination and B-ultrasonography demonstrated diffuse choroidal thickening without vitritis. Pars plana vitrectomy and subretinal biopsy were performed, and histopathologic analysis revealed choroidal B-cell lymphoid hyperplasia without evidence of neoplasia. Extraocular extension was ruled out, and transitory improvement was observed with oral steroids. After 1-year follow-up, she was referred to our hospital and clonality testing was performed using the samples taken months before. First, we used a forensic DNA extraction kit, and then, a multiplex polymerase chain reaction was carried out using the IgH Rearrangements Molecular Analysis Kit. Clonal rearrangement was identified for the immunoglobulin heavy chain framework regions 1 and 2, and B-cell choroidal lymphoma was confirmed. The patient began treatment with intravitreal rituximab, but no response was observed. Finally, complete regression was achieved using external beam radiotherapy. CONCLUSION: Polymerase chain reaction-based clonality testing can be a valuable tool to confirm a choroidal lymphoproliferative process.

Safety and financial analysis of outpatient dose-adjusted EPOCH for B-cell lymphoma at a tertiary comprehensive cancer center.

INTRODUCTION: Dose-adjusted (DA-) EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) is a front-line treatment option for aggressive B-cell lymphomas. Due to regimen complexity, inpatient administration of DA-EPOCH has been historically required. Moffitt Cancer Center (MCC) developed an Inpatient/Outpatient (IPOP) program to facilitate administration of complicated regimens in the outpatient setting. We hypothesized that outpatient administration of DA-EPOCH at a comprehensive cancer center is both safe and cost-effective. METHODS: We conducted a single-center, retrospective chart review including B-cell lymphoma patients who were 18 years or older and who had received DA-EPOCH at MCC from April 26, 2017 through August 10, 2019. The primary endpoint was hospital admissions during outpatient chemotherapy administration. Additional safety endpoints included hospitalizations between cycles, infectious complications, extravasations, drug spills, pump-malfunctions, and drug-related adverse events. Financial analysis included drug cost, resource utilization, and impact of hospital bed backfill. RESULTS: 56 patients received 219 cycles of DA-EPOCH with 193 cycles administered outpatient. Zero patients required hospitalization during outpatient administration of DA-EPOCH, resulting in 965 saved hospital days. 23 patients (41%) were hospitalized between cycles, most commonly due to neutropenic fever (52%). No extravasations were documented throughout the study period. There were few incidences of drug spills or pump malfunctions. Based on current regimen utilization, the annual transition of 84 cycles of DA-EPOCH to the outpatient setting has a positive impact on margin of $1,444,548. CONCLUSIONS: Routine outpatient administration of DA-EPOCH is both safe and feasible with a positive annual impact on margin of $1,444,548 at a comprehensive cancer center.

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies.

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.

Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma.

Importance: Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown. Objective: To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events. Design, Setting, and Participants: A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network. Intervention: The administration of CAR T-cell therapy. Main Outcomes and Measures: Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined. Results: The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs. Conclusions and Relevance: The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.

Outcomes of bendamustine- or cyclophosphamide-based first-line chemotherapy in older patients with indolent B-cell lymphoma.

Clinical trials comparing bendamustine/rituximab (BR) with cyclophosphamide-based regimens (RCHOP/RCVP) have pooled various histologies of indolent B-cell lymphomas. We examined real-life outcomes of older patients with follicular (FL), mantle cell (MCL), or marginal zone/lymphoplasmacytic lymphoma (MZL/LPL), treated with these first-line regimens. We identified Medicare beneficiaries with FL, MCL, or MZL/LPL, who received either first-line BR or RCHOP/RCVP in 2009-2016, and matched groups using a propensity score. Outcomes of claims-based event-free survival (EFS), overall survival (OS), toxicity, secondary cancers, and costs were compared in the aggregate cohort (N = 2736), and in separately matched histology-specific subcohorts. In the aggregate cohort, EFS was better with BR than with RCHOP/RCVP (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.70-0.87). Acute toxicity was lower with BR, including rates of hospitalizations (33% vs 45%), infections (21% vs 30%), cardiovascular events, and transfusions, yet OS did not differ (HR, 1.03; 95% CI, 0.91-1.17) and Medicare spending was higher. There was no difference in the cumulative incidence of secondary cancers (subhazard ratio, 1.11; 95% CI, 0.83-1.48). The EFS advantage of BR was pronounced in MCL (N = 690; HR, 0.64; 95% CI, 0.54-0.76), but less so in FL (N = 1330; HR, 0.83; 95% CI, 0.69-0.98) and absent in MZL/LPL (N = 574; HR, 0.92; 95% CI, 0.73-1.17). Despite improved EFS and lower toxicity, the shift from RCHOP/RCVP to BR in clinical practice did not improve OS for older patients with indolent B-cell lymphomas. Frequent infections and hospitalizations underscore the need for safer treatment approaches in this population. Secondary cancers do not appear to be increased after BR compared with RCHOP/RCVP.

Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma.

Importance: Axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option for B-cell lymphoma. It is expected to have long-term survival benefits; however, long-term survival data are limited. Objective: To estimate the long-term survival and cost-effectiveness of axicabtagene ciloleucel for treatment of relapsed or refractory B-cell lymphoma. Design, Setting, and Participants: Economic evaluation study using a survival analysis that digitized and extrapolated survival curves published in the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma), which enrolled patients between November 2015 and September 2016 and had a maximum follow-up of 24 months. Five different survival models (standard parametric, flexible parametric, 2 mixture cure models, and a flexible parametric mixture model) were used to extrapolate the survival curves to a lifetime horizon from January through June 2018. A cost-effectiveness analysis, from both a trial-based and lifetime horizon, was also conducted to inform the value of this novel therapy. The model was based on data from 111 patients with B-cell lymphoma who were enrolled in the ZUMA-1 trial. Interventions: One-time administration of axicabtagene ciloleucel compared with chemotherapy. Main Outcomes and Measures: Undiscounted and discounted life-years (LYs) and quality-adjusted life-years (QALYs), total costs, and incremental costs per LY and QALY gained. Results: The modeled cohort of 111 patients started at 58 years of age. At the end of the trial, treatment with axicabtagene ciloleucel resulted in 0.48 more LYs and 0.34 more QALYs than chemotherapy, producing a cost-effectiveness estimate of $896 600 per QALY for public payers and $1 615 000 per QALY for commercial payers. Extrapolated long-term survival for patients treated with axicabtagene ciloleucel ranged from 2.83 to 9.19 discounted LYs and from 2.07 to 7.62 discounted QALYs. Incrementally, treatment with axicabtagene ciloleucel was associated with 1.89 to 5.82 discounted LYs and 1.52 to 4.90 discounted QALYs vs chemotherapy. With the use of these incremental estimates of survival, cost-effectiveness estimates ranged from $82 400 to $230 900 per QALY gained for public payers and from $100 400 to $289 000 per QALY gained for commercial payers. Conclusions and Relevance: Treatment with axicabtagene ciloleucel appears to be associated with incremental gains in survival over chemotherapy. The range in projected long-term survival was wide and reflected uncertainty owing to limited follow-up data. Cost-effectiveness is associated with long-term survival, with further evidence needed to reduce uncertainty.

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.

Incidence and management of toxicity associated with ibrutinib and idelalisib: a practical approach.

The use of novel B-cell receptor signaling inhibitors results in high response rates and long progression-free survival in patients with indolent B-cell malignancies, such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma and Waldenström macroglobulinemia. Ibrutinib, the first-in-class inhibitor of Bruton tyrosine kinase, and idelalisib, the first-in-class inhibitor of phosphatidylinositol 3-kinase δ, have recently been approved for the treatment of several indolent B-cell malignancies. These drugs are especially being used for previously unmet needs, i.e., for patients with relapsed or refractory disease, high-risk cytogenetic or molecular abnormalities, or with comorbidities. Treatment with ibrutinib and idelalisib is generally well tolerated, even by elderly patients. However, the use of these drugs may come with toxicities that are distinct from the side effects of immunochemotherapy. In this review we discuss the most commonly reported and/or most clinically relevant adverse events associated with these B-cell receptor inhibitors, with special emphasis on recommendations for their management.

Cancer-specific geriatric assessment and quality of life: important factors in caring for older patients with aggressive B-cell lymphoma.

PURPOSE: To evaluate the efficacy and tolerability of chemotherapy, a geriatric assessment is recommended in elderly patients with cancer. We aimed to characterize and compare patients with aggressive lymphoma by objective response and survival status based on pre-treatment cancer-specific geriatric (C-SGA) and quality of life (QoL) assessments. METHODS: Patients not eligible for anthracycline-based first-line therapy or intensive salvage regimens completed C-SGA and QoL assessment before and after a rituximab-bendamustine-lenalidomide (R-BL) treatment in a phase II clinical trial. Clinical outcomes were compared based on pre-treatment individual and summary C-SGA measures, their cutoff-based subcategories and QoL indicators, using Wilcoxon rank sum or chi-square tests. RESULTS: A total of 57 patients (41 included in the clinical trial) completed a C-SGA. Participants with pre-treatment impaired functional status (Vulnerable Elders Survey-13 score ≥3) were more likely to experience worse outcomes: a higher proportion were non-responders, died before the median follow-up of 31.6 months (interquartile range (IQR) 27.9-37.9) or died during treatment. Non-responders were patients categorized as having possible depression (Geriatric Depression Scale-5 score ≥2) and with worse QoL scores for functional performance. Patients with worse C-SGA summary scores and with greater tiredness were more likely to die during treatment. CONCLUSION: A pre-treatment impaired functional status is an important factor with respect to clinical outcomes in patients receiving an R-BL regimen. Individual geriatric and related QoL domains showed similar associations with clinical outcomes. Whether interventions targeting specific geriatric dimensions also translate in better symptom- or domain-specific QoL warrants further research.

Rituximabe subcutâneo para o tratamento de linfoma não Hodgkin difuso de grandes células B, CD20 positivo / Rituximab subcutaneous for the treatment of diffuse non-Hodgkin's lymphoma of large B cells, CD20 positive

CONTEXTO: O linfoma não Hodgkin (LNH) é um câncer do tecido linfático, que causa aumento dos gânglios desse tecido e sintomas generalizados. A forma difusa de grandes células B (LDGCB) é o mais comum dos LNH agressivos, correspondendo a 40% dos novos casos diagnosticados e aproximadamente 30% de todos os casos registrados de LNH. É caracterizado pela proliferação maligna de linfócitos encontrados em vários estágios, formando um tumor com malignidade moderada a grave e com significativa heterogeneidade. Também tem a presença de células B com alto índice proliferativo, e manutenção com a natureza agressiva da doença. Os LDGCB podem manifestar sintomas relacionados ao crescimento rápido dos linfonodos, os quais são frequentemente cervicais e abdominais. TECNOLOGIA: Rituximabe subcutâneo (MabThera®SC®). INDICAÇÃO: Linfoma não Hodgkin difuso de grandes células B, CD20 positivo, em combinação à quimioterapia. TECNOLOGIA: Rituximabe subcutâneo (MabThera®SC®). INDICAÇÃO: Linfoma não Hodgkin difuso de grandes células B, CD20 positivo, em combinação à quimioterapia. PERGUNTA: O uso de rituximabe por via subcutânea é eficaz e seguro em pacientes com LNH difuso de grandes células B quando comparado ao rituximabe por via intravenosa? EVIDÊNCIAS CIENTÍFICAS: Um ensaio clínico randomizado, fase III, com o objetivo de avaliar a nãoinferioridade farmacocinética de rituximabe por via subcutânea (SC) 1.400mg versus rituximabe por via intravenosa (IV) 375mg/m2 combinado com quimioterapia, em pacientes com linfoma folicular CD20 positivo grau 1-3ª, e também para investigar se a via de administração SC prejudicaria a atividade antilinfoma do rituximabe. A média de concentração sérica mínima (Ctrough) foi 83,13 µg/ml no grupo IV e 134,58 µg/ml no grupo SC (Razão de 1,62, IC 90%: 1,36-1,94), mostrando a não inferioridade de rituximabe SC. O perfil de eventos adversos também foi similar em ambos os grupos. Os resultados sugerem a não inferioridade da formulação subcutânea do medicamento em relação à intravenosa. AVALIAÇÃO DE CUSTO-MINIMIZAÇÃO: No modelo de custo-minimização, foram comparados o rituximabe SC com a apresentação IV. Os resultados da análise apontam para custos de tratamento equivalentes entre ambas as formulações, indicando que a incorporação da formulação subcutânea ao SUS não deverá proporcionar gastos adicionais ao sistema. Na análise de sensibilidade a única variável da análise que foi considerada foi a superfície corpórea média, que influencia diretamente no custo total de tratamento. A superfície corporal implicou uma variação de ± R$ 3.486,84 nos gastos anuais. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: O preço proposto para incorporação do medicamento é igual ao custo anual de tratamento do rituximabe intravenoso (já disponível no SUS). Desse modo, independente da taxa de difusão da tecnologia ao longo do tempo ou da população que de fato irá migrar para a nova apresentação, o impacto orçamentário incremental com a incorporação da nova tecnologia será nulo. RECOMENDAÇÃO DA CONITEC: Após discussão sobre as evidências apresentadas, na 51ª reunião da CONITEC, realizada nos dias 30 de novembro e 1º de dezembro de 2016, o plenário recomendou preliminarmente a não incorporação do medicamento rituximabe subcutâneo para linfoma Não-Hodgkin Difuso de Grandes Células B. A matéria será disponibilizada em Consulta Pública com recomendação preliminar não favorável. CONSULTA PÚBLICA: O relatório foi colocado em Consulta Pública nº 48/2016, entre os dias 26/12/2016 e 06/02/2017. Foram recebidas 73 contribuições, sendo 16 pelo formulário para contribuições técnico-científicas e 57 pelo formulário para contribuições sobre experiência ou opinião. A grande maioria das contribuições foram contrárias à recomendação inicial da CONITEC. DELIBERAÇÃO FINAL: Os membros do plenário da CONITEC presentes na reunião do dia 09/03/2017 deliberaram, por unanimidade, recomendar a não incorporação do rituximabe SC para o tratamento de linfoma não Hodgkin difuso de grandes células B, CD20 positivo. As razões da não incorporação foram a expiração da patente do rituximabe IV, além da existência de PDP para produção do rituximabe IV pelo SUS. Dessa forma, os preços do rituximabe IV serão reduzidos. Por outro lado, a patente do rituximabe SC foi depositada no Brasil no ano de 2010 e, de acordo com o INPI, a validade da patente de invenção é de 20 anos a partir da data do depósito. Ademais, os estudos mostraram maior risco de ocorrência de reações adversas relacionadas à administração com a forma SC do que com a forma IV. Com a forma IV, é possível reduzir a velocidade de infusão ou mesmo interrompê-la, caso o paciente apresente alguma reação adversa durante a administração do medicamento. Ainda, o tratamento com rituximabe possui um tempo de duração definido, de 6 a 8 ciclos de administração, não sendo necessário seu uso contínuo.(AU)

Positron Emission Tomography/Computed Tomography Assessment After Immunochemotherapy and Irradiation Using the Lugano Classification Criteria in the IELSG-26 Study of Primary Mediastinal B-Cell Lymphoma.

PURPOSE: To assess the predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for disease recurrence after immunochemotherapy (R-CHT) and mediastinal irradiation (RT), using the recently published criteria of the Lugano classification to predict outcomes for patients with primary mediastinal large B-cell lymphoma. METHODS AND MATERIALS: Among 125 patients prospectively enrolled in the IELSG-26 study, 88 were eligible for central review of PET/CT scans after completion of RT. Responses were evaluated using the 5-point Deauville scale at the end of induction R-CHT and after consolidation RT. According to the Lugano classification, a complete metabolic response (CMR) was defined by a Deauville score (DS) ≤3. RESULTS: The CMR (DS1, -2, or -3) rate increased from 74% (65 patients) after R-CHT to 89% (78 patients) after consolidation RT. Among the 10 patients (11%) with persistently positive scans, the residual uptake after RT was slightly higher than the liver uptake in 6 patients (DS4; 7%) and markedly higher in 4 patients (DS5; 4%): these patients had a significantly poorer 5-year progression-free survival and overall survival. At a median follow-up of 60 months (range, 35-107 months), no patients with a CMR after RT have relapsed. Among the 10 patients who did not reach a CMR, 3 of the 4 patients (positive predictive value, 75%) with DS5 after RT had subsequent disease progression (within the RT volume in all cases) and died. All patients with DS4 had good outcomes without recurrence. CONCLUSIONS: All the patients obtaining a CMR defined as DS ≤3 remained progression-free at 5 years, confirming the excellent negative predictive value of the Lugano classification criteria in primary mediastinal large B-cell lymphoma patients. The few patients with DS4 also had an excellent outcome, suggesting that they do not necessarily require additional therapy, because the residual 18F-fluorodeoxyglucose uptake may not reflect persistent lymphoma.

Improved survival with combined modality therapy in the modern era for primary mediastinal B-cell lymphoma.

Primary mediastinal B-cell lymphoma (PMBCL) is an uncommon lymphoma for which existing data is limited. We utilized the National Cancer Database (NCDB) to evaluate PMBCL and the impact of radiotherapy (RT) on outcomes in the years following FDA approval of rituximab. We queried the NCDB for patients with PMBCL diagnosed from 2006 to 2011 and treated with multiagent chemotherapy. Kaplan-Meier overall survival (OS) estimates, univariate (UVA), and multivariate (MVA) Cox proportional hazards regression analyses were performed. Propensity score matched analysis (PSMA) was performed to account for indication bias and mitigate heterogeneity between treatment groups. 465 patients were identified with a median follow-up of 36 months. Median age was 36 years; 43% received RT. 5-year OS for the entire cohort was 87%, and for the no-RT and RT groups, 83% versus 93%, respectively. On UVA, OS was improved with RT (HR 0.34, P = 0.002). On MVA, RT remained significantly associated with improved OS (HR 0.44, P = 0.028) while Medicaid insurance status and increasing stage remained significantly associated with OS decrement. PSMA confirmed the OS benefit associated with RT. This analysis is the largest PMBCL dataset to date and demonstrates a significant survival benefit associated with RT in patients receiving multiagent chemotherapy in the rituximab era. More than half of patients treated in the United States during this time period did not receive RT. In the absence of phase III data to support omission, combined modality therapy with its associated survival benefit should be the benchmark against which other therapies are compared.

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.