Perspectives on outpatient administration of CAR-T cell therapy in aggressive B-cell lymphoma and acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.

Factors Associated with Costs in Chimeric Antigen Receptor T-Cell Therapy for Patients with Relapsed/Refractory B-Cell Malignancies.

BACKGROUND: Chimeric antigen receptor T cells (CAR-Ts) constitute a novel therapeutic strategy for relapsed/refractory B-cell malignancies. CAR-T therapy has been extensively applied in the clinical setting; however, few systematic studies have evaluated the cost of CAR-T treatment. This study was conducted to evaluate the total cost and cost structure of CAR-T therapy and identify potential risk factors leading to increased costs. METHODS: We identified the associated risk factors in 89 patients in a phase 1/2 study. The cohort included patients with acute lymphoblastic leukemia (ALL, n = 55) and non-Hodgkin's lymphoma (NHL, n = 34). RESULTS: Overall, the treatment of the ALL cohort was costlier than that of the NHL cohort (P < 0.001). Furthermore, in the ALL cohort, it was costlier to treat patients with a high tumor burden (P < 0.001), high cytokine release syndrome (CRS) grade (P < 0.001), and complications of infection after CAR-T cell infusion (CTI) in the whole cohort (P = 0.013) than patients with a low tumor burden, with low CRS grade, and without infection, respectively. CRS grade and length of stay (P ≤ 0.005) were independent risk factors associated with the total cost in both the ALL and NHL cohorts during CAR-T therapy. A high tumor burden, duration of fever, and treatment with tocilizumab were independent risk factors associated with the total cost in the ALL cohort (P < 0.05). CONCLUSIONS: CAR-T treatment should be extended to patients with a low tumor burden or patients in a state of complete remission, and a corticosteroid approach, as opposed to tocilizumab, may reduce costs.

How Should We Determine the Value of CAR T-Cell Therapy?

In 2017, the US Food and Drug Administration approved the first chimeric antigen receptor (CAR) T-cell therapies for patients with relapsed or refractory B-cell leukemia and selected B-cell lymphomas. This novel form of cellular immunotherapy creates a "living drug" that effectively reprograms a patient's T cells to target specific antigens on the surface of a tumor. The therapy has high response rates in patients with refractory disease, although a single infusion of CAR T cells costs hundreds of thousands of dollars. A value analysis is required to determine whether and how to offer patients these expensive, customized drugs.

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.

Tbo-Filgrastim versus Filgrastim during Mobilization and Neutrophil Engraftment for Autologous Stem Cell Transplantation.

There are limited data available supporting the use of the recombinant granulocyte colony-stimulating factor (G-CSF), tbo-filgrastim, rather than traditionally used filgrastim to mobilize peripheral blood stem cells (PBSC) or to accelerate engraftment after autologous stem cell transplantation (ASCT). We sought to compare the efficacy and cost of tbo-filgrastim to filgrastim in these settings. Patients diagnosed with lymphoma or plasma cell disorders undergoing G-CSF mobilization, with or without plerixafor, were included in this retrospective analysis. The primary outcome was total collected CD34(+) cells/kg. Secondary mobilization endpoints included peripheral CD34(+) cells/µL on days 4 and 5 of mobilization, adjunctive use of plerixafor, CD34(+) cells/kg collected on day 5, number of collection days and volumes processed, number of collections reaching 5 million CD34(+) cells/kg, and percent reaching target collection goal in 1 day. Secondary engraftment endpoints included time to neutrophil and platelet engraftment, number of blood product transfusions required before engraftment, events of febrile neutropenia, and length of stay. A total of 185 patients were included in the final analysis. Patients receiving filgrastim (n = 86) collected a median of 5.56 × 10(6) CD34(+) cells/kg, compared with a median of 5.85 × 10(6) CD34(+) cells/kg in the tbo-filgrastim group (n = 99; P = .58). There were no statistically significant differences in all secondary endpoints with the exception of apheresis volumes processed (tbo-filgrastim, 17.0 liters versus filgrastim, 19.7 liters; P < .01) and mean platelet transfusions (tbo-filgrastim, 1.7 units versus filgrastim, 1.4 units; P = .04). In conclusion, tbo-filgrastim demonstrated similar CD34(+) yield compared with filgrastim in mobilization and post-transplantation settings, with no clinically meaningful differences in secondary efficacy and safety endpoints. Furthermore, tbo-filgrastim utilization was associated with cost savings of approximately $1406 per patient utilizing average wholesale price.

[Alteration in antibody-mediated immunity in patients with rituximab-combined chemotherapy and incidence of herpes zoster].

Rituximab, a chimeric monoclonal antibody against the CD20 protein, has an antineoplastic effect resulting from antibody dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In patients with rituximab-combined chemotherapy, a decline in immunoglobulin can be observed. This is more likely to cause virus reactivation, such as Herpes (H) zoster. However, this fact has not reported in a large-scale study. In order to research immunodeficiency conditions in patients with rituximab-combined therapy, we examined the alteration in immunoglobulin level throughout the treatment among 205 cases with B-cell lymphoma. We also studied the prevalence of H. zoster in those cases. The IgG level throughout the treatment was measured in 89 patients in the research. The median post-chemotherapy IgG level was 41.1% lower than its pre-chemotherapy IgG level. In 58 cases, the IgG level following chemotherapy was below the normal level. In 22 cases, the IgG level dropped to less than half of the pre-chemotherapy level. H. zoster developed in 17 cases (8.3%). There was no significant difference in IgG level between H. zoster-onset cases and non-H. zoster-onset cases. Antibody-mediated immunity can decrease greatly and prolong in cases with rituximab in combination with chemotherapy. Therefore, infection control is considered to be important.

[Improvement in the results of treatment of selected blood diseases and changes in the costs of such treatment. Issues for economists and other experts]. / Zlepsování výsledku lécby vybraných krevních chorob a zmeny nákladu na tuto lécbu. Otázky pro ekonomy a dalsí odborníky.

The text maps the changes in treatment results and costs for three haematological diseases; multiple myeloma; diffuse large B-cell lymphoma and chronic myeloid leukaemia. At the beginning of the 1990's, the alkeran-prednisone combination was the golden standard in the treatment of myeloma. In the mid 1990's, the treatment results in younger patients were dramatically improved by high-dose chemotherapy with autologous transplantation. The first decade of the new millennium has brought about even better results after the introduction of thalidomide in the initial treatment in patients not indicated for transplantation. Improvement is also expected in patients of a younger age group thanks to the combination of new drugs with autologous transplantation. A breakthrough in the treatment of patients with diffuse large cell lymphoma was the introduction in the treatment regimen of high-dose chemotherapy with autologous transplantation, and primarily the introduction of a new drug--a monoclonal antibody antiCD20, rituximab, in initial treatment. The golden standard for patients with chronic leukaemia in the early 1990's was hydroxyurea treatment. This was replaced by a new golden standard--interferon alpha, which was, in turn, replaced by the specific blocker of bcr-abl thyrosine kinase-imatinib. The text contains tables and charts showing the therapeutic benefit of the options mentioned above and the related costs.

Cost-effectiveness analysis of rituximab combined with chop for treatment of diffuse large B-cell lymphoma.

PURPOSE: To estimate the cost-effectiveness from a French payer perspective of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) alone compared with CHOP plus rituximab (R-CHOP) for treatment of patients with diffuse large B-cell lymphoma. METHODS: Mean patient survival, days of hospitalization, and chemotherapy costs during treatment were estimated from a Phase III trial in France, Belgium, and Switzerland. Survival during the trial was estimated using the Kaplan-Meier method; survival beyond the trial period was projected based on mortality rates from the Scottish and Newcastle Lymphoma Group database. French diagnosis-related group (DRG) payment schedules were applied to trial data to estimate cost of adverse events and drug administration. We estimated survival and cost-effectiveness [the incremental cost per quality-adjusted life-year (QALY) gained] from 4 years (median clinical trial follow-up period) to 15 years, discounted at a fixed annual rate of 3%. We used published patient preferences. We converted currency to euros, based on 2003 exchange rates. RESULTS: R-CHOP resulted in a 20.6% relative increase in complete response rate (absolute increase from 63% to 76%), and a 31% decrease in risk of death at 4 years (95% CI 8-49%). Over a 15-year time horizon, mean overall survival (OS) duration was estimated to be 6.90 years for R-CHOP and 5.74 years for CHOP, a mean increase in OS of 1.16 years (or 1.07 QALYs). Total direct medical costs were 13,170 euro higher with R-CHOP, with an incremental cost-effectiveness ratio of 12,259 euro per QALY gained. CONCLUSION: R-CHOP significantly increases mean OS up to 4 years compared with CHOP, and its cost-effectiveness ratio compares favorably with other oncology treatments in widespread use.

Cost utility in the United States of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone for the treatment of elderly patients with diffuse large B-cell lymphoma.

BACKGROUND: Findings from the Groupe d'Etude des Lymphomes Adultes LNH 98-5 study showed that rituximab added to combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) prolonged progression-free survival and overall survival in adults age >/= 60 years with diffuse large B-cell non-Hodgkin lymphoma (DLBCL). The current study was conducted to investigate the incremental cost utility of the addition of rituximab to CHOP (R-CHOP) compared with CHOP alone. METHODS: Clinical prognosis of the time to disease progression and death was estimated using published evidence from the LNH 98-5 study (n = 399 patients) that was linked mathematically to published long-term outcome data on patients with DLBCL. Drug-acquisition costs were based on published data from formulary pricing sources, and the costs of cancer surveillance and end-of-life care were based on published literature sources. The authors assessed cost utility as the difference in costs between R-CHOP and CHOP divided by the increase in expected overall survival adjusted for quality of life. RESULTS: Over 5 years, it was projected that R-CHOP would prolong overall survival by 1.04 years. The mean cumulative cost of CHOP was 3358 dollars, and the mean cost of R-CHOP was 17,225 dollars, resulting in a cumulative net increase of 13,867 dollars. The posttreatment cancer surveillance cost for CHOP was 3950 dollars, compared with 5202 dollars for R-CHOP. It was estimated that R-CHOP would have a cost-utility ratio of 19,297 dollars per year of life gained compared with CHOP when adjusted for quality of life. R-CHOP remained cost effective over wide ranges of variables in sensitivity analyses. CONCLUSIONS: Compared with CHOP alone, it was predicted that R-CHOP would be cost effective in elderly patients with DLBCL.

Cost-effectiveness of rituximab (MabThera) in diffuse large B-cell lymphoma in The Netherlands.

OBJECTIVE: To determine the incremental cost-effectiveness ratio (ICER) of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) vs. CHOP plus rituximab (R-CHOP) in diffuse large B-cell lymphoma (DLBCL) patients in the Netherlands. METHODS: A state transition model was developed to estimate the clinical course, costs and quality of life of patients with stage II, III or IV DLBCL receiving initial treatment with CHOP or R-CHOP to arrive at the ICER. The base year for the cost analysis was 2002 and was performed from the societal perspective. Only direct medical costs were included. The time horizon of the model was 15 yr and both costs and effects were discounted at 4%. Sensitivity analyses were performed to determine the effect of varying base-line assumptions of the model. RESULTS: The incremental gain in quality adjusted life years (QALYs) was 0.88 in both the younger and the older patient groups. The costs were 12 343 higher in the younger group of patients and 15 860 in the older patients. This resulted in an ICER of 13 983 for the younger and 17 933 for the older patients per QALY gained. These results were sensitive to the time horizon of the model, other variations had a marginal impact on the outcome. CONCLUSION: The addition of rituximab to standard therapy for DLBCL results in a gain of 0.88 QALYs. The ICER of 13 983 for younger and 17 933 for older patients per QALY gained should, seen in the light of disease severity, be considered acceptable by most policy makers in priority setting for budget allocation.

Cost-minimization analysis of CHOP, fludarabine and rituximab for the treatment of relapsed indolent B-cell non-Hodgkin's lymphoma in the U.K.

The optimal therapy for patients with relapsed indolent B-cell non-Hodgkin's lymphoma is unclear. Combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or purine analogues including fludarabine are frequently used and the anti-CD20 monoclonal antibody rituximab has recently been licensed for use. However, no comparative studies of these therapies have been reported. Since relapsed indolent B-cell NHL is generally regarded as incurable with current therapies, the place of each of these therapies is likely to be determined by their relative efficacy, toxicity and cost. We undertook a literature review and a retrospective analysis of patients receiving combination chemotherapy for relapsed indolent B-cell NHL at our institution to determine the response rates and the duration of response when treated with CHOP or fludarabine. Reported response rates and median response duration for these regimens are similar, and similar to those reported in phase II studies of rituximab. A cost minimization analysis was therefore conducted. The per patient costs for the treatment of drug-related adverse events were pound 5049 for CHOP, pound 2953 for fludarabine and pound 109 for rituximab. When costs of a full course of each treatment were compared, the costs per patient for CHOP, fludarabine and rituximab were pound 7210 (pound 5975-8445), pound 10022 (pound 8917-11126) and pound 6080 (pound 5892-6267) respectively. In this preliminary analysis, rituximab appeared to have a similar efficacy rate to CHOP and fludarabine, but had significantly fewer adverse events and a lower total cost per patient. These data require confirmation in a prospective randomized study with formal assessment of cost-effectiveness.