Impact of the COVID-19 pandemic on utilization and cost for care of pediatric and young adult ALL.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States. RESULTS: Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.

A Systematic Review of Health Technology Assessments of Chimeric Antigen Receptor T-Cell Therapies in Young Compared With Older Patients.

OBJECTIVES: The objective of this review was to identify sources of variability in cost-effectiveness analyses of chimeric antigen receptor T-cell (CAR-T) therapies, tisagenlecleucel and axicabtagene ciloleucel, evaluated by health technology assessment (HTA) agencies, focusing on young compared with older patients. METHODS: HTA evaluations in pediatric acute lymphoblastic leukemia (ALL) and adult diffuse large B-cell lymphoma (DLBCL) were included from Australia, Canada, England, Norway, and the United States. Key clinical evidence, economic approach, and outcomes (costs, quality-adjusted life-years [QALYs] and incremental cost-effectiveness ratios) were summarized. RESULTS: Fourteen HTA evaluations were identified (5 ALL, 9 DLBCL [4 tisagenlecleucel, 5 axicabtagene]). Analyses were naive comparisons of prospective single-arm studies for the CAR-Ts with retrospective cohort studies for the comparators. Key clinical evidence and economic model approaches were generally consistent by CAR-T and indication, although outcomes varied. Notably, incremental QALYs varied substantially in ALL (3.67-10.6 QALYs gained), whereas variation in DLBCL was less (1.21-1.97 [tisagenlecleucel], 1.97-3.40 [axicabtagene]). Discounting of costs and outcomes varied, with the highest QALYs generated for tisagenlecleucel in ALL (10.95) associated with the lowest discount rate (1.5%) and vice versa (4.97 QALYs; 5% discount rate). The approach to extrapolation of overall survival data varied, even where the same empirical data were used. CONCLUSION: Modeled, long-term treatment benefit in young patients may be associated with greater uncertainty compared with adults because of potential life-long benefits with cell and gene therapies. This reflects the methodological challenges identified by HTA agencies associated with single-arm, short-term studies.

NUDT15 genetic testing-guided 6-mercaptopurine dosing in children with ALL likely to be cost-saving in China.

OBJECTIVE: The cost-effectiveness of NUDT15 genetic testing-guided initial 6-mercaptopurine (6-MP) dosing in children with acute lymphoblastic leukemia (ALL) was evaluated. METHODS: A decision tree model was used to evaluate the cost to China's medical system per quality-adjusted life-year (QALY) gained and cost per case of severe leukopenia avoided of NUDT15 genetic testing using public clinical data. RESULTS: Genetic testing-guided initial 6-MP dosing reduced overall costs by $518.61, and prevented 0.221 cases of Grade III-IV leukopenia and increased QALY by 0.00136 per patient. Results were robust in one-way analyses and probabilistic sensitivity analyses. CONCLUSION: NUDT15 genetic testing prior to the initial administration of 6-MP in pediatric ALL patients in China is less expensive than standard dosing without genetic testing.

Childhood cancer hospital resource utilization and costs in Egypt, 2013-2017; patterns, trends, and associated factors for 8886 patients from Children's Cancer Hospital, Egypt.

INTRODUCTION: There is a lack ofevidence about resource use and costs of childhood cancer care in Egypt. Knowledge about resource use/costs can help in better resource planning to improve care and outcomes efficiently. In this study, we estimated patterns and trends of hospital resource use and costs for children with cancer (n = 8886, aged 0-18 years) treated at Children's Cancer Hospital, Egypt (CCHE), between 2013 and 2017, by ICCC-3 groups, at one and three years post-diagnosis. METHODS: We estimated costs from the healthcare provider perspective, expressed in USD 2019. We also studied resource use/cost trends, and factors associated with inpatient days and costs. RESULTS: For all cancers combined, median costs were $14,774 (IQR: $6,559-$23,738) at one year and $19,799 (IQR: $8,921-$34,204) at three years post-diagnosis. Median inpatient days were 38 days (IQR: 17-60) at one year, and 43 days (IQR: 20-74) at three years post-diagnosis. Patients with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and neuroblastoma imposed the greatest financial burden on CCHE, representing 53.1% of total costs. AML patients had the highest costs/resource use of all childhood cancers. Cost trends decreased by 2.9% (P < 0.001) for all cancers combined, due to economic instability in Egypt between 2013 and 2017. The use of IV supportive drugs increased by 24.3% (P < 0.001) over time for children with solid tumors. CONCLUSION: These findings will inform hospital resource planning and budgeting to promote value in care delivery, with implications for pediatric oncology practice and policy in Egypt/CCHE. Estimated costs provide the foundation for cost-effectiveness analysis.

Health care utilisation and costs associated with different treatment protocols for newly diagnosed childhood acute lymphoblastic leukaemia: A population-based study in Ontario, Canada.

BACKGROUND: Although different treatment protocols for childhood acute lymphoblastic leukaemia (ALL) all achieve high cure rates, their health care utilisation and costs have not been rigorously compared. METHODS: Disease, treatment, and outcome data were chart abstracted for all children with ALL in Ontario, Canada, diagnosed 2002-2012. Linkage to population-based databases identified health care utilisation. Utilisation-associated costs were determined through validated algorithms. Chemotherapy-associated costs were calculated separately. Health care utilisation and costs were compared between patients receiving Children's Oncology Group (COG) versus Dana-Farber Cancer Institute (DFCI)-based treatment. FINDINGS: Of 802 patients, 146 (18.2%) were treated on DFCI-based protocols. COG patients experienced significantly higher rates of emergency department (ED) visits (adjusted rate ratio [aRR]: 1.3, 95% confidence interval [CI]: 1.1-1.5; p = 0·01), whereas outpatient visit rates were 60% higher among DFCI patients (aRR: 1.6, 95% CI: 1.5-1.7, p < 0.0001). In adjusted analyses, DFCI-associated cost intensity was 70% higher (aRR: 1.7, 95% CI: 1.5-1.9; p < 0.0001), mainly attributable to outpatient visit costs. Total chemotherapy costs were higher among COG-treated patients ($39,400 ± $1100 versus $33,400 ± $2800; p = 0.02). Among PEG-ASNase-treated patients, total chemotherapy costs were highest among DFCI patients (median $54,200 ± $7400; p = 0.003 versus COG patients). INTERPRETATION: COG and DFCI treatments were associated with higher ED visit rates and higher outpatient visit rates, respectively. Overall utilisation-associated costs were increased in DFCI-treated patients. Administration of some intravenous chemotherapy at home and decreases in PEG-ASNase cost would decrease health care utilisation and costs for all patients and mitigate differences between COG and DFCI protocols. FUNDING: C17 Research Network.

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.

Expenditures among young adults with acute lymphoblastic leukemia by site of care.

BACKGROUND: Individuals diagnosed with acute lymphoblastic leukemia (ALL) between the ages of 22 and 39 years experience worse outcomes than those diagnosed when they are 21 years old or younger. Treatment at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) mitigates these disparities but may be associated with higher expenditures. METHODS: Using deidentified administrative claims data (OptumLabs Data Warehouse), the cancer-related expenditures were examined among patients with ALL diagnosed between 2001 and 2014. Multivariable generalized linear model with log-link modeled average monthly health-plan-paid (HPP) expenditures and amount owed by the patient (out-of-pocket [OOP]). Cost ratios were used to calculate excess expenditures (CCC vs non-CCC). Incidence rate ratios (IRRs) compared CCC and non-CCC monthly visit rates. Models adjusted for sociodemographics, comorbidities, adverse events, and months enrolled. RESULTS: Clinical and sociodemographic characteristics were comparable between CCC (n = 160) and non-CCC (n = 139) patients. Higher monthly outpatient expenditures in CCC patients ($15,792 vs $6404; P < .001) were driven by outpatient hospital HPP expenditures. Monthly visit rates and per visit expenditures for nonchemotherapy visits (IRR = 1.6; P = .001; CCC = $8247, non-CCC = $1191) drove higher outpatient hospital expenditures among CCCs. Monthly OOP expenditures were higher at CCCs for outpatient care (P = .02). Inpatient HPP expenditures were significantly higher at CCCs ($25,918 vs $13,881; ꞵ = 0.9; P < .001) before accounting for adverse events but were no longer significant after adjusting for adverse events (ꞵ = 0.4; P = .1). Hospitalizations and length of stay were comparable. CONCLUSIONS: Young adults with ALL at CCCs have higher expenditures, likely reflecting differences in facility structure, billing practices, and comprehensive patient care. It would be reasonable to consider CCCs comparable to the oncology care model and incentivize the framework to achieve superior outcomes and long-term cost savings. LAY SUMMARY: Health care expenditures in young adults (aged 22-39 years) with acute lymphoblastic leukemia (ALL) are higher among patients at National Cancer Institute-designated Comprehensive Cancer Centers (CCC) than those at non-CCCs. The CCC/non-CCC differences are significant among outpatient expenditures, which are driven by higher rates of outpatient hospital visits and outpatient hospital expenditures per visit at CCCs. Higher expenditures and visit rates of outpatient hospital visits among CCCs may also reflect how facility structure and billing patterns influence spending or comprehensive care. Young adults at CCCs face higher inpatient HPP expenditures; these are driven by serious adverse events.

What are the volume and budget needs to provide chemotherapy to all children with acute lymphoblastic leukaemia in Thailand? Development and application of an estimation tool.

OBJECTIVE: Insufficient access to anticancer medicines may contribute to the wide survival differences of children with cancers across the globe. We developed a tool to estimate the volume of medicines and budget requirements to provide chemotherapy to children with acute lymphoblastic leukaemia (ALL). DESIGN: Development and application of an estimation tool. SETTING: Paediatric oncology hospital departments in Thailand. PARTICIPANTS: 318 children aged 0-14 years diagnosed with ALL and 215 children with undiagnosed ALL. INTERVENTIONS: Estimates of volume and budget requirements for administering a full course of chemotherapy for ALL and a further course for children who relapse, according to National Treatment Guidelines. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measures were the volume (mg) and cost (US$) of medicines needed to treat children with ALL. For medicines whose main indication is paediatric ALL (asparaginase and 6-mercaptopurine), we estimated the difference between volume needed and actual sales in 2017 (secondary outcome). RESULTS: Ten anticancer medicines and four chemoprotective agents are needed for the treatment of paediatric ALL according to the Thai treatment guidelines. Of these 14 medicines, 13 are included in the WHO essential medicines list for children. All are available as generics. We estimated that essential chemotherapy and chemoprotective agents to treat all children diagnosed with ALL in Thailand in 2017 would cost US$ 814 952 (US$ 1 365 422 for diagnosed and undiagnosed children), which corresponds to 0.005% (0.008%) of the country's total health expenditure. The volumes of asparaginase and 6-mercaptopurine available on the Thai market in 2017 were more than sufficient (2.3 and 1.5 times the amounts needed, respectively) to treat all children diagnosed with ALL. CONCLUSIONS: Procuring sufficient quantities of essential medicines to treat children with ALL requires relatively modest resources. Medicine cost should not be a major barrier to ALL treatment in similar settings.

Levofloxacin prophylaxis in hospitalized children with leukemia: A cost-utility analysis.

BACKGROUND: Infections are common and are a major cause of morbidity and mortality during treatment of childhood leukemia. We evaluated the cost effectiveness of levofloxacin antibiotic prophylaxis, compared to no prophylaxis, in children receiving chemotherapy for acute myeloid leukemia (AML) or relapsed acute lymphoblastic leukemia (ALL). PROCEDURES: A cost-utility analysis was conducted from the perspective of the single-payer health care system using a lifetime horizon. A comprehensive literature review identified available evidence for effectiveness, safety, costs of antibiotic prophylaxis in children with leukemia, and health utilities associated with the relevant health states. The effects of levofloxacin prophylaxis on health outcomes, quality-adjusted life-years (QALY), and direct health costs were derived from a combined decision tree and state-transition model. One-way deterministic and probabilistic sensitivity analyses were performed to test the sensitivity of results to parameter uncertainty. RESULTS: The literature review revealed one randomized controlled trial on levofloxacin prophylaxis in childhood AML and relapsed ALL, by Alexander et al, that showed a significant reduction in rates of fever and neutropenia (71.2% vs 82.1%) and bacteremia (21.9% vs 43.4%) with levofloxacin compared to no prophylaxis. In our cost-utility analysis, levofloxacin prophylaxis was dominant over no prophylaxis, resulting in cost savings of $542.44 and increased survival of 0.13 QALY. In probabilistic sensitivity analysis, levofloxacin prophylaxis was dominant in 98.8% of iterations. CONCLUSIONS: The present analysis suggests that levofloxacin prophylaxis, compared to no prophylaxis, is cost saving in children receiving intensive chemotherapy for AML or relapsed ALL.

Efficacy Oral Glutamine to Prevent Oral Mucositis and Reduce Hospital Costs During Chemotherapy in Children with Acute Lymphoblastic Leukemia.

OBJECTIVE: To investigate the use of glutamine administered orally during Methotrexate chemotherapy to prevent oral mucositis and reduce hospital costs in children with acute lymphoblastic leukemia (ALL). METHODS: Twenty-four children received oral glutamine (400 mg/kg body weight per day) and twenty four received placebo on days of chemotherapy administration and for at least 14 additional days. Oral mucositis  was graded daily at each day of treatment till completion of therapy. The study groups were compared for the oral mucositis development using the WHO scale. RESULTS: Oral mucositis occurred in 4.2 % of the glutamine group and 62.5% in the placebo group. The use of glutamine was directly associated with prevention of oral mucositis than placebo (OR 0,026; 95% CI: 0,003-0,228). The duration of length hospital stay was lower in the glutamine group than in the placebo group ((8 vs 12 days); p = 0,005). Hospital cost per day for glutamine group was 40 USD per day while placebo group was 48 USD per day. CONCLUSIONS: There was significant difference in the prevention of oral mucositis by oral glutamine vs placebo. The hospital cost for glutamine supplementation was lower than control group.

Hyperglycemia requiring insulin during acute lymphoblastic leukemia induction chemotherapy is associated with increased adverse outcomes and healthcare costs.

BACKGROUND: Hyperglycemia is a complication of induction chemotherapy in 10%-50% of pediatric patients with acute lymphoblastic leukemia (ALL). Though hyperglycemia in ALL patients is usually transient, it may be associated with adverse health outcomes. However, the risk factors for and consequences of hyperglycemia are poorly understood. We hypothesized that hyperglycemia significant enough to require insulin therapy during induction chemotherapy would be associated with increased morbidity and mortality in pediatric ALL patients during induction chemotherapy and in subsequent care. METHODS: We abstracted clinical and resource utilization data from the Pediatric Health Information System (PHIS) database utilizing ICD-9 codes and medication charges. We used logistic regression analysis to predict the development of hyperglycemia. The effects of hyperglycemia on binary and count adverse outcomes following induction chemotherapy were modeled using mixed-effect regression models. RESULTS: An increased risk of hyperglycemia requiring insulin was associated with older age, female sex, higher risk group and trisomy 21. Patients on insulin for hyperglycemia had increased mortality following induction chemotherapy. These patients were more likely to have subsequent infectious complications, need for bone marrow transplant, and risk of disease relapse. They also had greater length of inpatient stay, higher cost of care, and were more likely to require intensive care unit admission during induction chemotherapy. CONCLUSIONS: Hyperglycemia requiring insulin during induction chemotherapy in pediatric ALL is associated with an increased risk of short-term and long-term complications. Prospective studies are needed to analyze formal screening, preventive measures, and optimal management practices for hyperglycemia during ALL induction chemotherapy.

Estimation of Total Costs in Pediatric and Young Adult Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia Receiving Tisagenlecleucel from a U.S. Hospital's Perspective.

BACKGROUND: Tisagenlecleucel was approved for the treatment of pediatric and young adult patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL) based on the pivotal ELIANA trial. OBJECTIVE: To comprehensively evaluate the total costs associated with tisagenlecleucel treatment, including costs from pre- to postinfusion periods of tisagenlecleucel in addition to the cost of tisagenlecleucel. METHODS: An economic model was developed to estimate total costs associated with tisagenlecleucel treatment from the time of leukapheresis to 2 months postinfusion from a U.S. hospital's perspective. Costs were estimated based on resource use and safety management from the ELIANA trial and were considered during the pretreatment, tisagenlecleucel infusion, and follow-up periods of treatment. Cost components included leukapheresis, lymphodepleting chemotherapy, tisagenlecleucel infusion and hospital administration, inpatient and intensive care unit admissions, medical professional visits, laboratory tests and procedures, and management of major adverse events. Scenario analyses were conducted by varying key assumptions related to adverse events and hospitalization. RESULTS: The total cost associated with tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to be $612,779, of which $137,636 (22.5%) was in addition to the list price of tisagenlecleucel ($475,000) and the associated administration cost of $143.08. The top 3 drivers of the additional cost were adverse event management ($70,968; 51.6%), inpatient and intensive care unit admissions not attributed to adverse events ($57,952; 42.1%), and laboratory tests and procedures ($5,209; 3.8%). The costs incurred during the pretreatment, infusion, and follow-up periods were $29,002, $476,659, and $107,118, respectively. In the scenario analyses, the total costs ranged from $483,169 (tisagenlecleucel treatment in the outpatient setting without adverse events) to $672,373 (tisagenlecleucel treatment in the inpatient setting with grade 3/4 cytokine release syndrome and B-cell aplasia). CONCLUSIONS: In this economic model, tisagenlecleucel treatment among pediatric and young adult patients with r/r ALL was estimated to cost $612,779. The cost of care in addition to the price of tisagenlecleucel accounted for 22.5% of the total, with adverse event management and inpatient and intensive care unit admissions being main drivers. Further studies are warranted to assess the cost of tisagenlecleucel treatment in the context of current standards of care in real-world clinical practice. DISCLOSURES: This study was supported by Novartis. The study sponsor was involved in several aspects of the research, including the study design, the interpretation of data, the writing of the manuscript, and the decision to submit the manuscript for publication. Hao is an employee of Novartis and has stock/stock options. Yang, Chai, Qi, and Wu are employees of Analysis Group, which received consulting fees from Novartis for work on this study. Part of the material in this manuscript was presented at the American Society of Hematology Annual Meeting held December 7-10, 2019, in Orlando, FL.

Solitary serum methotrexate level 36 hours post high-dose methotrexate: A safe, efficacious, and cost-effective strategy to monitor methotrexate toxicities in childhood leukemia in resource-limited centers.

BACKGROUND: The standard practice during high-dose methotrexate (HD-MTX) in acute lymphoblastic leukemia (ALL) to mitigate toxicity is to serially monitor levels till serum MTX < 0.01 µmol/L. Most resource-limited centers lack in-house access to MTX levels, and therefore repeated monitoring is costly and cumbersome. We studied the efficacy and safety of "solitary 36 hours post HD-MTX levels (MTX36 )." PROCEDURE: This prospective observational study consecutively enrolled children with ALL receiving HD-MTX. Cycles with unavailable MTX36 and MTX36  > 10 µmol/L were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. MTX36 were performed at other centers. Leucovorin was given in six hourly doses 36 hours post HD-MTX. Hydration was continued until the last dose of leucovorin. MTX toxicities, including change of creatinine from baseline at 36 hours (∆Cr36 ), were noted. Two groups depending on MTX36 (≤1 µmol/L vs > 1 µmol/L) received six versus eight doses of leucovorin, and toxicities were compared. RESULTS: Twenty-nine children with median age five years (1-11) who received 100 HD-MTX cycles with a median MTX dose of 3 g/m2 (2-5) were analyzed. The median MTX36 level was 1.165 µmol/L (0.1-7.32). Toxicities of HD-MTX (CTCAE-4.0): transaminitis-22%; creatinine elevation ≥ 1.25 times baseline-24%; cytopenias-16%; mucositis-17%; acute kidney injury (AKI)-6%. All toxicities were ≤CTCAE grade 3. Creatinine elevation, AKI, and mucositis were significantly higher in the group with higher MTX36 . There was no correlation (r = 0.3) between ∆Cr36 and MTX36 . MTX36 was thrice more economical than the standard protocol. CONCLUSION: MTX36 is a potential cost-effective, efficacious, and safe limited sample strategy to monitor HD-MTX, particularly in centers where in-house MTX levels are unavailable.

Cost-effectiveness of Tisagenlecleucel vs Standard Care in High-risk Relapsed Pediatric Acute Lymphoblastic Leukemia in Canada.

Importance: Tisagenlecleucel, a chimeric antigen receptor T-cell therapy for relapsed or refractory pediatric acute lymphoblastic leukemia, has been approved for use in multiple jurisdictions. The public list price is US $475 000, or more than CaD $600 000. Assessing the cost-effectiveness of tisagenlecleucel is necessary to inform policy makers on the economic value of this treatment. Objective: To assess the value for money of tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible pediatric patients with acute lymphoblastic leukemia under unknown long-term effectiveness. Design, Setting, and Participants: A cost-utility analysis of tisagenlecleucel compared with current standard care using a Canadian population-based registry of pediatric patients with acute lymphoblastic leukemia was performed. Results from 3 pooled single-arm tisagenlecleucel clinical trials and a provincial pediatric cancer registry were combined to create treatment and control arms, respectively. The population-based control arm consisted of patients meeting clinical trial inclusion and exclusion criteria, starting at second relapse. Multistate and individual-level simulation modeling were combined to predict patient lifetime health trajectories by treatment strategy. Tisagenlecleucel efficacy was modeled across long-term cure rates, from 10% to 40%, to account for limited information on its long-term effectiveness. Uncertainty was tested with 1-way and probabilistic sensitivity analysis. Data were collected in September 2017, and analysis began in December 2017. Exposures: Tisagenlecleucel compared with current standard care for tisagenlecleucel-eligible patients. Main Outcomes and Measures: Relative health care costs, survival gains, and quality-adjusted life-years (QALYs) between tisagenlecleucel and current standard care. Results: The treatment and control arms were modeled on 192 and 118 patients, respectively. The mean (SD) age of control individuals was 10 (4.25) years, and the mean (SD) age of the pooled clinical trial sample was 11 (6) years. The control individuals had 78 boys (66%), and the pooled clinical trial sample had 102 boys (53%). Treatment with tisagenlecleucel was associated with an additional 2.14 to 9.85 life years or 1.68 to 6.61 QALYs, compared with current care. The average additional cost of tisagenlecleucel was CaD $470 013 (US $357 031). Accounting for the total discounted cost over the patient lifetime resulted in an incremental cost of CaD $71 000 (US $53 933) to CaD $281 000 (US $213 453) per QALY gain. Conclusions and Relevance: To our knowledge, this study offers the first cost-effectiveness analysis of tisagenlecleucel compared with current standard care for pediatric patients with acute lymphoblastic leukemia using a constructed population-based control arm. At a willingness-to-pay threshold of $150 000/QALY, tisagenlecleucel had a 32% likelihood of being cost-effective. Tisagenlecleucel cost-effectiveness would fall below $50 000/QALY with a long-term cure rate of over 0.40 or a price discount of 49% at its currently known effectiveness.

Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy.

Introduction: The new category of chimeric antigen receptor T - cell raised hopes for a more effective treatment of large B cell lymphoma and acute lymphoblastic leukemia. Nevertheless, their soaring acquisition costs will stretch the fiscal capacity of the health systems worldwide. To this direction, the scope of this study is to provide a systematic review of their economic evaluations. Areas covered: A systematic review of the economic evaluations of tisagenlecleucel and axicabtagene was performed. Expert opinion: The available data indicate that these products demonstrate a potentially favorable cost-effectiveness ratio. Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty.

Direct and indirect costs of families with a child with acute lymphoblastic leukaemia in an academic hospital in China: a cross-sectional survey.

OBJECTIVES: To estimate the direct and indirect costs in families with a child with acute lymphoblastic leukaemia (ALL) in China. DESIGN: A single-site, cross-sectional survey of primary caregiver of a child with ALL was performed. SETTING AND PARTICIPANTS: We analysed the total costs incurred on the completion of the first three-phase treatment (induction, consolidation and intensification), which requires intensive hospitalisation. Eligible patients were (1) diagnosed with ALL between 2010 and 2012 at Shanghai Children's Medical Center (SCMC), (2) aged 0-14 years at diagnosis and (3) completed the first three-phase treatment at SCMC. The data were collected between October 2014 and December 2014. OUTCOME MEASURES: We decomposed the total costs into three categories: (1) direct medical costs, which were further divided into outpatient and inpatient costs; (2) direct non-medical costs, which referred to expenses incurred in relation to the illness; and (3) indirect costs due to productivity loss. RESULTS: A total of 161 patients were included in the study. Direct medical costs accounted for about 51.7% of the overall costs, and the rest of 48.3% of the total costs were attributed to direct non-medical costs and indirect costs. Regarding families with different household registration type (rural vs urban), the total costs were significantly different between the two groups (US$36 125 vs US$25 593; p=0.021). Specifically, urban families incurred significantly larger indirect costs than rural families (US$12 343 vs US$4157; p=0.018). Although the direct non-medical costs were not significantly different, urban families spent more money on hygiene cleaning products and auxiliary treatment equipment (p=0.041) and gifts and treats (p=0.034) than rural families. CONCLUSIONS: The financial burden faced by the Chinese families with a child with ALL was tremendous, and the distributions of costs among the three categories were different between urban and rural families.

Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Pediatric Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy is a promising new class of cancer therapy but has a high up-front cost. We evaluated the cost-effectiveness of CAR-T therapy among pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). METHODS: We built a microsimulation model for pediatric patients with relapsed/refractory B-ALL receiving either CAR-T therapy or standard of care. Outcomes included costs, quality of life (health utility), complications, and survival. We measured cost-effectiveness with the incremental cost-effectiveness ratio (ICER), with ICERs under $100 000 per quality-adjusted life-year (QALY) considered cost effective. One-way and probabilistic sensitivity analyses were used to test model uncertainty. RESULTS: Compared to standard of care, CAR-T therapy increased overall cost by $528 200 and improved effectiveness by 8.18 QALYs, resulting in an ICER of $64 600/QALY. The model was sensitive to assumptions about long-term CAR-T survival, the complete remission rate of CAR-T patients, and the health utility of long-term survivors. The base model assumed a 76.0% one-year survival with CAR-T, although if this decreased to 57.8%, then CAR-T was no longer cost effective. If the complete remission rate of CAR-T recipients decreased from 81% to 56.2%, or if the health utility of disease-free survivors decreased from 0.94 to 0.66, then CAR-T was no longer cost effective. Probabilistic sensitivity analysis found that CAR-T was cost effective in 94.8% of iterations at a willingness to pay of $100 000/QALY. CONCLUSION: CAR-T therapy may represent a cost-effective option for pediatric relapsed/refractory B-ALL, although longer follow-up of CAR-T survivors is required to confirm validity of these findings.

A cost-effectiveness analysis of Erwinia asparaginase therapy in children with acute lymphoblastic leukemia.

OBJECTIVES: Erwinia asparaginase is used as a second-line formulation after a neutralizing hypersensitivity reaction to the first-line formulation of asparaginase. Here, we have performed a cost-effectiveness analysis of Erwinia asparaginase treatment. METHODS: Children with acute lymphoblastic leukemia treated according to the Dutch Childhood Oncology ALL-10 or ALL-11 protocol were included and initially treated with PEGasparaginase in the intensification phase. The total treatment costs of this treatment phase, quality of life (QoL), and life years saved (LYS) were studied for two scenarios: (a) patients were switched to Erwinia asparaginase treatment after a hypersensitivity reaction, or (b) asparaginase would have been permanently stopped. RESULTS: Sixty-eight patients were included. There was no difference in QoL between patients with and without a hypersensitivity reaction. The mean costs of the intensification phase per patient were $40,925 if PEGasparaginase could be continued, $175,632 if patients had to switch to Erwinia asparaginase, and $21,190 if asparaginase would have been permanently stopped. An extrapolation of the literature suggests that the 5-year event-free survival would be 10.3% lower without intensive asparaginase treatment if asparaginase is stopped after a reaction. Thus, the costs per LYS were $1892 for scenario 1 and $872 for scenario 2. CONCLUSIONS: Switching to Erwinia asparaginase increases the costs per LYS by $1020, which is modest in view of the total costs. Moreover, when asparaginase treatment can be completed by switching to Erwinia asparaginase, relapses-and consequential costs-will be avoided. Therefore, from a cost perspective, we recommend a switch to Erwinia asparaginase to complete asparaginase treatment.

No free rides: management of toxicities of novel immunotherapies in ALL, including financial.

Therapeutic options for acute lymphoblastic leukemia, especially in the relapsed/refractory setting, have expanded significantly in recent times. However, this comes at the cost of toxicities: medical as well as financial. We highlight some of the unique toxicities associated with the novel agents to apprise our readers about what to expect, how to recognize them, and how to manage these toxicities. One of the toxicities seen with inotuzumab, a CD22 antibody drug conjugate, is sinusoidal obstruction syndrome, which can be fatal in >80% of patients if associated with multiorgan failure. Blinatumomab, a monoclonal antibody targeting CD19, is associated with cytokine release syndrome (CRS) and neurotoxicity, both of which require prompt recognition and management primarily with corticosteroids. CRS and neurotoxicity are more common and more severe with chimeric antigen receptor T-cell therapy (CAR-T). The fact that CAR-T cannot be discontinued on demand adds a layer of complexity to the management of related toxicities of this therapy. Tocilizumab, an interleukin-6 receptor blocker, is used to treat severe CRS from CAR-T, whereas corticosteroids remain the mainstay for neurotoxicity management. Although effective, these drugs carry a high price tag, and we review the available data on cost-effectiveness of these agents, keeping in mind that median follow-up on most of these studies is limited and that long-term data on durability of response remain to be seen.