A single-center multidisciplinary approach to managing the global Erwinia asparaginase shortage.

The availability of Erwinia Asparaginase has been limited across the world due to manufacturing shortages or for some countries due to the high acquisition cost, putting patients at risk for inferior outcomes. This manuscript provides guidance on how to manage hypersensitivity reactions and utilize therapeutic drug monitoring (TDM) to conserve and limit Erwinia use. The clinical and financial impact of a multidisciplinary committee are also discussed. Faced with a global Erwinia shortage, a multidisciplinary asparaginase allergy committee was created to review all hypersensitivity reactions to asparaginase therapy, staff education was performed on the management of asparaginase hypersensitivity reactions, an institution-wide premedication policy was mandated, and standardized guidelines were created for TDM. This multidisciplinary approach reduced the PEG-asparaginase to Erwinia switch rate from 21% (35 of 163) to 7% (10 of 134) (p = .0035). A multifaceted approach can safely maintain patients on PEG-asparaginase and conserve Erwinia for patients who need it most.

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.

Cost comparison by treatment arm and center-level variations in cost and inpatient days on the phase III high-risk B acute lymphoblastic leukemia trial AALL0232.

The Children's Oncology Group (COG) develops and implements multi-institutional clinical trials with the primary goal of assessing the efficacy and safety profile of treatment regimens for various pediatric cancers. However, the monetary costs of treatment regimens are not measured. AALL0232 was a COG randomized phase III trial for children with acute lymphoblastic leukemia that found that dexamethasone (DEX) was a more effective glucocorticoid than prednisone (PRED) in patients younger than 10 years, but PRED was equally effective and less toxic in older patients. In addition, high-dose methotrexate (HD-MTX) led to better survival than escalating doses of methotrexate (C-MTX). Cost data from the Pediatric Health Information System database were merged with clinical data from the COG AALL0232 trial. Total and component costs were compared between treatment arms and across hospitals. Inpatient costs were higher in the HD-MTX and DEX arms when compared to the C-MTX and PRED arms at the end of therapy. There was no difference in cost between these arms at last follow-up. Considerable variation in total costs existed across centers to deliver the same therapy that was driven by differences in inpatient days and pharmacy costs. The more effective regimens were found to be more expensive during therapy but were ultimately cost-neutral in longer term follow-up. The variations in cost across centers suggest an opportunity to standardize resource utilization for patients receiving similar therapies, which could translate into reduced healthcare expenditures.

A cost analysis of individualized asparaginase treatment in pediatric acute lymphoblastic leukemia.

BACKGROUND: Therapeutic drug monitoring (TDM) of asparaginase is necessary to respond to variability in asparaginase activity levels, detect silent inactivation, and distinguish between real allergies and allergic-like reactions with and without asparaginase neutralization, respectively. In this study, the costs of an individualized and fixed asparaginase dosing schedule were compared. PROCEDURE: Patients, treated according to the Dutch Childhood Oncology Group ALL-11 protocol (individualized PEGasparaginase treatment, starting dose: 1,500 IU/m2 ) or ALL-10 protocol (native Escherichia coli asparaginase followed by 2,500 IU/m2 PEGasparaginase), were included. To focus on TDM of PEGasparaginase, the costs were also calculated excluding patients treated with Erwinia asparaginase and compared to a hypothetical protocol with a fixed dose of 1,500 IU/m2 PEGasparaginase. Direct asparaginase-related medical costs, including costs for asparaginase use (calculated with the absolute dose), TDM, laboratory tests, daycare treatment, and outpatient clinic visits, were calculated. RESULTS: Eighty-three ALL-10 patients and 51 ALL-11 patients were included. The asparaginase-related costs were 30.8% lower in ALL-11 than in ALL-10 ($29,048 vs. $41,960). The ALL-11 costs of nonallergic patients were 20.4% lower, when using TDM, than the hypothetical protocol with a fixed dose of 1,500 IU/m2 ($13,178 vs. $16,551). TDM accounted for 12.4% of the costs. Including asparaginase waste, TDM in ALL-11 will be cost saving if three doses can be prepared out of one vial compared to a fixed dose of 1,500 IU/m2 . CONCLUSIONS: TDM of asparaginase is cost saving if calculated with the absolute asparaginase dose and will be if the waste is minimalized by preparing multiple doses out of one vial.

Compras federais de antineoplásicos no Brasil: análise do mesilato de imatinibe, trastuzumabe e L-asparaginase, 2004-2013 / Federal procurement of antineoplastic drugs in Brazil: analysis of imatinib mesylate, trastuzumab and L-asparaginase, 2004-2013

Resumo Objetivo: Analisar o perfil das compras realizadas por órgãos federais brasileiros dos antineoplásicos mesilato de imatinibe, trastuzumabe e L-asparaginase, entre janeiro/2004 e dezembro/2013. Métodos: Dados de compras foram extraídos do Sistema Integrado de Administração de Serviços Gerais-SIASG. Foram analisados: quantidade, preço unitário, data e tipo de compra e órgão comprador. Para permitir comparação de preços, os valores correntes foram corrigidos para dezembro/2013, pelo IPCA. Resultados: As quantidades adquiridas do imatinibe e trastuzumabe aumentaram progressivamente, sendo o Ministério da Saúde (MS) o principal comprador. Seus preços médios ponderados (PMP) apresentaram tendência de queda. Observou-se redução nos PMP do imatinibe, mesmo antes da centralização da compra pelo MS. O PMP do transtuzumabe foi reduzido em 57% após a incorporação pela CONITEC e a centralização de compras. As quantidades e preços da L-asparaginase variaram entre os órgãos. Diferentemente dos outros medicamentos, verificou-se significativa elevação de 117% no PMP da L-asparaginase, refletindo o desabastecimento no mercado mundial. Conclusões: A inclusão em Parcerias de Desenvolvimento Produtivo e a centralização das compras pelo MS parecem justificar as reduções de preço do imatinibe e trastuzumabe, reforçando a tese do uso do poder de compra do Estado. Estas reduções podem contribuir na ampliação de seu acesso no SUS.

Abstract Objective: To analyze the Brazilian federal procurement profile for imatinib mesylate, trastuzumab and L-asparaginase from January 2004 to December 2013. Methods: Information was extracted from the Brazilian Federal Government procurement database and included volume, unit price, date and type of purchase, government agency buyer. Prices were deflated to December 2013 by the Brazilian Pricing Index. Results: Purchase volumes of imatinib and trastuzumab increased progressively. The Ministry of Health was the main buyer. Weighted average prices (WAP) for these medicines showed a downward trend. A WAP reduction for imatinibe occurred before centralized purchases by the Ministry of Health began. After incorporation by CONITEC and centralized purchases in 2012, trastuzumab WAP was reduced by 57%. For L-asparaginase volumes and prices varied among different government agencies, but contrary to the two other medicines, L-asparaginase presented a 117% WAP increase, possibly reflecting stockouts in the international market. Conclusions: The setting of Productive Development Partnerships (PDPs) and centralized purchasing by the Brazilian Ministry of Health suggest a decrease in prices for imatinib and trastuzumab, underlining the government´s purchasing power. These reductions may contribute to availability of these medicines in the Brazilian Public Health System.

Allergic Reactions With Intravenous Compared With Intramuscular Pegaspargase in Children With High-risk Acute Lymphoblastic Leukemia: A Population-based Study From the Maritimes, Canada.

Intravenous (IV) administration of pegaspargase in children with acute lymphoblastic leukemia (ALL) may be associated with an increased risk of allergic reactions, and thus the need for more costly intramuscular (IM) erwinia asparaginase. In 128 patients allergic reactions were documented in 3% and 14% of those who received IM and IV pegaspargase, respectively (P=0.029). These reactions were primarily contributed to by high risk (HR)-ALL patients (P<0.01). The possible decreased efficacy and quality of life and the substantial costs entailed by switching from IV pegaspargase to IM erwinia should prompt reconsideration of the IV administration route for pegaspargase in HR-ALL patients.

Cost-analysis of treatment of childhood acute lymphoblastic leukemia with asparaginase preparations: the impact of expensive chemotherapy.

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.

[The results of a multicenter trial of acute lymphoblastic leukemia treatment on ALL-MB 91/ALL-BFM 90m in children: analysis of efficacy and toxicity].

AIM: A comparative analysis of efficacy and toxicity of two chemotherapy regimens: standard German protocol ALL-BFM 90m and less intensive original test protocol ALL-MB 91 in a multicenter trial of acute lymphoblastic leukemia (ALL) in children. MATERIAL AND METHODS: In 1995-2002 a total of 834 patients with newly diagnosed ALL aged 0-18 years were admitted to 10 clinics of Russia. Of them, 713 were randomized in two groups: treatment program ALL-BFM 90m (n = 355) and ALL-MB 91 program (n = 358). RESULTS: In 7-year follow-up median, 10-year event-free survival (EFS) and overall survival (OS) did not differ significantly between the groups and was 67 +/- 3 and 68 +/- 3% (ALL-MB 91) and 74 +/- 2, 71 +/- 3% (ALL-BFM 90m), respectively. Though the rate of isolated recurrences in CNS in patients on the protocol ALL-MB 91 was 2.8%, they developed only in 0.8% patients of the standard risk group. Anemia, thrombocytopenia and agranulocytosis developed less frequently, hospital stay was significantly shorter on the test protocol vs the control one (p < 0.01). CONCLUSION: EFS and OS on the test (ALL-MB 91) and control (ALL-BFM 90m) protocols were equivalent in lower toxicity and cost of therapy.

A pharmacoeconomic analysis of pegaspargase versus native Escherichia coli L-asparaginase for the treatment of children with standard-risk, acute lymphoblastic leukemia: the Children's Cancer Group study (CCG-1962).

PURPOSE: The purpose of this pharmacoeconomic analysis was to compare pegaspargase. a newer chemotherapeutic agent used for treating acute lymphoblastic leukemia, with native Escherichia coli L-asparaginase in induction, delayed intensification 1 and delayed intensification 2. MATERIALS AND METHODS: A subset of patients with newly diagnosed, standard-risk, acute lymphoblastic leukemia enrolled in the Children's Cancer Group (CCG) study CCG-1962 at seven participating institutions gave consent and was enrolled in our pharmacoeconomic analysis study. Societal (transportation, lodging, missed workdays, food, babysitter) and payer (frequency of encounters) cost data were collected from diaries (n = 27). Additional payer costs, such as drug costs, cost per clinic visit, and cost per inpatient day stay were collected from patients in CCG-1962 and participating institutions. We considered costs of therapy, including higher pegaspargase costs when comparing regimens of pegaspargase versus native E. coli L-asparaginase in induction, delayed intensification 1, and delayed intensification 2. RESULTS: Our results showed that the costs of the two therapies were similar from the payer perspective, with pegaspargase costing 1.8% more than E. coli L-asparaginase. The difference between groups also was small (<1%) from the societal perspective. Inpatient stay accounted for 88% of pegaspargase payer costs and 91% of the native E. coli L-asparaginase costs. CONCLUSION: We recommend that pegaspargase not be withheld from treatment protocols solely because of its higher pharmacy costs.

Pegaspargase: an alternative?

OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, clinical activity, adverse effects, dosage, and administration guidelines for pegaspargase. DATA SOURCES: A MEDLINE search (1980-1996), a CANCERLIT search (1983-1996), and a CURRENT CONTENTS search (1980-1996) using the terms pegaspargase, PEG-asparaginase, PEG-L-asparaginase, polyethylene glycol L-asparaginase, polyethylene glycol conjugated L-asparaginase, and Oncaspar were conducted. STUDY SELECTION AND DATA EXTRACTION: All articles were considered for possible inclusion in this review. Abstracts were included only when they were judged to add critical information not otherwise available in the medical literature. DATA SYNTHESIS: L-Asparaginase has been a main component of treatment regimens for acute lymphocytic leukemia. A key limiting factor of L-asparaginase use has been the development of hypersensitivity to the drug. Recently, a polyethylene glycol (PEG) conjugated form of L-asparaginase, pegaspargase, has been made available. PEG modification of L-asparaginase has been shown to alter the tendency of the enzyme to induce an immune response and to extend the half-life of the drug. The majority of patients with hypersensitivity to the native enzyme preparations tolerate pegaspargase without further clinical hypersensitivity. The adverse effect profile of pegaspargase is similar to that of the native forms of L-asparaginase. The recommended dosage of pegaspargase is 2500 IU/m2 administered by intramuscular or intravenous injection every 2 weeks in combination with other chemotherapeutic agents. CONCLUSIONS: Pegaspargase is a safe, effective alternative to L-asparaginase in patients who have had clinical hypersensitivity reactions to both Escherichia coli- and Erwinia carotovora-derived L-asparaginase. However, pegaspargase should not be routinely substituted for L-asparaginase.

Pegaspargase versus asparaginase in adult ALL: a pharmacoeconomic assessment.

Asparaginase is an effective treatment for patients with acute lymphocytic leukemia (ALL). Unfortunately, asparaginase therapy is associated with a high incidence of hypersensitivity reactions (up to 73%), including life-threatening anaphylaxis, and its half-life of approximately 20 hours necessitates daily administration. Pegaspargase, a modification of L-asparaginase, has a longer half-life (357 hours), a decreased incidence of hypersensitivity reactions, and when doses every 14 days, provides comparable efficacy to asparaginase; however, it is much more expensive per single-dose vial ($980.00 vs $52.38). To determine the pharmacoeconomic impact of the two agents, we conducted a cost-minimization analysis for three common adult ALL protocols. Results showed that pegaspargase was significantly less costly to payers on an inpatient or outpatient basis and warranted addition to our formulary.