Individualized dosing guidelines for PEGasparaginase and factors influencing the clearance: a population pharmacokinetic model.

Considerable inter- and intra-patient variability exist in serum activity levels of PEGasparaginase, essential for pediatric acute lymphoblastic leukemia treatment. A population pharmacokinetic (popPK) model was developed, identifying patient characteristics explaining these variabilities. Patients (n=92) were treated according to the DCOG ALL-11 protocol, using therapeutic drug monitoring to individualize the PEGasparaginase doses. Non-linear mixed effects modeling (NONMEM) was used to analyze the popPK evaluating several covariates. The final model was validated using an independent database (n=28). Guidelines for starting doses and dose adjustments were developed. A one-compartment model with time-dependent clearance adequately described the popPK. Normalization of clearance and volume of distribution by body surface are (BSA) reduced inter-individual variability. Clearance was 0.084 L/day/m2 for 12.7 days, increasing with 0.082 L/day/m2/day thereafter. Clearance was 38% higher during an infection, and 11-19% higher during induction treatment than intensification and maintenance (p<0.001). Targeting an asparaginase activity level of 100 IU/L, a loading dose of 800 IU/m2 (induction) and 600 IU/m2 (intensification) is advised. In conclusion, variability of PEGasparaginase activity levels can be explained by BSA, treatment phase and the occurrence of an infection. With this popPK model, PEGasparaginase treatment can be individualized further, taking into account these covariates and the dosing guidelines provided.

Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia.

PURPOSE: In the DCOG ALL-11 protocol, polyethylene glycol-conjugated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported. PATIENTS AND METHODS: After induction with 3 fixed intravenous doses of 1,500 IU/m2 PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m2). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m2 Erwinia asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied. RESULTS: The final median PEGasparaginase dose was lowered to 450 IU/m2. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 µM in 96% and 67% of the PEGasparaginase and Erwinia asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% v 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification. CONCLUSION: TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.

The effect of asparaginase therapy on methotrexate toxicity and efficacy in children with acute lymphoblastic leukemia.

Asparaginase and methotrexate (MTX), both essential for pediatric acute lymphoblastic leukemia therapy, are often used concomitantly. Depending on the sequence, in vitro, asparaginase inhibits MTX-polyglutamate (MTXPG) formation, and side effects overlap. MTX toxicity and efficacy, reflected by intracellular erythrocyte MTXPG's, were compared between children treated with and without asparaginase during high dose MTX (HD-MTX) courses of the DCOG ALL-11 protocol (NL50250.078.14). Seventy-three patients, of whom 23 received asparaginase during the HD-MTX courses, were included. Grade 3-4 leukopenia and neutropenia occurred more often (59% and 86% vs. 30% and 62%). The number of infections, grade 3-4 hepatotoxicity, nephrotoxicity, and neurotoxicity did not differ. Patients with asparaginase had lower MTXPG levels, although to a lesser extent than in vitro studies. Although patients with asparaginase during HD-MTX courses showed more myelosuppression, this had no (serious) clinical consequences. Regarding the MTX efficacy, the schedule-related antagonism seen in in vitro seems less important in vivo.

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.

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.

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m2 three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM® A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher (P<0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m2 might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl).

Allergic-like reactions to asparaginase: Atypical allergies without asparaginase inactivation.

BACKGROUND: Asparaginase is an important component of pediatric acute lymphoblastic leukemia (ALL) therapy. Unfortunately, this treatment is hampered by hypersensitivity reactions. In general, allergies - regardless of severity - cause complete inactivation of the drug. However, we report atypical allergic reactions without inactivation of asparaginase, here called allergic-like reactions. PROCEDURE: Patients with an allergic-like reaction, who were treated according to the Dutch Childhood Oncology Group ALL-11 or the CoALL 08-09 protocol, were described. The reactions were identified by continual measurement of asparaginase activity levels. Characteristics, including timing of occurrence, symptoms, grade, and the presence of antiasparaginase antibodies, were compared to those of real allergies. RESULTS: Fourteen allergic-like reactions occurred in nine patients. Five reactions were to PEGasparaginase and nine to Erwinia asparaginase. Allergic-like reactions occurred relatively late after the start of infusion compared to real allergies. Antibodies were absent in all but one patient with an allergic-like reaction, while they were detected in all patients with a real allergy. Symptoms and grade did not differ between the groups. Asparaginase was continued with the same formulation in six patients of whom four finished treatment with adequate activity levels. CONCLUSIONS: In conclusion, allergic-like reactions occur relatively late after the start of infusion and without antibodies. Despite these clinical differences, allergic-like reactions can only be distinguished from real allergies by continually measuring asparaginase activity levels. If clinically tolerated, formulations should not be switched in case of allergic-like reactions. Moreover, failure to recognize these reactions may lead to a less favorable prognosis if asparaginase therapy is terminated unnecessarily.

The number of T cell allo-epitopes associates with CD4+ and CD8+ T-cell infiltration in pediatric cutaneous GVHD.

Risk factors for graft-versus-host disease (GVHD) following allogeneic hematopoietic stem-cell transplantation (HCST) include: HLA mismatches, sex-mismatch, and stem-cell source. We retrospectively analyzed if HLA- and sex-mismatching quantitatively affects the composition of GVHD-induced T-cell infiltrates. We quantified absolute numbers of CD4+ and CD8+ T cells present in tissue sections from skin biopsies of 23 pediatric HSCT-recipients with GVHD. HSCT with a sex-mismatched unrelated donor was associated with an increased number of CD4+ T cells when compared to a sex-matched unrelated donor (p=0.01). The absolute numbers of skin-infiltrating T cells were increased in patients expressing T-cell epitopes derived from the recipient's mismatched HLA, so called predicted indirectly recognizable HLA epitopes (PIRCHE). The combined expression of PIRCHE with a sex-mismatch resulted in the highest number of skin-infiltrating T cells. Our results indicate that an increased number of recipient-specific T-cell epitopes is associated with accumulation of CD4+ and CD8+ T cells in the skin.

Hemorrhagic cystitis in a cohort of pediatric transplantations: incidence, treatment, outcome, and risk factors.

Hemorrhagic cystitis (HC) can be a severe complication in hematopoietic stem cell transplantation (HSCT). To identify risk factors and etiology and to improve treatment, a number of factors were analyzed retrospectively in a cohort of 74 consecutive pediatric HSCTs between 2007 and 2009 in a single institution. The 74 transplantations were done in 67 children. Potential risk factors for HC were age, gender, underlying disease, ablative conditioning, graft-versus-host disease prophylaxis, unrelated donor, stem cell source, conditioning regime, acute graft-versus-host disease and cytomegalovirus reactivation. Fourteen patients developed HC (19%). In all but 4 cases (71%), HC appeared after engraftment. Severity was assessed as grade 1 in 1, grade 2 in 8, and grade 3 in 5 cases. In 79% of the patients with HC, urine samples showed BK virus. This may provide guidance for future prevention policies. In 11 children, treatment included forced hydration, spasmolytics, and bladder irrigation. Three children required cystoscopy, intravesical therapy and/or antiviral therapy. Statistical analysis revealed age over six years to be a risk factor for the development of HC. We conclude that current conditioning regimens lead to a still considerable incidence of HC in pediatric HSCT, necessitating the evaluation of screening protocols and preventive measures.