Nadir Serum Asparaginase Activity Research Articles

Efficacy and Safety of Recombinant Erwinia Asparaginase (JZP458) in Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL): Complete Follow-up of the Children's Oncology Group (COG) AALL1931 Study

Background: L-asparaginase is an important component of multi-agent treatment regimens for pediatric and adult patients with ALL/LBL. However, hypersensitivity reactions to E. coli-derived asparaginases often lead to treatment delay or discontinuation. JZP458, a recombinant Erwinia asparaginase (ASP) derived from a Pseudomonas fluorescens expression platform, was evaluated in study AALL1931, a 2-part, open-label, phase 2/3 trial conducted with the Children's Oncology Group investigating efficacy, safety, and pharmacokinetics (PK) of JZP458 in patients with ALL/LBL (ClinicalTrials.gov ID: NCT04145531). Based on interim results from part A of AALL1931, intramuscular (IM) JZP458 (Rylaze®) was approved by the US Food and Drug Administration for treatment of ALL/LBL in June 2021. Here, we report the efficacy and safety of JZP458 at the completion of AALL1931. Methods: Eligible patients with ALL/LBL who daeveloped hypersensitivity (grade ≥3 allergic reaction or silent inactivation) to E. coli-derived pegaspargase received JZP458 as part of their multi-agent treatment plan. Each dose of pegaspargase was substituted with 6 doses of JZP458 administered either IM (part A) or intravenously (IV, part B) on Monday/Wednesday/Friday (MWF) over 2 weeks, defined as 1 course. The study enrolled 3 IM cohorts [1a (25 mg/m 2 MWF), 1b (37.5 mg/m 2 MWF), and 1c (25/25/50 mg/m 2 MWF)], and 1 IV cohort (25/25/50 mg/m 2 MWF). Efficacy was assessed by proportion of patients maintaining therapeutic nadir serum ASP activity (NSAA) ≥0.1 IU/mL at the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) timepoint during course 1. A population PK (PPK) model was developed based on serum ASP activity (SAA) data from AALL1931 to characterize the PK of JZP458 and simulations using the PPK model were performed to provide additional information on alternative dosing regimens. Results: At the final cutoff date of November 22, 2022, a total of 167 patients received IM JZP458 (1a, n=33; 1b, n=83; 1c, n=51) and 61 patients received IV JZP458. The median (range) of JZP458 courses received was 5 (0, 14), 4 (0, 15), 5 (1, 10), and 3 (0, 15) for IM cohorts 1a, 1b, 1c, and IV cohort, respectively. Table 1 shows the proportion of patients who achieved therapeutic NSAA levels and the mean SAA levels per cohort in course 1. With IM cohort 1c (25/25/50 mg/m 2 MWF), the proportion (95% CI) of patients achieving NSAA levels ≥0.1 IU/mL at 72 and 48 hours were 90% (81, 98) and 96% (90, 100), respectively. Treatment-related adverse events (TRAEs) ≥ grade 3 occurred in 126/228 (55%) patients; but no TRAE led to death. Table 2 shows the most commonly reported (≥10% of patients) nonhematologic TRAEs. A total of 22 patients (13%) across all IM cohorts (2 patients in 1a, 14 in 1b, and 6 in 1c) and 20 patients (33%) in the IV cohort experienced a TRAE leading to treatment discontinuation.The most common TRAEs leading to treatment discontinuation were pancreatitis (6%) in the IM cohort, and drug hypersensitivity (15%) in the IV cohort. PPK model-based simulations predicted that therapeutic NSAA levels are achieved in the vast majority of patients when JZP458 is administered IM at 25 mg/m 2 every 48 hours (7 doses) or 25/25/50 mg/m 2 MWF (6 doses), when JZP458 is administered IV at 25 mg/m 2 every 48 hours (7 doses), or when JZP458 is administered IV at 25 mg/m 2 M/W and IM at 50 mg/m 2 F (6 doses). Conclusions: Results at the completion of AALL1931 in patients with ALL/LBL and allergic reactions or silent inactivation to E. coli-derived asparaginase show the safety profile of JZP458 is consistent with other asparaginases, with no new adverse safety signals. Treatment-related discontinuation rates with IV JZP458 were greater than with IM, primarily due to increased incidence of hypersensitivity/infusion-related reactions along with nausea and vomiting; however, the study was not statistically powered to compare different dosing cohorts. Observed and PPK modeling data demonstrate JZP458 achieves therapeutic NSAA levels via multiple IM and IV dosing schedules, with IM dosing having more sustained SAA, and therefore providing flexibility to patients and physicians.

Population pharmacokinetics of intramuscular recombinant Erwinia chrysanthemi asparaginase (JZP458) in patients with acute lymphoblastic leukemia.

JZP458 is a recombinant Erwinia chrysanthemi asparaginase for patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who have developed hypersensitivity to Escherichia coli-derived asparaginases. A population pharmacokinetic (PopPK) model was developed for intramuscular (i.m.) JZP458 using serum asparaginase activity (SAA) data from 166 patients with ALL/LBL enrolled in a phase II/III study conducted in collaboration with the Children's Oncology Group (AALL1931; NCT04145531). The pharmacokinetics of i.m. JZP458 is best characterized by a one-compartment model with mixed-order absorption and linear elimination, with body surface area included as an allometric covariate on JZP458 SAA clearance and volume, and race (i.e., Black/African American) and disease subtype (i.e., T-cell ALL) as covariates on JZP458 SAA clearance. The PopPK model was used to simulate SAA profiles to estimate the likelihood of achieving nadir SAA (NSAA) levels greater than or equal to 0.1IU/mL with different dosing regimens. Model-based simulations suggest when JZP458 is administered i.m. at 25/25/50 mg/m2 Monday/Wednesday/Friday (MWF), 92.1% of subjects (95% confidence interval [CI]: 90.9%, 93.3%) are expected to achieve the last 72-h (after 50 mg/m2 dose) NSAA level greater than or equal to 0.1IU/mL, and 93.8% (95% CI: 92.7%, 94.9%) are expected to achieve the last 48-h (after 25 mg/m2 dose) NSAA level greater than or equal to 0.1IU/mL. When JZP458 is administered 25 mg/m2 i.m. every 48 h, 93.8% (95% CI: 92.7%, 94.8%) are expected to achieve the last 48-h NSAA level greater than or equal to 0.1IU/mL. These data supported the i.m. dose of 25 mg/m2 every 48 h or 25/25/50 mg/m2 on a MWF dosing schedule in patients with ALL/LBL.

Recombinant Erwinia asparaginase (JZP458) in acute lymphoblastic leukemia: results from the phase 2/3 AALL1931 study

AbstractAALL1931, a phase 2/3 study conducted in collaboration with the Children’s Oncology Group, investigated the efficacy and safety of JZP458 (asparaginase erwinia chrysanthemi [recombinant]-rywn), a recombinant Erwinia asparaginase derived from a novel expression platform, in patients with acute lymphoblastic leukemia/lymphoblastic lymphoma who developed hypersensitivity/silent inactivation to Escherichia coli–derived asparaginases. Each dose of a pegylated E coli–derived asparaginase remaining in patients’ treatment plan was substituted by 6 doses of intramuscular (IM) JZP458 on Monday/Wednesday/Friday (MWF). Three regimens were evaluated: cohort 1a, 25 mg/m2 MWF; cohort 1b, 37.5 mg/m2 MWF; and cohort 1c, 25/25/50 mg/m2 MWF. Efficacy was evaluated by the proportion of patients maintaining adequate nadir serum asparaginase activity (NSAA ≥0.1 IU/mL) at 72 hours and at 48 hours during the first treatment course. A total of 167 patients were enrolled: cohort 1a (n = 33), cohort 1b (n = 83), and cohort 1c (n = 51). Mean serum asparaginase activity levels (IU/mL) at 72 hours were cohort 1a, 0.16, cohort 1b, 0.33, and cohort 1c, 0.47, and at 48 hours were 0.45, 0.88, and 0.66, respectively. The proportion of patients achieving NSAA ≥0.1 IU/mL at 72 and 48 hours in cohort 1c was 90% (44/49) and 96% (47/49), respectively. Simulated data from a population pharmacokinetic model matched the observed data well. Grade 3/4 treatment-related adverse events occurred in 86 of 167 (51%) patients; those leading to discontinuation included pancreatitis (6%), allergic reactions (5%), increased alanine aminotransferase (1%), and hyperammonemia (1%). Results demonstrate that IM JZP458 at 25/25/50 mg/m2 MWF is efficacious and has a safety profile consistent with other asparaginases. This trial was registered at www.clinicaltrials.gov as #NCT04145531.

Efficacy and safety of intramuscular (IM) recombinant Erwinia asparaginase in acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL): The Children’s Oncology Group (COG) AALL1931 study.

7001 Background: The inability to receive L-asparaginase (ASNase) therapy due to hypersensitivity is associated with inferior outcomes in patients with ALL or LBL. JZP458, a recombinant Erwinia-derived ASNase from a Pseudomonas fluorescens expression platform, is approved by the FDA for patients with ALL/LBL who have developed hypersensitivity to E. coli–derived ASNase. Here, we report the efficacy and safety of IM JZP458 from COG AALL1931, a phase 2/3, open-label, multicenter, pharmacokinetic (PK) study. Methods: Eligible patients with ALL/LBL had a grade ≥3 allergic reaction or silent inactivation to a pegylated E. coli–derived ASNase. Each remaining dose of pegylated E. coli–derived ASNase was replaced with 6 doses of IM JZP458 on Monday/Wednesday/Friday (M/W/F) over 2-weeks. Three dosing cohorts were enrolled: Cohort 1a, 25 mg/m2 M/W/F; Cohort 1b, 37.5 mg/m2 M/W/F; Cohort 1c, 25 mg/m2 M/W and 50 mg/m2 F. Efficacy was assessed by the proportion of patients who achieved the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) nadir serum asparaginase activity (NSAA) levels ≥0.1 IU/mL in the first treatment course. A population PK (PPK) model was developed based on SAA data from AALL1931 to characterize the PK of JZP458 and to inform dosing decisions. Results: 167 patients were enrolled for IM dosing (Cohort 1a, n = 33; Cohort 1b, n = 83; Cohort 1c, n = 51). The median (range) age was 10 (1, 25) years. The median (range) of JZP458 courses received was 5 (1, 14) for Cohort 1a, 5 (1, 15) for Cohort 1b, and 4 (1, 11) for Cohort 1c. Mean (95% CI) SAA levels (IU/mL) at 72-hour were 0.16 (0.12, 0.19) for Cohort 1a, 0.33 (0.27, 0.39) for Cohort 1b, and 0.47 (0.35, 0.59) for Cohort 1c; and 0.45 (0.37, 0.53), 0.88 (0.76, 1.01), and 0.66 (0.54, 0.77), respectively, at 48-hour. Simulated data from the PPK model matched the observed data well. For Cohort 1c, the proportions of patients (95% CI) achieving NSAA levels ≥0.1 IU/mL at the last 72- and 48-hour in Course 1 were 90% (81%, 98%) and 96% (90%, 100%), respectively, based on observed data; and were 92% (91%, 93%) and 94% (93%, 95%) based on modeled data. The Table shows the rates of treatment-related adverse events (TRAEs; all grades) of interest per cohort. Overall, TRAEs leading to discontinuation included pancreatitis (6%), drug hypersensitivity (4%), anaphylactic reaction (2%), increased alanine aminotransferase (1%), and hyperammonemia (1%). There were no TRAEs leading to death. Conclusions: The totality of the results from AALL1931 demonstrate the positive benefit-risk profile of the IM JZP458 dosing regimen of 25 mg/m2 M/W and 50 mg/m2 F with a safety profile consistent with other asparaginases. Clinical trial information: NCT04145531. [Table: see text]

Initial Results from a Phase 2/3 Study of Recombinant Erwinia Asparaginase (JZP458) in Patients with Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL) Who Are Allergic/Hypersensitive to E. coli-Derived Asparaginases

Background: In patients with ALL, inability to receive L-asparaginase therapy due to hypersensitivity is associated with higher relapse risk (Gupta S, et al. J Clin Oncol. 2020). JZP458 is a recombinant Erwinia asparaginase derived from a novel Pseudomonas fluorescens expression platform to produce a reliable supply of enzyme with minimal immunologic cross-reactivity to E. coli-derived asparaginases. It has an amino acid sequence identical to that of native Erwinia asparaginase and its activity on asparagine is comparable based on in vitro measurements. This report includes initial analyses from the phase 2/3 open-label, multicenter, confirmatory pharmacokinetic (PK) and safety study (NCT04145531) of JZP458 in patients with ALL/LBL who developed hypersensitivity or silent inactivation to a long-acting E. coli-derived asparaginase.Methods: For eligible patients, each remaining course of long-acting E. coli-derived asparaginase was substituted by six doses of intramuscular (IM) JZP458 on a Monday/Wednesday/Friday (M/W/F) schedule. The primary efficacy endpoint of the trial was evaluated by the proportion of patients with the last 72-hr (primary endpoint) and last 48-hr (key secondary endpoint) nadir serum asparaginase activity (NSAA) level ≥0.1 IU/mL during the first treatment course. Cohort 1a started with 25 mg/m 2 IM JZP458 (M/W/F) and Cohort 1b explored a higher dose of 37.5 mg/m 2 IM M/W/F. A preliminary population pharmacokinetic (PPK) model using Cohort 1a and 1b data predicted that a regimen of 25 mg/m 2 (M/W) and 50 mg/m 2 (F) would be optimal to support M/W/F dosing and Cohort 1c was initiated using this regimen.Results: This initial report (data cutoff of Jan 11, 2021) provides data from 102 study patients enrolled in Cohort 1a (n=33, 51.5% male), 1b (n=53, out of 87 patients enrolled, 62.3% male), and 1c (n=16, out of 52 patients enrolled, 50.0 % male). The median (range) number of courses received in Cohorts 1a, 1b, and 1c as of the data cutoff was 4 (1, 14), 3 (1, 12), and 1 (1, 2), respectively, and 53% of patients were ongoing in treatment. The mean serum asparaginase activity (SAA) levels (95% confidence intervals [CIs]) for evaluable patients in Cohorts 1a, 1b, and 1c at 48 hrs were 0.4489 IU/mL (0.3720, 0.5258), 0.8376 IU/mL (0.6813, 0.9939), and 0.5085 IU/mL (0.3261, 0.6908); and at 72 hrs were 0.1543 IU/mL (0.1162, 0.1924), 0.3000IU/mL (0.2269, 0.3730), and 0.3579 IU/mL (0.2184, 0.4974). The proportion of patients achieving NSAA ≥0.1 IU/mL at 48 and 72 hr time points are presented in Table 1. PPK modeling and simulation analysis suggested that JZP458 given IM as 25 mg/m 2 on M/W and 50 mg/m 2 on F was expected to achieve NSAA levels ≥0.1 IU/mL in 99.8% of patients (95% CI: 99.6%, 100%) at 48 hours and 97.3% of patients (95% CI: 96.5%, 98.0%) at 72 hours.Grade 3 or higher treatment-emergent adverse events, regardless of causality, occurred in 73/102 (72%) patients. Adverse drug reactions (ADRs) are shown in Table 2. These ADRs are consistent with the safety profile observed with other asparaginases.Conclusions: The JZP458 IM dosing regimen of 25 mg/m 2 M and W, and 50 mg/m 2 F demonstrates a positive benefit:risk profile, achieving SAA levels ≥0.1 IU/mL in >90% of patients studied at both 48- and 72-hrs and a safety profile that is consistent with what has been observed in published literature on asparaginases. [Display omitted] DisclosuresMaese: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees. Lin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Aoki: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Zanette: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Agarwal: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Jazz Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Choi: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Raetz: Pfizer: Research Funding; Celgene: Other: DSMB member. Rau: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Servier Pharmaceuticals: Consultancy; AbbVie Pharmaceuticals: Other: Spouse is employee and stock holder.

Impact of Age, Body Surface Area, and Body Mass Index on Pegaspargase Toxicity and Pharmacokinetics: A Report from the DFCI ALL Consortium

Introduction: Increased toxicity with pegaspargase (PEG) in older and higher body mass index (BMI) patients (pts) with acute lymphoblastic leukemia (ALL) has recently led to dose capping practices. We assessed the influence of age, body surface area (BSA), and BMI on PEG-related toxicity and pharmacokinetics from two consecutive DFCI ALL Consortium trials without dose capping.Methods: Patient (pts) aged 1 to <19 years (DFCI 05-001) or 1 to <22 years (DFCI 11-001) with newly diagnosed ALL were eligible for enrollment. Those who received PEG (2500 IU/m 2) were included in this analysis. Pts received 1 dose of IV PEG on day 7 of Induction and every 2 weeks for 15 doses post-induction. Serum asparaginase activity (SAA), considered therapeutic at >0.1 IU/mL, was assessed 4, 11, 18, and 25 days after the Induction dose and nadir SAA was assessed before each Post-Induction dose.Asparaginase-related toxicities were prospectively assessed and graded by CTCAE version 3.0 (DFCI 05-001) or 4.0 (DFCI 11-001). Asparaginase toxicity for this analysis was defined as ≥1 of the following: pancreatitis, thrombosis, ≥grade 4 hyperbilirubinemia, ≥grade 4 hypertriglyceridemia. Allergy was analyzed separately (due to presumed dose independence). Height and weight at diagnosis were used for analyses. BMI categories were assigned using standard percentile ranges based on gender specific 2000 CDC growth charts. BSA was calculated using the Mosteller formula.Univariate analyses evaluated the relationship of age, BMI, and BSA with asparaginase toxicity. Comparisons of toxicity across BMI and BSA categories were performed using a Jonckheere-Terpstra test. Categorical comparisons for dichotomized BMI and BSA utilized a Fisher's exact test or chi square test. The relationships between BMI and BSA with toxicity were explored using multivariable models.Results: Between 4/2005-12/2011 802 pts enrolled on DFCI 05-001 and between 6/2012-6/2015 240 pts enrolled on DFCI 11-001. Both trials included random assignment of asparaginase formulation. In total 911 patients received pegaspargase during Induction and 351 during Post-Induction.During Induction, pts ≥15 years of age had higher asparaginase toxicity rates (17.1% vs 6.2%, p=0.0003) (Figure 1a). Toxicity differed significantly across BSA categories (<1.5 m 2, 1.5 to <2.0 m 2, ≥2.0 m 2, p= 0.007) with increased toxicity in those with BSA ≥2.0m 2 (22.7% vs. 6.8% for those <2.0 m 2, p = 0.016) (Figure 1b). Age was highly correlated with BSA (Pearson r = 0.93, p <0.0001). There was numerically higher toxicity in the BMI category of overweight vs. those underweight or normal weight (11.3% vs 6.5%) however this did not extend to the obese category, and overall, increasing BMI was not associated with statistically higher toxicity (p= 0.13, Figure 1c).Post-Induction, age ≥15 years was associated with increased asparaginase toxicity (57.1% vs 21%, p<0.0001) (Figure 1d). Toxicity differed significantly across BSA categories (p<0.0001) but was similar between BMI categories (p=0.19, Figure 1e-f). The impact of BSA was observed when dichotomized at thresholds of 1.5m 2 (54% vs. 19%, p<0.0001) and 2.0m 2 (70% vs. 23%, p=0.003) (Figure 1e). Considering only those ≥10 years of age, trends for BSA/BMI and toxicity were similar. There was no significant association between BMI or BSA and allergy. In multivariable analysis, BSA was a significant predictor of Post-Induction toxicity (OR 4.21, p<0.0001). Age was significant in the univariate setting (OR 1.14, p<0.0001) however due to high correlation with BSA, was not included with BSA in the multivariable model.Post-Induction, median nadir SAA levels were ≥0.1IU/mL for all BSA and age categories. Median SAA was similar or lower at all time-points for those ≥15 years of age compared with younger children. Median SAA for pts with BSA ≥1.5m 2 were similar or lower compared to those with BSA <1.5m 2 (Figure 2a-d).Conclusion: Age ≥15 years and BSA ≥2m 2 were each associated with significantly increased asparaginase toxicity. Older patients and those with higher BSA had similar or lower median SAA levels at all time-points. These results suggest that the differential toxicity seen in older patients and those with higher BSA is not explained by these patients having higher SAA levels. Prospective exploration of interventions to decrease toxicity in older patients and those with high BSA are needed. [Display omitted] DisclosuresNeuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees.

Population Pharmacokinetic Model Development and Simulation for Recombinant Erwinia Asparaginase Produced in Pseudomonas fluorescens (JZP-458).

JZP‐458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme expected to lack immunologic cross‐reactivity to Escherichia coli–derived asparaginases. It is being developed as part of a multiagent chemotherapeutic regimen to treat acute lymphoblastic leukemia or lymphoblastic lymphoma patients who develop E coli–derived asparaginase hypersensitivity. A population pharmacokinetic (PopPK) model was developed for JZP‐458 using serum asparaginase activity (SAA) data from a phase 1, single‐dose study (JZP458‐101) in healthy adults. Effects of intrinsic covariates (body weight, body surface area, age, sex, and race) on JZP‐458 PK were evaluated. The model included SAA data from 24 healthy adult participants from the phase 1 study who received JZP‐458: intramuscular (IM) data at 12.5 mg/m2 (N = 6) and 25 mg/m2 (N = 6), and intravenous (IV) data at 25 mg/m2 (N = 6) and 37.5 mg/m2 (N = 6). Model simulations of adult and pediatric SAA profiles were performed to explore the likelihood of achieving a therapeutic target nadir SAA (NSAA) level ≥0.1 IU/mL based on different administration strategies. PopPK modeling and simulation suggest JZP‐458 is expected to achieve 72‐hour NSAA levels ≥0.1 IU/mL in 100% of adult or pediatric populations receiving IM administration at 25 mg/m2, and in 80.9% of adult and 94.5% of pediatric populations receiving IV administration at 37.5 mg/m2 on a Monday/Wednesday/Friday (M/W/F) dosing schedule. Based on these results, the recommended starting dose for the phase 2/3 pivotal study is 25 mg/m2 IM or 37.5 mg/m2 IV on a M/W/F dosing schedule in pediatric and adult patients.

A phase II/III study of JZP-458 in patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL) who are hypersensitive to E. coli-derived asparaginases.

TPS7568 Background: L-asparaginase is an important component of ALL therapy and the inability to receive asparaginase secondary to hypersensitivity has been associated with poor patient (pt) outcomes. Alternative options for pts after hypersensitivity reactions are needed. JZP-458 is a recombinant Erwinia asparaginase produced using a novel Pseudomonas fluorescens expression platform that yields an enzyme with no immunologic cross-reactivity to E. coli–derived asparaginases. In a phase 1 study, JZP-458 was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hrs in healthy adults. Methods: This is a pivotal, open-label, multicenter, dose confirmation, and pharmacokinetic (PK) study (NCT04145531) of JZP-458 in pts with ALL/LBL who develop hypersensitivity reactions to a long-acting E. coli–derived asparaginase and have ≥1 course of asparaginase remaining in their treatment plan (Table); 6 doses of JZP-458 will be substituted for each remaining course. Treatment duration will depend on the number of asparaginase courses remaining in the treatment plan. The study has 2 sequential parts: Part A will determine the dose of intramuscular (IM) JZP-458 and confirm safety/efficacy; Part B will explore the dose/schedule of intravenous (IV) JZP-458. Blood samples will be collected to determine SAA levels and pts will be monitored for adverse events. Immunogenicity of JZP-458 will be assessed. Primary objectives are to determine (1) the efficacy of IM JZP-458 measured by the last 72-hr nadir SAA (NSAA) level (≥0.1 IU/mL) during the first treatment course, and (2) the safety/tolerability of IM JZP-458. Secondary objectives are to determine the efficacy (measured by the last 48-hr NSAA level [≥0.1 IU/mL] and the last 48- and 72-hr NSAA levels [≥0.4 IU/mL]), PK, and immunogenicity of IM JZP-458. Exploratory objectives include efficacy, safety, PK, and immunogenicity of IV JZP-458. The trial is active and enrolling. Clinical trial information: NCT04145531 . [Table: see text]

FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults

On December 20, 2018, the Food and Drug Administration approved calaspargase pegol-mknl (CALASP), an asparagine-specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. Efficacy was determined on the basis of achievement and maintenance of steady-state nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using CALASP, 2,500 U/m2 intravenously, every 3 weeks. In a randomized comparison to pegaspargase (PEGASP) every 2 weeks, treatment with CALASP every 3 weeks had a similar safety profile and no substantial impairment in event-free survival. The pharmacokinetics of CALASP were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell ALL in Study AALL07P4 and Study DFCI 11-001. The results showed that 123 [99%, 95% confidence interval (CI), 96%-100%] of the 124 patients maintained NSAA >0.1 U/mL at weeks 6, 12, 18, 24, and 30 of post-induction phase. Maintaining adequate NSAA levels is critical to successful treatment of ALL. Herein, we describe the FDA review and approval of CALASP.See related commentary by Lew, p. 325.

Open-Label, Multicenter, Phase 2/3 Study of Recombinant Crisantaspase Produced in Pseudomonas Fluorescens (RC-P) in Patients with Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL) Following Hypersensitivity to Escherichia coli-Derived Asparaginases

Background: L-asparaginase, an important component of ALL therapy, hydrolyzes the nonessential amino acid asparagine, depleting plasma levels and selectively killing leukemic lymphoblasts that are asparagine autotrophs. L-asparaginases are immunogenic and can induce hypersensitivity reactions; high neutralizing antibody titers may limit their therapeutic effect. The inability to receive asparaginase secondary to hypersensitivity has prognostic implications for patients with ALL and has been associated with significantly worse outcomes (Silverman LB, et al. Blood 2001;97:1211-1218; Gupta S, et al. J Clin Oncol. 2019;37[suppl]: Abstract 10005). Alternative preparations are needed to ensure that all patients unable to receive E. coli-derived asparaginase due to hypersensitivity are able to receive adequate treatment. RC-P is a recombinant crisantaspase. Due to the use of a novel Pseudomonas fluorescens technology expression platform, RC-P has no immunologic cross-reactivity to E. coli-derived asparaginases. In a study of RC-P administration in healthy adults (JZP458-101), the enzyme was well tolerated and maintained adequate (≥0.1 IU/mL) serum asparaginase activity (SAA), a surrogate marker for asparagine depletion, for up to 72 hours. Study Design and Methods: This is an open-label, multicenter, dose confirmation and pharmacokinetic (PK) study (JZP458-201) of RC-P in patients with ALL or LBL who develop allergic reactions to an E. coli-derived asparaginase and have ≥1 dose of E. coli-derived asparaginase remaining in their treatment plan (Table). For these patients, 6 doses of RC-P will be substituted for each dose of long-acting E. coli-derived asparaginase. Individual patient treatment duration will vary depending on the number of E. coli-derived asparaginase doses that remain in the patient's original treatment plan. The study will consist of 2 sequential parts: Part A will determine the dose of RC-P for intramuscular (IM) administration and confirm safety and efficacy; Part B will define the optimal dose and schedule of intravenous (IV) RC-P. Blood samples will be collected at prespecified time points to determine SAA levels, and patients will be monitored for adverse events. Immunogenicity of RC-P treatment will also be assessed. The primary objectives are to (1) determine the efficacy of IM RC-P administration measured by the last 72-hour nadir SAA (NSAA) level being ≥0.1 IU/mL during the first course of treatment, and (2) assess the safety and tolerability of IM RC-P in patients with ALL/LBL who are hypersensitive to E. coli-derived asparaginases. Secondary objectives include determination of the efficacy of IM RC-P measured by the last 48-hour and last 72-hour NSAA levels being ≥0.4 IU/mL during the first course, characterization of PK of IM RC-P using a population PK approach, and assessment of immunogenicity following repeat administration of RC-P. Exploratory objectives include determination of the efficacy, safety, PK, and immunogenicity of IV RC-P. Disclosures Raetz: Pfizer: Research Funding. Lin:Jazz Pharmaceuticals: Employment, Equity Ownership. Zhu:Jazz Pharmaceuticals: Employment, Equity Ownership. Kim:Jazz Pharmaceuticals: Employment, Equity Ownership. Chandula:Jazz Pharmaceuticals: Employment, Equity Ownership. McClung:Jazz Pharmaceuticals: Employment, Equity Ownership. Gray:Jazz Pharmaceuticals: Employment, Equity Ownership. Choi:Jazz Pharmaceuticals: Employment, Equity Ownership. Loh:Medisix Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees. Adamson:Pfizer: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amneal Pharmaceuticals: Equity Ownership; Allergan: Equity Ownership; Gilad Sciences: Equity Ownership; Medtronic: Equity Ownership; Merck: Equity Ownership, Research Funding; Genentech/Roche: Research Funding; Novartis: Research Funding; Eisa: Research Funding; Celator: Research Funding; Seattle Genetics: Research Funding; United Therapeutics: Research Funding; Sanofi/Aventis: Research Funding; Jubilant Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Bayer: Research Funding; Amgen: Research Funding; AstraZeneca: Research Funding; Cancer Prevention Pharmaceuticals: Research Funding; Astellas Pharma: Research Funding; Lilly: Research Funding; Springworks: Research Funding; Millennium: Research Funding. OffLabel Disclosure: The abstract presents data from an investigational agent.

Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001.

10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( &gt; 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.

Randomized Study of Pegasparagase (SS-PEG) and Calaspargase Pegol (SC-PEG) in Pediatric Patients with Newly Diagnosed Acute Lymphoblastic Leukemia or Lymphoblastic Lymphoma: Results of DFCI ALL Consortium Protocol 11-001

▪Background: E.coli L-asparaginase (L-ASP) is an important component of treatment for childhood acute lymphoblastic leukemia (ALL), but the optimal preparation and dosing remain to be determined. Pegaspargase (SS-PEG) is a pegylated L-ASP formulation commonly used in frontline therapy. Calaspargase pegol (SC-PEG) is a novel formulation that uses the same ASP enzyme and PEG moiety as SS-PEG but a different linker molecule that is more hydrolytically stable, leading to a longer half-life. On Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols, patients (pts) typically receive a single dose SS-PEG during induction, and then 15 doses every 2-weeks (wks) during post-induction in order to maintain therapeutic serum asparaginase activity (SAA), defined as ≥ 0.1 IU/mL, for 30 consecutive wks. We hypothesized that SC-PEG could be administered less frequently than SS-PEG during post-induction therapy with a similar SAA and toxicity profile.Methods: Between 2012-2015, pts aged 1-21 years with newly diagnosed ALL or lymphoblastic lymphoma (LL) were eligible to enroll on DFCI ALL Consortium Protocol 11-001. Pts were randomized at study entry to receive either SS-PEG (N=120) or SC-PEG (N=119), each given intravenously (IV) at a dose of 2500 IU/m2. Both groups received a single dose during multi-agent remission induction. Post-induction, pts assigned to SS-PEG received 15 doses every 2-wks and those assigned to SC-PEG received 10 doses every 3-wks along with other risk-stratified chemotherapy. Serum samples were obtained 4, 11, 18 and 25 days after the induction dose to determine SAA and prior to each post-induction dose (2 wks after each SS-PEG and 3 wks after each SC-PEG dose) to determine nadir SAA (NSAA) by a validated biochemical assay. Pts were switched to Erwinia asparaginase for Grade 2 or higher allergy or for silent inactivation (defined as 2 consecutive non-detectable NSAA). Asparaginase was permanently discontinued for pancreatitis and held for thrombosis (but re-started once the clot improved). End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCRPCR assay, with low MRD defined as < 0.001.Results: 239 eligible pts were enrolled (230 ALL and 9 LL). There were no significant differences in presenting characteristics between randomized arms. SAA during induction and NSAA during post-induction are displayed in Figure 1. SAA was similar for the two preparations at 4, 11 and 18 days after the induction dose, with SAA ≥ 0.1 IU/mL in ≥ 95% of pts at these time points on both arms. 25 days after the induction dose, SAA was higher with SC-PEG (median 0.298 IU/mL vs 0.056 for SS-PEG), with significantly more pts on SC-PEG arm with SAA ≥ 0.1 IU/mL (88% vs 15%, p<0.0001). Post-induction NSAA was similar between arms, with median NSAA ≥ 1.0 IU/mL (10-times higher than goal NSAA) at 7, 13, 19 and 25 wks after beginning the 30-wk post-induction asparaginase treatment. NSAA was ≥ 0.1 IU/mL in ≥ 98% of pts on both arms at each time point. Two pts on the SC-PEG arm (1.7%) and none on the SS-PEG arm met criteria for silent inactivation. There was no significant difference in rates of ASP-related allergy (p=1.00), pancreatitis (p=1.00), thrombosis (p=0.22) or infections (p=0.86) during induction or post-induction treatment (Table 1). Of 230 evaluable pts, 97% achieved CR, with no difference in proportion of pts with low end-induction MRD by randomized arm (91% SC-PEG vs 90% SS-PEG, p=1.00).Conclusion: During remission induction, a single dose of SC-PEG (2500 IU/m2) leads to more sustained SAA without excess toxicity or significant difference in the proportion of pts with low end-induction MRD. During post-induction therapy, SC-PEG can be given less frequently (every 3-wks) than SS-PEG (every 2-wks) with similar NSAA and toxicity. The high NSAA observed during post-induction therapy with each preparation suggests that a longer dosing interval and/or reduced dose may be feasible while still maintaining NSAA ≥ 0.1 IU/mL. Longer follow-up is necessary to determine event-free survival by randomized arm. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Intravenous pegylated asparaginase versus intramuscular native Escherichia colil-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial

l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. National Cancer Institute and Enzon Pharmaceuticals.

Preliminary Results Of a Pharmacokinetic Study Of Intravenous Asparaginase Erwinia Chrysanthemi Following Allergy To E Coli-Derived Asparaginase In Children, Adolescents, and Young Adults With Acute Lymphoblastic Leukemia Or Lymphoblastic Lymphoma

BackgroundAsparaginase is an important component of therapy for acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL). However, up to 30% of patients (pts) develop an allergy to Escherichia coli (E coli)–derived asparaginase. In those pts, Erwinia asparaginase (Erwinia), an antigenically distinct preparation derived from Erwinia chrysanthemi, can be used. Although Erwinia is typically administered intramuscularly (IM), intravenous (IV) asparaginase would offer a more convenient, less painful administration route. In an open-label, single-arm, multicenter, pharmacokinetic (PK) study, we evaluated IV administration of Erwinia in children and adolescents with ALL who developed hypersensitivity to E coli–derived asparaginase. MethodsPts (aged ≥1 to ≤30 years) with ALL or LBL who developed hypersensitivity (grade ≥2) to E coli–derived asparaginase were eligible for enrollment. Pts received Erwinia IV, 25,000 IU/m2/dose, on a Monday/Wednesday/Friday (M/W/F) schedule for 2 consecutive weeks (6 doses=1 cycle) for each dose of pegaspargase remaining in the original treatment plan. All other chemotherapy was continued per the original treatment plan. Blood samples were collected during the 1st treatment cycle, including predose, 5 min, 48 hrs and 72 hrs postdose. The primary study objective was to determine the proportion of pts who achieved nadir serum asparaginase activity (NSAA) ≥0.1 IU/mL, which has been associated with complete asparagine depletion, at 48 hrs after dose 5 in cycle 1. Secondary objectives included determining the proportion of pts who achieved NSAA ≥0.1 IU/mL at 72 hrs after dose 6 in cycle 1 and the incidence of asparaginase-related toxicities. Only pts who completed 1 cycle of Erwinia were considered evaluable for NSAA assessment. ResultsBetween November 2012 and June 2013, 30 pts were enrolled from 10 centers; 26 pts completed cycle 1. Twenty-three pts were evaluable for the primary NSAA endpoint (3 pts were not evaluable; 2 for PK data collected outside the protocol-specified window and 1 for nonadherence to the dosing schedule). Median age was 6.5 years (1-17 years), 63% were male, and 83% Caucasian. Predose NSAA levels were below the limit of quantification (defined as 0.0129 IU/mL) for nearly all (91%) pts. Of the 23 evaluable pts who completed cycle 1, 19 (83%) achieved NSAA levels ≥0.1 IU/mL at 48 hrs postdose 5, with mean ±SD NSAA 0.32 ±0.23 (Table 1). At 72 hrs postdose 6, 9 pts (45%) achieved NSAA levels ≥0.1 IU/mL (mean ±SD 0.088 ±0.076).Four pts discontinued Erwinia treatment before completing cycle 1; 3 for hypersensitivity and 1 for pancreatitis. The toxicity analysis included all 30 enrolled pts. The most common asparaginase-related toxicities reported during cycle 1 were: hypersensitivity (23% of pts), vomiting (20%), nausea (20%), and hyperglycemia (13%). Pancreatitis occurred in 3% and thrombosis in 3% of pts. One pt experienced a transient ischemic attack. The most common grade 3 or 4 adverse event was febrile neutropenia (7%). There were no deaths. ConclusionsThe majority (83%) of children and adolescents with ALL or LBL receiving Erwinia IV at 25,000 IU/m2/dose on a M/W/F schedule, achieved NSAA ≥0.1 IU/mL at 48 hrs postdose 5 (considered the therapeutic goal); however the majority did not achieve this goal at 72 hrs post Erwinia dose 6. With IV administration, asparaginase-related toxicities appeared to be consistent with previous reports in children treated with IM Erwinia. Based on these results, we are now evaluating IV Erwinia at 25,000 IU/m2/dose administered every 48 hrs rather than on a M/W/F schedule.This study was funded by Jazz Pharmaceuticals plc. Disclosures:Off Label Use: ERWINAZE (asparaginase Erwinia chrysanthemi) is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL)who have developed hypersensitivity to E. coli-derived asparaginase. The recommended dose is 25,000 International Units/m2 administered intramuscularly three times a week (Monday/Wednesday/Friday) for six doses for each planned dose of pegaspargase. Hijiya:Jazz Pharmaceuticals: Consultancy. Brown:Jazz Pharmaceuticals: advisory board Other. Drachtman:Jazz Pharmaceuticals: Honoraria. Messinger:Jazz Pharmaceuticals: Advisory Board Other. Plourde:Jazz Pharmaqceuticals: Employee of Jazz Pharmaceuticals, Inc, who in the course of this emplyment has received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc Other, Employment. Silverman:Enzon Pharmaceuticals: Consultancy; Sigma Tau Pharmaceuticals: Advisory Board, Advisory Board Other; EUSA Pharma: Advisory Board Other.

Results Of The DFCI ALL Consortium Protocol 05-001 For Children and Adolescents With Newly Diagnosed ALL

Current treatment regimens for childhood ALL have resulted in long-term event-free survival (EFS) of approximately 80%. On DFCI ALL Consortium Protocol 05-001, patients (pts) with newly diagnosed ALL aged 1-18 years (yrs) who achieved complete remission (CR) were eligible to participate in a randomized comparison of native E.coli asparaginase (ASP) given intramuscularly (IM) and PEG ASP, the polyethylene glycol conjugate of E.coli ASP, given intravenously (IV). The objective was to compare the serum ASP activity (SAA), toxicity, and EFS of the two ASP preparations. An intensified consolidation regimen for VHR pts, including B-ALL pts with high end-induction minimal residual disease (MRD), was also evaluated. MethodsAll pts received 1 dose of PEG ASP (2500 IU/m2) during the 4-week (wk) multiagent induction phase. After CR was achieved, final risk group was assigned based on age, presenting WBC, CNS status, cytogenetics and end-induction MRD (assessed by PCR). All T-ALL pts were considered HR. Pts were considered VHR if they met one of the following criteria: i) B-ALL with high end-induction MRD; or ii) adverse cytogenetics (MLL gene rearrangement or hypodiploidy). BCR-ABL positive pts began daily imatinib at Day 18 and were allocated to allogeneic transplant in 1st CR. Beginning at wk 7, pts began the consolidation phase including 30 wks of ASP, either IM E.coli ASP 25000 IU/m2 weekly or IV PEG 2500 IU/m2 every 2 wks. In addition, SR pts received every 3-wk cycles with vincristine, dexamethasone, 6MP and low-dose methotrexate (mtx) during consolidation; HR pts received doxorubicin (cumulative dose 300 mg/m2) with dexrazoxane instead of mtx during this phase. VHR pts received 2 additional cycles beginning at week 7 (cyclophosphamide/low-dose araC/6-MP and then high-dose araC/etoposide/dexamethasone), followed by the HR consolidation phase. Continuation phase was identical for all pts. Total duration of therapy was 25 months. Serum samples were obtained every 6 wks just prior to an ASP dose to measure SAA. EFS rates were calculated from date of registration, except for EFS by randomized arm, risk group, and end-induction MRD, which were calculated from time of randomization. ResultsBetween 2005-2010, 551 evaluable pts enrolled, of whom 526 (95%) achieved CR. 463 pts participated in the ASP randomization. Median nadir SAA was significantly higher with IV PEG than with IM E.coli ASP,(Table 1) with more IV PEG-randomized pts achieving nadir SAA ≥ 0.1 IU/mL (p<0.01 at each time point). There was no significant difference in ASP-related allergy (p=0.36) and pancreatitis (p=0.54) between the two arms, and a trend toward more thrombotic events with E.coli ASP (p=0.07). With 4.5 yrs median follow-up, the 4-yr EFS for all 551 pts was 86% [95% CI 82-88%]. Outcome by pt characteristics are displayed in Table 2. The 4-yr EFS for B-ALL pts with high end-induction MRD was 77% [95% CI 60-88%]. There was no difference in EFS between the randomized arms (p=0.31).Table 1ASP-related Toxicity and Nadir Serum ASP activity (NSAA) during ConsolidationIM E.coli (N=231)IV PEG (N=232)p-valueAllergy9%12%0.36Pancreatitis9%11%0.54Thrombosis11%6%0.07Median NSAA (wk 11 of Consolidation)0.096 IU/mL0.758 IU/mL<0.01% pts with NSAA ≥ 0.1 IU/mL (wk 11 of Consolidation)46%99%<0.01Table 2Outcome by Patient CharacteristicsN4-yr EFSp-valueAll eligible pts55186%Risk GroupSR26894%<0.01HR19087%VHR5279%Age1-10 yrs39888%0.06≥10 yrs15380%PhenotypeB-precursor48285%0.58T-ALL6988%End-Induction MRD (B-ALL only)Low (<0.001)33891%0.03High (≥0.001)4077%CytogeneticsNormal13187%0.92High Hyperdiploid (HeH)14589%0.14HeH with trisomies 4 + 108895%0.07TEL/AML19798%<0.01Hypodiploid (<45)888%0.91MLL-R1060%<0.01BCR-ABL1669%0.01ASP RandomizationE.coli ASP23190%0.31PEG23292% ConclusionOverall EFS on Protocol 05001 compares favorably with previously published outcomes for pediatric ALL. Intensified consolidation improved outcome for B-ALL pts with high end-induction MRD. Relatively favorable outcomes were also observed in other high-risk pt subsets, including older children/adolescents and pts with T-ALL. We have demonstrated that IV PEG is as effective as and no more toxic than weekly IM E.coli ASP in children and adolescents with ALL. Disclosures:Silverman:Sigma Tau Pharmaceuticals: Consultancy. Andrew:Sigma Tau Pharmaceuticals: Consultancy. Neuberg:Synta Pharmaceuticals: Trust owns stock; I am a Trustee Other. Sallan:Sigma Tau Pharmaceuticals: Consultancy.

Erwinia asparaginase achieves therapeutic activity after pegaspargase allergy: a report from the Children's Oncology Group

AbstractAALL07P2 evaluated whether substitution of Erwinia asparaginase 25 000 IU/m2 for 6 doses given intramuscularly Monday/Wednesday/Friday (M/W/F) to children and young adults with acute lymphoblastic leukemia and clinical allergy to pegaspargase would provide a 48-hour nadir serum asparaginase activity (NSAA) ≥0.10 IU/mL. AALL07P2 enrolled 55 eligible/evaluable patients. NSAA ≥0.1 IU/mL was achieved in 38 of 41 patients (92.7%) with acceptable samples 48 hours and in 38 of 43 patients (88.4%) 72 hours after dosing during course 1. Among samples obtained during all courses, 95.8% (252 of 263) of 48-hour samples and 84.5% (125 of 148) of 72-hour samples had NSAA ≥0.10-IU/mL. Pharmacokinetic parameters were estimated by fitting the serum asparaginase activity-time course for all 6 doses given during course 1 to a 1-compartment open model with first order absorption. Erwinia asparaginase administered with this schedule achieved therapeutic NSAA at both 48 and 72 hours and was well tolerated with no reports of hemorrhage, thrombosis, or death, and few cases of grade 2 to 3 allergic reaction (n = 6), grade 1 to 3 hyperglycemia (n = 6), or grade 1 pancreatitis (n = 1). Following allergy to pegaspargase, Erwinia asparaginase 25 000 IU/m2 × 6 intramuscularly M/W/F can be substituted for a single dose of pegaspargase.

Postinduction Dexamethasone and Individualized Dosing of Escherichia Coli L-Asparaginase Each Improve Outcome of Children and Adolescents With Newly Diagnosed Acute Lymphoblastic Leukemia: Results From a Randomized Study—Dana-Farber Cancer Institute ALL Consortium Protocol 00-01

We assessed the toxicity and efficacy of dexamethasone and a novel dosing method of Escherichia coli L-asparaginase (EC-Asnase) in children and adolescents with newly diagnosed acute lymphoblastic leukemia (ALL). Patients achieving complete remission (CR) on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 were eligible for random assignment to 1) dexamethasone or prednisone, administered as 5-day pulses, every 3 weeks, and 2) weekly EC-Asnase, administered as a 25,000 IU/m(2) fixed dose (FD) or individualized dose (ID) starting at 12,500-IU/m(2), adjusted every 3 weeks based on nadir serum asparaginase activity (NSAA) determinations. Between 2000 and 2004, 492 evaluable patients (ages 1 to 18 years) enrolled; 473 patients (96%) achieved CR. Four hundred eight patients (86%) participated in the corticosteroid randomization and 384 patients (81%) in the EC-Asnase randomization. With 4.9 years of median follow-up, dexamethasone was associated with superior 5-year event-free survival (EFS; 90% v 81% for prednisone; P = .01) but higher rates of infection (P = .03) and, in older children, higher cumulative incidence of osteonecrosis (P = .02) and fracture (P = .06). ID EC-Asnase had superior 5-year EFS (90% v 82% for FD; P = .04), but did not reduce the frequency of asparaginase-related toxicity. Multivariable analysis identified both dexamethasone and ID EC-Asnase as independent predictors of favorable EFS. There was no overall difference in skeletal toxicity by corticosteroid type; dexamethasone was associated with more infections and, in older children, increased incidence of osteonecrosis and fracture. There was no difference in asparaginase-related toxicity by EC-Asnase dosing method. Dexamethasone and ID EC-Asnase were each associated with superior EFS. Monitoring NSAA during treatment with EC-Asnase may be an effective strategy to improve outcome in pediatric ALL.

Administration of Erwinia Asparaginase (Erwinase®) Following Allergy to PEG-Asparaginase In Children and Young Adults with Acute Lymphoblastic Leukemia Treated on AALL07P2 Achieves Therapeutic Nadir Serum Asparaginase Activity: A Report From the Children's Oncology Group (COG)

AbstractAbstract 2134 Introduction:L-asparaginase is a vital component of multi-agent chemotherapy for children and young adults with acute lymphoblastic leukemia (ALL). In the United States, there are 2 asparaginase preparations approved by the Food and Drug Administration, native E. coli (Elspar®) and PEG-asparaginase (Oncaspar®). PEG-asparaginase is the most commonly utilized asparaginase product due to its longer half-life and decreased immunogenicity. However, the incidence of clinical allergy to PEG-asparaginase approaches 20%, with repeated administration. Due to cross reactivity with native E. coli asparaginase, there is no FDA-approved preparation available for patients who develop clinical allergy to PEG-asparaginase. A third preparation, Erwinia asparaginase (Erwinase®), derived from Erwinia chrysanthemi, is not commercially available in the United States. The optimal dosing of Erwinase® necessary to obtain nadir asparaginase activity > 0.1 IU/mL similar to that obtained after conventional dosing of PEG-asparaginase is unknown. Patients and Methods:We hypothesized that substitution of Erwinase® 25,000 IU/m2 × 6 doses intramuscularly (IM) on a Monday/Wednesday/Friday schedule in children and young adults with ALL would provide a 48 hour nadir serum asparaginase activity ≥ 0.1 IU/mL, and effectively deplete plasma asparagine, a surrogate marker of asparaginase activity. Eligible patients on COG study AALL07P2 were >1 to <30 years of age, concurrently enrolled on a frontline COG ALL treatment study, and had documented ≥ grade 2 allergy (NCI Common Terminology Criteria 3.0) to PEG-asparaginase. Results:A total of 55 eligible/evaluable patients were enrolled from February 2008 to April 2010. Blood samples were obtained at scheduled time points during Erwinase® therapy and assayed for serum asparaginase activity and asparagine concentration in plasma. Nadir serum asparaginase activity ≥ 0.1 IU/mL was achieved in 49/53 patients (92.5%) at 48 hours after dosing and in 46/52 patients (88.5%) at 72 hours after dosing. Plasma asparagine was significantly depleted (<1.0 μM) in all 49 patients for whom samples were satisfactorily obtained. Grade 2–3 allergic reaction and grade 1–2 hyperglycemia related to Erwinase® were reported in 5 and 3 patients, respectively. There were no reports of hemorrhage, thrombosis, pancreatitis, or death. Conclusion:Erwinase® as administered using the AALL07P2 regimen was well tolerated and achieved nadir serum asparaginase activity at both 48 and 72 hours after dosing that was similar to that achieved with PEG-asparaginase. We conclude that following allergy to PEG-asparaginase, Erwinase® 25,000 IU/m2 × 6 doses IM on a Monday/Wednesday/Friday schedule can be substituted for a single dose of PEG-asparaginase. Disclosures:Supko: EUSA Pharma: Research Funding. Plourde: EUSA Pharma: Employment. Winick: EUSA Pharma: EUSA Advisory Board.

Dexamethasone and Individualized Asparaginase Dosing Are Each Associated with Superior Event-Free Survival in Childhood Acute Lymphoblastic Leukemia: Results From DFCI-ALL Consortium Protocol 00-01.

Abstract 321 BACKGROUND:The DFCI-ALL Consortium Protocol 00-01 aimed to determine the relative efficacy and toxicity of 1) dexamethasone (DEX) vs. prednisone (PRED) and 2) asparaginase (ASP) with individualized dosing (ID) based on pharmacokinetic measurements vs. standard fixed dosing (FD) based on body surface area, in the treatment of children with newly diagnosed acute lymphoblastic leukemia (ALL). PATIENTS and METHODS:Between 2000 and 2004, 492 eligible patients (pts) ages 1-18 years (yrs) with newly diagnosed ALL enrolled on Protocol 00-01 from 10 institutions. 282 pts were standard risk (SR) and 210 high risk (HR). Post-induction treatment for all patients included 30 weeks of intramuscular E. coli ASP (beginning at week 7) and vincristine/corticosteroid pulses every 3 weeks for 24 months. Pts who achieved complete remission (CR) were eligible for two randomized comparisons: 1) Steroids: Pts were randomized to receive either DEX or PRED given as 5-day pulses every 3-weeks, and 2) ASP: Pts were randomized to receive either FD (25,000IU/m2) or ID (starting dose 12,500 IU/m2) for 30 weeks. Nadir serum ASP activity (NSAA) was assessed every 3 weeks, and ASP doses on the ID arm were adjusted to maintain NSAA between 0.10-0.14 IU/mL. NSAA was assayed centrally by a validated biochemical assay. RESULTS:473 pts (96%) achieved CR. With a median follow-up of 4.9 years, the 5-year event-free survival (EFS) ± standard error for all 492 pts was 80 ± 2% and overall survival (OS) was 91 ± 1%. Steroid randomization:408/473 pts (86%) participated in the steroid randomization (DEX: 201, PRED: 207). Pts randomized to DEX had 5-yr EFS of 90 ± 2% compared with 81 ± 3% for PRED (p=0.01) [Table I]. For pts 10-18 yrs of age, there was a significant increase in the rate of osteonecrosis (ON) with DEX, with 5-yr cumulative incidence (CI) of 23% compared with 4.7% for PRED (p=0.02). There was no difference in the 5-yr CI of ON based on steroid type in pts 1-10 yrs of age (DEX: 2.6% vs. PRED: 4.3%, p=0.43). Fractures were also more common in pts 10-18 yrs of age randomized to DEX (p=0.06), but not in younger pts (p=0.25). Infection (positive blood culture or radiographic evidence of invasive fungal disease) developed in 38 pts (18.8%) randomized to DEX compared with 22 pts (10.6%) randomized to PRED (p=0.03). There was no difference in remission death rate based on steroid randomization (DEX 0% vs. PRED 2%, p=0.5).Table I:5-year EFS by Randomized ArmSteroidASPDEX (N)PRED (N)ID ASP (N)FD ASP (N)Overall90 ± 2% (201)81 ± 3% (207)90 ± 2% (189)82 ± 3% (195)SR89 ± 3% (114)84 ± 4% (121)89 ± 3% (115)86 ± 4% (110)HR91 ± 4% (87)78 ± 5% (86)93 ± 3% (74)78 ± 5% (85)1-10 yrs91 ± 3% (153)82 ± 3% (164)90 ± 3% (147)85 ± 3% (151)10-18 yrs88 ± 5% (48)77 ± 6% (43)90 ± 5% (42)72 ± 7% (44) ASP randomization:384/473 pts (81%) participated in the ASP randomization (FD: 195, ID: 189). Pts randomized to ID had superior EFS with 5-yr EFS of 90 ± 2% compared with 82 ± 3% for FD (p=0.04) [Table I]. There was no difference between the two arms in the frequency of ASP-related allergy (p=0.46), pancreatitis (p=0.66) or thrombosis (p=0.77). There was also no difference by treatment arm in the proportion of pts able to complete at least 25 weeks of ASP (FD: 88% vs. ID: 87%, p=0.76). There was no difference between the two arms in the proportion of pts with non-detectable NSAA, although fewer pts on the ID arm had high NSAA (>0.14 IU/mL). On multivariable analysis, both DEX and ID ASP were independent predictors of favorable outcome (hazard ratio 0.49 for DEX, p=0.02; hazard ratio 0.52 for ID, p=0.04), with no indication of an interaction. Only 5/92 (5%) pts randomized to both DEX and ID ASP experienced an event. CONCLUSIONS:DEX was associated with superior EFS, but also more bone and infectious toxicities, especially in older children/adolescents. Future studies should focus on minimizing DEX toxicity in older pediatric pts without compromising efficacy. ID of ASP was feasible and was associated with superior EFS. The improved EFS with ID was not due to a reduction in ASP-related toxicity or improved tolerability, but was associated with a reduction in the proportion of pts with high NSAA. Disclosures:Supko:Enzon Inc.: Research Funding. Sallan:Enzon Inc.: Research Funding; Enzon Inc.: Contributed to support of an investigator meeting.

Erwinia asparaginase after allergy to E. coli asparaginase in children with acute lymphoblastic leukemia

Escherichia coli asparaginase is an important component of treatment for childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity develops in up to 30% of patients. We assessed the nadir enzyme activity and tolerability of Erwinia asparaginase, an alternative preparation, in E. coli asparaginase-allergic patients. Between 2000 and 2002, 215 children with newly diagnosed ALL were enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 00-01 and were to receive 30 weekly doses of intramuscular E. coli asparaginase. If E. coli asparaginase allergy developed, patients were switched to twice-weekly intramuscular Erwinia asparaginase (25,000 IU/m(2)). Nadir serum asparaginase activity (NSAA) was measured every 3 weeks. Forty-two patients (20%) developed E. coli asparaginase allergy and switched to Erwinia. Of 38 patients with evaluable samples, 34 (89%) Erwinia-treated patients had at least one therapeutic NSAA (> or =0.1 IU/ml). The median NSAA was 0.247 IU/ml 3 days and 0.077 IU/ml 4 days after an Erwinia dose. Associated toxicities included allergy in 14 (33%) and pancreatitis in 3 patients (7%). At a median follow-up of 5.4 years, event-free survival (+/-standard error) of the 42 patients who switched to Erwinia was 86 +/- 5% compared with 81 +/- 3% for the 170 patients without E. coli asparaginase allergy (P = 0.55). Twice-weekly Erwinia asparaginase was well tolerated and achieved a therapeutically effective NSAA in most E. coli asparaginase-allergic patients. Development of E. coli allergy and subsequent treatment with twice-weekly Erwinia did not adversely impact event-free survival. Erwinia asparaginase should be considered for E. coli asparaginase-allergic patients.