Abstract
Pegaspargase, a well-established pediatric acute lymphoblastic leukemia (ALL) therapy, is available as a liquid formulation, and a lyophilized formulation with an improved shelf life. The pharmacokinetics and safety of lyophilized and liquid pegaspargase were assessed in pediatric patients with ALL in Russia. In Study 1, patients were randomly assigned (1:1) to receive 1 intravenous injection of lyophilized or liquid pegaspargase; patients who benefited from pegaspargase continued into Study 2 and received lyophilized pegaspargase every 2 weeks for 9 infusions. Of the 89 patients in Study 1, 74 continued into Study 2. In Study 1, maximum observed plasma asparaginase activity and area under the PAA-time curve were similar between groups. Geometric mean ratios were 93.5% (90% confidence interval [CI]: 82.9, 105.5) and 102.8% (90% CI: 91.4, 115.6), respectively; therefore, the 90% CIs were completely contained within the predefined acceptance interval of 80% to 125%. Pegaspargase-related adverse events occurred in 88.4% and 91.1% in the lyophilized and liquid groups, respectively, in Study 1. The safety profile of lyophilized pegaspargase after repeated infusion in Study 2 was consistent with the known safety profile of pegaspargase. Pharmacokinetic exposure does not depend on pegaspargase formulation. These studies support the use of lyophilized pegaspargase.
Key Words: acute lymphoblastic leukemia, lyophilized pegaspargase, pharmacokinetic, pediatric
Acute lymphoblastic leukemia (ALL) is the most frequent acute leukemia in childhood, accounting for 75% of acute leukemias and 25% of all childhood cancers.1,2 Approximately 1000 children are newly diagnosed with ALL each year in Russia.3 The treatment of ALL includes long-term use of multi-agent chemotherapy, of which asparaginase is a cornerstone component.4,5
Escherichia coli (E. coli) L-asparaginase has been used as treatment for ALL since the 1970s, but must be administered frequently (ie, 3 times weekly) because of its short elimination half-life.6 Pegaspargase (Oncaspar®, S95014, Servier, Suresnes, France) is a pegylated formulation of E. coli L-asparaginase with a longer half-life, which is an effective and well-established therapy for ALL in adults4 and in children.7,8 Pegaspargase was initially developed as a liquid formulation (LIQ), but subsequently, a lyophilized formulation (LYO) was developed to improve the stability (shelf life of 36 versus 8 mo for the LYO versus LIQ formulations, respectively) and ensure continuous drug availability.9 The LYO formulation of pegaspargase is approved in >45 countries, and is the only pegaspargase formulation approved in Russia. LYO pegaspargase is part of the standard of care treatment of ALL worldwide, including in Europe.4
A recently published study of Japanese patients with ALL receiving the LYO formulation of pegaspargase assessed efficacy, safety, and pharmacokinetics (PK), and showed that a plasma asparaginase activity (PAA) was above the threshold to achieve sustained asparagine depletion within 5 minutes of the first dose and was maintained for 14 days in all evaluable patients.10 However, as the study of Japanese patients with ALL was a single-arm study, outcomes with the LYO and LIQ formulations of pegaspargase were not compared. Here we present the results from 2 studies conducted in Russia. The aim of the first study (EudraCT No. 2020-004894-29; hereinafter referred to as Study 1) was to assess the PK of the LYO versus the LIQ formulation of pegaspargase during the induction phase in pediatric patients in Russia newly diagnosed with ALL. A rollover study (EudraCT No. 2020-004895-17; hereinafter referred to as Study 2) was then conducted to provide continued access to LYO pegaspargase for patients who were clinically benefiting from pegaspargase without major toxicity. The aim of Study 2 was to assess the safety profile of LYO pegaspargase.
MATERIALS AND METHODS
Study Design
Study 1 was a multicenter, parallel-group, randomized, open-label, phase II clinical study conducted in 7 centers in Russia to compare the PK of LYO and LIQ formulations of pegaspargase. Study 2 was a multicenter, nonrandomized rollover study of LYO pegaspargase conducted at the same centers to continue to provide treatment to those patients in Study 1 who were clinically benefiting from treatment with the LYO or LIQ formulations of pegaspargase.
Study 1 consisted of a screening period (up to 14 d), followed by randomization (1:1) to either LYO pegaspargase or LIQ pegaspargase administered once intravenously (IV) on Day 3 of the induction phase. Patients were assessed until the end of the induction phase (∼30 d after study treatment administration). Study 1 was conducted between May 2021 and May 2022. At the end of Study 1, patients who met the relevant inclusion criteria (see below) entered Study 2 and received LYO pegaspargase every 2 weeks for a total of 9 infusions during this consolidation phase.
Other standard chemotherapy agents, as per the Childhood Acute Lymphoblastic Leukaemia Treatment Protocol Moscow-Berlin 2015 (ALL-MB 2015) and local practice, were continued throughout both studies.
Both studies were performed in accordance with the ethical principles stated in the Declaration of Helsinki (1964), as revised in Fortaleza (2013), and adhered to good clinical practice (GCP) and the applicable regulatory requirements. Written consent was obtained from each patient when of appropriate intellectual maturity, as well as from the patient's parent(s) or legal representative.
Patients
Male and female patients aged 1 year or older to younger than 18 years, with cytologically confirmed and documented newly diagnosed ALL according to NCCN guidelines 2020,5 were included in Study 1. Other key inclusion criteria were: Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2; and female patients of childbearing potential had to be using effective birth control. Key exclusion criteria were: unlikeliness to cooperate in the study; pregnancy and lactating women; participation in another interventional study at the time of the screening visit; previous chemotherapy or radiotherapy (except steroids and intrathecal therapy), previous surgery or bone marrow transplant related to ALL; Down syndrome; mature B-cell ALL (eg, Burkitt ALL); carrier of HIV antibodies; previous or concurrent malignancy; sensitivity to polyethylene glycol (PEG) or PEG-based drugs; pre-existing coagulopathy; history of pancreatitis or significant liver disease; significant laboratory abnormalities; inadequate hepatic function (total bilirubin >1.5 times upper limit of normal [ULN], transaminases >5x ULN); inadequate renal function (serum creatinine >1.5x ULN); a currently active infection or poorly-controlled concurrent illness; or any illness or situation that may limit adherence to the study requirements.
Patients who completed Study 1 and were receiving clinical benefit from pegaspargase, according to the treating-physician’s judgment, had no major safety issue as a result of pegaspargase administration, and were not part of Group “E” (patients with B-cell precursor ALL who fail to achieve a complete response within 36 d of induction therapy initiation) and “T-HR” patients (patients with T-cell ALL who have a blast count of ≥30% within 15 d of induction therapy initiation, are CD1a-positive, or fail to achieve a complete response within 36 d of induction therapy initiation) according to ALL-MB 2015 classification, were included in Study 2.
Interventions
In Study 1, LYO or LIQ pegaspargase dosage was 2500 U/m2, per protocol, and was calculated based on body surface area (BSA). A single dose was administered on Day 3 of the induction phase, via a 1-hour IV infusion. Patients were allocated LYO or LIQ pegaspargase via interactive response system, using a central randomization (1:1). In Study 2, all patients received LYO pegaspargase and dosage was calculated based on BSA and could be 1000 (the standard dose used in local practice, and typically used in the ALL-MB 2015 protocol), 2000 (an intermediate dose used in addition to the protocol) or 2500 U/m2 (per protocol and as used in Study 1) at the investigator’s discretion. Doses were administered every 2 weeks during this consolidation phase at 7, 9, 11, 15, 17, 19, 23, 25, and 27 weeks after inclusion into Study 1.
Assessments
In Study 1, plasma samples for PK analysis were collected at each visit as follows: predose (Day 3), at the end of infusion (Day 3), and 4 (Day 3), 24 (Day 4), 48 (Day 5), 120 (Day 8), 168 (Day 10), 216 (Day 12), 336 (Day 17), 432 (Day 21), and 600 hours (Day 28) after the end of the infusion. During Study 1, the immunogenicity assessment included the detection of binding antibodies against pegaspargase and antibodies against PEG in samples collected predose on Day 3 and on Days 17 and 28. Information on concomitant treatment was collected at all visits in Study 1, and laboratory assessments (including blood hematology, blood biochemistry, blood coagulation, and urine biochemistry) were performed at screening, predose on Day 3, and on Days 10, 17, and 24.
In Study 2, at each visit when pegaspargase was administered, patients were assessed for adverse events (AEs), laboratory variables, by physical examination, vital signs, and had electrocardiogram (ECG) measurements at inclusion and withdrawal visits.
Study Endpoints
The primary endpoint of Study 1 was to compare the maximum observed PAA (Cmax) and area under the PAA-time curve (AUC) of LYO and LIQ pegaspargase during the induction phase. Secondary endpoints of Study 1 included additional PK parameters of: lowest observed PAA 14 days postdose (Cday14); time to reach the maximum PAA (Tmax); time to last observed PAA (Tlast); terminal half-life (T1/2); last observed PAA (Clast); achievement of PAA levels of ≥100 mU/ml on Days 10, 17, 21, and 28 (ie, 7, 14, 18, and 25 d postdose); and anti-pegaspargase ± anti-PEG antibodies at predose, Days 17 and 28 (ie, 14 and 25 d postdose). In Study 1, other endpoints included assessment of the safety and tolerability of pegaspargase: treatment-emergent AEs (TEAEs) classified according to Medical Dictionary for Regulatory Activities (MedDRA) coding, and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0; serious AEs (SAEs); AEs of special interest (AESI) including grade ≥3 alanine aminotransferase (ALT)/aspartate aminotransferase (AST) increase/hyperbilirubinemia/hemorrhage/thromboembolic event/pancreatitis or hypersensitivity/drug hypersensitivity; ECOG PS; laboratory assessments including hematology, blood biochemistry, urinalysis, and coagulation variables; vital signs; and ECG measurements.
The main endpoint of Study 2 was to assess the safety profile of LYO pegaspargase during longer-term use in the consolidation phase.
Statistical Analysis
In Study 1, PK analyses were performed on the Pharmacokinetic Analysis Set (PKAS; defined as all patients who completed the treatment period without deviations that affected PK interpretation). A noncompartmental PK analysis was performed on the individual plasma concentration-time profiles of PAA, using the actual administration and sampling times. A statistical analysis was used to compare the primary endpoints using an analysis of variance (ANOVA) model on the natural logarithm-transformed PK parameters (Cmax, AUCinf, and AUC0-Tlast) for the LYO formulation (test) versus the LIQ formulation (reference) using the PKAS. The 2 one-sided test procedures were performed on the geometric mean ratio (GMR) between test (LYO) and reference (LIQ) treatments. The 90% confidence interval (CI) was obtained by exponentiating the upper and lower 90% confidence limits for the difference in logarithm means. PK comparability was concluded if the 90% CI for AUC and Cmax GMR were within the predefined acceptance interval (80%, 125%). An additional comparison was performed on Cday14 for informational purposes.
Descriptive statistics of the PK parameters were summarized by treatment (arithmetic mean, standard deviation [SD], geometric mean [GM], geometric coefficient of variation [CV], median, minimum, and maximum). Additional summaries of PK parameters were presented by baseline anti-pegaspargase antibody status (positive or negative). Individual and mean PK parameters were presented. Descriptive statistics of PAA (eg, number of patients, arithmetic mean, GM, percentage coefficient of variation [%CV], SD, minimum, median, and maximum) were also calculated and tabulated for each sampling time. Plasma concentrations over time were plotted in semilogarithmic and linear formats as mean (SD) and as median (Q1, Q3).
The safety analyses were conducted on the safety analysis set population (SAS; all patients who received at least 1 dose of pegaspargase), with patients in Study 1 categorized in each treatment group according to the treatment they received.
It was estimated that a sample of 78 evaluable patients would provide 90% power to establish PK comparability, assuming a coefficient of variation of 0.30 and a true GMR of 100%.
RESULTS
Patient Population
Eighty-nine patients were included in Study 1 (44 randomly assigned to pegaspargase LYO and 45 randomly assigned to pegaspargase LIQ). Of these, 85 (95.5%) patients completed treatment (4 patients withdrew in the LIQ group), and 74 patients went on to participate in Study 2. Reasons for not completing Study 1 were: death of 2 patients; 1 patient was initially included despite having B-cell Burkitt ALL (an exclusion criterion); and 1 patient had an allergic reaction, and the treating physician took the decision to withdraw them from the study. The patient with B-cell Burkitt ALL was excluded from the SAS, which therefore included 88 patients; 1 patient randomized to the LYO group received pegaspargase LIQ and was therefore analyzed as part of the LIQ group. The PKAS consisted of 81 patients: from the SAS, 7 patients were excluded, 5 for protocol deviations that compromised the interpretation of the primary PK endpoint, 1 patient randomized to the LYO group received an expired LIQ formulation, and 1 patient had a fatal outcome, thus missing PK samples. In Study 2, 52/74 patients completed the study; 22 patients were prematurely withdrawn: 18 (24.3%) due to an AE, and 4 (5.4%) due to the investigator’s decision.
In Study 1, mean (SD) total exposure was 2452 U (1048.7) in the LYO group and 2122 U (737.2) in the LIQ group. When expressed per BSA, all patients received the per-protocol dose of 2500 U/m² (ie, relative dose intensity [RDI] of 1.0), except for 1 patient in the LYO group who had an RDI of 1.028 (corresponding to a dose of 2569 U/m²).
Baseline characteristics for the SAS populations in Study 1 and Study 2 are summarized in Table 1. There were no clinically relevant differences in disease characteristics between Study 1 treatment groups at baseline. Ten (11.6%) patients were positive for anti-pegaspargase antibodies at baseline (5 patients in each group). Of these 10 patients, 6 were also positive for anti-PEG antibodies at baseline (2 patients in the LYO group and 4 in the LIQ group). All 88 patients received ≥1 concomitant treatment during Study 1 (excluding the backbone therapy, as defined in ALL-MB 2015). The most frequent concomitant treatments were: antibacterials for systemic use, blood substitutes and perfusion solutions, antigout preparations (allopurinol), drugs for acid-related disorders, and antiemetics and antinauseants. During Study 2, 73 patients (98.6%) received ≥1 concomitant treatment, most frequently antiemetics and antinauseants, antibacterials for systemic use, and blood substitutes and perfusion solutions. Although patients in Study 2 could receive 3 possible doses, all patients received 1000 U/m2, the standard dose used in Russia in accordance with ALL-MB 2015. Patients included in Study 2 received a mean (SD) of 7 (3.23) doses of pegaspargase LYO over a mean (SD) of 5 (2.59) months at a mean (SD) relative dose intensity of 0.7 (0.2).
TABLE 1.
Baseline Patient Characteristics (SAS) for Study 1 and Study 2
| Pegaspargase LYO*Study 1 (N=43) | Pegaspargase LIQ*Study 1 (N=45) | Overall Study 1 (N=88) | Pegaspargase LYOStudy 2 (N=74) | |
|---|---|---|---|---|
| Median (minimum-maximum) age, y | 5.0 (1-17) | 4.0 (1-17) | 5.0 (1-17) | 5.0 (2-18) |
| Sex, n (%) | ||||
| Female | 17 (39.5) | 25 (55.6) | 42 (47.7) | 36 (48.6) |
| Male | 26 (60.5) | 20 (44.4) | 46 (52.3) | 38 (51.4) |
| Race, n (%) | ||||
| White | 40 (93.0) | 44 (97.8) | 84 (95.5) | 71 (95.9) |
| Asian | 2 (4.7) | 0 | 2 (2.3) | 2 (2.7) |
| Multiple | 1 (2.3) | 0 | 1 (1.1) | 1 (1.4) |
| Other | 0 | 1 (2.2) | 1 (1.1) | 0 |
| ECOG performance status, n (%) | ||||
| 0 | 9 (20.9) | 7 (15.6) | 16 (18.2) | 14 (18.9) |
| 1 | 24 (55.8) | 31 (68.9) | 55 (62.5) | 46 (62.2) |
| 2 | 10 (23.3) | 7 (15.6) | 17 (19.3) | 14 (18.9) |
| Median (minimum-maximum) BMI, kg/m2 | 15.6 (13.0-31.5) | 15.7 (10.9-28.4) | 15.7 (10.9-31.5) | 15.5 (10.9-31.5) |
| Median (minimum-maximum) BSA, m2 | 0.8 (0.5-2.3) | 0.7 (0.5-1.7) | 0.8 (0.5-2.3) | 0.8 (0.5-2.3) |
| ALL subtype, n (%) | ||||
| B-cell | 40 (93.0) | 42 (93.3) | 82 (93.2) | N/A |
| T-cell | 3 (7.0) | 3 (6.7) | 6 (6.8) | |
One patient randomized to the LIQ group was wrongly included (B-cell Burkitt ALL) and did not receive pegaspargase, so was excluded from the safety analysis set; 1 patient randomized to the LYO group received pegaspargase LIQ and was therefore analyzed as part of the LIQ group.
ALL indicates acute lymphoblastic leukemia; ECOG, Eastern Cooperative Oncology Group; BMI, body mass index; BSA, body surface area; LIQ, liquid; LYO, lyophilizate.
Pharmacokinetics (Study 1)
No differences were observed in PAA peak (Cmax) and total PAA exposure (AUCinf) between the LYO and LIQ formulations: GMRs were 93.5% (90% confidence interval [CI]: 82.9, 105.5) and 102.8% (90% CI: 91.4, 115.6), respectively, and therefore the 90% CIs were completely contained within the predefined acceptance interval of 80% to 125% (shown in Fig. 1 and Table 2).
FIGURE 1.
Geometric Mean for Plasma Asparaginase Activity (PAA) Level at 11 Nominal Time Points in Study 1*.*Pharmacokinetic Analysis Set, n=81. LLOQ Indicates Lower Limit of Quantification; PAA, Plasma Asparaginase Activity.
TABLE 2.
Summary of Pharmacokinetic Characteristics (PKAS) in Study 1
| Parameters | Pegaspargase LYO (N=41) | Pegaspargase LIQ (N=40) |
|---|---|---|
| Cmax (mU/ml) | ||
| GM | 1563.1 | 1672.1 |
| GMR, % (90% CI) | 93.5 (82.9, 105.5) | |
| AUCinf (mU×d/ml) | ||
| GM | 362,028.7 | 352,249.0* |
| GMR, % (90% CI) | 102.8 (91.4, 115.6) | |
| AUC0-Tlast (mU/ml) | ||
| GM | 341,906.0 | 295,025.2 |
| GMR, % (90% CI) | 115.9 (90.2, 148.9) | |
| Cday14 (mU×d/ml) | ||
| GM | 496.6 | 408.7* |
| GMR, % (90% CI) | 121.5 (98.7, 149.6) | |
| Clast (mU/ml) | ||
| Median (minimum-maximum) | 100.0 (19.6-427.0) | 73.2 (13.1-374.5) |
| GM | 89.4 | 65.6 |
| Tlast (h) | ||
| Median (minimum-maximum) | 600.5 (430.0-605.7) | 600.5 (24.9-605.9)* |
| GM | 586.3 | 530.1 |
| T1/2 (h) | ||
| Median (minimum-maximum) | 113.4 (65.45-202.5) | 100.3 (26.3-200.8)* |
| GM | 114.6 | 100.0 |
AUCinf, Cday14, Tlast , and T1/2 could not be calculated for 1 patient in the LIQ group, who had only 3 positive measurements above the LLOQ.
AUCinf indicates area under the plasma concentration-time curve from time 0 to infinity; AUC0-Tlast, area under the plasma concentration-time curve from time 0 to the time of the last observed non-zero PAA; Cday14, lowest observed plasma concentration 14 days postdose; Clast, last observed PAA; CI, confidence interval; Cmax, maximum plasma concentration; GM, geometric mean; GMR, geometric mean ratio; LIQ, liquid; LYO, lyophilizate; PAA, plasma asparaginase activity; Tlast, time to last observed PAA; T1/2, terminal half-life.
Partial PAA exposure (AUC0-Tlast) and Day 14 PAA levels (Cday14) were higher, increases of 16% and 22%, respectively, following administration of the LYO formulation compared with the LIQ formulation. The upper GMR 90% CI was >125% and partially contained within the 80% to 125% interval (shown in Table 2). The difference between PAA total exposure (AUCinf) and partial exposure (AUC0-Tlast) can be attributed to a lower exposure observed in 3 patients receiving pegaspargase LIQ. For these 3 patients, the PAA levels dropped below the lower limit of quantitation (LLOQ) at earlier time points and therefore resulted in marginal change (reduction) in the AUC0-Tlast in the LIQ group (shown in Fig. 2). A post hoc sensitivity analysis that excluded these 3 patients showed that the AUC0-Tlast GMR of 99.9% (90% CI: 88.6, 112.6) is completely within the acceptance interval (80% to 125%; shown in Table 3).
FIGURE 2.
Individual Plasma Asparaginase Activity (PAA) Level Profiles Across Actual Sampling Time Points in Study 1*. *Pharmacokinetic Analysis Set, n=81. LLOQ Indicates Lower Limit of Quantification; PAA, Plasma Asparaginase Activity.
TABLE 3.
Pharmacokinetic Characteristics—Sensitivity Analysis (PKAS) From Study 1
| Parameters | Pegaspargase LYO (N=41) | Pegaspargase LIQ (N=37) |
|---|---|---|
| Cmax (mU/ml), n | ||
| GM | 1563.1 | 1768.4* |
| GMR, % (90% CI) | 88.4 (81.0, 96.4) | |
| AUCinf (mU×d/ml), n | ||
| GM | 362,028.7 | 355,894.9* |
| GMR, % (90% CI) | 101.7 (90.2, 114.7) | |
| AUC0-Tlast (mU/ml), n | ||
| GM | 341,906.0 | 342,162.2* |
| GMR, % (90% CI) | 99.9 (88.6, 112.6) | |
| Cday14 (mU×d/ml), n | ||
| GM | 496.6 | 449.9* |
| GMR, % (90% CI) | 110.4 (94.9, 128.3) | |
The sensitivity analysis excluded 3 patients whose PAA dropped below the limit of quantitation unexpectedly early, potentially impacting the statistical analysis of AUC0-Tlast.
AUCinf indicates area under the plasma concentration-time curve from time 0 to infinity; AUC0-Tlast, area under the plasma concentration-time curve from time 0 to the time of the last observed non-zero PAA; Cday14, lowest observed plasma concentration 14 days postdose; CI, confidence interval; Cmax, maximum plasma concentration; GM, geometric mean; GMR, geometric mean ratio; LIQ, liquid; LYO, lyophilizate; PAA, plasma asparaginase activity.
Nearly all patients reached the PAA threshold level of ≥100 mU/ml and maintained this up to 18 days after infusion (shown in Fig. 2). At Day 10, 43/43 (100%) of patients in the LYO group, and 43/44 (97%) of patients in the LIQ group had PAA ≥100 mU/ml. At Day 17, 43/43 (100%) of patients in the LYO group, and 41/43 (95.3%) of patients in the LIQ group had PAA ≥100 mU/ml. At Day 21, 41/42 (97.6%) of patients in the LYO group, and 39/43 (90.7%) of patients in the LIQ group had PAA ≥100 mU/ml. At Day 28, 18/42 (42.9%) of patients in the LYO group, and 6/43 (14.0%) of patients in the LIQ group had PAA ≥100 mU/ml.
Other PK variables were similar between the pegaspargase LIQ and LYO groups (shown in Table 2).
Immunogenicity (Study 1)
Following treatment, 9 of 86 patients (10.5%) tested positive for anti-pegaspargase, including 5 in the LYO group (11.6%) and 4 in the LIQ group (9.3%). No impact on PK properties, safety, or efficacy was observed in patients with positive anti-pegaspargase.
Safety (Study 1)
All patients experienced ≥1 TEAE (shown in Table 4). Thirty-eight (88.4%) patients who received a single infusion of pegaspargase LYO had TEAEs considered related to pegaspargase, and 41 (91.1%) patients who received a single infusion of pegaspargase LIQ had TEAEs considered related to pegaspargase. TEAEs that were more frequent (≥3 patient difference) in the pegaspargase LIQ group than the pegaspargase LYO group were ALT increase, anemia, and thrombocytopenia (shown in Table 4). TEAEs occurring more frequently in the pegaspargase LYO group than the pegaspargase LIQ group were lymphocyte count decrease, white blood cell count decrease/leukopenia, and toxic neuropathy (shown in Table 4).
TABLE 4.
Treatment Emergent Adverse Events Occurring in ≥10 Patients in Study 1 and Study 2, n (%)
| Preferred term | Pegaspargase LYOStudy 1 (N=43) | Pegaspargase LIQStudy 1 (N=45) | Overall Study 1 (N=88) | Pegaspargase LYOStudy 2 (N=74) |
|---|---|---|---|---|
| Any TEAEs | 43 (100) | 45 (100) | 88 (100) | 74 (100) |
| Blood fibrinogen decreased* | 35 (81.4) | 38 (84.4) | 73 (83.0) | 48 (64.9) |
| Antithrombin III decreased | 32 (74.4) | 32 (71.1) | 64 (72.7) | 53 (71.6) |
| Lymphocyte count decreased | 32 (74.4) | 27 (60.0) | 59 (67.0) | 3 (4.1) |
| White blood cell count decreased | 19 (44.2) | 15 (33.3) | 34 (38.6) | 8 (10.8) |
| Leukopenia | 16 (37.2) | 12 (26.7) | 28 (31.8) | 21 (28.4) |
| Alanine aminotransferase increased* | 9 (20.9) | 17 (37.8) | 26 (29.5) | 35 (47.3) |
| Anemia* | 10 (23.3) | 16 (35.6) | 26 (29.5) | 33 (44.6) |
| Blood bilirubin increased* | 13 (30.2) | 12 (26.7) | 25 (28.4) | 11 (14.9) |
| Thrombocytopenia* | 9 (20.9) | 13 (28.9) | 22 (25.0) | 11 (14.9) |
| Protein S decreased | 10 (23.3) | 9 (20.0) | 19 (21.6) | 12 (16.2) |
| Hypoalbuminemia* | 10 (23.3) | 8 (17.8) | 18 (20.5) | 14 (18.9) |
| Aspartate aminotransferase increased* | 7 (16.3) | 10 (22.2) | 17 (19.3) | 24 (32.4) |
| Toxic neuropathy | 11 (25.6) | 6 (13.3) | 17 (19.3) | 5 (6.8) |
| Neutropenia | 8 (18.6) | 8 (17.8) | 16 (18.2) | 51 (68.9) |
| Ammonia increased* | 5 (11.6) | 6 (13.3) | 11 (12.5) | 3 (4.1) |
| Gamma-glutamyltransferase increased* | 4 (9.3) | 7 (15.6) | 11 (12.5) | 31 (41.9) |
| Neutropenic colitis | 6 (14.0) | 4 (8.9) | 10 (11.4) | 0 |
| Stomatitis | 5 (11.6) | 5 (11.1) | 10 (11.4) | 2 (2.7) |
| Hypersensitivity | 0 | 2 (4.4) | 2 (2.3) | 24 (32.4) |
| Neutrophil count decrease | 3 (7.0) | 3 (6.7) | 6 (6.8) | 11 (14.9) |
| COVID-19 infection | 1 (2.3) | 0 | 1 (1.1) | 10 (13.5) |
Known adverse reactions with pegaspargase. n, number of patients who had ≥1 TEAE in the presented preferred term. Percentages are based on N. AEs were coded using the MedDRA dictionary, version 25.0. A patient with multiple occurrences of an AE is counted only once in the preferred term.
LIQ indicates liquid; LYO, lyophilizate; TEAE, treatment-emergent adverse event.
Of all TEAEs reported, 48.9% were grade 3 or 4 in Study 1 (with a similar frequency with the 2 formulations). Grade 3/4 TEAEs reported with a higher frequency in the LYO group than the LIQ group were lymphocyte count decrease (65.1% and 51.1%, respectively), antithrombin III decrease (51.2% and 31.1%, respectively), and white blood cell count decrease (44.2% and 31.1%, respectively; shown in Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/JPHO/A780). The incidence of AESI was similar between groups (LYO: 25.6% vs. LIQ: 20.0%), with the most frequent being increased ALT. SAEs occurred at similar frequencies in the LYO and LIQ groups (44.2% and 40.0% of patients, respectively) during Study 1 (shown in Supplementary Table 2, Supplemental Digital Content 1, http://links.lww.com/JPHO/A780). The 4 most frequent SAEs were febrile neutropenia (LYO: 7.0%; LIQ: 11.1%), leukopenia (LYO: 9.3%; LIQ: 8.9%), decreased lymphocyte count (LYO: 7.0%; LIQ: 8.9%), and neutropenic colitis (LYO: 7.0%; LIQ: 8.9%). SAEs related to treatment were reported in more patients in the pegaspargase LYO group (18.6%) than in the pegaspargase LIQ group (8.9%), mainly due to a higher frequency of gastrointestinal disorders in the LYO group (2 events of edematous pancreatitis in 2 patients, 1 event of acute pancreatitis in 1 patient, and 1 event of neutropenic colitis in 1 patient in the LYO group compared with a single event of neutropenic colitis in 1 patient in the LIQ group).
There was no consistent trend in most laboratory variables to suggest a difference between pegaspargase LYO or LIQ formulations. However, in Study 1, mean and median leukocyte, neutrophil, lymphocyte, and platelet counts were lower in the pegaspargase LYO group than the pegaspargase LIQ group, and low antithrombin activity was more frequent in the pegaspargase LYO group than the pegaspargase LIQ group. Many of these hematological variables remained low in most patients during Study 2 (consolidation phase).
Safety (Study 2)
In Study 2, 50.9% of all TEAEs were grade 3 or 4; the most frequent were neutropenia (67.6% of patients), antithrombin III decrease (60.8%), ALT increase (36.5%), and gamma-glutamyltransferase increase (36.5%) (shown in Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/JPHO/A780). TEAEs led to discontinuation of pegaspargase LYO in 18 patients (14 hypersensitivity, 2 drug hypersensitivity, 1 anaphylactic shock, and 1 agranulocytosis). During repeated infusions of pegaspargase LYO, 27 patients (36.5%) experienced 56 emergent SAEs. Most frequent SAEs in this consolidation phase of the study were hypersensitivity (14.9% of patients), neutropenia (6.8%), febrile neutropenia (5.4%), and COVID-19 infection (4.1%) (shown in Supplementary Table 2, Supplemental Digital Content 1, http://links.lww.com/JPHO/A780). Of these, 18 SAEs were considered related to pegaspargase treatment and included 12 events of hypersensitivity in 11 patients and 2 events of drug hypersensitivity in 1 patient, and 1 event each of anaphylactic reaction, neutropenia, edematous pancreatitis, and hepatotoxicity, each occurring in 1 patient.
Safety (Study 1 and Study 2)
Incidence of TEAEs that occurred more frequently in the pegaspargase LYO group than the pegaspargase LIQ group in Study 1 decreased during Study 2 (shown in Table 4). Three patients (3.4%) died during Study 1, and no patient died during Study 2. The deaths in Study 1 are described here: 1 patient (LYO group) contracted sepsis with grade 4 multiple organ dysfunction, 23 days following infusion and the patient died 15 days later; 1 patient (LIQ group) was diagnosed with grade 3 sepsis, 18 days after infusion, which worsened to grade 4 by the following day and the patient died 9 days later; 1 patient (LIQ group) was diagnosed with grade 4 septic shock 13 days after infusion. The situation deteriorated to multiple organ dysfunction syndrome the following day, and the patient died. None of the deaths was considered related to pegaspargase.
DISCUSSION
The PK results from Study 1 showed that administration of pegaspargase LYO and LIQ formulations did not differ in PAA peak (Cmax) or total (AUCinf) exposure, with GMRs of 93.5% for Cmax and 102.8% for AUCinf. Study 2 was a rollover study that continued to provide pegaspargase LYO to patients who benefited from the treatment, and no new or unexpected safety issues arose. The safety profiles of both formulations were consistent with findings from previous studies11,12 and with the underlying pathology (ALL).
In Study 1, the median age was slightly higher in the LYO group: 5 years versus 4 years. Consistent with this slight age difference were slight differences in mean BMI and BSA. None of these differences was clinically relevant and unlikely to affect the PK profiles. The observed increases of 16% and 22% in the partial PAA exposure (AUC0-Tlast) and the Cday14 following administration of the LYO formulation, compared with the LIQ formulation, are attributed to lower exposure in 3 patients who received the LIQ formulation, as shown by the post hoc sensitivity analysis. The concentrations for these patients were quantifiable for only a short period, which affected the calculation of AUC0-Tlast. The PK results from Study 1 support the conclusion that PK exposure after pegaspargase does not depend on formulation.
Although all patients in the SAS of Study 1 had ≥1 TEAE during the study, there were no clinically significant differences in safety profiles between the 2 formulations, and no major differences in TEAEs between the 2 groups. The most common reason for discontinuing pegaspargase LYO treatment in Study 2 was hypersensitivity. However, the study protocol was not designed to investigate or explain hypersensitivity cases: plasma asparaginase activity was assessed according to local practice, and prophylactic treatment for hypersensitivity was administered as per local practice and the ALL-MB 2015 protocol.
One limitation of these studies was that therapeutic effects (minimal residual disease, overall survival, event-free survival) were not investigated. There was also no comparison between the LIQ and LYO formulations carried out in the consolidation phase of Study 2, meaning that the conclusions on long-term safety from this study are limited to the LYO formulation.
The longer shelf life of the LYO formulation allows continuous drug availability compared to the LIQ formulation. As PK exposure does not depend on the pegaspargase formulation, and the safety profile of LYO pegaspargase is consistent with that of asparaginases, these clinical studies support the use of the LYO formulation.
Supplementary Material
ACKNOWLEDGMENTS
The authors thank Emily Eagles, MBiol, of ESP Medical Communications Ltd, Crowthorne, UK, for providing medical writing support, which was funded by Servier in accordance with Good Publication Practice (GPP, 2022) guidelines (https://www.ismpp.org/gpp-2022).
Footnotes
Protocol No. CL2-95014-003 and No. CL2-95014-002, both dated December 2, 2020, were reviewed by an Independent Ethics Committee (IEC) at each enrolling center (Independent Interdisciplinary Committee of Ethics Expertise for Clinical Trials (Ref. No. 06), LEC of Chelyabinsk Regional Children Clinical Hospital (Ref. No. 03), Independent Ethics Committee of Children Regional Clinical Hospital of Krasnodar Region (Ref. No. 02), Local Ethics Committee at Nizhny Novgorod Regional Children Clinical Hospital (Ref. No. 48 for protocol No. CL2-95014-002, Ref. No. 49 for protocol No. CL2-95014-003), Local Ethics Committee at Russian National Research Medical University n.a. N.I. Pirogov (Ref. No. 207), Local Ethics Committee at Regional Children’s Clinical Hospital of Sverdlovsk Region (Ref. No. 65), and Ethics Committee of National Medical Research Center n.a. V.A. Almazov (Ref. No. 2910-21 for protocol No. CL2-95014-002, Ref. No. 2611-21 for protocol No. CL2-95014-003). The study was initiated only after the IEC approval, in accordance with the local regulations.
The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki (1964), as revised in Fortaleza, 2013, and with good clinical practice (GCP) and applicable regulatory requirements.
Each patient, in the presence of their parent(s)/legal guardians, was fully informed by the investigator (or their delegate) about the details of the study in language and terms they could understand. The patients were also informed that they could choose not to participate in the study and that they could withdraw their consent at any time. Written consent was obtained from each patient when of appropriate intellectual maturity, as well as from the patient's parent(s) or legal representative.
A.I.K., V.S., Q.M., S.G., and L.S. were involved in the conception and design of the study, and all authors were involved in patient inclusion and management, and data collection. Statistical and pharmacokinetic analyses were conducted by Q.M. and V.S., respectively. All authors were involved in data interpretation, all critically revised each draft of the manuscript, and all provided final approval of the submitted manuscript.
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information (Supplemental Digital Content 1, http://links.lww.com/JPHO/A780). De-identified patient- and/or study-level clinical trial data, including the clinical study report and study protocol, will be shared, in line with the Servier Data-Sharing Policy (available at: https://clinicaltrials.servier.com/data-request-portal/).
A.I.K. is a national coordinator for a Servier-funded study and a speaker for Servier. S.G.K., V.V.L., and O.I.P. are principal investigators for Servier-funded studies. V.S., Q.M., S.G., and L.S. are employees of Servier. Y.V.D. is an investigator for Servier-funded studies and an invited speaker for Servier. This study was funded by Institut de Recherches Internationales Servier and Les Laboratoires Servier, Moscow, Russia. The funder had a role in the conception, design, data collection, data analysis, and reporting of this study. The remaining authors declare no conflict of interest.
Supplemental Digital Content is available for this article. Direct URL citations are provided in the HTML and PDF versions of this article on the journal’s website, www.jpho-online.com.
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