U.S. Food and Drug Administration (FDA)-Approved Indications

Acute lymphoblastic leukemia (ALL):

Compendial Uses

Pegaspargase is available as Oncaspar (Servier Pharmaceuticals LLC) and is a conjugate of monomethoxypolyethylene glycol (mPEG) and L-asparaginase (L-asparagine amidohydrolase), an asparagine specific enzyme. L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacological effect of pegaspargase is thought to be based on selective killing of leukemic cells due to depletion of plasma L-asparagine. Leukemic cells with low expression of asparagine synthetase have a reduced ability to synthesize L-asparagine and therefore depend on an exogenous source of L-asparagine for survival (Servier Pharmaceuticals, 2020).

Per the prescribing information, pegaspargase (Oncaspar) carries the following contraindications:

Per the prescribing information, pegaspargase (Oncaspar) carries the following warnings and precautions:

Per the prescribing information, the most common (>5%) grade ≥ 3 adverse reactions included the following: hypoalbuminemia, elevated transaminase, febrile neutropenia, hypertriglyceridemia, hyperglycemia, bilirubin increased, pancreatitis, abnormal clotting studies, embolic and thrombotic events, and hypersensitivity.

Acute Lymphoblastic Leukemia (ALL)

On July 24, 2006, the U.S. Food and Drug Administration (FDA) granted approval to pegaspargase (Oncaspar; Enzon Pharmaceuticals, Inc., Bridgewater, NJ) for the first-line treatment of patients with acute lymphoblastic leukemia (ALL) as a component of a multiagent chemotherapy regimen. Oncaspar was previously approved in February 1994 for the treatment of patients with ALL who were hypersensitive to native forms of L-asparaginase.

The trial supporting this new indication was an open label, randomized, multicenter clinical trial that enrolled 118 children (age, 1–9 years) with previously untreated, standard risk ALL. Patients received either native Escherichia coli asparaginase (Elspar®; Merck, Whitehouse Station, NJ) or pegaspargase along with multiagent chemotherapy during remission induction and delayed intensification (DI) phases of treatment. Pegaspargase, at a dose of 2,500 IU/m

, was administered intramuscularly on day 3 of the 4-week induction phase and on day 3 of each of two 8-week DI phases. Native E. coli L-asparaginase (Elspar) was administered intramuscularly at a dose of 6,000 IU/m

, three times weekly for nine doses during induction and for six doses during each DI phase. This study allowed direct comparison of pegaspargase (Oncaspar) and native E. coli L-asparaginase (Elspar) for asparagine depletion, asparaginase activity, and development of asparaginase antibodies. An unplanned comparison of event-free survival (EFS) was conducted to rule out a deleterious pegaspargase efficacy effect. Following induction and DI treatment there was complete (≤1 μM) or moderate (1–10 μM) depletion of serum asparagine levels in the large majority of samples tested over the 4-week period in subjects in both treatment groups. Similarly, depletion of cerebrospinal fluid asparagine levels during induction was similar between both treatment groups. The number of days asparaginase activity exceeded >0.03 IU/ml in pegaspargase -treated subjects was greater than the number of days in native E. coli L-asparaginase -treated subjects during both the induction and DI phases of treatment. There was no correlation, however, between asparaginase activity and serum asparagine levels, making the former determination less clinically relevant.

Using the protocol-prespecified threshold for a positive result of >2.5 times the control, 7 of 56 (12%) pegaspargase subjects tested at any time during the study demonstrated antiasparaginase antibodies and 16 of 57 (28%) native E. coli L-asparaginase subjects tested at any time during the study had antiasparaginase antibodies. In both study arms event-free survival was in the range of 80% at 3 years.

The most serious, sometimes fatal, pegaspargase toxicities were anaphylaxis, other serious allergic reactions, thrombosis (including sagittal sinus thrombosis), pancreatitis, glucose intolerance, and coagulopathy. The most common adverse events were allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, central nervous system thrombosis, coagulopathy, hyperbilirubinemia, and elevated transaminases.

Combined Anti-PD-1 Antibody, Anlotinib and Pegaspargase Regimen with Radiotherapy for the Treatment of Natural Killer/T Cell Lymphoma

Sun et al (20220 noted that asparaginase-/pegaspargase-containing regimens combined with radiotherapy (RT) are highly effective and considered the cornerstone of localized natural killer/T-cell lymphoma (NKTL) treatment; however, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related AEs (TRAEs). In a retrospective study, these researchers examined the safety and effectiveness of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase "sandwich" with RT in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2,500 U/m2 were administered on day 1, while anlotinib (12 mg once-daily) was orally administered on days 1 to 14. The treatment was repeated every 3 weeks. All 8 patients included received 3 cycles of the regimen followed by RT and an additional 3 cycles. The ORR was 100 %, and the CR rate was 87.5 %. With a median follow-up time of 35.5 months (range of 34.03 to 40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100 % and 100 %, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade-4 TRAE was reported. No grade-3/grade-4 hematological toxicity was detected, and 50 % of the patients didn't report any hematological toxicity. The authors concluded that the findings of this study indicated that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance. These investigators stated that future prospective studies with large sample sizes could provide more accurate data on the safety and effectiveness of this regimen and could further identify predictive biomarkers of this novel therapy in NKTL patients.

The authors stated that this study had several drawbacks. First, this study was limited by its non-randomized nature with a relatively small sample size (n = 8). Second, effectiveness analyses were preliminary, and long-term follow-up is still needed. Third, these researchers could not perform prognostic analysis of biomarkers in this study. To overcome these pitfalls, a prospective, single-arm, phase-II clinical trial examining the safety and effectiveness of sintilimab, anlotinib and pegaspargase for localized NKTL has been initiated in multiple centers.

Sun et al (2023) stated that novel highly effective and low-toxicity combination therapy for localized extranodal natural-killer/T-cell lymphoma (ENKTL) remains a clinically unmet need. In a phase-II clinical trial, these investigators examined the safety and effectiveness of sintilimab, anlotinib, and pegaspargase sandwiched with RT as 1st-line treatment in patients with newly-diagnosed stage I-II ENKTL. Participants received sintilimab 200 mg plus pegaspargase 2,500 U/m2 on day 1 and anlotinib 12 mg once-daily on days 1 to 14 for three 21-day cycles, followed by intensity-modulated RT (IMRT) and another 3 cycles of systemic therapy. The primary endpoint was the complete response rate (CRR) after 6 treatment cycles. The secondary endpoints included PFS, OS, CRR after 2 cycles, overall response rate (ORR) after 6 cycles, duration of response (DOR), and safety. Between May 2019 and July 2021, a total of 58 patients were enrolled. The CRR was 55.1 % (27/49) after 2 cycles and 87.8 % (43/49) after 6 cycles. The ORR was 87.8 % (43/49; 95 % CI: 75.2 to 95.4) after 6 cycles. After a median follow-up of 22.5 months (95 % CI: 20.4 to 24.6 months), the median PFS, OS, and DOR were not reached. The 2-year PFS, OS, and DOR rates were 87.6 % (95 % CI: 78.8 to 97.4), 97.9 % (95 % CI: 94.0 to 100), and 91.1 % (95 % CI: 83.2 to 99.8), respectively. Grade 3 to 4 TRAEs occurred in 41.4 % (24/58) of patients, with the most common being hypertension (15.5 %), hypertriglyceridemia (8.6 %), oral mucositis (6.9 %), and anemia (5.2 %); no treatment-related deaths occurred. The authors concluded that 1st-line sintilimab, anlotinib, and pegaspargase sandwiched with RT showed promising effectiveness in the treatment-naive early-stage ENKTL patients with a favorable safety profile.

Extra-Nodal Natural Killer/T-Cell Lymphoma, Nasal Type

Wei and colleagues (2020) noted that extra-nodal natural killer/T cell lymphoma, nasal type (ENKTL) is a highly aggressive tumor with relatively poor prognosis. In a prospective, single-arm, single-center, phase-II clinical trial, these investigators examined the efficacy and toxicity of a novel combined gemcitabine, cisplatin, dexamethasone, methotrexate, and pegaspargase (GDP-ML) regimen as front-line treatment in newly diagnosed ENKTL. Eligible newly diagnosed stage I/II ENKTL patients received sandwich chemoradiation therapy. Patients with stage III/IV disease received an initial 4 cycles of GDP-ML regimen. After 4 cycles, responding patients continued to receive either autologous transplantation or additional 2 courses of GDP-ML. A total of 44 patients were enrolled with a median follow-up of 26 months. The overall response rate (ORR) were 78.6 % for the whole cohort, 84.6 % for stage I/II, and 66.7 % for stage III/IV, and corresponding complete remission (CR) rates were 61.9 %, 76.9 %, and 33.3 %. The 1-year and 2-year progression-free survival (PFS) rates were 69.3 % and 62.9 %, and 1-year and 2-year overall survival (OS) rates were 76.5 % and 67.4 %, respectively. Patients with stage I/II disease showed better 2-year OS rate compared with stage III/IV patients (88.1 % versus 33.2 %, p < 0.001). Patients who achieved CR had significantly better 2-year OS rate compared with non-CR patients (90.8 % versus 24.5 %, p < 0.001). The main adverse event (AE) was hematologic toxicity. Grade 3/4 neutropenia occurred in 59.1 % of patients. The authors concluded that these findings indicated that GDP-ML is an effective and well-tolerated induction regimen with newly diagnosed ENKTL patients.

Wang and colleagues (2020) stated that concurrent chemoradiotherapy (CCRT) is expected to improve local and systemic disease control and has been established as a standard therapy for several types of solid tumors. In a 2-center, phase-II clinical trial, these researchers examined the effects of frontline radiation and pegaspargase in localized ENKTL. A total of 30 patients with newly diagnosed nasal ENKTL in stages IE to IIE received CCRT (radiation 50 Gy and 2 cycles of pegaspargase 2,500 unit/m2 every 3 weeks); 4 courses of pegaspargase were carried out after CCRT. Subjects completed CCRT and 4 cycles of pegaspargase. The CR rate was 90 % with a 95 % confidential interval (CI ) of 73.5 % to 97.9 % after CCRT. The CR rate was 100 % (95 % CI: 88.4 % to 100 %) at the end of the treatment. The 2-year OS and PFS rates were 90.9 % (95 % CI: 78.4 % to 100 %) and 92.8 % (95 % CI: 83.2 % to 100 %), respectively. The major AEs were in grades 1 to 2. The authors concluded that preliminary data indicated that pegaspargase combined with concurrent radiotherapy for newly diagnosed patients with nasal ENKTL was effective and well-tolerated. Pegaspargase has a long half-life and is easy to administer via intra-muscular injection; thus, pegaspargase combined with concurrent radiotherapy for ENKTL patients can be completed in the out-patient setting. Moreover, these researchers stated that further investigation in large prospective trials should be conducted to confirm these findings. These investigators stated that the 2 main drawbacks of this study were its small sample size (n = 30) and short-term follow-up (median of 26.5 months).

Peripheral T-Cell Lymphoma

Zhang and colleagues (2019) stated that peripheral T-cell lymphomas (PTCL) are less responsive to anthracycline-containing regimen such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and carry a poor prognosis. In this prospective, open-label, single-center, phase-II clinical trial, these investigators examined the effects of gemcitabine, cisplatin, and dexamethasone (GDP) combined with methotrexate (MTX) and pegaspargase (PEG-L) as front-line treatment in PTCL. Eligible newly diagnosed PTCL patients received 4 cycles of the GDP-ML chemotherapy every 28 days. After 4 cycles, responding patients continued to receive either autologous stem cell transplantation or the MTX/cytarabine (MA) regimen for consolidation. A total of 65 patients were enrolled with a median follow-up of 38.5 months. The ORR was 55.4 %, and CR rate was 33.8 %. The median OS was 16 months, and the 1-year and 2-year OS were 59.1 % and 38.2 %, respectively. The median PFS was only 8 months. The major AE was hematologic toxicity: 50 % patients showed grade III/IV neutropenia. The authors concluded that GDP-ML for the 1st-line treatment of PTCL patients was an effective induction regimen compared with standard CHOP, and the toxicity was more significant but acceptable. Moreover, these researchers stated that future studies examining new drug combinations are needed to overcome relapse after remission.

Pre-Medication and Therapeutic Drug Monitoring for Pegaspargase for Prevention of Hypersensitivity Reactions

In a retrospective, cohort study Babcock et al (2022) examined the effectiveness of a standardized pre-medication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. This trial was carried out at Wolfson Children's Hospital (Jacksonville, Fl), and included pediatric ALL patients aged 0 to 21 years. Subjects were excluded if they had not received the appropriate pre-medication after protocol implementation or had received pre-medication before protocol implementation. They were separated into 2 groups: those who received pre-medication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. A total of 38 patients (50 doses in no pre-medication group; 80 doses in pre-medication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving pre-medication and TDM (5.3 % versus 6.4 %, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. The authors concluded that a standardized pre-medication protocol did not reduce the incidence of hypersensitivity reactions. Pre-medication to prevent hypersensitivity reactions may provide a potential drug cost savings. Moreover, these researchers stated that further investigation is needed to examine the effectiveness of a standardized pre-medication and TDM protocol to prevent hypersensitivity reactions.

These investigators stated that in theory, if a significant difference in the incidence of hypersensitivity reactions was demonstrated via the findings of this study, then the institution would experience a cost savings solely on medication costs alone. This does not include the added costs of additional clinic visits when switching from pegaspargase to asparaginase Erwinia or intensive care unit (ICU) admissions for severe reactions. The limited patient population and unevenly matched groups made it difficult to draw conclusions based on the findings of this study.

Etoposide, Dexamethasone, and Pegaspargase with Radiotherapy for the Treatment of Natural Killer/T-Cell Lymphoma

Zhong et al (2023) noted that methotrexate, etoposide, dexamethasone, and pegaspargase (MESA) with sandwiched RT is known to be effective for early-stage NKTL. In a randomized, multi-center, phase-III clinical trial, these investigators examined the safety and effectiveness of reduced-intensity, non-intravenous etoposide, dexamethasone, and pegaspargase (ESA) with sandwiched RT in patients with early-stage NKTL. This study enrolled patients aged between 14 and 70 years with newly diagnosed early-stage nasal NKTL from 27 centers in China. Patients were randomly assigned (1:1) to receive ESA (pegaspargase 2,500 IU/m2 intramuscularly on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2 to 4) or MESA (methotrexate 1 g/m2 intravenously on day 1, etoposide 200 mg orally, and dexamethasone 40 mg orally on days 2 to 4, and pegaspargase 2,500 IU/m2 intramuscularly on day 5) regimen (4 cycles), combined with sandwiched RT. The primary endpoint was ORR. The non-inferiority margin was -10.0 %. From March 16, 2016, to July 17, 2020, a total of 256 patients underwent randomization, and 248 (ESA [n = 125] or MESA [n = 123]) made up the modified intention-to-treat (ITT) population. The ORR was 88.8 % (95 % CI: 81.9 to 93.7) for ESA with sandwiched RT and 86.2 % (95 % CI: 78.8 to 91.7) for MESA with sandwiched RT, with an absolute rate difference of 2.6 % (95 % CI: -5.6 to 10.9), meeting the non-inferiority criteria. Per-protocol and sensitivity analysis supported this result. AEs of grade-3 or higher occurred in 42 (33.6 %) patients in the ESA arm and 81 (65.9 %) in the MESA arm. The authors concluded that ESA with sandwiched RT was an effective, low-intensity, non-intravenous regimen, and could be administered in a day-care unit or outpatient clinic as a promising 1st-line treatment in early-stage NKTL.

The authors stated that the main drawback of this trial pertained to the change of the primary endpoint from 2-year PFS rate to ORR, since these researchers believed that accurate ORR of MESA with sandwiched RT obtained from external evidence of a phase-II clinical trial on newly diagnosed early-stage NKTL provided solid evidence for sample size consideration. They noted that it was worth pointing out that, even as the key secondary endpoint, the 2-year PFS rate was met, which was similar between the ESA arm and the MESA arm (85.5 % versus 79.7 %), with an absolute rate difference of 5.8 % (95 % CI: -3.6 to 15.3; p value of non-inferiority < 0.001). Indeed, if the primary endpoint remained 2-year PFS rate, the power would be 90 % based on the final sample size of 256 to detect a non-inferiority margin difference of −10 %, which was greater than the power of 80 % based on the initial sample size of 190. Moreover, results of the sensitivity analysis that excluded the 14 patients enrolled before the protocol amendment were consistent with those of the primary analysis.

Pegaspargase-COEP Plus Radiotherapy in Patients with Newly Diagnosed Extra-Nodal NK/T-Cell Lymphoma

Hu et al (2022) stated that the optimal 1st-line treatment for ENKTL has not been well-defined. In a prospective, open-label, single-arm, phase-II clinical trial, these investigators examined the safety and effectiveness of pegaspargase, cyclophosphamide, vincristine, etoposide and prednisone (COEPL) regimen combined with RT for the treatment of patients with newly diagnosed ENKTL. Patients with newly diagnosed ENKTL and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 were eligible for enrollment. For patients with stage I/II nasal ENKTL, treatment included 2 cycles of induction COEPL regimen followed by concurrent chemoradiotherapy, then by 2 cycles of COEPL regimen as consolidation. For patients with stage III/IV or primary extra-nasal ENKTL, treatment included 6 to 8 cycles of COEPL regimen with or without RT to local sites, and autologous stem cell transplantation (auto-SCT) was given in selected patients. A total of 80 patients were enrolled. The median age was 41 years (range of 15 to 76 years); 16 patients (20 %) had stage III/IV disease, and 10 (12.5 %) had a PINK score of 2 or higher. CR and ORR were 75.9 % and 87.3 %, respectively. With a median follow-up of 41.4 months (range of 2.7 to 76.2 months), the 3-year PFS and OS rates were 71.3 % (95 % CI: 61.1 % to 81.5 %) and 73.3 % (95 % CI: 63.1 % to 83.5 %), respectively. For patients with stage I/II nasal ENKTL (n = 62), the 3-year PFS and OS were 78.1 % and 81.2 %, respectively. For patients with stage III/IV or primary extra-nasal ENKTL (n = 18), 3-year PFS and OS were 48.1 % and 45.7 %, respectively. Major grade-3 to grasde-4 AEs were anemia (21.3 %), leucopenia (22.5 %), neutropenia (18.8 %), and thrombocytopenia (7.6 %). No treatment-related death was observed. The authors concluded that pegaspargase-COEP chemotherapy in combination with RT was safe and effective for patients with newly diagnosed ENKTL.

Thie authors stated that this study had several drawbacks. First, this was a single-arm study that consisted of mainly patients with low- or intermediate-risk ENKTL; therefore, results from this study could not be directly compared with the other regimens reported in the literature. Second, EBV-DNA testing was not routinely carried out in this study; thus, the impact of EBV-DNA level on risk stratification and treatment outcome could not be analyzed. Third, the group of patients with advanced-stage disease was relatively small (n = 16); therefore, it was difficult to adequately examine the effectiveness of COEPL regimen in this group of patients. In light of these drawbacks, these researchers have initiated another prospective study of COEPL chemotherapy in patients with newly diagnosed stage III/IV ENKTL, and results of this ongoing trial will be presented as a separate report.

Criteria for Initial Approval

Aetna considers pegaspargase (Oncaspar) medically necessary for

of the following:

Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma (LL)

For the treatment of ALL or LL when the requested medication is used in conjunction with multi-agent chemotherapy;

Extranodal Natural Killer/T-cell Lymphoma (ENKL)/Agressive NK-cell Leukemia (ANKL)

For for the treatment of ENKL or ANKL when the requested medication is used in conjunction with multi-agent chemotherapy;

Hepatosplenic T-cell Lymphoma

or the treatment of hepatosplenic T-cell lymphoma as subsequent therapy when the requested medication is used in conjunction with multi-agent chemotherapy.

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of pegaspargase (Oncaspar) therapy medically necessary in members for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

Pegaspargase (Oncaspar) is available as a 3,750 International Units/5 mL (750 International Units/mL) solution in a single-dose vial for intramuscular or intravenous use.

Acute Lymphoblastic Leukemia

Pegaspargase (Oncaspar) is administered intramuscularly or intravenously no more frequently than every 14 days and the recommended dosage is as follows:

Source: Servier Pharmaceuticals, 2021

Experimental and Investigational

Aetna considers combined anti-PD-1 antibody, anlontinib and pegaspargase (Oncaspar) regimen with radiotherapy for the treatment of natural killer/T-cell lymphoma experimental and investigational.

Aetna considers therapeutic drug monitoring protocol for pegaspargase (Onaspar) for prevention of hypersensitivity reactions experimental and investigational.