Pegaspargase (Oncaspar)

Number: 0959

Policy

Aetna considers pegaspargase (Oncaspar) medically necessary for either of the following:

• For the treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma when the requested medication is used in conjunction with multi-agent chemotherapy; or
• For the treatment of extra-nodal natural killer/T-cell lymphoma, nasal type when the requested medication is used in conjunction with multi-agent chemotherapy; or
• As an alternative induction regimen if there was no response to primary treatment of hepatosplenic gamma-delta T-cell lymphoma when the requested medication is used in conjunction with multi-agent chemotherapy.

Aetna considers continued treatment with pegaspargase medically necessary in members requesting re-authorization for a medically necessary indication listed above  when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers pegaspargase (Oncaspar) experimental and investigational for all other indications because its effectiveness for other indications has not been established.

Dosing Recommendations

Oncaspar is administered intramuscularly or intravenously no more frequently than every 14 days.

• Individuals aged 21 years and younger: 2,500 International Units/m²
• Individuals aged over 21 years: 2,000 International Units/m²

Source: Prescribing Information. Oncaspar. Baxalta US Inc.; 2020.

Background

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

Acute lymphoblastic leukemia (ALL):

• Oncaspar is indicated as a component of a multi-agent chemotherapeutic regimen for the first line treatment of pediatric and adult patients with ALL.
• Oncaspar is indicated as a component of a multi-agent chemotherapeutic regimen for the treatment of pediatric and adult patients with ALL and hypersensitivity to native forms of L-asparaginase.

Compendial Uses

• Extranodal natural killer/T-cell lymphoma, nasal type: as a component of multi-agent chemotherapeutic regimen
• Lymphoblastic lymphoma (managed in the same manner as ALL)
• Acute lymphoblastic leukemia (ALL) as a component of multi-agent chemotherapeutic regimen or central nervous system directed therapy as systemic therapy (IV/IM route)
• Pediatric acute lymphoblastic leukemia (ALL) as a component of a multi-agent chemotherapeutic regimen
• Hepatosplenic gamma-delta T-cell lymphoma as an alternative induction regimen if no response to primary treatment as a component of a multi-agent chemotherapeutic regimen

Acute Lymphoblastic Leukemia (ALL)

Pegaspargase (Oncaspar) 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.

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/m², 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/m², 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.

Hypersensitivity to Asparaginase

The safety and effectiveness of ONCASPAR was evaluated in 4 open-label studies enrolling a total of 42 patients with multiply-relapsed, acute leukemia [39 (93%) with ALL] with a history of prior clinical allergic reaction to asparaginase. Hypersensitivity to asparaginase was defined by a history of systemic rash, urticaria, bronchospasm, laryngeal edema, hypotension, or local erythema, urticaria, or swelling, greater than 2 centimeters, for at least 10 minutes following administration of any form of native E. coli L-asparaginase. All patients received ONCASPAR at a dose of 2,000 or 2,500 International Units/m2 administered intramuscularly or intravenously every 14 days. Patients received ONCASPAR as a single agent or in combination with multi-agent chemotherapy. The re-induction response rate was 50% (95 confidence interval: 35%, 65%), based upon 36% complete remissions and 14% partial remissions. These results were similar to the overall response rates reported for patients with ALL receiving second-line, native E. coli L-asparaginase-containing re-induction chemotherapy. Anti-tumor activity was also observed with single-agent ONCASPAR. Three responses (1 complete remission and 2 partial remissions) were observed in 9 adult and pediatric patients with relapsed ALL and hypersensitivity to native E. coli L-asparaginase. The National Comprehensive Cancer Network Drugs and Biologics Compendium (NCCN, 2018) recommends that Erwinaze can be substituted for pegaspargase in cases of systemic allergic reaction or anaphylaxis due to pegaspargase hypersensitivity. The NCCN Drug and Biologics Compendium (NCCN, 2017) recommends pegasparaginase (Oncaspar) for acute lymphoblastic leukemia and for extranodal NK/T-Cell Lymphoma, nasal type The NCCN Drugs and Biologics Compendium (NCCN, 2016) recommends asparaginase (Elspar) for lymphoblastic lymphoma.

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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96401	Chemotherapy administration, subcutaneous or intramuscular; non-hormonal anti-neoplastic
96413 - 96417	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9266	Injection, pegaspargase, per single dose vial
ICD-10 codes covered if selection criteria are met:
C83.51 - C83.59	Lymphoblastic (diffuse) lymphoma
C86.0	Extranodal NK/T-cell lymphoma, nasal type
C86.1	Hepatosplenic T-cell lymphoma
C91.00 - C91.02	Acute lymphoblastic leukemia [ALL]

The above policy is based on the following references: