In late 2018, calaspargase pegol-mknl, an asparagine-specific enzyme, was approved for use as a component of a multiagent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients aged 1 month to 21 years.1,2 The new product provides for a longer interval between doses compared with other available pegaspargase products.
Supporting Efficacy Data
Approval was based on demonstration of the achievement and maintenance of nadir serum asparaginase activity above the level of 0.1 U/mL when using calaspargase pegol-mknl at 2,500 U/m2 intravenously every 3 weeks.2 The pharmacokinetics of calaspargase pegol-mknl were studied when administered in combination with multiagent chemotherapy in 124 patients with B-cell lineage ALL. The median age of patients was 11.5 years (range = 1–26 years), 50% were female, and 82% were white. The results showed that 123 patients (99%) maintained nadir serum asparaginase activity greater than 0.1 U/mL at weeks 6, 12, 18, 24, and 30.
How It Works
L-asparaginase is an enzyme that catalyzes the conversion of the amino acid L-asparagine into aspartic acid and ammonia. The pharmacologic effect of calaspargase pegol-mknl is believed 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.
How It Is Used
The recommended dose of calaspargase pegol-mknl is 2,500 units/m2 given intravenously no more frequently than every 21 days.
Patients should be monitored at least weekly with evaluation of bilirubin, transaminases, and glucose and clinical examinations until recovery from the cycle of therapy. Product labeling provides instructions on treatment modification for infusion reaction or hypersensitivity reaction, hemorrhage, pancreatitis, thromboembolism, and hepatotoxicity. Treatment should be permanently discontinued for grade 3 or 4 infusion reaction or hypersensitivity reaction, confirmed clinical pancreatitis, severe or life-threatening thrombosis, and total bilirubin more than 10 times the upper limit of normal.
The safety of calaspargase pegol-mknl was investigated in Study DFCI 11-001, an open-label, randomized, active-controlled multicenter clinical trial that treated 237 children and adolescents with newly diagnosed ALL or lymphoblastic lymphoma with calaspargase pegol-mknl at 2,500 U/m2 (n = 118) or pegaspargase at 2,500 U/m2 (n = 119) as part of a Dana-Farber Cancer Institute ALL Consortium backbone therapy. The median age of study patients was 5 years (range = 1–20 years), 62% were male, 70% were white, 59% were considered to be at standard risk, and 87% had B-cell lineage ALL. The median number of doses was 11 for calaspargase pegol-mknl (given every 3 weeks) and 16 for pegaspargase (given every 2 weeks).
Not all grade 1 and 2 adverse events were prospectively collected. The most common grade 3 or 4 adverse events (≥ 10%) with calaspargase pegol-mknl were elevated transaminase (52% vs 63% with pegaspargase), increased bilirubin (20% vs 25%), pancreatitis (18% vs 24%), and abnormal clotting studies (14% vs 21%).
In the subgroup of patients with B-cell lineage ALL, the complete remission rates were 98% with calaspargase pegol-mknl and 99% with pegaspargase. Kaplan-Meier estimates of overall survival were comparable in the two groups.
Calaspargase pegol-mknl has warnings/precautions for hypersensitivity, pancreatitis, thrombosis, hemorrhage, and hepatotoxicity. The agent is contraindicated in patients with a history of serious hypersensitivity reactions to pegylated L-asparaginase, a history of serious thrombosis during L-asparaginase therapy, a history of serious pancreatitis related to previous L-asparaginase treatment, a history of serious hemorrhagic events during previous L-asparaginase therapy, and severe hepatic impairment. Patients should be advised not to breastfeed while receiving calaspargase pegol-mknl.
1. U.S. Food and Drug Administration: FDA approves longer-acting calaspargase pegol-mknl for ALL. Available at https://wayback.archive-it.org/7993/20190423133217/https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm628980.htm. Accessed November 11, 2019.
2. Asparlas (calaspargase pegol-mknl) injection prescribing information, Servier Pharmaceuticals, December 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/761102s000lbl.pdf. Accessed November 11, 2019.