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Delayed pegaspargase reduces hepatotoxicity without affecting outcomes.
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy in which significant strides have been made in treatment strategies with the development of immune and targeted therapies. Pegaspargase (Oncaspar; Servier Pharmaceuticals LLC), a modified form of the enzyme L-asparaginase, is a cornerstone of modern ALL therapy. It depletes circulating L-asparagine, an essential amino acid required for protein synthesis, thereby inhibiting the growth of leukemia cells.1 Although it is efficacious, pegaspargase is associated with a range of adverse effects, including hepatotoxicity, pancreatitis, thrombosis, and hypersensitivity reactions. These toxicities can significantly impact treatment tolerability and may necessitate dose reductions or treatment interruptions, potentially compromising overall treatment outcomes.2
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Jose Tinajero, PharmD, BCOP, is a clinical pharmacist specialist at City of Hope National Medical Center in Los Angeles, California. His areas of specialization include cellular therapies, hematologic malignancies, and hematopoietic stem cell transplantation.
Sharon Xu, PharmD, BCOP, is a clinical pharmacist specialist at City of Hope in Irvine, California.
Children with ALL have better outcomes than adults with ALL, which is due in part to the delivery of more intense therapy protocols in children that incorporate asparaginase.3,4 Several reports and series have evaluated the use of prophylactic or therapeutic strategies to manage pegaspargase toxicities; however, data regarding the timing of pegaspargase administration have not been described.5,6
A recent study by Tinajero et al evaluated the impact of timing pegaspargase administration on treatment outcomes in adult patients with ALL with the aim of describing early vs delayed delivery of pegaspargase.7 The study compared 2 groups: One received pegaspargase early in induction (day 4) and the other received it later (day 15) as per physician discretion. Patients in the delayed pegaspargase group had a lower risk of grade 3 or higher hepatotoxicity than patients in the early pegaspargase group (OR, 0.44; 95% CI, 0.20-0.97; P = .04) despite being significantly older at baseline (median age, 38 vs 30 years; P < .01) and frequently having elevated liver enzymes/bilirubin at baseline (30.8% vs 50.8%; P < .01). Importantly, this delay did not adversely impact treatment efficacy as measured by complete remission rates (89.7% vs 79.4%; P = .13), minimal residual disease negativity (61.4% vs 58%; P = 1), and overall survival (P = .59).
The authors concluded that several factors may contribute to the reduced hepatotoxicity associated with delayed pegaspargase administration. First, early administration of pegaspargase may coincide with the nadir of bone marrow suppression induced by other chemotherapy agents, increasing the risk of infections and sepsis. Delaying pegaspargase administration may allow for spacing between myelosuppressive chemotherapy agents and pegaspargase—reducing the risk of infectious complications. Second, early delivery of pegaspargase may overlap with combined liver toxicity of other chemotherapy agents, such as anthracyclines. By delaying pegaspargase, the cumulative liver injury may be reduced.
Although this study’s findings are interesting and promising, further research is needed to optimize the delivery of pegaspargase in adult patients with ALL. In addition to optimizing the timing of pegaspargase administration, several other strategies may be employed to mitigate its toxicities. These include the following:
In conclusion, pegaspargase remains a valuable therapeutic agent in treating adult patients with ALL. By optimizing its administration schedule and employing strategies to mitigate its toxicities, clinicians can improve treatment tolerability and maximize the therapeutic benefits of this important drug.
