Use of Intravenous Pegaspargase in Adapted Pediatric Regimen Is Feasible in Adults With Newly Diagnosed ALL
Asparaginase treatment, standard in pediatric acute lymphoblastic leukemia (ALL) regimens, is excluded or used for shorter durations in treatment of adults with ALL due to risk of toxicity. In a study reported in Journal of Clinical Oncology, Douer et al evaluated a pegaspargase (Oncaspar) dosing strategy based on pharmacokinetic characteristics in adults. They found that nearly half of patients could receive a full course of treatment and that treatment had to be discontinued due to toxicity in 20%.
Study Details
In the study, performed between 2004 and 2009, 51 adults aged 18 to 57 years with newly diagnosed ALL were treated with a pegaspargase regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m2 per dose along with steroids to reduce hypersensitivity. Intervals between doses were > 4 weeks and synchronized with other chemotherapy drugs to prevent overlapping toxicities.
Dosing Success
The 51 patients received a total of 192 doses (mean, 3.8 doses per patient), with 23 (45%) receiving all six doses, and 31 (61%) receiving three or more doses. Ten patients (20%) discontinued pegaspargase due to toxicity, including pancreatitis (12%) and severe allergy (6%), nine (18%) did not complete all doses due to treatment failure or death in consolidation, and nine (18%) discontinued for reasons unrelated to treatment failure or toxicity.
Toxicity
No deaths occurred due to pegaspargase toxicity. Grade 3 or 4 deep-vein thrombosis occurred in 16% of patients, clinical pancreatitis in 14%, and allergic reaction in 6%. In five of eight patients, thrombosis occurred in an upper extremity with a central venous device. None of these patients had bleeding complications.
Grade 3 or 4 hyperglycemia occurred in 33% of patients and hypertriglyceridemia in 18%, with all abnormalities spontaneously resolving. Grade 3 or 4 hyperbilirubinemia occurred in 31%of patients and transaminitis in 63%. Although hepatotoxicity resolved spontaneously, resolution was prolonged, with median durations of 34 days (range, 13–63 days) to recovery to grade 1 for hyperbilirubinemia and 38 days (range, 6–83 days) to recovery to grade 2 for transaminitis. Subsequent chemotherapy was delayed after 14 pegaspargase doses due to hepatotoxicity.
Outcomes
Complete remission was achieved in 96% of patients, usually within 4 weeks. Seven-year overall survival was 51% in all 51 patients and 58% in 40 Philadelphia chromosome–negative patients, 73% in the 17 patients with standard-risk disease, and 40% in the 34 patients with high-risk disease.
All five patients with T-cell ALL were alive and in first remission after 28 to 66 months. Seven-year disease-free survival was 58% in all patients and in Philadelphia chromosome–negative patients. Seven-year overall survival and disease-free survival were 55% and 58% in patients not undergoing hematopoietic stem cell transplantation.
Three patients died in first complete response due to transplantation-related complications, and three died due to neutropenic sepsis.
The investigators concluded, “Our dose and schedule of pegaspargase, based on its pharmacokinetics, and our detailed toxicity profile could be applied for safer adaptation of pediatric ALL protocols in adults.”
The study was supported in part by Sigma Tau Pharmaceuticals.
Dan Douer, MD, of Memorial Sloan Kettering Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.
Dr. Douer receives honoraria and research funding from Sigma Tau Pharmaceuticals.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
