Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia Journal Article

Authors: Douer, D.; Aldoss, I.; Lunning, M. A.; Burke, P. W.; Ramezani, L.; Mark, L.; Vrona, J.; Park, J. H.; Tallman, M. S.; Avramis, V. I.; Pullarkat, V.; Mohrbacher, A. M.
Article Title: Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia
Abstract: Asparaginase treatment is standard in all pediatric acute lymphoblastic leukemia (ALL) regimens, whereas in adults, it is either excluded or administered for a shorter duration. Several adult ALL protocols are adapting pediatric regimens, but the optimal implementation of asparaginase is not well studied, considering its potential higher toxicity. We studied a pegaspargase dosing strategy based on its pharmacokinetic characteristics in adults. Between 2004 and 2009, 51 adults age 18 to 57 years with newly diagnosed ALL were treated with a regimen adapted from a pediatric trial that included six doses of intravenous pegaspargase at 2,000 IU/m(2) per dose. Intervals between doses were longer than 4 weeks and rationally synchronized with other chemotherapy drugs to prevent overlapping toxicities. Pegaspargase was administered with steroids to reduce hypersensitivity. Asparaginase-related toxicities were monitored after 173 pegaspargase doses. The most common grade 3/4 asparaginase-related toxicities were lengthy hyperbilirubinemia and transaminitis, occasionally resulting in subsequent treatment delays. All toxicities resolved spontaneously. Forty-five percent of patients were able to receive all six doses of pegaspargase, and 61% received ≥ three doses. In only 20% of patients, the drug was discontinued after pegaspargase-related serious toxicity. Ninety-six percent achieved complete remission, almost all within 4 weeks, and a low induction death rate was seen. Seven-year disease-free and overall survival were 58% and 51%, respectively. 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.
Keywords: adult; treatment outcome; disease-free survival; middle aged; clinical trial; neutropenia; disease free survival; antineoplastic agent; antineoplastic combined chemotherapy protocols; drug administration schedule; acute lymphoblastic leukemia; blood; feasibility study; feasibility studies; chemically induced disorder; asparaginase; sepsis; precursor cell lymphoblastic leukemia-lymphoma; hyperbilirubinemia; drug administration; infusions, intravenous; polyethylene glycols; induction chemotherapy; intravenous drug administration; drug-induced liver injury; macrogol derivative; asparaginase macrogol; toxic hepatitis; humans; human; male; female; article
Journal Title: Journal of Clinical Oncology
Volume: 32
Issue: 9
ISSN: 0732-183X
Publisher: American Society of Clinical Oncology  
Date Published: 2014-03-20
Start Page: 905
End Page: 911
Language: English
DOI: 10.1200/jco.2013.50.2708
PROVIDER: scopus
PUBMED: 24516026
Notes: J. Clin. Oncol. -- Export Date: 2 June 2014 -- Source: Scopus
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MSK Authors
  1. Matthew Alexander Lunning
    26 Lunning
  2. Martin Stuart Tallman
    408 Tallman
  3. Jae Hong Park
    132 Park
  4. Dan Douer
    80 Douer
  5. Patrick William Burke
    7 Burke