title: Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: Dan Douer, Matthew A. Lunning, Patrick W. Burke, Jae H. Park, and Martin S. Tallman, Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College, New York, NY; Ibrahim Aldoss, Laleh Ramezani, Lisa Mark, Janice Vrona, Vinod Pullarkat, and Ann M. Mohrbacher, Keck School of Medicine, University of Southern California; and Vassilios I. Avramis, Children's Hospital of Los Angeles, University of Southern California, Los Angeles, CA.
authors: Dan
authors: D
authors: Douer
authors: Ibrahim
authors: I
authors: Aldoss
authors: Matthew A
authors: MA
authors: Lunning
authors: Patrick W
authors: PW
authors: Burke
authors: Laleh
authors: L
authors: Ramezani
authors: Lisa
authors: L
authors: Mark
authors: Janice
authors: J
authors: Vrona
authors: Jae H
authors: JH
authors: Park
authors: Martin S
authors: MS
authors: Tallman
authors: Vassilios I
authors: VI
authors: Avramis
authors: Vinod
authors: V
authors: Pullarkat
authors: Ann M
authors: AM
authors: Mohrbacher
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D006932:Hyperbilirubinemia / Q000139:chemically induced; D060828:Induction Chemotherapy; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced / Q000150:complications; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D018805:Sepsis / Q000209:etiology; D016896:Treatment Outcome
chemical_list: D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase