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

Dan Douer, Ibrahim Aldoss, Matthew A. Lunning, Patrick W. Burke, Laleh Ramezani, Lisa Mark, Janice Vrona, Jae H. Park, Martin S. Tallman, Vassilios I. Avramis, Vinod Pullarkat, Ann M. Mohrbacher

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Abstract

Purpose: 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. Patients and 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/m2 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. Conclusion: 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.

Original languageEnglish (US)
Pages (from-to)905-911
Number of pages7
JournalJournal of Clinical Oncology
Volume32
Issue number9
DOIs
StatePublished - Mar 20 2014

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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Pharmacokinetics
Asparaginase
Pediatrics
Hyperbilirubinemia
pegaspargase
Pharmaceutical Preparations
Disease-Free Survival
Appointments and Schedules
Hypersensitivity
Steroids
Drug Therapy
Mortality
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. / Douer, Dan; Aldoss, Ibrahim; Lunning, Matthew A.; Burke, Patrick W.; Ramezani, Laleh; Mark, Lisa; Vrona, Janice; Park, Jae H.; Tallman, Martin S.; Avramis, Vassilios I.; Pullarkat, Vinod; Mohrbacher, Ann M.

In: Journal of Clinical Oncology, Vol. 32, No. 9, 20.03.2014, p. 905-911.

Research output: Contribution to journalArticle

Douer, D, Aldoss, I, Lunning, MA, Burke, PW, Ramezani, L, Mark, L, Vrona, J, Park, JH, Tallman, MS, Avramis, VI, Pullarkat, V & Mohrbacher, AM 2014, 'Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia', Journal of Clinical Oncology, vol. 32, no. 9, pp. 905-911. https://doi.org/10.1200/JCO.2013.50.2708
Douer, Dan ; Aldoss, Ibrahim ; Lunning, Matthew A. ; Burke, Patrick W. ; Ramezani, Laleh ; Mark, Lisa ; Vrona, Janice ; Park, Jae H. ; Tallman, Martin S. ; Avramis, Vassilios I. ; Pullarkat, Vinod ; Mohrbacher, Ann M. / Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia. In: Journal of Clinical Oncology. 2014 ; Vol. 32, No. 9. pp. 905-911.
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abstract = "Purpose: 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. Patients and 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/m2 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. Conclusion: 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.",
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T1 - Pharmacokinetics-based integration of multiple doses of intravenous pegaspargase in a pediatric regimen for adults with newly diagnosed acute lymphoblastic leukemia

AU - Douer, Dan

AU - Aldoss, Ibrahim

AU - Lunning, Matthew A.

AU - Burke, Patrick W.

AU - Ramezani, Laleh

AU - Mark, Lisa

AU - Vrona, Janice

AU - Park, Jae H.

AU - Tallman, Martin S.

AU - Avramis, Vassilios I.

AU - Pullarkat, Vinod

AU - Mohrbacher, Ann M.

PY - 2014/3/20

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N2 - Purpose: 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. Patients and 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/m2 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. Conclusion: 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.

AB - Purpose: 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. Patients and 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/m2 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. Conclusion: 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.

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