Abstract Purpose: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. Experimental Design: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. Results: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91–100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. Conclusions: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.
The study of minimal residual disease (MRD) is an attempt to detect and define the significance of leukemia invisible to normal morphologic examination. In many circumstances the clinical significance of MRD detection is unclear, because the technical ability to detect and quantify it has outpaced studies demonstrating its clinical significance. The detection of minimal residual disease most consistently has been associated with relapse in acute lymphoblastic leukemia, t(15;17) acute myeloid leukemia, and chronic myeloid leukemia posttransplant, especially after T-cell depletion. But, in many types of leukemia, including acute myeloid leukemia and acute lymphoblastic leukemia, MRD can be detected in long-term remission patients without subsequent relapse. The study of MRD is evolving from detecting residual disease and predicting relapse to the study of the mechanisms that explain how minimum residual disease can coexist in a “cured” patient.
Abstract: All forms of hematopoietic stem‐cell transplantation are complicated by delayed immune reconstitution, which results in an increased risk of infectious complications and relapse of disease. Donor lymphocyte infusions have been used in an attempt to enhance immune recovery and for the prevention and treatment of specific infections following transplantation. While there is little data to support the use of donor lymphocytes for the enhancement of general immune function post‐transplant, unselected and virus‐specific donor T cells may have efficacy for the prophylaxis and treatment of infections and disease caused by Epstein–Barr virus (EBV) and cytomegalovirus (CMV). While donor lymphocyte infusions may cause significant morbidity and mortality, they are a novel and potentially powerful approach for the treatment of frequently fatal post‐transplant infectious complications.
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