Background. L‐asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia (ALL) in children for almost 30 years. Because L‐asparaginase is a foreign protein, the potential exists for severe, dose‐limiting hypersensitivity reactions. To reduce this toxicity, L‐asparaginase has been linked with polyethylene glycol (PEG).
Methods. Patients with ALL in relapse were entered in a Phase II, open‐label clinical trial (ASP‐201A) to evaluate the toxicity and efficacy of PEG‐L‐asparaginase. PEG‐L‐asparaginase has demonstrated potential low immunogenicity and a prolonged plasma half‐life relative to native enzyme. PEG‐L‐asparaginase (2000 IU/m2 every 2 weeks) was used as single‐agent induction therapy during an initial 14‐day investigational window. Thereafter, the regimen consisted of PEG‐L‐asparaginase, vincristine, and prednisone. Patients also were allowed to receive doxorubicin and intrathecal chemotherapy beginning on day 14. All patients had been treated previously with one or more courses of native L‐asparaginase; one of these patients was hypersensitive to L‐asparaginase at enrollment.
Results. During the 14‐day investigational window with PEG‐L‐asparaginase monotherapy, 22% of patients examined achieved a complete or partial remission. By completion, of the 35‐day induction period, 78% (or 14 of 18) of evaluated patients achieved complete or partial remission. Anaphylaxis did not occur during treatment. Mild urticaria and mild local allergic reactions occurred in five patients but did not cause discontinuation of treatment. The incidence of hyperglycemia and pancreatitis was less than expected from historic data published for previous studies with native L‐asparaginase.
Conclusions. As administered in this study, PEG‐L‐asparaginase can be given safely with a spectrum of toxicity similar to that of native L‐asparaginase. Single‐agent activity was documented in patients with ALL in bone marrow relapse. Cancer 1995;75:1176–81.
Despite intensive therapy, the survival of children with medulloblastoma remains disappointing. Moreover, children who survive are affected by serious long-term sequelae of treatment that impair their quality of life. In search of chromosomal aberrations indicative of sites involved in oncogenic transformation and in an attempt to find reliable prognostic markers, the authors analyzed 15 medulloblastomas by comparative genomic hybridization. All neoplasms showed chromosomal abnormalities. The most frequent losses were 17p (7/15 tumors), 8p and 11p (6/15), 10p, 1lq, 16q, and 20q (5/15), and 20p (4/15). Gains were recurrently found at 7q (10/15 tumors), 17q and 18q (9/15 tumors), 7p and 13q (7/15), 18p (6/15), and 1q, 4q, 6q. and 9p (5/15 tumors). Four tumors showed loss of 17p together with gain of 17q, suggesting an isochromosome 17q. High-level amplifications were seen at 1p34, 5p15, 13q34, and 18p11 (one tumor each), and at 2p15 in two tumors, one of which was proven to be N-Myc amplification. The overall pattern of alterations found in this study confirms the findings of other studies and adds two novel regions with chromosomal gains, at 13q and 18q. Previous reports on the relation between 17q gain and survival could not be confirmed, whereas amplification of N-myc or L-myc seems to indicate poor clinical outcome.
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