Clinical evaluation of succinylated Acinetobacter glutaminase-asparaginase in adult leukemia.
We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.
D000150:Acinetobacter / Q000201:enzymology; D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001215:Asparaginase / Q000008:administration & dosage / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D005972:Glutaminase / Q000008:administration & dosage / Q000627:therapeutic use*; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D007945:Leukemia, Lymphoid / Q000188:drug therapy*; D007951:Leukemia, Myeloid / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*
D000970:Antineoplastic Agents; C027700:succinylated glutaminase-asparaginase; D001215:Asparaginase; D005972:Glutaminase