L-asparaginase toxicity.

The discovery that guinea pig serum inhibits some mouse lymphomata (6), and the delineation of the enzyme L-aspara ginase as the active factor (1), resulted in a search for sources of L-asparaginase which might be useful in treating human neoplasms. Such a source was found in E. coli (8), and subse quent use of an E. coli L-asparaginase by Hill et a!. (5) and Oettgen et al. (9) suggested that it could produce remissions in children with acute lymphoblastic leukemia (ALL). These re ports suggested that L-asparaginase acted with a minimum of toxicity (2, 4, 10, 11). However, in our clinical trials, L-aspara ginase has produced unusual toxicity and serious morbidity. We feel that these observations are of sufficient importance to warrant this preliminary communication. Forty-nine patients were treated with intravenous doses of 50 to 1500 international units/kg/day of L-asparaginase,1 but the majority were treated with 200 lU/kg/day. The patients treated had the following diseases: childhood ALL (10 patients); adult ALL (7 patients); acute granulocytic leukemia (AGL) (5 patients); chronic granulocytic leuke mia (CGL), including 1 patient with blastic crisis (3 patients); chronic lymphocytic leukemic (CLL, 1 patient); myeloma (1 patient); lymphosarcoma (7 patients); Hodgkins's disease (3 patients); Burkitt's lymphoma (1 patient); melanoma (4 patients); undifferentiated carcinomas of unknown primary site (2 patients) ; breast cancer (1 patient) ; bronchogenic carci noma (1 patient); teratocarcinoma of the testis (1 patient); osteogenic sarcoma (1 patient); and, hypernephroma (1 patient). Clinically significant abnormalities not attributable to prior therapy or to the basic disease included the following relative ly expected problems: nausea or vomiting (41%); weight loss over 5% (46%); temperature elevations of 1°C or more over baseline levels (42%); hypersensitivity, including res piratory distress in 3 cases (22%); a drop in hemoglobin of more than 2 gm %, usually occurring after 3—4 weeks and ascribed to combined bone marrow depression and mild he molysis (46%); and liver function abnormalities (68%). In addi tion, there was a mean fall in serum albumin of 27% with a S.D. of 16% for 37 patients studied and a mean fall in serum cholesterol of 24% with a S.D. of 18% for 24 patients studied. These results extend a preliminary report from the National Cancer Institute (3) and corroborates reports of others (7, 10). In an effort to more clearly define the mechanism of serum cholesterol depression, 1 patient was studied on a metabolic