Joseph H. Burchenal

Toxicity of E. coli L-asparaginase in man.

During therapeutic trials with E. coli L‐asparaginase in 131 children and 143 adults with neoplastic disease the following signs of toxicity have been observed: fever, nausea and vomiting, weight loss, somnolence, lethargy, confusion, hypolipidemia, hyperlipidemia, hypoproteinemia, abnormal liver function tests, fatty metamorphosis of the liver, pancreatitis (in rare instances), azotemia, granulocytopenia, lymphopenia, thrombocytopenia, and hypersensitivity reactions. While these effects have been moderately severe and reversible in most instances, some patients have shown dangerous degrees of toxicity. This has been the case most frequently in adult patients receiving a dose of 5000 IU/kg/day.

E. coli L‐asparaginase in the treatment of leukemia and solid tumors in 131 children

One hundred thirty‐one children between 1 and 15 years of age have been treated. Ninety‐five children had acute lymphoblastic leukemia (ALL); 13 had other types of leukemia; 8 had lymphoma; and 15 had other solid tumors. The dosage ranged from 10 to 5,000 IU/kg daily. Treatment schedules included maintenance after remission and no maintenance. Nine patients in bone marrow remission with other chemotherapy prior to treatment with A‐ase received a 28‐day course. Six patients received the enzyme intrathecally for meningeal leukemia. Of the 73 adequately treated (over 14 days) ALL patients, the overall remission rate was 62%; the median duration of remission was 60 days with a range of 15 to 248 days. The duration of remission appeared to be independent of dose. Six nonlymphoblastic leukemias demonstrated transient fall in WBC and decreased organ size but no bone marrow remission. One of 4 with Hodgkins disease demonstrated decrease in size of nodes, liver, and spleen. None of the solid tumors responded. The usual side effects of conventional chemotherapeutic agents, mucous membrane ulcerations, alopecia, and diarrhea were not seen. Side effects included reversible abnormal biochemical liver function tests, fever, and anaphylaxis.

Clinical results of treatment with E. coli L‐asparaginase in adults with leukemia, lymphoma, and solid tumors

E. coli L‐asparaginase (A‐ase) was administered to 163 adults with different forms of leukemia, lymphoma, and solid tumors. Six of 11 patients with acute lymphoblastic leukemia and 4 of 32 patients with acute myeloblastic, myelomonoblastic, or undifferentiated leukemia had complete or good partial remissions. Doses of 10 to 5000 IU/kg/day were used, but there was no clear correlation between dose and therapeutic response, nor with any particular preparation of A‐ase. Some of the others had transient physical and/or hematologic improvement, but remission was not achieved. Nineteen patients with myeloblastic leukemia, 4 with lymphoblastic and 3 with undifferentiated, had no response. Eight patients with acute leukemia (7 lymphoblastic and one myeloblastic), who were already in complete remission induced with other agents, were treated with 1000 IU/kg/day or higher doses of A‐ase for one month or longer. Seven were given no further therapy. The disease relapsed within 2‐5 months in 6 patients, but one is still in remission after 8 months. The eighth patient is still in remission after 3 months but is receiving other chemotherapy. Partial hematologic responses occurred in one patient with untreated chronic granulocytic leukemia, in 4 of 5 patients in a blastic phase of chronic granulocytic leukemia, and in 2 of 3 patients with chronic lymphocytic leukemia, but in none of these patients was the response of substantial clinical benefit. Two patients with disseminated lymphosarcoma or reticulum cell sarcoma had excellent therapeutic responses to A‐ase, and 4 others showed some improvement while 14 had no detectable response. Eight patients with advanced Hodgkins disease showed no response. One patient with malignant melanoma with multiple cutaneous metastases had temporary regression of his metastatic nodules with A‐ase on several occasions, but evaluation of this case was complicated by other chemotherapy. Twenty‐nine other patients with melanoma had no response nor did 45 patients with other types of solid tumors. Some toxic manifestations of A‐ase occurred in almost all patients; these were generally more severe and sometimes were intolerable at higher dosage levels. The toxicity will be discussed in detail in an accompanying report.

Long-Term Survivors in Acute Leukemia

It is obvious from the many publications on the subject that long-term survivors, defined as those patients who survive either with or without evidence of the disease for more than 5 years from the diagnosis, do occur in acute leukemia [1–5]. Previous studies have shown that those patients surviving for 5 years have a 50% chance of surviving indefinitely [6]. Most of those who relapse will do so between the 5th and 8th years, and only a very few after the 9th year. For instance, of the 101 patients reported as 5-year survivors in 1964, 64 were living and well at that time with no evidence of the disease. In the ensuing 4 years, 6 of these had relapsed so that there were 58 out of 101 surviving with no evidence of the disease, or an annual drop-off of approximately 2.5% [7].

New cancer chemotherapeutic agents.

The new agents available for the clinical chemotherapy of cancer can be divided into four groups: 1. agents of relatively proven value, such as adriamycin, DTIC, bleomycin, asparaginase, BCNU, and CCNU; 2. agents with suggestive evidence of clinical activity in small series, such as Streptozotocin, N‐demethylepipodophyllotoxin thenylidine glucoside (VM‐26), azacytidine, hydroxyurea, guanazole, and 5‐hydroxypicolinaldehyde thiosemicarbazone (5‐HP); 3. agents in Phase I studies, such as methyl‐CCNU, ICRF 159, Iphosfamide, platinum diamminodichloride, and N‐demethylepipodophyllotoxin ethylidine glucoside (VP‐16), and 4. agents with considerable promise of activity at preclinical levels which have not as yet reached Phase I trials, at least in this country, such as palmo ara‐C, cyclo‐cytidine, and 2,2′‐anhydro‐1‐(β‐D‐arabinosyl)‐5‐fluorocytosine. In addition to their clinical activity, these agents have many diverse mechanisms of action and differing limiting toxicity. For these reasons, they may offer unique opportunities for use in combination chemotherapy.

Clinical experience with L-asparaginase.

Inhibition of acute leukemia in man by L-asparaginase was first reported in 1967 [7, 10]. As larger enzyme supplies became available, clinical trials have been conducted by several groups of investigators, and the therapeutic activity as well as toxic effects have been evaluated in patients with many types of neoplastic disease [1–8, 10–17]. This report is an account of the experience gained over a period of 2½ years at the Memorial Hospital in New York.

Chemotherapy for Leukemia and Lymphoma

By treating acute leukemia and lymphoma in the conventional way, a physician can inadvertently deny patients the full benefit of potentially curative therapy. During the last 10 years, intensive combination therapy with agents belonging to five new classes has produced long-term remissions. However, patients who have been treated conventionally do not respond as well as previously untreated patients and may become resistant to one or more of these agents.

False positive trichina precipitin reactions in neoplastic disease.

Summary Patients with certain neoplastic diseases involving the reticuloendothelial system (Hodgkins disease, lymphosarcoma and acute leukemia) exhibited a high percentage of false positive trichina precipitin reactions. Such reactions were much less frequently encountered in sera from patients with metastatic carcinomas and no positive reactions were observed in the normal controls. The false-positive reaction does not appear to be related to medication.