Can liver enzyme elevations be caused by the combination therapy including vincristine, cytarabine,

Fråga: Can liver enzyme elevations be caused by the combination therapy including vincristine, cytarabine, daunorubicin, cyclophosphamide and betamethason?

Background: A 20-year-old man with acute lymphatic leukemia was treated with a regimen which included the above mentioned drugs in ordinary doses. About one week later his bilirubin increased to 117 umol/l (reference <20 umol/l). Also alkaline phosphatase (ALP) 30 ukat/l (reference 0.8-4.6 ukat/l) and gamma-glutamyl transpeptidase (GGTP) 6 ukat/l (reference <1.30 ukat/l) increased. Now, about 4 weeks later bilirubin has normalized and gamma-glutamyl transpeptidase has decreased. However, ALP remained unchanged (30 ukat/l). Investigation including liver biopsy has excluded other reasons to the hepatic toxicity. A new course is planned.

Sammanfattning: Vincristine, cytarabine, daunorubicin and cyclophosphamide could possibly cause hepatic toxicity, the latter being most frequently reported. The increases observed in liver enzyme levels seem to be reversible. However, combination therapy with other drugs or radiation can complicate the assessment of a causal relationship.

Svar: Vincristine, cytarabine, daunorubicin and cyclophosphamide are all mainly inactivated in the liver (1). All drugs are capable of producing hepatic toxicity (2).

Hepatic injury or liver enzyme elevations attributed to vinca alkaloids such as vincristine has been reported, although this side-effect seems to be uncommon. Concomitant radiation therapy has in several cases resulted in severe liver toxicity, being fatal in some cases (2). A patient on combination therapy including vincristine, cyclophosphamide and etoposide developed increased levels of transaminases( 2-6 fold), ALP and GGTP (1.5-2 fold). This occurred 6 days after drug administration and disappeared 2-7 weeks later, except for the GGTP increase which persisted longer. In this case a challenge with vincristine led to a relapse (2,3). The files of Swedish Adverse Drug Reaction Advisory Committe (SADRAC) contain two cases of mixed liver reaction ie with increases of aminotransferases, ALP, GGTP, and bilirubin.

Cytarabin as high-dose monotherapy has been connected with severe hepatotoxicity including cholestatic jaundice. In combination therapy with vincristine and prednison elevations of bilirubin and aminotransferase were seen after the first course in two patients (2). In SADRAC one case of unspecified hepatitis is mentioned in connection with cytarabin treatment.

Liver enzyme elevations have been observed during therapy with daunorubicin. Nodular regenerative hyperplasia has occurred during concomitant treatment with cytarabine (2). No such cases were found in SADRAC.

Cyclophosphamide seems to be most frequently reported among the above mentioned cytostatic agents. Some studies report aminotransferase elevations in a wide range from 10 to 85 percent of patients who received combination therapy including cyclophosphamide. These elevations were dose-dependent and occurred 1-4 weeks after treatment was started. The underlying mechanism is unknown, although an increased formation of acrolein and/or a decreased gluthatione conjugation have been suggested (2).

There are 16 cases of hepatic side-effects due to cyclophosphamide treatment reported to SADRAC, all judged as possible. These include four cases of increased transaminases, two cases each of liver necrosis, mixed liver reaction and elevated transaminases, ALP and GGTP. Sporadic cases of intrahepatic cholestasis, jaundice, toxic hepatopathy, hepatitis, and elevated transaminases and bilirubin were retrieved. Half of the cases concerned monotherapy with cyclophosphamide and in the rest of the cases concomitant treatment with other drugs were described.

One case concerned an 82-year-old woman who developed elevated transaminases, ALP and GGTP during treatment for five weeks with cyclophosphamide. These were normalised 5-6 weeks after discontinuation of therapy. In another case of elevated transaminases, levels returned to normal two weeks after treatment with cyclophosphamide had stopped. 1 Dollery, Therapeutic drugs, 1991 2 Stricker BH, Drug-induced ocular side-effects, 1992; 2nd ed: 3 Saghir NS el, Hawkins KA: Hepatotoxicity following vincristine therapy. Cancer 1984; 54: 2006-2008 (abstract)