Intrathecal chemotherapy with antineoplastic agents in children.

Intrathecal chemotherapy with antineoplastic agents is mainly utilised in children with leukaemia and lymphoma, and in selected brain tumours. In these diseases, intrathecal use is restricted to methotrexate (MTX), cytosine arabinoside (Ara-C) and corticosteroids. A number of other agents are, at the present time, under evaluation. Intrathecal MTX administered sequentially with systemic high dose MTX infusion prolongs therapeutic cerebral spinal fluid (CSF) levels of the drug. Prolonged therapeutic CSF levels can also be achieved by giving repeated small intrathecal doses of MTX over an extended period in selected patients, with an implanted Ommaya reservoir. In the CSF, the metabolic inactivation of Ara-C is significantly lower than in plasma with a CSF clearance similar to the rate of CSF bulk flow. A slow-release formulation of Ara-C may be given intrathecally, resulting in a prolonged cytotoxic concentration in the CSF. CNS relapse and neurotoxicity in patients with acute lymphoblastic leukaemia, especially younger children, may be reduced by using age-related dosing of intrathecal MTX and Ara-C. Hydrocortisone is used in combination with MTX and Ara-C for so-called 'triple intrathecal chemotherapy' in the treatment of meningeal leukaemia. Intrathecal thiotepa does not appear to be advantageous over systemic administration in patients with brain and meningeal leukaemia. Monoclonal antibodies, reactive with tumour-associated antigens, can be used as delivery systems for chemotherapeutic agents and radionuclides. However, the development of this new approach is currently under evaluation in larger clinical studies. Neurological adverse effects may be expected with intrathecal chemotherapy and are increased by high dose systemic therapy, concomitant cranial radiotherapy or meningeal infiltration by neoplastic cells. Inadvertant intrathecal administration of antineoplastic agents that are indicated for systemic administration only, is dangerous and may result in a fatal outcome.

L-asparagine depletion and L-asparaginase activity in children with acute lymphoblastic leukemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure.

PURPOSE: The present study was aimed at investigating L-asparaginase (L-ASE) activity (in plasma) and L-asparagine (L-ASN) depletion (in plasma and CSF) in children with newly diagnosed acute lymphoblastic leukemia (ALL) exposed for the first time to different L-ASE products. PATIENTS AND METHODS: During the induction treatment of the AIEOP ALL 95 study, 62 patients were treated with either Erwinase (n = 15), or E. coli medac (n = 47) L-ASE products, given either i.m. or i.v., at the standard dosage of 10,000 IU/m2, q 3 days x 8 (first exposure). RESULTS: Plasma and CSF L-ASN trough levels were undetectable in all cases, including those with L-ASE trough activity < 50 mU/ml. L-ASE trough activity during the administration of medac was however significantly higher when compared with that of Erwinase. CONCLUSIONS: L-ASN depletion after a first exposure to standard doses of Erwinase or medac is obtained in virtually all patients. No differences are seen between the I.M. or I.V. administration routes but the medac product is associated with a significantly higher enzyme activity in respect of Erwinase. L-ASN levels may be undetectable also in patients with L-ASE trough activity levels < 50 mU/ml, challenging the current opinion that an activity level of 100 mU/ml is needed to obtain L-ASN depletion.

Infections with hepatotropic viruses in children treated with allogeneic bone marrow transplantation.

Patients treated with BMT are extremely susceptible to infection with blood-borne viruses that can cause liver disease of variable clinical severity, from minimal biochemical changes to fulminant hepatic failure. Facing a patient with liver disfunction after BMT, one must bear in mind that more than one cause of liver disease, of viral and/or non-viral origin, may coexist. Moreover, besides the most important hepatotropic viruses, other agents, like herpesviruses (including CMV, adenoviruses, Epstein-Barr virus) may also be implicated, sometimes causing a life-threatening fulminant hepatitis, due to their cytopatic effect. Liver disease history and viral markers before transplant, together with the accurate assessment of the timing and type of clinical and biochemical deterioration are useful tools for a differential diagnosis. Liver biopsy, if taken in the early posttransplant period, is often difficult to interpret, while in case of liver disease occurring during immunosuppression tapering, histologic examination may discriminate between an exacerbation of viral hepatitis and an acute onset of chronic liver GVHD. While it seems that hepatitis G virus does not cause liver disease, the presence of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is a matter of concern for its consequences both early after BMT and for long-term survivors. Despite screening for blood and marrow donors for HBV and, more recently, for HCV markers, the rate of post-transplant infection (4% and 4-15% respectively, confirmed in prospective studies) with those viruses indicates that viral hepatitis still remains an important clinical problem in this setting, although the prognosis of chronic HCV and HBV infection appears more benign than expected, especially in children.

Morbidity and mortality due to liver disease in children undergoing allogeneic bone marrow transplantation: a 10-year prospective study.

We have conducted a long-term prospective study of children undergoing bone marrow transplantation (BMT) to assess morbidity and mortality for liver disease. One hundred eleven consecutive children were enrolled between June 1985 and June 1995 and were followed-up for a median of 5.5 years after BMT. Before transplant 48/111 children (43%) had abnormal alanine aminotransferase (ALT), none were HBsAg+ and 4/111 were anti-HCV+. After BMT 4/111 patients (3. 6%) died of liver failure. No relationship was found between pretransplant hepatitis B (HBV) or C (HCV) infection or elevated transaminases and development of severe liver damage. Eighty-two out of one hundred and eleven patients (74%) had abnormalities of ALT after BMT, transient (n = 54) or persistent (n = 28). None developed clinical signs or symptoms of end stage liver disease or of cirrhosis during follow-up. No significant difference in prevalence of liver disease, was found between children with normal or abnormal ALT at BMT (relative risk [RR] = 1.04). HCV infection could be implicated in the etiology of chronic liver disease in 14/28 patients; 2 other patients were found infected by HBV alone (1 case) or combined with HCV (1 case). In the remaining 12 the etiology of chronic liver disease could not be defined. Posttransplant hepatitis B occurred in 4/111 children (3.6%), including a recipient from a donor who had been previously vaccinated against HBV, while no patient who had been vaccinated developed hepatitis B. The rate of posttransplant seroconversion to anti-HCV was 15%.