Intracellular drug measurements to predict toxicity in high-dose methotrexate therapy in leukaemia and central nervous system lymphoma: a pilot study

High-dose Methotrexate (HD-MTX) chemotherapy is the cornerstone of the
treatment of central nervous system lymphoma (PCNSL) and acute lymphoblastic
leukaemia (ALL).The anti-folate MTX is cytotoxic by depleting folate co-factors
necessary for RNA and DNA synthesis with consequent arrest of cellular
proliferation. MTX is an effective drug because high plasma levels are
relatively well tolerated resulting in penetration of the blood brain barrier
and increased bioavailability.Although MTX is a relatively safe and quite
effective drug, there is a large inter-individual variation in MTX
pharmacokinetics and treatment outcome is variable.[3-6] Moreover, >35% of
patients experience adverse events such as renal dysfunction, neurotoxicity,
and severe mucositis. Especially nephrotoxicity, which has been reported in 26%
of patients may necessitate delay or abortion of subsequent cycles and is not
always reversible. Dosing algorithms have been developed to target an area
under the curve (AUC) for plasma MTX between 1000 and 1100 *mol/L. However,
there is little information what plasma dose/AUC is optimal to reach remission
of the disease without adverse events. Moreover, conflicting data exist
regarding association between plasma MTX levels, AUC, and clinical outcome. In
contrast, intracellular MTX levels are difficult to measure but are probably
better related to efficacy and also toxicity. Scarce data also exist about the
relation between the maximum plasma MTX levels and accumulation of
intracellular MTX in target tissue or cerebral spinal fluid (CSF).

A) To investigate the pharmacokinetics and determinants of MTX-PG accumulation
in plasma and erythrocytes in adult CNS lymphoma and leukemia patients treated
with HD-MTX;
B) To investigate whether intracellular MTX levels are related to toxicity in
adult HD-MTX therapy.

open label

Most of the patients treated with MTX for lymphoma or leukemia have a central
line or Hickman catheter. During routine blood tests, extra blood samples for
this study will be withdrawn, in most cases this will be done via the central
line / Hickman.
Burden and risks for the patient is very limited