Coproporphyrine Isomers and Methotrexate Elimination (COMETH)

• The UCP I/(I+III) ratio [ Time Frame: before and at the end of MTX infusion and at the end of hospitalisation. ] [ Designated as safety issue: Yes ]
• Five polymorphisms of the ABCC2 gene (-24C/T, 1249G/A, 3563T/A, 4544G/A) [ Time Frame: during the study ] [ Designated as safety issue: Yes ]
• Blood cells count . [ Time Frame: before MTX infusion and at the end of hospitalisation ] [ Designated as safety issue: Yes ]
• Renal function [ Time Frame: before MTX infusion and at the end of hospitalisation ] [ Designated as safety issue: Yes ]

High dose methotrexate (MTX) is responsible of severe toxicity in patients in whom elimination from plasma is delayed. Factors responsible for MTX accumulation are partly known but some patients still experience toxicity despite adequate measures being taken. Our hypothesis is that renal tubular secretion may be impaired in these patients. This study aims at evaluating the performance of the UCP ratio (urinary ratio of coproporphyrins), a putative biomarker of tubular secretion, in predicting delayed MTX elimination.

MTX is a substrate of MRP2, a renal tubular transporter encoded by the ABCC2 gene. It has been shown that single nucleotide polymorphisms (SNPs) on the ABCC2 gene are associated with impairment of MTX elimination. Mutations on the ABCC2 gene are also responsible for the Dubin-Johnson syndrome, characterised by the absence of a functional MRP2 protein. Apart from hyperbilirubinaemia, the main biological perturbation observed in this disease is a typical increase of the urinary ratio of coproporphyrins I (I+ III) (UCP ratio). Our hypothesis is that the UCP ratio could be used as a biomarker of MRP2's activity, thus predicting MTX elimination. One hundred patients treated with high dose MTX will be recruited in this prospective study. Their UCP ratio will be measured before and after MTX administration and correlated with MTX clearance. A genetic analysis will be conducted to study the five more frequents SNPs of ABCC2 in each patient.

• Patients aged more than 18 y, hospitalized in the neurology or in the haematology department at PSP hospital of Paris or in the haematology department at CHU of Tours
• Who should receive high-dose methotrexate (> 1 g/m2) for one of the following conditions : Central Nervous System Neoplasms; Lymphoma, Large B-Cell, Diffuse; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma or Burkitt lymphoma

• Central Nervous System Neoplasms
• Lymphoma, Large B-Cell, Diffuse
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma
• Burkitt Lymphoma

Inclusion criteria :

• Patients receiving HDMTX (≥1g/m2) for a primitive cerebral lymphoma, a large cell lymphoma, a lymphoblastic lymphoma, a Burkitt's lymphoma or an acute lymphoblastic leukaemia,
• over 18 years old,
• Signed informed consent.
• Affiliated to a medical assurance.
• Able to respect the protocol.
• Effective contraception for women.

Exclusion criteria :

• renal failure,
• liver failure,
• hepatic cytolysis,
• chronic respiratory deficiency,
• pregnancy,
• breast-feeding,
• Concomitant medication: phenytoin, probenecid, trimethoprim, phenylbutazone, salicylates, non steroid anti-inflammatory, yellow fever vaccine.
• Patient included in another study in the four weeks preceding his inclusion.