SEVERE UNEXPECTED IMPAIRMENT OF RENAL MET HOTREXATE ELIMINATION AFTERHIGH-DOSE THERAPY

Even in patients with normal renal function, high-dose methotrexate th erapy (HDMTX) may be followed by extremely prolonged MTX elimination t hough alkaline diuresis is performed correctly. By inquiry in Germany, Austria and Switzerland for HDMTX infusions with MTX plasma concentra tion 42 h after start of exposure (MTX-42) higher than 5 mumol/l (muM) , we analyzed data from 21 patients in whom impairment of renal methot rexate elimination had occurred at an age of 2 to 21 years. 18 patient s had received 5 g/m2.24 h, 3 had received 12 g/m2.4 h. They presented with MTX-48 serum level between 1.7 and 1404 muM. There was no recogn izable causative factor. As early signs for impaired elimination. we i dentified enhanced vomiting during MTX infusion in 8/21, elevated stea dy-state-MTX in 11/15, and a rise of serum creatinine greater than 50% in 14/16 patients in whom respective data were available. Creatinine rose to a maximum of 1.0-4.9 mg/dl within 1-4 days in 19/21 patients ( accompanied by diuresis problems in only 5 patients) and normalized wi thin 3-17 days in all but two patients. Creatinine maximum correlated weakly with MTX-48 (r=0,34) and with extrarenal toxicity. 8 patients h ad normal (WHO 0-II-degrees), 8 other had intensified (III-IV-degrees) but not critical extrarenal MTX toxicity with calciumfolinate (CF) do ses of 0.2-1.6 mg/kg.muM MTX q 6 h started 28-54 h after beginning of MTX exposure. 5 patients had unusual toxicity. 2 patients suffered fro m severe but reversible encephalopathies with CF doses of 0.05 and 1 m g/kg.muM MTX q 6 h started after 51 and 36 h, respectively. Severe muc ositis after CF doses lower than 0.1 mg/kg.muM MTX after 41 and 48 h l ed to reversible exfoliative dermatitis in one and to lethal hepatic a nd cardiac failure in another patient. Plasmapheresis reduced MTX plas ma concentration significantly without rebound in one patient with sev ere hepatopathy and MTX-24 of 857 muM. Cholestyramine had no effect in 4 patients. HPLC analysis in 40 serum aliquots from 4 patients confir med MTX concentrations measured by commercial immunoassays (EMIT(R), T Dx(R)) and showed reduced formation of 7-hydroxy-MTX without enhanced toxicity. With CF doses above 1 mg/kg.muM MTX, relation of 5-methyltet rahydrofolate to MTX was higher than isomolar. Before or after prolong ed MTX elimination, 20/21 patients tolerated HD or intermediate dose M TX without any problems. We conclude that it is important to look for early signs of this elimination disorder. Sufficient amounts of CF for doses as high as 0.5 mg/kg.muM MTX q 6 h (which might be lowered to 0 .2 mg/kg.muM MTX when calculated single doses exceed 5 g) must be avai lable for HDMTX therapies. Only with sufficient rescue, prognosis seem s favourable. Recurrence of MTX elimination impairment has not been ob served.