Toxicity and Risk Factors Contributing to Delayed Methotrexate (MTX) Elimination in Adult/Elderly Patients (pts) Treated with High-Dose Methotrexate Therapy (HDMTX), a 2-Year, Single Center Survey.

Abstract

HDMTX is a well-established regimen used in a variety of neoplasms, including acute lymphoblastic leukemia (ALL) or lymphoma (NHL). Risk factors contributing to a delayed MTX-elimination and toxicity have been studied in pediatric pts with HDMTX (Relling MV, J Clin Oncol 1994, 12: 1667–72). However, data are scarce on risk factors contributing to delayed MTX elimination in adult pts, on toxicities in elderly pts and from pts treated with HDMTX outside clinical trials. We assessed toxicities and risk factors in all non-pediatric pts treated with HDMTX at the Charité in 2003/04. 141 pts (age 16–81y, median 44y) received 614 HDMTX cycles (median dose MTX/m2: 3000mg, range 320–12000mg) for ALL (39), NHL (38), CNS-NHL (36), sarcoma or other solid tumor (28) within (69) or outside (72) clinical trials. In 99/614 (16%) of HDMTX cycles a 15–85% (median 50%) dose reduction was carried out due to renal dysfunction (58), severe toxicity of prior chemotherapy (18) or other reasons (23). Toxicities in 62/614 (10%) HDMTX cycles caused delays of 1–50 days (median 7 days) of scheduled therapy. 61/614 (10%) HDMTX cycles resulted in an increase of serum creatinine values above the upper limit of normal (ULN) (median of 112μmol/L, range 81–386μmol/L). Delayed MTX-elimination (MTX blood level >150μM 24h, >3μM 36h, >1μM 42h, >0.4μM 48h or >0.1μM 68h) occurred in 156/614 (25%) HDMTX cycles. Grade 3/4 toxicities were recorded in 224 (36%) cycles for leukopenia, 127 (21%) cycles for liver toxicity, 116 (19%) cycles for thrombocytopenia, 88 (14%) cycles for fever with neutropenia and 63 (10%) cycles for mucositis/gastrointestinal toxicity. Presence of a 3rd space and comedications with known interference with MTX elimination or nephrotoxic potential were associated with a delayed MTX elimination (p<0.01). Overweight (BMI≥25kg/m2), urine pH<7 at some time after HDMTX and presence of a 3rd space were associated with an increase of serum creatinine values above ULN (p≤0.05). Pts with delayed MTX elimination or an increase of serum creatinine above ULN were older compared to pts with regular MTX elimination (median age 51y vs. 30y and 54y vs. 35y, p<0.01). Pts receiving HDMTX outside clinical trials more frequently experienced delayed MTX elimination (p<0.01). HDMTX frequently causes grade 3/4 hematotoxicity and increases of serum creatinine. Delayed MTX elimination is associated with advanced age and therapy outside clinical trials. Improved supportive care strategies are needed, especially in pts with advanced age, to ensure predictable MTX-elimination and reduce toxicities associated with HDMTX.