Solitary serummethotrexate level 36 hours post high-dose methotrexate: A safe, efficacious, and cost-effective strategy to monitormethotrexate toxicities in childhood leukemia in resource-limited centers

Abstract

Background: The standard practice during high-dose methotrexate (HD-MTX) in acute lymphoblastic leukemia (ALL) to mitigate toxicity is to serially monitor levels till serum MTX < 0.01 mu mol/L. Most resource-limited centers lack in-house access to MTX levels, and therefore repeated monitoring is costly and cumbersome. We studied the efficacy and safety of "solitary 36 hours post HD-MTX levels (MTX36)." Procedure: This prospective observational study consecutively enrolled childrenwith ALL receiving HD-MTX. Cycles with unavailable MTX36 and MTX36 > 10 mu mol/L were excluded. HD-MTX was administered over 24 hours (BFM-2009 protocol) with 12 hours of prehydration. MTX36 were performed at other centers. Leucovorin was given in six hourly doses 36 hours post HD-MTX. Hydrationwas continued until the last dose of leucovorin. MTXtoxicities, including change of creatinine from baseline at 36 hours (Delta Cr-36), were noted. Two groups depending on MTX36(<= 1 mu mol/L vs > 1 mu mol/L) received six versus eight doses of leucovorin, and toxicities were compared. Results: Twenty-nine childrenwith median age five years (1-11) whoreceived 100HD-MTXcycles with a medianMTXdose of 3 g/m(2) (2-5) were analyzed. The medianMTX36 levelwas 1.165 mu mol/L (0.1-7.32). Toxicities of HD-MTX (CTCAE-4.0): transaminitis-22%; creatinine elevation >= 1.25 times baseline-24%; cytopenias-16%; mucositis-17%; acute kidney injury (AKI)-6%. All toxicities were <= CTCAE grade 3. Creatinine elevation, AKI, and mucositis were significantly higher in the group with higher MTX36. There was no correlation (r = 0.3) between Delta Cr-36 and MTX36. MTX36 was thrice more economical than the standard protocol. Conclusion: MTX36 is a potential cost-effective, efficacious, and safe limited sample strategy to monitor HD-MTX, particularly in centers where in-houseMTX levels are unavailable.