Background: High-dose methotrexate (HD-MTX) with or without other drugs is a common regimen for treating and preventing central nervous system involvement in patients with leukemia and lymphoma. Despite leucovorin rescue combined with appropriate hydration and urine alkalinization, some patients still have delayed MTX excretion. While avoiding HD-MTX in patients with several prior known risk factors such as pre-existing renal dysfunction, third space fluid collection, and co-administration of nephrotoxic agents, delayed MTX excretion remains a risk factor for serious adverse effects that may cause treatment cessation, serious organ damage, and death. This study aimed to identify risk factors of HD-MTX by examining clinical and laboratory characteristics of patients with and without delayed MTX excretion and understand prognostic effects of delayed MTX excretion.

Method: We included patients with leukemia or lymphoma who received HD-MTX at Kameda Medical Center, Japan between September 2011 and April 2017. The primary and secondary end points were risk factors associated with delayed MTX excretion and evaluation of the relationship between delayed MTX excretion and survival, respectively. Patients received adequate hydration and alkalinization to maintain urine pH > 7.0, leucovorin rescue, and other supportive care based on institutional guidelines. Delayed MTX excretion was defined as plasma MTX levels ≥ 1 μmol/L at 48 h or ≥ 0.1 μmol/L 72 h after HD-MTX commenced. Risk factors contributing to delayed MTX excretion were identified using univariate and multivariate analyses, and overall survival (OS) was estimated using the Kaplan-Meier method. This study conformed to the principles of the Declaration of Helsinki.

Result: We identified 120 patients (16 to 84 yr) who received HD-MTX during the study (mean, 2.24 g/m2, 95%CI:2.13-2.36) administered in 318 cycles (median, 2 cycles; range, 1-12 cycles/patient) with or without chemotherapy. Delayed MTX excretion occurred in 70 cycles (22.0%), 23 at 48 h and 49 at 72 h, and 2 in both, in 51 (42.5%) patients. The demographic baseline patient characteristics showed that delayed MTX excretion occurred more frequently in aged (median, 70 yr; range, 35-84 yr vs 64 yr; range, 16-80 yr, p < 0.006) and male (70.6 vs 53.6%, p = 0.008) patients than in other patients. Delayed MTX excretion occurred more frequently in patients receiving therapy than in those on prophylaxis (25 [49.0%] vs 9 [13.0%] patients, p < 0.01). The disease category proportion (leukemia or lymphoma) and chemotherapy protocol did not differ between groups.

The risk factors were analyzed by comparing the 248 and 70 cycles of not delayed and delayed MTX excretion, respectively. Risk factors analyzed in this study were age > 65 yr, male sex, serum albumin< 3 g/dL, body mass index > 25 kg/m2, creatinine clearance (CCr) < 60 mL/min, MTX dose > 3 g/m2, urine pH < 7.0 during treatment, ascites, pleural fluid, and co-administration of interactive agents for MTX excretion (NSAIDs, PPI, sulfamethoxazole-trimethoprim, or furosemide), which were considered risk factors for delayed MTX excretion.

Univariate analysis showed that delayed MTX excretion was associated with age > 65 yr (75.7 vs 51.1% in the delayed vs not delayed cohorts, p = 0.002), male sex (74.2 vs 51.1%, p = 0.02), serum albumin < 3 g/dL (25.7 vs 11.1%, p = 0.007), CCr < 60 mL/min (30.0 vs 13.0%, p = 0.003), urine pH < 7.0 during treatment (28.5 vs 7.4%, p < 0.01), presence of pleural fluid (5.7 vs 0.7%, p = 0.02). In the multivariate analysis, male sex [odds ratio (OR) 2.07, 95% confidence interval (CI): 1.09-3.92, p < 0.01], CCr < 60 mL/min (OR 3.57, 95% CI: 1.84-6.95, p < 0.01), urine pH during treatment < 7.0 (OR 4.97, 95% CI: 2.39-10.3, p < 0.01), and presence of pleural effusion (OR 10.6, 95% CI: 1.6-70.6, p < 0.01) were identified as an independent risk factor of delayed MTX excretion.

Patients with delayed MTX excretion had higher nephrotoxicity incidences than those without delayed excretion did (23.5 vs 4.3%, p = 0.003). In the survival analysis, patients with delayed MTX excretion had shorter OS than those without delayed excretion did [n = 51, median OS: 47 months, 95% CI: 19-99 vs n = 69 median OS: not reached (NR), 95% CI: 52-NR].

Conclusion: To the best of our knowledge, this is the first study to identify clinical risk factors associated with delayed MTX excretion in patients on HD-MTX. We also showed that delayed MTX excretion was associated with poor OS.

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Disclosures

No relevant conflicts of interest to declare.

Topics:
excretory function, leukemia, lymphoma, methotrexate, urine ph, cardiocerebral resuscitation, chemotherapy regimen, adverse effects, anti-inflammatory agents, non-steroidal, ascites

Author notes

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Asterisk with author names denotes non-ASH members.

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© 2017 by The American Society of Hematology
2017
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