Abstract
Study Objective:
To determine whether there is a drug-drug interaction precluding the concomitant use of levetiracetam and high-dose methotrexate (HDMTX).
Design:
Retrospective analysis.
Setting:
Large academic tertiary care medical center.
Patients:
Adult lymphoma patients who received HDMTX as a 4-h infusion with or without concomitant levetiracetam.
Measurements and Main Results:
Generalized estimating equations clustered on patient were used to assess each outcome. The primary outcome was the incidence of delayed MTX elimination (MTX level >1 μmol/L at 48 h). Secondary outcomes included incidence of acute kidney injury (AKI) and hospital length of stay (LOS). The 430 included patients receiving 1993 doses of HDMTX had a median (IQR) age of 66 (57.5, 72.6) years, 88 (20.5%) received concomitant levetiracetam with at least one dose of MTX, 267 (62.1%) were male, and 397 (92.3%) were Caucasian. HDMTX doses ranged from 1 to 8 g/m2. The most common lymphoma diagnoses were systemic diffuse large B-cell lymphoma (DLBCL; 58.5%) and systemic DLBCL with central nervous system (CNS) involvement (32.8%). Rates of delayed elimination with and without levetiracetam were 13.4% and 16.3%, respectively (OR = 0.80, 95% CI 0.47–1.34, p = 0.39). AKI occurred in 15.6% and 17.0% of patients with and without concomitant levetiracetam, respectively (OR = 0.83, 95% CI 0.52–1.33, p = 0.28). The median LOS with and without levetiracetam was 4.2 and 4.1 days, respectively (p = 0.039). On multivariable analyses, only age, body surface area, diagnosis of systemic DLBCL with CNS involvement, serum creatinine, hemoglobin, total bilirubin, and dose of HDMTX were associated with delayed elimination.
Conclusions:
High-dose methotrexate administered with concomitant levetiracetam was not associated with increased risk for delayed MTX elimination or AKI. These results support that levetiracetam and HDMTX are safe for coadministration.
Keywords: acute kidney injury, drug interactions, levetiracetam, lymphoma, methotrexate
1 |. INTRODUCTION
High-dose methotrexate (HDMTX), defined as ≥1 g/m2, is commonly used in patients with lymphoma for treatment of central nervous system (CNS) disease involvement and prevention in those at high-risk for CNS relapse.1,2 After administration of HDMTX, monitoring of serum methotrexate (MTX) levels is required as delayed elimination can be associated with significant toxicities, including nephrotoxicity, mucositis, myelosuppression, hepatotoxicity, and, in severe cases, death.2–5 MTX levels of >1 μmol/L at 48 h after the start HDMTX infusion are associated with increased risk for MTX toxicity. This definition of delayed elimination remains consistent with adult dosing regimens including HDMTX.5,6 Higher MTX levels also correlate with increased severity of toxicity.5
Patients with CNS involvement of their malignancies have a high prevalence of seizures and often require anti-epileptic drugs (AEDs).7 Older AEDs, such as carbamazepine, valproate, and phenytoin, have significant drug-drug interactions which limit their potential for use in patients receiving chemotherapy.8,9 Compared to other AEDs, levetiracetam is ideal for use in cancer patients due to fewer drug-drug interactions and proven efficacy.10–13
Medications that alter MTX pharmacokinetics should be avoided during HDMTX therapy to prevent an increase in toxicity or decreased efficacy.6,8,14,15 The safety of concomitant use of levetiracetam and HDMTX has not been well characterized, so questions remain surrounding this practice. Two case reports have been published describing a possible interaction between HDMTX and levetiracetam, and one of the patients exposed to the interaction required glucarpidase for supratherapeutic levels of MTX.16,17 As a result of these case reports, two commonly used drug information resources state that use of the two medications together could result in increased MTX toxicity which raised concern and almost led to a practice change at our institution.18,19 Two retrospective studies have evaluated the possible interaction between HDMTX and levetiracetam, and neither study found evidence to support the interaction.20,21 These studies, however, were limited by small sample sizes, variable administration schedules, and heterogeneous malignancy diagnoses, so it remains unclear if this medication combination should be avoided.
At our institution, levetiracetam is often prescribed when an intracranial mass lesion consistent with CNS involvement by lymphoma is detected or if patients present with seizures. One key exception to this prescribing practice is in those patients who are diagnosed using cerebrospinal fluid analysis and do not require a biopsy of their CNS lesion. Levetiracetam may be continued throughout therapy with HDMTX due to concern for first time or breakthrough seizures or it may be discontinued at the discretion of the providers. This retrospective study aims to compare incidence of delayed MTX elimination at 48 h in patients with and without coadministration of levetiracetam.
2 |. METHODS
The institutional investigational review board approved this single-center, retrospective cohort study conducted through electronic health record (EHR) review. Consecutive, adult patients with lymphoma were included if they received a HDMTX infusion over 4 h at Mayo Clinic in Rochester, MN between January 1, 2009, and August 31, 2019, and had at least one MTX level drawn 48 ± 3 h after the start of HDMTX administration documented in the EHR. Patients were excluded if they were <18 years of age at the time of administration. All patients had their consent for review of their medical records for research purposes verified through Minnesota Research Authorization prior to data abstraction.
Patients with lymphoma were identified using international classification of diseases (ICD)-9 and ICD-10 codes. Patients diagnosed with diffuse large B-cell lymphoma (DLBCL) were further classified into those with systemic DLBCL, if there was no evidence of CNS involvement, or systemic DLBCL with CNS involvement. EHR data were compiled utilizing a standardized form developed by the investigators. Creatinine clearance was calculated using the Cockcroft-Gault formula.22 Serum creatinine was measured prior to HDMTX administration and at least once daily after administration until MTX clearance. Patients were followed until 14 days after their last dose of HDMTX or until the end of the study period, whichever occurred first. Current institutional practices regarding HDMTX administration, supportive care measures, and dose adjustments are described in Appendix 1.
The primary end point of the study was to determine whether coadministration of levetiracetam with HDMTX was associated with increased incidence of delayed MTX elimination, defined as MTX level >1 μmol/L at 48 h. Secondary end points included a cohort comparison of the incidence of MTX-associated acute kidney injury (AKI) based on Kidney Disease Improving Global Outcomes (KDIGO) staging criteria and hospital length of stay (LOS).23
The incidence of delayed MTX elimination at 48 h was compared in patients with and without coadministration of levetiracetam using generalized estimating equations (logistic regression) clustered on patient to account for multiple MTX doses per person.24 Variables that were significantly associated with delayed MTX elimination on univariate analysis were included in a multivariable analysis to see if this association held true after adjusting for other variables. Levetiracetam was also included in the multivariable model. Generalized estimating equations (logistic and linear as appropriate) clustered on patient were also used to assess if there were bivariate differences in characteristics between those with and without coadministration of levetiracetam as well as if coadministration of levetiracetam with HDMTX was associated with an increased incidence of MTX-associated AKI or with hospital LOS. Patients who received multiple doses of HDMTX in a single hospitalization were excluded from LOS analysis. Using similar methods as mentioned above, we also performed a sensitivity analysis that restricted the analysis to only the first three doses per patient to reduce any potential issues with the imbalance in the number of observations per patient. All tests were two-sided, and p-values ≤0.05 were considered statistically significant. Analyses were performed using SAS version 9.4 software (SAS Institute Inc.). With 1993 doses, 15% of doses receiving concomitant levetiracetam, and about 19% of those not receiving concomitant levetiracetam having an elevated MTX level at 48 h, we had 80% power to detect an odds ratio of 1.5 or more for the association between receiving concomitant levetiracetam and having an elevated MTX level at 48 h.
3 |. RESULTS
A total of 430 patients receiving 1993 doses of HDMTX met inclusion criteria and were split into two cohorts for analysis: 379 doses (in 88 patients) with concomitant levetiracetam and 1614 doses (in 372 patients) without concomitant levetiracetam. There were thirty patients included in both cohorts as they received doses of HDMTX with and without levetiracetam during our study time-frame. Patients had a median (IQR) age of 66 (57.5, 72.6) years, 267 (62.1%) were male, and 397 (92.3%) were Caucasian. Systemic DLBCL (58.5%) and systemic DLBCL with CNS involvement (32.8%) were the most common lymphoma diagnoses. Additional baseline characteristics are described in Tables 1 and S1. Statistically significant differences identified between the two cohorts included age (p = 0.030), serum creatinine (p = 0.018), and aspartate aminotransferase (p = 0.047).
TABLE 1.
Baseline characteristics of 430 patients with lymphoma receiving 1993 doses of high-dose methotrexate between 2009 and 2019 at Mayo Clinic
| Characteristic | Levetiracetam N = 379 administrations | No levetiracetam N = 1614 administrations | p-Value |
|---|---|---|---|
| Male, no. (%) | 162 (42.7%) | 896 (55.5%) | 0.13 |
| Age, years, median (IQR) | 66 (53, 72) | 68 (60, 75) | 0.030 |
| Race, no. (%) | |||
| Caucasian | 338 (94.9) | 1533 (95.3) | 0.12 |
| Non-Caucasian | 18 (5.1) | 75 (4.7) | |
| Lymphoma diagnosis, no. (%) | |||
| Systemic DLBCL | 201 (53.0) | 964 (59.7) | 0.49 |
| Systemic DLBCL with CNS involvement | 141 (37.2) | 513 (31.8) | |
| Other | 37 (9.8) | 137 (8.5) | |
| Serum creatinine, mg/dl, median (IQR) | 0.8 (0.7, 0.9) | 0.9 (0.7, 1.1) | 0.018 |
| Estimated creatinine clearance, no. (%) | |||
| >60 ml/min | 337 (89.2) | 1310 (82.0) | 0.25 |
| 30–60 ml/min | 41 (10.8) | 287 (18.0) | |
| <30 ml/min | 0 (0.0) | 0 (0.0) | |
| Aspartate aminotransferase, units/L, median (IQR) | 22 (18, 28) | 21 (17, 27) | 0.047 |
| Alanine aminotransferase, units/L, median (IQR) | 33 (22, 59) | 30 (18, 52) | 0.13 |
| Total bilirubin, mg/dl, median (IQR) | 0.4 (0.3, 0.5) | 0.4 (0.3, 0.5) | 0.34 |
Abbreviations: CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; IQR, interquartile range.
Tables 2 and S2 highlight MTX-based regimen characteristics. MRT (methotrexate 8 g/m2, rituximab, and temozolomide) was administered in 203 patients (47.2%) and was the most frequently prescribed regimen. Other commonly administered regimens included MR-CHOP (methotrexate 3.5 g/m2, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in 131 patients (30.5%), HDMTX 8 g/m2 monotherapy in 42 patients (9.8%), and HDMTX 3.5 g/m2 monotherapy in 38 patients (8.8%). The median number of HDMTX doses was two for patients with concomitant levetiracetam compared to three doses for patients without concomitant levetiracetam (p = 0.94). Those with concomitant levetiracetam received significantly higher doses of MTX compared to those without concomitant levetiracetam (6.3 and 4.4 g/m2, respectively, p < 0.001). In the levetiracetam group, 97.1% of HDMTX administrations were used for treatment of CNS lymphoma involvement compared to 83.1% of administrations in the group without levetiracetam (p < 0.001).
TABLE 2.
Methotrexate treatment information during management of lymphoma in patients receiving high-dose methotrexate with or without concomitant levetiracetam
| Levetiracetam N = 379 administrations | No levetiracetam N = 1614 administrations | p-Value | |
|---|---|---|---|
| Chemotherapy regimen | |||
| MRT | 331 (87.3) | 965 (59.8) | <0.001 |
| MR-CHOP | 22 (5.8) | 322 (20.0) | |
| HDMTX monotherapy 8 g/m2 | 19 (5.0) | 172 (0.7) | |
| HDMTX monotherapy 3.5 g/m2 | 4 (1.1) | 127 (7.9) | |
| Other | 3 (0.8) | 28 (1.7) | |
| HDMTX dose, g, median (IQR) | 12.3 (8.6, 15.5) | 8.4 (6.3, 13.3) | <0.001 |
| HDMTX dose, g/m2, median (IQR) | 6.3 (5.0, 7.9) | 4.4 (3.4, 6.6) | <0.001 |
| Intended HDMTX dose, no. (%) | |||
| 8 g/m2 | 351 (92.6) | 1149 (71.2) | <0.001 |
| 3.5 g/m2 | 26 (6.9) | 439 (27.2) | |
| Other | 2 (0.5) | 26 (1.6) | |
| HDMTX indication CNS treatment, no. (%) | 368 (97.1) | 1342 (83.1) | <0.001 |
Abbreviations: CNS, central nervous system; HDMTX, high-dose methotrexate; IQR, interquartile range; MR-CHOP, methotrexate, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; MRT, methotrexate, rituximab, and temozolomide; MTX, methotrexate.
The median 48 h MTX level was 0.31 μmol/L in patients receiving levetiracetam compared to 0.37 μmol/L in those without levetiracetam (p = 0.54, Table 3). Of 349 administrations with concomitant levetiracetam, delayed elimination was noted in 49 (14.0%), compared to 261 of 1614 (16.2%) administrations without levetiracetam (OR = 0.80, 95% CI 0.47–1.34, p = 0.39). AKI occurred in 15.6% and 17.0% of patients with and without concomitant levetiracetam, respectively (OR = 0.83, 95% CI 0.52–1.33, p = 0.28). After excluding patients who received multiple doses of HDMTX in a single hospitalization, median hospital LOS was 4.2 days in the levetiracetam cohort compared to 4.1 days in the cohort without levetiracetam (p = 0.039). There were 11 (0.6%) administrations of HDMTX that resulted in use of glucarpidase or need for hemodialysis. Of these, 4 were with concomitant levetiracetam (1.1%), and 7 did not have concomitant levetiracetam (0.4%) (p = 0.24). Figures 1 and 2 display cumulative incidence of delayed MTX elimination and incidence of AKI, respectively.
TABLE 3.
Evaluation of delayed MTX elimination, acute kidney injury, and hospital length of stay in lymphoma patients receiving HDMTX with or without concomitant levetiracetam
| Levetiracetam N = 349 administrations | No levetiracetam N = 1614 administrations | OR (95% CI) | p-Value | |
|---|---|---|---|---|
| MTX level at 48 h, μmol/L, median (IQR) | 0.31 (0.18, 0.59) | 0.37 (0.18, 0.79) | NA | 0.54 |
| Patients with 48 h MTX level >1 μmol/L, no. (%) | 49 (14.0%) | 261 (16.2%) | 0.80 (0.47–1.34) | 0.39 |
| Patients with AKI, no. (%) | ||||
| No AKI | 323 (85.4) | 1326 (83.0) | 0.83 (0.52–1.33) | 0.28 |
| Stage I | 38 (10.1) | 204 (12.8) | ||
| Stage II | 12 (3.2) | 54 (3.4) | ||
| Stage III | 5 (1.3) | 13 (0.8) | ||
| LOS, days, median (IQR)a | 4.2 (3.9, 6.1) | 4.1 (3.8, 5.8) | NA | 0.039 |
Abbreviations: AKI, acute kidney injury; CI, confidence interval IQR, interquartile range; LOS, length of stay; MTX, methotrexate.
Excluding patients who received multiple HDMTX administrations in a single hospitalization.
FIGURE 1.
Cumulative incidence of delayed MTX elimination in lymphoma patients receiving sequential HDMTX doses. MTX, methotrexate
FIGURE 2.
Cumulative incidence of AKI in lymphoma patients receiving sequential HDMTX doses. AKI, acute kidney injury
Univariate analysis demonstrated that concomitant levetiracetam was not significantly associated with an increased risk (OR = 0.80, 95% CI 0.41–1.34, p = 0.39) of delayed elimination. Findings were similar on multivariate analysis (OR = 1.00, 95% CI 0.55–1.82, p = 0.99). Increasing age, increasing body surface area, diagnosis of systemic DLBCL with CNS involvement, increasing serum creatinine, decreasing hemoglobin, increasing total bilirubin, and increasing dose of HDMTX were associated with increased risk of delayed elimination on multivariable analysis (Table 4). Appendix 2 outlines our findings from the sensitivity analysis restricted to only the first three doses per patient.
TABLE 4.
Multivariable association of patient characteristics with delayed methotrexate elimination at 48 h
| Characteristic | Odds ratio (95% CI)a | p-Value |
|---|---|---|
| Levetiracetam | 1.00 (0.55, 1.82) | 0.99 |
| Age (year) | 1.07 (1.04, 1.10) | <0.001 |
| Male | 1.37 (0.74, 2.53) | 0.32 |
| Race | ||
| Caucasian | 1.14 (0.44, 2.96) | 0.79 |
| Other/unknown | Reference | |
| Body surface area, m2 | 1.16 (1.03, 1.31)b | 0.014 |
| Lymphoma diagnosis subtype | ||
| DLBCL | Reference | |
| Primary DLBCL of the CNS | 1.74 (0.50, 2.75) | 0.018 |
| Other | 1.23 (0.50, 3.05) | 0.65 |
| Intended HDMTX dose, g/m2 | ||
| 3.5 | Reference | |
| 8 | 0.95 (0.50, 1.82) | 0.88 |
| Other | 0.30 (0.01, 13.58) | 0.54 |
| HDMTX dose, g | 1.14 (1.06, 1.23) | <0.001 |
| Serum creatinine, mg/dl | 1.15 (1.04, 1.23) | 0.005 |
| Hemoglobin, g/dl | 0.65 (0.58, 0.74) | <0.001 |
| Total bilirubin, mg/dl | 1.12 (1.05, 1.18)b | <0.001 |
Abbreviations: CI, confidence interval; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; HDMTX, high-dose methotrexate.
Odds ratios for continuous variables are per 1 unit increase unless otherwise specified.
Per 0.1 unit increase.
4 |. DISCUSSION
Our findings demonstrated that elevated 48-h serum MTX concentrations and AKI occurred with an incidence that was similar between those receiving HDMTX with and without concomitant levetiracetam. Although we demonstrated a statistically significant difference in the median hospital LOS between groups, the clinical significance of this difference (0.1 days) is negligible. These results strongly suggest the lack of a significant drug-drug interaction between HDMTX and levetiracetam.
Multivariable analyses demonstrated that multiple patient characteristics were associated with increased incidence of delayed MTX elimination at 48 h, including increasing age, body surface area, serum creatinine, total bilirubin, and dose of HDMTX. Conversely, increasing hemoglobin was associated with a decreased incidence of delayed elimination. Previous studies have found correlations between older age, increasing weight, larger MTX doses, and worsening renal function with an increased incidence of delayed MTX elimination.19,25,26 A relationship between hemoglobin and hematocrit has been identified with MTX clearance and volume of distribution; the proposed mechanism is uptake of MTX into red blood cells.26 To our knowledge, no published models have identified a relationship between total bilirubin and delayed MTX elimination. Although a majority of HDMTX elimination is through the kidney, up to 10% of MTX clearance occurs through hepatic metabolism which could explain our finding.27 Measures should be taken to accurately assess renal function and limit modifiable risk factors to optimize MTX dose selection and minimize the risk of delayed elimination.
HDMTX is an integral component in the treatment of CNS lymphoma and prevention of CNS relapse.28 Patients with primary CNS lymphoma are at an increased risk for seizures, and it has been reported that up to one-third of patients will experience a clinical seizure during the course of the disease.29 Historically, levetiracetam has been widely used in this setting because of its efficacy and minimal drug-drug interactions, particularly with HDMTX.7,12,30 Our study showing no difference in clinical end points of MTX elimination and AKI justifies this practice and affirms coadministration of HDMTX and levetiracetam as a preferred management strategy in patients with lymphoma.
Two case reports describing delayed elimination of HDMTX in patients receiving concomitant levetiracetam have been published.16,17 A 15-year-old boy with acute lymphoblastic leukemia received two doses of HDMTX without adverse effects and was initiated on anti-epileptic therapy with levetiracetam prior to his third dose.17 After dose three of HDMTX, glucarpidase was administered due to delayed MTX elimination and associated toxicities.17 No other changes were noted between the second and third doses, and the authors attributed the complications to the potential drug interaction between MTX and levetiracetam. Although possibly due to levetiracetam, it is known that repeated insults to the kidney with HDMTX can cause slow, progressive, subclinical, renal impairment that eventually can lead to AKI without risk factors being present.31,32 This was also evident in our study. The second case was a 46-year-old man with relapsed osteosarcoma receiving HDMTX who reached a MTX level <0.1 μmol/L in <4 days after the first HDMTX dose.16 His second, third, and fourth HDMTX doses were administered with concomitant levetiracetam and each took more than 4 days to clear. Interestingly, after a change from levetiracetam to lorazepam prior to the fifth HDMTX dose, MTX was eliminated within 4 days.16 Using the drug interaction probability scale, the authors determined the interaction to be probable and attributed the delayed MTX elimination to levetiracetam.16,33 The role of previous cisplatin exposure as an additive risk factor and the shortened time to MTX elimination with each subsequent MTX dose until levetiracetam was eventually discontinued makes this interaction possible, but questionable.34
Our findings are similar to the results found by Reeves and colleagues in their retrospective review of 81 patients; however, all of our patients had a lymphoma diagnosis and were receiving a 4-h bolus infusion of HDMTX.20 Lou et al.21 utilized time to MTX clearance as their primary end point and only evaluated the initial dose of HDMTX in their retrospective review of the effect of concomitant levetiracetam in patients with hematologic malignancies treated with HDMTX. In our study, we utilized hospital LOS as a surrogate marker for time to MTX elimination. Unlike Lou et al, we did find a difference in median hospital LOS between the two cohorts, although the difference is not clinically meaningful.
The proposed mechanism for the interaction between MTX and levetiracetam is that the inactive metabolite of levetiracetam, UCB L057, may compete with MTX for tubular secretion in the kidney.35–37 Based on this mechanism, it is possible that higher doses of levetiracetam would result in an increased risk of delayed MTX elimination. In both case reports, the patients were receiving levetiracetam for treatment of seizures.16,17 A majority of the patients in our study had no history of previous seizures and were receiving levetiracetam for prophylaxis. At our institution, prophylactic dosing of levetiracetam is at the discretion of the provider, and the most common doses are 500 mg twice daily and 750 mg twice daily. Whether or not there is a concentration-dependent interaction between high-dose levetiracetam for seizure treatment and HDMTX remains unknown and should be a point of future investigation.
To our knowledge, this is the largest study evaluating the potential interaction between HDMTX and levetiracetam to date; however, there are several limitations. First is our retrospective, non-randomized design and dependence on the accuracy of electronic medical records. We attempted to overcome this limitation through consecutive patient enrollment over a substantial timeframe to ensure a representative sample for analysis. Unfortunately, the choice of a 10-year time frame makes it possible that several practice changes occurred regarding HDMTX administration and supportive care that may have affected our results. One example is the discovery of the interaction between HDMTX and proton pump inhibitors.38,39 Third, we chose an adult lymphoma patient population receiving HDMTX as a 4-h infusion, which may limit the generalizability of our findings to other disease states or patients receiving HDMTX at different infusion rates. Fourth, we did not account for all administration variables that may affect MTX elimination in our analyses including presence of other interacting medications or occurrences of urinary pH <7. However, preadmission medication reconciliation makes the administration of interacting medications unlikely and protocol adherence is high ensuring that adequate alkalinization occurs and is maintained throughout therapy with little variability (Appendix 1). Lastly, levetiracetam dose-intensity and therapeutic drug monitoring as a surrogate for the UCB L057 metabolite was not analyzed and should be a potential consideration for future research.
5 |. CONCLUSION
Coadministration of levetiracetam with HDMTX does not appear to result in an increased incidence of delayed MTX elimination at 48 h in patients with lymphoma receiving HDMTX as a 4-h infusion. Providers can feel safe prescribing levetiracetam with HDMTX without negatively impacting clinical outcomes as other contemporary anti-epileptics are evaluated for potential use concurrently with MTX.
Supplementary Material
Funding information
This project was supported in part by CTSA Grant Number TL1 TR002380 from the National Center for Advancing Translational Science (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.
APPENDIX 1: Standard operating procedure for high-dose methotrexate 4-hour administrations
Prior to administration, patients are screened to ensure they have not received any of the following medications for at least 24 h prior to the initiation of HDMTX: ciprofloxacin, non-steroidal anti-inflammatory drugs, penicillins, probenecid, proton pump inhibitors, salicylates, sulfisoxazole, and sulfamethoxazole.
Creatinine clearance is calculated using the Cockcroft-Gault equation using actual body weight. For patients who have a creatinine clearance of <100 ml/min, percentage for MTX dose reduction is calculated using 100—creatinine clearance (ml/min) = percent dose reduction. For example, in a patient with a creatinine clearance of 70 ml/min, the suggested dose reduction would be 30% of calculated dose (100–70 ml/min = 30% dose reduction). If the intended dose of MTX is 3.5 g/m2, providers could consider a dose adjustment to 1.5 g/m2 for those over the age of 65 years and those with poor performance status at their discretion. Additionally, doses could be adjusted by the multidisciplinary hospital care team in cases of advanced age, poor performance status, or based on outcomes of previous MTX doses.
Hydration is initiated with a 2-h bolus of sodium bicarbonate 75 mEq in 1000 ml of NaCl 0.45% at 500 ml/h. Following the bolus, patients receive the same fluid at 200 ml/h. 24 h after the end of the HDMTX infusion, the rate is decreased to 125 ml/h if the past two consecutive urine pH results have been ≥7. Urine pH is checked with every void. If at any point urinary pH is <7, sodium bicarbonate 50 mEq IV is administered.
MTX administration does not occur until patients achieve a urine output of >100 ml/h and a urine pH of ≥7 for two consecutive voids.
Leucovorin begins 24 h after the start of the HDMTX infusion. Standard dosing is 25 mg IV every 6 h until methotrexate has been cleared. At any point, if serum creatinine increases to ≥50% of the pre-methotrexate level, leucovorin dosing is increased to 200 mg/m2 every 6 h IV. In the case of elevated MTX levels, leucovorin is adjusted as follows:
48 h MTX level 1–4.99 μmol/L: 50 mg/m2 IV every 6 h
48 h MTX level 5–9.99 μmol/L: 100 mg/m2 IV every 6 h
48 h MTX level 10–19.99 μmol/L: 200 mg/m2 IV every 6 h
48 h MTX level 20–50 μmol/L: 500 mg/m2 IV every 6 h
Leucovorin may be empirically increased for patients who have previously experienced delayed elimination or MTX toxicity at the discretion of the provider.
APPENDIX 2: Sensitivity analysis restricted to only doses one through three for each patient
TABLE A1.
Baseline Characteristics of 430 patients with lymphoma receiving 1025 doses of HDMTX between 2009 and 2019 at Mayo Clinic
| Characteristic | Levetiracetam N = 176 administrations | No levetiracetam N = 849 administrations | p-Value |
|---|---|---|---|
| Male, no. (%) | 93 (52.8) | 526 (62.0) | 0.15 |
| Age, years, median (IQR) | 65 (54, 70) | 66 (58, 73) | 0.11 |
| Race, no. (%) | |||
| Caucasian | 158 (89.8) | 792 (93.3) | 0.30 |
| Non-Caucasian | 18 (10.2) | 57 (6.7) | |
| Lymphoma diagnosis, no. (%) | |||
| Systemic DLBCL | 71 (40.3) | 511 (60.2) | 0.004 |
| Systemic DLBCL with CNS involvement | 84 (47.7) | 243 (28.6) | |
| Other | 21 (11.9) | 95 (11.2) | |
| Serum creatinine, mg/dl, median (IQR) | 0.8 (0.6, 0.9) | 0.8 (0.7, 1.0) | 0.042 |
| Estimated creatinine clearance, no. (%) | |||
| >60 ml/min | 164 (93.7) | 745 (88.9) | 0.14 |
| 30–60 ml/min | 11 (6.3) | 93 (11.1) | |
| <30 ml/min | 0 (0.0) | 0 (0.0) | |
| Aspartate aminotransferase, units/L, median (IQR) | 22 (17, 31) | 21 (17, 27) | 0.037 |
| Alanine aminotransferase, units/L, median (IQR) | 37 (24, 65) | 33 (19, 57) | 0.091 |
| Total bilirubin, mg/dl, median (IQR) | 0.4 (0.3, 0.5) | 0.4 (0.3, 0.5) | 0.30 |
Abbreviations: CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; IQR, interquartile range.
TABLE A2.
Methotrexate treatment information during management of lymphoma in patients receiving HDMTX with or without concomitant levetiracetam
| Levetiracetam N = 176 administrations | No levetiracetam N = 849 administrations | p-Value | |
|---|---|---|---|
| Chemotherapy regimen | |||
| MRT | 137 (77.8) | 377 (44.4) | <0.001 |
| MR-CHOP | 18 (10.2) | 285 (33.6) | |
| HDMTX monotherapy 8 g/m2 | 15 (8.5) | 78 (9.2) | |
| HDMTX monotherapy 3.5 g/m2 | 3 (1.7) | 83 (9.8) | |
| Other | 3 (1.7) | 26 (3.1) | |
| HDMTX dose, g, median (IQR) | 12.2 (8.2, 15.7) | 7.8 (6.0, 13.4) | <0.001 |
| HDMTX dose, g/m2, median (IQR) | 6.3 (4.6, 7.9) | 3.6 (3.1, 6.8) | <0.001 |
| Intended HDMTX dose, no. (%) | |||
| 8 g/m2 | 152 (86.4) | 464 (54.7) | <0.001 |
| 3.5 g/m2 | 22 (12.5) | 361 (42.5) | |
| Other | 2 (1.1) | 24 (2.8) | |
| HDMTX indication CNS treatment, no. (%) | 166 (94.3) | 263 (31.0) | <0.001 |
Abbreviations: CNS, central nervous system; HDMTX, high-dose methotrexate; IQR, interquartile range; MR-CHOP, methotrexate, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; MRT, methotrexate, rituximab, and temozolomide; MTX, methotrexate.
TABLE A3.
Evaluation of delayed MTX elimination, acute kidney injury, and hospital length of stay in lymphoma patients receiving HDMTX with or without concomitant levetiracetam
| Levetiracetam N = 176 administrations | No levetiracetam N = 849 administrations | p-Value | |
|---|---|---|---|
| MTX level at 48 h, μmol/L, median (IQR) | 0.47 (0.21, 1.10) | 0.31 (0.15, 0.73) | 0.15 |
| Patients with 48 h MTX level >1 μmol/L, no. (%) | 44 (26.7%) | 140 (16.5%) | 0.009 |
| Patients with AKI, no. (%) | |||
| No AKI | 129 (73.7) | 653 (77.9) | 0.66 |
| Stage I | 32 (18.3) | 133 (15.9) | |
| Stage II | 9 (5.1) | 39 (4.7) | |
| Stage III | 5 (2.9) | 13 (1.6) | |
| LOS, days, median (IQR)a | 6.1 (4.1, 10.5) | 4.2 (3.3, 6.0) | <0.01 |
Abbreviations: AKI, acute kidney injury; IQR, interquartile range; LOS, length of stay; MTX, methotrexate.
Excluding patients who received multiple HDMTX administrations in a single hospitalization.
TABLE A4.
Multivariable association of patient characteristics with delayed methotrexate elimination at 48 h
| Characteristic | Odds ratio (95% CI)a | p-Value |
|---|---|---|
| Levetiracetam | 1.73 (1.01, 2.98) | 0.047 |
| Age (year) | 1.05 (1.02, 1.07) | <0.001 |
| Male | 1.22 (0.68, 2.16) | 0.50 |
| Race | ||
| Caucasian | 1.04 (0.41, 2.63) | 0.93 |
| Other/unknown | Reference | |
| Body surface area, m2 | 1.20 (1.09, 1.33)b | <0.001 |
| Lymphoma diagnosis subtype | ||
| DLBCL | Reference | |
| Primary DLBCL of the CNS | 1.14 (0.67, 1.92) | 0.63 |
| Other | 1.20 (0.50, 2.87) | 0.68 |
| Intended HDMTX dose, g/m2 | ||
| 3.5 | Reference | |
| 8 | 1.72 (0.87, 3.42) | 0.12 |
| Other | 0.47 (0.03, 8.79) | 0.62 |
| HDMTX dose, g | 1.13 (1.04, 1.22) | 0.003 |
| Serum creatinine, mg/dl | 1.21 (1.10, 1.34) | <0.001 |
| Hemoglobin, g/dl | 0.68 (0.59, 0.77) | <0.001 |
| Total bilirubin, mg/dl | 1.08 (1.02, 1.15)b | 0.007 |
Abbreviations: CI, confidence interval; CNS, central nervous system; DLBCL, diffuse large B-cell lymphoma; HDMTX, high-dose methotrexate.
Odds ratios for continuous variables are per 1 unit increase unless otherwise specified.
Per 0.1 unit increase.
Footnotes
CONFLICTS OF INTEREST
The authors have no conflicts of interest to declare.
Previous presentation: The material found in this work was presented as a poster at the Hematology Oncology Pharmacy Association Annual Meeting on March 12, 2020, in Tampa Bay, FL.
SUPPORTING INFORMATION
Additional supporting information may be found online in the Supporting Information section.
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