BMI Is Not Associated with Toxicity to High Dose Methotrexate: A Single Institution Retrospective Study of 147 Patients
Authors: Bhaskar Shakthi , Pullarkat Priyanka , Wan Fei , Butler Sara , Mehta-Shah Neha 
Published: November 2020

Background:
High-dose methotrexate (HD-MTX) with leucovorin rescue is frequently used in the treatment of various lymphomas, breast cancer, and sarcomas and remains an important therapy for lymphoma with CNS involvement. Despite its efficacy, HD-MTX can carry considerable toxicity which can lead to prolonged hospital stays, invasive therapies, and delays/discontinuation of a potentially curative treatments. Previous studies have shown that advanced age, male sex, use of proton pump inhibitors and impaired creatinine clearance are associated with higher rates of MTX toxicity (May et al 2014). However, the impact of body mass index (BMI) on the risk of toxicity with HD-MTX has not previously been reported. We performed a retrospective analysis of all patients at Washington University in St. Louis who were treated with HD-MTX to evaluate the relationship between BMI and risk of toxicity.
Methods: Consecutively treated adult patients at Washington University in St. Louis who were treated with HD-MTX (&gt;1,000mg/m2) for any malignancy (excluding leukemia) from 2005-2011 were identified via our pharmacy database. Baseline patient data was collected via retrospective review of the medical record including age, sex, diagnosis, methotrexate dose received, baseline renal and liver function tests, evidence for HD-MTX toxicity, concomitant medications. HD-MTX toxicity was defined as by delayed methotrexate clearance, acute kidney injury, liver function abnormalities, mucositis, or acute kidney injury, disease status and survival. Delayed methotrexate clearance was defined as serum methotrexate level of greater than 15umol/L at 24 hours, greater than 1.5umol/L at 48 hours, or greater than 0.15umol/L at 72 hours based on prior studies (May et al 2014).
Results: 147 patients were included who received a total of 496 cycles of methotrexate (58 CNS lymphoma, 26 DLBCL, 11 T-cell lymphoma, 12 Burkitt's lymphoma, 2 mantle cell lymphoma, 27 sarcoma, 10 breast cancer, 1 other). 2 patients with B-ALL were excluded. The median age was 50 years (range 19-80) with 14 patients who were ≥70 years. Patients each received a median of 2.5 cycles of HD-MTX (range 1-12) at doses of ≤3.5g/m2 (n=248) and &gt;3.5g/m2 (n=248). The total incidence of HD-MTX toxicity in this cohort was 52.4% (260/496 administrations) and did not differ between those who received doses ≤3.5g/m2 (n=248) or &gt;3.5g/m2 (n=248) (OR: 0.875, 95% CI: 0.61-1.25). Median OS was not impacted by presence or absence of MTX toxicity (66 mo vs 84 mo p=0.78). Patients who experienced toxicity had longer clearance than those who did not (5.8 days vs 3.1 days, p=&lt;0.001). Use of proton pump inhibitors was associated with a higher risk of MTX toxicity (OR 1.8, 95% CI: 1.25-2.6). Use of concomitant antibiotics (OR 1.024, 95% CI: 067-1.6) and age &gt;70 (OR 0.64, 95% CI: 0.185-2.2) were not independent risk factors for HD-MTX toxicity.
The median BMI of patients was 25.3 (range 14.7-44.9). 6.1%, 40.8%, 27.2%, and 25.9% had BMIs of underweight (&lt;18.5), normal (18.5-25), overweight (25-30), obese (&gt;30) respectively. We used the restricted cubic spline smoothing method to model the functional form of the association between BMI and MTX toxicity. We found that there is no significant association between BMI and MTX toxicity (p=0.898). The 95% confidence bands contain a flat line such that there is no associated change in the probability of having a MTX toxicity event for any given change in BMI. When comparing patients who had normal BMI or underweight compared to those who had BMIs above normal, there was no significant difference in the rate of methotrexate toxicity.
Conclusions: In this cohort of patients treated with HD-MTX, we found that BMI is not a risk factor in the development of toxicity. Our analysis also suggests that a single incidence of HD-MTX toxicity does not significantly impact patient survival, which is similar with previous findings (May, Leukemia & Lymphoma 2013). Determining potential risk factors for HD-MTX toxicity will allow clinicians to be better prepared to manage complications and tailor treatment regimens based on individual patient characteristics.

Disclosures
Mehta-Shah: Genetech: Research Funding; Karyopharm Therapeutics: Consultancy; Bristol Myers-Squibb: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Kyowa Kirin: Consultancy; Verastem: Research Funding.