Comparison of two doses of leucovorin in severe low-dose methotrexate toxicity – a randomized controlled trial

(2023) 25:82 Bhargava et al. Arthritis Research & Therapy https://doi.org/10.1186/s13075-023-03054-2 Arthritis Research & Therapy Open Access RESEARCH Comparison of two doses of leucovorin in severe low‑dose methotrexate toxicity – a randomized controlled trial Mudit Bhargava1†, Chirag Rajkumar Kopp1†, Shankar Naidu1, Deba Prasad Dhibar2, Atul Saroch2, Alka Khadwal3, Tarun Narang4, Siddharth Jain1, Aastha Khullar1, Bidya Leishangthem1, Aman Sharma1, Susheel Kumar1, Shefali Sharma1, Sanjay Jain1 and Varun Dhir1* Abstract Background Leucovorin (folinic acid) is a commonly used antidote for severe toxicity with low-dose methotrexate, but its optimum dose is unclear, varying from 15 to 25 mg every 6-h. Methods Open-label RCT included patients with severe low-dose (≤ 50 mg/week) methotrexate toxicity defined as WBC ≤ 2 × 10^9/L or platelet ≤ 50 × 10^9/L and randomized them to receive either usual (15 mg) or high-dose (25 mg) intravenous leucovorin given every 6-h. Primary outcome was mortality at 30-days and secondary outcomes were hematological recovery and mucositis recovery. Trial Registration number: CTRI/2019/09/021152. Results Thirty-eight patients were included, most with underlying RA who had inadvertently overdosed MTX (taken daily instead of weekly). At randomization, the median white blood and platelet count were 0.8 × 10^9/L and 23.5 × 10^9/L. 19 patients each were randomized to receive either usual or high-dose leucovorin. Number (%) of deaths over 30-days was 8 (42) and 9 (47) in usual and high-dose leucovorin groups (Odds ratio 1.2, 95% CI 0.3 to 4.5, p = 0.74). On Kaplan–Meier, there was no significant difference in survival between the groups (hazard ratio 1.1, 95% CI 0.4 to 2.9, p = 0.84). On multivariable cox-regression, serum albumin was the only predictor of survival (hazard ratio 0.3, 95% CI 0.1 to 0.9, p = 0.02). There was no significant difference in hematological or mucositis recovery between the two groups. Conclusion There was no significant difference in survival or time-to hematological recovery between the two doses of leucovorin. Severe low-dose methotrexate toxicity carried a significant mortality. Keywords Methotrexate, Toxicity, Folinic acid, Leucovorin, Overdose, Poisoning, Adverse drug reaction, Cytopenia, Neutropenia, Randomized controlled trial † Mudit Bhargava and Chirag Rajkumar Kopp contributed equally to this work. *Correspondence: Varun Dhir Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Bhargava et al. Arthritis Research & Therapy (2023) 25:82 Key messages 1) What is already known about this area? We searched the PUBMED using the terms "Methotrexate"[Mesh] AND “toxicity” and could not find any randomized controlled study which compared different doses of leucovorin in low-dose methotrexate toxicity. Leucovorin is generally used at a dose of 10 to 25 mg every 6hourly (varies by center) in low-dose methotrexate toxicity – extrapolated from regimens followed for high-dose MTX rescue. 2) What new does this study add? (a) First RCT to compare two different doses of leucovorin in severe-low dose methotrexate toxicity (b) There was no significant difference in mortality or time-to-hematologic recovery or mucositis recovery between the doses of 15 or 25 mg every 6-h in low-dose methotrexate toxicity. There was substantial mortality in both groups ranging from 42-47% despite leucovorin, with the common cause of death being sepsis. 3) How might this impact clinical practice or future development? (a) Higher doses of leucovorin than 15 mg every 6 h unlikely to help to improve mortality, rather better critical care may help. Unclear whether lower doses may be as beneficial. (b) Need to emphasize preventive aspect of MTX toxicity– physicians should emphasize the unique dosing of MTX to patients and give a warning against daily use at the time of consultation. Introduction Methotrexate (MTX) was introduced in the late 1950s and quickly replaced its congener aminopterin as the preferred antifolate drug [1]. Its uses can be classified into three major categories—high dose (HD-MTX, more than 500 mg) used for malignancies, medium dose for gestational trophoblastic diseases and low-dose (LD-MTX, up to 50 mg per week) for its anti-inflammatory/immunomodulatory property in rheumatological and dermatological diseases [2]. Apart from superior efficacy and long-term continuation rates, LD-MTX also has an excellent safety profile, and these features have led to its widespread use in rheumatology for a variety of indications, most common Page 2 of 9 being rheumatoid arthritis [3]. However, severe toxicity can arise with inappropriate use, like inadvertent daily intake or administration in renal failure. The consequent toxicity which arises can be severe and be associated with high mortality rates [4]. Leucovorin or folinic acid (initially called citrovorum factor) was discovered in 1948 as a growth factor for the bacterium Leuconostoc Citrovorum [5]. Its property of reversing the folate block by antifolate drugs led to its being launched as a drug (calcium salt) for antifolate toxicity in 1957 (Lederle, American Cyanamid Co) [6]. Currently, it is primarily used as rescue therapy (prevent severe toxicity) with HD-MTX infusion, at a dose of 10 to 15 mg per m 2 IV every 6 h till MTX levels are below 0.1 μM. However, depending on the serum MTX levels, its dose can increase to 150 mg q3hourly [7]. In LD-MTX toxicity, monitoring serum MTX levels has no established role and the dose of leucovorin used is empirical varying from 10–25 mg q6 hourly. At our tertiary care referral center, we had been treating severe LD-MTX toxicity with leucovorin at a dose of 15 mg every 6 h but found significantly high mortality (unpublished). We speculated that a higher dose of leucovorin may lead to faster hematological recovery and consequently improve outcomes. Thus, we pl (...truncated)