Discussion
death, toxicity, renal failure, psoriasis, cytopenia, leucopenia, sepsis, aplasia
RESPIRATORY FAILURE, THROMBOCYTOPENIA, RENAL FAILURE, PSORIASIS, SECONDARY, CYTOPENIA, LEUCOPENIA, SEVERE SEPSIS, SEPSIS, APLASIA
This pragmatic open-label RCT compared two doses of IV leucovorin, 15 and 25 mg given 6 hourly, in patients with severe methotrexate toxicity who were on low-dose MTX therapy, but failed to detect any significant difference in mortality at 30-days or time-to-hematologic recovery between the groups.A major finding has been the high mortality rate of 42–47% at 30-days in the two groups. On review of previous literature, all of which are retrospective series, mortality rates were reported to be 10–33% [However, a critical analysis finds that previous studies also included patients with mild MTX toxicity, categorized as mild leucopenia or thrombocytopenia. If one closely examines the mortality for patients with severe MTX toxicity, as defined in this study, they were as high or higher than the current study. Scott et al. reported a mortality of 50% among 10 patients with severe toxicity (WBC ≤ 2.0, Hb ≤ 10 g/dl and platelet count ≤ 50 × 109/l) from the United Kingdom [Most patients died due to severe sepsis and respiratory failure, complicated by ongoing cytopenia. Faster recovery of cytopenia could be reasonably expected to improve mortality by possibly controlling sepsis. In the current study, hematological recovery took a median of 6–7 days, with no significant difference between the two doses of leucovorin. This lag-time (and the failure of higher dose to shorten it) is probably related to rescue being possible only of progenitors on the ‘brink’ but not those that are fatally or irreversibly damaged. A previous report showed severe aplasia in bone marrow aspirates from patients who died suggesting extensive death of progenitors in some patients [Similarly, for the same reason we feel it is unlikely that alternate antidotes like thymidine would improve mortality in these patients. Another antidote which has found use in the last decade is Glucarpidase. This works by hydrolyzing MTX in circulation and had found use in severe toxicity in context of HD-MTX with renal failure [In the current study, serum albumin at presentation was found to be inversely associated with survival on multivariable analysis. Although previous studies have reported serum albumin to be a risk factor for MTX toxicity (for both HD and LD MTX) [This study reiterates the most common reason of toxicity to be erroneous dosing (taking weekly dose either daily or alternate days). This is similar to previous studies starting from early studies in psoriasis where patient error was noted in 2/24 patients [This study had limitations, most importantly of which was the small sample size. In addition, it was open label, although that is unlikely to influence the hard-end points like mortality or hematologic recovery. There was a significant difference in baseline albumin and cumulative methotrexate dose, due to a play of chance. The primary outcomes were adjusted for the former, however, in view of the cumulative dose being only available in 25 patients, it was not adjusted for the latter as that would have reduced the power of the study. We changed the primary outcome from time-to-hematological recovery to 30-day mortality (initially a secondary outcome) after the study had been initiated. This was done as it was thought to be more robust endpoint with more relevance considering the high mortality associated with the condition.To conclude, this study did not find any significant difference in mortality between two doses of leucovorin 15 and 25 mg IV q6h in low-dose MTX associated severe toxicity. This suggests that a dose of 15 mg every 6 h remains appropriate for these patients. Whether a lower dose might suffice has not been studied yet, and would warrant future studies to find appropriate doses/ dosing schedule for leucovorin rescue.