Folate Supplementation during Induction Chemotherapy for Acute Myeloid Leukemia (AML)

Background

The management of patients with new acute myeloid leukemia (AML) who are incidentally found to be folate-deficient poses a unique challenge. Sydney Farber and others observed that administering folate supplementation to untreated pediatric leukemia patients accelerated disease progression (New England Journal of Medicine, 1948). However, withholding folate supplementation in deficient patients could theoretically lead to suboptimal bone marrow function and, by extension, increased transfusion requirements and infections. There is a paucity of studies evaluating the impact of administering folate supplementation to acute leukemia patients who are simultaneously undergoing induction chemotherapy.

Methods

We identified a cohort of 95 patients who underwent induction chemotherapy with a hypomethylating agent-based regimen in the inpatient setting at Weill Cornell Medical Center between October 2020 and February 2024. We did not include patients with antecedent MDS/MPN who received any prior treatment aside from transfusions and growth factors. We conducted retrospective chart review and extracted patients' folate exposure during induction chemotherapy (any concurrently administered folic acid or multivitamin), date of chemotherapy initiation and date of death/last known alive, and whether there were positive blood cultures within the first 30 days after starting induction. We used a log-rank test to generate survival curves and the chi-square test for blood culture data.

Results

72 patients received no folate during induction, 11 received folic acid 1 mg or more for at least half of the days of induction, and 12 received a multivitamin (containing about 0.3 mg folic acid) for at least one day of induction. There was no significant difference in median survival between the non-folate exposed group and the patients receiving any form of folate, including folic acid or a multivitamin (20 months vs 12 months, p = 0.56); there was also no significant difference in median survival between the non-folate exposed group and the subgroup of patients receiving folic acid 1 mg or more (20 months vs 10 months, p = 0.11). There was also no significant difference in whether patients had at least one positive blood culture during the first 30 days after induction between the non-folate exposed group and the folic acid group (12.5% vs 18.2%, p = 0.61) or between the non-folate exposed group and the entire group of patients receiving any form of folate (12.5% vs 17.4%, p = 0.55).

Conclusions

Our results show that there is no significant difference in survival or rates of bacteremia between folate-exposed and non-exposed patients during induction, suggesting that supplementing folate-deficient patients could be safe. However, there was a non-significant trend towards decreased survival and increased rates of bacteremia, and the small sample size in the study may have been insufficient to detect a true difference between groups. Further investigation with a larger cohort or, ideally, a prospective or interventional study, is warranted. Given historical concerns about folate accelerating leukemia progression, supplementation in the setting of active disease should still be approached with caution.

No relevant conflicts of interest to declare.