Hypomagnesemia Is Associated with an Increased Risk of Failure in Patients Diffuse Large B-Cell Lymphoma Undergoing Autologous Stem Cell Transplantation

Magnesium is an essential element that is involved in the regulation of cell growth, division and differentiation. Epidemiologic studies have demonstrated that a diet poor in magnesium is associated with an increased risk of developing cancer. There are few studies investigating whether magnesium deficiency is associated with a poor prognosis in lymphomas. The recent discovery of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus, and neoplasia (XMEN) disease, suggests a role of magnesium in the development of hematologic malignancies and lymphocyte function. Furthermore, a recently published study found that hypomagnesemia prior to chemotherapy is associated with inferior overall survival (OS) in patients with Burkitt Lymphoma. We hypothesized that low magnesium levels prior to autologous hematopoietic stem cell transplant (AHSCT) may lead to inferior outcomes via impaired lymphocyte recovery.

We evaluated whether low serum magnesium levels were associated with inferior survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who underwent autologous hematopoietic stem cell transplant (AHSCT) between January 1998 and May 2020 using a retrospective study design. We cross-referenced our search with patients who had a magnesium level as part of their pre-transplant workup between 7 and 28 days prior to their first transplant. Two-sided Wilcoxon rank sum test and Chi square/Fischer's exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards.

Our study included 581 patients of which 82 (14.1%) had hypomagnesemia (magnesium < 1.7 mg/dL) prior to AHSCT. Our study found that hypomagnesemia was associated with inferior OS and event-free survival (EFS) defined as re-transplant, relapse or death, compared to those with a normal magnesium level; median OS: 7.3 years (95% CI: 2.91 - upper limit not estimable) versus 9.7 years (95% CI: 6.92 - 12.3 years), p=0.0041; and median EFS: 3.9 years (95% CI: 1.63 - 8.98 years) versus 6.29 years (95% CI: 4.73 - 8.95 years), p = 0.016 respectively(B).

Higher serum magnesium (HR 0.199 per doubling, 95% CI 0.078 - 0.503; p<0.001) and higher albumin (HR 0.090 per doubling, 95% CI 0.021 - 0.394; p=0.001) were associated with lower mortality rates, and higher creatinine (HR 1.669 per doubling, 95% CI 1.03 - 2.52; p=0.04) was associated with greater mortality up to 1 year post-transplantation. In a multivariate Cox regression excluding albumin, hypomagnesemia (p < 0.001) and elevated creatinine (p = 0.038) were independent predictors of poor overall survival(A). There was no significant difference between day 15 absolute lymphocyte count between patients with normal magnesium levels and low serum magnesium levels prior to their conditioning regimen. Although we hypothesized that we would find a significant difference between 15 day absolute lymphocyte count recovery and hypomagnesemia, this was not apparent. However, magnesium is an important nutrient for immune function and immune recovery is important after the bone marrow is restored post ablative therapy. Thus, low serum magnesium levels may lead to impaired OS and EFS via impaired lymphocyte function. In vitro studies will be necessary to understand this mechanism further. Magnesium may simply be a marker of illness and replacement of magnesium may not improve outcomes. However, further investigations are needed to determine whether outcomes would improve with replacement of magnesium in patients with hypomagnesemia, which our study did not address. Overall, our preliminary data suggests that hypomagnesemia is an independent prognostic factor and predictor of inferior OS and EFS in this cohort of patients.

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