Phosphorus levels in children treated with intravenous ferric carboxymaltose
Authors: Susan E. Kirk, Michael E. Scheurer, Melanie Brooke Bernhardt, Donald H. Mahoney, Jacquelyn M. Powers
Journal: American Journal of Hematology (2021)

Iron deficiency anemia (IDA) is the most common hematologic condition worldwide. Intravenous (IV) iron therapy has previously been limited to those patients with chronic kidney disease or severe and/or refractory IDA. Development of IV iron formulations with improved safety profiles, however, has increased its utilization in both adult and pediatric patient populations. Ferric carboxymaltose (FCM) was approved by the Food and Drug Administration (FDA) in 2014 for use in adults with iron deficiency who are intolerant of or have failed oral iron therapy. Adult trials have found that up to 75% of patients receiving FCM develop hypophosphatemia.1 Conditions related to hypophosphatemia range from asymptomatic hypercalciuria to osteomalacia. Prolonged severe hypophosphatemia (<1 mg/mL) can be associated with end organ complications. The effects of transient, non-severe hypophosphatemia are not well described.2 Overall rates of hypophosphatemia in children treated with FCM are unknown. A retrospective review of children treated with FCM from November 2016 through April 2019 found that of 1081 infusions administered to 656 children, only 247 (165 patients) had phosphorus levels within 6 weeks post-infusion.3 Thirty-six (15%) infusions (32 patients [19%]) were associated with hypophosphatemia. In May 2019, our Hematology Center instituted a clinical guideline to monitor phosphorus levels in children treated with FCM. The objective of this study was to assess the effect of FCM on phosphorus levels in children since initiation of this guideline. This is a retrospective cohort study of patients who received IV FCM from May 1, 2019 through April 30, 2020 per pharmacy records. Inclusion criteria were age ≤21 years at time of infusion and phosphorus levels both within 4 weeks prior and 6 weeks after the infusion. Demographic information, clinical data, and laboratory assessments were extracted from the electronic health record (EHR). Extracted clinical data included etiology of IDA and/or indication for IV iron therapy (Table 1) and receipt of phosphorus therapies known to impact phosphorus levels (furosemide, acetazolamide, sevelamer, phosphorus supplementation, and TPN). The most recent phosphorus levels prior to infusion were utilized if multiple measurements were available. Post-infusion phosphorus levels were analyzed if collected within 6 weeks after infusion and prior to any further FCM. If multiple post-infusion levels were available, the lowest one was utilized within the first 4 weeks and then the lowest level 4 to 6 weeks post-infusion. Hematologic and iron parameters were collected both pre-infusion and post-infusion, when available. Pre-infusion vitamin D levels, when available, were also collected. Pre-infusion a a Values obtained less than 4 weeks pre-infusion. mean (IQR) Post-infusion b b Values obtained >4 and ≤12 weeks post-infusion. mean (IQR) The primary outcome was incidence of hypophosphatemia (defined as phosphorus level below reference range [Table S1]) ≤6 weeks of receipt of FCM. Our a priori hypothesis was that the incidence of hypophosphatemia would be <20% of all patients. Secondary outcomes included a change in phosphorus level, incidence of severe hypophosphatemia (defined as phosphorus level <1 mg/dL), receipt of phosphorus supplementation, and hematologic response 4 to 12 weeks post-infusion. Planned exploratory analysis included evaluation of age, sex, race/ethnicity, FCM indication, degree of anemia, number of FCM doses, pre-infusion phosphorus and vitamin D levels, and concomitant medications known to affect phosphorus as predictor variables for the development of hypophosphatemia. An additional 22 infusions administered in 21 patients who met age criteria, but had no pre-infusion levels, were reviewed to identify any severe hypophosphatemia. Demographic and clinical characteristics were summarized using standard descriptive statistics. Differences between patients who did or did not develop hypophosphatemia were compared using the chi-square or Fisher exact test for categorical variables and Student t test for continuous variables. Univariable and multivariable multilevel mixed-effects logistic regression was used to determine the effects of individual variables on the development of hypophosphatemia after each infusion accounting for the clustering of observations within patients and the unbalanced nature of the data. All models were adjusted for pre-infusion phosphorus levels. For the multivariable modeling, all variables that were significantly associated with hypophosphatemia in the univariable models were included in an initial multivariable model. A stepwise selection process using the likelihood ratio test was used to develop the most parsimonious reduced model. All analyses were conducted using Stata SE version 16.1 (College Station, TX). Two-sided p values <0.05 were considered statistically significant. Over the one-year study period, 492 FCM infusions were administered to 337 patients. Three-hundred thirteen infusions in 225 patients were included in the final analysis (Figure S1). The majority were female (n = 139, 62%) with median age 9.2 years (range 2 months to 20.3 years). Additional demographic and clinical data are included in Table 1. Hypophosphatemia occurred after 44 (14%) of the 313 infusions, administered in 40 patients (18%; Table 1). The mean post-infusion phosphorus level was 4.2 mg/dL (SD 1.16). Mean change in phosphorus level was −0.49 mg/dL (p < .001, SD 1.09) ≤4 weeks post-infusion (n = 281 infusions). No severe hypophosphatemia developed ≤6 weeks after the 313 FCM infusions (Table 1). Of the 40 patients who developed hypophosphatemia, none had symptoms documented in the EHR; seven (18%) were prescribed supplemental phosphorus. Mean pre-infusion and post-infusion hematologic and iron parameters all demonstrated incremental changes (Table 1). Pre-infusion phosphorus level and indication for FCM were both associated with development of hypophosphatemia (Table S2). Each 1 mg/dL increase in the pre-infusion phosphorus level was associated with a 70% decrease in the odds of development of hypophosphatemia (adjusted odds ratio [aOR] = 0.30, 95%CI0.14, 0.63, p = .001). The remaining variables were not associated with development of hypophosphatemia; concomitant medications known to affect phosphorus levels are also described (Table S2). There were 22 infusions (administered to 21 patients) with no pre-infusion phosphorus levels. One patient developed severe hypophosphatemia with a nadir phosphorus level of 0.9 mg/dL within 4 weeks of the patient's second infusion. No symptoms of hypophosphatemia were documented. Phosphorus supplementation was prescribed for 30 days, and the level was sustained in the normal range 68 days after the last FCM infusion. This is the largest report of phosphorus levels in children and adolescents treated with FCM in routine clinical care at a large tertiary center. Our findings were similar to our previous review, with both finding that 18–20% of FCM infusions in children were associated with hypophosphatemia.3 In the current study, lower pre-infusion phosphorus level was the strongest predictor for the development of hypophosphatemia. Consistent with previous literature, children treated with FCM demonstrated incremental increases in both hematologic indices and serum ferritin.4 Literature on the utilization, efficacy, and safety of IV iron therapies in pediatrics is largely limited to case series and smaller cohorts.5 A cohort of 36 pediatric patients in Austria from 2007 to 2018 reported that hypophosphatemia occurred after 8 of 71 (11.3%) FCM infusions.6 The study utilized a wider timeframe to include pre-infusion and post-infusion phosphorus levels relative to infusion, thus it is possible that episodes of hypophosphatemia went undetected. Two randomized trials in adults comparing FCM to iron isomaltoside (ferric derisomaltose in the U.S.) reported that approximately 75% treated with FCM developed hypophosphatemia within 35 days compared to approximately 8% treated with ferric derisomaltose.1 Those receiving FCM demonstrated decreased 1,25-dihydroxyvitamin D and ionized calcium levels and increased PTH level. Other IV iron formulations have also been associated with hypophosphatemia. Though the precise mechanism remains unclear, it is likely due to a post-infusion increase in fibroblast growth factor 23 (FGF23), which leads to decreased renal tubular phosphorus reabsorption and increased urinary phosphorus excretion, thereby decreasing serum phosphorus levels. Adult data suggest that repeated doses of FCM may result in more profound hypophosphatemia, though specific dose-stacking effects have not been formally studied. Our multivariable analysis found no significant difference in the occurrence of hypophosphatemia based on the number of FCM doses received. However, only a subset of patients in our cohort received ≥2 doses. Our findings demonstrate that while children and adolescents treated with FCM have an incremental decrease in serum phosphorus, the majority maintain phosphorus levels within the normal range for age. These findings contrast with the higher incidence reported in adults and suggest that further work is indicated to characterize risk factors in children. Our clinical practice remains assessing phosphorus levels both pre-infusion and post-FCM infusion and providing supplementation for levels <2.0 mg/dL regardless of symptomatology. Given that the long-term implications of transient hypophosphatemia in children are unknown, alternative IV iron formulations may need to be considered in those with lower pre-infusion phosphorus levels or who require ongoing therapy. This study has several limitations including its retrospective nature, variability in timing of phosphorus levels, and lack of symptom documentation. Despite these limitations, this study is the largest reported cohort of diverse pediatric patients receiving FCM and describes both phosphorus levels as well as hematologic and iron parameters. In conclusion, hypophosphatemia developed in a subset of pediatric patients treated with FCM at our center. The full extent of hypophosphatemia in children is unknown but appears to be less common compared to adults. A prospective clinical trial that formally evaluates phosphorus levels, associated laboratory markers, as well as other long-term clinical outcomes, in children and adolescents treated with FCM is needed. This work was supported by grant K23HL132001 from National Heart, Lung, and Blood Institute. The funders of the study had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript or the decision to submit for publication. All authors have contributed in a significant manner to the concept, design, data acquisition and/or analysis, and have reviewed and approved this manuscript. Dr. Powers discloses research support to her institution from American Regent. Ms. Kirk discloses honoraria from BioMarin. Dr. Bernhardt discloses research funding from Bristol-Myers Squibb and Celgene and is a member of an Advisory Board for Mesoblast and Servier. These disclosures are unrelated to the content of this manuscript. Scheurer and Mahoney declare no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Figure S1. Flow chart of ferric carboxymaltose infusions based on phosphorus levels and receipt of phosphorus supplementation Table S1. +Reference range values for serum phosphorus by age Table S2. Multivariate analysis on predictors of hypophosphatemia within 6 weeks in children receiving ferric carboxymaltose Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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