Therapy induced iron deficiency in children treated with eltrombopag for immune thrombocytopenia
Authors: Michele P. Lambert, Char M. Witmer, Janet L. Kwiatkowski
Journal: American Journal of Hematology (2017)

Pediatric immune thrombocytopenia (ITP) is a rare disease occurring in approximately 1.9–6.4:100,000 children.1 Many children with ITP have few bleeding symptoms,2 but for those who do require intervention and fail conventional first line therapy, a variety of second-line therapies are used.3-6 Less than 10% of patients with chronic ITP (adult and childhood) develop refractory ITP which requires treatment beyond splenectomy.7 Eltrombopag is a second generation thrombopoietin (TPO) receptor (TPO-R) agonist approved for the treatment of chronic ITP in both pediatric and adult patients. Several clinical trials have been conducted demonstrating that eltrombopag can increase platelet counts, decrease bleeding, decrease use of concomitant therapies, and improve quality of life.6, 8-10 Eltrombopag is an orally bioavailable, small molecule which, in addition to binding to the TPO-R, is structurally similar to molecules that have been developed for oral iron chelation therapy (Figure 1A). Pharmacokinetic studies showed that absorption of eltrombopag was significantly altered in the presence of divalent cations resulting in the recommendation that it be taken on an empty stomach and remotely from any dietary supplements.11 Preclinical studies also suggest that eltrombopag can inhibit cell growth and may have antiproliferative effects on malignant cells by directly reducing intracellular iron levels in a TPO-R independent manner.12 These characteristics suggest that iron deficiency (ID) might be a complication of eltrombopag therapy. We report the development of ID requiring iron supplementation in pediatric patients treated with eltrombopag for ITP in the absence of blood loss. (A) Eltrombopag structure in comparison to other iron chelators. The (B) MCV, (C) ferritin, (D) platelet count, and (E) hemoglobin level (E) pretreatment and after 3 months of therapy with eltrombopag. Bars represent mean ± SEM; (F) For the 5 subjects treated with both eltrombopag and romiplistin, MCV pretreatment and after 3 months of therapy on each agent. P values are shown This study was granted an exemption by the Institutional Review Board. A retrospective chart review was performed to examine the hematologic parameters, clinical features, chemistry values, and bleeding manifestations of patients treated with eltrombopag at a single institution between January 1, 2011 and March 31, 2016. ID was defined as serum ferritin <20 ng/dL. Iron deficiency anemia (IDA) was defined as serum ferritin <20 ng/dL and hemoglobin values below the reference range for age and sex. Mean ± standard error of the mean for hematologic and chemistry values were compared for patients' value prior to the initiation of eltrombopag and after at least 3 months of therapy using Student's t test or ANOVA as appropriate. P values <.05 were considered significant and were corrected for multiple comparisons. Twelve patients were identified who were treated with eltrombopag during the study period; one patient was iron deficient prior to starting eltrombopag and was excluded from the analysis. Supporting Information Table 1 describes the key patient demographic data. The indication for eltombopag treatment for all patients was failure of first line therapy. There was a decrease in MCV of approximately 4 fL (5%) over >3 months of therapy (Figure 1B) with mean corpuscular volume (MCV) in the ID group 76.1 ± 0.9 fL versus 83.3 ± 1.1 fL in the nondeficient group (P = .004). More dramatic was the decrease in ferritin over the observation period. Pre-eltrombopag ferritin levels were available and normal for 8 patients. In the cohort, the ferritin decreased by 20.8 ng/dL: mean 12.8 ± 1.8 ng/dL (10/11 after at least 3 months) versus 33.6 ± 5.1 ng/dL (8/11 prior to treatment, P < .001) (Figure 1C). If only those with pretreatment ferritin levels were analyzed, there was a decrease in ferritin of 20.1 ng/dL with a pretreatment mean of 32.3 ± 3.9 ng/dL versus on treatment ferritin of 12.2 ± 1.4 ng/dL (P = .004). While receiving eltrombopag, 8/11 patients were ID with ferritin <20 ng/dL; 7 had microcytosis with MCV <80 fL and 3 had IDA. There was no clinical evidence of bleeding in any of the patients, and the majority of patients demonstrated at least a transient platelet count response (Figure 1D). Mean hemoglobin values remained relatively stable for the majority of patients (Figure 1E). Five of the patients (3/5 ID on eltrombopag) also received romiplostim (a second TPO-RA) either before or after eltrombopag, and none developed ID/IDA during this time (Figure 1F). In 6 of 11 patients, the ID was noted within 3 months of initiation of eltrombopag, but in 1 patient it was >9 months after starting. While eltrombopag was recently FDA approved for use in children with chronic ITP8 and has been approved for use in adults with chronic ITP since 2011,13 there are no prior reports of the development of ID in patients treated for ITP. Eltrombopag has also started to be used to manage inherited thrombocytopenias.14-16 In children and adolescents, ID has been associated with deficits in cognition.17 With potential new indications to treat young children with eltrombopag, and documented concerns with early onset ID,18 it is important to understand whether this is a true risk. Limitations of this study include its retrospective nature so that the data are limited to what was collected for clinical purposes. Because this is a retrospective study, it is difficult to be certain that none of these patients had occult bleeding, however other bleeding symptoms had improved as did (in most) the platelet count. Complete investigation in a subset of patients looking for occult blood loss was negative. A similar observation of dropping ferritin was not seen in those who were treated with romiplostim. It is interesting to note that in the adult trials in which almost 400 patients participated19-22 and in the pediatric trials (Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT) and PETIT2) which included almost 130 patients,9, 10 there is no reporting of ID or of changes in MCV values over the 24 weeks of study participation, although it is possible that this parameter was not evaluated and if subjects did not develop overt anemia, a decrease in MCV may have been overlooked. Ferritin levels were not a routine study parameter. Additionally, clinicians may have attributed clinically overt ID to subclinical bleeding and reacted by treating the ID. This is the first report of a series of pediatric patients who developed ID/IDA while on eltrombopag for ITP. All of patients had significant thrombocytopenia at the initiation of therapy, and the majority had a platelet count response to therapy (platelet counts >50 × 109/L) without evidence of bleeding (7/11). This study suggests that patients on eltrombopag should be monitored for ID/IDA with ferritin and careful attention to changes in hemoglobin parameters. A larger prospective study could address these concerns more definitively. M.L. has been a consultant for GSK, Novartis, and Amgen. C.W. and J.L. report no relevant conflict of interest. Initial observation, cohort collection, and wrote the main draft of the manuscript: Michele P. Lambert Contributed patients, data analysis as well as manuscript editing: Char M. Witmer, Janet L. Kwiatkowski Additional Supporting Information may be found in the online version of this article. Supporting Information Table 1. 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