Deferasirox-induced robust and dose-dependent reversal of anemia in a patient with variants in the TRIB2 and ABCB6 genes.

The iron chelator deferasirox (DFX) can improve anemia, as observed in patients with transfusional iron overload, such as patients with myelodysplastic syndrome (MDS),(1-4 ) myeloproliferative neoplasms,(5 ) aplastic anemia,(2,6 ) pure red cell aplasia,(7 ) and the iron metabolism disorder aceruloplasminemia.(8 ) How DFX improves anemia is unclear. It may increase erythropoietin production, improve iron availability for hematopoietic tissue,(9 ) and modify the bone marrow (BM) microenvironment by reducing oxidative stress(10,11 ) and inflammation.(12 ) Here, we describe the sustained and dose-dependent erythroid improvement in a patient with constitutional variants in the TRIB2 and ABCB6 genes. A 55-year-old woman presented with chest pain and a 2-week history of dyspnea on exertion. A diagnosis of macrocytic anemia was made (hemoglobin [Hb], 10.8 g/dL; mean corpuscular volume, 103 fL) and, 5 weeks later, she was referred to our hospital because of hyporegenerative, transfusion-dependent anemia (Hb, 7.8 g/dL). Laboratory evaluation revealed moderate thrombocytosis and leukopenia, hyperferritinemia, and elevated inflammatory parameters (C-reactive protein [CRP], alpha-1-globulin; Table 1). Her last documented Hb level from 2013 had been normal. She had received 1 red blood cell (RBC) transfusion a few days before the referral but no other lifetime transfusions. Further workup was notable for mild splenomegaly, type C gastritis, and IgM-kappa monoclonal gammopathy of undetermined significance. RBC morphology on the peripheral blood smear was overall normal. BM examination showed mild hypercellularity, megakaryocytic and erythroid hyperplasia, impaired erythroid maturation, and interstitial lymphocytosis (Figure 1A). Plasma cell percentage was normal. Ferritin and hemosiderin were considerably increased and ring sideroblasts were absent on examination of iron staining on BM smears. The karyotype was normal, no mutations were detected with a panel of 54 genes associated with myeloid disorders, and the cause of anemia remained unclear. The patient subsequently required about 4 RBC units per month (Figure 1B) because of symptomatic anemia. After 4 months and a total of 15 transfusions, iron chelation therapy (DFX 12 mg/kg daily) was initiated because of iron overload indicated by serum ferritin levels (Figure 1B). Four months after starting DFX, Hb levels increased, the patient became transfusion-independent, and DFX was stopped. However, 2 months later, erythroid normalization was lost. Findings of a BM reexamination were unchanged from initial consultation. Three weeks after reinitiated transfusions plus standard-dose DFX (17 mg/kg daily), Hb levels increased and the patient became transfusion-independent again, this time within several weeks (Figure 1C). DFX remained the only plausible cause of this second remission of anemia and the regained erythroid response was maintained (median Hb, 14.1 g/dL; Figure 1B,D) with DFX. Six months later, treatment was interrupted because of cholestatic liver disease, Coombs-negative hemolysis, abdominal discomfort, and cholecystolithiasis. Both the cholestatic disease and the hemolysis were pre-sumed to be due to DFX because no other cause could be identified, and liver and hemolysis parame-ters normalized after stopping DFX. The patient subsequently maintained Hb levels $12 g/dL for 6 months without DFX (Figure 1B).