Clinico-Pathological Features and Outcomes in Patients with Congenital Sideroblastic Anemias

Abstract

▪Background: Ring sideroblasts (RS) are erythroid precursors with perinuclear mitochondrial iron accumulation seen in clonal disorders, such as myelodysplastic syndromes (MDS), and non-clonal conditions, including copper deficiency, lead poisoning, and congenital sideroblastic anemias (CSAs). CSAs involve a broad clinical and pathological spectrum related to mutations in ALAS2, ABCB7, etc. or mitochondrial aberrations (Pearson Syndrome; Myopathy, Lactic Acidosis and Sideroblastic Anemia (MLASA); etc.). MDS-RS is often associated with SF3B1 mutations, which have not been reported in other SAs. This study sought to further describe the characteristics and outcomes of patients with CSAs.Methods: After due IRB approval, we retrospectively identified all patients with a CSA diagnosis seen at our institution from 1990-2014. All bone marrow (BM) slides were re-reviewed to confirm the presence of RS. Secondary causes of SA were excluded. Genetic testing on the BM specimen was carried out when possible through research collaborations with the Boston Children's Hospital. Data was retrospectively extracted and is reported in Table 1. Data was analyzed based on the presence or absence of mitochondrial inheritance.Results: Seventeen patients with CSA were identified, 3 (17.6%) with mitochondrial inheritance. In the non-mitochondrial inheritance group, the median age at diagnosis was 29 years (range, 1-61 years). Six (42.9%) were males. At a median follow-up of 119 months (range, 1-401 months), 1 (7.1%) death was documented. The median overall survival (OS) has not been reached. Six of 14 (42.9%) underwent genetic testing, and a mutation was identified in 4 (ALAS -2, FECH -1, and a novel mutation, currently being validated). Six of 6 (100%) samples analyzed for SF3B1 mutations were negative. Median laboratory values at diagnosis included hemoglobin 9.5 g/dL, MCV 85.8, WBC 6.4, and platelets 297,000. Three (21.4%) patients had splenomegaly. Nine (64.3%) had iron overload; 3 (33%) were treated with iron chelation therapy, with only 1 documented response (≥ 500 µg/L reduction in serum ferritin). Twelve (85.7%) were treated with pyridoxine. Outcomes of pyridoxine treatment are described in Table 1. Three of 14 (21.4%) received red blood cell transfusions, and 3 (21.4%) received erythropoiesis stimulating agents (ESA). One (7.1%) patient underwent allogeneic stem cell transplant.Three patients had SAs of mitochondrial inheritance; aberrations were identified in 2 (YARS2 and a 4 kilobase mitochondrial deletion). In this group, the median age at diagnosis was 2 years (range, 1-13 years), and all were males. At a median follow-up of 173 months (range, 119-329 months), 2 (66.7%) deaths were documented. Median laboratory values at diagnosis included hemoglobin 9.0 g/dL, MCV 97.0, WBC 5.2, and platelets 175,000.Conclusions: Congenital SAs are rare, and the majority are of non-mitochondrial inheritance. The molecular basis for disease can be ascertained in less than 50% of patients. Unlike MDS with RS, CSAs are not characterized by the SF3B1 mutation, which may be used to establish clonality. With appropriate supportive care measures, survival for non-mitochondrially inherited CSA remains favorable.Table 1Demographics and Outcomes for 17 Patients with CSAAge at Diagnosis (Years)GenderMolecular MutationAdditional FeaturesPyridoxine ResponseIron OverloadSurvival (Months)OutcomesNon-Mitochondrial Inheritance5MR452H in ALAS2NY2Y173Alive33MMutation being validatedSplenomegalyY2Y254Alive36MUnknown, PTPN11, ALAS 2, ABCB7 negativeSplenomegalyNY137Alive, status-post transplant29FUnknown1NN/AN131Alive341FUnknown1NY2N83Alive440MPromoter mutation in ALAS2SplenomegalyNN106Alive431FUnknown1NNY401Deceased54MUnknown1NLost to follow-upY1Alive33MFECHNN/AN189Alive31FSCAD -VUSNLost to follow-upY13Alive329FUnknown1NNY205Alive358FUnknown1NNY47Alive, unknown transfusion status61FUnknown1NY2Y58Alive323FUnknown1Alpha-thalassemia-2-traitY2N37Alive3Mitochondrial Inheritance13MYARS2MLASANY329Alive42MUnknown, mitochondrial deletions and ABCB7 negativeMyopathy, AtaxiaN/AN173Deceased1M4 kilobase mitochondrial deletionPearson Syndrome, B cell lymphomaY2N119Deceased1No molecular testing performed2Sustained hemoglobin response of ≥ 1 g/dL over baseline for ≥ 12 weeks3Transfusion-independent4Transfusion-dependent DisclosuresSteensma:Incyte: Consultancy; Onconova: Consultancy; Amgen: Consultancy; Celgene: Consultancy.