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

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 1: Demographics and Outcomes for 17 Patients with CSA

Age at Diagnosis (Years)	Gender	Molecular Mutation	Additional Features	Pyridoxine Response	Iron Overload	Survival (Months)	Outcomes
Non-Mitochondrial Inheritance
5	M	R452H in ALAS2	N	Y2	Y	173	Alive3
3	M	Mutation being validated	Splenomegaly	Y2	Y	254	Alive3
6	M	Unknown, PTPN11, ALAS 2, ABCB7 negative	Splenomegaly	N	Y	137	Alive, status-post transplant
29	F	Unknown1	N	N/A	N	131	Alive3
41	F	Unknown1	N	Y2	N	83	Alive4
40	M	Promoter mutation in ALAS2	Splenomegaly	N	N	106	Alive4
31	F	Unknown1	N	N	Y	401	Deceased
54	M	Unknown1	N	Lost to follow-up	Y	1	Alive3
3	M	FECH	N	N/A	N	189	Alive3
1	F	SCAD-VUS	N	Lost to follow-up	Y	13	Alive3
29	F	Unknown1	N	N	Y	205	Alive3
58	F	Unknown1	N	N	Y	47	Alive, unknown transfusion status
61	F	Unknown1	N	Y2	Y	58	Alive3
23	F	Unknown1	Alpha-thalassemia-2-trait	Y2	N	37	Alive3
Mitochondrial Inheritance
13	M	YARS2	MLASA	N	Y	329	Alive4
2	M	Unknown,  mitochondrial deletions and ABCB7 negative	Myopathy, Ataxia	N/A	N	173	Deceased
1	M	4 kilobase mitochondrial deletion	Pearson Syndrome, B cell lymphoma	Y2	N	119	Deceased

 

¹No molecular testing performed

²Sustained hemoglobin response of ≥ 1 g/dL over baseline for ≥ 12 weeks

³Transfusion-independent

⁴Transfusion-dependent

Disclosures: Steensma: Incyte: Consultancy ; Onconova: Consultancy ; Amgen: Consultancy ; Celgene: Consultancy .

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