Congenital sideroblastic anaemia successfully treated using allogeneic stem cell transplantation


Mouhab Ayas, MD, Department of Oncology, King Faisal Specialist Hospital and Research Centre, MBC 64, P.O.Box 3354, Riyadh 11211, Saudi Arabia. E-mail:


Therapy for patients with congenital sideroblastic anaemia has been limited to blood transfusions and chelation. Three children with congenital sideroblastic anaemia (SA) who were blood transfusion dependent underwent stem cell transplantation (SCT) from matched sibling donors. Conditioning consisted of cyclophosphamide 50 mg/kg/d for 4 d, busulphan 4 mg/kg/d for 4 d and anti-thymocyte globulin (ATG) 30 mg/kg for four doses pretransplant. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporin A and methotrexate. All patients engrafted, and are alive and transfusion independent. SCT can be curative for patients with SA.

Sideroblastic anaemias are a heterogeneous group of disorders characterized by the presence of large numbers of ‘ringed’ sideroblasts in the bone marrow, ineffective erythropoiesis and increased total body iron (Bridges, 1997; Andrews & Bridges, 1998). The anaemia is hypochromic and microcytic, except in some rare syndromes such as Pearson's syndrome and Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (DIDMOAD) syndrome (May & Fitzsimons, 1994; Pearson, 1997; Bazarbachi et al, 1998) in which the anaemia is macrocytic. The unifying element in sideroblastic anaemias appears to be a defect at the mitochondrial level (May & Fitzsimons, 1994; Bridges, 1997); this defect could be hereditary or acquired. Several hereditary defects that affect the mitochondrion directly (e.g. deletions of mitochondrial DNA) or indirectly (e.g. defects in haem biosynthetic gene products) have been reported (May & Fitzsimons, 1994; Bridges, 1997; Andrews & Bridges, 1998). Drugs and toxins such as lead and isoniazid can impair mitochondrial function and thus produce sideroblastic anaemia (Yunis & Salem, 1980; May & Fitzsimons, 1994; Bridges, 1997). This mitochondrial defect results in decreased production of haem and triggers iron accumulation and the formation of ringed sideroblasts (Andrews & Bridges, 1998). The hereditary form may be X-linked or autosomal (dominant or recessive). Management of this disorder has been limited to supportive care with blood transfusions and chelation therapy.

Patients and methods

Between June 1999 and February 2000, three patients (two girls and one boy) with blood transfusion-dependent congenital sideroblastic anaemia (SA) received allogeneic stem cell transplantation (SCT) at the King Faisal Specialist Hospital and Research Centre. Diagnosis was confirmed in all patients by demonstration of the ringed sideroblasts using light microscopy in bone marrow after Perl's stain. None had evidence of leukaemic transformation. Their ages at SCT were 1, 2 and 8 years. All patients had failed a trial of high-dose pyridoxine and were transfusion dependent. Serum ferritin levels prior to SCT were 856, 209 and 2047 μg/l, respectively, and thus only the last patient had required chelation therapy with deferoxamine. All had hepatosplenomegaly at transplant, with normal liver function tests. No liver biopsies were done (Table I). All donors were human leucocyte antigen (HLA)-identical siblings and all had normal blood counts. Cytomegalovirus (CMV) serology indicated that two patients were CMV-seronegative, all donors were CMV-seropositive. The harvested bone marrows (BMs) were not manipulated, and the CD34 positive cell counts were 13, 20 and 6 × 106/kg of recipient body weight for each of the three patients respectively. The conditioning regimen consisted of busulphan (BU) 4 mg/kg p.o. in divided doses daily on d −10, −9, −8 and −7 (total dose of 16 mg/kg), and cyclophosphamide (CY) 50 mg/kg once daily i.v. on d −5, −4, −3 and −2 (total dose of 200 mg/kg). Anti-thymocyte globulin (ATG) was given i.v. at a dose of 30 mg/kg on d −5, −4, −3 and −2 (total of four doses), graft-versus-host disease (GVHD) prophylaxis was with cyclosporin A and methotrexate. All patients were treated in HEPA filtered rooms and were isolated until engraftment. The first two patients received CMV i.v. Ig (CMV-seronegative recipient and CMV-seropositive donors) at a dose of 4 ml/kg on d −2 and 1 ml/kg weekly post SCT for six doses. The third patient (CMV-seropositive) was given i.v. Ig every 2 weeks at a dose of 0·5 g/kg from d −4 until d +90. All patients received acyclovir 45 mg/kg/d from d −3 to d +28. All blood products were leucocyte-filtered and irradiated.

Table I.  Patient and SCT details.
PatientSexAge at SCT (years)Serum ferritin levels (μg/l)CD 34 cells/kg (× 106)
1Female1856 μg/l13 × 106
2Male2209 μg/l20 × 106
3Female82047 μg/l6 × 106


Engraftment was defined as increase in the absolute neutrophil count (ANC) to geqslant R: gt-or-equal, slanted 0·5 × 109/l for three consecutive days. All three patients engrafted at 20, 13 and 19 d post SCT, and the days for a self-sustaining platelet count of geqslant R: gt-or-equal, slanted 20 × 109/l were 30, 21 and 25 d post SCT respectively. All patients had bone marrow biopsies carried out on d 28 post SCT and all confirmed trilineage engraftment with no evidence of ringed sideroblasts.

Acute skin GVHD grade 2 was observed in only one patient. She responded to treatment with steroids. No patient has developed chronic GVHD thus far. Two patients developed mild self-limited veno-occlusive disease of the liver. All three patients are now alive at 455, 360 and 230 d respectively. They have normal cell blood counts (CBCs) and are transfusion independent.


With the exception of those pyridoxine- or thiamin-responsive patients, therapy for patients with SA has mainly been supportive with blood transfusions and chelation with deferoxamine (Dolan & Reid, 1991). SCT is increasingly used for the radical cure of haemoglobinopathies (Lucarelli et al, 1991; Giardini & Lucarelli, 1999); outcomes are greatly influenced by the presence of hepatomegaly, portal fibrosis and ineffective chelation therapy before transplantation. Patients in thalassaemia class I have none of these risk factors, patients in class II have one or two, and patients in class III have all three risk factors. Protocols employing busulphan and cyclophosphamide have resulted in excellent results, with a probability of disease-free survival of 91%, 83% and 58% for thalassaemic children in classes I, II and III respectively (Giardini & Lucarelli, 1999). Because the anaemia in SA results from haemolysis produced by ineffective erythropoiesis, it is expected that allogeneic SCT could represent a curative alternative for afflicted patients. Urban et al (1992) reported a successful SCT in a 34-month-old male patient with SA after conditioning with busulphan and cyclophosphamide. The patient engrafted and maintained his graft 3 years post SCT. Similarly, González et al (2000) reported a successful peripheral stem cell transplant in a 19-year-old man with SA, conditioning was with busulphan and cyclophosphamide, the patient engrafted, and is alive and well 3 years post SCT.

In our series, we transplanted three children with pyridoxine-refractory SA using busulphan and cyclophosphamide for conditioning. The addition of ATG was to help reduce the risks of graft rejection in our patients who were heavily transfused prior to SCT. All patients engrafted and tolerated the transplantation with no major toxicity.

We suggest that SCT be considered early in patients with congenital sideroblastic anaemia before the development of consequences of chronic transfusions such as haemosiderosis, alloimmunization and possible infections.