The efficacy of phlebotomy in a patient with prior pure red cell aplasia and iron overload secondary to transfusions

Introduction

Pure red cell aplasia (PRCA) is a severe, acquired disorder, characterised by the selective reduction or absence of erythroblasts in the bone marrow and of circulating reticulocytes. It can present in an acute form, most frequently in childhood, or in a chronic form, typical of adults and the elderly^1–4. From an aetiological point of view, PRCA can be primary or secondary to haematological or solid malignancies (chronic lymphocytic leukaemia, Hodgkin's and non-Hodgkin's lymphomas, thymoma, carcinoma of the stomach, lung and breast), infections (parvovirus B19, Epstein-Barr virus, cytomegalovirus), autoimmune diseases (autoimmune haemolytic anaemia, systemic lupus erythematosus, rheumatoid arthritis) or drugs (diphenylhydantoin, isoniazide, chloramphenicol, azathioprine).

There are two facets to the treatment of chronic PRCA: on the one hand supportive transfusion therapy with red cell concentrates, and, on the other hand, the removal of the underlying cause – if identified and if possible. Immunosuppressive therapy is occasionally effective, but sometimes the disease recurs when such treatment is withdrawn⁵. Patients who achieve haematological recovery usually have marked accumulation of iron in various organs, because of the repeated transfusions, with their relative consequences, and must, therefore, be treated promptly with iron-chelating therapy (deferoxamine administered by continuous subcutaneous infusion through a portable pump)⁶. This therapy usually only partially reduces the excessive iron accumulation.

In this case report, we describe the management of post-transfusional iron overload using phlebotomy, in additional to classical iron-chelating therapy, in a patient with previous PRCA.

Case Report

A 67-year old woman was admitted to the General Medicine ward of the S. Cuore di Negrar Hospital (Verona) in July 1995, because of dyserythropoietic anaemia [bone marrow findings: rich marrow cellularity with impaired maturation; signs of dyserythropoiesis (Jolly bodies and intercytoplasmic bridges); myelopoiesis with nuclear-cytoplasmic asynchrony and hypolobulated megakaryocytes; blast percentage less than 5%].

The past medical history included hysterectomy with removal of adnexae, because of uterine fibromatosis at the age of 52 and an episode of thyroiditis, probably of an autoimmune nature, at the age of 55, which was treated with steroids.

In 1988, the woman was found to have hypogammaglobulinaemia (mean value 4 g/L), which persisted. During the admission, the woman underwent a bone marrow aspirate (maturing marrow with discrete erythropoiesis) and a bone biopsy (40% cellularity dyshomogeneous and maturing). She was subsequently admitted to hospital numerous times (a total of 13, with the last admission in April 1997) because of progressive anaemia. During her second admission, in October 1995, she started oral steroid therapy (initial dose of prednisone of 75 mg/die with a progressive reduction to a maintenance dose of 25 mg/die), which was continued for about 2.5 years (until March 1998). Intravenous infusion of high doses of immunoglobulins was ineffective. A bone marrow aspirate, carried out during the fourth admission, documented an almost complete absence of cells of the erythroid lineage, leading to the diagnosis of PRCA. A karyotypic study in peripheral blood was normal. The immunohaematological investigations (direct and indirect Coombs' tests) were negative, as were numerous other examinations aimed at determining a possible cause of the anaemia.

The steroid treatment was complicated by severe osteoporosis, with a fracture of the L1 vertebra in May 1996. From December 1995 to August 1997, the patient was transfused with red blood cell concentrates (RCC) at roughly monthly intervals, receiving a total of 60 units of RCC. As a consequence of this heavy transfusion therapy, the woman developed severe secondary haemosiderosis (her ferritin concentration in July 1997 was 6,000 μg/L, and her transferrin saturation 90%). A search for mutations in the haemochromatosis gene HFE (C282Y and H63D) was negative. From June 1996, because of the persistent anaemia, cyclosporine (100 mg twice daily, subsequently reduced to 100 mg/die and then to 50 mg/die) was added to the steroid and continued until November 1997. In April 1997, the woman had a deep vein thrombosis in the right leg, which required long-term oral anticoagulant therapy. From July 1997, azathioprine (75 mg/die subsequently reduced to 25 mg/die) was added to the steroid and cyclosporine and continued until March 1998.

Contemporaneously, there was progressive normalisation of the woman's haemoglobin concentration with reduction, until complete cessation, of transfusion needs. From March 1998, the patient was no longer being treated with immunosuppressive therapy. Once the red cell aplasia had been resolved, attention was given to the management of the severe haemosiderosis (serum ferritin levels of 5,700 μg/L in March 1998). The patient was, therefore, referred to the outpatient department of the Service of Immunohaematology and Transfusion of Verona Hospital, where she started, in December 1997, iron-chelating therapy with deferoxamine (30 mg/kg die), first as a continuous subcutaneous infusion delivered by a portable pump and, subsequently, as subcutaneous bolus injections every 12 hours. However, given the poor response, the iron-chelating therapy was interrupted in May 2002 (serum ferritin: 4,140 μg/L). In May 2006, in the light of the persistently high levels of ferritinaemia (4,557μg/L) in the presence of normal haemoglobin concentrations for the previous 8 years, a decision was taken to start a careful phlebotomy programme (monthly removal of 200 mL blood without volume replacement). From May 2006 to April 2007 (latest follow-up), the patient underwent 12 phlebotomy sessions with a notable reduction in ferritinaemia (latest level of serum ferritin in April 2007: 3,120 μg/L) and good maintenance of haemoglobin levels, which never fell below 14 g/dL post-phlebotomy.

Discussion and conclusions

Phlebotomy is the treatment of choice for iron overload⁶. However, in some situations it is not feasible since the haemosiderosis is secondary to repeated transfusions to correct severe congenital or acquired anaemia (for example, anaemia associated with thalassaemia major, myoledysplastic syndromes, leukaemias and PRCA). In these cases, iron-chelating treatment with parenterally administered deferoxamine must be used. This treatment is, however, very demanding for the patient, since the drug must be infused subcutaneously in a continuous manner using a portable infusion pump. The compliance of patients, particularly elderly ones, is often poor and not infrequently the treatment is carried out irregularly with poor control of the iron overload.

Patients with haemosiderosis secondary to transfusions for anaemia, but whose underlying anaemia has been cured, deserve a discussion apart. Although these patients would be candidates for phlebotomy, this is rarely prescribed by physicians⁷. The main reason for the reluctance to use this therapeutic strategy in such patients is their presumed poor haematological tolerance given the underlying disease. However, we have previously shown that patients cured of prior acute leukaemia with haemosiderosis secondary to transfusions can be treated safely and efficiently with phlebotomy⁸.

To the best of our knowledge, this is the first report of a patient with prior PRCA, in whom iron overload was treated with phlebotomy.

Our clinical experience has shown that this therapeutic approach was safe and efficient as well as being haematologically and psychologically well supported by the patient. Of course, the phlebotomy programme will need to be continued for a long period in order to reach satisfactory levels of ferritinaemia (<1,500 mg/L). Nevertheless, further reports such as this are necessary to confirm these initial positive results and to optimise the therapeutic approach.

Figure 1.

Ferritin levels during the patient's clinical course