A Phase II Trial of the Safety and Efficacy of Iron Reduction by Phlebotomy in Recipients of Hematopoietic Stem Cell Transplants

Background Hematopoietic stem cell transplantation (HSCT) is increasingly used as a treatment for a variety of malignant and non-malignant conditions. With improvements in conditioning regimens and post-transplant care, more HSCT recipients are becoming long-term survivors and therefore increasing attention is being directed to studying the long-term consequences of successful HSCT.

Iron overload is surprisingly common after HSCT. The pathophysiology of iron overload or siderosis is related to transfusional iron, inhibition of normal erythropoiesis and released iron stores from hepatocytes, tumour cells and bone marrow. It is associated with chronic liver disease in this patient population, as well as with increased rates of infection. Studies suggest that iron overload may also affect survival in this population, as has been shown in other populations who are susceptible to iron overload such as those with thalassemia and hereditary hemochromatosis (1,2).

McKay et al. described 76 survivors of allogeneic and autologous HSCT who were at least 1 year post-transplant (3). Sixty-seven (88%) had a ferritin level above the normal range. Thirty-one (41%) had abnormal liver enzymes and 30/31 also had elevated ferritin. At the time of publication, 10 of the patients had begun a venesection program; all showed a reduction in ferritin levels and nine patients had a reduction in alanine aminotransferase (ALT). Strasser et al. showed an increase of hepatic iron concentration in 10 consecutive patients who died post-HSCT (4). In a retrospective study to determine the characteristics of chronic liver disease post-HSCT, iron overload was felt to contribute to chronic liver dysfunction in 52.4% of patients post-HSCT who had liver disease (5).

Iron overload has also been associated with an increased frequency of infection in HSCT recipients. A single-centre retrospective study of autopsies conducted post-HSCT revealed an association between high liver iron concentration and invasive Aspergillus infection (6). In a consecutive series of 263 allogeneic HSCT patients, 5 cases of mucormycosis all occurred in patients with severe iron overload (7).

Iron overload prior to transplantation may also have a negative effect on survival. In a prospective study of 25 consecutive patients, Altes et al. showed that a very high ferritin level and a high transferrin saturation prior to conditioning was associated with a decreased overall survival and a high transferrin saturation was associated with an increase in transplant-related mortality (8).