Bone Marrow Transplantation (2015) 50, 457–458
© 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15
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LETTER TO THE EDITOR
A prospective cohort study of the feasibility and efficacy
of iron reduction by phlebotomy in recipients of
hematopoietic SCT
Bone Marrow Transplantation (2015) 50, 457–458; doi:10.1038/
bmt.2014.273; published online 15 December 2014
Transfusional iron overload is common in hematopoietic SCT (HSCT)
patients and is a potential cause of morbidity and mortality. Iron
overload, estimated by increased ferritin, appears to be associated
with adverse outcomes and decreased survival.1–4
There are several unanswered questions in this area. First, it is
not clear how to best measure iron overload in these patients.
Second, the exact mechanism whereby iron overload causes
increased mortality has not been definitively established. Finally,
the impact of reducing iron and the best method to achieve iron
reduction in these patients are unknown.
The simplest method to estimate iron overload is by measurement of serum ferritin. However, this strategy is not specific
because ferritin is an acute phase reactant and can be elevated in
a variety of inflammatory conditions.5 In the pre- and posttransplant setting, patients may have an elevated ferritin for
reasons other than iron overload. Interestingly, a recent study
demonstrated that elevated ferritin was associated with decreased
survival, but there was no survival impact of iron overload as
measured by magnetic resonance imaging (MRI).6 A meta-analysis
also found that there was no association between the iron
overload measured by MRI and whilst a serum ferritin of
41000 ng/mL was associated with increased mortality, an even
higher ferritin of 42500 ng/mL was not.7
The ‘gold standard’ for the measurement of total body iron is
the liver biopsy stained with Perls’ Prussian blue8 but MRI is
increasingly used to measure the liver iron content and correlates
with the liver biopsy.9
There are two approaches to remove excess iron: phlebotomy
and iron chelation. Phlebotomy is generally well tolerated with
minimal toxicities and has been used in HSCT patients successfully.10
We undertook a prospective cohort study in HSCT patients with
iron overload to evaluate the safety, feasibility and efficacy of
decreasing total body iron by phlebotomy.
Institutional Research Ethics Board approval was obtained to
perform this study and all patients provided informed consent. We
enrolled patients who were between the ages of 18 and 65 and
who were at least 60 days after HSCT. Patients were eligible for the
study if they were red cell transfusion independent and had a
serum ferritin of at least 1000 μg/L at study entry. Patients
underwent phlebotomy of 500 mL of whole blood for 12
procedures. Initially, phlebotomies were done monthly. If the
ferritin remained significantly elevated (41000 μg/L) after six
phlebotomies, the frequency of phlebotomies was increased to
weekly as tolerated. Complete blood count was assessed before
each phlebotomy and if the Hb level was o 100 g/L, the
phlebotomy was not performed. Iron stores were estimated
biochemically by measuring serum ferritin and transferrin saturation levels in each patient before the start of phlebotomy and at
6 and 12 months. Total body iron was estimated from hepatic iron
concentration as measured by MRI (signal intensity ratio method)
at the same time points.
Serum samples were also collected at baseline to screen for the
most common mutations of the HFE gene (C282Y and H63D
mutations) as hereditary hemochromatosis is common and may
contribute to iron overload in HSCT recipients.
The effect of iron overload was studied by laboratory testing of
the liver, the heart and the endocrine functions at baseline,
6 and 12 months.
There were 22 patients enrolled in the study between January
2007 and December 2011. The types of transplant included sibling
allogeneic (n = 15), matched, unrelated donor (n = 5) and autologous (n = 2). The median number of RBC transfusions before
study entry was 38 (range 7–100). Indications for transplant were
acute leukemia (n = 11), myelodysplastic syndrome (n = 4), nonHodgkin lymphoma (n = 5), myelofibrosis (n = 1) and aplastic
anemia (n = 1). Given that the impact of iron overload in patients
who are recipients of auto-HSCT may be different than in patients
who receive an allo-HSCT, this analysis is reported only for the alloHSCT group. Of the 20 allogeneic patients, 14 (70%) were able to
complete the series of 12 planned phlebotomies. The reasons for
not completing all 12 treatments were relapse (n = 1), extensive
GVHD (n = 1), non-compliance (n = 2) and intolerance (n = 2).
At baseline, the mean ferritin was 1911.2 μg/L and decreased to
974.7 μg/L at 12 months (P = 0.0001). The mean MRI hepatic iron
concentration at baseline was 226.7 μmoL/g and decreased to
157.2 μmoL/g at 12 months (P = 0.0003).
Four patients had an HFE gene mutation. One was homozygous
for H63D, two were heterozygous for H63D and one was
heterozygous for C282Y.
We were unable to demonstrate an effect of iron reduction on
end-organ function using biochemical measurements of organ
function.
There are limitations of this study. First, the sample size is small
and there were some challenges with recruitment. Given the
complicated clinical course that transplant patients undergo, it is
sometimes difficult to enroll patients in a study that involves yet
another intervention. Second, we were unable to show an effect
on organ function. Although biochemical assessment of organ
function is simple and noninvasive, it is unlikely to be sufficiently
sensitive. Further studies in this area should consider functional
assessment of end-organ function, together with longer follow-up.
In consideration of the small sample size of this study and the
heterogeneity of transplant indications and transplant types,
we did not evaluate OS, relapse or non-relapse mortality. Third, we
did not evaluate potential confounding factors that may have
contributed to elevations in ferritin.
This study demonstrates that early phlebotomy, starting as soon
as 60 days post transplant, was feasible, safe and well tolerated in
most patients. Phlebotomy was demonstrated to be effective at
reducing iron stores with statistically significant reductions in
mean ferritin and mean MRI hepatic iron concentration. Given the
positive results in this pilot study, we plan to undertake a larger
study with longer follow-up using MRI evaluation of iron and
phlebotomies to remove excess iron, to determine the effect on
morbidity and mortality in this patient population.
Letter to the Editor
458
CONFLICT OF INTEREST
The authors declare no conflict of interest.
AK Kew1, S Clarke2, A Ridler2, S Burrell2, J-A Edwards1, S Doucette3
and S Couban1
1
Division of Hematology, Queen Elizabeth II Health Sciences Centre
and Dalhousie University, Halifax, Nova Scotia, Canada ;
2
Department of Diagnostic Imaging, Queen Elizabeth II Health
Sciences Centre and Dalhousie University, Halifax, Nova Scotia,
Canada and
3
Department of Medicine Queen Elizabeth II Health Sciences Centre
and Dalhousie University, Halifax, Nova Scotia, Canada
E-mail: [email protected]
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© 2015 Macmillan Publishers Limited