Correction of anemia in a transfusion-dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade, ICL670).

Abstract

Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not receive chelation therapy due to short-life expectancy and the difficulties associated with the administration of the current reference standard chelator, deferoxamine. There have, however, been some reports of reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion requirement, ultimately resulting in long-lasting transfusion-free survival.

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Correction of anemia in a transfusion-dependent patient
with primary myelofibrosis receiving iron chelation therapy
with deferasirox (Exjade?
R, ICL670)
Anna Angela Di Tucci1, Roberta Murru1, Daniele Alberti2, Bertrand Rabault2, Simona Deplano1,
Emanuele Angelucci1
1Unita ` Operativa Ematologia e Centro Trapianti Midollo Osseo, Ospedale Oncologico ‘Armando Businco’, Cagliari, Italy;2Novartis Pharma AG,
Basel, Switzerland
OnlineOpen:This article is available free online at www.blackwell-synergy.com

Case report
The patient (female) was diagnosed in March 2002 at
the age of 61 with primary myelofibrosis (PMF) accord-
ing to the World Health Organization diagnostic criteria
(1). The initial symptom was fatigue. The disease was
classified as ‘intermediate risk’ according to the prog-
nostic classification of Dupriez et al. (LILLE system)
(2), which is associated with a median survival of
26 months. From the time of diagnosis the patient’s
hemoglobin was 5–7 g/dL, necessitating packed red blood
cell (PRBC) transfusions. The mean cellular volume was
78 fL and blood smear showed red cell poikilocytosis
with dacryocytes. The Direct Coombs test was positive
without any sign of hemolysis. There was mild thromb-
ocytopenia (platelets 90 · 103/lL) and a normal white
blood cell count; BCR/ABL was negative. Bone marrow
biopsy showed 20% cellularity with advanced stage of
fibrosis, MF-2 according to Thiele et al. (3). From May
2002 to June 2003 the patient required approximately
2–3 PRBC units per month (total of 29 units) to main-
tain a pretransfusional hemoglobin level of 8.5 g/dL.
In June 2003, the patient entered a phase II trial
evaluating the efficacy and safety of once-daily oral
chelator deferasirox in adults and children with a range
of transfusion-dependent anemias. Baseline assessment
of this patient (Table 1) showed that bone marrow
cellularity had decreased to 10% with no modification
in fibrosis score.
Withdosingbasedon
deferasirox was administered at 20 mg/kg/d for the
duration of the 1-yr study. No other hematological
therapy was administered during the study period.
liverironconcentration,
Abstract
Transfusional iron overload in patients with chronic anemias can result in multiple organ failure. Experience
in the management of iron overload in patients with myelodysplastic syndromes is limited, as many do not
receive chelation therapy due to short-life expectancy and the difficulties associated with the administra-
tion of the current reference standard chelator, deferoxamine. There have, however, been some reports of
reduced transfusion requirement associated with chelation therapy in patients with myelodysplastic
syndromes and myelofibrosis. Here, we discuss a patient with primary myelofibrosis and related transfusion-
dependent anemia who received chelation therapy with the once-daily oral iron chelator, deferasirox. In
addition to the reduced iron levels, the patient demonstrated an unexpected reduction in blood transfusion
requirement, ultimately resulting in long-lasting transfusion-free survival.
Key words myelofibrosis; iron overload; chelation
Correspondence Emanuele Angelucci, Unita ` Operativa Ematologia, Ospedale Oncologico ‘Armando Businco’, via Edward Jenner,
09121 Cagliari, Italy. Tel/Fax: +39 070 6095312; e-mail: emnang@tin.it
Accepted for publication 3 February 2007doi:10.1111/j.1600-0609.2007.00840.x
CASE REPORT
European Journal of Haematology ISSN 0902-4441
540
ª 2007 The Authors
Journal compilation 78 (540–542) ª 2007 Blackwell Munksgaard

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After 2 months of deferasirox therapy the patient’s
transfusion requirementprogressively
PRBC units were administered during the initial chela-
tion therapy period) and transfusion therapy was ceased
5 months after study entry due to stable hemoglobin
levels of 11.4–12.4 g/dL. At study end, liver iron concen-
trationandserumferritin
reduced (Table 1). Re-evaluation of myelofibrosis by
routine hematological evaluation and bone marrow
biopsy revealed increased hemoglobin levels (12.5 g/dL),
decreased CD34-positive cell counts, a negative Direct
Coombs test, a reduction in teardrop cells, and normal-
ization of mean corpuscular volume (90 fL). Bone
marrow cellularity had increased to 15% with no
modification in fibrosis score. Even if chelation therapy
was not directly targeted to PMF a clinical improvement
was obtained according to the international working
group for myelofibrosis research and treatment response
criteria (4). Due to the reduction in transfusions,
deferasirox therapy was reduced to a dose of 5 mg/kg/d.
Chelation therapy was finally interrupted in January
2005 when the patient’s body iron content was within an
acceptable range (serum ferritin 953 lg/L and transferrin
saturation 42%). To date (January 2007), the patient
remains transfusion free (serum ferritin 499 lg/L and
transferrin saturation 34%), with a hemoglobin level of
approximately 11 g/dLand
parameters (platelet count 120 · 103/lL).
decreased (10
levelsweresignificantly
normalhematological
Discussion
Primary myelofibrosis is an uncommon but severe condi-
tion associated with poor prognosis. For the majority of
patients, therapyispalliative
transfusion dependent. Transfusion requirement often
increases during the course of the disease due to collagen
and manybecome
deposition in the bone marrow and progressive impair-
ment of erythropoiesis. The patient described here
received iron chelation therapy as part of the clinical
evaluation of oral deferasirox and experienced not only
the anticipated fall in iron levels, but also an unexpected
improvement in erythropoiesis. This improvement was so
markedthat thetransfusion
progressively and was ultimately deemed unnecessary, an
effect that continued after cessation of chelation therapy.
Clinical improvement (4) was evident as the patient
became transfusion free, leading to a dramatic improve-
ment in quality of life. This has been sustained to date
(3 yr after cessation of transfusion requirement and more
than 22 months after stopping chelation). Although iron
chelation therapy has not been widely evaluated in
patients with acquired anemia, reports have shown an
improvement in bone marrow function in patients with
myelodysplastic syndromes receiving deferoxamine (5)
and in a patient with PMF receiving deferiprone (6). A
variety of mechanisms are possible in different diseases
(7), those postulated include: a limited cytoreductive
effect (5), iron redistribution to the hemopoietic tissue
(8), ferrokinetic changes (9), suppression of increased
apoptosis, and mitochondrial damage secondary to intra-
cellular iron deposition (as it has been demonstrated that
iron chelators can pass the erythroblast membrane) (10).
Because of the persistent effect after chelation with-
drawal, the latter appears to be the most promising
mechanism to be investigated. Of course, a stochastic
effect cannot be excluded, particularly in PMF in which a
‘bizarre’ behavior has been described (7), but the
increasing number of similar reports in the literature
support the need for a controlled clinical trial in
transfusion-dependent acquired hemopoietic stem cell
disorders to investigate the potential benefit of chelation
on erythropoiesis.
requirement decreased
Table 1 Patient’s characteristics before
chelation and after 1 yr of chelation therapy
Baseline values prior to
chelation (May 2002)End of study (June 2003)
Hemoglobin (g/dL)(transfusion therapy required) 12.5
(no transfusion therapy)
1.0
Negative
2.8
1100
38
15
MF-2
3
11.1
438
12.0
Absent
Reticulocytes (%)
Direct Coombs test
LIC (mg/g dw)
Serum ferritin (lg/L)
Transferrin saturation (%)
Bone marrow cellularity (%)
Fibrosis grading (3)
Teardrop cells (dacryocytes, %)
CD34+ (per lL)
Lactate/dehydrogenase (U/L)
Longitudinal diameter of spleen (cm) 13.5
Bone marrow iron
1.8
Positive
10.1
3001
71
10
MF-2
15
16.4
530
Present
LIC, liver iron concentration.
Di Tucci et al.
Correction of anemia in a patient receiving deferasirox
ª 2007 The Authors
Journal compilation 78 (540–542) ª 2007 Blackwell Munksgaard
541

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ª 2007 The Authors
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