12th Congress of the European Hematology ... - Haematologica

0809
CURRENT APPROACH TO CHELATION THERAPY IN THALASSAEMIA MAJOR FOLLOWING 6
YEARS OF COMBINED CHELATION THERAPY
K. Farmaki, I. Tzoumari, Ch. Pappa, G. Anagnostopoulos,
N. Angelopoulos
Thalassaemia Unit, CORINTH, Greece
Aims. To identify the golden standard in chelation therapy in order to
reduce total body iron overload, reverse hemosiderosis complications
and improve quality of life of Thalassaemia major patients. Patients. 50
patients (24 males, 26 females), 8-48 years, on combined chelation with
oral Ferriprox ® (75-9 0 mg/kg daily) and Desferal ® (20-50 mg/kg, SC or
IV 2-6 days/week), in a 6 year regimen strictly adjusted and closely monitored
on individual needs. Methods. - Monthly ferritin. - 10d CBC with
leukocyte differential & monthly biochemical evaluation. - Biannual cardiac
function evaluation by ECG & Cardiac Echo. - Annual heart &
hepatic iron quantification by MRI, T2 & T2*. - Annual endocrine evaluation
included OGTT, IVGTT, Insulin, TSH, FSH, LH dynamic tests,
FT3 and FT4. Results. 1) Mortality was eliminated after combined chelation.
On Desferal ® monotherapy mortality ranged from 13.3-14.3% in
the last decade. 2) Currently, 35% of the highest compliers switched to
Ferriprox ® monotherapy (75-100 mg/kg daily). 3) Ferritin levels decreased
dramatically: - In the highest compliers (35%) mean ferritin is 68 µg/L.
-In the moderate compliers (54%) mean ferritin is 232 µg/L. - In the low
compliers (11%) mean ferritin is 2.421 µg/L. 4) In 12/50 (24%) patients
with pre-existing heart dysfunction, symptoms reversed and heart medications
stopped. Ventricular dimensions and function in Echo normalized.
LVEF increased from 54 to 72% (p5
IU/mL or increased TSH during TRH test. 23/50 pts were euthyroid.
Following combined chelation, TSH quantitative secretion, calculated as
the AUC, significantly decreased. 5/14 hypothyroid patients stopped
treatment and 7/13 pts with subclinical hypothyroidism normalized. 8)
12/24 males were hypogonadal on testosterone every 20-30d. After combined
chelation, FSH levels improved significantly at times: 0’ & 30’.
Testosterone remained unchanged. 4/12 hypogonadal patients showed
normal pituitary response and normal testosterone levels after they
stopped treatment for the dynamic test. 8) 19/26 females were hypogonadal
and received hormone substitution. 2 became pregnant with IVF
and 2 (eugonadal) with spontaneous ovulation. Conclusions. In our Unit
combined chelation with Ferriprox ® & Desferal ® is the treatment of
choice in thalassaemia major. The safety profile was acceptable. Cardiac
function improved with reversal of cardiac complications. Abnormal
glucose tolerance reversed. Thyroid function improved, particularly at
early stages of hypothyroidism. Intensification of iron chelation might
also be of benefit for the pituitary-gonadal axis. The quality of life of
Thalassaemia patients has improved tremendously. Most importantly
mortality was eliminated.
0810
INCREASED MATRIX METALLOPROTEINASE-9 LEVELS AND ACTIVITY IN SICKLE CELL
DISEASE PATIENTS
C.F. Franco Penteado, C. Lanaro, D.M. Albuquerque, S. Hyslop,
S.T.O. Saad, F.F. Costa
University of Campinas, CAMPINAS, Brazil
Sickle cell disease (SCD) is characterized by a chronic inflammatory
state; however, the mechanisms underlying this inflammation are
unclear. Zinc matrix metalloproteinases (MMPs) are members of a family
of enzymes that cleave extracellular matrix (ECM) proteins. MMPs
play an important role in physiological and pathological processes,
including embryogenesis, wound healing, inflammation, arthritis, cardiovascular
diseases, pulmonary diseases and cancer. MMP-9 is not limited
to the ability to break down ECM but is also extended to the modulation
of cytokines as well as to leukocyte migration. The aim of this study
was to compare MMP-9 and TIMP-1 levels and the activity of MMP-9
in the plasma and mononuclear cells (MC) of healthy subjects (HS) and
12 th Congress of the European Hematology Association
in SCD patients on or off HU therapy. Gelatin zymography was used to
measure MMP-9 activity and ELISA was used for MMP-9 and TIMP-1
determination. The expressions of the MMP-9 and TIMP-1 gene were
measure in MC by Real-Time PCR. Results are expressed as the fold
change in gene expression as compared to the negative calibration control.
After densitometric analysis of zymograms, a significant increase
(p=0.03) in the activity of pro-MMP-9 was observed in the plasma of
SCD patients (27.09±1.99 average pixel, n=30) compared with the HS
(20.96±1.35 average pixel, n=29). Pro-MMP- 9 activity in the plasma of
SCD patients on HU (SCDHU) was greater (27.2±1.35 average pixel,
n=17); however this difference was not quite significant (p=0.07). MC-
MMP-9 activity was significantly higher in SCD patients compared with
HS (66.2±6.0 average pixel, n=11, 22.5±5.5 average pixel, n=13, respectively,
p=0.0001) and HU therapy significantly reduced MMP-9 activity
(31.5±6.3 average pixel, n=8, p=0.001). MMP-9 levels were significantly
increased in the plasma of SCD patients (20.99±1.52, n=32), compared
to HS (13.96±1.64, n=16, p=0.02), although no effect of HU therapy
on these augmented levels was observed (SCDHU; 23.66±2.93,
n=22, p>0.05). MMP-9 levels correlated significantly with total WBC
counts (r=0.4221, p=0.01) in SCD patients (on and off HU), as well as
with neutrophil counts (r=0.4436, p