AHMED KADHIM THALASSEMIA CENTER - DUBAI

Background Iron chelating agents (desferroxamine and deferazirox) are mainly used to prevent the deleterious effect of iron overload resulted from repeated transfusions in thalassemia and other type of iron loading anemias.

Background The insight into the mechanism of iron and oxygen radicals poisoning extended the use of iron chelaters to conditions in which there is no iron overload, such as :- antioxidant effect - as in rheumatoid arthritis and favism(2, 9,10),

Background antiproliferative effect (some solid tumors) & antiprotozoal effect (2) aluminum intoxication as chelater (as in renal failure) (3)

Background Number of articles report an increase in erythropoiesis or a reduction in the transfusion requirement during iron chelation therapy. (1, 4, 6, 7, 9) A variety if mechanisms are possible

Background Mechanisms limited cytoreductive effect (4, 6) iron redistribution to the haemopoietic tissue (1, 9) ferrokinetic changes (4) suppression of increased apoptosis and mitochondrial damage (4, 8)

Background Mechanisms (cont.) in patients with renal failure desferroxamine and rHu Epo may increase transferrine receptors to enhance cellular uptake of iron. (3, 5)

Aim This study is conducted to evaluate the effect of using the oral iron chelater deferazirox (Exjade) on the hemoglobin level in thalassemia patients receiving regular blood transfusion in Dubai thalassemia center - UAE.

Material and Methods A retrospective study. 135 B thalassemia major patients receiving regular blood transfusion every 3-4 weeks and taking Exjade as an iron chelater, started to be given in Sep Desferal taking patients group used for comparison, during the same period of time. Hemoglobin readings were collected from patients medical records, for the period Mar.-Aug ( pre Exjade era - Pre) and Feb.-Jun (post Exjade era – Post ), for both groups.

Material and Methods Mean of 16 hemoglobin readings were calculated using Microsoft excel software. Comparison between the means (pre- and post-) was done with T-test and p value calculated.

Material and Methods As p value results were showing highly significant degrees, for the purpose of comparison these values giving a significance scale with color coding in order to make comparison easier, as in below extremely sig.<= , very high sig.<= , high sig.<= , very sig.<=0.0005, sig.<=0.005, less sig.<=0.05, non sig.>0.05.

Material and Methods Stratification of data had been done according to age groups, sex, serum Ferritin level, HCV status, and presence of complications like, hypoparathyroidisim, hypothyroidism, diabetes, hypogonadisim, cardiac dysfunction, and size of liver and spleen, and whether splenectomy done or not. (Maisem et. al., unpublished data)

Results ExjadeDesferal No. of pat13563 mean age(yrs) mode age(yrs)1012 Median(yrs)1316 Study Groups

Results mean Hb differencep value postpre All PAT E-06 Exjade Pat Desferal Pat mean Hb differencep value postpre All PAT E-05

Results mean Hb differencep value postpre age E-05 age age > Exjade Pat Desferal Pat mean Hb differencep value postpre age E-06 age age > Age2-20 Exjade1.28E-07

Results mean Hb differencep value postpre female E-05 male Exjade Pat Desferal Pat mean Hb differencep value postpre female male

Results hcv mean Hb differencep value postpre no E-05 yes Exjade Pat Desferal Pat hcv mean Hb differencep value postpre no yes

Results S Ferritin mean Hb differencep value postpre < E-05 => Exjade Pat Desferal Pat S Ferritin mean Hb differencep value postpre < =>

Results Diabetes mean Hb differencep value postpre no E-06 yes Exjade Pat Desferal Pat Diabetes mean Hb differencep value postpre no E-06 yes

Results Hypothyroidism mean Hb differencep value postpre no E-06 yes Exjade Pat Desferal Pat Hypothyroidism mean Hb differencep value postpre no E-06 yes

Results Hypoparathyroidisim mean Hb differencep value postpre no E-05 yes Exjade Pat Desferal Pat Hypoparathyroidisim mean Hb differencep value postpre no E-05 yes

Results Hypogonadisim mean Hb differencep value postpre no E-06 yes Exjade Pat Desferal Pat Hypogonadisim mean Hb differencep value postpre no yes

Results Liver Size(cm) mean Hb differencep value postpre < E-06 >= Exjade Pat Desferal Pat Liver Size(cm) mean Hb differencep value postpre < >=

Results Spleen Size (cm) mean Hb differencep value postpre < E-06 >= Exjade Pat Desferal Pat Spleen Size (cm) mean Hb differencep value postpre < E-05 >=

Results Splenectomy mean Hb differencep value postpre No E-06 yes Exjade Pat Desferal Pat Splenectomy mean Hb differencep value postpre no E-07 yes

p values ExjDesf all pat1.01E E-05 Age<=122.98E E > SexF3.86E M HcvNeg1.98E Pos s ferrit< E >= DiabNeg1.27E E-06 Pos Sig.Code Extr. sig. Very H.sig High sig. Very sig. Signif. Less sig. Non sig. Inverse age2-20 Exjade1.28E-07

ExjDesf HypothyNeg6.28E E-06 Pos HypoparatNeg1.06E-051.3E-05 Pos HypogonaNeg5.05E Pos Liver<31.24E >= Spleen<32.54E E-05 >= SplenectomyNo3.12E E-07 Yes Sig.Code Extr. sig. Very H.sig High sig. Very sig. Signif. Less sig. Non sig. Inverse

Mean Hb of All Exjade Patients Mean Hb of All Desferal Patients P value Comparison between the Mean Hb Difference of Both groups

Discussion Despite absolute raise in Hb levels was more prominent in Desferal group (not sig.), it was the Exjade group that had the more significant P value between the pre- and post- means. Sample size could explained this difference. However knowing that subjects in both groups exposed to a similar conditions, an Exjade effect cannot be neglected.

Discussion All of the highly significant P values seen where complications are not present, an exception is found in HCV +ve and s. Ferritin >2000 patients in the Desferal group. All the post Hb levels are higher than the pre Hb levels in both groups except Desferal taking splenectomized patients who are older in age and remnant splenic tissue may be responsible.

Discussion Younger patients had the best P values in both groups, those also had more reduction in their s.ferritin (Khawla et. al., unpublished data) when using Exjade, better compliance is a possible explanation. Gender was not conclusive. Smaller liver and spleen size was associated with a valuable P.

Discussion The mean, median and mode age for Desferal group were 2-3 yrs higher than that of Exjade group, this could be a partial contributor to the difference in P values. The absolute raise in Hb level is clinically not significant ( g/dl), however in a center serving more than 400 patients such raise may have an economic impact on blood supply to the center.

Conclusion Both groups had raise in their Hb levels. Desferal raise was bigger, but not significant. Exjade raise was more significant. The raises are minute but may have effect on making better blood economy. More studies are needed to prove or disprove effect of Exjade on Hb levels in transfusion dependent thalassemia patients.

THANK YOU

Thanks To Dr. Khawla Belhoul Dr. Maisem Baker Dr. Hamid Al Qaissy Miss Maitha Mohamed Hassan Rashid Medical library staff.

References 1- Vreugdenhil G.,Smeets M.,Feelders R.A. et al. Iron chelators may enhance erythropoiesis by increasing iron delivery to haemopoietic tissue and erythropoietin response in iron-loading anemia. Acta Haematol 1993;89: Voest E.E,Vreugdenhil G.,Marx J.J.Iron-Chelating Agents in Non-Iron Overload Conditions. Ann Int Med. 1994; vol 120;6: Aucella F.,Vigilante M.,Scalzulli P. et. al. Desferrioxamine improves burst-forming unit-erythroid (BFU-E) proliferation in haemodialysis patients. Nephrol Dial Transplant 1998;13: Tucci A. A.,Murru R.,Alberti D. et. al. Correction of anemia in a transfusion- dependent patient with primary myelofibrosis receiving iron chelation therapy with deferasirox (Exjade,ICL670).Eurep. J. of Haematol. Journal compilation 2007;78: Aucella F.,Vigilante M.,Scalzulli P. et. al. Synergistic effect of desferrioxamine and recombinant erythropoietin on erythroid precursos proliferation in chronic renal failure. Nephrol Dial Transplant 1999;14:

References 6- P. D.,Heickendorff L.,Pedersen B. et.al. The effect of iron chelation on hemopoiesis in MDS patients with transfusional iron overload. B. J. of Haematol ;92(2): Garma J. D., Lago F.,Fonrodona B. Deferrioxamine in the treatment of myelodysplastis syndroms. Haematologica Sep-Oct;82(5): Marsh JH, Hundert M, Schulman P. Desferoxamine-indiced restoration of haematopoiesis in myelofibrosis secondary to myelodysplasia. Br J Haematol Sep;76(1): Giordano N, Fioravanti A, Sancasciani S. et. al. Increased storage of iron and anemia in rheumatoid arthritis: usefulness of desferrioxamine. Br Med J (Clin Res Ed) Oct 13;289(6450): Ekert H, Rawlinson I. Deferoxamine and favism. N Engl J Med May 9;312(19):1260.