Effects of monotherapy and combined therapy on LPI

Transcription

1 Effects of monotherapy and combined therapy on LPI DFO 40 mg/kg/day Deferiprone 75 mg/kg/day Deferiprone 75 mg/kg/day DFO 40 mg/kg/day DFO 40 mg/kg/day LPI (μm) LPI (μm) LPI (μm) Time (hours) Time (hours) Time (hours) Reproduced from Cabantchik ZI, et al. Best Pract Res Clin Hematol. 2005;18:

2 Diagnosis Thalassemia Major Chelation Therapy 47 patients Total N 0 of Patients 36 Deferasirox 21 Desferrioxamine 5 Combination DFO + DFP 9 Thalassemia Intermedia Sickle Cell Anemia Sickle Cell Thalassemia Total patient DFP + DFX

3 Conclusions: Cardiac Iron Chelation Deferoxamine (DFO) Major cardiac mortality with long-term use. Slow cardiac iron clearance - High dose IV. Deferiprone (DFP) Cardiac iron clearance > deferoxamine. Can be combined with deferoxamine. Deferasirox (DFX) Removes cardiac iron including EF effect. Randomised controlled data are awaited. Combination Therapy DFO + DFX or DFP + DFX still in trial

4 Increased serum iron concentration Hepcidin Iron deficiency Anemia Hemolysis Blood loss Hypoxia

5 Iron overload Inflammation Infections IL-6 LPS Hepcidin Decreased serum iron concentration

6 Iron overload Inflammation Infections IL-6 LPS Hepcidin? Iron deficiency Anemia Hemolysis Blood loss Hypoxia How does the liver express Hepcidin in thalassemia?

7 Hepcidin in β-thalassemia Results

8 Increased Erythropoiesis Increased GDF 15 Iron overload Inflammation Infections IL-6 LPS Hepcidin? Iron deficiency Anemia Hemolysis Blood loss Hypoxia Hepcidin expression in thalassemia

9 NTBI - LPI Non Transferrin Bound Iron Labile Plasma Iron Absent in healthy people. Increased in iron overload. Present when transferrin saturation is above 80 %. Probable important role in toxicity. Target for Iron chelators.

10 Labile Cell Iron (LCI) Iron Absorption Altered Metabolism Friederich Ataxia Sideroblastic Anemia Transferrin LCI Altered Efflux Anemia of Chronic Disease Ferroportin Disease Increased Influx Hemosiderosis LCI should be maintained at constant level Transferrin Receptors

11 GDF 15 Growth Differentiation Factor 15 Member of GDF β superfamily. Expressed in erythroblastic maturation. Over-expressed in β thalassemia pg/ml vs 450 pg/ml. Tanno T et al - Nature 9:1096/2007. In β thalassemia the erythroid compartment is expanded Extramedullary Erythropoiesis GDF 15 may inhibit hepcidine in thalassemia and contribute to Iron overload.

12 Erythroferrone Bleeding or erythropoietin administration induced the release of this erythroid factor. Erythroferrone is produced by the erythroblasts and suppress hepcidin. Low hepcidin allowed intestinal iron absorption. Leon Kautz Presented in ASH Meeting December 2013

13 Iron Regulation in β Thalassemia Hemolysis Erythropoiesis GDF 15 or Erythroferrone? Hepcidine Blood Transfusions Iron absorption Transferrin Saturation > 75 % Non Transferrin Bound Iron Labile Cell Iron CELL TOXICITY Cardiac and Endocrine INCREASED FERRITIN

14 β Thalassemia Intermedia Clinical phenotype between transfusion dependent Thalassemia Major and asymptomatic Thalassemia Trait. Considerable variability in clinical spectrum and in blood transfusion requirements. Commonly maintain Hgb level 6 8 gr/dl. Interaction with α thalassemia: α deletion or ααα.

15 β Thalassemia Intermedia Th Minor Thalassemia Intermedia Th Major

16 βthalassemia Intermedia Clinical signs Extramedullary erythropoiesis: minimal to extremely severe. Bone deformities and tumor like masses leading to nerve or spinal cord compression. Splenomegaly: Minimal to severe. Arthritis. Ulcus cruris

17 Hg F synthesis induction in β Thalassemia Intermedia Erythropoietin Rachmilewitz Hydroxyurea - Antioxidants Curcumin vs Coenzyme Q 10 - Fucharoen Thailand. Arginine Butyrate ± Hu or Epo

18 β THALASSEMIA HYDROXYUREA TREATMENT Hgb (gr/dl) Before Months Ha Emek Ped Hem

19 β THALASSEMIA HYDROXYUREA TREATMENT * Blood Transfusions Units / patient Before (-2 ys - 0) 0.5 After Tx ( ys) 0.1 After Tx (+ 3ys / +4ys) Ha Emek Ped Hem * 15 Units transfused because pregnancy (HU suspended)

20 β THALASSEMIA HYDROXYUREA TREATMENT Conclusions No significant increase in Hgb levels. Hgb F return to baseline levels (β o ). Significant decrease in Blood transfusions requirement transfusion independent. Xmn1 a prognostic factor of response. (Frequency in normal population ). α mutation irrelevant. Better feeling at the onset of treatment.

21 SCA Clinical Presentation SCA is characterized by chronic hemolytic anemia and a variety of crises: - Vaso-occlusive crises - Hemolytic crises - Acute chest syndrome - Acute splenic sequestration - Aplastic crises - Infections: Encapsulated bacteria (S Pneumoniae) and Osteomyelitis. - Priapism. - Avascular necrosis of femoral or humeral head.

22 SCA Frontal Brain Infarct

23 Who is at risk? Ethnic origin is critical!

24 Sickle Cell Anemia in Israel (129 patients) Hgb CC Others Sickle Cell Disease 52 Sickle Cell β Thalassemia Emek Medical Center - Afula Shneider Medical Center Petach Tikva Meyer Rambam Medical Center - Haifa Dana Medical Center Tel Aviv Sharey Tzedek Jerusalem Hadassah Medical Center Jerusalem Soroka Medical Center Beer Sheva Missing Data - Tzafed Others SC Disease 3 SD Disease 1 S Hgb Lepore 1 CβThalassemia - 3

25 Sickle Cell Anemia in Israel Patients Ethnic Origin African Afro American Israel Arabs Bedouins - Saudiarabia - Jordan - Sudan - African Others SC Disease 3 SD Disease 1 S Hgb Lepore 1 CβThalassemia - 3

26 The origin of Sickle Cell in Israel Arab India The geographical dispersion of the SCA gene Tel Aviv University -Yael Levi

27 The origin of Sickle Cell in Israel Genetic characterization of sickle-cell anemia in Israeli Arabs Kirschmann C, Shalmon L, Goshen Y, Zaizov R. Harefuah Nov 1;113(9): The origin of sickle cell alleles in Israel Deborah Rund, Naomi Kornhendler, Oded Shalev, and Ariella Oppenheim. Human Genetics 85: ;1990 Arab families: Benin haplotype Central African Republic (Bantu) haplotype Jewish Family: Benin haplotype.

28 Blood Transfusions in SCD Hemolytic crises. Acute splenic sequestration. Acute chest syndrome. Hypersplenism common in Sβ Thal. Aplastic crises. Stroke Prevention - Primary due to TCD findings. - Secondary after first stroke.

29 Inflammation in SCD (1) Endothelial Function in Patients with Sickle Cell Anemia during and after SC Crises. High levels of endothelial adhesion molecules (VCAM-1) and inflammatory markers (CD 40) in steady state and not only in crises. Study Limitations: 10 patients and short period of follow up. Bloom A & al J Thromb & Thrombolysis 19:83-86;2005

30 Inflammation in SCD (2) Oxidative stress and inflammation in iron overloaded patients with β thalassemia or sickle cell disease. Increased IL 6, IL 5 and IL 10 compared to thalassemia. NTBI increased in thalassemia compared to SCD. γ tocopherol, a NO selective antioxidant is increased in SCD. Walter PB et al. Br J Hem 135: ;2006.

31 Inflammation in SCD (2) Parameter Th M SCD p Liver Iron (mg/g dw) 9.2 ± ± Ferritin (µg/l) 1868 ± ± 1153 <0.001 Tf Saturation (%) 82.5 ± ± NTBI (µmol/l) 4.0 ± ± 2.1 <0.001 The biology of SCD may show increased inflammation and increased levels of protective anti oxidants compared with thalassemia. Walter PB et al. Br J Hem 135: ;2006.

32 Relationship of liver iron to duration of transfusion therapy. The significant correlation (P <.001) between transfusion duration, in months, and liver iron on biopsy specimen. Harmatz P et al. Blood 2000;96: by American Society of Hematology

33 Relationship of liver iron to duration of transfusion therapy. Plasma Ferritin did not correlate to liver iron. Mean Ferritin 2686 ± 1039 ng/dl. Fever, infection, inflammation and hepatic dysfunction affects ferritin levels All are present in SCD. Mild to moderate abnormalities of inflammation or fibrosis in 16 out of 20 patients. Harmatz P et al. Blood 2000;96:76-79

34 Relationship of liver iron to duration of transfusion therapy. Liver iron score correlate to fibrosis and not to inflammation severity. Intensity of iron staining in Kupffer cells is greater than in the hepatocytes (p<0.001) Overflow of iron from the Kupffer cells to the hepatocytes? In SCD may be a different response to iron overload in the liver compared to Thalassemia. Harmatz P et al. Blood 2000;96:76-79

35 Sickle cell vs Thalassemia on Chronic Transfusion Patient characteristic Thalassemia (n=30) SCD (n=43) Age 18 ± 2 15 ± 1 Ys transfused 12 ± 2 6 ± 1 Serum Ferritin 2122 ± ± 233 Liver Iron 15 ± 2 14 ± 1 Cardiac disease 20 % 0 Growth delay 27 % 9 % Gonadal Failure 33 % 0 Liver Fibrosis > 0 81 % 39 % Vichinsky Am J Hem 2005

36 Sickle cell vs Thalassemia Hemosiderosis Despite prolonged exposure to Iron, NO SCD patients demonstrated elevated cardiac iron by T2* MRI or abnormal function!!! In contrast to 42 % of the thalassemia patients with similar iron exposure Wood et al, Blood 2004.

37 Iron Overload in Sickle Cell β 0 Thalassemia No cardiac symptoms No arrhythmias Chest X rays: 40-4 cardiac enlargement (Age 37, 33, 31 and 19 ys). ECG: Normal. ECHO: Normal SF in 22 / 23 pts. Mild cardiomyopathy in 1 (7 ys - BT) T2*MRI 10 patients No iron in myocardium Ghoti, Rachmilewitz, Konen et al, ASH European Journal of Hematolgy 84:59 63,2010. Emek Ped Hem

38 Iron Overload in SCD Serum Iron (mcgr/dl) Transferrin (mcgr/dl) SCA Sthal Th Major Th Int 0 SCA Sthal Th Major Th Int Transferrin Saturation (%) SCA Sthal Th Major Th Int ** p = < SCD vs Thal Serum Ferritin (ng/dl) SCA Sthal Th Major Th Int

39 Iron Overload in SCD NTBI and LPI results SCA Sickle β Thal β Thal Major β Thal Intermedia NTBI (Units) No Positive (>0.7) p = < ± 0.1 (0) 0 ± 0.1 (0) 0.56 ± 0.52 (14) 0.5 ± 0.65 (3) LPI (Units) No Positive (>0.7) p = ± 0.2 (1) 0 ± 0.1 (0) 0.22 ± 0.33 (3) 0.2 ± 0.35 (1) Ha Emek Ped Hem

40 Iron Overload in Sickle Cell Disease Less Blood requirements than Thalassemia. Ferritin levels above 1000 ng/dl after age 10. Mean Transferrin saturation under 40 %. Absent or Minimal levels of NTBI and LPI. No chelation therapy provided. Ha Emek Ped Hem