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HYDROXYUREA TREATMENT in b THALASSEMIA

HYDROXYUREA TREATMENT in b THALASSEMIA. Ariel Koren, MD 1,7 , Carina Levin, MD 1,7 , Orly Dgany, PhD 2 , Tatyan Kransnov,MSc, 2 , Ronit Elhasid, MD 3,7 , Lucia Zalman, PhD 4 , Haya Palmor 4 , Hannah Tamary MD 5,6 .

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HYDROXYUREA TREATMENT in b THALASSEMIA

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  1. HYDROXYUREA TREATMENT in b THALASSEMIA • Ariel Koren, MD1,7, Carina Levin, MD1,7, Orly Dgany, PhD2, Tatyan Kransnov,MSc,2, Ronit Elhasid, MD3,7, Lucia Zalman, PhD4, Haya Palmor4, Hannah Tamary MD5,6. • 1) Pediatric Hematology Unit and Pediatric Department B, Ha’Emek Medical Centre - Afula. • 2) Felsenstein Medical Research Center, Beilinson Campus, Petach Tiqva • 3) Pediatric Hemato-Oncology Department, Mayer Children’s Medical Centre, Haifa. • 4) Hematology Laboratory, Ha’Emek Medical Centre, Afula. • 5) Pediatric Hematology Unit, Schneider Children’s Medical Centre of Israel, Petach Tiqva. • 6) Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv. • 7) The Ruth and Baruch Rappaport School of Medicine, Technion, Israel Institute of Technology, Haifa, ISRAEL.

  2. b 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 a thalassemia:a deletion or aaa.

  3. b Thalassemia Intermedia Th Minor Thalassemia Intermedia Th Major

  4. Thalassemia IntermediaClinical 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

  5. Thalassemia IntermediaLaboratory findings • Ineffective erythropoiesis: NRBC, Thrombocytosis. • Hgb F: 20 to 98 %, Hgb A2: 3 – 7 %. • Increased Indirect Bilirubin. • High Incidence of RBC Antibodies. • Common Mutations:IVS 1,1 - IVS 1,5 - IVS 1,6IVS 2,1 - IVS 2,745TATA – -86

  6. Hg F synthesis induction in  Thalassemia Intermedia • Erythropoietin – Rachmilewitz – 1991. • Hydroxyurea - • Antioxidants – Curcumin vs Coenzyme Q10 - Fucharoen – Thailand. • Arginine Butyrate ± Hu or Epo

  7. Hg F synthesis induction in  Thalassemia Intermedia Erythropoietin • Rachmilewitz E. - Blood 1991.Preliminary results in three patientsSlight increase in Hgb levels: 7 – 8.5 gr/dl. • Olivieri N. – Blood 1992.Three patients – Increase in Hgb levels: 7.5 to 11 gr/dl.No increase in Hgb F levels. • Risk of Bone Marrow expansion controlled by the increase in Hgb level. • Iron supplementation to provide enough available iron.

  8. Hg F synthesis induction in  Thalassemia Intermedia HYDROXYUREA • Leukopoulos – 8 patients- Better feeling at the onset of Tx !!- No significant increase in Hgb Levels.- Increase in MCV and Hgb F (%).- Decrease in NRBC. • Dosage: 20 mg/kg.- No adverse effects. • HU + EPO: Increase in Hgb levels only using very high doses of EPO - 50.000 U x 3/wk. Ann NY Acad Sci 1998.

  9. Hg F synthesis induction in  Thalassemia Intermedia HYDROXYUREA • Kattamis A. –TIF conference – 2001 – 5 patients.- No significant increase in Hgb Levels.- Globin chain synthesis did not correlate with response.- No adverse effects. • Conclusions:- Clinical improvement may not solely be related to γchain synthesis.

  10. Hg F synthesis induction in  Thalassemia Intermedia HYDROXYUREA • De Paula – Brazil.Eur J Haematol Mar 2003. • 11 patients. • 1 pt Thalassemia Major/Transfusion dependentHgb increase – 4 gr/dl.Transfusion independent. • 3/7 Th Intermedia: Hgb increases 1.3 to 2 gr/dl.

  11. Hg F synthesis induction in  Thalassemia Intermedia HYDROXYUREA • Karimi – Iran – 2005. • 106 BT dependent patients. • Started BT at age > 2 ys. • 78 % response -> BT independent. • Xmn 1 polymorphism not a significant factor in response. • Ped Hematol Onc 2005;27:380-5.

  12. THALASSEMIA HYDROXYUREA TREATMENTPatients • 18 patients (17 Arab origin – 1 Jewish)15 - Ha’Emek, 2 – Mayer, 1 Schneider. • Age start treatment: 9 to 34 yrs (Mean: 22.6 ± 7 yrs). • Follow up: 46 ± 25 months (Range 6 – 96 mo). 11 pts > 3 yrs on Tx – 7 pts > 4 ys on Tx. • HU dose: 0.5 gr/day (10.9 mg/kg) 4 to 7 days/wk.Higher dose induced neutropenia !!Am J Hematol 2008 Ha’Emek Ped Hem - 2008

  13. IVS 1,6 : 9 N 39 : 5 IVS 1,1 : 2 IVS 2,1 : 6 IVS 2,745: 2 FS 8 : 6 IVS 1,110 : 2 Poly A: 1 Unknown : 1 ND: 2 THALASSEMIA HYDROXYUREA TREATMENTbMutations Prof A. Openhaim and D. Filon Hem Dpt – Hadassah Medical Center - Jerusalem Ha’Emek Ped Hem - 2008

  14. THALASSEMIA HYDROXYUREA TREATMENT • a Mutations: 1 silent carrier a3.7Prof Tamary – Pediatric Hematology Unit – Felsenstein Medical Research Center and Schneider Children’s Medical Center of Israel – Petach Tikva. • Splenectomy : Before HU Treatment : 4During HU Treatment : 1 Ha’Emek Ped Hem - 2008

  15. THALASSEMIA HYDROXYUREA TREATMENT • Regularly transfused11 patients - 9 BT independent.Hgb 8.2 ± 0.7 gr/dl on 4 ys follow up.2 non responders. • Intermittently transfused5 patients – all BT independent. Hgb 6.7 – 6.9 gr/dl on 4 ys follow up. • Untransfused patients 2 patients (Ulcus cruris – Antibodies).Hgb 6.6 –> 8.4 gr/dl on 4 ys follow up. Ha’Emek Ped Hem - 2008

  16. THALASSEMIA HYDROXYUREA TREATMENT • Xmn 1 polymorphism *:- increased synthesis of Hgb F.Regularly transfused: 11 patients - 9 responders: 5 homozygous – 1 heterozygous- 2 non responders - negative • Intermittently transfused4 patients negative – 1 ND.Untransfused patients2 patients – negative.* Prof Tamary, et al – Pediatric Hematology Unit – Felsenstein Medical Research Center and Schneider Children’s Medical Center of Israel – Petach Tikva. Ha’Emek Ped Hem - 2008

  17. THALASSEMIA HYDROXYUREA TREATMENT Ha’Emek Ped Hem - 2008

  18. THALASSEMIA HYDROXYUREA TREATMENT Ha’Emek Ped Hem - 2008

  19. THALASSEMIA HYDROXYUREA TREATMENT Ha’Emek Ped Hem - 2008

  20. THALASSEMIA HYDROXYUREA TREATMENT Ha’Emek Ped Hem - 2008

  21. THALASSEMIA HYDROXYUREA TREATMENT Ha’Emek Ped Hem - 2008

  22. THALASSEMIA HYDROXYUREA TREATMENT * * 15 Units transfused because pregnancy (HU suspended) Ha’Emek Ped Hem - 2008

  23. b THALASSEMIA HYDROXYUREA TREATMENTFailures • Two patients failed to maintain “acceptable” Hgb level during HU treatment: • K.I. – 18 ys. Compound Major / Intermedia mutations (N39 / IVS 1,6) Transfusion dependent. • U. T. – 10 ys. Intermedia mutations (IVS 2,745)Transfusion dependent.

  24. b THALASSEMIA HYDROXYUREA TREATMENTFailures Ha’Emek Ped Hem - 2003

  25. THALASSEMIA HYDROXYUREA TREATMENT Conclusions • No significant increase in Hgb levels. • Hgb F – return to baseline levels (bo). • Significant decrease in Blood transfusions requirement transfusion independent. • Xmn1 – a prognostic factor of response.(Frequency in normal population 0.32 – 0.35). • a mutation – irrelevant. • Better feeling at the onset of treatment.

  26. THALASSEMIA HYDROXYUREA TREATMENT Literature • Globin chain synthesis did not correlate with response. • Clinical improvement may not solely be related to γchain synthesis. • Better survival of erythroid precursors in BM and RBC in Peripheral Blood.

  27. THALASSEMIA Effect of HU in thalassemic RBC • Increase production of g chains. • Amelioration of b / a imbalance. • Improvement in RBC morphology.

  28. THALASSEMIA Effect of HU in thalassemic RBC • Low doses of HU:- Increases Hgb F with increase in total Hgb content.- Increase b globin production (b+).- No effect on GATA 1 expression - prevents apoptosis.- Increased expression of egr 1 gene – regulation of early growth response. • High doses of HU:- Increase the Hgb F but decrease the total Hgb production due to upregulation of the death receptors DR-5 and Caspase 3 (determined by micorarray cDNA analysis).- Decrease b globin production.- Depressed the GATA 1 expression -> apoptosis.-

  29. THALASSEMIA Effect of HU in thalassemic RBC • bo patients: Hgb F returned to the range obtained at diagnosis. • b+ patients: Slight increase in Hgb F15 ± 14 % vs 28 ± 20 % at 1 yr (p=0.3).

  30. THALASSEMIA Effect of HU in thalassemic RBC • Distinct signal transduction pathways are regulated by different doses of HU. • Thalassemia patients receive significant lower doses of HU compared to SCA patients10 mg/kg/day compared to 20 – 30 mg/kg/day in SCA.

  31. An invitation postcard to visit the Jezreel Valley Medical Center

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