1 / 31

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 .

kane
Download Presentation

HYDROXYUREA TREATMENT in b THALASSEMIA

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related