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Transfusion Therapy in Patients with Hemoglobinopathies Isaac Odame Division of Hematology/Oncology Hospital for Sick Children Department of Pediatrics,

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Presentation on theme: "Transfusion Therapy in Patients with Hemoglobinopathies Isaac Odame Division of Hematology/Oncology Hospital for Sick Children Department of Pediatrics,"— Presentation transcript:

1 Transfusion Therapy in Patients with Hemoglobinopathies Isaac Odame Division of Hematology/Oncology Hospital for Sick Children Department of Pediatrics, University of Toronto

2 Objectives Two case studies Review principles and indications for transfusion therapy in hemoglobinopathy patients Discuss the challenges of transfusion therapy in hemoglobinopathy patients Review clinical trials examining alternatives to transfusion therapy

3 Case # 1 Male born in 1997 in Pakistan Diagnosed thalassemia major aged 6 mo Red cell transfusion- monthly with no iron chelation therapy Emigrated to Canada in 2001 Splenomegaly Anti- HCV Ab +veNormal LFTs Rx. RBC transfusion to maintain Hb  90 g/L Deferoxamine SC 45 mg/kg/day X 7/7 Hep B vaccination

4 Case # 1 After 6 mo of deferoxamine Liver iron content (biopsy)21.1  11.4 mg Fe/g dry wt HLA-typing: sibling match identified Age 6 years Plans for BMT  RBC transfusions 2-3 wkly? Alloantibody GI consult:HCV RNA +ve genotype 3ANormal LFT Age 7 years  ALT 227  AST 110 Liver biopsy: mild focal siderosis + portal fibrosis Liver enzymes settled

5 Case # 1 Age 10 years Rx HCV infection:PEG-IFN & Ribavirin x 24 wks Complications: hemolytic anemia, neutropenia Blood bank:Autoantibody + alloantibody RBC transfusions: every days 3 months into anti-HCV therapy Severe IFN/Ribavirin –induced hemolysis Hb 49 g/L IFN/Ribavirin discontinued PEG-IFN monotherapy restarted

6 Case # 1 4 months anti-HCV therapy HCV PCR- Neg IFN stopped RBC transfusion requirements  weekly  Liver iron content (MRI) 15 mg Fe/g (ferritin 2220) Deferoxamine switched to deferasirox (oral chelator) Age 11 years RBC transfusions 3 weekly Liver iron content (MRI) 5.3 mg Fe/g Ferritin 1300 Liver biopsy:mild fibrosis (0 - 1+)

7 Case # 1 Age 11 years – Sibling-donor BMTBu/Cy/ATG conditioning – Complications: ALT 750, hemorrhagic cystitis – HCV PCR- neg – Engraftment 4 weeks – Blood bank: DAT pos (anti-C3D and anti-IgG) Ab screen- Jk(a) DAT negative at discharge post- BMT

8 Transfusion Therapy in Thalassemia Major

9 Thalassemia in the early 1960s Ehlers KH, et al. J Pediatr. 1991;118;540-5.

10 Goals of Transfusion Therapy in TM Treat anemia and eliminate hypoxia Normal growth pattern Suppress endogenous erythropoieisis Pre-transfusion Hb g/L ↓Extramedullary hematopoiesis ↓Bony deformities Minimize alloantibody formation and transfusion reactions D, C, E, c, e, and K matching Leucodepletion Manage iron overload Quantification of iron load: hepatic and cardiac Effective iron chelation therapy

11 Survival in β-thalassemia Major Risk factors for mortality in β-thalassemia major include: serum ferritin levels > 2,500 μg/L (HR: 3.7); arrhythmia (HR: 2.4); male sex (HR: 1.9); heart failure (HR: 11.3) Borgna-Pignatti C, et al. Haematologica. 2004;89: Survival probability (p < ) Age (years) Birth cohort 1960– – – – – –1997 Survival probability (p = ) Age (years) Males Females HR = hazard ratio.

12 Modell B, 2008

13 The Challenge of Compliance Iron Overload Overview Kaplan-Meier analysis of survival in 257 consecutive thalassemia patients according to the mean compliance with subcutaneous DFO therapy Gabutti V and Piga A. Acta Haematol. 1995;95:26-36 Age, years Survival, % Deferoxamine infusions/year

14 Sideroblastic anemias Thalassemias Sickle cell disease Rare anemias Iron overload Anemia

15 Fe 200 mg

16 Sideroblastic anemias Thalassemias Sickle cell disease Rare anemias Iron overload Anemia Dyserythropoiesis hepcidin

17 Case # 2 Male born in 2003 in Nigeria Diagnosed SCD aged 7 mo Recurrent painful VOC No RBC transfusion Age 2 years Emigrated to Canada  Transcranial Doppler (TCD) velocities: – MCA244/201 – dICA 110/210 Brain MRI: T2 hyperintense area in Lt parietal, no restricted diffusion Parents resisted prescribed chronic RBC transfusion therapy

18 Case # 2 Age 4 years TCDMCA 201/187 Sleep study: obstructive sleep apnea Underwent tonsillectomy & adenoidectomy Pre-operative RBC transfusion (first) – Blood Gp A POSAb screen- NEG Age 5 years TCDMCA: 217/173 dICA: 118/247 RX options presented to parents – Chronic RBC transfusions to keep Hb S < 30% (preferred) – Hydroxyurea therapy

19 Case # 2 Transfusion history – April 08 transfusion # 2Ab screen: Anti-S DAT neg – May 08 DAT- posanti- C3D posanti-IgG neg DAT- neg in June 08 – Aug 08 Ab screen : anti-S, anti-Jk(b), unidentified Ab (?autoAb) – Dec 08 Anti-S, anti-Jk(b)

20 Case # 2 Clinical progress: 2009 HLA typing: no sibling match Hb S: 27-40%anti-S, anti-Jk(b) TCD velocities conditional range: < 200 cm/s Liver iron content (MRI):6.7 mg Fe/g RBC transfusion # 16 Commenced Deferasirox (oral Fe chelator) 2010 Hb S: 16-28% Brain MRI/MRA: moderate narrowing of A1 segment of ACA Blood bank:DAT weakly POS anti-IgG (probable autoAb)

21 Transfusion Therapy in Sickle Cell Disease

22 Major RCT in SCD Preoperative transfusion in SCD – Simple Tx to Hb 100 g/L is as effective as exchange Tx to reduce Hb S to 30% – Vichinsky et al. NEJM 1995;333: Prophylactic transfusion in pregnancy – Prophylactic Tx to Hb 100 g/L vs. Tx to Hb < 60 g/L or for emergent situations did not improve obstetric or perinatal outcome – Koshy et al. NEJM 1988;319:

23 Major RCT in SCD Stroke prevention in SCD (STOP I) – Children at risk of stroke based on abnormal TCD velocity benefit from prophylactic transfusions – Adams et al. MEJM 1998; Optimizing primary stroke prevention in SCD (STOP II) – Prophylactic transfusions for patients with high-risk TCD cannot be stopped safely at 30 months – Adams et al. NEJM 2005;353:5-11

24 Stroke Incidence Ohene-Frempong et al. Blood 1998;91:

25 TCD Screening

26 STOP I Trial Age: 2 to 16 years old Genotype: SS and S  °-thal Adams et al. NEJM 1998; 339: 5-11

27 STOP II Trial How long should transfusions be continued? Transfusion-halted group: – 2 strokes – 14 abnormal TCD Transfusion continued group: – No event STOP II Trial Investigators. NEJM, 2005.

28 TCD and Incidence of Stroke Fullerton et al. Blood. 2004; 104:

29 Copyright ©2006 American Society of Hematology. Copyright restrictions may apply. Platt, O. S. Hematology 2006;2006:54-57 Approximate stroke rates in different sickle cell anemia (SS) populations (incidence per person-years)

30 Indications for transfusion therapy in SCD Acute/episodicLong-term management Anaemia Splenic sequestration Severe or long-lasting aplastic crises Malaria-associated severe haemolytic anaemia Stroke Acute chest syndrome Preoperative (selected cases) Multiple-organ failure syndrome Acute multiple-organ failure syndrome Priapism Prophylaxis against recurrent stroke Prevention of first episode of stroke in high-risk paediatric patients Heart failure Chronic pulmonary hypertension Chronic pain in hydroxyurea non- responders Previous splenic sequestration in children aged ≤ 2–3 years Short programme: pregnancy Ohene-Frempong K. Semin Hematol. 2001;38:5-13. Stuart MJ, et al. Lancet. 2004;364: Vichinsky E. Semin Hematol. 2001;38:2-4.

31 Relationship between blood viscosity and hematocrit Viscosity relative to H 2 O Hematocrit (%) O 2 transport Viscosity O 2 transport ( viscosity x Hct) 1 Reproduced from Wayne AS, et al. Blood. 1993;81: © 1993 by The American Society of Hematology. Hct = haematocrit.

32 Chronic transfusion methods Simple transfusion Manual exchange transfusion Erythrocytaphere sis Easy to perform; one venous access Time-consuming; manual Expensive; requires 2 good venous accesses Iron overload+++Iron overload+No iron overload; good clinical tolerance Allo-immunization +++ infections Standards for the clinical care of adults with sickle cell disease in the UK. Sickle Cell Society; Available from: Accessed March 2009.

33 Complications of Transfusion Volume overload – physiological changes with chronic anemia – chronic renal or cardiac disease Hyperviscosity – consequences of elevated hematocrit in presence of Hb S-containing red cells Alloimmunization – 18-36% of multiply transfused SCD patients Iron overload – chelation therapy (deferasirox / deferoxamine) – erythrocytapheresis

34 Delayed Hemolytic Transfusion Reaction Typical presentation – 7-10 days after transfusion – positive direct antiglobulin test Atypical presentation in SCD – severe painful episode – post-transfusion Hb dropping below pre-transfusion level – hemoglobinuria – pulmonary infiltrates – life-threatening or fatal anemia

35 Selection of Blood Components Blood lacking hemoglobin S Limited antigen matching: C, E, K Extended antigen matching for patients with known allo-antibodies Leukocyte depletion

36 Hydroxyurea in Sickle Cell Disease Increased fetal hemoglobin levels Increased hydration of erythrocytes Decreased adhesion of erythrocytes to vascular endothelium Decreased neutrophils Enhancement of nitric oxide

37 Multicenter Study of Hydroxyurea in Sickle Cell Anemia Methods: Randomized clinical trial of hydroxyurea therapy in symptomatic Hb SS disease Study Population: 152 patients assigned to hydroxyurea treatment 147 patients given placebo Mean follow-up: 21 months Charache et al., 1995;NEJM 332:1317

38 Results HydroxyureaPlacebo Annual rate of crisis 2.5/year4.5/yearp< Median time to first crisis 3.0 months1.5 monthsp=0.01 Median time to second crisis 8.8 months4.6 months p<0.001 Acute chest syndrome 25 patients51 patients p<0.001 Transfusion therapy 48 patients73 patients p=0.001

39 Indications for Hydroxyurea Therapy Frequent moderate - severe painful episodes 3 or more VOC significant episodes in the previous 1 year Very frequent non-hospitalized painful episodes Recurrent or severe acute chest syndrome Symptomatic anemia

40 New/Ongoing Clinical Trials: Transfusion vs. Hydroxyurea Stroke With Transfusions Changing to Hydroxyurea (SWiTCH)- Phase III randomized study- ongoing TCD With Transfusions Changing to Hydroxyurea (TWiTCH)- Phase III randomized study-commencing 2010

41 Ongoing Clinical Trials: Transfusion vs. No Transfusion Silent Infarct Transfusion Trial (SIT)- Phase III randomized study- ongoing Transfusion Alternatives Pre Operatively in Sickle Cell disease (TAPS)- randomized controlled trial-ongoing

42 Summary Transfusion therapy is the bedrock of management of patients with thalassemia major Chronic transfusion therapy is increasingly being used as disease-modifying therapy for SCD Efforts should be made to recruit regular blood donors from the African Canadian population The advent of oral iron chelators has significantly reduced the burden of iron chelation therapy

43 Summary Hydroxyurea therapy could be an alternative to blood transfusion in SCD patients The indications for blood transfusion in hemoglobinopathies need evidence-based evaluation The challenges of chronic blood transfusion should be an impetus for exploring alternative therapies e.g. Hb F-inducing agents

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