Transfusion Therapy in Patients with Hemoglobinopathies

Isaac OdameDivision of Hematology/Oncology

Hospital for Sick ChildrenDepartment of Pediatrics, University of Toronto

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

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 +ve Normal LFTs• Rx. RBC transfusion to maintain Hb 90 g/L• Deferoxamine SC 45 mg/kg/day X 7/7• Hep B vaccination

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 3A Normal LFT

• Age 7 years• ALT 227 AST 110• Liver biopsy: mild focal siderosis + portal fibrosis• Liver enzymes settled

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 10-14 days

• 3 months into anti-HCV therapy• Severe IFN/Ribavirin –induced hemolysis Hb 49 g/L• IFN/Ribavirin discontinued• PEG-IFN monotherapy restarted

Case # 1

• 4 months anti-HCV therapy• HCV PCR- Neg• IFN stopped• RBC transfusion requirements 2.5- 3 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+)

Case # 1

• Age 11 years– Sibling-donor BMT Bu/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

Transfusion Therapy in Thalassemia Major

Thalassemia in the early 1960s

Ehlers KH, et al. J Pediatr. 1991;118;540-5.

Goals of Transfusion Therapy in TM

• Treat anemia and eliminate hypoxia• Normal growth pattern

• Suppress endogenous erythropoieisis• Pre-transfusion Hb 90-100 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

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;89:1187-93.

Surv

ival

pro

babi

lity

(p < 0.00005)

0

1.00

0.75

0.50

0.25

0 5 10 15 20 25 30Age (years)

Birth cohort

1960–19641965–19691970–19741975–19791980–19841985–1997

Surv

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lity

(p = 0.0003)

0

1.00

0.75

0.50

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0 5 10 15 20 25 30Age (years)

MalesFemales

HR = hazard ratio.

Modell B, 2008

The Challenge of Compliance Iron Overload Overview

Kaplan-Meier analysis of survival in 257 consecutive thalassemia patientsaccording to the mean compliance with subcutaneous DFO therapy

Gabutti V and Piga A. Acta Haematol. 1995;95:26-36

Age, years

Surv

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, %

0102030405060708090

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0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

0 - 7575 - 150150 - 225225 - 300300 - 365

Deferoxamineinfusions/year

Sideroblastic anemiasThalassemiasSickle cell diseaseRare anemias

Iron overload

Anemia

Fe

200 mg

Sideroblastic anemiasThalassemiasSickle cell diseaseRare anemias

Iron overload

Anemia

Dyserythropoiesis

hepcidin

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: – MCA 244/201– dICA 110/210

• Brain MRI: T2 hyperintense area in Lt parietal, no restricted diffusion

• Parents resisted prescribed chronic RBC transfusion therapy

Case # 2

• Age 4 years• TCD MCA 201/187• Sleep study: obstructive sleep apnea• Underwent tonsillectomy & adenoidectomy• Pre-operative RBC transfusion (first)

– Blood Gp A POS Ab screen- NEG

• Age 5 years• TCD MCA: 217/173 dICA:

118/247• RX options presented to parents

– Chronic RBC transfusions to keep Hb S < 30% (preferred)– Hydroxyurea therapy

Case # 2

• Transfusion history– April 08

• transfusion # 2 Ab screen: Anti-S DAT neg– May 08

• DAT- pos anti- C3D pos anti-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)

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)

Transfusion Therapy in Sickle Cell Disease

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;333:206-13

• 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;319:1447-52

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;3395-11

• 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

Stroke Incidence

Ohene-Frempong et al. Blood 1998;91:288-294

TCD Screening

STOP I Trial

Age: 2 to 16 years oldGenotype: SS and S°-thal

Adams et al. NEJM 1998; 339: 5-11

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.

TCD and Incidence of Stroke

Fullerton et al. Blood. 2004; 104:336-339

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 100 000 person-years)

Indications for transfusion therapy in SCD

Acute/episodic Long-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;364:1343-60.

Vichinsky E. Semin Hematol. 2001;38:2-4.

Relationship between blood viscosity and hematocrit

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0 20 40 60 80 100

Visc

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Hematocrit (%)

O2 transportViscosity

O2 transport (viscosity x Hct)1

Reproduced from Wayne AS, et al. Blood. 1993;81:1109-23.© 1993 by The American Society of Hematology.Hct = haematocrit.

Chronic transfusion methods

Simple transfusion

Manual exchange transfusion

Erythrocytapheresis

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; 2008.Available from: http://www.sicklecellsociety.org/CareBook.pdf. Accessed March 2009.

Complications of TransfusionComplications 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

Delayed Hemolytic Transfusion ReactionDelayed 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

Selection of Blood ComponentsSelection of Blood Components

• Blood lacking hemoglobin S

• Limited antigen matching: C, E, K

• Extended antigen matching for patients with known allo-antibodies

• Leukocyte depletion

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

Multicenter Study of Hydroxyurea in Multicenter Study of Hydroxyurea in Sickle Cell AnemiaSickle 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

ResultsResults Hydroxyurea Placebo

Annual rate of crisis 2.5/year 4.5/yearp<0.0001

Median time to first crisis 3.0 months 1.5 months p=0.01

Median time to second crisis 8.8 months 4.6 monthsp<0.001

Acute chest syndrome 25 patients 51 patientsp<0.001

Transfusion therapy 48 patients 73 patientsp=0.001

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

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

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

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

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