TREATMENT OF TREATMENT OF THALASEMIATHALASEMIA

DR. ARGHYA KUSUM PALDR. ARGHYA KUSUM PAL

CARDIO

CLINICA

L PSY

ENDOCRINORTH

O

OPTHAL

NEURO

GENE THERAPYHbF MODULATION

TRANSFUSION THERAPYTRANSFUSION THERAPY

1.1. WHOM TO TRANSFUSEWHOM TO TRANSFUSE

2.2. EVALUTION PRIOR TO TRANSFUSIONEVALUTION PRIOR TO TRANSFUSION

3.3. TRANSFUSION REGIMENSTRANSFUSION REGIMENS

4.4. WHAT TO TRANSFUSEWHAT TO TRANSFUSE

5.5. FREQUENCY OF TRANSFUSIONFREQUENCY OF TRANSFUSION

6.6. AMOUNT OF TRANSFUSIONAMOUNT OF TRANSFUSION

7.7. EFFICACY OF TRANSFUSION REGIMENEFFICACY OF TRANSFUSION REGIMEN

8.8. ADVERSE REACTIONSADVERSE REACTIONS

WHOM TO TRANSFUSE WHOM TO TRANSFUSE

Confirmed lab diag of thalasemia majorConfirmed lab diag of thalasemia major

Lab criteria : Hb < 7gm/dl on 2 occasions, >2 wks Lab criteria : Hb < 7gm/dl on 2 occasions, >2 wks

apartapart

Lab & Clinical criteria : Hb > 7gm/dl withLab & Clinical criteria : Hb > 7gm/dl with

Facial changesFacial changes

FracturesFractures

Extramedullary Extramedullary erythropoiesiserythropoiesis

Poor growthPoor growth

EVALUATION PRIOR TO EVALUATION PRIOR TO TRANSFUSIONTRANSFUSION

Extended red cell antigen typing that includes at Extended red cell antigen typing that includes at least C, c, E, e and Kell. least C, c, E, e and Kell.

Serologic testing for HIV, HepA,HepB, HepC.Serologic testing for HIV, HepA,HepB, HepC.

LFT.LFT.

Immunize all against HepB and HepA.Immunize all against HepB and HepA.

TRANSFUSION REGIMENTRANSFUSION REGIMENTYPETYPE PRETRAN.HPRETRAN.H

bbMEAN HbMEAN Hb RECOMMDRECOMMD

PALLIATIVEPALLIATIVE <7<7 <8.5<8.5 NONO

MODERATEMODERATE 9-10.59-10.5 >12>12 YESYES

HYPERHYPER >10>10 >12>12 NONO

SUPERSUPER >12>12 >14>14 NONO

What to transfuse?What to transfuse? Leuko-reduced packed red cells: reduction of Leuko-reduced packed red cells: reduction of

leucocytes.leucocytes.

Critical threshold - <5 x 10Critical threshold - <5 x 1066/bag/bag

International guide- <1x 10International guide- <1x 1066 /bag /bag..

Methods of leuko-reduction:Methods of leuko-reduction:1. Pre-storage filtration.1. Pre-storage filtration. 2. Pre-2. Pre-transfusion.transfusion.

3.Bed side filtration3.Bed side filtration

Blood products Blood products for special situationsfor special situations

Irradiated Red CellsIrradiated Red Cells: who received transplant or : who received transplant or aspirants.aspirants.

Washed red cellsWashed red cells: 1.IgA def. patients and : 1.IgA def. patients and 2.patients having severe allergic 2.patients having severe allergic

reactions. reactions. Frozen red cells/ deglyceralized red cellsFrozen red cells/ deglyceralized red cells: : patients with patients with

rare RBC antigen.rare RBC antigen. Neocyte transfusion.Neocyte transfusion. Erythrocytopheresis or automated red cell exchangeErythrocytopheresis or automated red cell exchange..

Frequency of transfusionFrequency of transfusion

WEEKS WEEKS BETWEEN BETWEEN

TRANSFUSIOTRANSFUSIONN

Hb LEVEL gm/dlHb LEVEL gm/dl

PRETRANFUPRETRANFUSIONSION

POST-POST-TRANSFTRANSF

MEANMEAN

22 11.011.0 13.013.0 1212

33 10.510.5 13.513.5 1212

44 10.010.0 14.014.0 1212

55 9.59.5 14.514.5 1212

66 9.09.0 15.015.0 1212SOURCE: MANAGEMENT PROTOCOL FOR TRT OF THAL.TIF,NICOSIA,CYPRUS

Usually every 3-4 wks

HOW MUCH TO TRANSFUSEHOW MUCH TO TRANSFUSE Various with different anti-coagulant and hematocrit.Various with different anti-coagulant and hematocrit. CPD-A unit with 75% hct = 10-15 ml/kgCPD-A unit with 75% hct = 10-15 ml/kg

TARGET Hb TARGET Hb

Hct of donor cellHct of donor cell

50%50% 60%60% 75%75% 80%80%

1 gm/dl1 gm/dl 4.2 4.2 ml/kgml/kg

3.53.5 2.82.8 2.62.6

22 8.48.4 7.07.0 5.65.6 5.25.2

33 12.612.6 10.510.5 8.48.4 7.87.8

44 16.816.8 14.014.0 11.211.2 10.410.4

EFFICACY OF TRANSFUSION REGIMENEFFICACY OF TRANSFUSION REGIMEN Rate of fall of Hb should not exceedRate of fall of Hb should not exceed

a. 1 g/dl /week for splenectomiseda. 1 g/dl /week for splenectomisedb. 1.5 g/dl/week for non-splectomised. b. 1.5 g/dl/week for non-splectomised.

IF Hb FALLS AT A GREATER RATE , R/OIF Hb FALLS AT A GREATER RATE , R/O

ADVERSE REACTIONS OF BTADVERSE REACTIONS OF BT

REACTIONREACTION CAUSECAUSE TREATMENTTREATMENTNHFTRNHFTR LeukocytesLeukocytes Anti-pyreticAnti-pyreticALLERGIC RXNALLERGIC RXN Plasma ProtPlasma Prot Washed red cellsWashed red cellsAc. Hemolytic rxnAc. Hemolytic rxn Faulty typing & Faulty typing &

CMCM1.Stop .1.Stop .2.IVF with 2.IVF with diuretic.diuretic.3.Maintain vitals3.Maintain vitals

Auto immune Auto immune Hemolytic rxnHemolytic rxn

AlloimmunisationAlloimmunisation 1.Steroid.1.Steroid.2.Immunosuppresi2.Immunosuppresivesves3.IV Ig3.IV Ig

Delayed transf.rxnDelayed transf.rxn AlloantibodyAlloantibody -do--do-TRALITRALI Anti-neutophil or Anti-neutophil or

Anti HLA.Anti HLA.1.1. O2O22.2. Steroid.Steroid.3.3. DiureticDiuretic

GVHDGVHD

INFECTIONSINFECTIONS Treat as per causeTreat as per cause

Hypersensitivity Hypersensitivity reactionreaction

IgA def. pt.IgA def. pt.

IRON OVERLOAD IN THALASSEMIAIRON OVERLOAD IN THALASSEMIA The source of iron overload in thalassemia areThe source of iron overload in thalassemia are

1. Transfused Red cells (Thal. major)1. Transfused Red cells (Thal. major)

2. Increased absorption from gut(Thal. intermedia2. Increased absorption from gut(Thal. intermedia))

Annual Blood Requirement (Haematocrit 60%)

Annual Blood Requirement (Haematocrit 75%)

Volume of Pure RBCs/kg (Haematocrit 100%)

Daily IronLoadin

g

100 – 150 ml/kg100 – 150 ml/kg 80 – 120 ml/kg80 – 120 ml/kg 60 -90 ml/kg60 -90 ml/kg 0.18 -0.27 0.18 -0.27 mg/kgmg/kg

150 – 200 ml/kg150 – 200 ml/kg 120 -160 ml/kg120 -160 ml/kg 90 – 120 90 – 120 ml/kgml/kg

0.27 – 0.27 – 0.36 0.36 mg/kgmg/kg

200 -250 ml/kg200 -250 ml/kg 160 – 200 ml/kg160 – 200 ml/kg 120 – 150 120 – 150 ml/kgml/kg

0.36 – 0.36 – 0.44 0.44 mg/kgmg/kg

IRON OVERLOAD REDUCTION STRATEGYIRON OVERLOAD REDUCTION STRATEGY

CHELATION CHELATION THERAPYTHERAPY

1.1. WHEN TO STARTWHEN TO START

2.2. DESFERIOXAMINEDESFERIOXAMINE

3.3. DEFERIPRONEDEFERIPRONE

4.4. DEFERASIROXDEFERASIROX

When to startWhen to start??

1.1. Serum ferritin >1000-1500µg/L Serum ferritin >1000-1500µg/L

2.2. After 15-20 transfusion.After 15-20 transfusion.

3.3. Liver iron conc. >3.2mg/g of dry wt. or Liver iron conc. >3.2mg/g of dry wt. or liver.liver.

DESFERIOXAMINEDESFERIOXAMINE TT1/21/2 = 20 mins. = 20 mins.

FERRITIN LEVEL µg/L FERRITIN LEVEL µg/L DOSE mg/kg/dayDOSE mg/kg/day

< 2000< 2000 2525

2000-30002000-3000 3535

>3000>3000 5555

Not to exceed 100 mg/kg/dayNot to exceed 100 mg/kg/dayTHERAPEUTIC INDEX(PORTER’S INDEX)

= MEAN DAILY DOSE(mg/kg) / FERRITIN LEVEL(µg/L )KEEP INDEX <0.025 AT ALL TIMES

MEAN DAILY DOSE = (ACTUAL DOSE ON EACH OCCAS. X DOSES PER WEEK) /7

• Hexadentate

Mode of administrationMode of administration Standard recomm. Standard recomm.

Slow sc over 8-12 hrs using Slow sc over 8-12 hrs using infusion pump.infusion pump.

Strength: 10%Strength: 10%

Site: 1.Ant. Abd. Wall.Site: 1.Ant. Abd. Wall. 2. Lat. Side of Thigh 2. Lat. Side of Thigh

3. Deltoid. 3. Deltoid.

Type of needle: 1. ButterflyType of needle: 1. Butterfly 2. 2.

Thalaset.Thalaset.

Use of Vitamin C with DFOUse of Vitamin C with DFO Increases the availability of the chelatable iron to Increases the availability of the chelatable iron to

DFO.DFO. Start after, DFO therapy in progress for one Start after, DFO therapy in progress for one

month.month. Should be administered 30 – 60 mins after Should be administered 30 – 60 mins after

starting infusion.starting infusion. Dose: 50 mg - <10 yrsDose: 50 mg - <10 yrs

100 mg - >10 yrs 100 mg - >10 yrs 200 mg – adult 200 mg – adult(Not to exceed 2-3 mg/kg/day)(Not to exceed 2-3 mg/kg/day)

Not to be given in patients with cardiomyopathy.Not to be given in patients with cardiomyopathy.

Continuous IV admin. Of DFOContinuous IV admin. Of DFOIndications:Indications:

Severe iron overload Severe iron overload 1. 1. Ferritin persistently >2500µg/LFerritin persistently >2500µg/L 2. Liver fe 2. Liver fe >15mg/gm of dry wt.>15mg/gm of dry wt.

Significant cardiac diseaseSignificant cardiac disease 1. 1. Cardiac dysrrhythmiaCardiac dysrrhythmia 2. 2. Evidence of failing ventricular function.Evidence of failing ventricular function.

Port a Cath: Surgically implanted venous access device.Port a Cath: Surgically implanted venous access device.

MONITORING IRON OVERLOADMONITORING IRON OVERLOAD

Sr. Ferritin 1. Target recommendation Sr. Ferritin 1. Target recommendation <1000µg/L<1000µg/L 2. Hepatitis, Infection , 2. Hepatitis, Infection , Ascorbate status – affectsAscorbate status – affects 3. Trend of 3. Trend of level more imp than single value.level more imp than single value.

Liver FeLiver Fe1. Best method.1. Best method.2. Techniques : Liver biopsy/ MRI/SQUID.2. Techniques : Liver biopsy/ MRI/SQUID.

3. Target LIC <7mg/gm of dry wt.3. Target LIC <7mg/gm of dry wt. Myocardial iron estimation:Myocardial iron estimation:

1.MRI – T2 value<20 ms associated with LV 1.MRI – T2 value<20 ms associated with LV functionfunction

deterioration deterioration NTBI : Labile plasma iron assay.NTBI : Labile plasma iron assay.

DEFERIPRONE(L1)DEFERIPRONE(L1) BidentateBidentate T1/2 = 135 minutesT1/2 = 135 minutes Food and Vitamin C do not change chelation capacity.Food and Vitamin C do not change chelation capacity. It chelates iron from parenchymal tissue, RE cell, It chelates iron from parenchymal tissue, RE cell,

transferrin.transferrin. Dose = 75 mg/kg/day in 2-4 div. dosesDose = 75 mg/kg/day in 2-4 div. doses Side effects:Side effects:

1.Neutropenia – 5% 1.Neutropenia – 5%2. Agranulocytosis – 1%2. Agranulocytosis – 1%3. Arthropathy – 10-30%3. Arthropathy – 10-30%

4. GI symptoms – 5%4. GI symptoms – 5%5. Zinc def.5. Zinc def.

Monitor CBC weekly then 2-3 weekly.Monitor CBC weekly then 2-3 weekly.

COMBINATION THERAPYCOMBINATION THERAPY (DFO+L1)(DFO+L1)

Shuttle effect : LMW L1 enters cell – Transfers Shuttle effect : LMW L1 enters cell – Transfers intracellular Fe to DFO in plasma.intracellular Fe to DFO in plasma.

Beneficial for patients with cardiomyopathy on Beneficial for patients with cardiomyopathy on DFO.DFO.

No additional side effect.No additional side effect. Regimens:Regimens:

L1 daily + DFO – 2 days/weekL1 daily + DFO – 2 days/weekL1 daily + DFO – 2-6 days/weekL1 daily + DFO – 2-6 days/week

L1 – 4 days /week + DFO 2 L1 – 4 days /week + DFO 2 days/weekdays/week

DEFERASIROX(ICL 670)DEFERASIROX(ICL 670) TridentateTridentate New class of Fe selective synthetic chelatorNew class of Fe selective synthetic chelator Twice as effective as s.c. DFOTwice as effective as s.c. DFO T1/2 = 11-16 hrs.T1/2 = 11-16 hrs. Chelates Fe from parenchymal tissue, RE cell, Chelates Fe from parenchymal tissue, RE cell,

Myocardial cell.Myocardial cell. Dose = 20-30mg/kg ODDose = 20-30mg/kg OD Administer on empty stomach atleast 30 mins before Administer on empty stomach atleast 30 mins before

foodfood To be dispersed in a glass of water or Orange juice.To be dispersed in a glass of water or Orange juice. Not with milk or carbonated water.Not with milk or carbonated water. Side effects : GI disturbances – 26%, Skin rash – 7%, Side effects : GI disturbances – 26%, Skin rash – 7%,

Mild non-progressive increase in serum cr. – 34%.Mild non-progressive increase in serum cr. – 34%.

SPLENECTOMYSPLENECTOMY Indications: Indications:

1. Annual req. of BT increased 1.5 times or 1. Annual req. of BT increased 1.5 times or

more of previous value more of previous value 2. When 2. When transf. req. >200-220ml/kg/yrtransf. req. >200-220ml/kg/yr

red cellsred cells

3. Clinically sign of Hypersplenism.3. Clinically sign of Hypersplenism. 4. 4. Sympt. of splenic enlargement andSympt. of splenic enlargement and

danger of rupturedanger of rupture

Surgical approaches:Surgical approaches: 1. Total splenectomy: Open / 1. Total splenectomy: Open /

LaparoscopyLaparoscopy

2. Partial Splenactomy2. Partial Splenactomy

ComplicationsComplications SepsisSepsis (OPSI) (OPSI)

Risk factors :Risk factors : 1. Age <2 yrs1. Age <2 yrs2. first 4 years of 2. first 4 years of

splenectomysplenectomy 3. Iron overload.3. Iron overload.

4. DFO therapy4. DFO therapy5. Assoc. G6PD def.5. Assoc. G6PD def.6.Assoc. PTH dysfunction.6.Assoc. PTH dysfunction.

Organisms: Strep.Pneum. – 75%Organisms: Strep.Pneum. – 75% Others - H.Inf.,N.Mening.,etc Others - H.Inf.,N.Mening.,etc

Presentations: Sudden onset of fever with Presentations: Sudden onset of fever with chills,Vomiting, headache- progressing to chills,Vomiting, headache- progressing to hypotensive shock and DIC. Mortality = 50%hypotensive shock and DIC. Mortality = 50%

PREVENTIVE MEASURESPREVENTIVE MEASURES

Immunoprophylaxis:Immunoprophylaxis:Vaccination : 23 valent PneumoVac. Atleast Vaccination : 23 valent PneumoVac. Atleast

2 wks 2 wks before.before.H.Infl., Meningococc. & H.Infl., Meningococc. &

TyphoVac.TyphoVac. Chemoprophylaxis: Oral penicillin – 125 mg BD < Chemoprophylaxis: Oral penicillin – 125 mg BD <

2 yr2 yr 250 mg BD > 2 yr. 250 mg BD > 2 yr.Till 5 yrs of age or 2 yrs postop., whichever Till 5 yrs of age or 2 yrs postop., whichever

is later.is later.

Education: To parents & to Physician.Education: To parents & to Physician.

Other compl. Of Splenec.Other compl. Of Splenec.

BleedingBleeding AtelectasisAtelectasis Sub-phrenic abscessSub-phrenic abscess Post- op thrombocytosis – low dose Post- op thrombocytosis – low dose

aspirin(75 mg OD)aspirin(75 mg OD)

STEM CELL STEM CELL TRANSPLANTATIONTRANSPLANTATION

BMTBMT Donor – HLA – A,B,DR identical.Donor – HLA – A,B,DR identical.(Bld.grp (Bld.grp

– not essential).– not essential).

TRANSPLANTATION PROCEDURETRANSPLANTATION PROCEDURE

Post- transplant carePost- transplant care PROTECTIVE ISOLATIONPROTECTIVE ISOLATION..-- 2-3 weeks 2-3 weeks MANAGEMENT OF INFECTIONS MANAGEMENT OF INFECTIONS – – early institution early institution

of empirical antibiotics & antifungals.of empirical antibiotics & antifungals. BLOOD COMPONENTBLOOD COMPONENT (Irradiated)support & (Irradiated)support &

Hematopoetic growth factor.Hematopoetic growth factor. MANAGEMENT OF TOXICITY DUE TO MANAGEMENT OF TOXICITY DUE TO

CONDITIONINGCONDITIONING 1. Veno-occulusive dis.1. Veno-occulusive dis.2. Hemorrhagic cystitis2. Hemorrhagic cystitis..

FAILURE OF ENGRAFTMENTFAILURE OF ENGRAFTMENT::1. Inadequate Stem cell numbers.1. Inadequate Stem cell numbers.

2. GVHD – Acute - <100 days-2. GVHD – Acute - <100 days-skin/gut/liverskin/gut/liver Chronic - >100days-skin rash/ sicca Chronic - >100days-skin rash/ sicca complex/Sclerosing bronchiolitis/ hepatic dysfunction.complex/Sclerosing bronchiolitis/ hepatic dysfunction.

PBSCTPBSCT

Same as BMT except method of collection of Stem Same as BMT except method of collection of Stem cells.cells.

Administer G-CSF 4-5 days prior -> leads to high Administer G-CSF 4-5 days prior -> leads to high circulating stem cells -> collected by cell circulating stem cells -> collected by cell separator.separator.

No anesthesia and less painful procedure.No anesthesia and less painful procedure. Rapid engraftment but more chances of GVHD.Rapid engraftment but more chances of GVHD.

CBSCTCBSCT No. of Stem cells are very less.No. of Stem cells are very less. Engraftment takes longer time.Engraftment takes longer time. Advantage: incidence and severity of Advantage: incidence and severity of

GVHD is less.GVHD is less. 1-2 HLA antigen mismatch allowed.1-2 HLA antigen mismatch allowed.

ALTERNATIVE APPROACHALTERNATIVE APPROACH

MODULATION OF FETAL Hb.MODULATION OF FETAL Hb.1.Cytotoxic 1.Cytotoxic

agents :Hydroxyurea/azacytidine/ agents :Hydroxyurea/azacytidine/ Cytosine arabinoside. Cytosine arabinoside.

2. Butyric acid derivatives.2. Butyric acid derivatives. 3.Others – 3.Others –

Erythropoetin. Erythropoetin.

4.Combination therapy.4.Combination therapy.

GENE THERAPYGENE THERAPY

WHEAT GRASS THERAPYWHEAT GRASS THERAPYIn a study conducted by In a study conducted by Marwaha Marwaha et al in PGI, et al in PGI,

Chandigarh showed Chandigarh showed

1.1.All pts., receiving wheat grass therapy All pts., receiving wheat grass therapy experienced decreased BT requirement.experienced decreased BT requirement.

2.2.50% pts., showed atleast 25% reduction in BT.50% pts., showed atleast 25% reduction in BT.

3.3.Mean interval between BT increased in 29.5%Mean interval between BT increased in 29.5%

Mechanism behind:Mechanism behind:

Chlorophyll similar molecular structure to Hb. ?Chlorophyll similar molecular structure to Hb. ?

MONITORING IN THALASSEMIAMONITORING IN THALASSEMIA

TRANSFUSION DAYTRANSFUSION DAY DATEDATE AMOUNTAMOUNT PRE-TRANSF. HbPRE-TRANSF. Hb LIVER/SPLEENLIVER/SPLEEN DFO/L1 DOSEDFO/L1 DOSE NEXTDATENEXTDATE

CONTD.CONTD.

QUATERLYQUATERLY WEIGHTWEIGHT HEIGHT (SITTING/STANDING)HEIGHT (SITTING/STANDING) SERUM FERRITINSERUM FERRITIN CA/PO4/ALPCA/PO4/ALP SERUM CREATININESERUM CREATININE LFTLFT

CONTD…CONTD…

YEARLYYEARLY HBsAgHBsAg ANTI-HCVANTI-HCV HIVHIV BONE DENSITYBONE DENSITY AUDIOGRAM (IF ON DFO)AUDIOGRAM (IF ON DFO) EYE CHECKUP (IF ON DFO)EYE CHECKUP (IF ON DFO) CARDIAC EVALUATION (ECHO)CARDIAC EVALUATION (ECHO) ENDOCRINE EVALUATION (> 10 yrs)ENDOCRINE EVALUATION (> 10 yrs)

DIET IN THALASSEMIADIET IN THALASSEMIA HIGH CALORIE + HIGH PROTEIN NUTRITIOUSHIGH CALORIE + HIGH PROTEIN NUTRITIOUS AVOID IRON RICH FOODS AVOID IRON RICH FOODS DON’T COOK IN IRON UTENSILSDON’T COOK IN IRON UTENSILS DO TAKE -BREADS, CEREALS, MOONG DAL , DO TAKE -BREADS, CEREALS, MOONG DAL ,

SOYA BEANS- TO REDUCE IRON ABSORPTIONSOYA BEANS- TO REDUCE IRON ABSORPTION AVOID VIT. C RICH FRUITS WITH MEALSAVOID VIT. C RICH FRUITS WITH MEALS TAKE -STRONG TEA/COFFEE WITH MEALSTAKE -STRONG TEA/COFFEE WITH MEALS TAKE MILK & MILK PRODUCTS - FREQUENTLYTAKE MILK & MILK PRODUCTS - FREQUENTLY

STRATEGIES FOR CONTROL STRATEGIES FOR CONTROL OFOF ββ-THAL. IN -THAL. IN INDIAINDIA

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