ผศ.พญ.พรพรรณ ศรพรสวรรค

ภาควชากมารเวชศาสตร

คณะแพทยศาสตร ม.สงขลานครนทร

Update in Thalassemia Management

23th May 2018

Scope of talk

• Thalassemia definition TDT/ NTDT

• Thalassemia management Guidelines

• Current Iron Chelation Therapy

• New standard to assess iron overload

• New hope for thalassemia patients

Classification of thalassemia syndromes

Occasional transfusions required

Intermittent transfusions required

Regular, lifelong transfusions required

Non-deletional HbHβ-thalassemia major

Severe HbE/β-thalassemia

β-thalassemia intermedia

Mild HbE/β-thalassemia Deletional HbHModerate HbE/β-thalassemia

1Muncie HL & Campbell JS. Am Fam Physician 2009;80:339–344; 2Galanello & Origa. Orphanet Journal of Rare Diseases

2010, 5:11; 3Harteveld & Higgs. Orphanet Journal of Rare Diseases 2010, 5:13; 4Cohen AR et al. Hematology Am Soc Hematol

Educ Program 2004;14–34

Transfusions seldom required

α-thalassemia traitβ-thalassemia minorHbC/β-thalassemia

Non-transfusion-dependent thalassemias: NTDTPhenotype

Genotype

Transfusion-dependent thalassemias: TM

Thalassemia management challenges change with age

1. Musallam K et al. Pediatrics 2008;121:e1426–e1429.

AnaemiaIron overload

Child2–10 years

Adolescent10–18 years

Adult>18 years

• Growth

• Sexual

development

• Sexual

development

• Adherence

• Transition of care

• Osteoporosis

• Organ failure

• Fertility and

pregnancy

Treatment of thalassemia

Parent education

Supportive treatment

Blood transfusion & Iron chelation therapy

Splenectomy

Hematopoietic stem cells transplantation

Novel treatment: stimulate HbF synthesis/ targeted therapy

Genetic counseling

Supportive treatment

Nutritional support

Folic acid (5 mg)

อาย < 1 ป 0.5 tab/day, อาย > 1 ป 1 tab/day

Vitamin E supplement

Avoid oxidative drugs eg. sulfonamide

Prevention of unnecessary iron therapy

Need vaccination as normal child

Why transfusion is needed?

Pediatric TDT patients require adequate blood transfusions for normal growth

Suppress ineffective erythropoiesis

Ensure appropriate growth and

development

Goals of blood transfusion therapy in pediatric TDT patients:

Guidelines for pediatric patients:• Maintain average Hb of 12 g/dL

• Pre-transfusion Hb of 9–10 g/dL

• Aim to transfuse whole units only; start with low transfusion

frequency in young patients and increase as they grow

1. Gibson BES et al. Br J Haematol 2004;124:433–453;

2. Thalassaemia International Federation. Guidelines for the clinical management of

thalassemia, 2nd revised edition 2008;

3. Goss C et al. Transfusion 2014;doi:10.1111/trf.12571. [Epub ahead of print].

How to know who needed blood?

Hb < 7 g/dL อยางนอย 2 คร ง หางกนมากกวา 1 เดอนโดยไมมปจจยกระตน

Severe thalassemia (present at age < 2yrs)

Marked hepato-splenomegaly

Poor growth & limit physical activity

Cardiovascular compromise

Severity of Thalassemia disease Molecular abnormality of β thalassemia

b0 thalassemia

codons 41/42 (-TCTT), codon 17, A-T

IVS-1 nt 1, G- T, codons 71/72 (+A)

severe b+ thalassemia

IVS-1 nt 5, G-C, IVS-2 nt 654, C-T

mild b++ thalassemia

-28 ATA, A-G

codon 19, A-G หรอ Hb Malay

codon 26, G-A หรอ HbE

Molecular of β-thalassemia gene in Southern Thailand n=78

• 92% found 6 common mutations

• 4bp deletion (Codon 41-42) Chinese

• IVS1 # 5 Muslim

• Codon 19 (Hb Malay)

• Codon 17

• -28 A-G

• IVS1#1

Loasombat V, et al. Am J Hematol 1992; 41: 194-8

Transfusion regimens

Correction of anemia: keep Hb > 9.5 gm/dL

Suppression of erythropoiesis

Inhibition of GI absorption of Fe

pre-transfusion Hb

“supertransfusion regimen” 12 g/dL

“hypertransfusion regimen” 10 g/dL

“low transfusion regimen” 6-8 g/dL

Transfusion guideline

Collection from donor within 7days

“Leucocyte poor/depleted” packed red cells

Blood group compatibility

Major : ABO, Rh

Minor : E, Mia, Lea, Leb, c

Screen for VDRL, HBsAg, anti-HIV, HIV Ag, anti-HCV

Red cell antigen typing: C, c, E, e และ Mia

HBV vaccine if anti-HBs negative

Transfusion dependent thalassemia (TDT)

Homozygous b-thalassemia

Severe β-thalassemia/Hb E disease

Hb Bart’s hydrop fetalis that survived

• Regular transfusion: maintain Hb > 9.5-10 g/dL at all time

• PRC 10-15 ml/kg q 2-6 wks

Non-transfusion dependent thalassemia (NTDT)

Hb H disease

β thalassaemia/Hb E disease ชนดไมรนแรง

• On-demand / Occasional transfusion

• Acute hemolysis (infection)

keep Hb > 7 g/dL & F/U at 4-12 wks

• PRC 10-15 ml/kg

Thalassemia clinic at PSU

TDT n= 72

• Homozygous β-thalassemia 17

• Severe β-thalassemia/Hb E disease 50

• Hb H with Cs/ AE Bart’s Cs 5

NTDT n= 120

ขอมลทควรบนทก

Demographic data: Dx, DOB, Wt. & Ht, Pedigree

LAB at first dx Serial CBC: Baseline HB

Hb typing of patient & family, molecular study

Blood group & minor blood group

Each visit

Wt. & Ht., type & volume of blood, reaction ?

CBC q visit, Cr, LFT, Serum ferritin q 3 month

Anti-HIV, HBsAg, Anti-HCV q year

No need to check post transfused Hct

Transfusion Reaction

ถามไขระหวางใหเลอด หยดการใหเลอด, V/S

ตรวจสอบความถกตอง,ให NSS แทน, H/C

Dx: Febrile non-hemolytic transfusion reaction

Cause: Ab to donor WBC, cytokine

Rx: Pre-medication : Paracet + CPM, LDPRC

หากอาการไมดข น DDx Hemolytic transfusion rxn, bacterial contamination

1 blood unit contains 200 mg

iron

PRC 1 ml Fe 1.16 mg

In addition, up to 4 mg/day

may be absorbed from the gut

Up to 1.5 g iron/year

Overload can occur after 10–20

transfusions

200–250 mg iron:

Whole blood: 0.47 mg iron/mL

‘Pure’ red cells: 1.16 mg iron/mL

Transfusion therapy results in iron overload

Porter JB. Br J Haematol 2001;115:239–52.

Iron overload is an inevitable consequence of multiple blood transfusions

Prevalence of complications in TDT

Cardiac siderosisLeft-sided heart failure

Hepatic failureViral hepatitis

HypothyroidismHypoparathyroidism

Diabetes mellitus

Hypogonadism

Osteoporosis

All patients (N = 1,073)Born after 1970 (n = 720)

6.8

1.8

6.8

4.1

4.1

3.6

3.2

2.7

50.8

6.6

14.8

3.3

3.3

3.3

8.2

9.7

600 5 10 15 20 25 30 35 40 45 50 55

Cardiacfailure

Arrhythmia

Myocardialinfarction

Infection

Cirrhosis

Thrombosis

Malignancy

Diabetes

Unknown

Other*

60.2

6.7

%

*Accident, renal failure, HIV/AIDS, familial autoimmune disorder, anorexia, haemolytic anaemia, thrombocytopenia.

Borgna-Pignatti C, et al. Ann N Y Acad Sci. 2005;1054:40-7.

Serum ferritin > 1,000 ng/mL

Liver iron concentration (LIC) from liver biopsy or

MRI (T2*) >/= 7 mg/g dry weight

Regular transfusion > 1 yr or > 10-20 times

Indication for Iron chelation therapy

Drug Desferrioxamine Deferiprone Deferasirox

Chelator:iron 1:1 3:1 2:1

Usual dosage 25-40 mg/kg/d 75 mg/kg/d 20-30 mg/kg/d

Route of

administration

Subcut,

Intravenous

Oral,

2-3 times daily

Oral,

Once daily

Half-life 20-30 min 3-4 hr. 12-16 hr.

Excretion Urinary, fecal Urinary Fecal

Adverse effect

Local reaction

Ophthalmologic

Auditory, Bone

abnormalities

GI disturbance

Agranulocytosis

Neutropenia

Arthralgia

Liver enzymes

GI disturbance

Rash

StatusLicensed

USALicensed in Europe

for who are unable to

use DFX effectively

Licensed

USA

Cost500 mg/Bottle

200 Baht

500 mg/tablet

GPO-L1® 5 B

Kelfer® 40B

250 mg/tab/500 B

TIF 2014 recommendation for Iron chelation therapy

Flow chart on Iron chelation in TM patients

Initiation of blood transfusion

Keep Hb level 9.5 -10.5 gm/dL

(pre-transfusional)

Upto 14 -15 gm/dL

(post-transfusional)

Iron chelation

First line treatment

Deferasirox 20-30 mg/kg/d

Desferrioxamine 30-50 mg/kg/day

Intolerance, switch Desferal DFX

Unsucessful, switch to Deferiprone

Monotherapy If not success

Combined with Desferal + L-1

Success, continue Desferal or DFX

การใหยาขบเหลกชนดฉด ควรใหเมอ serum ferritin > 1,000 ng/dl

ยาขบเหลก deferoxamine (desferal)

25-50 มก./1 กก. ฉดเขาใตผวหนงโดยใชเคร อง

pump นาน 8-10 ชม, 4-7 (5) คร ง/wk

ตรวจตาและการไดยนของผปวยกอนใหยา

ควรใหยาแกผปวยเมออาย >3-4 ป

ผปวยทไดรบยาอยางเหมาะสมท าใหมชวตยนยาวมากขน

การใหยาขบเหลกชนดฉด

การใหยาขบเหลกชนดรบประทาน

Deferiprone หรอ L1 75-100 มก/กก/วน แบงใหรบประทานวนละ 2-3 คร ง สามารถขบธาตเหลกมประสทธภาพด

ท าใหธาตเหลกทสะสมอยในหวใจมปรมาณลดลง

การใหยา Deferiprone 50-75 มก/กก/วนรวมกบ desferal S.C. 40-50 มก/กก/วน, 2-5 วน/สปดาหสามารถขบธาตเหลกมประสทธภาพเพมขน

ผลขางเคยงของยาขบเหลก L-1

คลนไส 10.8%

อาเจยน 8.6%

ปวดศรษะ 7.5%

เบออาหาร 5.4%

ปวดขอ 5.4%

ขออกเสบ 1.1%

ถายอจจาระบอย 2.2%

ผลขางเคยงของยาขบเหลก L-1

เมดเลอดขาวต า 11.8%

กดการท างานของไขกระดก 2.2%

เกลดเลอดต า 16.1 %

เอนไซมตบเพม 1.1%

การใหยาขบเหลกชนดรบประทาน

Deferasirox หรอ Exjade® 20-30 มก/กก/วน

โดยรบประทานวนละคร ง

สามารถขบธาตเหลกมประสทธภาพด

ผลขางเคยง:ผนทผวหนง ทองเสย

คลนไส อาเจยน ปวดทอง

Creatinine เพมขนเลกนอย

สามารถใหในเดกอาย 2 ปขนไป

ผลขางเคยงของยาขบเหลก Exjade®

ผนทผวหนง 25.8%

ถายอจจาระบอย 16.1%

เบออาหาร 4.8%

น าหนกลด 4.8%

บวม 4.8%

ปวดทอง 3.2%

Use of serum ferritin

• Assesses body iron stores (mainly in macrophage)

• Assesses “trend” of iron & monitor response to Rx

compliance, dose, regime monitoring

• Ferritin > 2,500 ug/L predict cardiac risk

• Ferritin < 1,000 ug/L increase DFO toxicity

• Unreliable screening in NTDT

Date Serum

ferritin

LIC T2*

12/7/56 1358 6.4 41.4

24/11/57 2053 12.1 42.3

22/12/58 2183 21.8 31.8

3/11/59 1437 11.5 36

1/11/60 2027 7.1 41.2

Can we still count on serum ferritin?

APIA study PSU site data

Why not just use serum ferritin?

• Also raised by inflammation or tissue damage

• Lowered by vitamin C deficiency

• Unreliable when ferritin > 4,000 ug/L

• Low SF relative to LIC in Thal intermedia

(hepatocellular > macrophages)

• Relationship of ferritin to LIC differ with different drugs

Fischer et al. Br J Hematol 2003,121: 938-48

Most reliable estimate of body iron/ Non invasive

Evaluate iron status before BMT

Those who serum ferritin doesn’t correlate with clinical (identify iron balance)

LIC >/= 7 mg/g dry weight Chelation Rx

High LIC > 15-20 liver fibrosis, poor prognosis

Clinical application of MRI

LIC may not reflect myocardial iron

Anderson et al. Eur Heart J. 2001;22:2171

Normal cardiac iron

Severe liver iron overload

Severe cardiac iron deposit

Minimal liver iron

MRI liver interpretation

LIC(mg/g dry wt of liver)

Severity Interpretation

< 1.8 normal No Rx

1.8-7 mild Goal of Rx

7-15 moderate complications

>15 severe Cardiac risk

MRI cardiac T2* interpretation

T2* (msec) Interpretation

> 20 normal

10-20 Moderate to severe

< 20 severe

Iron overload in Thalassemia pt

TDT n= 62

Median SF level 2,348 ng/ml (633-17,118)

Median LIC 11.4 mg/g dry wt. (3- 40)

Severe liver iron overload 39% (24)

Cardiac iron overload 3% (2)

Iron overload is underestimated & could occur since childhood. APIA study PSU site 2016

New hope for Thalassemia patients ?

Transfusional therapy HSCT, Gene therapy Targeted therapy

Impaired α : β globin genes

Erythroid cell pathology

Minihepcidins

Hepcidin analogs

TMPRSS inhibitors

Hemolysis

Iron overload

Ineffective erythropoiesis

Alpha chain

synthesis reduction

JAK2 inhibitor

Sotatercept

Luspatercept

HSCT

Gene therapy

Gene editing

Hb F induction

Hematology Am Soc Hematol Educ Program. 2017; 1: 278-283

New therapeutic targets for TDT & NTDT

Only curable treatment for thalassemia patients

Matching probability: Sibling 1/4, Unrelated donor 1/ 50,000

Stem cell sources: bone marrow, cord blood, peripheral blood

DFS ~ 80-90%

Success depend on age & risk score

High cost treatment 400,000 – 1 M THB

Hematopoietic stem cell transplantation

ขนตอนการปลกถายเซลลตนก าเนดเมดเลอด

Donor

Stem cells

ยากดภมคมกน

ผปวย

Conditioning

ระยะปลกถาย หลงปลกถายกอนปลกถายEngraftment

ผปวย

Pesaro risk classification

Hepatomegaly

Hepatic fibrosis

Inadequate iron chelation ( DFO start >18 mo after dx)

Class I 0 risk factor ( OS 94%,DFS 87%)

Class II 1-2 risk factors ( OS 84%, DFS 81%)

Class III > 2 risk factors ( OS 65%, DFS 62%)

HSCT in children PSU experience

Total n= 21

• Transfusion dependent thalassemia 13

• Relapse/refractory leukemia 5

• Severe aplastic anemia 1

• WAS/Gaucher diesease 2

PSU experience 2017

Pre-HSCT management

Early HSCT yield the best outcome

Detect early if has sibling refer early

Choose LDPRC if plan for HSCT

Avoid blood from family to avoid graft failure

Adequate iron chelation PSU experience 2017

To cure … sometimesTo relief … often To comfort… always….

Thank you for your kind attention