Thalassemia management¸_กิตติ ต่อจรัส - Thalassemia... · 2CPG, Diagnosis...

Thalassemia management

Kitti torcharus, M.D.

Department of Pediatrics,

Phramongkutkloa Hospital and College of Medicine

Scope of presentation

1. TDT & NTDT

2. Blood transfusion & Iron chelation

3. Splenectomy

4. Treatment related complications

5. Thalassemia survival

6. Hematopoietic stem cell transplantation

7. Alternative treatment

29/19/2019 Kitti Torcharus, M.D.

19/09/2019 Torcharus K 3

CBC Result Reference

Hb (g/dL) 6.5 12.0-16.0

Hct (%) 15.2 36.0-47.0

MCV (fL) 57 80.0-97.0

MCH (pg) 18.8 27.0-32.0

MCHC (g/dL) 32.5 32.0-34.0

RDW (%) 25.8 12.3-15.1

WBC (x109/L) 17.9 4.5-10.0

Plt (x109/L) 480 150-450

◼ เด็กชายอายุ 9 เดือนตรวจทีค่ลินิกสุขภาพเด็กดีพบ ซีด

◼ พอ่แม่เป็น couple at risk for thalassemia ปฏิเสธ PND

◼ Cord blood Hb type: Hb F = 100%

◼ PE: pale, no jaundice, liver & spleen just palpable

Case 1

Hb Typing of Family

• พ่อ beta-thalassemia trait

• แม่ beta-thalassemia trait

• พ่ีชาย beta-thalassemia trait

• ผูป่้วย Homozygous beta-thalassemia


Hb(g/dL)

Hct(%)

MCV(fL)

MCH(pg)

Hb type A2

(%)F

(%)A

(%)พ่อ 14.0 42.0 69.0 21.0 A2 A 5.7 1.6 92.7แม่ 12.2 34.0 68.0 23.0 A2 A 4.5 1.5 94.0พีช่าย 13.0 39.0 67.0 22.0 A2 A 5.0 2.0 93.0ผู้ป่วย 6.1 35.0 56.0 18.8 A2 F 3.0 87.3 -

Clinical course of Homozygous beta-thalassemia


10 11 12 13 14 15 16 17 18 19 20 21

PCR 1 1 1 1 1 1 1 1 1 1 1 1

PRC_SUM 1 2 3 4 5 6 7 8 9 10 11 12

Hb 6.5 5.9 7.1 8.5 8.8 7.6 8.1 10.1 9 9.8 9.3 8

0

5

10

15

20

25

Age (months)

PRC transfusion and base line Hb

PCR

PRC_SUM

Hb

Bas

e li

ne

Hb

(g/

dL)

Classification: Clinical severity

6

Severity Clinical Hb(g/dL)

Type

Severe Age onset of anemia < 2 yrs,Age at first blood transfusion < 4 yrs,Weight & Height lower than normal,Facial bone change,Huge splenomegaly

< 7 Homo. b0-thal (b0/b0, b0/b+),b0-thal/Hb E,surviving Hb Bart’s hydrops,Non-deletional Hb H

Moderate Anemia, jaundice, hepatomegaly, splenomegaly

7-9 Homo. b0-thal (b0/b+),b0-thal/Hb E,

Mild Anemia, jaundice, mild splenomegaly >9 Homo. b+-thal (b+/b+),b+-thal/Hb E,Hb H

Asymptomatic No symptoms normal Thal trait, Hb E trait, Homo Hb E

Musallam KM, et al.Haematologica 2013;98(6):833-44.9/19/2019 Kitti Torcharus, M.D.

Transfusion-dependent thalassemia (TDT)

• Clinical severity: Severe type • Age onset, first blood transfusion, Hb < 7g/dL, etc.

• Require regular transfusion with iron chelation• maintain Hb level 9.5-10.5 g/dL

• Thalassemia type (genotype):• Homo. b0-thal (b0/b+, b0/b+)• b0-thal/Hb E (b0/bE)• Surviving Hb Bart’s hydrops fetalis (- -SEA/- -SEA)• Non-deletional Hb H (- -SEA/aCS a)• Hb AEBart’s disease (- -SEA/- a, b/bE)

7

Musallam KM, et al.Haematologica 2013;98(6):833-44.9/19/2019 Kitti Torcharus, M.D.

Non-transfusion-dependent thalassemia (NTDT)

• Clinical severity: Mild to moderate type • Age onset at diagnosis 2-6 yrs. • Steady-state Hb level 7-10 g/dL• Non/occasional transfusion requirement

• Develop anemia or hemolytic crisis after infection• may require blood transfusion (occasional transfusion)

• Thalassemia types (genotype):• Hb H disease (- -SEA/- a)

• b-thalassemia/Hb E (b+/bE, b0/bE)• b-thalassemia intermedia (b0/b+, b+/b+)• db-thalassemia • HPFH (hereditary persistence of fetal hemoglobin)

8Musallam KM, et al.Haematologica 2013;98(6):833-44.


Management Strategy

• Prevention of the disease

• Genetics counseling• Screening of thalassemia trait/hemoglobinopathies• Prenatal diagnosis

• Proper treatment of existing patients

• Best patient care and management• Folic acid, nutrition and health education, vaccine, etc.

• Blood transfusion: High transfusion VS. Occasional transfusion regimen• Iron chelation

• Treatment of complications• Hematopoietic stem cell transplantation• Alternative treatment (Hb F stimulation, Gene therapy, etc.)


Indications for regular transfusion

Age < 15 yrs

• Hb < 8 g/dL

• Hb > 8 g/dL with• Facial bone change

• Poor growth

• Fracture

• Extramedullary hematopoiesis

Age >15 yrs

• Hb < 7 g/dL

• Hb > 7 g/dL with• Chronic anemia

• Fracture

• Pulmonary artery hypertension

• Chronic leg ulcer

9/19/2019 Torcharus K, M.D. 10

Transfusion regimen

Transfusion dependent thalassemia (TDT)

• High transfusion:

• Children: • Pre-transfusion Hb 9-10.5 g/dL,

10-15 mL/kg, 2-4 wks. interval

• Adult TDT if high transfusion can’t available• Pre-transfusion Hb < 7 g/dL,

received 1-2 units/visit

Non-transfusion dependent thalassemia (NTDT)

• Occasional transfusion:• Indication:

• acute hemolysis after infection e.g. Hb H disease with hemolytic crisis

• Pre-transfusion Hb < 7 g/dL, in children

• Pre-transfusion Hb < 5 g/dL, in adult with vital sign change


Standard of Packed red cell

• Preparation: from healthy and voluntary donner• Screening for infectious: Syphilis, HIV, Hepatitis A, B, and C• Leukocyte-poor packed red cells (LPRC), wbc < 1.2 x 109 cells/unit

• Leukocyte-depleted packed red cells (LDPRC), wbc < 1 x 106 cells/unit • Decrease antibody to wbc (anti-HLA), patient plan for HSCT • Prestorage filter: preparation < 24 hr., decrease prevalence of febrile non-hemolytic

transfusion reaction (FNHTR)• Poststorage filter preparation > 24 hr., e.g. bedside filter

• Apheresis technique (single donor red cell, SDR) • 2 units, 250-350 mL each, wbc < 1 x 106 cells/unit • decrease prevalence of transfusion transmitted disease• For patients which antibody to rbc Ag or rare blood group


Immune-mediated transfusions-reactions and reported frequencies

Acute Frequency

Febrile non-hemolytic 1/100

Allergic (urticarial) 1/100

Hemolytic (intravascular) 1/25,00

Transfusion –related acute lung injury (TRALI) 1/10,000

Anaphylactic 1/50,000

13

Delayed frequency

Alloimmune 1/100

Hemolytic (extravascular) 1/2,500

Garft vs Host Disease Rare


Red cell alloimmunization:Phramongkutkloa Hospital (N=83)

Gender N (%)-Male 49 (59.04)-Female 34 (40.96)Age-Median 12-Range 2-28Blood gr-A 16 (19.28)-B 32 (38.55)-O 34 (40.96)-AB 1 (1.20)PCR type-LPRC 21 (25.30)-LDPRC 62 (74.70)

Red Cell Alloantibodies N (%)

▪ NO 75 (90.36)

▪ Yes 8 (9.64)

▪ ant-E,-Mia 1 (1.20)

▪ anti-c,-E,-Mia 1 (1.20)

▪ anti-E 3 (3.61)

▪ anti-Mia 1 (1.20)

▪ anti-c,-E,-Mia, -Fyb 1 (1.20)

▪ autoantibody 1 (1.20)

9/19/2019 Kitti Torcharus, M.D. 14

Fyb=Duffy

Case 2

15

• เด็กชาย อาย ุ6 ปี ภูมิล าเนา นนทบุรี Refer มารับเลือด (20 ต.ค.59)• 4 ปี PTA (อาย ุ2 ปี) มีไขแ้ละซีลง ไดว้นิิจฉยัเป็น b-thal/Hb E และไดรั้บ LPRC ติดตามการรักษาท่ีคลินิกโรคเลือดได ้LPCR เม่ือเวลาซีดทุก 4-6 เดือน

• ตรวจร่างกาย: T 370C, PR 100/ min, R 30 / min, weight 16.6 kg, height 110 cm., marked pallor, no jaundice, tachycardia, systolic murmur gr. III/VI, liver 4 cm. spleen 7 cm.<LCM

• ตรวจทางหอ้งปฏิบติัการ• CBC: Hb 5.2 g/dL, Hct 16.0%, wbc 1.3x109/L, N 49, L 43, M 7, E 1%, MCV 69.0 fL, MCH

19 pg, MCHC 30 g/dL, platelets 160x109/L• PBS: hypochromia 1+, microcytosis 2+, anisocytosis 1+, poikilocytosis 1+, target cells 1+

• การรักษาท่ีคลินิกโรคเลือดระหวา่ง 20 ต.ค.59-6 ก.พ.61• ไดรั้บเลือด LDPRC 200 mL ทุก 4 สัปดาห์ ยา Deferiprone (500 mg) 1x3• ภาวะซีดไม่ดีข้ึน, spleen 12 cm.<LCM (huge splenomegaly) , Hb 6 g/dL• ปรึกษาศลัยกรรมเพือ่ Splenectomy

• After splenectomy:• Day 30: Hb 8.1 g/dL, Plt 1,070X109/L

• Pen V (125 mg) 1x2, ASA 3mg/kg/day


Splenectomy

• Before splenectomy:• Ultrasound abdomen: gall stone

• Pneumococcal conjugated vaccine

Splenectomy in NTDT: indication

• Worsening anemia leading to poor growth and development • when transfusion therapy is not possible or iron chelation therapy is

unavailable

• Hypersplenism leading to worsening anemia, leukopenia, or thrombocytopenia • resulting in recurrent bacterial infection or bleeding

• Splenomegaly accompanied by symptoms such as left upper quadrant pain or early satiety or massive splenomegaly • largest dimension >20 cm with concern about possible splenic rupture

Haematologica. 2013;98(6):833-44.


Splenectomy in TDT: indication

• Increase blood transfusion requirement > 225-250 mL/kg/year

• Hypersplenism

• At the current time, according the Guidelines for the Management, splenectomy is not recommended as a standard procedure in TDT subjects

Mediterr J Hematol Infect Dis 2015;7(1):e2015057


Overwhelming post-splenectomy infection (OPSI)

• Medical emergency, symptoms:• fever, shivering, vomiting, headache, septic shock, DIC, • progress to multiorgan failure and death occurs within the first 24 hours

• Risks of OPSI and associated death are highest in the first year after splenectomy

• Organism: • Streptococcus pneumoniae, Haemophilus influenzae type B, Neisseria meningitides, • Klebsiella pneumoniae, Pseudomonas aeruginosa

• Treatment: • empirical antibiotics, third generation cephalosporin, combined with gentamicin or

ciprofloxacin or vancomycin

Mediterr J Hematol Infect Dis 2015;7(1):e2015057


Before and after splenectomy

• Avoid splenectomy before 5 years of age

• Education of the patient and parents:• seek early care when fever develops

• keep an emergency supply of antibiotics for the event of febrile illness

• Vaccination: • Pneumococcal vaccine 2 weeks before splenectomy and then in 3-5 years

• Antibiotic prophylaxis:• oral penicillin for at least two years after splenectomy

• alternative antibiotic (if penicillin allergy): trimethoprim-sulfamethoxazole or erythromycin

Mediterr J Hematol Infect Dis 2015;7(1):e20150579/19/2019 Torcharus K, M.D. 20

Iron chelation in TDT: indication

• Received PRC >10-20 units

• Ferritin > 1,000 ng/mL measure 2 times 1-3 months

• Liver iron concentration (LIC) by liver biopsy or MRI (T2*) > 7 mg/g dry weight of liver


Iron chelation: administration

• First line: • Deferoxamine (DFO) 40-60 mg/kg/day, sc.

• Deferasirox (DFX) 20-30 mg/kg/day, oral (age 2-6 yrs)

• Second line:• Deferiprone (L1, DFP) 75-100 mg/kg/day, oral

• Deferasirox (DFX) 20-30 mg/kg/day, oral

• Combination therapy*:• L1: 80-100 mg/kg/day + DFO: 40-60 mg/kg 3-5 days/wk

*Kontoghiorghes GJ. Hemoglobin. 2009;33(5):332-8


Iron chelator Iron chelator Administration

Deferoxamine (DFO), 500 mg/vial

40-60 mg/kg/day, subcutaneous infusion 8-10 hour by infusion pump

Deferiprone (DFP), 500 mg/tab

75-100 mg/kg/day

Deferasirox (DFX) ,250 mg/tab

20-30 mg/kg/day


Assessment of iron overload and therapeutic gold of iron chelations

Assessment Normal Mild Moderate Severe

Ferritin (ng/ml)1 30-300 < 1,000 1,000-2,500 > 2,500

MRI(T2*)mg Fe/g dw2 < 1.8 1.8 to 7 7 to <15 >15

CMR, T2*(ms)3 > 20 <20 to 10 < 10 - 5 < 5

Iron chelations No treatment

Target of iron chelation

Risk of iron complications

Risk of cardiac complication

1Olivieri NF, N Engl J Med. 1994 ;331(9):574-8

2CPG, Diagnosis & management.of thalassemia syndromes 2014:26-31

MRI = Magnetic resonance imaging, CMR =Cardiovascular Magnetic resonance

3Wood JC. Hematology Am Soc Hematol Educ Program. 2011;2011:443-50.9/19/2019 Torcharus K, M.D. 24

Iron Chelator: PropertiesProperty Deferoxamine (DFO) Deferiprone (DFP) Deferasirox (DFX)

Usual dose (mg/kg/day)

25-60 75-100 20-40

Route Sc, iv (8-12 hr, 5 days/week)

Oral 3 times dialy

OralOnce daily

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

Excretion Urinary, fecal Urinary fecal

Main adverse effects

-local reaction-allergy-auditory (SNHL)1

-ophthalmologic-growth retardation

-gastrointestinal (vomiting)-arthralgia-elevated liver enzymes (ALT, AST)-neutropenia(ANC<1,500/10-6/L)-agranulocytosis(ANC<500/10-6/L)

-gastrointestinal (abdominal pain, nausea, vomiting)-rash-increase creatinine-increase liver enzymes (ALT, AST)

1SNHL=sensorineural hearing loss, 2ANC= absolute neutrophil count


Iron Chelator: monitor and safetyMonitor Deferoxamine(DFO) Deferiprone (DFP) Deferasirox (DFX)

CBC (ANC) - 1-2 wk (first 3 months) then monthly or when fever/infection occur

-

Ferritin Every 3-6 months

Proteinuria - - Every month

BUN/Creatinine Every 3 months 1-3 month or dose adjustment

Liver function (AST, ALT)

Every 3 months -monthly for the first 3 months, then very 3 months

-adjust dose or stop if AST, ALT > 2.5 x normal

Ophthalmic evaluation

Before start treatment then every year

Audiometry Before start treatment then every year


Emergency therapy: Intravenous deferoxamine• Indications:

• Severe hemosiderosis & vital organ dysfunction

• Cardiac arrhythmia, left-ventricular ejection fraction (LVEF) < 56%

• LIC > 15 mg/g dw, cardiac T2* < 10 ms

• Deferoxamine:• Dose 50-60 mg/kg/day, iv. dirp 24 hr. 5-6 days per wk


TDT 2-6 yearsDFO1 20-40 mg/kg/day SC, 5-7 days/week orDFX2 20-40 mg/kg/day od

TDT*: hypertransfusion > 1 year, received transfusion > 10 times, SF > 1000 ng/mL, LIC > 7 mg Fe/g DW

TDT > 6 yearsDFO 20-40 mg/kg/day SC 8-12 hr., 5-7 days/week orDFP3 50-100 mg/kg/day tid

Adverse effect of DFP: 1.Systemic allergic reaction2.ALT, AST > 2.5 ULN3.Neutropenia (ANC < 1,000/µL)4.Severe neutropenia (ANC < 500/µL)5.Severe arthropathy6.DFP intolerance: nausea, vomiting

Failure of DFP:1.DFP maximum dose 100 mg/kg/day2.SF > 2500 ng/mL-SF > 2500 ng/mL for 1 year or

-SF decrease < 15% from start for 2 years

Second line: DFX start 20 mg/kg/day od, adjust 5-10 mg (max. 40 mg/kg/day)

Not response: try combination therapy Deferiprone + Desferoxamine or Deferiprone + Deferaxirox

Response to therapy -Continue treatment -Target SF < 500 ng/mL

No adverse effect

Diagram of iron chelation therapy

Indication

Drug

*TDT = Transfusion dependent thalassemia1DFO = Deferrioxamine, 2DFX = Deferasirox ,3DFP = Deferiprone


Iron chelation in NTDT:

• Assessment: • serum ferritin every 3-6 month or LIC every 1-2 years

• Indication• age > 10 years, serum ferritin > 800 ng/mL or LIC 5 mg/g dry weight

• Drugs• Deferiprone 50 mg/kg/day (max. 100 mg/kg/day)• Deferasirox 10-20 mg/kg/day (max. 30 mg/kg/day)

• Adjust dose • if Serum ferritin < 500 ng/mL, stop if < 300 ng/mL or • LIC < 3 mg/g dry weight


Deferasirox: drug-related adverse events(N=472)

Adverse event Frequency, N (%)

Abdominal pain 62 (13.1)

Nausea 55 (11.7)

Diarrhea 40 (8.5)

Vomiting 32 (6.8)

Rash 23 (4.9)

30Taher A, Ther Clin Risk Manag 2009;5:857-68


Deferiprone (GPO-L-ONE@R ) monotherapy(phase III, 1-year results from a multicenter (Siriraj, Rama, Chula and PMK)

• 73 of severe b-thalassemia (TDT), age 3.2–19 yrs• 64 patients (87.6%) completed the study

• average dose 79.1 + 64.3 mg/kg/day• good compliance (94%)

• Response group(SF reduced >15%), 45% of patients• median reduction of SF = 1,065 ng/ml• reduce LIC and normalize levels of ALT at 1 year

• Baseline SF>3,500 ng/ml, significant fall of SF at 1 year• Drug-related adverse events (AEs)

• gastrointestinal irritation 20.5% • transaminitis 16.4% • neutropenia 6.8%

31

Viprakasit V, et al. Am J Hematol. 2013;88(4):251-60


Survival of b-thalassemia major in UK

32

Weidlich D, et al. Transfusion 2016 May;56(5):1038-45

0.63


Expected probability of health outcomes at 50 years

33

Weidlich D, et al. Transfusion 2016 May;56(5):1038-45


Treatment related complications

Major complication* Prevalence (per 1,000 admissions)

Heart failure 11.9

Cholelithiasis 5.6

Pulmonary hypertension 3.37

Hypothyroidism 1.56

Spinal cord compression 0.25

34

Teawtrakul N, et al. J Med Assoc Thai. 2012 Jul;95 Suppl 7:S211-6

*A cross-sectional study. Data included inpatients and outpatients, fiscal year 2010 (October1, 2009 to September 30, 2010), Faculty of Medicine, Khon Kaen University.


Treatment related complications

Symptom and laboratory diagnosis:

• Gall stone (asymptomatic, 60-80%)

• Biliary colic, common bile duct stone, ascending cholangitis, acute cholecystitis

• Chronic HBV infection

• Serum HBsAg (+ve), HBeAg (–ve), anti HBe Ab (+ve)

• HBV viral load> 2,000 IU/ml, ALT > 80 IU

• Chronic HCV infection

• Anti HCV (+ve), HCV-RNA virus, ALT > 80 IU

• Diabetes mellitus

• Fasting glucose > 126 mg/dl

• Oral glucose tolerance test (2 hr) >200 mg/dl


Hematopoietic Stem Cell Transplantation( HSCT)


Hematopoietic Stem Cell Transplantation( HSCT)

• Indication: severe thalassemia• homozygous β-thalassemia (β0/β 0, β0/β+)

• severe β-thalassemia/HbE disease

• surviving Hb Bart’s hydrops fetalis syndrome

• severe non-deletional Hb H diseases

• Donor• match-related donor (MRD): Human Leukocyte Antigen (HLA) compatible

• match-unrelated donor (MRD)

• haploidentical donor


Hematopoietic stem cell transplantation (HSCT): in Thailand (1987-2018)*

HSCT N (%) Cure (%) Alive with disease

Death

Related 213 (65.5) 178 (83.6) 16 (7.5) 19 (8.9)

Unrelated 77 (23.7) 62 (80.5) 7 (9.1) 8 (10.4)

Haploid 35 (10.8) 30 (85.7) 2 (5.7) 3 (8.6)

Total 325 (100) 270 (83.1) 25 (7.7) 30 (9.2)

*Data from CPG working group, Red cell subcommittee, Thai Society of Hematology


Alternative treatment

• Hb F stimulation: Hydroxyurea• transfusion-dependent thalassemia

• extramedullary hematopoiesis

• red cell alloimmunization

• dose 10 mg/kg/day

• Gene therapy1

• 12 cases: homo. b-thal and b-thal/Hb E


1Biffi A. N Engl J Med 2018;378(16):1551-2

Thank you for your attention


Gene therapy procedures: Cells were collected from the bone marrow of a patient with β-

thalassemia (Cavazzano-Calvo et al. 2010).

Arthur W. Nienhuis, and Derek A. Persons Cold Spring Harb

Perspect Med 2012;2:a011833

©2012 by Cold Spring Harbor Laboratory Press9/19/2019 Torcharus K, M.D. 41

Summary

• Clinical severity of TDT & NTDT

• Blood transfusion & Iron chelation

• Splenectomy

• Treatment related complications

• Hematopoietic stem cell transplantation

• Alternative treatment


Thalassemia management¸_กิตติ ต่อจรัส - Thalassemia... · 2CPG, Diagnosis...

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