Updates on Thalassemia

Pustika Amalia Wahidiyat

Hematology-Oncology Division
Department of Child Health
Cipto Mangunkusumo Hospital
Faculty of Medicine Universitas Indonesia
 Outline

Brief review about thalassemia and its burden

in Indonesia

Preparing thalassemia patients for HSCT

procedures

Clinical trial drugs (Luspatercept and

Sotatercept) and Gene therapy
 Thalassemia
Luspatercept

α-thalassemia β-thalassemia

Transplant & Gene Therapy Transfusion & Iron chelators

Gene frequencies of thalassemia-β and HbE in Indonesia

Lanni, 2008
 Thalassemia patients in Indonesia
Frequency of carriers in Indonesia
(Eijkman Institute, 2016)
Each year 2.500 children born
• β-thalassemia : 3-10% with thalassemia major
• α-thalassemia : 2.6-11%
• Hb E : 1.5-36%

Supportive and Preventive programs

curative treatments  Immediate family screening
 Pre-marital screening effective
 General population screening
 Prenatal diagnosis not useful in
Indonesia
(current
abortion law
does not
allow <6
weeks)

(Wahidiyat I, Wahidiyat PA, 2005)

Thalassemia in Indonesia
(10.555 patients)

What should we do for these patients?

Hematology Oncology Working Group Data - Indonesian Pediatric Society 2016

*Updated data 2019

 Treatment options
INDONESIA
• Routine blood transfusion
Supportive treatment
• Daily iron chelation
• Organ function monitoring
• Psychological support
• Splenectomy, if indicated with cautious consideration

Other countries
• Hematopoietic stem cell transplantation (HSCT)
Curative treatment  allogenic HSC
• Gene therapy  gene replacement in
autologous hematopoietic stem cells (autoHSCs)
using viral vectors
At present, it is still under trials, but it will be used
widely in future, for sure
Preparing thalassemia patients for
transplantation procedures
 Current HSCT data in Indonesia

The oldest: 10 years old ±50 patients have been referred

The youngest: 1.7 years old to abroad hospital

≥ 47 patients: successful
(reduced blood transfusion rate or 3 patients: graft failure
no need for further transfusion)

2 patients: loss to
1 patient: death
follow up
 Hematopoietic Stem Cell
Transplantation
• HSCT in Thalassemia was developed in 1980-early
1990
• Transplantation approach for non-malignant
disease is different from transplantation for
malignant disease
• Conditioning regimen
• Graft-versus-host disease (GVHD) prophylaxis
• Rate of rejection is much higher in thalassemia because massive
exposure to blood products from different donors, expanded
erythropoiesis, and hepato-splenomegaly
• Post-transplant therapies

Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology Am Soc Hematol Educ Program. 2010;2010:456-62
Accepted and experimental HSCT approaches

Approaches Current status

HLA identical sibling transplant ACCEPTED

HLA well matched unrelated donor transplant ACCEPTED
Haploidentical donor transplant ACCEPTED
HLA identical sibling cord blood transplant Not recommended

HLA mismatched related donor transplant Experimental

Angelucci E. Hematopoietic stem cell transplantation in thalassemia. Hematology Am Soc Hematol Educ Program. 2010;2010:456-62
 Risk classification (Lucarelli classification)
• Pre-transplant prognostic factors:
• Chelation prior to transplantation (regular vs irregular)
• Hepatomegaly (defined as 2 cm below the costal margin)
• Liver fibrosis (determined by liver biopsy)

Class Chelation Hepatomegaly Liver

fibrosis
I Regular No No

II Regular/ No/Yes No/Yes

(at least 2 irregular
favorable
factors)
III Irregular Yes Yes

Lucarelli G, Galimberti M, Angelucci E, Baronciani D, Giardini C. Bone marrow transplantation in patients with
thalassemia. N Engl J Med. 1990;222(7):417-21.
 Stratification for class III patients
• Previous classification does not work well in patients with
poor chelation
• For Class III patients, patients will be classified as high
risk if age ≥ 7 years and hepatomegaly ≥ 5 cm

Matthews V, et al. A new stratification strategy that identifies a subset of class III patients with an adverse prognosis among children with beta
thalassemia major undergoing a matched related allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13(8):889-94.
Sabloff M, et al. HLA-matched sibling bone marrow transplantation for β-thalassemia major. Blood. 2011;117(5):1745-50.
 Cord blood transplant
• Unrelated matched cord blood transplantation

OS: 62%
DFS: 21%

Ruggeri A, Eapen M, Scaravadou A, Cairo MS, Bhatia M, Kurtzberg J, et al. Umbilical cord blood transplantation for children
with thalassemia and sickle cell disease. Biol Blood Marrow Transplant. 2011;17(9):1375-82
 Cord blood transplant… (2)
• Sibling matched cord blood transplant

EFS: 79%

Locatelli F, Rocha V, Reed W, Bernaudin F, Ertem M, Grafakos S, et al. Related umbilical cord blood transplantation in patients with thalassemia and
sickle cell disease. Blood. 2003;101(6):2137-43.
 Transplantation protocol
• Every center has their own protocol
• Example:
• HSCT protocol in Thailand
Travel back and forth Indonesia-Bangkok
Stay in Bangkok

1 month 1 month 1 month 2-3 months 2-3 months

Total sterile

HLA typing Soft Soft Hard chemo

• Patients chemo chemo &
• Donor transplantation

After 2-3 weeks:

Check whether the patient’s DNA has already originated from donor or not
 Preparation approach for high risk
class III thalassemia patients
• Pre-transplant management
• Hyper transfusion, adequate iron chelation, evaluating organ
functions
• Pre-transplant immunosuppression prior to
conditioning regimen (soft chemo)
• Fludarabine + dexamethasone
• 5 days, 2 courses, a month interval between courses
• Conditioning regimen (hard chemo)
• Myeloablative ablative conditioning (MAC)
vs
• Reduced-toxicity conditioning (RTC) regimen
Anurathapan U, et al. Pretransplant immunosuppression followed by reduced-toxicity conditioning and stem cell transplantation in high-risk
thalassemia: a safe approach to disease control. Biol Blood Marrow Transplant. 2013;19(8):1259-62.
Anurathapan U, et al. Outcomes of thalassemia patients undergoing hematopoietic stem cell transplantation by using a standard
myeloablative versus a novel reduced-toxicity conditioning regimen according to a new risk stratification. Biol Blood Marrow Transplant.
2014;20(12):2066-71.
 Pre-transplant management
Hypertransfusion
• Aim: reduce spleen and liver size, suppress erythroid
expansion
• Target: pre-transfusional Hb level > 9 g/dL
• Use irradiated-leucodepleted or fixed donor blood  reduce
antigen/antibody exposure from donor
• NAT screening for the donor blood is necessary
• DO NOT use donor blood from family member

Adequate iron chelation

• No specific recommendation for chelation regimen
• Always maintain ferritin value < 2500 ng/mL
• Adequate iron chelation should be given at least 6-12 months
• Lifelong chelation therapy is more important, rather than
intensive chelation in pre-transplant period
 Pre-transplant management….. (2)
Treating organ complications

• All organ functions must be evaluated

1. Hormone levels
2. Chest X-Ray and other radiology evaluations (if indicated)
3. Dental evaluation
4. T2*MRI to evaluate iron deposition in organ
• Every single abnormality must be treated prior to the transplantation
procedure

Hydroxyurea *

• Aim: reduce erythroid marrow expansion

• NOT EFFECTIVE for common Indonesian thalassemia mutation
Anurathapan U, et al. Outcomes of thalassemia patients undergoing hematopoietic stem cell transplantation by using a standard
myeloablative versus a novel reduced-toxicity conditioning regimen according to a new risk stratification. Biol Blood Marrow Transplant.
2014;20(12):2066-71.
 New approach for hard chemo
• In the past:
8% suffered graft failure
• MAC (Busulfan + cyclophosphamide)
• Too much alkylating agents and too toxic
• RTC (Fludarabine + busulfan + ATG) None with graft failure

EFS: 86% vs 90% OS: 95% vs 90%

Anurathapan U, et al. Outcomes of thalassemia patients undergoing hematopoietic stem cell transplantation by using a standard
myeloablative versus a novel reduced-toxicity conditioning regimen according to a new risk stratification. Biol Blood Marrow Transplant.
2014;20(12):2066-71.
 Future target for Indonesia?
• HLA test and soft chemo administration are done in
Indonesia
• Establishment of HSCT unit
• Support from government  we have expressed the
importance of this project to the government for the
past 10 years
• Direction and assistance from other centers which have
extensive experience in HSCT
• Training for the hematologist, lab staff, and technician
• Sources of fund
Luspatercept (ACE-536)
 Background
• Luspartecept is an investigational first-in-class
erythroid maturation agent.
• It repairs the defect in RBC’s maturation hence
resulting in better erythropoiesis.
• It is aimed to decrease transfusion burden by
reducing its frequency and subsequently reducing
complication due to iron overload toxicity.
• Route of administration: Subcutaneous injection,
once every 3 weeks.

Fenaux P, et al. Luspatercept for the treatment of anemia in myelodysplastic syndromes and primary myelofibrosis.
Blood. 2019;133:790-4.
Luspartecept Mechanism of Action
 Luspatercept phase 3
Primary endpoints

Capellini MD, et al. The Believe Trial: results of a phase 3, randomized, double-blind, placebo-controlled study of Luspatercept in adult beta-thalassemia
patients who require regular red blood cell (RBC) transfusions. Blood. 2018;132: 163
http://acceleronpharma.com/wp-content/uploads/2018/12/BELIEVE-ASH-2018-Oral-Presentation-for-upload.pdf
 Conclusions
• Optimal therapy is compulsory for thalassemia patient
management.
• Curative option is still not available in Indonesia. – as
neighboring countries have performed HSCT, we are
responsible to optimize patient’s condition prior to
transplant.  Indonesia must establish our own HSCT
unit.
• Luspatercept and gene therapy are both promising
option for thalassemia patient in the future.
• As of now, prevention is key to alleviate Thalassemia
burden in Indonesia by eliminating new cases of
Thalassemia major.  SCREENING!
Thank You