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Hemoglobinopathies burden
>330,000 yearly births: - ¾ Sickle cell diseases
- ¼ Thalassemia major
Hemoglobinopathies are the most common life-threatening non-
communicable diseases in the pediatric age group globally
In many countries they are a substantial burden on national health care
expense and blood consumption
Global burden on the rise as childhood mortality decreases
http://sasi.group.shef.ac.uk/worldmapper
Thalassemia
Thalassemia survival in Pakistan
120
100
80
1996
60
2006
40
20
0
2 4 6 8 10 12 14 16 18 20 22 24 25
1996: data from HBB Karachi, 2006: data from BTIHS, Karachi
Bone marrow transplantation
for severe thalassemia
BMT in thalasemia mayor
BMT in thalasemia mayor
Matched-related HCT (BMT) for hemoglobinopathies
Thalassemia vs. Sickle Cell Disease
P < .00005
0
0 5 10 15 20 25 30
Age (years)
Borgna-Pignatti C, et al. Haematologica. 2004;891:187
Hemoglobinopathies Registry of the European Group for Blood and Marrow
Transplantation
Open issues
• Drug/transfusion tollerance
• Blood-borne infections
• Ospeoporosis and pain
• Pulmonary hypertension
• Quality of life
• Financial burden
BMT in Thalassemia
Standard preparation with Busulfan-Cyclophosphamide (BuCy)
Adults
OS TFS
67% 63%
Emanuele Angelucci: Hematopoietic stem cell transplantation for Thalassemia. ASH Educational Book 2010
HR BMT in Thalassemia (class 3)
Modified conditining with Hydroxyurea+Azathioprine from day -45, Fludarabine,
Bu and reduced Cy (protocol 26) in class 3 pts < 17 yrs old
OS TFS
93% 85%
Long-term health-related quality of life, employment status and birth rate similar to the
general population
VOD incidence <10% (DFB prophylaxis probably not justified unless HCV+
or abnormal LFTs)
GVHD/Rejection prophylaxis
Methotrexate 10mg/m2 at day +1, 8mg/m2 at +3, +6 & +11
Cyclosporin A 5 mg/kg/day at days -2 to +5 then 3mg/kg/day till day +22, then
oral dose of 10mg/kg/day, blood level-adjusted. Tapered at day +180
Methylprednisolone 0.5 mg/kg/day from day -1 to +30 then tapered gradually
over 15 days
Timing of ATG for thalassemia BMT
For doses of ATG Fresenius in the 10-15 mg/kg range from day -6 to -2 the peak
level is on day 0 and decrease with a half life of 3-5 days
↓ Rejection
↑ GVHD (?)
↑ Immune recovery
↓ EBV-LPD
Empowers medical centers and paves the way for the cure of related disorders
Fertility preservation
Post-BMT Cy
clonal selection bidirectional clonal selection
allo-depletion
GVHD Rejection
T-reg resistance to Cy through expression of aldehyde
dehydrogenase, the major in vivo mechanism of Cy
resistance, may contribute to the clinical activity of
PTCy in preventing GVHD
Prospects
Days of RBC Tx
Days of RBC Tx
independency
independency
Second BMT
neutropenic
neutropenic
prophylaxis
prophylaxis
Age at first
First BMT
rejection
rejection
regimen
regimen
Plt Tx
Plt Tx
GVHD
GVHD
Total
Total
days
days
BMT
Bu 14 mg/kg CSA
13 TT 10 mg/kg Cy 50 mg/kg
1.6 y TT 10 mg/kg PDN 15 240 5 Bu 14 mg/kg (day +3 & +4)
20 2yrs+ 5
Cy 200 mg/kg MTX mo