Dr Josu de la Fuente
St. Mary’s Hospital
London
alternative donor transplantation in
haemoglobinoapthies
BMT in Haemoglobinopathies
UK Paediatric BMT Group
DiseaseAllogeneic matched
related
Allogeneic
unrelated
Haploidentical
related
Autologous
blood or
marrow
Donor specifics
10/10 sibling
other 10/10 related
9/10 related
10/10 adult
9-10/10 adult
4-6/6 cord
<9/10 related
Stem Cell Source BM/PBPCs/cord BM/PBPCs/cord PBPCs/BM PBPCs/BM
Thalassaemia S CO CO N/A
Sickle cell disease S * CO CO N/A
HH SMH Total
TM 56 110 166
SCD 15 46 61
Total 71 158 229
1. VOC despite hydroxycarbamide: four or more episodes a year
requiring hospitalisation or impacting in schooling despite
hydroxycarbamide treatment
2. Recurrence of acute chest syndrome despite hydroxycarbamide
3. CNS disease:
a. Stroke
b. Abnormal TCD and silent infarct or abnormal psychometric
tests/poor school performance formally assessed
c. Silent infarcts with cognitive deficiency
d. Significant abnormalities in MRA despite transfusions
e. Abnormal TCD and generation of red cell alloantibodies
f. CNS disease requiring transfusions leading to significant iron
overload despite best attempt at adequate management
4. Suboptimal medical care
5. AVN
Criteria for BMT in Sickle Cell Disease
SCD 27
β thal 64
SCD 15
β thal 32
2011 to 2013
aGvHD II-IV: 15.9%
limited cGvHD: 9.1%
extensive cGvHD: 6.8%
cGVHD at 18 months: 2%
n = 47
• Viral reactivations
• PRES
La Nasa, Blood 2013
role
limitation
physical
functioning
bodily
pain
general
health vitalitysocial
functioning
emotional
functioningmental
health
p = 0.05p = 0.04
Availability of donors
Related donors:
• Using broad criteria of Collaborative Study: 38% of SCD patients qualify
• Only 18% of patients have an HLA-matched sibling donor who is not
affected
• Thus, as few as 1-2% of the total population of children with sickle cell
anaemia ultimately qualify for bone marrow transplantation
Mentzer, Am J Pediatr Hematol Oncol 1994
Unelated donors:
HLA-A,B,DRB1 matched donor projected increase in NMDP:
• 27% to 34% for Black Americans
• 45% to 54% for AsianKollman, Transplantation 2004
Locatelli, Blood 2003
Use of Cord Blood
Adamkiewicz, J Pediatr Hematol Oncol 2006
TM SCD
4 1
Haploidentical Transplantation
Bolanos-Meade, 2012
hypertransfusions
hydroxycarbamide 30 mg/kg
azathioprine 3 mg/kg
3 months
thiotepa 10 mg/kg
haploidentical BMT in paediatric SCD
1 2 3 4 5
ABO incompatibility major no no no minor
Cell dose TNC (x 108/kg) 5.13 11.82 10.11 9.49
CD34+ (x 106/kg) 1.123 5.15 2.61 2.77
Engraftment day +16 day +17 day +21 day +26
Chimerism day +28 100% WB and 100% T cells 100% WB and 100% T cells 100% WB and 100% T cells 100% WB and 55% T cells
latest 100% WB and 100% T cells 100% WB and 100% T cells 100% WB and 100% T cells
Discharge day +110 day +63 day +81 day +31
Mucositis TPN no day +6 to day +10 no day 0 to day +3
Infections day +21 possible lung IFI day +28 fungal mastoditis day +19 possible lung IFI day +14 to +28 typhlitis
day +26 CMV pneumonitis day +46 pneumonia day +140 HHV6 haemophagocytosis day +59 VZV infection
day +50 HVS type II
day +67 BK haemorrhagic cystitis
day +76 HSV type I
day +109 EBV reactivation
Immunosuppresion day +119 day +189 day +188 ongoing
GvHD day +40 skin stage 1: topical day +66 skin stage 1: topical day +32 skin stage 3: MSC day +36 skin stage 1: topical
Ishak 2 0 1 1 0
FerriScan (mg/g DW) 4.3 3.6 1.6 0.9 5.5
VOD no no no no
Conclusion
• BMT is feasible & able to offer long-term cure
• The challenge is to extend the number of
patients who may benefit
• Time is ready for alternative sources of stem
cells but this requires caution
• Understanding of the morbidity and end-
organ damage
• Identification of appropriate patients who
may benefit
• Consortium