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