Professor Jaap Van Lar, Professor of Clinical Rheumatology

1. Horizon scanning:
stem cell transplantation and beyond
Jacob M van Laar
Professor & Chair Department of Rheumatology & Clinical Immunology
University Medical Centre Utrecht, the Netherlands

2. http://www.dept-med.pitt.edu/paccm/faculty/Feghali-Bostwick.html
The scleroderma puzzle

3. Scleroderma is a disease of the immune system

4. The immune system is like an orchestra of
like-minded musicians. Practice and fine-tuning are everything.

5. Autoimmune diseases arise when the immune system goes awry.
Scleroderma is an autoimmune, connective tissue disease.

6. Stem cell transplantation is a complex, multistep treatment
involving infusion of high dose chemotherapy and antibodies, and
reinfusion of stem cells that have been isolated from the patient
before the high dose chemotherapy.

7. Stem cell transplantation is a complex, multistep treatment
involving infusion of high dose chemotherapy and antibodies, and
reinfusion of stem cells that have been isolated from the patient
before the high dose chemotherapy.

8. Leukapheresis involves isolation of stem cells from blood
after ‘mobilisation’

9. Stem cell transplantation is a complex, multistep treatment
involving infusion of high dose chemotherapy and antibodies, and
reinfusion of stem cells that have been isolated from the patient
before the high dose chemotherapy.

10. ‘Conditioning’ (special room) =
High dose chemotherapy (cyclophosphamide) antithymocyte
globuline (ATG)

11. 11
Positive selection of CD34+
haematopoietic stem cells
Cyclophosphamide Anti-thymocyte globulin Methylprednisolone
Filgrastim (G-CSF)
HSCT

13. ‘The goal of stem cell transplantation is to reset the immune system by
erasing sick immune cells with high dose chemotherapy and antibodies.’

14. Stem cell transplantation is teamwork.
... and £££

15. 15
Stem cell therapy: hype and hope.

16. Potential benefits of stem cell transplantation
• Improvement of skin thickening
• Improvement of functional ability
• Improvement of QoL
• Stabilisation of organ dysfunction
• Improved survival prospects?

17. Chemotherapy is a blunt instrument as it cannot distinguish healthy
from sick immune cells, hence healthy immune cells are also killed as
‘collateral damage’.

18. Risks of stem cell transplantation
• Infertility (esp in women > 35 yrs)
• Hair loss
• Nausea
• Infections
• Bleeding (eg bladder)
• Heart/lung failure
• Malignancy

19. Benefit
Risks
cure
remission
Conventional
immunosuppression
Stem cell
transplantation

21. Mobilisation CYC 2x2 g/m2, G-CSF 10 µg/kg
Leukapheresis + CD34-selection
Conditioning CYC 200 mg/kg, rbATG 7.5 mg/kg
Reinfusion CD34+ PBSC
12x monthly i.v. pulse CYC 750 mg/m2
RS E
ASTIS trial
Autologous Stem Cell Transplantation International Scleroderma trial
ISRCTN54371254
ASTIS trial Jan 2012 JvL

23. van Laar JM et al, JAMA 2014

24. van Laar JM et al, JAMA 2014

25. 0
20
40
60
80
100
41 33 32 31 24 20 13 11 7 7 5Transplant
43 39 37 34 25 21 14 10 7 5 2Control
Number at risk
0 1 2 3 4 5 6 7 8 9 10
Years
Control Transplant
Smoking status / (yes)
0
20
40
60
80
100
Projectedoverallsurvival(%)
38 35 35 33 31 19 13 8 5 4 2Transplant
34 30 28 21 15 10 7 5 3 2 1Control
Number at risk
0 1 2 3 4 5 6 7 8 9 10
Years
Control Transplant
Smoking status / (no)
Smoking status is a determinant of overall survival

26. Risk factors influencing severity of scleroderma
• Male gender
• Higher age
• Smoking

27. -20
0
20
40
60
80
100
mRSS HAQ VC DCLO Creat cl LVEF
HSCT
CYC
Changes in secondary outcome parameters*
* Measured as % change AUC in first 2 years.
WorseningImprovement
P<0.001 0.04 0.006 0.84 0.017 0.96

28. van Laar JM et al, JAMA 2014

29. • Most scleroderma patients do not need SCT.
• SCT is effective in early, severe scleroderma, notably in non-
smoking patients.
• SCT in scleroderma is a complex, specialised treatment.
Take home messages

30. How to identify poor prognosis patients?

32. j.m.vanlaar@umcutrecht.nl