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Professor Jaap Van Lar, Professor of Clinical Rheumatology
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Horizon scanning:stem cell transplantation and beyond
Jacob M van LaarProfessor & Chair Department of Rheumatology & Clinical Immunology
University Medical Centre Utrecht, the Netherlands
http://www.dept-med.pitt.edu/paccm/faculty/Feghali-Bostwick.html
The scleroderma puzzle
Scleroderma is a disease of the immune system
The immune system is like an orchestra of like-minded musicians. Practice and fine-tuning are everything.
Autoimmune diseases arise when the immune system goes awry.
Scleroderma is an autoimmune, connective tissue disease.
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.
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.
Leukapheresis involves isolation of stem cells from blood
after ‘mobilisation’
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.
‘Conditioning’ (special room) = High dose chemotherapy (cyclophosphamide) antithymocyte globuline (ATG)
11
Positive selection of CD34+ haematopoietic stem cells
Cyclophosphamide Anti-thymocyte globulin Methylprednisolone
Filgrastim (G-CSF)
HSCT
‘The goal of stem cell transplantation is to reset the immune system by erasing sick immune cells with high dose chemotherapy and antibodies.’
Stem cell transplantation is teamwork.
... and £££
15
Stem cell therapy: hype and hope.
Potential benefits of stem cell transplantation
• Improvement of skin thickening• Improvement of functional ability• Improvement of QoL• Stabilisation of organ dysfunction• Improved survival prospects?
Chemotherapy is a blunt instrument as it cannot distinguish healthy from sick immune cells, hence healthy immune cells
are also killed as ‘collateral damage’.
Risks of stem cell transplantation
• Infertility (esp in women > 35 yrs)• Hair loss• Nausea• Infections• Bleeding (eg bladder)• Heart/lung failure• Malignancy
Benefit
Risks
cure
remission
Conventional immunosuppressio
n
Stem cell transplantation
Mobilisation CYC 2x2 g/m2, G-CSF 10 µg/kgLeukapheresis + CD34-selectionConditioning CYC 200 mg/kg, rbATG 7.5 mg/kgReinfusion CD34+ PBSC
12x monthly i.v. pulse CYC 750 mg/m2
RS E
ASTIS trialAutologous Stem Cell Transplantation International Scleroderma trial
ISRCTN54371254
ASTIS trial Jan 2012 JvL
van Laar JM et al, JAMA 2014
van Laar JM et al, JAMA 2014
0
20
40
60
80
100
Pro
ject
ed o
vera
ll su
rviv
al (
%)
41 33 32 31 24 20 13 11 7 7 5Transplant43 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
Pro
ject
ed o
vera
ll su
rviv
al (
%)
38 35 35 33 31 19 13 8 5 4 2Transplant34 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
Risk factors influencing severity of scleroderma
• Male gender
• Higher age
• Smoking
mRSS HAQ VC DCLO Creat cl LVEF
-20
0
20
40
60
80
100
HSCT
CYC
Changes in secondary outcome parameters*
* Measured as % change AUC in first 2 years.Wors
en
ing Im
pro
vem
ent
P<0.001 0.04 0.006 0.84 0.017 0.96
van Laar JM et al, JAMA 2014
• 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
How to identify poor prognosis patients?
![Ameliorative Morphological and Functional Effect of …...agent for organ transplantation, systemic lupus erythromatosus, multiple sclerosis and other benign diseases [5-9]. Cyclophosphamide](https://img.pdfslide.us/doc/110x75/6043ec4da1a715581e06a965/ameliorative-morphological-and-functional-effect-of-agent-for-organ-transplantation.jpg)
