Horizon scanning: stem cell transplantation and future potential therapeutic targets in Systemic Sclerosis

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?

[email protected]