STEM CELL

THERAPEUTIC
CENTRE

HEALTH TECHNOLOGY ASSESSMENT SECTION

MEDICAL DEVELOPMENT DIVISION
MINISTRY OF HEALTH
MALAYSIA
i
008/2010

DISCLAIMER
Technology review is a brief report, prepared on an urgent basis, which draw on restricted
reviews from analysis of pertinent literature, on expert opinion and / or regulatory status where
appropriate. It has been externally reviewed. While effort has been made to do so, this document
may not fully reflect all scientific research available. Additionally, other relevant scientific
findings may have been reported since completion of this review.

Please contact: htamalaysia@moh.gov.my, if you would like further information.

Health Technology Assessment Section,

Medical Development Division
Ministry of Health Malaysia
Level 4, Block E1, Precinct 1
Federal Government Administrative Centre
62590 Putrajaya
Tel: 603 88831246

Fax: 603 8883 1230

Available at the following website: http://www.moh.gov.my

ii

Prepared by:
Dr. Izzuna Mudla bt Mohamed Ghazali
Principal Assistant Director
Health Technology Assessment Section
Ministry of Health Malaysia
Reviewed by:
Datin Dr. Rugayah bt Bakri
Deputy Director
Health Technology Assessment Section
Ministry of Health Malaysia
External reviewer:
Dato Dr. Md. Hanip bin Rafia
Senior Consultant Neurologist and Head
Department of Neurology
Hospital Kuala Lumpur
Dr. Hussein Imam bin Muhammed Ismail
Senior Consultant Paediatric and Head
Paediatric Department
Paediatric Institute
Hospital Kuala Lumpur
Dr. Khoo Teik Beng
Consultant Paediatric Neurologist
Paediatric Department
Paediatric Institute
Hospital Kuala Lumpur

DISCLOSURE
The authors of this report have no competing interest in this subject and the preparation of this
report is totally funded by the Ministry of Health, Malaysia

iii

EXECUTIVE SUMMARY
Introduction
There are major changes happening in stem cell therapies that are setting a new paradigm for
regenerative medicine. These developments are building on the successes of bone marrow
hematopoietic stem cell (HSC) transplants that have more than 30 years of patient
applications in blood diseases and cancer.
This review was requested by the Deputy Director of Private Medical Practice Control
Section, Medical Practice Division, Ministry of Health Malaysia, following a request to
initiate a stem cell therapeutic centre in Kuala Lumpur.
Aims/objectives
1. To determine the safety, efficacy and cost implication of direct to consumer stem cell
therapeutic centre.
2. To determine the safety, efficacy and cost implication of stem cells transplantation for
cerebral palsy, motor neuron disease, stroke, multiple sclerosis, muscular dystrophy,
femoral head necrosis, diabetic foot, lower limb ischaemia, spinal cord injury and optic
nerve hyperplasia.
Results and conclusion
There was insufficient evidence to support the efficacy of direct to consumer stem cell therapy.
Weak evidence showed that the treatment given was not based on evidence.
There was insufficient and inconclusive evidence on the efficacy and safety of stem cell therapy
for neurologic diseases in adult. The evidence on stem cells therapy for multiple sclerosis
showed that it is still at experimental stage. Similarly, the evidence on stem cell therapy for
stroke and spinal cord injury was insufficient and showed that it was still in the developmental
stage. There was also no evidence retrieved on motor neuron disease, femoral head necrosis,
diabetic foot, lower limb ischaemia, and optic nerve hyperplasia. There was no evidence
retrieved on cost effectiveness of stem cells therapy for neurologic diseases in adults..
As for paediatric neurological disorders such as cerebral palsy, autism and spinal muscular
atrophy, no evidence could be retrieved from the published literature to date on the use of stem
cell therapy with regards to its efficacy, safety and cost-effectiveness.
Ethical issues regarding stem cell therapeutic centre includes commercial supply of stem cells
and direct interaction of manufacturer and patients. Adverse events are common with stem cells
therapy and range from minor to severe adverse events.

Methods
Literature were searched through electronic databases which included Medline,
Library, Science Direct and general databases such as Google and Yahoo.
iv

Cochrane

The search strategy used the terms, which were either used singly or in various combinations:
stem cells OR stem cells transplantation OR stem cells clinic, cerebral palsy, motor
neuron disease, stroke, multiple sclerosis, spinal cord injury, diabetic foot, autism, optic
nerve hyperplasia, muscular dystrophy, femoral head necrosis, lower limb ischaemia and
spinal muscular atrophy.
The search was limited to articles on human and in English language only.

STEM CELL THERAPEUTIC CENTRE

1. INTRODUCTION
Stem cells have the ability to build every tissue in the human body. For cells to fall under the
definition of stem cells they must display two essential characteristics. First, stem cells must
have the ability of unlimited self-renewal to produce progeny exactly the same as the
originating cell. Second, they must be able to give rise to specialized cell type that becomes
part of the healthy human.1
There are major changes happening in stem cell therapies that are setting a new paradigm for
regenerative medicine. These developments are building on the successes of bone marrow
haematopoietic stem cell (HSCs) transplants that have more than 30 years of patient
applications in blood diseases and cancer.2
A key issue in the treatment of neurologic diseases is that injurious processes are often
irreversible because neurons in the brain and spinal cord are unable to spontaneously
regenerate.3 However, recently, neural plasticity has been observed experimentally in both
global and focal brain ischaemia in animal models. Whether neurogenesis increases in
response to brain and neural lesions or stem cells can be used for transplantation are the
potential questions to be answered.4
This review was requested by the Deputy Director of Private Medical Practice Control
Section, Medical Practice Division, Ministry of Health Malaysia, following a request by
Beike Biotechnology to initiate a stem cell therapeutic centre in Kuala Lumpur that produces
stem cells and provides direct treatment to patients.
Beike Biotechnology Malaysia is a joint venture partnership entity of Beike Biotechnology,
China and Siricell Technologies Inc. of Bangkok, Thailand. Beike Biotechnology China is a
biotechnology company dedicated to the development and commercialization of adult stem
cell therapies since 1999. The company claimed that they have treated more than 7,500
patients. Beike Biotechnology Malaysia proposed to treat these conditions in their Phase 1
implementation:
Cerebral palsy
Motor Neuron Disease
Stroke
Multiple sclerosis
Muscular dystrophy
Femoral head necrosis

Diabetic foot
Lower limb ischaemia
Spinal cord injury
Autism
Spinal Muscular Atrophy
Optic nerve hyperplasia

2. OBJECTIVES
1. To determine the safety, efficacy and cost implications of direct to consumer stem cell
therapeutic centre.
2. To determine the safety, efficacy and cost implications of stem cells transplantation for
cerebral palsy, motor neuron disease, stroke, multiple sclerosis, muscular dystrophy,
femoral head necrosis, diabetic foot, lower limb ischaemia, spinal cord injury and optic
nerve hyperplasia.

3. TECHNICAL FEATURES
A stem cell is defined by its ability of self-renewal and its totipotency. Self-renewal is
characterized by the ability to undergo an asymmetric division in which one of the resulting
cells remains a stem cell without signs of aging and the other daughter cell becomes
restricted to one of the germ layers. A stem cell may become quiescent and at later stages reenter the cycle of cell division. 5 A true stem cell is a totipotent cell. It can become any cell
type present in an organism. Other terms commonly used in stem cell are defined in Table 1.

Source : Tewarie RSN, Hurtado A, Bartels RH, et al.. Stem cell-based therapies for spinal cord injury.
The Journal of Spinal Cord Medicine. 2009;32(2):105-114.

There are three commonly used sources of stem cells for transplants: bone marrow, the
bloodstream (peripheral or circulating blood), and umbilical cord blood from newborns.
Haematopoietic stem cell transplantation (HSCT) is the transplantation of blood stem
cells derived from the bone marrow (in this case known as bone marrow transplantation) or
blood.
Autologous HSCT requires the extraction (apheresis) of haematopoietic stem cells (HSC)
from the patient and storage of the harvested cells in a freezer. The patient is then treated
2

with high-dose chemotherapy with or without radiotherapy with the intention of eradicating
the patient's malignant cell population at the cost of partial or complete bone marrow ablation
(destruction of patient's bone marrow function to grow new blood cells). The patient's own
stored stem cells are then returned to his or her body, where they replace destroyed tissue and
resume the patient's normal blood cell production.6
Allogeneic HSCT involves two people: the (healthy) donor and the (patient) recipient.
Allogeneic HSC donors must have a tissue (HLA) type that matches the recipient. Matching
is performed on the basis of variability at three or more loci of the (HLA) gene, and a perfect
match at these loci is preferred. Even if there is a good match at these critical alleles, the
recipient will require immunosuppressive medications to mitigate graft-versus-host disease.
Allogeneic transplant donors may be related (usually a closely HLA matched sibling),
syngeneic (a monozygotic or 'identical' twin of the patient - necessarily extremely rare since
few patients have an identical twin, but offering a source of perfectly HLA matched stem
cells) or unrelated (donor who is not related and found to have very close degree of HLA
matching).6
The release of stem cells from the bone marrow into the peripheral blood circulation for the
purpose of leukapheresis, prior to stem cell transplantation is called as
mobilization. Haematopoietic growth factors or chemotherapeutic agents often are used
to stimulate the mobilization.6
The chemotherapy or irradiation given immediately prior to a transplant is called the
conditioning or preparative regimen, the purpose of which is to help eradicate the patient's
disease prior to the infusion of HSC and to suppress immune reactions. The bone marrow can
be ablated with dose-levels that cause minimal injury to other tissues. In allogeneic
transplants a combination of cyclophosphamide with busulfan or total body irradiation is
commonly employed.6
After several weeks of growth in the bone marrow, expansion of HSC and their progeny is
sufficient to normalize the blood cell counts and reinitiate the immune system. This is known
as engraftment.6
During engraftment, engraftment syndrome may occur. Engraftment syndrome (ES) is a
febrile syndrome that occurs in the early neutrophil recovery phase following HSCT. It is
characterized by noninfectious fever and various clinical findings, such as skin rash
mimicking acute graft-versus-host disease, diarrhoea, pulmonary infiltrates, weight gain and
neurological manifestations.7
Beike Biotechnology utilizes adult stem cells for all the therapies and uses both allogeneic as
well as autologous cell types. The major source is cord blood.

4. METHODOLOGY
4.1 SEARCH METHODS
Literature were searched through electronic databases which included Ovid Medline,
PubMed, Ovids Evidence Based Medicine Review Collection(EBMR) which include ACP
Journal Club (ACP), NHS Economic Evaluation Database (CLHTA), Cochrane Database of
Systematic Review (CDSR). National Health Service Economic Evaluation Database
(CLEED), Database of Abstracts of Review of Effectiveness (DARE), Cochrane Central
Register of Controlled Trials (CCTR), and general databases such as Google and Yahoo.
The search strategy used the terms, which were either used singly or in various combinations:
stem cells OR stem cells transplantation OR stem cells clinic, cerebral palsy,
motor neuron disease, stroke, multiple sclerosis, spinal cord injury, diabetic foot,
autism, optic nerve hyperplasia, muscular dystrophy, femoral head necrosis, lower
limb ischaemia and spinal muscular atrophy.
The search was limited to articles on human. Only articles in English were included.
No limit in year of publication was applied. The last search was done on 9 April 2010.
SELECTION OF STUDIES INCLUDED /EXCLUDED
Systematic reviews, meta-analysis and all primary studies pertaining to safety, effectiveness
and cost effectiveness of stem cells therapy for cerebral palsy, motor neuron disease, stroke,
multiple sclerosis, muscular dystrophy, femoral head necrosis, diabetic foot, lower limb
ischaemia, spinal cord injury, autism, spinal muscular atrophy, optic nerve hyperplasia and
stem cell clinic were included in this review.
Articles on cell based therapy for the treatment of the above diseases were excluded.
A critical appraisal of all the relevant literature was performed using Critical Appraisal
Checklist Project (CASP) checklists and the evidence was graded according to the
US/Canadian Preventive Services Task Force Level of Evidence (2001).
5. RESULTS AND DISCUSSION
There were 12 articles retrieved on stem cells clinic or treatment centre and stem cells
treatment for spinal cord injury, multiple sclerosis and stroke. There was no published article
retrieved on other diseases in the available databases.
5.1 EFFICACY
5.1.1 Stem cell therapeutic centre
Darren Lau et al. analyzed stem cell clinic websites and appraised the relevant
clinical evidence of stem cell therapies to address three questions: what sorts of
4

therapies are being offered? How are they portrayed? Is there clinical evidence to
support the use of these therapies? They found 19 websites claiming the use of stem
cells for the treatment of disease found. All the websites advertised improvement in
disease state as a benefit of therapy whereas 74% sites did not mention particular
risks. The researcher searched for evidence to support the use of therapies in a routine
clinical setting by performing PubMed search for neurologic and cardiovascular
diseases namely multiple sclerosis (MS), Parkinsons disease, stroke, Alzheimers
disease, spinal cord injury (SCI) and spinal muscular atrophy. They revealed that
evidence for SCI and stroke is generally underdeveloped and there was no evidence
retrieved for Parkinsons disease and Alzheimers disease. As for multiple sclerosis,
they found that findings from one large case series suggested autologous hematopietic
stem cell transplantation (AHSCT) may have a role to play in slowing the progression
of disease. However, clinical outcomes are variable and not obviously better than
natural history of patients with multiple sclerosis. The author also found that stem cell
therapies recommended by the centres for MS, Parkinsons disease, stroke,
Alzheimers disease, and SCI, were of low grade. As many of the centres offered
treatment for neurologic conditions, the author concluded in his paper that the
treatments offered were generally unsupported by the clinical evidence.8 Level III
5.1.2 Spinal cord injury
Spinal cord injury (SCI) often results in devastating dysfunction and disability.9 Less
than 1% of people who sustain significant injury to their spinal cord recover complete
neurological function and many of these injuries result in partial or complete
paralysis.10
There was only one case report retrieved on stem cells therapy for spinal cord injury.
The case was the single case of a planned clinical trial aimed to treat damaged spinal
cord by a novel method of injecting bone marrow stromal cells (BMSCs) into CSF
through the lumbar puncture, and assess the safety and efficacy of the procedure.9 Level
III
The report showed that there was slight improvement in the motor and sensory
scores.
On 21st January 2009, the United States Food and Drug Administration (US FDA)
approved the first clinical trial to assess the safety of therapeutic embryonic stem cells
in human subjects for spinal cord injury. It was reported that the phase 1 study will
include eight to ten people who have sub acute functionally complete injury between
the T3 and T10 spinal segments and will focus on trauma cases only.11
5.1.3 Multiple sclerosis
Multiple sclerosis (MS) is a common disease of the central nervous system affecting
approximately 2.5 million adults, mostly young women worldwide. MS treatment
involved immunosuppressive and immunomodulating agents.12 The clinical course of
the disease is very heterogenous. However, it typically presents with a relapsingremitting course (RRMS; 80%), which is followed after 5 to 15 years in about 70% of
patients by a so-called secondary progressive phase (SPMS). Ten to fifteen percent of
5

patients have a primary progressive course, which is characterized by a steady

progression from onset with or without any acute exacerbations (progressive
relapsing MS (PRMS) and primary progressive MS (PPMS), respectively.13
There were eight studies retrieved on stem cells therapy for MS. All the studies were
case series where there were no comparison or control, thus provide weak evidence.
The number of patients in each series range from six to 50 patients. The median
duration of follow up varies from 11 to 39 months.
Shevchenko et al. studied patients with multiple sclerosis from five Russion centres
who were treated with high-dose immunosuppressive therapy and AHSCT. They
employed three strategies in delivering the treatment, namely early transplantation,
conventional transplantation and salvage or late transplantation. Out of the 50
patients, 62.3% of them improved by at least 0.5 point on the Expanded Disability
Status Scale (EDSS) as compared with baseline. Another 37.7% had disease
stabilization but two patients progressed after stabilization. The progression free
survival after 6 years was 72%.13 Level II-3
Saccardi et al. in their study, include 19 patients from seven Italian centres. These
patients received AHSCT. Eighteen patients (95.0%) experienced a clinical
stabilization or improvement. One patient had relapse 4.5 years after transplantation
which resolved spontaneously within 3 weeks without EDSS worsening. The
confirmed progression-free survival was (95% 5%) at 6 years after AHSCT and
disease activity-free survival, where all signs of disease activity were considered
events, was 64.0% at 4.5 years since AHSCT.14 Level II-3 Significant improvement
observed in both physical health (p = 0.002) and mental health (p = 0.05) score
measured with the 54-item MS quality of life (MSQOL). As for magnetic resonance
imaging (MRI) results, all the patients have negative MRI scans at 36 months follow
up. One lesion was detected in the patient who relapsed 4.5 years after the
transplantation.14 Level II-3
Nash et al. conducted a multicentre study involving 26 patients with severe multiple
sclerosis. These patients received high dose immunosuppressive therapy (HDIT)
followed by transplantation of autologous CD-34 selected stem cells. From the 25
evaluable patients, six patients (24%) experienced treatment failure (increase in
EDSS score of more than 1.0 point), three patients had unconfirmed increases of 0.5
point in EDSS score, two patients had decreases of 0.5 point and 14 patients remained
stable at last follow-up. Kaplan Meir estimated treatment failure was 27% at three
years. There was no significant change in 100 points Scripp neurologic rating scale
when compared to baseline. As for nine hole peg test for fine motor coordination,
only one patient improved, 13 patients remained stable and seven patients worsened.
The estimated survival rate was 91%, at 45 months after HDIT.15 Level II-3
Juan et al. studied 22 patients with SPMS. The median EDSS score at last follow up
was 4.3 (range 1.0 to 8.0). Neurological improvement observed in 13 patients where
6

the median EDSS score decreased from 6.0 (range 4.5 to 7.0) to 3.0 (range 1.0 to 4.5).
Stabilization of neurological function observed in another four patients and in five
patients the disease either progressed or relapsed. The neurological function
deteriorated within 6 to 19 months post-transplantation. The confirmed progression
free survival rate was 77% and the median length of remission reached was 43
months (95% CI 33 53) which was significantly more than nine months (95% CI 7
-11) of pre-tranplantation.16 Level II-3
In a study by Burt et al. among 21 patients with RRMS, the progression free survival
was 100% after a mean follow up of 3 years (p < 0.0001). These patients received
non-myoablative AHSCT. EDSS score improved in all patients after AHSCT
compared with baseline scores. Seventeen (81%) patients had an improvement 1 point
or more, two patients improved 0.5 points and two patients had no change in EDSS
score.17 Level II-3 NRS score improved by 10 or more points in 14 patients and by fewer
than 10 points in five patients at the last follow up compared with baseline. The timed
25 foot walk improved in all the patients assessed (p<0.001). The scores on righthand nine-hole peg test and left-hand nine-hole peg test improved but did not change
significantly (p=0.10 and p=0.12, respectively). The patients also perceived that their
general status to be improved during the study period, scores in all domains were
statistically significant except for emotional role.17 Level II-3
Encouraging outcome was also observed in an earlier study conducted by Burt et al.
among six patients with clinically definite MS. All these patients experienced
subjective and objective neurologic improvements. EDSS score remains unchanged.
The Scripps NRS test demonstrated more than 10 point improvement in three
patients. These patients had gadolinium enhancement on their pretransplant MRI and
had lower EDSS scores (6.0 to 7.5). Two of the three patients who had stabilization of
disease but no significant improvement did not have pretransplant gadolinium
enhancement and higher pretransplant EDSS scores (8.0 to 8.5). MRI showed no new
or enhancing lesions after transplantation.18 Level II-3
Carreras and Saiz papers were from the same study but focused on different aspects
of the study.12,19 Level II-3 In the study conducted among 15 patients with clinically
definite SPMS or RRMS, the EDSS score remained stable in eight patients, improved
in four patients and worsened in two patients. In one patient, the deterioration was
related to the procedure. The 3-year actuarial probability of progression-free survival
was 85.7% (95% CI, 60% to 96%) and that of disease activity-free survival was
46.4% (95% CI, 24% to 76%).19 Level II-3
5.1.4 Stroke
Stroke remains a significant clinical unmet condition with only 3% of ischaemic
patient population benefiting from the thrombolytic drug tissue plasminogen activator
largely because of the drugs narrow 3-hour therapeutic window.20 Functional
recovery may occur in a small or a localized brain injury using rehabilitation
7

measures, but for large ischaemic strokes the restoration may require new synaptic
connections within and away from the damaged tissue. For these reasons, the
prospects of repairing the neuron system, using cell transplantation seems promising
and may offer a unique approach for brain repair and restoration of function.4
A study was retrieved on stem cells therapy for stroke patients. Kondziolka et al. did
an open trial among 12 patients with stroke. These patients were either given two
million or six million human neuronal cells. At 24 weeks of follow up, six of the 12
patients had improved scores on the European Stroke Scale (ESS) score (range 3 to
10 points), in three patients the score were unchanged and in three patients the score
deteriorated (range -1 to -3 points) compared to their baseline scores. The mean
change in ESS from baseline to week 24 for all implanted patients was 2.9 points (p =
0.046). Size of infarction or time since infarction did not correlate with clinical
outcome. Motor elements contributed for much of the change noted in patients treated
with LBS-Neurons. The mean change in ESS-motor score was 2.5 (p = 0.026), for the
two million neurons group the score was 1.9 (p = 0.185) and for the six million
neurons group the score was 3.8 (p = 0.08). Eight patients had improved scores (range
-1 to -4 points) in the NIHSS score at 24 weeks follow up, in one patient the score
was unchanged. In three patients the score deteriorated (range 1 to 2 points). There
was no significant change in Barthel index and SF-36 in both groups. Serial MRI
showed no anatomic or structural changes in the brain after surgery when compared
with baseline. There was no evidence of oedema, contrast enhancement, mass effect
or change in the contour of the infarction.21 Level II-3

5.2 SAFETY
Beikes stem cells products have not yet received China State Food and Drug
Administration (China SFDA) or US FDA approval.
There was no toxic deaths or engraftment syndrome reported among 50 patients treated
with BEAM regimen without graft manipulation in Shevchenko et al. study. The
common adverse effects reported were neutropaenic fever (51.6%), hepatic toxicity grade
I and II (48.1%), transient neurological dysfunction (22.2%) and enteropathy (18.5%).13
Level II-3

Mobilisation was successful in all cases in Saccardi et al. study. No major clinical events
were reported. Four patients developed fever and one patient developed hemorrhagic
cystitis, one patient had urinary tract infection, CVC-related phlebitis and inappropriate
secretion of antidiuretic hormone (ADH) each. Engraftment was uneventful and no
engraftment syndrome reported. Following transplantation, 16 patients developed fever
where five of them documented sepsis. Six patients had cytomegalovirus (CMV)
reactivation where one of them was symptomatic. Three patients had urinary tract
infection (UTI), three patients had enteritis, one patient had transient increase in aspartate
transaminase (AST) or alanine transaminase (ALT) levels and one patient had gastric
8

ulcer bleeding. Between two to four months post-transplantation, two patients had
Varicella Zoster infection and three patients developed transient monoclonal
gammopathy.14 Level II-3
Engraftment syndrome occurred in the first 18 patients in Nash et al. study and in some
of them associated with neurologic complications. In order to prevent the engraftment
syndrome, the final eight patients of the study were given a short course of prednisone
after transplantation. Infections were quite common where eight patients had urinary tract
infection, four patients had bacteraemia and one patient developed infection at the exit
site of the central venous catheter. There was no serious outcome of these infections. As
for viral infection, one patient each had parainfluenza 3 infection, rotavirus infection and
herpes simplex infection. Two patients developed varicella zoster, four out of nine
patients with seropositive cytomegalovirus infection had reactivation and one patient died
of progressive Epstein-Barr Virus Post-transplantation Lymphoproliferative Diseases
(EBV-PTLD). Another patient died 23 months after HDIT from aspiration pneumonia. 15
Level II-3

Diarrhoea without infection evidence lasted 3 to 7 days occurred in 13 patients

immediately following the conditioning regimen in Juan et al. study. Six patients had
abrupt fever. Eight patients had transient neurological worsening including fatigue,
headache, numbness and paraesthesia during transplantation. Seven of the patients had
bacterial infection where five of them had UTI due to bladder dysfunction and two of
them had perianal soft tissue infection. No fungal or viral infection observed in this
study.16 Level II-3
In Burt et al. study, 10 patients developed adverse events. Two of these patients
developed dermatomal zoster at 20 months and 22 months post-transplantation
respectively, one of them developed perforated peptic ulcer at 28 months. Other five
patients developed neutropaenic fever. The first patient had fever for 2 days; grade 1
haemorrhagic cystitis; deep vein thrombosis at 6 months, immune thrombocytopaenia at
7 months, which was treated and resolved. The second patient had fever for a day; he also
developed filgastrim-related transient MS flare with left-sided paraesthesia which
resolved without treatment. The third patient had fever on day 0 with coagulase-negative
staphylococci in blood culture in one specimen which was deemed a contaminant. The
fourth patient had fever on day 3 with negative culture. He had diarrhoea due to
Clostridium difficile at 1 month after discharge. The fifth patient developed neutropaenic
fever for 4 days. One patient developed grade 1 rash which resolved without treatment,
one patient had grade II elevation of transaminase concentration, which resolved with
discontinuation of fluconazole and one patient developed immune thrombocytopenia at
14 months, which resolved with treatment.17 Level II-3
In Carreras et al. study, one of the patients did not reach the required leucocyte and CD34
counts after second attempt of mobilization thus not transplanted. One patient
experienced leg paresis and another patient had mild haemorrhagic cystitis in the
mobilization stage. During conditioning, one patient developed grade II liver toxicity
where the transaminase level raised more than 20 times after BCNU administration. Six
9

of the first eight patients who were not given methylprednisolone prior to ATG
administration developed high fever, three patients developed skin rash and one patient
developed vasculitis that required prolonged treatment with steroids. Post transplantation,
one patient developed severe persistent paraparesis that increased her EDSS from 6.5 to 8
and another patient had transient deterioration of her hemiparesis. Both coincides with
high fever related to ATG administration. During neutropaenia, 12 patients developed
fever (7 culture negative, one E. coli, one MARSA, 3 coagulase negative Staphylococci
isolated in blood and E. coli in urine in one case). One patient developed two consecutive
episodes of CMV positive antigenemia on days +20 and +38, both successfully treated
with gancyclovir. Two patients developed herpes zoster 7 and 10 months after
transplantation respectively. Three patients developed engraftment syndrome and one
patient had an episode of uveitis that resolved with steroid treatment 2.5 months after
transplantation.12 Level II-3
In a trial for stroke patients, one patient had severe nausea and vomiting several days
after surgery which was presumed due to cyclosporine-A and associated with decline in
renal function. The symptoms resolved after medication stopped. Another patient
developed urinary tract infection one month after surgery and treated with antibiotics.
One patient with infarction of the temporal lobe had generalized seizure 6 months after
surgery and started on phenytoin. She developed allergic reaction and changed to
carbamazepine. One patient was hospitalized shortly before the week 24 visit with a new
brainstem stroke remote from the site of neuronal cell implantation. There was no death
or cell-related serious adverse events occurred. There was no clinically significant
laboratory, radiographic or electrocardiographic abnormalities that could be attributed to
the neuronal cell implantation seen up to the 12 month visit.21 Level II-3
5.3 COST EFFECTIVENESS
In early 2009, Beike quoted a price of US$26,300 for an initial course of six stem-cell
injections to treat a patient with spinal muscular atrophy, with additional injections
costing US$3,500 each.22
5.4 ETHICAL ISSUES
Ethical issues regarding stem cells are major concern. Ministry of Health Malaysia has
produced National Guidelines for Haemopoietic Stem Cell Therapy and Guidelines for
Stem Cell Research and Therapy in 2009. Ethical issue raised in the guidelines is
regarding the morality of destroying embryos or using remnants of aborted fetuses to
improve medical wellbeing of other human beings in embryonic stem cell research.23
Malaysian Medical Council has also produced a guideline on stem cell research and stem
cell therapy.24 Among the ethical issues is producing stem cell for commercial purposes.
The guideline stated that sale and commercial supply of stem cells should preferably be
disallowed, in favour of some system of distribution that recognizes and evaluates the
clinical and research intentions of prospective users.
10

Regarding direct to consumer centre, David Magnus, Director of the Stanford Center for
Biomedical Ethics in California in an article stated that having the company that
provides the cells interacting directly with patients at an independent hospital or
institution should be prohibited. In his opinion the situation seems to be the equivalent
of a drug rep selling an unproven product directly to the patients at the hospital.22
6. CONCLUSION
There was insufficient evidence to support the efficacy of direct to consumer stem cell
therapy. Weak evidence showed that the treatment given was not based on evidence.
There was insufficient and inconclusive evidence on the efficacy and safety of stem cell
therapy for neurologic diseases in adult.
The evidence on stem cells therapy for multiple sclerosis showed that it is still at
experimental stage. Only phase 2 non-comparison studies available. However the weak
evidence showed that the progression free survival rate range from 72% to 100%, lower rate
in the group of patients treated with HDIT and higher in the group of patients treated with
non-myoablative regime. Stem cells therapy was able to induce clinical stabilization in
multiple sclerosis patients and improve their quality of life; however the adverse events are
also substantial.
Similarly, the evidence on stem cell therapy for stroke and spinal cord injury was insufficient
and showed that it was still in the developmental stage. There was also no evidence retrieved
on motor neuron disease, femoral head necrosis, diabetic foot, lower limb ischaemia, and
optic nerve hyperplasia
As for paediatric neurological disorders such as cerebral palsy, autism and spinal muscular
atrophy, no evidence could be retrieved from the published literature to date on the use of
stem cell therapy with regards to its efficacy, safety and cost-effectiveness. There have also
been grave concerns among paediatric neurologists with regards to the impact of
commercialization of unproven therapy, its unethical use generating false hope among
desperate parents and redirection of their effort from more evidence-based treatment.
Ethical issues regarding stem cell therapeutic centre includes commercial supply of stem
cells and direct interaction of manufacturer and patients.
Adverse events are common with stem cells therapy and range from minor to severe adverse
events. There was no evidence retrieved on cost effectiveness of stem cells therapy for
neurologic diseases.

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