Stem cell transplants

[Guest guest]

Interesting reading. Thanks for sending us the site. I'll admit though, it

scares me to even contemplate going through such a procedure.

Marilynn

[Guest guest]

Thank you . I would be interested in learning where you got the number

of 30 kids worldwide. I know my rheumy publishes papers and has used our

daughter as a subject in her speeches and papers, If I say to her only 30

kids have ever had it done for jra, I would like to be able to name a source.

appreciate it.

bob

[Guest guest]

Thank you nutsomom5 ( great screen name lol). We are not on brink of doing

these things, but rheumy mentioned them as options when (not if) remicaide

becomes ineffective. As you know, all the dmards and smards etc. run a

course until the body doesn't respond to them after awhile.

Hopefully we won't get to that point.

Thanks to all for all responses lately. You all have been helpful.

bob

[Guest guest]

Bob-

As mentioned, a little boy on this list named had this procedure done in Canada. I think it was about a year ago. As I recall, his father (I think his name is Oliver) posted several times with information about the procedure, the risks, how many had been done, etc. You might want to check the archives for those posts. Maybe I'll try it later. I recall that the mortality rate was something like 25%, and ' family had made the decision because his condition was so severe his quality of life was nonexistant. We haven't had any posts about ' condition since shortly after the surgery. I'd love to know how he's doing if anyone here knows.

Diane (, 2, pauci)

[Guest guest]

thank you cindy.

[Guest guest]

Dear Bob, There is a little girl that had the stem cell transplant here in

Portland. I think it is done as a last resort--it can be quite dangerous.

There was a little boy on the list, , that had it done in Canada,

but it seems they aren't on the list anymore. To the best of my knowledge

only about 30 kids have had it done worldwide.

>From: " bskae2000 " <bskae@...>

>Reply-

>

>Subject: stem cell transplants

>Date: Wed, 03 Apr 2002 14:42:25 -0000

>

>hi everyone,

>

>This is the latest thing we've heard from rheumy. Cytoplams (chemo)

>and stem cell transplants. I know chemo has been mentioned on list,

>but does anyone have experience with Stem cell transplants? and under

>what conditions?

>

>Thank you.

>

>bob

>

>

>

>

>

>

>

>

[Guest guest]

Bob..I am going to give my opinion and I hope you don't take it wrong..but

before you go the route of chemo and stem cell transplant..I personally

would seek another opinion of another rheumatologist..

What meds are Mitch on and what has meds has the rheumy tried through the

years..

I honestly don't know anything about the stem cell transplant but I asked my

Tabs rheumy one time about it..and he said it is very dangerous. As far as

chemo..what amount would be given? I personally have never heard of this as

a treatment.

Sorry I know this hasn't helped..

Good luck

karen(tab17..poly)

From: " bskae2000 " <bskae@...>

Reply-

Subject: stem cell transplants

Date: Wed, 03 Apr 2002 14:42:25 -0000

hi everyone,

This is the latest thing we've heard from rheumy. Cytoplams (chemo)

and stem cell transplants. I know chemo has been mentioned on list,

but does anyone have experience with Stem cell transplants? and under

what conditions?

Thank you.

bob

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[Guest guest]

Hi Bob,I hope you and the rheumy were just talking,and not considering

it.From what Ive read it is highly experimental and very dangerous.It is only

tried when it is life and death and there is no hope.I know a few systemic

children died from it,because they had systemic symptoms when they did it.If

your dr is considering it get another opinion,get an application to a

shriners hospital,thats my plan if ever gets to where his rheumy cant

help him.Good luck Becki and 3systemic

bskae2000 wrote:

> hi everyone,

>

> This is the latest thing we've heard from rheumy. Cytoplams (chemo)

> and stem cell transplants. I know chemo has been mentioned on list,

> but does anyone have experience with Stem cell transplants? and under

> what conditions?

>

> Thank you.

>

> bob

>

>

>

>

>

[Guest guest]

Dear Bob, Well, I don't have a great source--it was on our radio and tv

stations in Nov. 1999. That is when the little girl in Portland had it

done. At that time there were like 22-24 kids that had the procedure done

according to the Portland news sources. I am sure there is some research

somewhere with the exact details. Georgina may know best. Maybe she will

chime in.

>From: bskae@...

>Reply-

>

>Subject: Re: stem cell transplants

>Date: Wed, 3 Apr 2002 13:56:49 EST

>

>Thank you . I would be interested in learning where you got the

>number

>of 30 kids worldwide. I know my rheumy publishes papers and has used our

>daughter as a subject in her speeches and papers, If I say to her only 30

>kids have ever had it done for jra, I would like to be able to name a

>source.

>

>appreciate it.

>

>bob

>

>

>

>

>

[Guest guest]

The screenname fits someone like me who has 5 kids..lol! Tabitha also has

been on remicade since Sept. of 2000...Hopefully it keeps working!

Good luck ..please keep us posted!

karen(tab17..poly)

From: bskae@...

Reply-

Subject: Re: stem cell transplants

Date: Wed, 3 Apr 2002 14:10:09 EST

Thank you nutsomom5 ( great screen name lol). We are not on brink of doing

these things, but rheumy mentioned them as options when (not if) remicaide

becomes ineffective. As you know, all the dmards and smards etc. run a

course until the body doesn't respond to them after awhile.

Hopefully we won't get to that point.

Thanks to all for all responses lately. You all have been helpful.

bob

_________________________________________________________________

Join the world’s largest e-mail service with MSN Hotmail.

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[Guest guest]

Hi Bob,

I went and did a brief search through the archived messages and found a few posts that might be of interest to you.

Aloha,

Georgina

Thank you nutsomom5 ( great screen name lol). We are not on brink of doing these things, but rheumy mentioned them as options when (not if) remicaide becomes ineffective. As you know, all the dmards and smards etc. run a course until the body doesn't respond to them after awhile.Hopefully we won't get to that point.Thanks to all for all responses lately. You all have been helpful.bob

[Guest guest]

Hi Diane,

I got an email just yesterday, from Leonard (' Dad) ! He has been doing well : ) At first, seemed to have a remission, as a result of his bone marrow transplant .... but he later flared up again. He also had MAS (macrophage activation syndrome). He is currently taking 4.5ml prednisone per day but they are working at reducing the amount. He has been well enough to attend school regularly without needing a walker or wheelchair and he hasn't been to the hospital for a long time, so his Dad says he is doing much better than before the transplant (which Leonard does not regret doing).

I had written, once again, to let them know I was thinking of them ... as ' birthday is one day before 's. ' celebrates his 9th birthday today : ) If anyone would like to send Electronic Greetings, their email address (which is now working just fine) is: lkroft@...

Aloha,

Georgina

Re: stem cell transplants

Bob- As mentioned, a little boy on this list named had this procedure done in Canada. I think it was about a year ago. As I recall, his father (I think his name is Oliver) posted several times with information about the procedure, the risks, how many had been done, etc. You might want to check the archives for those posts. Maybe I'll try it later. I recall that the mortality rate was something like 25%, and ' family had made the decision because his condition was so severe his quality of life was nonexistant. We haven't had any posts about ' condition since shortly after the surgery. I'd love to know how he's doing if anyone here knows. Diane (, 2, pauci)

[Guest guest]

Below is an excerpt re: " real " stem cell transplants, not the pseudo

cord stem cell transplants. Real transplants require

immunosuppression and are not without risk. It may be heavy reading

for some, in which case just go to the end for the summary.

Yash

-----------------------------------------

Stem cell transplantation for multiple sclerosis: What is the

evidence?

Athanasios Fassas, , a and Vassilios K. Kimiskidisb, 1

a Hematology Department and BMT unit, Papanicolaou Hospital,

Thessaloniki, Greece

b Department of Neurology, Aristotle University School of Medicine,

Papanicolaou Hospital, Thessaloniki, Greece

Available online 3 May 2003.

Abstract

Experimental and clinical observations have indicated that high-dose

immunosuppression followed by autologous stem cell transplantation

(ASCT) can induce remissions in severe, refractory, autoimmune

diseases including multiple sclerosis (MS), a T cell-mediated

autoimmune disorder against CNS myelin components, causing severe

chronic disability. Control of the disease is unsatisfactory in most

of the patients, especially those with rapidly evolving relapsing–

remitting course and those with chronic progressive disease. The

rationale for treating autoimmune diseases with ASCT is based on the

immunosuppressive and immunomodulating effects of ASCT which may

shift the immunological balance towards disease quiescence, a

hypothesis supported by the results of ASCT in animal models of MS

and by clinical observations in MS patients transplanted for

concurrent malignancies. A number of phase I–II studies of ASCT in

patients with active MS, conducted worldwide since 1995, and a

comprehensive analysis of 85 patients, recently reported by the

European Group for Blood and Marrow Transplantation (EBMT), have

shown the feasibility of the method, a prominent anti-inflammatory

effect on magnetic resonance imaging (MRI) disease, and a possible

clinical benefit for active and refractory cases. The impact on MRI

disease parameters appears superior with ASCT than with conventional

therapies but the clinical results, in terms of stabilization of

disease and prevention of disability, need to be validated in

prospective, controlled trials. The procedure is also associated

with a transplant-related mortality risk, of about 5% in high-risk

cases, i.e., in older patients, those with high disability scores,

those receiving strong myeloablative conditioning regimens and those

undergoing intensive in vivo or ex vivo T cell-depletion. Therefore,

it could be recommended for the treatment of a chronic, non-lethal,

disease like MS only if it proved superior to standard therapies. A

randomized trial is now launched by the EBMT to compare ASCT to

mitoxantrone, currently regarded as one of the best available

treatments, in properly selected patients having high chance of

response at minimal mortality risk.

Author Keywords: stem cell transplantation; multiple sclerosis

Article Outline

• Introduction

• Rationale and experimental models

• Clinical studies

• The EBMT study

• Other studies

• Concluding remarks

• References

Introduction

Multiple Sclerosis (MS) is an incurable, crippling disease of the

central nervous system (CNS), relatively common among neurological

disorders of young adults, with a prevalence of 1.2 cases per 1000

population and a life-time risk of one in 400.[1] It causes serious

physical and psychological impairment in the majority of cases and

is accompanied by considerable social cost. The etiology is unknown.

Environmental factors are believed to trigger an abnormal autoimmune

response against myelin structural components in subjects with a

susceptible genetic background. MS is consequently regarded as an

organ-specific, T cell-mediated, autoimmune process causing

inflammatory destruction of myelin (demyelination), and subsequent

axon loss and gliosis. [1, 2 and 3] Accumulation of disability,

however, may not be caused only by inflammation and chronic

demyelination, but also by axonal degeneration that may occur early

in the course of the disease. Neurodegeneration has recently been

recognized as an important component of MS; its cause is unclear,

but it may also be due to immune attack directed at axonal

components. [4, 5 and 6] The clinical course of MS ranges from

benign (10%) to highly " malignant " (1–3%). In the great majority

(80%), MS starts with a relapsing/remitting course (RR-MS) which

after 5–15 years is followed by a secondary progressive phase (SP-

MS) with or without superimposed disease exacerbations (relapses).

MS may also have a progressive form from onset (10–15%), called

primary progressive MS (PP-MS), which is notoriously refractory to

therapies. Standard treatment modalities for MS include

immunosuppression with steroids and/or cytotoxic drugs,

immunomodulation with interferon- (IFN-) or glatiramer acetate

(copaxone), and, in certain cases, antibody removal by

plasmapheresis or intravenous administration of immunoglobulins.[2,

7, 8 and 9]

The aim of MS treatment is to reduce the frequency of relapses,

limit lasting effects, relieve symptoms, but mainly to prevent

disability, that is to halt disease progression. Unfortunately, the

available treatments are not curative; they can reduce CNS

inflammation and may delay progression, but control of disease is

unsatisfactory in many patients. For the chronic progressive forms

in particular, i.e., SP-MS and PP-MS, there is no universally

accepted therapeutic agent able to influence meaningfully the course

of the disease, that is to prevent worsening of disability.[10, 11

and 12] Only recently, mitoxantrone was demonstrated to have a

positive effect, slowing the progression of disability and

decreasing the number of enhancing areas visible with magnetic

resonance imaging (MRI). [13 and 14] Mitoxantrone has received MS

indication but the duration of therapy is limited because of the

drug's well-known cumulative cardiotoxicity. Current

immunobiological and pathophysiological concepts have led to a

variety of immunotherapeutic approaches, namely blockade of 4

integrin, the use of altered peptide ligands, inhibition of Th1

cytokines, and DNA vaccination. However, the experience with these

agents has been negative as they may be no more efficacious than

conventional therapies or they may be associated with unforeseen

adverse effects.[15 and 16]

Based on experimental data, bone marrow or blood stem cell

transplantation (BMT, SCT) has been proposed for the treatment of

severe and refractory autoimmune diseases,[17, 18, 19, 20, 21 and

22] including multiple sclerosis, in view of the lack of effective

treatments for this disease. [23, 24, 25, 26, 27, 28, 29, 30 and 31]

The hypothesis that SCT might cure or alter the course of MS was

also supported by sporadic clinical observations, in patients with

MS who underwent allogeneic, syngeneic, or autologous,

transplantation for concurrent malignancies and were subsequently

improved or stabilized. [32, 33 and 34] Clinical, phase I–II,

studies of autologous SCT (ASCT) after high-dose immunosuppression

were started in 1995. They have been conducted ever since, on small

scales, mainly in Europe and the USA, and MS has become the most

frequently transplanted autoimmune disease: the Autoimmune Disease

Working Party (ADWP) registry of the European Group for Blood and

Marrow Transplantation (EBMT) contains 140 reports of cases

(November 2002) and around 60 more patients have so far been

transplanted in North America (USA and Canada). In a small number of

published papers [35, 36, 37, 38, 39, 40, 41, 42 and 43] the results

of ASCT have been reported promising as they appeared superior to

the results achieved by other available therapies in terms of

clinical stabilization and impact on magnetic resonance imaging

(MRI) disease parameters. [41 and 42] Despite controversies caused

mainly by the morbidity and mortality in the initial open-label

studies, the general feeling of the investigators is that phase III,

control trials of ASCT against a " best standard " therapy are now

justifiable. [44] We review, in this communication, the existing

evidence supporting the hypothesis that ASCT might positively modify

the course of MS and further discuss major clinical as well as

ethical issues related to the application of this still

investigational treatment.

Rationale and experimental models

The idea of treating autoimmune disease with SCT dates back to 1968

when Lindsey and Woodruff demonstrated that the spontaneous

autoimmune hemolytic anemia of NZB/B1 mice could be ameliorated or

cured by syngeneic or allogeneic SCT.[45] Subsequent studies showed

that allogeneic, syngeneic, and autologous, BMT could modify and

reverse a variety of models of animal autoimmune disease (reviewed

in Ref. [19]), either spontaneous or antigen-induced. Spontaneous

autoimmune diseases, believed to originate from defects in

hematopoietic stem cells, [46] are best treated with allogeneic BMT,

whereas antigen-induced diseases can be successfully treated also

with autologous BMT. [47 and 48] In man, it is impossible to make

this sort of distinction between spontaneous and antigen-induced

autoimmune disease and, given the well-known toxicity and mortality

of allogeneic SCT, autologous SCT was proposed in 1993 for the

treatment of autoimmune disorders. [49 and 50] Marmont was the first

to treat a patient suffering from CREST syndrome with

cyclophosphamide (CY) at 150 mg/kg.b.wt. and autologous BMT in

January 1994.[51] In June 1995 we initiated a pilot study of high-

dose chemotherapy (BEAM) and autologous blood SCT in patients with

multiple sclerosis, [35] based on the conclusions of experimental

transplants performed independently by the groups of Jerusalem [23,

24 and 25] and Rotterdam [26, 27 and 29] who used autologous BMT to

treat the animal MS model experimental autoimmune encephalomyelitis

(EAE) in rats. [29 and 52] The rationale for using autologous SCT

was based on the hypothesis that recapitulation of lymphocyte

ontogeny after complete elimination of the aberrant immune system

might lead to immune tolerance by exposure of the developing immune

system to antigens within the injured tissue during thymic or

peripheral re-education. Remission of EAE was attained in all

animals after TBI (10 Gy) or CY followed by pseudo-autologous BMT

(marrow from syngeneic animals brought to an identical stage of

disease). High-dose conditioning was necessary to achieve remission

and also prevent from spontaneous relapse, which was, however, more

frequent in the autologous (30%) than in the allogeneic setting

(5%); also, induced relapses were more frequent after autologous BMT

(72%) than after syngeneic BMT (44%). These results indicated that

both residual T cells of the host and re-infused cells contribute to

relapses after an autologous transplant and, therefore, apart from

an immunoablative conditioning regimen, T cell-depletion of the

graft is also necessary,[52] a situation analogous to autografting

in acute leukemia.

It is well-known that, in contrast to malignancy, human autoimmune

diseases are not one cell-type disorders: they are polyclonal

disorders resulting from an inbalance of immune-enhancing and immune-

protective genes affecting cytokines, costimulatory molecules,

apoptosis, antigen receptor and signalling, regulatory cells, etc.

[53] This is true also for MS in which the pivotal role is played by

myelin-specific CD4 T cells that, upon activation, invade the CNS.

Deletion of autoreactive clones might partly explain the yet

undefined mechanism by which ASCT could influence the course of MS.

ASCT has a profound and prolonged immunosuppressive effect which may

last for even more than two years. It is possible that apart from

its immediate anti-inflammatory effect, high-dose immunosuppression

with ASCT might tip the immunological balance towards quiescence and

shift the disease-line to an earlier time period, analogous to the

latent period of autoimmune disease development, restoring self-

tolerance. In this way, ASCT acts not only as an immunosuppressive,

but also as an immunomodulatory therapy. This is substantiated by

the fact that cases of resistant autoimmune diseases may become,

after ASCT, sensitive to standard treatments and significant dose-

reduction of medications, e.g., steroids, is possible. [39, 54 and

55]

The recently discovered phenomenon that stem cells have the capacity

to enter the CNS and transdifferentiate into, or acquire properties

of, microglia and possibly neurons (stem cell plasticity) may be of

significant importance considering remyelination and neuronal repair.

[56] At the present stage, however, these considerations are merely

theoretical.

Clinical studies

The EBMT study

The largest study of clinical outcomes of ASCT in MS has been

published recently by the EBMT.[57] It is a comprehensive analysis

of the first 85 cases reported from 19 European and one American

centers to the ADWP registry of the EBMT. Fifty-two (61%) patients

were female; the patients' median age was 39 years (range, 20–58

years); the majority (70%) had SP-MS, 26% had PP-MS, and 3 patients

had RR-MS. The median time-interval from diagnosis to transplant was

7 years (range, 1–29 years). Most of the patients were severely

disabled: the median disability score on the Expanded Disability

Status Scale (EDSS) was high, 6.5 (i.e., need of bilateral

assistance to walk about 20 m), ranging from 4.5 (ability to walk

without assistance for some 300 m) to 8.5 (restriction to bed). All

patients had failed a variety of therapies and had evidence of

clinical disease progression during the 12 months preceding

enrollment; 33% of them had also evidence of active lesions in MRI,

i.e., they had gadolinium enhancing (Gd+), enlarging, or new,

lesions on serial scans. High-dose conditioning included mostly the

BEAM regimen (BCNU-etoposide-cytarabin-melphalan; 54/85; 63%), CY-

based regimens (12%), total body irradiation (TBI) at 1000 cGy plus

CY at 120 mg/kg b.wt. (6%; 5/85), busulfan-based regimens (18%), and

fludarabine plus antithymocyte globulin (ATG) (1%). ATG was given to

66 patients (78%) in the peri-transplant period to deplete T cells

in vivo. Six patients received bone marrow grafts (7%); the majority

(93%) received peripheral blood stem cells mobilized with CY at 2–4

g/m2 plus G-CSF. Ex vivo graft manipulation (CD34+ cell-selection, T

cell-depletion, etc.) was performed in 60% of the cases. The only

remarkable toxicity during mobilization was transient neurological

worsening in 3 patients (4%), ascribed to G-CSF, which is now known

to cause MS flares.[58 and 59] A degree of neurological

deterioration occurred also in the early post-transplant period in

22 patients (27%) owing, possibly, to fever and infection or to G-

CSF. It was transient in all but six patients (7%) who continued to

deteriorate, and two of them died 3 months after ASCT from disease

progression. These were severely disabled patients with EDSS scores

of 7.5 (restriction to wheelchair) before transplantation, and it

cannot be excluded that ASCT might have accelerated the progression.

In relation to medical toxicities, infections were common, as during

ASCT for lymphomas or solid tumors. There were five toxic deaths

(6%): four patients died from infection and one from cardiac

failure. Older age, (above 40 or 45), high EDSS scores (above 6),

and intense lymphocyte depletion (CD34+ selection plus ATG) seemed

to be high-risk factors in theses cases.

The median follow-up time was relatively short for a chronic disease

like MS, 16 months (3–59 m). The patients had regular neurological

assessments at the treating centers, who reported the EDSS scores

and MRI results to the registry, where the progression of the

disease (of disability) was evaluated in every case by comparing the

last EDSS score (confirmed with two assessments in a 6 months'

interval) to the score at enrollment. According to standard

definitions of progession, stabilization, or improvement,[57] the

probability of confirmed progression-free survival (including the

seven deaths) was 74% at three years, being higher for SP-MS (78%)

and for patients below 40 years of age (89%), but lower in PP-MS

(66%) and in patients over 40 years (58%). In addition, fewer

patients had MRI activity after ASCT (at different time points): 8%

compared to 33% before ASCT. There were no significant differences

in outcome with respect to conditioning regimen, ex vivo lymphocyte

purging, or duration of disease before ASCT. Median CD4+ cell count

fell dramatically and remained below normal level for more than two

years, but no serious late events developed. Median EDSS score

dropped (improved) from 6.5 before ASCT to 6 at two years after

ASCT. Eighteen patients (21%) improved clinically by more than one

EDSS step, four of which had already improved after CY given for

mobilization.. These significant improvements, which reflected the

repression of inflammation in the CNS, were stable in 12 patients,

six patients progressed later, but only one of these worsened beyond

baseline (enrollment) measurement.

The clinical outcome in the EBMT study appears very encouraging and

superior to the results obtained by IFN-[10 and 12] or placebo. [60]

ASCT seems to stabilize progressive MS, although associated with a

significant, for a non-malignant disease, risk of toxic death.

However, this multicenter, retrospective, observational study (with

obvious methodological weaknesses) was mainly aimed at making

available a large amount of world data concerning feasibility and

safety. The information of this combined experience could further be

utilized in planning comparative trials, enrolling patients selected

for high chance of response and minimal treatment-related risk.

Other studies

Seven individual studies from different centers have come out in the

literature since 1997 (Table 1). A number of the patients described

in these were also included in the EBMT retrospective analysis.

However, the individual studies will be reviewed below because the

number and follow-up of patients have increased in the meantime, and

the results have been updated contributing important information.

Table 1. Published phase I-II studies of ASCT for MS

Thessaloniki study.[35, 38 and 61] Our study has included 35

patients: 19 with SP-MS, 14 with PP-MS, and two with rapidly

progressive RR-MS. Median EDSS score was 6 (unilateral assistance

needed to walk about 100 m) (range, 4.5–8). Twenty-five patients

were conditioned with BEAM and 10 with busulfan (BU) at 16 mg/kg

b.wt. For T cell-depletion, ATG was given to all patients and graft

CD34+ cell-selection was performed in 10 cases. One patient died

(3%) of invasive aspergillosis. Median follow-up is 34 months

(range, 2–66). There were two late effects: one patient developed

autoimmune thyroiditis 11 months post ASCT and one patient, who was

also receiving IFN-, developed a refractory factor VIII-inhibitor

that caused episodes of massive hemorrhage resulting in his death,

28 months after ASCT. Considering also the two deaths, confirmed

progression-free survival was 81% and 67% for patients with SP-MS

(plus RR-MS) and PP-MS, respectively, at three and at five years

(Fig. 1). Furthermore, ASCT resulted in a profound and long-lasting

suppression of pathological MRI activity: only 25 Gd+ lesions (in

five patients) were detected in 197 MRI scans performed after ASCT,

compared to 87 Gd+ lesions (in 11 patients) found in 40 scans pre-

transplant.[61] Despite this impressive anti-inflammatory effect,

atrophy indices (corpus callosum area, third and lateral ventricle

width) continued to deteriorate at 12 and 24 months post-transplant,

indicating that ASCT did not affect the pathophysiological

mechanisms underlying brain atrophy in the patients.

(4K)

Fig. 1. Confirmed progression-free survival of 35 MS patients by

disease-type.

The Greek study showed a possible benefit for patients with SP- and

RR-MS and also an associated mortality risk. Interestingly, two of

the patients developed other autoimmune disorders after transplant:

autoimmune thyroiditis and factor VIII-inhibitor. The development of

autoimmune events after transplantation is well-known. Antibody-

mediated thyroid disease may also develop after IFN-[62] or Campath-

1H [63] therapy, possibly because of imbalances between lymphocyte

subsets. Interferon- has been implicated in the development of

factor VIII-inhibitor in a patient auto-grafted for multiple myeloma,

[64] while factor VIII-inhibitor has also been reported in

association with MS. [65] It is possible that not only ASCT, but

also IFN-, was the cause of this coagulation disorder in our patient.

Italian study.[42 and 66] This is a cooperative study of the Italian

BMT group and a group of Neurology centers coordinated by G.

Mancardi. The main objective was to study the disease activity in

MRI after ASCT, only in patients with SP-MS treated in the same way

as in the Thessaloniki study ( Table 1). No patient died as a result

of protocol therapy. Patients were followed for a median of 18

months (range, 2–42). Marked, impressive, reduction in the number of

Gd+ lesions was observed after CY-mobilization and ASCT, dropping to

zero in all patients from 341 detected before mobilization. No new

(active) lesions developed. However, brain atrophy was still ongoing

at 1 year, although at slower pace after the 6th month. Oligoclonal

bands could still be detected at two years post transplant. [66]

The groups of Prague[39 and 67] and Hospital Clinic Barcelona[41 and

43] had similar results in patients with active, deteriorating, MS (

Table 1). Kozak and Havrdova have treated 15 patients with SP-MS,

and EDSS scores ranging from 6 to 7.5, using BEAM for conditioning

and ATG for in vivo T cell-depletion. Blood stem cell grafts were

manipulated ex vivo in 9 cases by CD34+ cell-selection plus

antiCD2/3 monoclonals. Toxicity was mild with no transplant-related

mortality. At 20-months' median follow-up (range, 4–38), eleven

patients were stable or improved and four had progressed. One of

these died of disease progression three years after transplant. [39

and 67] Carreras, Saiz, and Graus have treated nine patients with SP-

MS and six patients with RR-MS, having a median of three relapses

(range, 1–7) in the year preceding ASCT. EDSS scores ranged from 4.5

to 6.5 (median, 6). The patients were conditioned with a combination

of BCNU, high-dose CY and ATG, and received CD34+ cell-selected

blood stem cell autografts. There was no mortality. At one year post

ASCT, 12 of 15 patients were stable or improved, three had worsened,

and only two of 15 patients had experienced a decreased number of

relapses. [43] Saiz has also reported on the MRI results of the

first five patients of this series: after ASCT, lesional load

decreased, no enhanced or new lesions were detected, but atrophy of

the corpus callosum continued during the first year and oligoclonal

bands were still present. [41]

North American studies were initiated in 1996. Burt et al. have

reported on a study developed jointly at Northwestern Medical

Center, Chicago and Medical College of Wisconsin, Milwaukee.[36, 37

and 68] Twenty-seven patients were treated with CY (120 mg/kg b.wt.)

and TBI (1200 cGy), and received CD34+ cell-selected blood

autografts. There was no mortality or serious complications. With a

median follow-up of 2 years (range, 1 month–5 years), ASCT appeared

to have reduced clinical relapse frequency and CNS inflammation in

MRI. However, axonal atrophy continued, as did progression of

disability in patients with high EDSS scores.[68] At City of Hope

Medical Center,[40] five patients were treated with busulfan (16

mg/kg b.wt.), CY (120 mg/kg b.wt.), and CD34+ cell-selected blood

autografts (the cases were also included in the EBMT analysis). This

is the only study reporting on histopathological findings of autopsy

in a patient who died early after transplant: demyelinated plaques

were surrounded by macrophages but only rare T cells could be found.

[40] Nash et al. have reported the results of a phase I trial with

26 patients treated in seven American centers (Seattle Consortium):

they found that intense immunosuppression (TBI plus CY) with

extensive T cell-depletion (ex vivo manipulation plus ATG) carries a

important risk of inducing Ebstein–Barr virus associated

lymphoproliferative disease.[69]

Concluding remarks

The studies reviewed above are phase I–II, open trials mainly

investigating the feasibility of the method and, also, its

therapeutic potential. The results do not seem to differ between

centers: ASCT is feasible in MS and has a toxicity and mortality

similar to the observed in transplantation for lymphomas or solid

tumors; ASCT has a proven prominent, sustained, effect on MRI

disease parameters, i.e., it can significantly suppress inflammation

in the CNS. With regard to clinical efficacy, it appears to

positively affect the clinical course of the disease by delaying the

progression of disability. The issue of clinical efficacy, however,

is questionable, given the well-known difficulty in demonstrating

the efficacy of a treatment in chronic progressive MS, in which

unblinded neurological assessments can easily overestimate the

clinical benefits. Controlled trials against a standard treatment,

e.g. mitoxantrone, are needed to show a possible superior and more

durable effect of ASCT, and whether this effect counterbalances the

associated mortality risk. Additional single-arm studies can achieve

very little and any improper use of ASCT should be discouraged.

Therefore, the ADWP of the EBMT is about to launch a prospective,

randomized trial named ASTIMS (Autologous Stem Cell Transplantation

International Multiple Sclerosis Trial) comparing the sequence CY-

BEAM-ATG with mitoxantrone in patients with poor-risk RR-MS or SP-

MS. It will be a large study of more than 200 patients and will take

at least five years to be completed.

The transplant-related mortality has caused much discussion and

concern over the ethics of a trial randomizing patients into an arm

of about 5% mortality risk compared to 0% mortality in the control

arm of conventional treatment. However, with proper patient

selection, the transplant-related toxicity is possible to be

lowered. Morbidity and mortality seem to be more frequent with

extensive T depletion, old age, and severe disability (high EDSS

scores). Also, strong conditioning regimens (TBI, BUCY) are

associated with higher mortality risk than intermediate (BEAM) or

low (CY) intensity regimens (ADWP registry data). It is of interest

that, according to the Milan Consensus on patient inclusion criteria,

[70] three of the seven deceased patients in the EBMT study should

not have been treated with ASCT. Furthermore, mitoxantrone, which is

currently considered the best available treatment for the same

indications, is not devoid of toxicity [71 and 72] and can be used

only once in life-time, because of the cardiotoxicity. In addition,

the duration of the effect after discontinuation of the drug is

unknown. On the other hand, the apparently superior effect of ASCT

on MRI parameters seems to justify its comparison to mitoxantrone,

provided the transplant mortality does not exceed an acceptable

level during the course of the study.

Recent developments in understanding MS have stressed that

progression of disability does not depend only on inflammation but

also on axon degeneration, especially at higher EDSS levels.[4, 5

and 6] Therefore, the anti-inflammatory effect of immunosuppressive

therapies may not benefit patients whose clinical progression

evolves in the absence of an inflammatory process in the CNS.

Consequently, brain atrophy will continue in such cases despite

suppression of inflammation. As described in the above-mentioned

studies, brain atrophy seemed to continue also after ASCT, either

because the patients were treated at a late stage or because of the,

noninflammatory, neurodegenerating, immunopathological subtype of

their disease. It is, therefore, important to use ASCT early in the

course of MS, in patients at lower EDSS levels, at which the

inflammatory component is most active.

In conclusion, ASCT yields promising results in certain patients

with MS, which may appear better that those obtained with other

available treatments, at an associated small mortality risk. Only

comparative trials, however, with long follow-up, will define its

role in the management of MS.

Practice points

• ASCT is an investigational treatment for MS. About 200 patients

have been treated so far worldwide.

• ASCT seems to be the best anti-inflammatory treatment as evidenced

in MRI scans. Its clinical value remains to be validated in

controlled trials.

• MS types characterized by neurodegenerative pathogenic components

are unlikely to benefit from ASCT: PP-MS; long-standing disease;

high EDSS scores.

• Good candidates are young patients with rapidly evolving RR-MS

or " malignant " MS. Also, patients with SP-MS having EDSS scores

below 6.5, evidence of inflammation in the CNS, and clinical

worsening during the last year.

• Intense conditioning or extensive T depletion increase the

morbidity and mortality risk.