RESEARCH - Stem-cell transplantation holds promise for autoimmunity

[Guest guest]

Rheumawire

Jan 18, 2005

Mann

Stem-cell transplantation holds promise for autoimmunity

New York, NY - Hematopoietic stem-cell transplantation is slowly but surely

becoming a viable treatment option for autoimmune disease. Worldwide, more

650 such patients have been transplanted in phase 1 and 2 clinical trials,

and phase 3 trials are now beginning in the US and Europe.

While obstacles remain, researchers are growing more and more optimistic

that they will someday have the tools in hand to reconstitute the immune

system. As it stands, the use of embryonic stem cells is restricted, but

hematopoietic stem cells are not, and as a result much progress is being

made in refining such transplantations for the treatment of systemic lupus

erythematosus (SLE), juvenile rheumatoid arthritis (JRA), systemic

sclerosis/scleroderma, rheumatoid arthritis (RA), and Crohn's disease.

" There is a very active and very aggressive search for new therapies in

rheumatology, and we are thinking about stem cells in lots of different

ways, including how to replace cartilage and the immune system and regrow

organs, " says Dr Hardin (National Institute of Arthritis and

Musculoskeletal and Skin Diseases in Bethesda, MD). " We have the advantage

that the immune system can be reconstituted with stem cells from bone

marrow, so potentially, we have a lead over the groups who are trying to

replace brain tissue and heart muscle, which is limited to embryonic stem

cells, " he tells rheumawire.

But that's not to say that other fields will not be able to piggyback on

this progress and catch up. " Within 15 to 20 years, we will be

reconstituting injured and weak organs, " Hardin predicts. " Assuming the

progress over the past 5 years can be sustained, we will have the prospects

to repair damaged hearts, treat diseases like Parkinson's, and possibly

reconstitute joints where cartilage has been lost through the aging

processand that means a lot to an 80-year-old who would like to have a

functional life for another 20 years, " he says.

" Stem-cell therapy is going to go 2 directions in arthritis, " says Arthritis

Foundation CEO Dr H Klippel. " In autoimmune diseases, we are talking

about reconstituting or replacing the immune system, so if you believe that

any autoimmune disease, including lupus, RA, scleroderma, or JRA, occurs

because of fundamental immune-system deficits, stem-cell therapy will become

increasingly important as a way to correct these deficits. "

In osteoarthritis (OA), " what will be asked of stem-cell therapy is to

reconstitute damaged tissue and cartilage, " he says. " I definitely see a day

when one knows that there is damage in the hip or knee and instead of

surgery, one begins to think about rebuilding cartilage with stem cells, " he

tells rheumawire. But questions remain, he says. For example, he offers,

" How do you get cartilage to grow to the shape that it needs to be for a

joint surface? "

For the research to meet its potential, many practical questions need to be

addressed, Hardin says. In particular, scientists must figure out ways to

use some of the conventional immunoablation drugs safely and also better

understand genetic markers to determine drug response.

" We need to learn how to perform [these transplants] safely enough so we can

offer them to patients with nonmalignant disease, because the risk/benefit

ratios are different with noncancers, " he says. Clinical trials currently

under way are addressing these issues, and below rheumawire offers a brief

review of the findings so far.

Hemopoietic stem-cell transplants (HSCT) produced durable responses with

acceptable mortality in two thirds of 57 patients with scleroderma (systemic

sclerosis), French researchers reported last year in the ls of the

Rheumatic Diseases [1]. As a result, the researchers have moved forward to a

randomized phase 3 trial comparing HSCT with monthly cyclophosphamide in

patients culled from the registry maintained by the European Group for Blood

and Marrow Transplantation (EBMT) and the European League Against Rheumatism

(EULAR).

Also in scleroderma patients, the Autologous Stem Cell Transplantation

International Scleroderma Trial (ASTIS) began in March 2001. The trial is

comparing a regimen of high-dose immunosuppression with cyclophosphamide and

the antirejection drug antithymocyte globulin (ATG) with standard

chemotherapy (pulse-therapy cyclophosphamide). As of October 18, 2004, 41

patients have been randomized. All patients were enrolled because of severe

systemic sclerosis with extensive skin thickening and involvement of heart,

lung, or kidneys. Researchers intend to enroll 200 patients in 3 years. The

primary end point is event-free survival defined as the time in days from

the day of randomization until the occurrence of death or the development of

persistent major organ failure (heart, lung, kidney) during the study period

of 2 years.

" I think that ASTIS will be the first randomized controlled trial to

establish the place of HSCT in the treatment of systemic sclerosis, [and]

the NIH is planning a similar study, " Dr Alan Tyndall (University of Basel,

Switzerland) tells rheumawire. He points out: " In scleroderma, however,

there are no other treatment options, and severe forms of this disease are

fatal. " With other diseases such as RA, the risk/benefit ratio is far more

complicated, he says.

Autologous HSCT has been used experimentally to treat severe RA since 1996.

In the March 2004 issue of the Journal of Rheumatology [2], Dr Snowden

(University of Basel) and colleagues reported that autologous HSCT might be

a safe salvage treatment among patients with treatment-resistant RA. In

addition, the group notes that this treatment is relatively safe and may

help restore sensitivity to disease-modifying antirheumatic drugs (DMARDs).

To that end, the Autologous Stem Cell Transplantation International

Rheumatoid Arthritis (ASTIRA) trial, which opened in early 2002, is

enrolling RA patients who have failed at least 4 DMARDs and who have had RA

for 2 to 15 years. All ASTIRA patients receive stem-cell mobilization with

cyclophosphamide and granulocyte-colony stimulating factor (G-CSF). They

will then be randomized to HSCT (Cy 200 mg/kg) or continued best available

treatment of methotrexate (MTX) or leflunomide (Arava, Aventis). The primary

end point will be the number of patients reaching a good or moderate EULAR

response or an ACR20 at 6 months. The protocol calls for 16 patients in each

arm and is powered to detect a 50% or greater difference in outcomes in the

2 groups.

Tyndall is less optimistic about this trial, commenting to rheumawire that

he believes that " ASTIRA will not proceed due to the availability of

alternative therapies in RA. " The future of the ASTIRA trial will be

discussed at the EBMT meeting in March.

As these treatments become more widely studied, transplant-related morbidity

and mortality has, of course, been observed. This is primarily due to

complications related to either the stage of the disease at transplant or

infections. Although the number of deaths related to cardiotoxicity is low,

caution is required when cyclophosphamide is used in patients with possible

underlying heart damage, including those with systemic sclerosis,

researchers report in a recent consensus statement on the issue [3].

A National Institutes of Health (NIH) pilot study is currently actively

recruiting 14 severe SLE patients to undergo autologous HSCT. The new study

will be evaluating high doses of cyclophosphamide (Cytoxan, Bristol-Myers

Squibb) in combination with fludarabine (Fludara, Schering AG) and rituximab

(Rituxan, Genentech/IDEC) to see whether it induces a longer-term remission

without additive toxicity, compared with other regimens that have been

studied, says lead researcher Dr Pavletic (National Cancer Institute

[NCI], Bethesda, MD). Initial treatment requires several outpatient visits

followed by a 3-week hospital stay.

" We expect realistically that within a year or 2, we will have completed

enrollment, " he says. " If this study turns out to be successful to the level

that we would like it to be and safe to the level that we would like it to

be, the ultimate goal is to open the doors to patients at the earliest stage

of disease, " he tells rheumawire.

" Ultimately we are hoping that allogenic transplantsas have been done in

other diseases and in which safety is getting betterwill also be an option

in SLE, " he says.

The very idea of transplanting autoimmune patients came about rather

serendipitously. " There are case reports of patients that receive allogenic

transplants who have RA, lupus, or scleroderma and their autoimmune disease

is cured, " Hardin says. " These patients happened to have other diseases as

well as the autoimmune condition. "

In the June 2004 issue of Best Practice & Research Clinical Haematology [4],

Dr Alberto M Marmont (S o's Hospital, Largo nna Benzi Genoa,

Italy) writes that while both allogenic and autologous transplants have been

performed, there is considerably more information on autologous transplants

for primary autoimmune diseases.

On the other hand, he points out, allogenic stem-cell transplantation for

very severe autoimmune diseases is being cautiously explored in current

protocols. Allogenic transplants in coincidental disease have also suggested

a graft-vs-autoimmunity effect, which may become relevant in conjunction

with nonmyeloablative, less toxic condition regimens.

Crohn's disease is another area where stem-cell transplantation is being

contemplated. The Autologous Stem Cell Transplantation International Crohn's

Syndrome (ASTICS) trial is in its final organization stage. In this trial,

patients will be randomized to either transplantation (mobilization with

cyclophosphamide and conditioning with ATG) or to best available treatment.

" The protocol is agreed on, and we are awaiting results of the funding

application, " Dr Hawkey (University Hospital, Nottingham, UK) tells

rheumawire.

" We are reserving [entry] for the most resistant cases, " he says. While

there are some case reports of benefit in Crohn's, there has been no

controlled trialuntil now. " It may well be the process of mobilizing stem

cells that is beneficial rather than transplantation, " Hawkey says. " We need

to find out. "

Autologous HSCT was first performed on a 6-year-old girl with JRA in March

1997. Since then, researchers have continued to study the procedure in

patients with JRA who are refractory to conventional treatment. Japanese

researchers evaluated the safety and efficacy of autologous CD34+ stem-cell

transplantation in 3 patients with severe, systemic JRA refractory to

conventional therapy [5]. In the study, 2 patients eventually achieved

complete remission of disease and 1 experienced a flare-up in disease with

swelling of and pain in the knee joint that could not be controlled. A

multicenter pilot center in the US is currently recruiting 20 children with

refractory autoimmune disorders, including JRA. Its aim is to determine the

safety and long-term complications of total body irradiation in combination

with cyclophosphamide, ATG, and autologous CD34-selected peripheral blood

stem-cell (PBSC) transplantation.

As practical matters get settled in the lab with available and acceptable

cell lines, a recent vote in California may help move the cause forward in

the political arena. During the US elections in November, the state of

California voted " yes " on stem-cell research by voting for Proposition 71,

which provides $3 billion in state funding over next decade for human

embryonic stem-cell experiments. The passage of the measure is designed to

get around the Bush administration's restrictions on the funding of such

research.

As it stands, US federal funding is currently limited to adult stem cells

and a few lines of embryonic stem cells, which many scientists say are of

poor quality and as a result are unfit for research.

Similar to the miners' migration to California during the 1849 Gold Rush,

many are predicting that the best and the brightest scientists will soon be

heading to the Golden State so that they can be on the front lines when

diseases such as Parkinson's and spinal-cord injuries are cured. " The top

scientists will probably move to California, and I think it's a big

concern, " Hardin says. " That's where industry will go as well, " he says.

But scientists should not buy those plane tickets yet. Acting New Jersey Gov

J Codey recently vowed to spend more money on stem-cell research. In

his first State of the State speech, he proposed $150 million for the

construction of the New Jersey Stem Cell Institute. He said he plans to ask

voters to approve an additional $230 million to nurture research in the new

technology.

Sources

Farge D, Passweg J, van Laar JM, et al. Autologous stem

cell transplantation in the treatment of systemic sclerosis: report from the

EBMTEULAR Registry. Ann Rheum Dis 2004; 63:974-981.

Snowden JA, Passweg J, JJ, et al. Autologous

hemopoietic stem cell transplantation in severe rheumatoid arthritis: a

report from the EBMT and ABMTR. J Rheumatol 2004 Mar; 31(3): 482-488.

Saccardi R, Tyndall A, Coghlan G, et al. Consensus

statement concerning cardiotoxicity occurring during haematopoietic stem

cell transplantation in the treatment of autoimmune diseases, with special

reference to systemic sclerosis and multiple sclerosis. Bone Marrow

Transplant 2004; 34(10):877-881.

Marmont AM. Stem cell transplantation for autoimmune

disorders. Coincidental autoimmune disease in patients transplanted for

conventional indications. Best Pract Res Clin Haematol 2004; 17(2):223-232.

Kishimoto T, Hamazaki T, Yasui M, et al. Autologous

hematopoietic stem cell transplantation for 3 patients with severe juvenile

rheumatoid arthritis. Int J Hematol 2003; 78(5):453-456.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org