Stem cell transplants may be alternative for TNF-inhibitor-resistant severe RA

[Guest guest]

Rheumawire

Mar 26, 2004

Stem cell transplants may be alternative for TNF-inhibitor-resistant

severe RA

Basel, Switzerland - Autologous hemopoietic stem-cell transplantation

(HSCT) can produce notable responses in patients with

treatment-resistant RA, is relatively safe, and may help restore

sensitivity to disease-modifying antirheumatic drugs (DMARDs), Dr

Snowden and colleagues report in the March 2004 issue of the Journal of

Rheumatology [1].

" At this point, our opinion and the opinion of the European League

Against Rheumatism (EULAR)/European Group for Blood and Marrow

Transplantation (EBMT) working party for HSCT in RA is that autologous

HSCT should be considered only for patients who have failed both

conventional DMARDs and TNF antagonists, " coauthor Dr J Bingham

(University of Leeds, UK) tells rheumawire. Bingham is study coordinator

for an ongoing randomized clinical study that will test autologous HSCT

in RA patients whose disease is insufficiently controlled despite trials

of 4 or more DMARDs, including a TNF inhibitor.

The Snowden group used data from the EBMT Autoimmune Disease Database

and the Autologous Bone and Marrow Transplant Registry (ABMTR) to

analyze worldwide experience with autologous HSCT for treatment of

severe RA. They conclude that such transplants are relatively safe and

that they produce significant responses in more than 50% of patients.

They found that most patients who had responses required DMARDs again

within 6 months but often had better responses to DMARDs than before

transplant, suggesting that the transplants might have an effect of

" debulking of inflammation " or " resetting of the immune system. "

It is important to recognize that only 4 of the 73 patients in this

study had been treated with TNF inhibitors, since the data covered

patients entered into the registries during the period 1996 to 2000.

" Clearly, given its potential morbidity and mortality, autologous HSCT

can now be considered only within the estimated 25% of patients who fail

TNF antagonists as well as conventional DMARDs, " the authors write.

Seventy-six patients were registered from 15 centers, but in 3

hematopoietic stem cells were mobilized but not transplanted, so they

were not included in the analysis. Median age of transplanted patients

was 42 years, 74% were female, and 86% were rheumatoid factor (RF)

positive. Patients had previously been treated with a mean of 5 DMARDs

(range 2-9). Median Health Assessment Questionnaire (HAQ) score was 1.4,

and Steinbrocker score mean was 2.39.

Patients underwent high-dose cytotoxic therapy followed by autologous

HSCT. The cytotoxic regimen was cyclophosphamide alone (typically 200

mg/kg) in 62/73 patients. Seven patients received antithymocyte globulin

(ATG) in addition to cyclophosphamide. Two received busulfan plus

cyclophosphamide, and 1 received total-body irradiation in addition to

ATG and cyclophosphamide. One received fludarabine with ATG.

Peripheral blood stem cells were mobilized using granulocyte

colony-stimulating factor (G-CSF) and/or chemotherapy. Some form of

lymphocyte depletion of the harvested cells was used in 45 patients,

mostly through CD34+ selection. Median follow-up was 16 months.

Responses were judged according to American College of Rheumatology

(ACR) criteria, tender joint count, and HAQ score.

The investigators found that at each assessment (6, 12, and 18 months),

substantial numbers of transplanted patients achieved ACR responses of

60, 70, or 100 and that in many cases these were sustained for 18

months. This included ACR50 or better in 49 patients (67%) at some

point. Best responses were complete remission in 3 patients, ACR70 in 33

patients, ACR50 in 13 patients, and ACR20 in 12 patients. These

responses were accompanied by improvements in tender joint counts and in

HAQ scores.

They note, " At 6 months posttransplant, slightly more than half of the

evaluable patients with an ACR response of 50 or more had not restarted

DMARDs. " At 12 months, half of the patients who had achieved ACR70

maintained their improvement and had not restarted DMARD treatment.

Fifty-eight of 63 evaluable patients (92%) had recurrence of disease

activity at some point after transplant. Limited data were available for

patients who restarted DMARDs, but the response to drug treatment was

described as better than before transplant in 21 of 43 patients (49%).

The investigators suggest that this might indicate a need for

posttransplant maintenance therapy with DMARDs.

There was a single death from sepsis posttransplant but none in patients

treated with high-dose cyclophosphamide with or without ATG or with

total-body irradiation. The researchers conclude that cyclophosphamide

200 mg/kg is a safe regimen for use in this setting in future studies.

Results of the registry review support further clinical trials of

autologous HSCT in RA, and 1 such trial, the Autologous Stem Cell

Transplantation International Rheumatoid Arthritis (ASTIRA) trial,

opened in early 2002. This study is enrolling RA patients who have

failed at least 4 DMARDs, including methotrexate and anti-TNF- programs

and have disease duration between 2 and 15 years. " Recruitment has been

disappointing, as TNF blockers became more widely available at the same

time as the study was launched. However, this is still good news for

patients, who now have further treatment options, " Bingham says.

All ASTIRA patients receive stem-cell mobilization with cyclophosphamide

and G-CSF. They are then randomized either to continued conventional

therapy (methotrexate or leflunomide) or to conditioning with

cyclophosphamide 200 mg/m2 and ATG and autologous HSCT. Maintenance with

methotrexate or leflunomide is given after transplant. The primary end

point is 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.

Janis

Source

1. 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):482-8.

I'll tell you where to go!

Mayo Clinic in Rochester

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