RESEARCH - Stem-cell transplants enter phase 3 trial in systemic sclerosis

[Guest guest]

Stem-cell transplants enter phase 3 trial in systemic sclerosis

Rheumawire

Sep 2, 2004

Janis

Paris, France - Autologous hematopoietic stem-cell transplantation

(HSCT) produced durable responses with acceptable transplant-related

mortality in two thirds of patients with severe systemic sclerosis (SSc)

recorded in an international registry of such cases and has moved

forward to a randomized phase 3 trial comparing HSCT with monthly

cyclophosphamide, French researchers report in the August 2004 issue of

the ls of the Rheumatic Diseases [1].

Dr Dominique Farge (Hôpital Saint-Louis, Paris, France) and colleagues

reported data from the registry maintained by the European Group for

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

Rheumatism (EULAR). " This study demonstrates long-term efficacy and

improved safety of autologous HSCT in patients with severe SSc. HSCT had

a marked and lasting impact on skin involvement, allowing a significant

fall in skin score >25% of initial values in 79% of the 19 patients with

data available at 2 years after the procedure. To our knowledge, this

result has never been previously reported in such severe forms of the

disease, with any other treatment, " the investigators conclude.

This study was done to assess the durability of responses after HSCT for

patients with SSc. This report included follow-up on patients with SSc

treated by HSCT in European phase 1/2 studies between 1996 and 2002.

Early data from the use of HSCT in patients with systemic sclerosis had

shown " striking improvement in the skin score . . . with a trend toward

stabilization of lung disease, " Farge et al write. The next questions

were whether these responses were durable and at what cost in

transplant-related mortality.

European clinicians considered patients eligible for HSCT if they had

early, rapidly progressive diffuse SSc developing over the previous 3

years despite continuous treatment and in the absence of end-stage organ

failure or if they had limited SSc with life-threatening pulmonary

fibrosis or pulmonary hypertension.

This report included follow-up data on 57 (47 female, 10 male) such

patients treated with HSCT, median age 40 years (range 9.1-68.7 years).

Of the patients, 50 had diffuse disease, 4 had limited disease, and 3

had unspecified disease patterns. Median disease duration was 36 months

(range 2.2-159.4 months).

At a median follow-up of 20 months (range 0.3-81.1 months), 45 of 57

patients were alive, with a projected 5-year survival of 72%.

Transplant-related mortality was 8.7%, and mortality related to disease

progression was 14%.

Skin scores were evaluated in 47 patients at inclusion and in serial

measurements after HSCT. Farge reported that a significant fall in skin

score (defined as a decrease of at least 25% from baseline values) was

lower in 26/37 patients at 6 months and remained lower in 20/30 patients

at 12 months, in 15/19 patients at 24 months, and in 6/10 patients at 36

months of follow-up (p<0.005).

" Overall, among the 50 patients with at least 6 months of follow-up, a

partial (n=32) or a complete response (n=44) was seen in 92% of the

cases, and nonresponse was observed in 8% (n=4) within 22.9 months after

autologous HSCT. Longer follow-up showed that 35% of the initial

patients with partial (n=13/32) or complete response (n=3/14) eventually

relapsed within 9 months (range 2.2-48.7) after HSCT. . . . The

cumulative probability of disease progression at 5 years, calculated

according to the Kaplan-Meier method, was 48%, " the investigators write.

Outcomes were particularly notable in the 5 children included in this

database. All had lung disease at inclusion. All received stem

mobilization with cyclophosphamide and granulocyte colony-stimulating

factor (G-CSF), and 3 had cell selection before transplantation with

either CD34+ selection alone or CD34+/4+/8+. At a median 37.5 months of

follow-up, all 5 children were alive: 4 had complete remission, 1 had a

partial remission, and there was 1 relapse at 9.2 months after a

complete remission.

The experience in these phase 1 and phase 2 studies is being expanded

under the auspices of the EULAR and EBMT in an ongoing phase 3

prospective randomized controlled study, the Autologous Stem Cell

Transplantation International Scleroderma (ASTIS) trial. The

investigational treatment arm includes the following consecutive steps:

mobilization of hematopoietic stem cells with IV cyclophosphamide (2x2

g/m2) and filgrastim (10 mg/kg per day), leukapheresis and selection of

CD34+ stem cells, conditioning with IV cyclophosphamide (200 mg/kg) and

rabbit antithymocyte globulin (rbATG)(7.5 mg/kg), followed by HSCT. The

standard treatment arm includes 12 monthly IV pulses of cyclophosphamide

(750 mg/m2).

The ASTIS primary end point is event-free survival, defined as the time

in days from the day of randomization until death or the development of

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

period of 2 years. The investigators plan to enroll 200 patients within

3 years.

Source

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.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org