This multicenter prospective randomized controlled phase III study will compare efficacy and safety of high dose immunoablation and autologous hematopoietic stem cell transplantation (HSCT)(considered the investigational treatment), versus monthly intravenous pulse-therapy cyclophosphamide (considered the standard treatment) in patients with diffuse systemic sclerosis and heart, lung or kidney involvement. These patients are at risk for severe organ dysfunction and as a consequence premature mortality. The goal of the treatments is to prolong survival by arresting or retarding the disease process. It is postulated that the investigational treatment has superior efficacy based on observations of longterm remissions in a number of patients, although this has to be balanced against potentially higher toxicity.
The investigational treatment arm comprises the following consecutive steps: mobilization of hematopoietic stem cells with i.v. cyclophosphamide (2x2 gr/m2) and filgrastim (10 mg/kg/day), leukapheresis and selection of CD34+ stem cells, conditioning with i.v. cyclophosphamide (200 mg/kg) and rabbit antithymocyte globulin (rbATG)(7.5 mg/kg), followed by HSCT. The standard treatment arm consists of 12 monthly i.v. pulses cyclophosphamide (750 mg/m2). This treatment has been shown to stabilize pulmonary function and improve skin thickening in open studies, and is frequently employed in many institutions for this patient group (34-36).
The primary endpoint is event-free survival defined as the time in days from the day of randomization until the occurence of death or the development of persistent major organ failure (heart, lung, kidney) during the study period of 2 years. It is intended to enroll 200 patients in 3 years.
Progressive systemic sclerosis (SSc) is a heterogeneous condition characterised by the deposition of excess collagen in skin and internal organs (1). Two forms are generally recognized. Limited cutaneous and diffuse cutaneous forms of the disease are distinguishable by the extent of skin involvement, their autoantibody profile, the pattern of organ involvement, and the specific cutaneous manifestations of limited disease (formerly referred to as the CREST syndrome). Both forms of the disease are associated with vascular abnormalities clinically manifest as Raynaud’s phenomenon.
Numerous lines of evidence suggest that an inflammatory process which may be autoimmune in origin precedes the development of fibrosis. Antibodies to nuclear proteins are frequently present prior to the development of disease (2). Reactivity to the nuclear auto-antigens topoisomerase I and the centromere proteins are rarely seen other than with this disease and are associated with particular HLA-D genotypes (3). An inflammatory response with lymphocytic infiltration is evident early in the disease, and is well documented in skin (4) and lung (5-8). The similarity of the condition with aspects of graft versus host disease (GVHD) further suggests that immune allo-reactivity is capable of inducing excessive fibrosis (9,10). An increased frequency of microchimerism by haematopoietic cells derived from offspring has been reported in SSc patients (11, 12). Allogeneic cells could trigger immune responses analogous to GVHD and drive the secondary events of fibrosis. Immunological involvement in the pathogenesis of the disease is supported by the clear thymic and T cell abnormalities found prior to the development of disease in the UC Davis spontaneous chicken model of scleroderma (13-15). Despite this evidence, the relationship between autoimmune responses and the vascular pathology is unclear (16). Vascular abnormalities may be evident many years prior to the onset of disease (17). Similarly, the extent to which autoimmune responses and inflammation contribute to the maintenance of fibrosis remains unresolved. The perceived failure of immunosuppressive treatments in the reversal of established fibrosis suggests that once initiated, the fibrotic process becomes independent of the immune drive and continues as an autonomous process.
Severe forms of the disease, and rapidly progressive diffuse SSc in particular, are associated with a significant mortality (estimated to be 40-50% in 5 years) secondary to pulmonary, cardiac, and renal involvement (18-24). There exists no proven effective therapy to prevent disease progression or reverse fibrosis. Blinded randomised clinical trials of D-Penicillamine (25) and alpha-interferon (26) have been unable to demonstrate a clinically significant effect. Low dose oral methotrexate showed beneficial effects on skin thickening but not on organ dysfunction in a small placebo-controlled cross-over study (27). Cyclophosphamide has been shown to improve skin thickening, stabilize pulmonary function and increase survival in nonrandomized studies (28,29).
Autologous hemopoietic stem cell transplantation (HSCT) has been developed as a potential therapy for autoimmune disease in the light of several converging lines of evidence which have been reviewed elsewhere (30,31). First is the observation that patients with autoimmune disease who undergo allogeneic, and more recently autologous bone marrow transplant for hemopoietic or other malignancy, are frequently noted to experience a remission of their autoimmune disease. Second is the evidence from disease susceptible strains of animals that autologous hemopoietic stem cells may cure the autoimmune disease and induce tolerance to the inciting agent. Last, the perception prevails that immunosuppressive therapy acts with a clear dose response pattern. Higher dose regimens requiring some form of bone marrow rescue may therefore be superior in the treatment of some individuals with severe autoimmune disease.
Autologous haemopoietic stem cell transplantation is performed routinely today for several hemopoietic or other malignancies. It carries a substantially lower transplant related mortality (TRM) when compared to allogeneic transplantation (5% vs. >15% respectively). Relative to the mortality associated with severe forms of autoimmune disease this risk has been considered acceptable in the context of the potential benefits of long term remission or the prevention of progressive tissue damage.
In view of the poor prognosis of SSc, the presumed autoimmune origin, and the lack of available therapies, this disease was considered suitable for initial investigation of the tolerability and efficacy of autologous HSCT (32). An international collaborative committee was established in 1995 under the auspices of the European Group for Blood and Marrow Transplantation (EBMT) and the European League Against Rheumatism (EULAR), which later included other active groups in North America. Entry criteria and treatment protocols were established in a Phase I/II like study to assess feasibility, mortality and preliminary response of such an approach (33). Most groups followed a core protocol written along these guidelines (H G Prentice), which allowed some flexibility of local methodologies. The results of the first 41 patients with at least 3 months follow up have suggested a significant impact on skin score with a trend to stabilization of lung function: 69% of the patients achieved an improvement of 25% or more in skin score (submitted). With registration of 65 patients at the time of this writing the transplant related mortality was 12.3% at 1 year, and 7.7% with exclusion of patients who did not meet the consensus guidelines on patient selection; of course, it is unknown what the mortality would have been without the procedure. These data provide sufficient information to test whether indeed this novel approach will provide a survival advantage over conventional approaches in the long term.
Primary goal
To evaluate the potential clinical benefit of high dose immunoablation and autologous stem cell transplantation in comparison to intravenous pulse therapy cyclophosphamide, with respect to:
- Survival and prevention of major organ failure (referred to as ‘event-free survival’ which is considered the primary endpoint)
Safety
Impact on skin thickening, visceral involvement, functional status, and quality of life
Secondary goals
- To evaluate (in both treatment arms) whether disease activity correlates with immunological parameters, including immunopathology of skin, immune reconstitution, and autoantibodies.
- To search for predictive factors (clinical and immunological) of response.
Inclusion criteria
1. Age
between 16 and 60 years (or 65 if biological age younger).
2. Established
diagnosis of systemic sclerosis according to ACR-criteria (appendix C)
3. Diffuse
scleroderma with:
a) disease duration £ 4 years since development of first sign of skin thickening plus modified Rodnan skin score ³ 15 plus major organ involvement (with documented evidence of onset or clinically significant worsening in the previous 6 months) as defined by either:
respiratory involvement = DLCO and/or (F)VC £ 80% (of predicted) and evidence of interstitial lung disease (chest X-ray and/or HR-CT scan and/or bronchoalveolar lavage and/or biopsy of the lungs) with clinically relevant obstructive disease and emphysema excluded.
renal involvement = any of the following criteria: persistent urinalysis abnormalities (proteinuria, hematuria, casts), microangiopathic hemolytic anemia, new renal insufficiency (serum creatinine > upper limit of normal); non-scleroderma related causes (e.g. medication, infection etc.) must be reasonably excluded.
cardiac involvement = any of the following criteria: reversible congestive heart failure, atrial or ventricular rhythm disturbances such as recurrent episodes of atrial fibrillation or flutter, recurrent atrial paroxysmal tachycardia or ventricular tachycardia, 2nd or 3rd degree AV-block, pericardial effusion; non-scleroderma related causes must have been reasonably excluded by an experienced cardiologist.
b) diffuse
scleroderma with disease duration £ 2 years since development of first sign of skin thickening plus modified
Rodnan skin score ³ 20 plus involvement of trunk plus ESR > 25 mm/1st hour
and/or Hb < 11 g/dL, not explained by other causes than active
scleroderma.
4. Informed
consent
Exclusion criteria
1. Pregnancy
or unwillingness to use adequate contraception during study
2. Concomitant
severe disease =
2.1
respiratory: mean PAP
> 50 mmHg (by cardiac echo or right heart
catheterization), DLCO < 40% predicted, respiratory failure as defined by the primary
endpoint (see 7.1)
2.2
renal: creatinine
clearance < 40 ml/min (measured or estimated)
2.3
cardiac:
clinical evidence of
refractory congestive heart failure; LVEF < 45% multigated radionuclide angiography
(MUGA); chronic atrial fibrillation necessitating oral anticoagulation; uncontrolled
ventricular arrhythmia; pericardial effusion with hemodynamic consequences as evaluated by an experienced
echocardiographist
2.4 liver failure as
defined by a sustained 3-fold increase in serum transaminase or bilirubin
2.5 psychiatric disorders
including active drug or alcohol abuse
2.6 concurrent neoplasms
or myelodysplasia
2.7 bone marrow
insufficiency defined as neutropenia < 4.0 x 199/L, thrombocytopenia < 50
x
109/L, anemia < 8 gr/dL, CD4+ T lymphopenia < 200 x 106/L
2.8 uncontrolled
hypertension
2.9
uncontrolled acute or chronic infection, including HIV, HTLV-1,2 positivity
3. Previous
treatments with TLI, TBI or alkylating agents including cyclophosphamide
(> 5 g i.v. cumulative, or > 3 months oral up to 2
mg/kg b.wt)
4. Significant
exposure to bleomycin, tainted rapeseed oil, vinyl chloride, trichlorethylene or silica;
eosinophilic myalgia syndrome; eosinophilic fasciitis.
5. Poor
compliance of the patient as assessed by the referring physicians
6. Lack
of funding
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