Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years�� experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases

Background

Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors.

Design and Methods

In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996–2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days.

Results

Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant-related mortality was associated with the transplant centers’ experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival.

Conclusions

This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers’ experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases.     

Crohn's disease complicated by relapsed extranodal Hodgkin's lymphoma: prolonged complete remission after unmanipulated PBPC autotransplant

Crohn's disease and ulcerative colitis are inflammatory bowel diseases (IBD), which are thought to result from an inappropriate immunologic (autoimmune) response to luminal antibodies. Allogeneic stem cell transplantation (SCT) performed for coincidental diseases is able to cure both leukaemia and Crohn's disease. Autologous SCT is currently performed worldwide for severe autoimmune diseases (SADs) because of its reduced transplant-related mortality (TRM). We report the case of a 30-year-old male patient with a 10-year history of severe Crohn's disease, who developed Hodgkin's disease and received an unmanipulated peripheral blood autologous transplant. Three years after the transplant the patient is in complete treatment-free remission of both diseases.     

Stem cell transplantation for autoimmune disorders. Coincidental autoimmune disease in patients transplanted for conventional indications

The practice of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy originated from two landmark discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. The latter include patients with an often long-standing autoimmune disease who have developed a haematological condition (aplasia, leukaemia, lymphoma) requiring stem cell transplantation (from marrow as well as from blood). Allogeneic and autologous transplants have been performed. The initial information deriving from both procedures is their feasibility, even more convincing since the patients were affected by two simultaneous severe diseases. The information derived from autologous transplants has, however, now been superseded by the considerable and increasing number of those transplants performed for primary autoimmune diseases. On the other hand, allogeneic stem cell transplantation for very severe autoimmune diseases is being cautiously explored in current protocols. Allogeneic transplants in coincidental disease have also suggested a graft-versus-autoimmunity effect, which may become relevant in conjunction with non-myeloablative, less toxic condition regimens.     

Haematopoietic stem cell transplantation in the treatment of autoimmune diseases

PURPOSE: During the past ten years, more than 1000 patients suffering from severe autoimmune disease have received an autologous haematopoietic stem cell transplant. These new therapeutic have been used in systemic sclerosis (scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis and systemic lupus erythematosus. CURRENT KNOWLEDGE AND KEY POINTS: Autologous haematopoietic stem cell transplantation has become a curative option for condition with very poor prognosis as severe systemic sclerosis, lupus erythematosus or other systemic diseases. This review summarizes the current experience in the phase I and II clinical trials in Europe and North America. We describe the main results and the limits of stem cell transplantation in systemic diseases. FUTURE PROSPECTS AND PROJECTS: Autologous haematopoietic stem cell transplant in the treatment of autoimmune disease has evolved from a experimental concept to a clinically feasible and powerful therapy for selected patients with severe disease.     

Hematopoietic stem cell transplantation for the treatment of autoimmune diseases

Systemic autoimmune diseases that are resistant to conventional treatment cause considerable morbidity and mortality. Although aggressive new approaches to treating autoimmune diseases have been developed over the past decade, there are still patients with a severe, progressive, and life-threatening course. Based on animal studies and experience in the treatment of hematological disorders with preexisting autoimmune disease, hematopoietic stem cell transplantation has been proposed for the treatment of severe autoimmune diseases. Immunoablation and subsequent autologous peripheral blood stem cell transplantation using CD34⁺ hematopoietic cells with T cell depletion have been used for selected severe autoimmune diseases at many institutes in Australia, Europe, and the United States. However, it is necessary to assess the efficacy and safety of this therapy compared with conventional and other newly emerging therapies.     

Haemopoietic stem cell transplantation in autoimmune diseases: a European perspective

The potential of haemopoietic stem cell transplantation (HSCT) for the treatment of autoimmune and inflammatory diseases was originally supported by almost three decades of animal experiments and by the serendipitous remissions of autoimmune disease observed in patients undergoing transplantation for haematological disorders. Improved safety of both autologous and allogeneic HSCT over the last decade has been followed by increasing acceptance of HSCT as an experimental treatment for severe autoimmune diseases that are resistant to conventional treatment. International databases have collated over 700 procedures performed specifically for a variety of autoimmune diseases. Phase III clinical trials are in progress for some diseases. This review provides a comprehensive update on the efficacy and toxicity of HSCT in severe autoimmune disease. Future directions in the context of other evolving therapies are discussed.     

A pilot randomized trial comparing CD34-selected versus unmanipulated hemopoietic stem cell transplantation for severe,refractory rheumatoid arthritis

OBJECTIVE: Evidence from animal studies, case reports, and phase I studies suggests that hemopoietic stem cell transplantation (HSCT) can be effective in the treatment of rheumatoid arthritis (RA). It is unclear, however, if depletion of T cells in the stem cell product infused after high-dose chemotherapy is beneficial in prolonging responses by reducing the number of infused autoreactive T cells. This pilot multicenter, randomized trial was undertaken to obtain feasibility data on whether CD34 selection (as a form of T cell depletion) of an autologous stem cell graft is of benefit in the HSCT procedure in patients with severe, refractory RA. METHODS: Thirty-three patients with severe RA who had been treated unsuccessfully with methotrexate and at least 1 other disease-modifying agent were enrolled in the trial. The patients received high-dose immunosuppressive treatment with 200 mg/kg cyclophosphamide followed by an infusion of autologous stem cells that were CD34 selected or unmanipulated. Safety, efficacy (based on American College of Rheumatology [ACR] response criteria), and time to recurrence of disease were assessed on a monthly basis for up to 12 months. RESULTS: All patients were living at the end of the study, with no major unexpected toxicities. Overall, on an intent-to-treat basis, ACR 20% response (ACR20) was achieved in 70% of the patients. An ACR70 response was attained in 27.7% of the 18 patients who had received CD34-selected cells and 53.3% of the 15 who had received unmanipulated cells (P = 0.20). The median time to disease recurrence was 147 days in the CD34-selected cell group and 201 days in the unmanipulated cell group (P = 0.28). There was no relationship between CD4 lymphopenia and response, but 72% of rheumatoid factor (RF)-positive patients had an increase in RF titer prior to recurrence of disease. CONCLUSION: HSCT can be performed safely in patients with RA, and initial results indicate significant responses in patients with severe, treatment-resistant disease. Similar outcomes were observed in patients undergoing HSCT with unmanipulated cells and those receiving CD34-selected cells. Larger studies are needed to confirm these findings.     

Long-term endoscopic remission of crohn disease after autologous stem cell transplantation for acute myeloid leukaemia

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation. and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.     

Long-term Endoscopic Remission of Crohn Disease after Autologous Stem Cell Transplantation for Acute Myeloid Leukaemia

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation, and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.     

Immunoablation or otherwise followed by hematopoietic cell stem as intensive treatment of severe autoimmune diseases

The treatment of severe autoimmune diseases has been recently revitalized by the increasing utilization of clinical interventions aimed at ablating/abrogating autoimmune lymphoid clones followed (but not in certain procedures) by transplantation of allogeneic, but also autologous, hematopoietic stem cells. Two different investigative avenues have paved the way to specific clinical studies. The first originates from the epochal murine experiments of the '70s, and has been greatly expanded in the last decade. A graft-versus-autoimmunity effect could also be demonstrated. In addition, it could also be shown that induced experimental autoimmune diseases such as adjuvant arthritis and autoimmune encephalomyelitis could, surprisingly, be cured following autologous transplantation. The first results in humans were observational and derived from studies including patients with coincidental diseases (severe autoimmune diseases plus leukemia/aplasia) treated with allogeneic hematopoietic stem cell transplants. Although the concept of an allogeneic transplant is indisputably more appealing, very few patients with an isolated severe autoimmune disease have been treated using such a therapeutic approach. Reduced intensity conditioned transplants relying on subsequent graft-versus-autoimmunity effects strengthened by donor lymphocyte infusions are being explored cautiously. On the other hand, autologous transplants are being performed quite extensively. To date, transplanted severe autoimmune diseases include multiple sclerosis, connective tissue diseases (systemic sclerosis, systemic lupus erythematosus, rheumatoid arthritis) and many others. It is uncertain if the main mechanism is solely immunoablative, or whether tolerized lymphocytes may also develop during a postulated "window of opportunity" following the transplant.     

Stem cell therapies for systemic sclerosis

The presence of autoimmune diseases, including Systemic Sclerosis (SSc), suggest failure of the normal immune regulatory processes leading to activation and expansion of autoreactive effector immune cells. Recently, stem cell transplantation emerged as a novel rescue therapy for a variety of refractory autoimmune diseases. The therapeutic strategy involves the ablation of the aberrant self‐reactive immune cells by chemotherapy and the regeneration of a new self‐tolerant immune system formed by the transplanted stem cells. In the last few years, thousands of patients worldwide have received haematopoietic stem cell transplantation (HSCT), mostly autologous, as treatment for severe irreversible autoimmune diseases, with promising results. Here we review the results of published small series of SSc patients treated with allogeneic and autologous HSCT, as well as three randomized trials, exploring the safety and efficacy of autologous HSCT in SSc. Although the results are encouraging, nonetheless, the correct application of stem cell transplantation remains an area of active investigation. Results of larger randomized, double blind clinical trials, will certainly improve our knowledge of the appropriate clinical use of stem cell therapy in SSc patients.     

Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used

Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.     

Disappearance of lupus anticoagulant after allogeneic bone marrow transplantation

Lupus anticoagulant antibodies have never been reported to disappear after either allogeneic or autologous bone marrow transplantation in humans. We report the first case of disappearance of lupus anticoagulant antibodies in a patient without systemic lupus erythematosus or clinical evidence of other autoimmune disorders, who received an allogeneic bone marrow transplant as treatment for chronic myeloid leukemia. Although marrow transplantation is not a recognized therapy for antiphospholipid syndrome, our observation should be considered another example of the capability of intensive chemo-radiotherapy followed by stem cell transplantation to ablate a pathologic marrow clone resulting in an autoimmune disorder and improve, or even cure, some severe autoimmune diseases.     

Cellular therapy of systemic sclerosis

Cell-based therapies bear promise as a means to dampen autoaggressive immune reactions and induce tolerance in patients with severe rheumatic autoimmune diseases. Of the various types of cell-based therapies, immunoablative treatment combined with autologous hematopoietic stem cell transplantation has been used in more than 1000 patients with severe autoimmune diseases worldwide, including patients with rheumatoid arthritis, juvenile idiopathic arthritis, systemic lupus erythematosus, and systemic sclerosis. Long-term improvements of disease activity have been documented, albeit at the expense of treatmentrelated toxicity and mortality. Based on the results of pilot studies, prospective randomized controlled trials have been initiated to compare safety and effi cacy of hematopoietic stem cell transplantation versus conventional treatment. Therapies involving mesenchymal stromal cells are currently being explored in clinical settings because of their anti-infl ammatory and tissue regenerative properties and their favorable risk/benefit ratio.     

Autologous hematopoietic stem cell transplantation for autoimmune diseases

Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune disease treated with autologous HSCT between 1995 and 2003, from 110 centers participating in the European Group for Blood and Marrow Transplantation (EBMT) autoimmune disease working party database. Survival, transplant-related mortality, treatment response and disease progression were assessed. In all, 420 patients (89%; 86+/-4% at 3 years, median follow-up 20 months) were alive, 53 (11%) had died from transplant-related mortality (N=31; 7+/-3% at 3 years) or disease progression (N=22; 9+/-4% at 3 years). Of 370 patients, 299 evaluable for response (81%) showed a treatment response, which was sustained in 213 (71% of responders). Response was associated with disease (P<0.001), was better in patients who received cyclophosphamide during mobilization (relative risk (RR)3.28 (1.57-6.83)) and was worse with increasing age (>40 years, RR0.29 (0.11-0.82)). Disease progression was associated with disease (P<0.001) and conditioning intensity (high intensity, RR1; intermediate intensity, RR1.81 (0.96-3.42)); low intensity, RR2.34 (1.074-5.11)). These data from the collective EBMT experience support the hypothesis that autologous HSCT can alter disease progression in severe autoimmune disease.     

Stem cells in the aetiopathogenesis and therapy of rheumatic disease

Animal models of autoimmune disease and case reports of patients with these diseases who have been involved in bone marrow transplants have provided important data implicating the haemopoietic stem cell in rheumatic disease pathogenesis. Animal and human examples exist for both cure and transfer of rheumatoid arthritis, systemic lupus erythematosus (SLE) and other organ-specific diseases using allogeneic haemopoietic stem cell transplantation. This would suggest that the stem cell in these diseases is abnormal and could be cured by replacement of a normal stem cell although more in vitro data are required in this area. Given the morbidity and increased mortality in some patients with severe autoimmune diseases and the increasing safety of autologous haemopoietic stem cell transplantation (HSCT), pilot studies have been conducted using HSCT in rheumatic diseases. It is still unclear whether an autologous graft will cure these diseases but significant remissions have been obtained which have provided important data for the design of randomized trials of HSCT versus more conventional therapy. Several trials are now open to accrual under the auspices of the European Bone Marrow Transplant Group/European League Against Rheumatism (EBMT/EULAR) registry. Future clinical and laboratory research will need to document the abnormalities of the stem cell of a rheumatic patient because new therapies based on gene therapy or stem cell differentiation could be apllied to these diseases. With increasing safety of allogeneic HSCT it is not unreasonable to predict cure of some rheumatic diseases in the near future.     

Haemopoietic stem cell transplantation--an evolving treatment for severe autoimmune and inflammatory diseases in rheumatology, neurology and gastroenterology

The concept of haemopoietic stem cell transplantation (HSCT) to treat severe autoimmune diseases has been around for several decades. Advances in the safety of HSCT have made it a clinical reality since 1995. Databases have registered around a thousand patients treated specifically for a wide range of diseases, predominantly multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Phase I/II prospective and retrospective studies have supported the potential of autologous HSCT as a treatment option in severely affected patients, with profound and prolonged clinical responses in some diseases, although procedures are generally not curative. Allogeneic HSCT appears to offer curative potential, but the potential of high toxicity has limited its use in this context. The exact role of HSCT remains to be defined, particularly in the context of other advances in the treatment of autoimmune disease. Along with other groups, the European Group for Blood and Marrow Transplantation (EBMT) are overseeing several phase III trials in autologous transplantation. Given the risks of the HSCT, eligibility is restricted to patients who have severe, treatment resistant disease, in whom the prognosis is otherwise poor. This review aims to summarise the current published data in this evolving treatment for relatively rare patients with resistant or rapidly progressive disease where treatment options are otherwise limited. This cross-fertilization of knowledge between many specialties may provide increasing therapeutic opportunities in otherwise untreatable diseases. Moreover, destroying and rebuilding immune systems may provide insights into autoimmune diseases.     

Hematopoietic stem cell transplantation in systemic autoimmune diseases. State of the art

The use of stem cell transplantation for severe autoimmune diseases refractory to conventional therapy arose from two discoveries: the excellent results of animal experiments, and serendipitous observations in human coincidental diseases. Experimental data and early phase I-II trials in highly selected patients suggest that highdose chemotherapy followed by autologous hematopoietic stem cell transplantation can arrest progression of severe autoimmune diseases with an acceptable risk/benefit ratio. The present article reviews the phase II-III prospective, multicenter, randomized trials that have been performed in distinct autoimmunediseases. In addition, allogeneic stem cell transplantation for autoimmune diseases is being cautiously explored in current protocols.     

Cytomegalovirus viremia, viruria and disease after autologous peripheral blood stem cell transplantation: no need for surveillance.

A retrospective evaluation of 200 consecutive recipients of autologous peripheral blood stem cell transplantation (PBSCT) was conducted to ascertain the incidence, risk factors, clinical features, complications, and outcome of cytomegalovirus (CMV) infection. A total of 26 patients (13%) developed CMV viremia (n = 5), DNAemia (n = 3), viruria (n = 18) and/or disease (n = 3) at a median of 45 days following stem cell infusion. None of the patients underwent surveillance testing for CMV. A diagnosis was established by culture and polymerase chain reaction of blood, urine or other tissue samples submitted when patients exhibited clinical features suggestive of CMV infection. Cytomegalovirus seropositivity prior to transplantation was the only statistically significant risk factor predicting subsequent identification of CMV (P < 0.001). The symptoms were severe enough in 23 patients to warrant treatment with intravenous ganciclovir. Three patients developed CMV disease; two developed fatal CMV pneumonia and one developed CMV gastritis which responded to antiviral treatment. Clinical signs and symptoms as well as viremia and viruria resolved with (20 patients) and without (three patients) treatment in the remaining individuals. All instances of CMV viremia, DNAemia, viruria and disease occurred within 3 months of stem cell infusion. These results demonstrate that CMV is a common pathogen after autologous PBSCT and may result in fatality in rare instances. Surveillance programs appear to be neither useful nor cost-effective. Diagnostic evaluation should be performed only in patients exhibiting suspicious clinical features and antiviral chemotherapy should be administered for persistent and severe signs and symptoms.     

Comparison of two different methods for CD34+ selection and T cell depletion in peripheral blood stem cell grafts--our experiences with CellPro, E rosetting and CliniMACS technique

The aim of this study was to establish a suitable method for in vitro T cell depletion in peripheral blood stem cell grafts for mismatched/haploidentical transplantation in children and adults with severe hematological disorders and for autologous transplantation in patients with autoimmune diseases refractory to conventional immunosuppressive treatment. Two different selection techniques have been used: CD34+ selection using immunoaffinity columns (CellPro Ceprate) followed by T cell depletion by E-rosetting or CD34+ selection using submicroscopic paramagnetic beads (CliniMACS device) with T cell depletion in a one step procedure. The mean purity and recovery of CD34+ cells and efficiency of T cell removal in the final product were compared. From March 1995 to December 1998 we prepared twelve allografts using Cell Pro system for eight children with high-risk hematological malignancies and six autografts for six patients with severe autoimmune diseases. From January 1999 to October 2000 we prepared fifteen allografts using CliniMACS system for ten children with high-risk hematological diseases and inborn metabolic disorders or primary immunodeficiences, five allografts for three adult patients with high-risk hematological malignancies and two autografts for two patients with autoimmune diseases. In allogeneic transplantation the median purity of CD34+ cells in the final products after CellPro and E-rosetting was 85.6% (55.3%-95.7%); median recovery was 24.8% (17%-35%), median transplanted doses of T cells per kilogram of body weight were 0.66x10(4) (0-2.8); in autologous transplantation the median purity of CD34+ was 92.6% (55.6%-96%), median recovery was 28% (22%-46.2%), median transplanted doses of T cells per kilogram of body weight were 0.39x10(4) (0.0-3.6). After CliniMACS technique the median purity of CD34+ cells was 94.87% (69.15%-99%),medianrecoverywas 58% (30%-79.6%), median transplanted doses of T cells per kg of body weight were 0.254x10(4) (0-14.15); in autologous transplantation the median purity of CD34+ was 94% (94%-94%, median recovery was 97.4% (95%-99.8%), median transplanted doses of T cells per kilogram of body weight were 0.87x10(4) (0.49-1.24). We consider both methods of CD34+ selection and T cell depletion suitable for peripheral blood stem cell processing before mismatched hemopoietic stem cell transplantation in patients without identical donor or before autologous transplantation for severe autoimmune diseases. However, magnetic separation using CliniMACS system results in higher levels of purity and recovery with efficient T cell depletion.