Stem cell transplantation for treatment of severe autoimmune diseases: current status and future perspectives

Autoimmune diseases include a heterogeneous group of disorders with variable presentation and severity. Immunosuppressive and immunomodulatory therapies are often used for treatment with considerable success in some cases. These diseases may also be severe and refractory to conventional treatment. Thus more aggressive intervention might be indicated in a subset of patients. Animal studies suggest that high-dose therapy supported by stem cell transplantation may lead to remissions in experimental autoimmune disease models. Anecdotal case reports suggest that the same may be the case in some human autoimmune diseases as well. This review attempts to summarise some current concepts and future perspectives on stem cell transplantation in the treatment of severe autoimmune diseases.     

High-dose chemotherapy with autologous hematopoietic stem cell support for solid tumors in adults

Supported by experimental evidence and convincing results of early phase II studies, since the 1980s high-dose chemotherapy (HDC) with autologous hematopoietic stem cell support (AHSCT) has been uncritically adopted by many oncologists as a potentially curative option for several solid tumors. As a result, the number (and size) of randomized trials comparing this approach with conventional chemotherapy initiated (and often abandoned before completion) in this setting was limited and the benefit of a greater escalation of dose of chemotherapy with stem cell transplantation in solid tumors remains, with the possible exception of breast carcinoma (BC) and germ cell tumors (GCT), largely unsettled. In this article, we review and comment on the data from studies to date of HDC for solid tumors in adults.     

Hematopoietic stem cell transplantation for autoimmune diseases in developing countries: current status and future prospectives

In this paper we present preliminary results of hematopoietic stem cell transplantation for autoimmune diseases in Brazil and China. Chinese experience transplanting lupus is significant and the Brazilian experience with several autoimmune diseases is growing. We discuss peculiar conditions in developing countries which could affect the results, and future prospectives for the organization of phase III randomized trials in those countries.     

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation as a treatment option in multiple sclerosis

High-dose immunosuppressive therapy (HDIT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is a new and promising approach to the treatment of multiple sclerosis (MS) patients because currently there are no effective treatment methods for this disease. In this article, we present results of a prospective clinical study of efficacy of HDIT + auto-HSCT in MS patients. The following treatment strategies were employed in the study: "early," "conventional," and "salvage/late" transplantation. Fifty patients with various types of MS were included in this study. No toxic deaths were reported among 50 MS patients; transplantation procedure was well-tolerated by the patients. The efficacy analysis was performed in 45 patients. Twenty-eight patients achieved an objective improvement of neurological symptoms, defined as at least 0.5-point decrease in the Expanded Disability Status Scale (EDSS) score as compared to the baseline and confirmed during 6 months, and 17 patients had disease stabilization (steady EDSS level as compared to the baseline and confirmed during 6 months). The progression-free survival at 6 years after HDIT + auto-HSCT was 72%. Magnetic resonance imaging data were available in 37 patients before transplantation showing disease activity in 43.3%. No active, new, or enlarging lesions were registered in patients without disease progression. In conclusion, HDIT + auto-HSCT suggests positive results in management of patients with different types of MS. Identification of treatment strategies based on the level of disability, namely "early," "conventional," and "salvage/late" transplantation, appears to be feasible to improve treatment outcomes.     

High-dose chemotherapy and hematopoietic stem cell rescue in patients with relapsed Hodgkin's disease

Summary Fifty-one consecutive patients with Hodgkin's disease (HD) have been treated with high-dose chemotherapy (HDT) and transplantation of autologous bone marrow (BM) (n=44), autologous BM plus peripheral blood stem cells (PBSC) (n=2), PBSC (n=1), syngeneic (n=1), or allogeneic BM (n=3). All patients had received standard salvage chemotherapy prior to HDT and were classified as sensitive (n=33) or resistant (n=17) to this treatment; one patient was in untreated relapse prior to BMT. The preparative regimens for patients receiving autologous BM and/or PBSC consisted of cyclophosphamide, VP 16, and BCNU (CVB) (n=44) or BCNU, etoposide, ara-C, and melphalan (BEAM) (n=3). The patients receiving allogeneic transplants were treated with the CVB regimen (n=2) or busulfan (16 mg/kg body wt.) and cyclophosphamide (200 mg/kg body wt.). With a median follow-up of 12 months, overall survival for 44 patients grafted with autologous BM is 61%±9%, progression-free survival for patients with sensitive disease is 44%±11%; no patient with resistant relapse survived beyond 1 year post transplant. Two of three patients grafted with allogeneic BM still survive 15 and 24 months after BMT with Karnofsky performance scores of 70% and 100%, respectively. The main toxicity encountered with the CVB regimen was interstitial pneumonia (IP), seen in four of 15 patients (27%) receiving 600 mg/m² of BCNU. Three of these patients have died. The results show that HDT followed by hematopoietic stem cell rescue may effectively salvage an important fraction of patients with relapsed HD who respond to standard chemotherapy. The same approach is largely unsuccessful in patients with proven refractoriness to standard chemotherapy. Whether HDT followed by BMT or PBSC support is superior to intensive chemotherapy without stem cell support can be answered only by a prospectively randomized trial.     

Allogeneic hematopoietic stem cell transplantation: current issues and future prospects

Major developments have occurred in the field of hematopoietic stem cell transplantation since the first successful transplants from HLA-identical siblings in the late 60's. The formally experimental procedure has become established therapy for a number of congenital or acquired disorders of the hematopoietic system and for chemotherapy-sensitive malignancies. Reduced transplant-related mortality has led to a widening of indications. The present review summarizes current issues and future prospects in allogeneic stem cell transplantation. These issues and prospects will include; stem cell sources, alternative donors, graft-versus-host disease, indications and long-term survival following allogeneic stem cell transplantation.     

High-dose therapy with hematopoietic stem cell rescue in patients with poor prognosis Ewing family tumors

The purpose of the study was to evaluate the feasibility and safety of two cycles of high-dose chemotherapy (HDT) followed by autologous hematopoietic SCT (HSCT) in patients with poor prognosis Ewing family of tumors (EFT). Twenty patients with primary metastatic bulky disease or recurrent EFT were enrolled to a treatment protocol with two cycles of HDT and HSCT. Patients tolerated well the first (n=20) and second (n=13) cycles, with limited and predictable toxicities. Only one (5%) TRM occurred during the second cycle. Myeloid engraftment occurred at the median of 11 days after both cycles. At 3 years, the overall and EFS were 45% (confidence interval; CI 0.22, 0.69) and 47% (CI 0.25, 0.70), respectively, for the entire group and 58% (CI 0.30, 0.86) for patients who completed two cycles. Dose intensification with two cycles of HDT and HSCT is feasible and safe, with low and acceptable treatment-related morbidity and mortality. Adding a second course of therapy does not impair engraftment. However, only 65% of the patients were able to proceed to the second cycle. Further studies are required to define the optimal mode of delivery of HDT and HSCT in treatment of advanced EFT.Bone Marrow Transplantation (2008) 42, 311-318; doi:10.1038/bmt.2008.169; published online 30 June 2008.     

High-dose caspofungin combination antifungal therapy in patients with hematologic malignancies and hematopoietic stem cell transplantation

Pneumocandins have concentration-dependent antifungal activity and higher dose of caspofungin (HD-CAP) in combination with other licensed antifungal therapy (OLAT) may improve response. Thirty-four patients who received HD-CAP were compared with 63 patients who received standard dose (SD)-CAP. There were no differences between the groups in either patient or disease characteristics. Significantly more patients in the HD-CAP arm had extrapulmonary infections (29 vs 8% in SD group; P=0.0053), and non-Aspergillus species infection (21 vs 6%; P=0.05) and had received prior antifungal therapy (71 vs 33%; P=0.0004). No serious adverse reactions were noted in patients receiving HD- or SD-CAP therapy. Twelve weeks after treatment commenced 44% had a complete or partial response compared with 29% in SD-CAP group (P=0.1). Logistic regression analysis showed a significant probability of a favorable outcome at 12 weeks in patients who received HD-CAP (OR 3.066, 95% CI, 1.092-8.61; P=0.033). This may in part reflect higher number of patients in HD group had received granulocyte-macrophage colony-stimulating factor (41 vs 14% in SD group; P=0.04) and/or interferon gamma (26 vs 5% in SD group; P=0.003) immune enhancement. Further studies are needed to evaluate efficacy of HD-CAP in severely immunosuppressed cancer patients with invasive fungal infections.     

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.     

Clinical application of hematopoietic progenitor cell expansion: current status and future prospects

In the past decade, we have witnessed significant advances in ex vivo hematopoietic stem cell culture expansion, progressing to the point where clinical trials are being designed and conducted. Preclinical milestone investigations provided data to enable expansion of portions of hematopoietic grafts in a clinical setting, indicating safety and feasibility of this approach. Data derived from current clinical trials indicate successful reconstitution of hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo-expanded perfusion cultures. Future avenues of exploration will focus upon refining preclinical and clinical studies in which cocktails of available cytokines, novel molecules and sophisticated expansion systems will explore expansion of blood, marrow and umbilical cord blood cells.     

High-dose immune suppression and autologous hematopoietic stem cell transplantation in refractory Crohn disease

Two patients with severe Crohn disease, defined by a Crohn Disease Activity Index (CDAI) higher than 250 despite anti-tumor necrosis factor alpha (TNF-alpha), were treated by intense immune suppression and autologous hematopoietic stem cell transplantation (HSCT). Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m2) and granulocyte colony-stimulating factor (G-CSF; 5 micro g/kg/d), enriched ex vivo by CD34+ selection, and reinfused after immune conditioning with cyclophosphamide (200 mg/kg) and equine anti-thymocyte globulin (ATG; 90 mg/kg). Patients have remained in remission (CDAI < 100) for 1 year since HSCT. We conclude that further HSCT studies for severe Crohn disease appear warranted.     

Interventional endoscopic ultrasonography: current status and future direction

Although first performed more than 20 years ago, endoscopic ultrasonography (EUS) has only recently been used for interventional/therapeutic purposes. The recognition and application of this versatile procedure by gastroenterologists who perform endoscopy has reached an all-time high, and the demand for symposia and tutorials devoted to EUS rivals that of endoscopic retrograde cholangiopancreatography 20 to 25 years ago. EUS has become an established part of the endoscopic armamentarium for many gastroenterologists. Despite its proved clinical utility for staging gastrointestinal (and lung) cancers, and its use in delineating the nature of "submucosal" tumors of the gastrointestinal tract, EUS has continued to evolve. Within the past 10 years, the safety and efficacy of EUS as a means of guiding tissue acquisition via fine-needle aspiration has been demonstrated, increasing its utility in gastrointestinal oncology. Newer indications currently under clinical investigation include the use of EUS as a delivery mechanism for novel immune-based and viral-based "chemo" therapeutic agents for patients with pancreatic cancer. Finally, the role of EUS as a reliable method to guide therapy to control the often refractory abdominal pain in patients with pancreatic cancer and/or chronic pancreatitis is being verified in clinical trials. The following is a brief overview of the current state-of-the-art in interventional EUS.     

DNA vaccine therapy for Alzheimer's disease: present status and future direction

Alzheimer's disease is the most common cause of dementia characterized by progressive neurodegeneration. Based on the amyloid cascade hypothesis, a vaccine therapy for Alzheimer's disease (AD) was developed as a curative treatment. In 1999, the amyloid beta (Abeta) reduction in AD model transgenic mice with active vaccination with Abeta peptide was first reported. Although the clinical trials of active vaccination for AD patients were halted due to the development of meningoencephalitis in some patients, from the analysis of the clinical and pathological findings of treated patients, the vaccine therapy is thought to be effective. Based on such information, the vaccines for clinical application of human AD have been improved to control excessive immune reaction. Recently, we have developed non-viral DNA vaccines and obtained substantial Abeta reduction in transgenic mice without side effects. DNA vaccines have many advantages over conventional active or passive immunization. In this article, we review conventional vaccine therapies and further explain our non-viral DNA vaccine therapy. Finally, we show some data regarding the mechanisms of Abeta reduction after administration of DNA vaccines. DNA vaccination may open up new avenues of vaccine therapy for AD.     

Anticoagulation in heart failure: current status and future direction

Despite therapeutic advances, patients with worsening heart failure (HF) requiring hospitalization have unacceptably high post-discharge mortality and re-admission rates soon after discharge. Evidence suggests a hypercoagulable state is present in patients with HF. Although thromboembolism as a direct consequence of HF is not frequently clinically recognized, it may contribute to mortality and morbidity. Additionally, many patients with HF have concomitant disorders conferring additional thrombotic risk, including atrial fibrillation (AF) and coronary artery disease (CAD). Acute coronary syndrome (ACS), a known consequence of coronary thrombosis, is a common precipitating factor for worsening HF. Coronary thrombosis may also cause sudden death in patients with HF and CAD. Because data are largely derived from observational studies or trials of modest size, guideline recommendations on anticoagulation for HF vary between organizations. The recently presented Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction trial of HF patients in sinus rhythm suggested anticoagulation reduces the risk of stroke, although rates of the combined primary endpoint (death, ischemic stroke, or intracerebral hemorrhage) were similar for acetylsalicylic acid and warfarin. Newer oral anticoagulants dabigatran, apixaban, and rivaroxaban have successfully completed trials for the prevention of stroke in patients with AF and have shown benefits in the subpopulation of patients with concomitant HF. Positive results of the Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome—Thrombolysis in Myocardial Infarction 51 (ATLAS ACS 2—TIMI 51) trial of rivaroxaban in ACS are also encouraging. These data suggest there is a need to assess the potential role for these newer agents in the management of patients hospitalized for HF who continue to have a high post-discharge event rate despite available therapies.     

High-dose therapy with autologous haemopoietic stem cell support for Waldenström's macroglobulinaemia

Standard doses of alkylating agents or purine analogues effect response rates of up to 50% in Waldenström's macroglobulinaemia (WM); however, complete responses are infrequent and there are no cures. We have evaluated the feasibility, safety and efficacy of high-dose chemotherapy with peripheral blood stem cell support in six patients aged 45–69 years (median 51.5) with WM; four patients relapsed after prior therapy inclusive of purine analogues and two patients proceeded with transplant after minimal therapy. Four patients mobilized adequate numbers of stem cells; however, two patients with more extensive fludarabine therapy failed to mobilize and required a second attempt at stem cell collection. Five patients were treated with melphalan 200 mg/m², including one patient who received tandem transplants and one patient who received melphalan 140 mg/m² with added total body irradiation (TBI). There was no treatment-related mortality and non-haematological toxicities were manageable. Engraftment was prompt except in one patient with extensive prior use of fludarabine. All the six patients achieved at least partial response (PR), including one who achieved complete response (CR). Five patients are alive and four are event-free at 52+, 15+, 12+ and 2+ months post transplant. This pilot study suggests safety and efficacy of high-dose therapy in WM and suggests that the peripheral blood stem cells should preferably be procured prior to extensive use of purine analogues.     

Haploidentical hematopoietic transplantation: current status and future perspectives

For patients with hematologic malignancies at high risk of relapse who do not have matched donors, a suitable alternative stem cell source is the HLA-haploidentical 2 or 3-loci mismatched family donor who is readily available for nearly all patients. Transplantation across the major HLA barrier is associated with strong T-cell alloreactions, which were originally manifested as a high incidence of severe GVHD and graft rejection. The present review shows how these obstacles to successful transplantation were overcome in the last 15 years, making full haplotype-mismatched transplantation a clinical reality that provides similar outcomes to transplantation from matched unrelated donors. The review also discusses the advantages and drawbacks of current options for full haplotype-mismatched transplantation and highlights innovative approaches for re-building immunity after transplantation and improving survival.     

High-dose cyclophosphamide with autologous lymphocyte-depleted peripheral blood stem cell (PBSC) support for treatment of refractory chronic autoimmune thrombocytopenia

Patients with refractory chronic autoimmune thrombocytopenia (AITP) have a significant risk of morbidity and mortality related to hemorrhage. High-dose (HD) cytotoxic therapy may produce remissions but entails risks related to myelosuppression. Hematopoietic stem cell support with lymphocyte-depleted grafts may accelerate hematologic recovery and concomitantly reduce repopulation by autoreactive immunocytes. Fourteen patients with chronic AITP, in whom multiple prior therapies including corticosteroids, splenectomy, intravenous immunoglobulin, and various cytotoxic or immunomodulatory regimens had failed, were treated with HD cyclophosphamide (50 mg/kg/d) and autologous granulocyte colony-stimulating factor (G-CSF)-mobilized leukocytes depleted of lymphocytes by immunomagnetic CD34(+) selection. There were no significant adverse events related to G-CSF, intravenous device insertion, or leukapheresis. Treatment-related complications included transient hemorrhagic cystitis (1 patient), vaginal bleeding (2 patients), gastrointestinal bleeding (1 patient), epistaxis (1 patient), and antibiotic-responsive febrile neutropenia (all patients). The mean time to absolute neutrophil count (ANC) more than 500/mm(3) was 9 +/- 0.6 days. Eight patients experienced antibiotic-responsive gram-positive bacteremia. A median of 2 platelet transfusions was required for stem cell mobilization, intravenous catheter insertion, and apheresis and a median of 9 platelet transfusions was required during hematopoietic recovery. Six patients obtained durable complete responses (platelet counts > 100 000/mm(3) without other therapy) with maximum follow-up of 42 months. Two additional patients obtained durable partial responses (platelet counts significantly increased over baseline with reduced medication requirements and cessation of bleeding complications). This therapeutic approach is feasible for patients with severe chronic AITP, a substantial proportion of whom may obtain durable remissions. Larger controlled trials are recommended.