Yvonne Loh

Clinical Applications of Blood-Derived and Marrow-Derived Stem Cells for Nonmalignant Diseases

CONTEXT Stem cell therapy is rapidly developing and has generated excitement and promise as well as confusion and at times contradictory results in the lay and scientific literature. Many types of stem cells show great promise, but clinical application has lagged due to ethical concerns or difficulties in harvesting or safely and efficiently expanding sufficient quantities. In contrast, clinical indications for blood-derived (from peripheral or umbilical cord blood) and bone marrow-derived stem cells, which can be easily and safely harvested, are rapidly increasing. OBJECTIVE To summarize new, nonmalignant, nonhematologic clinical indications for use of blood- and bone marrow-derived stem cells. EVIDENCE ACQUISITION Search of multiple electronic databases (MEDLINE, EMBASE, Science Citation Index), US Food and Drug Administration [FDA] Drug Site, and National Institutes of Health Web site to identify studies published from January 1997 to December 2007 on use of hematopoietic stem cells (HSCs) in autoimmune, cardiac, or vascular diseases. The search was augmented by hand searching of reference lists in clinical trials, review articles, proceedings booklets, FDA reports, and contact with study authors and device and pharmaceutical companies. EVIDENCE SYNTHESIS Of 926 reports identified, 323 were examined for feasibility and toxicity, including those with small numbers of patients, interim or substudy reports, and reports on multiple diseases, treatment of relapse, toxicity, mechanism of action, or stem cell mobilization. Another 69 were evaluated for outcomes. For autoimmune diseases, 26 reports representing 854 patients reported treatment-related mortality of less than 1% (2/220 patients) for nonmyeloablative, less than 2% (3/197) for dose-reduced myeloablative, and 13% (13/100) for intense myeloablative regimens, ie, those including total body irradiation or high-dose busulfan. While all trials performed during the inflammatory stage of autoimmune disease suggested that transplantation of HSCs may have a potent disease-remitting effect, remission duration remains unclear, and no randomized trials have been published. For reports involving cardiovascular diseases, including 17 reports involving 1002 patients with acute myocardial infarction, 16 involving 493 patients with chronic coronary artery disease, and 3 meta-analyses, the evidence suggests that stem cell transplantation performed in patients with coronary artery disease may contribute to modest improvement in cardiac function. CONCLUSIONS Stem cells harvested from blood or marrow, whether administered as purified HSCs or mesenchymal stem cells or as an unmanipulated or unpurified product can, under appropriate conditions in select patients, provide disease-ameliorating effects in some autoimmune diseases and cardiovascular disorders. Clinical trials are needed to determine the most appropriate cell type, dose, method, timing of delivery, and adverse effects of adult HSCs for these and other nonmalignant disorders.

Mobilization, harvesting and selection of peripheral blood stem cells in patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation

Peripheral blood stem cells (PBSC) were mobilized in 130 patients with autoimmune diseases undergoing autologous hematopoietic stem cell transplantation using cyclophosphamide 2 g/m2 and either granulocyte colony-stimulating factor (G-CSF) 5 mcg/kg/day (for systemic lupus erythematosus (SLE) and secondary progressive multiple sclerosis, SPMS) or G-CSF 10 mcg/kg/day (for relapsing remitting multiple sclerosis (RRMS), Crohns disease (CD), systemic sclerosis (SSc), and other immune-mediated disorders). Mobilization-related mortality was 0.8% (one of 130) secondary to infection. Circulating peripheral blood (PB) CD34+ cells/μl differed significantly by disease. Collected CD34+ cells/kg/apheresis and overall collection efficiency was significantly better using Spectra apheresis device compared to the Fenwall CS3000 instrument. Patients with SLE and RRMS achieved the lowest and the highest CD34+ cell yields, respectively. Ex vivo CD34+ cell selection employing Isolex 300iv2.5 apparatus was significantly more efficient compared to CEPRATE CS device. Circulating PB CD34+ cells/μl correlated positively with initial CD34+ cells/kg/apheresis and enriched product CD34+ cells/kg. Mean WBC and platelet engraftment (ANC>0.5 × 109/l and platelet count >20 × 109/l) occurred on days 9 and 11, respectively. Infused CD34+ cell/kg dose showed significant direct correlation with faster white blood cell (WBC) and platelet engraftment. When adjusted for CD34+ cell/kg dose, patients treated with a myeloablative regimen had significantly slower WBC and platelet recovery compared to non-myeloablative regimens.

Autologous non-myeloablative haematopoietic stem cell transplantation for refractory systemic vasculitis.

Objective: For patients with systemic vasculitis (SV) refractory to conventional therapy, new treatment strategies aimed at aggressive induction of remission and relapse prevention are being sought. We herein report our single-centre experience in treating four patients with refractory SV employing non-myeloablative autologous haematopoietic stem cell transplantation (HSCT). Methods: Four patients with refractory SV (two with neurovascular Behcet disease, one with neurovascular Sjögren syndrome, and one with Wegener granulomatosis) were involved in an Institutional Review Board (IRB) and US Food and Drug Administration (FDA) approved phase I clinical trial of high dose chemotherapy and autologous HSCT. Peripheral blood stem cells were mobilised with cyclophosphamide (Cy) and granulocyte-colony stimulating factor (G-CSF). Conditioning regimen consisted of Cy 200 mg/kg and rabbit anti-thymocyte globulin 5.5 mg/kg intravenously (iv). Results: All four patients tolerated HSCT well without transplant related mortality or any significant toxicity. At median follow-up of 28 (range 22–36) months all patients were alive. Three patients (one with Behcet disease, one with Sjögren syndrome, and one with Wegener granulomatosis) entered a sustained remission at 6, 6 and 24 months, respectively, after transplant. They had significant decrease in disease activity and disease or treatment related damage, as measured by the Birmingham Vasculitis Activity Score and Vasculitis Damage Index, respectively. All three patients who achieved remission discontinued immunosuppressive therapy at the time of transplant and have not required treatment since. One patient with Behcet disease and positive for human leukocyte antigen (HLA)-B51 has not improved after HSCT. Conclusion: We suggest non-myeloablative autologous HSCT is an alternative therapy for select patients with SV refractory to conventional immunosuppressive therapies.

NONMYELOABLATIVE AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR REFRACTORY CIDP

Most patients with chronic inflammatory demyelinating polyneuropathy (CIDP) initially respond to corticosteroids, immunosuppressive drugs, IV immune globulin (IVIg), and plasma exchange (PE). However, more than half relapse, with some developing a recurrent or persistent clinical course resulting in severe disability and even death.1,2 Nonmyeloablative autologous hematopoietic stem cell transplantation (HSCT) for severe autoimmune diseases has demonstrated promising results, with reports of durable remissions and lower toxicity compared to myeloablative HSCT.3 Herein, we report the first patient treated in a phase I trial of autologous HSCT utilizing a nonmyeloablative regimen for refractory CIDP. ### Methods. Eligibility criteria include age 65 years or less; definite or probable CIDP according to the criteria of the Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force; failure of standard therapy, i.e., incomplete response or relapse after corticosteroids, IVIg, or PE; and failure to respond to at least one second-line immunosuppressive drug (methotrexate, azathioprine, cyclosporine, tacrolimus, or mycophenolate mofetil [MMF]). CD34-enriched peripheral blood stem cells …

A phase I/II clinical trial of autologous cytokine-induced killer cells as adjuvant immunotherapy for acute and chronic myeloid leukemia in clinical remission

BACKGROUND AIMS Cytokine-induced killer (CIK) cells have shown remarkable cytotoxicity against various tumors in vitro and in animal studies. We report on the clinical outcome of autologous CIK cells for patients with acute (AML) and chronic (CML) myeloid leukemia in remission. METHODS Eleven of the 13 recruited AML patients undergoing autologous peripheral blood stem cell transplant (autoPBSCT) were given autologous CIK cell infusion upon engraftment post-transplant and followed-up for disease relapse. Eleven CML patients on Imatinib with residual disease detectable by polymerase chain reaction (PCR) were given infusion and monitored by quantitation of the bcr-abl transcript. RESULTS Despite the presence of interferon (IFN)-γ-secreting T cells against various AML- and CML-associated peptides at sporadic time-points and demonstration of in vitro cytotoxicity of CIK cells against autologous and allogeneic AML targets, there was no survival benefit in AML patients post-autoPBSCT given CIK cells compared with historical controls. For CML patients, all continued to have a detectable bcr-abl transcript fluctuating within a range comparable to their pre-treatment baseline, although two had a transient but non-sustainable disappearance of bcr-abl transcript. There were no adverse reactions except for fever within the first day of infusion. CONCLUSIONS Our small series, while confirming safety, failed to demonstrate a clinical benefit of autologous CIK cells given in its current form for AML and CML. Further manipulation of CIK cells to improve anti-leukemic potency and specificity, together with the preparation of patients to create a more conducive milieu for in vivo expansion and persistence of infused CIK cells, should be explored.

Non-myeloablative allogeneic hematopoietic stem cell transplantation for severe systemic sclerosis: graft-versus-autoimmunity without graft-versus-host disease?

Non-myeloablative allogeneic hematopoietic stem cell transplantation for severe systemic sclerosis: graft-versus-autoimmunity without graft-versus-host disease?

Risks of immune system treatments

IN THE POLICY FORUM “CHINA’S ROAD TO SUSTAINABILITY” (2 APRIL, P. 50), J. LIU OVERLOOKS AN important cultural force. China’s worsening environmental conditions have catalyzed a spirit of environmental civilian activism. For example, in 2003, a consortium proposed erecting 13 dams on the Nujiang River. China’s environmental nongovernmental organizations and scholars launched a protest campaign through the Internet and newspapers. The critics argued that as reservoirs behind the dams fi lled up, fl ooding and landslides would imperil habitats. In response, Premier Wen Jiabao suspended the dam project pending an environmental review in 2004 (1). The landmark of environmental civilian activism occurred in Xiamen City in 2007. The local government supported construction of a

Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus patients with cardiac dysfunction: feasibility and reversibility of ventricular and valvular dysfunction with transplant-induced remission

1.4-billion paraxylene plant near the center of the city. Information about the environmental impact of this project was not made available to the local residents. The people of Xiamen City were outraged when—through cell phone messages and the Internet—they learned of the plant’s environmental risks. A phone text message was circulated among Xiamen citizens in late May calling for a “collective walk” (demonstration). On 1 June 2007, more than 1000 citizens gathered in front of the municipal building to protest. The demonstration forced the local government to cancel the largest industrial project in the history of Xiamen (2). The burgeoning middle class has become the driver of environmental civilian activism. For example, operation of the Likeng trash incinerator in Guangzhou City started in 2005 without any protest, although local farmers worried about health risk (3). In contrast, the proposed Panyu trash incinerator in Guangzhou City in 2009 triggered protests that were led by the middle class (4), who used science-based evidence to openly challenge prevailing notions formulated by the authorities. (In earlier years, standard practice was to obey Beijing-based experts in environmental protection.) In addition, the self-organized middle class forced the local government to open discussion by Internet. By seizing the opportunity for an open discussion, the newly empowered locals took to the streets to protect their environmental rights (4). Recent years have witnessed an impressive growth in environmental protests in China. The number of petitions and mass public protests related to environmental issues has increased by 30% per year in the past few years, although the number of petitions lodged with the Chinese government has dropped (5). The current environmental civilian activism movements have several common characteristics: (i) They are confi ned to one specifi c geographical space. (ii) Their goal is protecting the environment, rather than political rights or commercial interests. (iii) They focus on a specifi c pollutant, rather than general environmental degradation. The local nature of the movement enables the organization of a large number of citizens with little effort in a very short time. Given more open social and political conditions and the increasing size of the middle class in China, environmental civilian activism will certainly be a key driver in China’s transition to sustainability.

Comparing peripheral blood stem cell collection using the COBE Spectra, Haemonetics MCS+, and Baxter Amicus

Patients with cardiac dysfunction may be at increased risk of cardiac toxicity when undergoing hematopoietic stem cell transplantation (HSCT), which may preclude them from receiving this therapy. Cardiac dysfunction is, however, common in systemic lupus erythematosus (SLE) patients. While autologous HSCT (auto-HSCT) has been performed increasingly for SLE, its impact on cardiac function has not previously been evaluated. We, therefore, performed a retrospective analysis of SLE patients who had undergone auto-HSCT in our center to determine the prevalence of significant cardiac involvement, and the impact of transplantation on this. The records of 55 patients were reviewed, of which 13 were found to have abnormal cardiac findings on pre-transplant two-dimensional echocardiography or multi-gated acquisition scan: impaired left ventricular ejection fraction (LVEF) (n=6), pulmonary hypertension (n=5), mitral valve dysfunction (n=3) and large pericardial effusion (n=1). At a median follow-up of 24 months (8–105 months), there were no transplant-related or cardiac deaths. With transplant-induced disease remission, all patients with impaired LVEF remained stable or improved; while three with symptomatic mitral valve disease similarly improved. Elevated pulmonary pressures paralleled activity of underlying lupus. These data suggest that auto-HSCT is feasible in selected patients with lupus-related cardiac dysfunction, and with control of disease activity, may improve.

Effect of missing killer-immunoglobulin-like receptor ligand in recipients undergoing HLA full matched, non-T-depleted sibling donor transplantation: a single institution experience of 151 Asian patients.

Peripheral blood stem cells (PBSC) have become the most common source of hematopoietic cells for allogeneic or autologous blood and marrow transplantation (BMT). We performed an evaluation of PBSC collections using three different apheresis systems in two major transplantation centers in Singapore. Patients undergoing autologous BMT and donors collecting for allogeneic BMT were harvested using the COBE Spectra, Haemonetics MCS+, or Baxter Amicus. There were 99 Spectra collections (61 were autologous), 81 MCS+ collections (35 were autologous) and 38 Amicus collections (33 were autologous). Our data shows that the Amicus not only processed larger peripheral blood volumes but also yielded larger PBSC volume (P-value<0.05). In terms of PBSC products, the Spectra produced more WBC, WBC/liter blood processed, and WBC/kg (P-value<0.05). The Spectra and MCS+ produced comparable amount of CD34+ cells. Amicus collected 50% less platelets compared to Spectra and MCS+. The total CD34+ cells in the PBSC products was linearly correlated to the circulating CD34+ cells using Spectra, MCS+, and Amicus. Our results suggest that, compared to MCS+ and Amicus, collecting PBSC using the COBE Spectra can produce more WBC with a similar number of CD34+ cells. With a linear correlation of circulating CD34+ cells to the total CD34+ cells in the products, the availability of an automated procedure, no rotating seal, and a small extracorporeal volume, the Spectra appears to be the preferred machine for PBSC collection.