Kathleen Quigley

Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up

We evaluated the safety and clinical outcome of autologous nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with severe Crohn disease (CD) defined as a Crohn Disease Activity Index (CDAI) greater than 250, and/or Crohn Severity Index greater than 16 despite anti-tumor necrosis factor therapy. Stem cells were mobilized from the peripheral blood using cyclophosphamide (2.0 g/m(2)) and G-CSF (10 μg/kg/day), enriched ex vivo by CD34(+) selection, and reinfused after immune suppressive conditioning with cyclophosphamide (200 mg/kg) and either equine antithymocyte globulin (ATG, 90 mg/kg) or rabbit ATG (6 mg/kg). Eighteen of 24 patients are 5 or more years after transplantation. All patients went into remission with a CDAI less than 150. The percentage of clinical relapse-free survival defined as the percent free of restarting CD medical therapy after transplantation is 91% at 1 year, 63% at 2 years, 57% at 3 years, 39% at 4 years, and 19% at 5 years. The percentage of patients in remission (CDAI < 150), steroid-free, or medication-free at any posttransplantation evaluation interval more than 5 years after transplantation has remained at or greater than 70%, 80%, and 60%, respectively. This trial was registered at www.clinicaltrials.gov as NCT0027853.

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 …

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?

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

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.

Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores: is neoangiogenesis occurring?

Summary:Systemic sclerosis (SSc) is presumed to be an immune-mediated vasculopathy of unknown etiology. SSc is unresponsive to most immune-modulating therapies except for intravenous cyclophosphamide, which is reported to demonstrate some benefit. We, therefore, dose-escalated cyclophosphamide to 200 mg/kg and added rabbit ATG 7.5 mg/kg along with infusion of unselected hematopoietic stem cells to minimize the cytopenic interval. Engraftment occurred rapidly (day 8) with minimal unexpected toxicity, no infections, and unexpectedly rapid improvement in the modified Rodnan Skin Score.