“The most important take-home message from the stem cell transplant data is that it is now time for clinicians to start actively and aggressively enrolling scleroderma patients into phase III randomized controlled trials such as SCOT or into phase II pilot studies.”—Keith M. Sullivan, MD
Keith M. Sullivan, MD, principal investigator of the SCOT (Scleroderma: Cyclophosphamide or Transplantation) study discussed the current state of stem cell transplants for SSc in an interview with MSKreport.com.
“The most important take-home message from the stem cell transplant data is that it is now time for clinicians to start actively and aggressively enrolling scleroderma patients into phase III randomized controlled trials such as SCOT or into phase II pilot studies,” said Dr. Sullivan, who is the James B. Wyngaarden Professor of Medicine in the Division of Cellular Therapy at Duke University Medical Center in Durham, North Carolina. He has extensive experience in stem cell transplant research, both in oncology and autoimmune diseases.
“Autologous stem cell transplant is the safest of all the transplant approaches. We have 8-year follow-up data on autologous SCT that show they are both safe and durable,” Dr. Sullivan said.
Transplanters picked scleroderma as top autoimmune disease target for stem cell studies
Stem cell transplants are being tested in the SCOT study in the US and the ASTIS (Autologous Stem Cell Transplantation International Scleroderma) trial in Europe.
“There is convincing evidence from animal models of genetically caused or antigen caused autoimmune syndromes resembling human SSc that some autologous or allogenic stem cell transplants can prevent disease development and even reverse organ damage. The phase II data in humans was similar, and there is a biologically plausible explanation for why this might work. Now we and others are moving ahead with major randomized, controlled trials, and these may produce practice-changing results within the next few years,” Dr. Sullivan said.
The objective of the SCOT study is to determine whether high-dose immunosuppressive therapy and hematopoietic stem cell transplantation (HDIT + HSCT) is better than conventional treatment with cyclophosphamide in patients with early, active, diffuse SSc.
"We as transplanters wanted to perfect our methods until transplant-related mortality was low enough to justify offering transplants to patients with autoimmune disease that were not immediately life threatening. A major international meeting convened in 1995 to consider how to proceed. Based on animal models and on ‘experiments in nature’ -- mostly patients with an autoimmune disease plus cancer, both of which had improved after the patient received high-dose chemotherapy with hematopoietic stem cell rescue to treat the cancer -- we decided that SSc, with its 50% 5-year mortality and no effective therapy, should be a first target. If we can make stem cell transplants work there, we can move forward to some of the other 50 autoimmune diseases on the list,” Dr. Sullivan said.
Rheumatologists urged to enroll SSc patients into SCOT trial
The SCOT trial (www.sclerodermatrial.org) will enroll about 226 people with severe scleroderma. Dr. Sullivan predicted that accrual should take ~2 more years, and he urged physicians to contact the trial website if they have patients who might be eligible for the study.
Dr. Sullivan noted that one problem delaying completion of these trials is that rheumatologists do not yet have many of the cooperative group networks that have helped move forward stem cell transplant trials in oncology, such as the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG).
In the SCOT study, the active control arm uses high-dose cyclophosphamide (750 mg/m2 intravenous infusion) pulsed monthly for 12 months. The experimental arm mobilizes autologous hematopoietic stem cells (AHSC) with byblophosphamide 4 g/m2 plus granulocyte colony stimulating factor (G-CSF), then uses a conditioning regimen of cyclophosphamide 200 mg/kg plus anti-thymocyte globulin (ATG) 7.5 mg/kg, which wipes out the old immune system. The stem cells to be reinfused are then manipulated to select CD34+ cells. The primary endpoints are differences in mortality and in significant organ damage at 44 months after enrollment.
“This is the safest type of transplant—your own cells, cleared of cells that promulgate scleroderma, and reinfused,” Dr. Sullivan said.
Interim ASTIS safety data look good
The parallel European study is the ASTIS trial. Jacob M. van Laar, MD, reporting on behalf of ASTIS investigators, said that interim safety analysis showed that ASCT transplant added no significant safety risk compared with the control cyclophosphamide.1
Dr van Laar said that 118 SSc patients with early active diffuse disease have been enrolled in 25 centers from 10 countries. He reported a comprehensive interim safety analysis on the first 91 patients enrolled with at least 6 months follow-up, including 43 patients randomized to the transplant arm and 48 to the control arm. Most of these patients had lung involvement.
“No unexpected toxicities were observed in either arm with a median follow-up of 29 months (range 1-72). Grade 3, 4 toxicities occurred in 15/43 transplant patients and in 13/48 controls (P = .42). Fifteen patients had died, including one patient with heart and lung involvement who died from refractory heart failure precipitated by the conditioning regimen,” Dr. van Laar reported..
The investigators concluded that the interim-safety analysis reflected the severity of the underlying disease. There were more serious adverse events on the transplant arm, but the difference between the two treatment arms was not statistically significant.
Promising data from pilot work with mesenchymal stem cells in scleroderma
Mesenchymal stem cells (MSCs) are yet another cell source that might prove useful in treatment of autoimmune diseases. MSC transplant have produced improvement in patients with graft-versus-host disease (GVHD), which resembles aspects of SSc in histological appearance, localization, and clinical symptoms.
Fick et al reported pilot data from single MSC infusions in 5 SSc patients who had severe and refractory skin and esophageal involvement. The investigators obtained allogeneic MSC from cross-gender related donors by bone marrow aspiration, expanded adherent cells over four passages in fresh frozen human plasma and platelet lysate. and in two cases, froze cells with DMSO and stored then for 3 weeks before transplant. Corticosteroid and immunosuppressive therapy continued, and patients received between 18 to 108 x 106 cells via a single infusion. Follow-up was 6 to 19 months.
Dr. Fick reported the following:
- Improvement in modified Rodnan Skin Score (mRSS) that started after 2, 8, 13, and 16 weeks in all five patients and lasted between 1 and 6 months, with an improvement rate between 15% and 40%
- Healing or marked reduction in acral necroses 3/3 patients
- Stable or improved pulmonary fibrotic changes at 6 months in three of four patients who had pulmonary manifestation
There was no treatment related toxicity, but one patient died 5 months after MSCt for reasons not related to treatment.
The researchers concluded, “A single infusion of MSCt is feasible and well tolerated in SSc and does apparently have a beneficial effect as to the skin involvement and acral necroses. These results justify prospective investigations to compare the efficacy of MSCt with that of autologous hematopoietic stem cell transplantation in SSc and to determine the optimal time point of therapeutic interventions.”
Dr. Sullivan said that work with mesenchymal stem cell transplants is in very early stages and that large phase II trials are needed. “Let’s try it in enough SSc patients to develop useful data,” he said. He suggested studies in 20 to 50 patients who would be followed for perhaps 20 years to determine safety and potential benefit.
“Mesenchymal cell transplant aims at a different cell type (not the hematopoietic line) thus with very different goals--these would be parallel and complimentary approaches, not competing ones. Mesenchymal efforts are early and will need significant further basic work before being appropriately launched into significant human trials,” Daniel E. Furst, MD, told MSKreport.com. Dr. Furst, who is protocol co-chair for the SCOT trial, is the Carl M. Pearson Professor of Medicine at the division of rheumatology at UCLA's Geffen School of Medicine in Los Angeles, California.
References
1. van Laar JM, Farge D, Tyndall A, et al. Autologous stem cell transplantation for severe systemic sclerosis: Update on the ASTIS-trial . Presented at: American College of Rheumatology 2008 Meeting; October 27, 2008; San Francisco, CA. Presentation 1223.
2. Fick S, Christopeit M, Schendel M, et al. Allogeneic mesenchymal stem cell transplantation in progressive systemic sclerosis. Presented at: American College of Rheumatology 2008 Meeting; October 28, 2008. San Francisco, CA. Presentation 1769.
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