Initial Trials Indicate Reduced Intensity Stem Cell Transplant Safe for Scleroderma Patients

Newswise — A phase I trial of non-myeloablative or reduced intensity hematopoietic stem cell transplantation (HSCT) in patients with systemic sclerosis (scleroderma) has proven safe and well tolerated, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Washington, DC.

Myeloablative stem cell transplantation, which can destroy all of the bone marrow cells, has been used to treat patients with certain types of malignant diseases for many years. Some of these patients who also happened to have an autoimmune disease showed improvement in both disorders. On occasion, their autoimmune diseases actually disappeared for extended periods of times. However, this intensive chemotherapy, which can be accompanied by total body irradiation, introduces significant risks for morbidity and even mortality from the therapy itself. For most patients with autoimmune diseases, this level of toxicity outweighs the potential beneficial results.

To determine if a non-myeloablative HSCT transplant " the same type of transplant treatment but delivered at a reduced intensity " would prove safe and well tolerated, researchers conducted a phase I trial on 10 individuals with systemic sclerosis and poor prognosis. Systemic sclerosis, which affects one to two people in every 10,000, is a chronic rheumatic disease that causes progressive changes of damage to blood vessels and scarring in the skin, joints and internal organs especially the lungs, heart and kidneys. While the skin hardening caused by the disease is not life-threatening, it can cause disability and significant emotional distress to affected patients, whereas involvement of the lungs, heart and kidney can lead to early mortality.

The 10 participants, each less than 65 years of age with the disease for less than 5 years, had extensive skin hardening plus evidence of lung, kidney or heart involvement. The hematopoietic stem cells used were taken from the blood of each patient and later reinfused back into that patient after the patient was treated with drugs that suppress the immune system and the blood counts. No myeloablative chemotherapy or radiation was included in the treatment regimen thus making it a "reduced intensity" treatment regimen.

Within 12 months most patients showed a significant improvement in skin scores and their cardiac, pulmonary and renal functions remained stable. Two years later, 7 out of 10 had no signs of worsening disease. One patient died of complications related to the underlying disease, but there were no treatment-related deaths. Preliminary efficacy data suggest that the reduced intensity approach to HSCT brought about improvements in skin comparable to those reported for the more intensive myeloablative approach.

"This is a controversial area of treatment and one in which more study is warranted," states Walter G. Barr, MD, Professor, Division of Rheumatology, Northwestern University Medical School, Chicago, Illinois, and an investigator in the study. "That said, we do believe this phase I trial demonstrates that reduced intensity HSCT is safer and better tolerated in the short run than the more intense approaches to transplantation and the preliminary data looks positive with regards to efficacy. If these initial observations hold up over time, HSCT may become an acceptable therapeutic option for more individuals afflicted with severe forms of autoimmune disease."

The American College of Rheumatology is the professional organization for rheumatologists and health professionals who share a dedication to healing, preventing disability and curing arthritis and related rheumatic and musculoskeletal diseases. For more information on the ACR's annual meeting, see http://www.rheumatology.org/annual.

Presentation Number: 688

Autologous Non-Myeloablative Peripheral Blood Stem Cell Transplantation in Patients with Systemic Sclerosis

Walter G. Barr, Yu Oyama, Laisvyde Statkute, Thomas Corbridge, Kimberly Yaung, Kathleen Quigley, Larissa Verda, Nela Krosnjar, Delphine Bronesky, Richard K. Burt. Northwestern University, Chicago, IL

Purpose: Autologous hematopoietic stem cell transplantation using a myeloablative regimen has shown promising results in the treatment of systemic sclerosis (SSc) but has been accompanied by substantial treatment related mortality (TRM) and morbidity. We have performed autologous peripheral blood stem cell (PBSC) transplantation utilizing a non-myeloablative but intense immunoablative conditioning regimen in order to reduce TRM and morbidity.

Methods: A Phase I autologous PBSC study was conducted in 10 patients with SSc and poor prognostic features. Candidates were less than 65 years old with a modified Rodnan skin score ( mRSS ) greater than 14 or a diffusion capacity less than 80%, interstitial lung disease, elevated ESR, renal involvement, or abnormal ECG. Only one patient had a mRSS less than 23 at entry into the trial. Eight of the ten patients had pre-transplant high resolution chest CT ( HRCT ) findings consistent with interstitial lung disease. Patients with severe pulmonary hypertension ( > 45 mm Hg ) were excluded. PBSC were mobilized with cyclophosphamide and granulocyte colony-stimulating factor. The PBSC graft was cryopreserved without manipulation and reinfused after the patient was treated with a lymphoablative but non-myeloablative conditioning regimen of 200 mg/kg cyclophosphamide and 7.5 mg/kg rabbit antithymocyte globulin ( rATG ).

Results: The median number of days for neutrophil and platelet engraftment were 9 ( range 7-11 ) and 9 ( range 0-14 ), respectively. The median infused CD 34+ and CD3+ cell counts were 7.38 x 106/ kg ( range 2.35 - 14.7 ) and 2.14 x 108/ kg ( range 0.41-6.83 ), respectively. There was a marked improvement of mRSS in most of patients whereas cardiac ( ejection fraction, pulmonary artery pressure ), pulmonary function (DLCO) and renal function (creatinine) remained stable. One patient with advanced disease and poor pre-transplant performance status died 2 years after transplant in a nursing home. That patient had a normal pre-transplant HRCT and enjoyed improvement in skin score after transplant. After median follow-up of 25.5 months ( range 5-40 ), the overall survival is 90% ( nine out of ten) and progression-free survival is 70% ( seven out of ten ). Two patients had recurrence of skin thickening at 12 and 24 months respectively. One of these two patients stabilized and one improved the mRSS after initiation of mycophenylate mofitel.

Conclusions: Autologous PBSC transplantation with a non-myeloablative conditioning regimen of Cy/rATG appears safe with no TRM in our first 10 patients and no deterioration of PFTs observed in the 12 months post-transplantation. These results suggest that further evaluation of this regimen in a randomized controlled trial is warranted

Disclosure Block: W.G. Barr, None; Y. Oyama, None; L. Statkute, None; T. Corbridge, None; K. Yaung, None; K. Quigley, None; L. Verda, None; N. Krosnjar, None; D. Bronesky, None; R.K. Burt, None