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Successful treatment of refractory GVHD in an infant with malignant osteopetrosis with a human adult mesenchymal stem cell based drug

2006; Elsevier BV; Volume: 12; Issue: 2 Linguagem: Inglês

10.1016/j.bbmt.2005.11.208

1523-6536

Gary Kleiner, P. Gordon, John W. Kuluz, G. McLaughlin, R. Pahwa, Camillo Ricordi, Norma S. Kenyon, R. Monroy,

Telomeres, Telomerase, and Senescence

It has been suggested that adult human mesenchymal stem cells (hMSCs) have a potential to treat graft-versus-host Disease (GVHD). At the present time, Osiris Therapeutics is in clinical development with Prochymal™, a cellular therapy consisting of allogeneic bone marrow derived adult hMSCs for the treatment of acute gastrointestinal GVHD. The present work reports a successful treatment of an 8-month-old infant with grade III skin and gut GVHD using Prochymal™. The infant was born with hypocalcemia with normal phosphorus and carbonic anhydrase II, and elevated PTH. Skeletal survey and bone marrow biopsy were consistent with osteopetrosis. The infant received a 4/6 unrelated cord blood transplant after standard Busulfan/Cyclophosphamide/ATG conditioning. The first graft failed and the patient developed autologous reconstitution. A second transplant (4 of 6 matched cord blood) was given at 5 months of life after Fludaribine/Cyclophosphamide/ATG conditioning regimen. The patient developed severe acute grade III skin GVHD with gastrointestinal involvement in the form of bloody diarrhea that was resistant to high dose steroids, Tacrolimus, Cellcept, and anti-CD25 antibody. A compassionate use protocol was developed for the treatment of the patient with Prochymal™. Two intravenous infusions of Prochymal™ were given at a dose of 8 × 106 cells/kg body weight each 3 days apart starting on day 100 post transplant. Both infusions were well tolerated with no associated toxicity or reaction. By the fourth day of treatment, there were initial signs of improvement of the skin. By day 7, the skin improvement was dramatic and episodes of diarrhea had ceased. By day 14, the resolution of this patient's refractory GVHD was essentially complete. Grade IV skin GVHD recurred approximately 1 month following initial treatment after weaning of immune suppression. Repeat treatment with Prochymal™ was administered starting on day 120 post transplant and GVHD symptoms diminished within 1 week. The patient developed 100% donor chimerism. The patient's myeloid engrafted improved from 8% on day 105 post transplant to 100% by day 145. Data suggest that MSCs suppressed the adverse immunological response, healed damaged skin and gut tissue, and aided in engraftment. We conclude that Prochymal™ may be clinically useful for treatment of refractory cases of GVHD.