Engraftment of a T-cell depleted matched unrelated donor stem cell graft using nonmyeloablative conditioning

Abstract

Non-myeloablative conditioning (NMC) for hematopoietic stem cell transplantation (SCT) has recently been employed as an alternate means of decreasing regimen-related toxicity. When using NMC, donor T-cells are believed to facilitate engraftment of donor stem cells, yet also play a role in GVHD and GVL. Recently, megadoses of highly purified CD34 cells have been used to transplant across HLA barriers and reduce OVHD. An ideal protocol would utilize megadoses of highly purified CD34 cells with NMC, particularly for non-malignant disorders in which GVL is not needed. However, a low T-cell dose may preclude consistent donor stem cell engraftment. Here, we report a second allogeneic SCT using NMC and a T-cell depleted matched unrelated donor graft demonstrating the potential for donor engraftment with a reduced T-cell dose. The patient is a 9-year-old female who was diagnosed with MDS (+8) in 11/96. She received an HLA matched sibling graft after completing our standard conditioning regimen of cytarabine, cylcophosphamide, and TB1 (12 Gy) and attained 99.6% donor engraftment. Twenty-seven months later, she relapsed with AML (+8) including a right maxillary chloroma and CNS disease (CNS-2 status). She received 2 courses of 2-chloro-deoxyadenosine and topotecan, 8 doses of intrathecal therapy, and radiation therapy (23.7Gy) to the right maxillary sinus chloroma. She underwent a second allogeneic SCT utilizing NMC, that included fludarabine, busulfan, ATG, and TBI (2 Gy). The matched unrelated donor graft was T-cell depleted by an anti CD6/CD8 antibody cocktail and complement ( 1.5 log reduction) resulting in a graft containing 3.39x10 CD34 cells/kg, and 1.67 x 106 CD3 cells/kg. Her BM revealed 100% donor engraftment on day + 18, and engraftment confirmed on day +52 and day +222. She achieved myeloid reconstitution on day 20 when her ANC was 550/mm3 and sustained a platelet count >20K without support on day 21. We have illustrated that complete donor cell engraftment can be achieved using NMC and a T-cell depleted HSC graft. We conclude that combining a treatment regimen of NMC and megadoses of highly purified CD34 cells may be a viable approach to reduce treatment toxicity. This strategy may be especially valuable in the treatment of non-malignant disorders in which GVL is not required. A pilot clinical trial is warranted to investigate this approach.