Session: 732. Clinical Allogeneic Transplantation: Results: Poster I
Hematology Disease Topics & Pathways:
Biological, Therapies, Pediatric, Young Adult, Study Population, Clinically relevant, transplantation, stem cells
Methods: In an effort to modulate disease activity with decreased toxicity, we investigated the safety of and preliminary responses to BMT with a reduced-intensity conditioning regimen (rabbit anti-thymocyte globulin 2.5 mg/kg with a methylprednisolone taper, cyclophosphamide 28 mg/kg, fludarabine 150 mg/m2, and low dose total body irradiation 300-400 cGy). Graft-versus-host disease (GvHD) prophylaxis included post-transplant cyclophosphamide (PTCy, 50 mg/kg recipient weight/dose on days +3 and 4) and mycophenylate mofetil from day +5 to 35. All except HLA-matched related donor recipients received tacrolimus from day +5 until tapered at day +100. Immunomodulatory donor-derived mesenchymal stromal cells (MSCs, 2 x 106 cells/kg recipient weight/dose) were infused at 60, 100 and 180 days post-BMT. Skin biopsies, medical photography, and dynamic assessments of RDEB disease activity by providers and parents were completed at baseline, day +100, +180 and 1 year post-BMT.
Results: Ten RDEB patients were transplanted at a median age of 9.9 years (range 1.8 to 22.1), with a median follow-up of 16 months (1 year evaluations available for only 4 of 10). Donors were haploidentical related (n=6), HLA-matched related (n=3), and HLA-matched unrelated (n=1). BMT complications included graft failure in 3 patients (2 elected to pursue a 2nd PTCy BMT), veno-occlusive disease in 2, posterior reversible encephalopathy in 1, and chronic GvHD in 1, the latter deceased. Infectious complications in the first 100 days were limited to 3 viremia, 7 bacteremia, and 0 fungemia episodes. No serious adverse events were observed with MSC infusions. In the 9 ultimately engrafted patients, median donor chimerism at day +180 was 100% in both myeloid and lymphoid fractions of peripheral blood and 27% in skin. Skin biopsies at day +180 show stable (n=7) to improved (n=2) type VII collagen protein expression by immunofluorescence (IF) and gain of anchoring fibril components by transmission electron microscopy in 4 of 9 patients. Early clinical response included a trend toward reduced body surface area of blisters/erosions from a median of 45.5% at baseline to 27.5% at day +100 (p=0.05), with parental measures indicating stable quality of life. Select medical photography and skin biopsy results are shown for Patient 1 [IF: 40x merged dapi (blue) and C7 collagen antibody (red); immunoelectron microscopy with C7 collagen-directed immunostain (black)].
Conclusions: BMT using reduced-intensity conditioning, PTCy and donor-derived MSC infusion for RDEB was largely well tolerated with low rates of GvHD and death from regimen-related toxicity in 1 of 10 patients undergoing 12 total BMTs. Early follow-up suggests this treatment modulates RDEB disease activity but requires longer follow-up for evaluation of efficacy. Importantly, the PTCy BMT platform provides a means of attaining immunotolerance for future donor-derived cellular grafts.
Disclosures: Wagner: Magenta Therapeutics: Consultancy, Research Funding; Novartis: Research Funding.
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