First report of successful, lifesaving and timely graft rescue using an off-the-shelf cryopreserved, cadaveric marrow in myeloablative transplant with an unexpected unavailability of a living matched unrelated donor.

Abstract

Abstract BACKGROUND: Allogeneic hematopoietic cell transplantation (alloHCT) remains a curative therapy for patients with acute myeloid leukemia (AML) and relies on timely donor availability. When a donor becomes unavailable after conditioning, outcomes can be catastrophic, especially following myeloablative regimens. This case report describes the successful use of cryopreserved, off-the-shelf, hematopoietic progenitor cells (HPC) derived from cadaveric bone marrow (BM), enabling timely stem cell infusion after an unexpected living donor unavailability. METHODS: A 34-year-old male with AML (NPM1, FLT3 TKD, KRAS, PTPN11, WT1, and RAD21 mutations) in first complete remission (CR1) began myeloablative fludarabine/busulfan conditioning in preparation for a 10/10 HLA-matched unrelated donor peripheral blood stem cell transplant. On Day -3 of conditioning, the donor experienced a severe allergic reaction to filgrastim, rendering the donor ineligible. Conditioning was interrupted after receiving 3 of 4 planned doses of fludarabine 40 mg/m2/d and busulfan 131 mg/m2/d (target AUC 20.5 mg*h/L per day). A haploidentical donor was available for a harvest seven days beyond planned day 0 and other MUD or mismatched MUD options were available three weeks past day 0. To facilitate faster receipt of an allograft, an emergency request for a cryopreserved HPC-BM product from a deceased donor was submitted. Within 24 hours of request, a 6/8 HLA-matched, bidirectional ABO mismatched marrow graft was chosen among six allograft options and within 72 hours, the product was shipped to the treating institution. The deceased donor was a 41-year-old White female and 6/8 HLA matched to the recipient. The BM was available as an off-the-shelf product, obtained by harvest from vertebral bodies and processed and cryopreserved via proprietary methods. The product contained 5.57 × 10⁶ CD34+ cells/kg,4.58 × 10⁷ CD3+ cells/kg, and 5.57 × 10⁸ total nucleated cells/kg. Hematocrit was <5% (ABO-depleted), CFU-GM/GEMM count was 110 per 10⁵ TNC, and viability was 91.6%. A fourth fludarabine 40 mg/m2 dose was given and the HPC-BM infusion was infused 48 hours after the planned day 0 and was well tolerated. GVHD prophylaxis consisted of tacrolimus, mycophenolate mofetil, and post-transplant cyclophosphamide (PTCy, 50 mg/kg/d on Days +3 and +4). Patient received filgrastim post-transplant. RESULTS: Neutrophil engraftment was achieved on Day +14 (ANC: D+14 = 1.17 K/µL; D+15 = 5.61 K/µL; D+16 = 10.36 K/µL) with robust platelet engraftment reported by Day +16 (D+16 = 108 K/µL; D+17 = 115 K/µL; D+18 = 138 K/µL). Peripheral blood sorted chimerism on Day +16 showed 6% donor CD3+ and 100% donor CD33+. By day +30, donor chimerism increased to 61% for CD3+ cells and remained 100% donor in the CD33+lineage. Engraftment occurred promptly with discharge on day + 14 with a 26-day length-of-stay. The patient developed steroid-responsive grade II acute upper GI GVHD (stage 1) on Day +27, and Grade 1 skin GVHD responsive to topical therapy. Day +30 marrow biopsy showed molecular and morphologic remission. CONCLUSIONS: This case report illustrates the feasibility and life-saving potential of using cryopreserved bone marrow from deceased donors in urgent allo-HCT scenarios. Day 0 was delayed by only 48 hours and the product was identified within 24 hours of request. Timely access to an off-the-shelf marrow product prevented catastrophic graft failure or debilitating opportunistic infections. Such grafts provide a reliable alternative when living donors become unavailable such as during conditioning and may help overcome critical access barriers in allo-HCT. A clinical trial using cryopreserved, off-the-shelf marrow grafts as primary graft option is underway (NCT #05589896).