Outcomes of omidubicel-expanded umbilical cord blood transplantation in patients with severe aplastic anemia

Abstract Introduction Severe Aplastic Anemia (SAA) is a life-threatening disorder characterized by bone marrow failure, pancytopenia, infections, and transfusion dependence. While immunosuppressive therapy (IST) and eltrombopag can lead to long-term survival, many patients fail to respond or experience relapse and/or clonal evolution. For patients who do not have a HLA-matched donor for salvage allogeneic hematopoietic stem cell transplantation, umbilical cord blood transplantation (UCBT) provides a viable alternative but is often complicated by slow engraftment and high rejection rates due to low cord total nuclear cells (TNC) and stem cell (CD34+) numbers. To enhance UCBT outcomes, we initiated a trial to evaluate the effectiveness of omidubicel (nicotinamide ex-vivo expanded UCBT) for SAA refractory to IST treatment. Methods Eligible SAA patients aged 4-60 years with severe neutropenia (ANC<1000 cells/µL), lacking an HLA-matched related or unrelated donor, and unresponsive to standard IST underwent omidubicel transplantation in a single-center phase II trial (NCT03173937). Additional criteria included having a ≥4/8 HLA matched UCB unit with ≥1.8 x 109 and ≥1.5x107/kg TNC and ≥8 x 106CD34+ cells pre-expansion. The conditioning regimen included horse anti-thymocyte globulin (ATG 40 mg/kg, D-11 to -8), cyclophosphamide (60 mg/kg, D-7 and -6), fludarabine (25 mg/m2, D-5 to -1) and 2 Gy total body irradiation (TBI) on D-1. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus/mycophenolate mofetil (MMF). The study aimed to transplant 3-6 patients with omidubicel combined with CD34+ selected haploidentical cells as a stem cell backup (Cohort 1), followed by the enrollment of 23 patients receiving a single expanded UCBT (Cohort 2). The primary end point was sustained early engraftment at days 26, 42 and 100. Secondary endpoints include overall survival and standard transplant outcomes. Results From August 2017 to June 2025, 18 SAA patients (3 in Cohort 1 and 15 in Cohort 2) who failed ATG/cyclosporine/eltrombopag were transplanted. Median age at transplant was 19 years (range 6- 45), with 10 (56%) male and 8 (44%) female, 6 (33) identifying as Asian, 5 (28%) as Black, 3 (17%) as White and 4 as Latino or Hispanic. At baseline, patients had pre-transplant ANC 440/µL (IQR 92-615), ferritin 4,265 µg/L (IQR 3,427- 6,804), 72% with HLA allo-immunization. UCB units were matched at a median of 5/8 HLA-alleles; omidubicel contained a median of 2.4 x 105(pre-expansion) and 95 x 105 (post-expansion) CD34 cells/kg, representing a median 38-fold (IQR 26-57) expansion. With a median follow-up of 2.3 years (range 35 days - 5 years), 17 (94%) achieved neutrophil recovery at a median of 8 days (IQR 7-13), 16 (89%) had platelet recovery at a median of 24 days (IQR 20-30), 17 (94%) reached full (³95%) myeloid chimerism at a median of 14 days (IQR 14-15), and 14 (77%) reached full T-cell chimerism at a median of 21 days (IQR 14-27). Among 17 patients (with 100+ days of follow-up or off-study), 15 (88%) had sustained engraftment by day 100 and transfusion independence. The cumulative incidence of grade II acute GVHD was 17%, and no occurrences of grade III-IV acute GVHD or chronic GVHD. The GVHD/relapse-free survival and overall survival rate was 94%, with one patient who died at day 62 after adenovirus infection. Immune recovery post-transplant was rapid: At day 100, median CD4 count was 123/µL [IQR 86-322] and median IgG level was 454 (IQR 351 -587); At day 180, median CD4 count was 405/µL [IQR 200-498] and median IgG level was 399 (IQR 314-690). There were 5 (28%) patients with CMV reactivation requiring treatment and 6 (33%) with EBV reactivation requiring treatment; one patient had CMV disease and one patient had PTLD, both resolved following treatment. Conclusion These results suggest that omidubicel is a promising alternative graft source for treatment-refractory SAA patients lacking an HLA-matched donor. Despite high-risk features, patients experienced extremely rapid and sustained engraftment, early immune recovery, low rates of GVHD, and encouraging survival outcomes. These promising interim results warrant further investigation.