Omidubicel May Replace Current Standard in UCB Transplant Eligible Hematologic Malignancies

In a phase 3 study, hematopoietic recovery following myeloablative transplantation with omidubicel was faster than standard myeloablative umbilical cord blood (UCB) transplantation and correlated with promising clinical benefit, according to data presented during the 2021 Transplantation & Cellular Therapy Meetings.¹

Transplantation with the investigational advanced cell therapy also resulted in fewer early bacterial or invasive fungal infections and fewer days in the hospital, during the first 100 days post transplantation.

Moreover, no excessive toxicity was observed with omidubicel versus standard UCB transplantation, and long-term follow-up data from recent studies suggest durable engraftment of greater than 10 years with ex-vivo expanded stem cells.

“We believe that these data suggest omidubicel as a new standard of care for patients eligible for umbilical cord blood transplantation,” study author Mitchell Horwitz, MD, a cell therapy and hematologic malignancies specialist at Duke Health, said during an oral presentation of the data. “[The sponsor], Gamida Cell, will be submitting these data for regulatory review in the coming months.”

The use of UCB as a stem cell source for allogeneic transplantation comes with several advantages: it is a readily available source, there is less evidence of chronic graft-versus-host-disease (GVHD) compared with matched unrelated donor transplantation, it exhibits potent antitumor activity, and it has been utilized for almost 30 years in the field.

The primary disadvantage of this treatment is that it can result in a low stem cell dose, which can lead to delayed hematopoietic and immunologic recovery and increased transplant-related morbidity and mortality, said Horwitz. This approach may also result in increased resource utilization, particularly in adult transplant recipients. However, ex-vivo expansion of the umbilical cord blood graft prior to transplantation may present a possible solution to these limitations, according to Horwitz.

Omidubicel is a cryopreserved allogeneic stem cell-based product comprised of ex-vivo expanded UCB-derived CD34-positive progenitor cells and non-expanded myeloid and lymphoid cells. It is derived from a single, best matched UCB unit, selected by the transplant center, Horwitz explained.

After CD133 selection, a negative T-cell containing fraction is cryopreserved, and the CD133-positive fraction is cultured for 21 days in the presence of nicotinamide, which is the critical point of the culture system, Horwitz added. Nicotinamide plays a key role in metabolic reprogramming of cells, is a master regulator of NAD-related signaling pathways, is directly involved in control of redox-sensitive enzymes, and preserves cellular functionality and phenotype during expansion.

Previously, a phase 1/2 study demonstrated robust hematopoietic reconstitution with omidubicel. For the phase 3 trial, investigators sought to evaluate the efficacy of omidubicel compared with standard UCB in patients with hematologic malignancies.

To be eligible for enrollment, patients had to be between the ages of 12 years and 65 years, have a high-risk hematologic malignancy, be a candidate for allogeneic bone marrow transplantation, and not have a matched donor.

Participants in the intent-to-treat (ITT) population were randomized to receive omidubicel (n = 62) versus standard UCB (n = 63). Of those patients, 108 were transplanted with either omidubicel (n = 52) or standard UCB (n = 56); these patients comprised the as-treated population of the trial.

Cord blood units were selected before randomization and patients were stratified by treatment center, disease risk index (DRI), age, and intent to perform a single or double cord transplant in the control arm. Myeloablative conditioning was limited to either a chemotherapy-only regimen or 2 total body irradiation (TBI)–based regimens.

The primary end point of this study was time to neutrophil engraftment, and secondary end points included time to platelet engraftment, the incidence of grades 2/3 invasive bacterial or fungal infections at 100 days, and days alive out of the hospital following the first 100 days post transplantation.

The patient demographics were well balanced, according to Horwitz. The median age of participants in the ITT population was 41.5 years and 57.5% were male. The majority, or 48%, had acute myeloid leukemia, 32.5% had acute lymphocytic leukemia, 7.5% had myelodysplastic syndromes, 5% had chronic myeloid leukemia, 4% had lymphoma, and 3% had a rare leukemia. Additionally, the majority, or 58%, of patients were White, 16% were Black, 13.5% were Asian, and 13% were other.

“Half of the patients received a TBI-containing myeloablative conditioning regimen,” noted Horwitz.

When looking at graft characteristics, regarding the total CD34-positive cell content, the omidubicel unit was expanded to a median of 6.6 x 108 CD34-positive cells, noted Horwitz; this provided patients with a median CD34-positive cell dose of 9.0 x 106 cells/kg, “a cell dose larger than that collected from many healthy adult stem cell donors,” said Horwitz. In contrast, those in the control arm received a median CD34-positive cell dose of 0.3 x 106 cells/kg.

Median time to neutrophil engraftment in the ITT population was 12 days (95% CI, 10-15) in the omidubicel ITT arm, and 22 days (95% CI, 19-25) in the control ITT arm (P <.001). “This difference was highly statistically significant,” noted Horwitz.

Moreover, in the AT population who received the omidubicel engraftment, the median time to neutrophil recovery was 10 days (95% CI, 8-13) versus 20.5 days (95% CI, 18-24) in those who received the control (P <.001). The cumulative incidence of neutrophil engraftment was 96% in those who received omidubicel versus 89% for those who received the control.

Platelet engraftment by day 42 was achieved in 55% of those in the ITT population who received omidubicel versus 35% of those who received the control, translating to a 20% difference in cumulative incidence between the arms (P = .028). Additionally, the cumulative incidence of platelet engraftment in the AT population at day 100 was 83% at a median of 37 days (95% CI, 33-42) with omidubicel versus 73% at a median of 50 days (95% CI, 42-58) with the control (P <.023). “This was also a difference that was statistically significant,” noted Horwitz.

Moreover, patients in the ITT population who received omidubicel were found to be less likely to develop grade 2/3 bacterial or invasive fungal infection by day 100, added Horwitz. The incidence of these infections was 37% in the investigative arm versus 57% in the control arm (P = .027).

“In an unexpected, but positive finding, recipients randomized to omidubicel were less likely to experience grade 3, severe viral infections,” reported Horwitz. The incidence of these infections in the omidubicel arm was 10% versus 26% in the control arm. “[We also saw a] significant reduction in human herpesvirus 6 and cytomegalovirus in those who received omidubicel,” added Horwitz.

Investigators also conducted a quantitative lymphocyte analysis and showed that there were significant differences in B cell and natural killer cell recovery, said Horwitz; this was found to favor patients who received omidubicel.

Moreover, patients in the ITT population who were given omidubicel spent a median of 60.5 days alive and out of the hospital during the first 100 days post transplant versus 48.0 days in those who received the control (P = .005); this translated to about a 13-day difference and “it was due primarily to a shorter initial period of hospitalization,” explained Horwitz.

No difference in grade 2 or higher acute GVHD was observed between the arms. Fifty-six percent of patients on the investigative arm experienced grade 2 to grade 4 acute GVHD versus 43% of those on the control arm. Grade 3 and 4 acute GVHD was reported in 8% of patients who received omidubicel versus 12% of those given the control.

“No difference in the incidence of chronic GVHD was observed between the 2 arms [at 1 year],” added Horwitz; here, the P value was 0.57.

The cumulative incidence of non-relapse mortality at 210 days post randomization “trended slightly lower” for those who received omidubicel compared with those who received the control, at 11% versus 24%, respectively (P = .09). Incidence of relapse at 15 months post randomization was 25% in the investigative arm versus 17% in the control arm (P = .32), although this difference was not determined to be statistically significant.

No differences in the probability of disease-free survival (P = .68) and overall survival (P = .16) were observed between the arms. “It should be noted that the study was not powered to detect differences in these end points and the 10-month median follow-up also compromised analysis of these end points,” concluded Horwitz.

_Reference:

_{Horwitz ME, Stiff P, Rezvani AR, et al. Improved clinical outcomes with omidubicel versus standard myeloablative umbilical cord blood transplantation: results of a phase III randomized, multicenter study. Presented at: 2021 Transplantation and Cellular Therapy Meetings; February 8-12, 2021; Virtual. Abstract 34.}