In addition to showers, flowers and warmer weather, this spring also brought renewed hope for patients with hematological malignancies undergoing stem cell transplants (SCTs) in the form of the approval of Gamida Cell’s Omisirge® (omidubicel). This cell-based therapy will reduce the risk of life-threatening infections that these patients face during the process of their life-saving SCT.
If you read my most recent post on matching stem cell donors and recipients, you’ll recall that there is a significant challenge in finding an appropriate match. Individuals suffering from hematological malignancies (e.g. leukemia, lymphoma and myelodysplastic syndrome), often require a SCT as curative therapy. But without a suitable match, these patients typically die from their illness. The advent of using umbilical cord blood (UCB), as a source for stem cells, has allowed many of these patients to undergo a SCT.
However, as with all treatments, transplant with UCB-derived stem cells (UCB-SCs) comes with its own risk. Part of any hematopoietic transplant process involves a myeloablative regimen (total body radiation and/or chemotherapy) that destroys the patient’s existing bone marrow stem cells prior to transplantation of the donor cells. During the period between the conditioning and transplant, patients are extremely vulnerable to infections as they have no immune system, and need time for the transplanted cells to engraft and produce cells. Compared to adult stem cells (derived from bone marrow), UCB-SCs have a delayed hematopoietic recovery and immune reconstitution, which leads to increased morbidity and mortality as patients remain immunocompromised for longer.
In attempts to improve time to engraftment, double UCB-SC grafts have been introduced. The idea behind using two UCB units, rather than a single unit, is that there is a higher number of cells at the time of transplantation, which would translate to increased engraftment rates, and earlier reconstitution of the patient’s immune system. Other approaches, though far from being adopted as the standard of care, include ex vivo expansion of the hematopoietic lineages, prior to transplantation.
Gamida scientists developed a culture technique that expands robust HSCs from UCB-SCs prior to transplantation. The approach involves fractionating UCB-SCs into CD133+ and CD133- populations, where the CD133+ cells were cultured in conditions that allow for the expansion of HSCs. The Gamida group found that by incorporating nicotinamide (a form of vitamin B3) in their culture conditions, they were better able to inhibit differentiation into non-HSC lineages, while enhancing the function of the expanded HSC and progenitor cell populations. They were also able to demonstrate increased homing to the bone marrow niche, after infusion into recipients. Phase I/II clinical trials were promising in comparison to historical controls, in that neutrophil recovery time was significantly reduced.
The company published their Phase III clinical data in Blood, in October 2021. The randomized control trial tested the efficacy of omidubicel (n=62) versus standard double UCB-SC transplant (n=63) in adult and pediatric patients with hematological malignancies. Patients were required to have an HLA-matched UCB donor and not have any anti-donor antibodies, as the use of cord blood does not remove the need for proper matching. All patients underwent one of three permitted myeloablative therapies prior to transplantation, and had the same graft versus host disease (GVHD)-prophylaxis regimen. Treatment with omidubicel had higher overall engraftment rates than standard double UCB-SC, and a significantly shorter time to neutrophil engraftment. Secondary endpoints included platelet recovery by 42 days, incidence of first bacterial infection, and time out of hospital during the first 100 days post-transplant – all of which had significantly improved measures in the treatment arm. There was a slightly higher number of cases of GVHD and disease relapse in the omidubicel arm, but this was not found to be statistically significant.
To expand on the longer-term safety and efficacy of omidubicel, a more recent long-term effects study was published in Transplantation and Cellular Therapy in May 2023. This study was a pooled analysis of patients receiving omidubicel across several multi-centre clinical trials. The three-year overall survival and disease-free survival was 62.5% and 54.0%, respectively. Most commonly, causes of mortality or morbidity were related to disease relapse, serious infection, or chronic GVHD. Patients who were 10 years post-engraftment had well-established hematopoetic lineages of red blood cells, platelets and white blood cells (including helper and killer T cells, B cells and natural killer cells). This study did not include comparison values for control groups – likely since only one of the included trials would have had a non-omidubicel control – so it is unclear whether the status of the omidubicel-treated patients is significantly different from those who would have received conventional double UCB-SC therapy. However, the long-term presence of immune cells is encouraging.
Omidubicel – marketed as Omisirge® – having demonstrated sufficient safety and efficacy data in clinical trials, was granted Breakthrough Therapy Designation from the FDA, and is now on the U.S. market for specific conditions. The cell-based therapy also has the benefit of Orphan Drug Designation in both the U.S. and European Union, which gives the drug sponsors (Gamida Cell Ltd.) various process incentives to develop new treatments for rare diseases.
While this therapy is newly approved, I’m looking forward to seeing if it starts to become the standard of care for those undergoing UCB-SC transplant. With such a clear early benefit in infection-reduction and improved engraftment, omidubicel seems to be an obvious preferred choice. Approval for use outside of clinical trials will increase the number of patients who receive the treatment, which will provide additional data to clarify any longer-term risks associated with omidubicel. Hopefully, the results aren’t too good to be true!
Sara M. Nolte
Latest posts by Sara M. Nolte (see all)
- Ottawa researchers make tumour-marker negative cancers positive with oncolytic viruses - December 19, 2024
- Cell-based therapy approved as alternative to standard UCB transplant for hematological malignancies - June 21, 2023
- Finding the perfect match: breaking down the science of organ and stem cell transplant matching - April 18, 2023
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