Novel Allogeneic Stem Cell Transplant Strategies to Mitigate Graft-Versus-Host Disease

Caspian Oliai, MD, MS, UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA discusses findings from a phase 1b/2 study on reducing graft-versus-host-disease (GVHD) and toxicity in allogeneic stem cell transplantation using precision-engineered cell therapy orca-t. Dr Oliai compared this therapy to a strategy of post-transplant cyclophosphamide with myeloablative conditioning.

He presented these insights at the 2022 American Society of Hematology (ASH) Annual Meeting & Exposition in New Orleans, LA.

Transcript:

Hi, I'm Dr. Caspian Oliai from University of California Los Angeles. And I'd like to discuss 2 different strategies that could potentially change practice in allogeneic stem cell transplantation in the near future. The most compelling studies in allo transplant use 2 different strategies to mitigate graft-versus-host disease, making [allogeneic stem cell] transplant more tolerable while maintaining a curative intent of the transplant itself.

The first strategy is using orca-T with myeloablative conditioning, and the other strategy is using post-transplant cyclophosphamide with myeloablative conditioning. I'd like to first discuss the orca-T strategy, which is a cellular immunotherapy from an allogeneic donor that contains a highly purified polyclonal treg population that is infused on the same day as the hematopoietic stem cells, followed by conventional T-cell infusion 2 days later.

 One of the other major differences, just as a note with orca-T, is that it uses single-agent GVH prophylaxis compared to a standard allo transplant that uses multiple-agent prophylaxis. The data presented at ASH  reported on efficacy outcomes of the phase 1b/2 trial, which complimented the data that I presented at EHA this past summer, which demonstrated that orca-T was associated with a large reduction in the rates of graph-versus-host disease.

Efficacy outcomes presented at ASH included 126 patients with AML, ALL and MDS, who underwent allo transplant with Orca-T, which demonstrated an impressive relapse-free survival of 81% at one year. Most importantly, patients who were NCR but had MRD positivity had a substantially better relapse-free survival of 71% compared to 48% in a historical CIBMTR control. Orca-T was well tolerated with a 1-year non-relapse mortality of 0% in patients who received the most common conditioning regimen, which was busulfan, and fludarabine, and thiotepa. The excellent tolerability with low rates of graft-versus-host disease and promising efficacy has led to a phase 3 trial that is currently accruing across the country.

In comparison, an emerging alternative approach to mitigate graft-versus-host disease by adding post-transplant cyclophosphamide in graft-versus-host disease regimen has been published and presented at ASH as well. At ASH, results from a single-center phase 2 trial using post-transplant cyclophosphamide were reported. 125 patients receiving triple-agent GVH prophylaxis with post-transplant Cy, tacrolimus and mycophenolate was reported. This achieved a low rate of severe acute graft-versus-host disease and chronic graft-versus-host disease requiring treatment of only 4%, which was the same rate of graft-versus-host disease in the orca-T outcomes that I presented at EHA this past summer. Relapse rates at 2 years were 25%, and the non-relapse mortality was approximately 10%.

Overall, the outcomes of these two strategies are both promising, but the major difference is that the post-transplant [cyclophosphamide] approach uses multi-agent GVH prophylaxis, in this trial, triple-agent prophylaxis, while the Orca-T approach uses single-agent GVH prophylaxis with tacrolimus only. Due to the lower immunosuppression, I expect relapse and infectious complications may be lower with the orca-T approach. However, a phase 3 trial will be needed to determine if this assumption is true and statistically significant. And a phase 3 trial, again, is accruing across the country.

Source:

Oliai C, Hoeg R, Pavlova A, et al. Precision-Engineered Cell Therapy Orca-T Demonstrates High Relapse-Free Survival at 1 Year While Reducing Graft-Versus-Host Disease and Toxicity. Presented at the ASH Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA, and virtual. Abstract 265.