A novel therapeutic approach is showing promise in improving outcomes for patients undergoing hematopoietic stem cell transplantation (HSCT) from half-matched donors. The regimen, known as CAST, combines post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus. Recent research published in Transplantation and Cellular Therapy supports the potential of this regimen to prevent graft-versus-host disease (GVHD) and improve overall survival in these patients.
The CAST regimen was initially evaluated in a phase 1b/2 trial, the results of which were published in Blood Advances in July 2023. The trial, which enrolled 46 patients, found that the CAST regimen was associated with excellent rates of GVHD prevention, nonrelapse mortality, relapse rate, overall survival, and GVHD- and relapse-free survival over a median follow-up of 15.3 months.
Haploidentical transplants, which utilize healthy cells from a half-matched donor (often a family member), offer a lifeline for patients lacking fully HLA-matched donors. While HLA-matched donors are preferred, siblings only have a 25% chance of being a full HLA match. The use of haploidentical HSCT has been particularly beneficial in improving access to transplantation for patients from minority groups, who are often underrepresented in donor registries. However, outcomes following haploidentical transplantation have historically been inferior to those achieved with HLA-matched unrelated donor transplants.
In the latest study, researchers conducted a propensity score-matched analysis using data from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. The analysis compared outcomes in patients treated with the CAST regimen to those receiving the standard GVHD prevention regimen of PTCy, tacrolimus, and mycophenolate mofetil between 2017 and August 2022.
Key Findings
The study revealed that at 120 days post-treatment, the rate of acute GVHD grades 2-4 was 16.7% in the CAST cohort, compared to 28.6% in the control cohort. Furthermore, the 1-year GVHD- and relapse-free survival rate was 66.7% in the CAST cohort versus 47.6% in the control cohort. While these trends did not reach statistical significance due to the small sample size, other key outcomes did show significant improvements.
Notably, the CAST regimen was associated with a statistically significant reduction in the incidence of relapse. The relapse rate was 9.5% for patients on CAST compared with 26.2% for patients on the standard regimen. CAST also led to a statistically significant improvement in disease-free survival (85.7%) compared with the standard treatment (61.0%).
Implications for Transplantation
The need for HLA-matched donors has historically limited the use of HSCT, a potentially curative therapy for high-risk and advanced hematological malignancies. As the authors note, "This limitation disproportionately affects patients belonging to specific ethnic and racial groups, and it is particularly challenging for an increasing number of mixed-race individuals." The greater availability of haploidentical donors offers a potential solution to this challenge.
The study authors suggest that the CAST regimen can improve outcomes of haploidentical HSCT, thereby reducing disparities for patients who lack readily available matched donors. They conclude that the data from this analysis support further evaluation of the CAST regimen in a randomized controlled trial to definitively establish its efficacy and safety.
