Significant Risk of Graft-versus-Host Disease with Exposure to Checkpoint Inhibitors before and after Allogeneic Transplantation

Abstract

Investigators are using checkpoint inhibitors (CPIs) to treat aggressive hematologic malignancies in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) and in some patients with relapsed disease after allo-HSCT. CTLA-4 inhibitors and PD-1 inhibitors are 2 main types of CPIs, which work through activation of the immune system. On one hand, CPIs can achieve graft-versus-tumor effect, and on the other hand, there is a risk of graft-versus-host disease (GVHD). After a comprehensive literature review, we included data (n = 283) from 24 studies (11 original manuscripts and 13 case reports or case series) and evaluated the results to assess the safety and efficacy of CPI use in conjunction with allo-HSCT. Among the 283 patients, 107 received CPI before allo-HSCT, and 176 received CPI after allo-HSCT. The most common indication for CPI use was for Hodgkin lymphoma. The CPIs used in various studies included ipilimumab, nivolumab, and pembrolizumab. Among the patients exposed to CPI before allo-HSCT, 56% developed acute GVHD and 29% developed chronic GVHD. Investigators reported 20 deaths, 60% of which were GVHD-related. The overall mortality risk with GVHD is 11%. In this group, investigators noted an objective response rate (ORR) in 68% of patients, with complete remission (CR) in 47%, partial remission (PR) in 21%, and stable disease in 11%. Among the patients who received a CPI after allo-HSCT for disease relapse, 14% developed acute GVHD and 9% developed chronic GVHD. Investigators reported 40 deaths, 28% of which were GVHD-related. The mortality risk with GVHD is approximately 7%. Investigators reported ORR in 54% of patients, with CR in 33%, PR in 21%, and disease stabilization in 5%. After careful evaluation of collective data, we found that CPI use both before and after allo-HSCT can be highly effective, but exposure can lead to a significantly increased risk of GVHD-related morbidity and mortality in this patient population. Despite limited availability of data, there is need for extreme caution while making decisions regarding the use of CPIs. Detailed discussions and prospective well-designed clinical trials are needed to explore this issue further.

Exploiting autoimmunity unleashed by low‐dose immune checkpoint blockade to treat advanced cancer

“…Our studies in mouse models highlighted the potential risks of combining lymphoablative therapy and HSCT with ICIs . By now, the GVM effect of ICIs has been confirmed by several studies in the allogeneic setting (see in reference). One hundred seven patients received ICIs before allo‐HSCT and 176 patients received ICIs after allo‐HSCT.…”

Effect of <i>CTLA4</i> gene polymorphism on relapse probability among patients with acute leukemias after allogenic hematopoietic stem cells transplantation

“…Активно исследуется использование блокаторов иммунологических контрольных точек до алло-ТГСК и после нее для терапии онкогематологических заболеваний. Например, блокатор CTLA-4 может применяться до алло-ТГСК и после нее [23].…”

Harnessing the immune system after allogeneic stem cell transplant in acute myeloid leukemia

“…This represents a remarkably high rate of death from GVHD (7%) among patients receiving checkpoint inhibitors after allo‐SCT. However, the overall response rate to post‐transplant checkpoint inhibition for relapsed disease was 54%, with complete response in 33% of patients, though the majority of patients were being treated for Hodgkin lymphoma (89 of 176) . Thus, while the safety of post‐transplant checkpoint inhibition remains a major concern, this should be interpreted in the context of promising response rates for a patient population with very limited treatment options.…”