EBMT 2018 | PD-1, PD-L1 and LAG3 expression may predict post allo-SCT lymphoma outcomes

An oral session on lymphoma took place at the 44^th European Society for Blood and Marrow Transplantation (EBMT) annual meeting on 19 March 2018. Abstract OS1-7 was presented by Enrico Derenzini from the European Institute of Oncology, Milan, Italy, on the effect of immune checkpoint activation following allogeneic stem cell transplantation (allo-SCT) in lymphoma patients.

Immune checkpoint inhibitors, like the anti-programmed death 1 (PD-1) and the anti-programmed death ligand 1 (PD-L1) antibodies have attracted a lot of clinical attention due to their high therapeutic potential in lymphoma, as immune cell-tumor interaction suppressors. Moreover, it has been reported that PD-1/PD-L1 and the lymphocyte activation gene-3 (LAG3)—a known PD-1/PD-L1 interactor protein—cooperate in promoting immune escape in cancer. In this retrospective study, the authors investigated whether the expression levels of PD-1, PD-L1 or LAG3 can predict clinical outcomes in pre-transplant tumors of lymphoma patients that received allo-SCT. Primary endpoints included progression-free survival (PFS), overall survival (OS)

Study design & patient characteristics

• Retrospective analysis of patients undergoing allo-HSCT for relapsed/refractory (R/R) mature B- or T-cell lymphoma, with pre-transplant tissue biopsies, at the European Institute of Oncology, Milan, Italy between 2003 and 2016
• N = 24 patient biopsies
• Median patient age (range): 45 (22–66) years (n = 15 males)
• Patient diagnosis:
  • Hodgkin lymphoma (HL): n = 9 (37.5%)
  • B-cell non-Hodgkin lymphoma (NHL): n = 9 (37.5%)
    • Diffuse large B-cell lymphoma (DLBCL): n = 3
    • Follicular lymphoma (FL): n = 3
    • Chronic lymphocytic leukemia (CLL): n = 3
  • Peripheral T-cell lymphoma (PTCL): n = 6 (25%)
• Transplantation:
  • Receiving HLA matched SCT: n = 17 (71%) or haploidentical SCT: n = 7 (29%)
  • Receiving reduced intensity conditioning (RIC): n = 18 (75%) or myeloablative conditioning (MAC): n = 6 (25%)
  • Patients with prior autologous-SCT: n = 17 (71%)
  • Median time from biopsy to allo-SCT (range): 14 (3–37) months
• Semi-quantitative immunohistochemical H-score method was used to quantify the expression levels of PD-1 and LAG3 in T-lymphocytes, and PD-L1 in lymphoma cells.
• Positivity was defined as > 1% cells expressing the marker of interest

Key findings

• Median follow-up (range): 29 (1.5-166) months
• PFS (whole cohort): 62%
• OS (whole cohort): 38%
• PD-1-positive expression: n = 10 patients (42%) (6, HL; 4, B-cell NHL)
• PD-L1-positive expression: n = 10 patients (42%) (8, HL; 2, PTCL)
• LAG3-positive expression: n = 13 patients (54%) (7, HL; 3, B-cell NHL; 3, PTCL)
• Combined H-score ratio (PD-1, PD-L1, LAG3) was higher in patients progressing or relapsing after allo-SCT, compared to those who did not relapse (146.3 vs 9; P = 0.03)
• Significantly inferior 5-year PFS following allo-SCT in patients with high H-scores (H > 100 in at least one biomarker or H > 50 in two out of three biomarkers), compared with patients with low H-scores (P < 0.01)
• Significantly inferior 5-year OS following allo-SCT in patients with high H-score, compared to patients with low H-scores (P = 0.01)
• Toxicities:
  • Deaths due to infections or graft versus host disease (GvHD)-related complications: n = 7 (29%)
  • Acute GvHD: n = 7 (29%)
  • Chronic GvHD: n = 9 (37.5%)
• Neither disease status at transplant nor GvHD incidence were significantly associated with clinical outcome

The results of this retrospective pilot study further validate the therapeutic potential of anti-PD-1/PD-L1 immune checkpoint inhibitors and the hypothesis that immune checkpoint activation can lead to poorer clinical outcomes, since significantly inferior 5-year PFS was observed in patients after allo-SCT with higher PD-1, PD-L1 and/or LAG3 expression. Moreover, combined PD-1, PD-L1 and LAG3 expression was higher in lymphoma patients progressing or relapsing after allo-SCT. These preliminary results are suggestive of the biomarker potential of PD-1, PD-L1 and/or LAG3 expression for predicting clinical outcomes in lymphoma patients undergoing allo-SCT.