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Disabling immune tolerance by programmed death-1 blockade with pidilizumab after autologous hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: results of an international phase II trial.

ABSTRACT:

Purpose

The Programmed Death-1 (PD-1) immune checkpoint pathway may be usurped by tumors, including diffuse large B-cell lymphoma (DLBCL), to evade immune surveillance. The reconstituting immune landscape after autologous hematopoietic stem-cell transplantation (AHSCT) may be particularly favorable for breaking immune tolerance through PD-1 blockade.

Patients and methods

We conducted an international phase II study of pidilizumab, an anti-PD-1 monoclonal antibody, in patients with DLBCL undergoing AHSCT, with correlative studies of lymphocyte subsets. Patients received three doses of pidilizumab beginning 1 to 3 months after AHSCT.

Results

Sixty-six eligible patients were treated. Toxicity was mild. At 16 months after the first treatment, progression-free survival (PFS) was 0.72 (90% CI, 0.60 to 0.82), meeting the primary end point. Among the 24 high-risk patients who remained positive on positron emission tomography after salvage chemotherapy, the 16-month PFS was 0.70 (90% CI, 0.51 to 0.82). Among the 35 patients with measurable disease after AHSCT, the overall response rate after pidilizumab treatment was 51%. Treatment was associated with increases in circulating lymphocyte subsets including PD-L1E-bearing lymphocytes, suggesting an on-target in vivo effect of pidilizumab.

Conclusion

This is the first demonstration of clinical activity of PD-1 blockade in DLBCL. Given these results, PD-1 blockade after AHSCT using pidilizumab may represent a promising therapeutic strategy in this disease.

SUBMITTER: Armand P

PROVIDER: S-EPMC4878008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Lymphoma patients treated with autologous transplantation (ASCT) live an increasingly long life with the recent advancement in therapeutic modalities. This has resulted in an increase in the incidence of therapy-related myeloid neoplasms (t-MN), which is one of the leading causes of non-relapse mortality. Several observational studies have linked the development of t-MN after ASCT with the intensity and frequency of chemotherapy, particularly alkylating agents, use of total body irradiation (TBI), and peripheral blood progenitor cells. In addition, role of genetic factors is increasingly being identified. It is postulated that the use of chemotherapy prior to ASCT results in DNA damage of progenitor cells, mitochondrial dysfunction, and altered gene expression related to DNA repair, metabolism as well as hematopoietic regulation. Cytogenetic studies have shown the presence of abnormalities in the peripheral blood progenitor cells prior to ASCT. It is, therefore, likely that the reinfusion of peripheral blood progenitor cells, proliferative stress on infused progenitor cells during hematopoietic regeneration and associated telomere shortening ultimately result in clonal hematopoiesis and blastic transformation. Cytopenias, myelodysplasia, or cytogenetic abnormalities are common and can be transient after ASCT; therefore, only when present together, they do confirm the diagnosis of t-MN. Attempts to reduce the occurrence of t-MN should be directed toward minimizing the exposure to the identified risk factors. Although the median survival is few months to less than a year, studies have shown the promising role of allogeneic transplantation in select young t-MN patients without high-risk cytogenetics. In this review we will explain the recent findings in the field of t-MN in lymphoma patients that have implications for identifying the molecular and genetic mechanisms of leukemogenesis and discuss potential strategies to reduce the risk of t-MN in this patient population.