In support of this, our finding of increased donor CD3+ chimerism at the site of disease involvement in one of our patients, suggests that anti-tumor effects are preferentially driven by donor-derived T cells following PD-1 blockade. received nivolumab therapy at our institution. All individuals were free of graft-versus-host disease and were off of all systemic immunosuppressive medications at the time of nivolumab treatment. Nivolumab was well-tolerated in two of the individuals. However, nivolumab had to be discontinued in one patient due to development of immune-related polyarthritis requiring treatment with systemic corticosteroids and methotrexate. Objective responses were observed in all three patients. Conclusions Our case series demonstrates that anti-PD-1 therapy with nivolumab can be highly effective following allogeneic transplant for Hodgkins lymphoma, but severe immune-related adverse events can occur, requiring very close monitoring and interruption of NSC 42834(JAK2 Inhibitor V, Z3) therapy. strong class=”kwd-title” Keywords: Checkpoint blockade, PD-1, Hodgkin lymphoma, Allogeneic transplant Background Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be a curative treatment for high-risk and recurrent hematological malignancies [1]. A major therapeutic effect of alloHSCT lies within the graft-versus-tumor (GVT) response, where donor-derived lymphocytes identify antigens expressed on the surface of malignant cells, and eliminate them from your host [2]. However, it has become obvious that disease relapse following alloHSCT can be associated with immune evasion and loss of GVT effects [3]. Concrete examples include upregulation of programmed death-ligand 1 (PD-L1) on leukemia cells, and programmed death-1 (PD-1) on donor-derived T cells at the time of post-alloHSCT relapse, as well as deletion of human leukocyte antigen alleles in some leukemia patients relapsing after haploidentical alloHSCT [4, 5]. New strategies to NSC 42834(JAK2 Inhibitor V, Z3) restore GVT effects in these patients are needed because patients who relapse after alloHSCT have few treatment options and dismal outcomes [6]. Recently, the defined activity of checkpoint blockade therapy (CBT) with anti-PD-1 and anti-cytotoxic lymphocyte antigen-4 (CTLA-4) antibodies in a number of malignancies has generated interest in their use to treat disease relapse following alloHSCT. Preclinical studies of CBT have demonstrated augmentation of GVT effects [7C9], and two phase I studies of the anti-CTLA-4 antibody, ipilimumab, have been reported in patients with relapse after alloHSCT, where objective responses were observed [10, 11]. In the most recently published study, ipilimumab treatment was associated with a 31% objective response rate, including complete responses in patients with leukemia cutis, myeloid sarcoma, and myelodysplastic syndrome [11]. However, there is concern that enhancing the GVT effect through administration of CBT might also induce or exacerbate graft-versus-host disease (GVHD). Indeed, ipilimumab treatment was discontinued in 4 of 29 patients due to GVHD in the aforementioned study, and 6 patients had other immune-related adverse advents (IrAE) including one treatment-related death [11]. Further, PD-1 blockade has also been associated with induction of severe GVHD in murine models, and a report of fatal GVHD in a patient treated with the anti-PD-1 antibody, pembrolizumab, was recently published [12, 13]. These observations have somewhat tempered enthusiasm for the exploration of PD-1 blockade after alloHSCT to anecdotal reports and a retrospective case series which has been published in abstract form NSC 42834(JAK2 Inhibitor V, Z3) [14C16]. However, PD-1 blockade has been associated with a lower incidence of severe IrAE in non-transplant settings compared to CTLA-4 blockade, and is clearly more effective across a number of malignancies, including classical Hodgkin lymphoma (cHL) [17, 18]. We therefore sought to examine the security and efficacy of PD-1 blockade Mouse monoclonal to SUZ12 following alloHSCT, and present data summarizing our experience with nivolumab for the treatment of relapsed cHL after alloHSCT. Case presentation We treated three cHL patients who had relapsed after alloHSCT with off-label nivolumab at a dose of 3?mg/kg every 2?weeks. Patient and disease characteristics are summarized in Table?1. Briefly, all patients experienced multiply relapsed cHL despite treatment with standard chemotherapy NSC 42834(JAK2 Inhibitor V, Z3) regimens and autologous hematopoietic stem cell transplantation. Patients received T cell-depleted grafts after reduced-intensity conditioning regimens. None developed acute GVHD, although two patients developed limited-stage chronic GVHD requiring short courses of steroids. Disease relapse occurred at an average of 1,008?days from alloHSCT (181, 389, and 2456?days), and was NSC 42834(JAK2 Inhibitor V, Z3) histologically confirmed in all cases. One individual received a donor lymphocyte infusion (DLI) at the time of relapse, but failed to achieve an objective response. After exhausting all standard treatment options, patients were consented to treatment with nivolumab after discussing potential risks including life-threatening GVHD. Table 1 Patient characteristics, adverse events, and response to nivolumab treatment thead th rowspan=”1″ colspan=”1″ /th th rowspan=”1″ colspan=”1″ Patient 1 /th th rowspan=”1″ colspan=”1″ Patient 2 /th th rowspan=”1″ colspan=”1″ Patient 3 /th /thead Age472555SexMaleMaleMalePrior therapies (no.)665Stem cell sourceMatched-relatedMatched-relatedHaploidentical and umbilical cord bloodConditioning regimenReduced intensityReduced intensityReduced intensityT cell depleted graftYesYesYesPrior GVHDNoChronic GVHD of gutChronic oral GVHDDays to relapse following AlloHSCT (no.)1812456389Localization and.