Pembrolizumab for the treatment of disease relapse after allogeneic hematopoietic stem cell transplantation

Abstract

A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse following allogeneic hematopoietic cell transplantation (alloHCT). While targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. We therefore developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8 AML, 1 MDS, 1 cHL, 2 DLBCL). All subjects received reduced-intensity preparative regimens with in vivo T cell depletion. Median time from alloHCT to enrollment was 587 days (range, 101-4211). Three subjects (25%) experienced grade 3-4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1-2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. IrAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response rates were 22% (2/9). Both patients achieving complete responses had PD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pre-treatment biopsies. An acquired EZH2 mutation was identified at relapse in a DLBCL patient who achieved an initial complete response to pembrolizumab, which was associated with downregulated HLA expression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism following PD-1 blockade therapy. In conclusion, post-alloHCT pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies, but can induce severe irAEs, requiring vigilant monitoring.

Remission of relapsed/refractory classical Hodgkin lymphoma induced by brentuximab vedotin and pembrolizumab combination after allogeneic hematopoietic stem cell transplantation: a case report

“…Blocking the PD1/PD-L1 interaction in malignancies that acquire PD-L1 as an adaptative response to immune pressure relieves T cell inhibition exerted by tumor cells on CD8+ T cells against minor histocompatibility antigens ( 26 ). Early-phase clinical trials have shown the efficacy and feasibility of PD-1 blockade in the post-allo-HSCT relapse setting ( 27 , 28 ). Our data support the potential of CPIs even after DLI failure and suggest a potential synergistic effect between allo-HSCT and checkpoint blockade therapy.…”

“…Several studies showed brentuximab with DLI for HL relapsing after allo-HSCT to be effective with minimal toxicity, hypothesizing the immunomodulating role of BV in preventing GvHD ( 43 , 44 ). A recent study highlights the use of pembrolizumab to induce the GVL effect in relapsed hematologic malignancies after HSCT ( 28 ). The association of both agents has rarely been described in the literature but has mostly been described in r/r HL as a bridge to autologous transplant ( 11 ).…”

Progress of research on PD-1/PD-L1 in leukemia

“…A number of clinical trials on leukemia treatment with PD-1/PD-L1 mAbs have been performed nowadays. The overall response rate (ORR) of pembrolizumab alone is 0% in eight patients with AML ( 158 ). When combined with cytarabine, the ORR is 46% ( 116 ); the former grade 3–4 iRAEs are 25% ( 158 ), and the latter grade ≥3 iRAEs are 14% and self-limiting ( 116 ).…”

“…The overall response rate (ORR) of pembrolizumab alone is 0% in eight patients with AML ( 158 ). When combined with cytarabine, the ORR is 46% ( 116 ); the former grade 3–4 iRAEs are 25% ( 158 ), and the latter grade ≥3 iRAEs are 14% and self-limiting ( 116 ). The median recurrence-free survival (RFS) of AML patients treated with nivolumab alone is 8.48 months ( 159 ).…”

“…Regarding the data from the current sample, the efficacy of pembrolizumab combined with low-dose cytarabine is superior to that of the high-dose one, and the efficacy of pembrolizumab combined with decitabine or high-dose cytarabine is similar. The iRAEs are 42% in AML patients treated with pembrolizumab alone, the grade 3–4 iRAEs are 25% ( 158 ), the iRAEs are 40% when treated with nivolumab alone, the grade 3–4 iRAEs are 27% ( 159 ), and the incidence of adverse events is similar for both drugs. The mOS for AML treated with avelumab–azacitidine combination is 4.8 months ( 161 ), and that with durvalumab–azacitidine combination is 13.0 months ( 162 ).…”