Pembrolizumab for the treatment of disease relapse following allogeneic hematopoietic stem cell transplantation.
James GodfreyHongtao LiuJovian YuMichael TallaricoEmily CurranAndrew S ArtzPeter A RiedellWendy StockTheodore KarrisonCarrie FitzpatrickGirish VenkataramanAlan CooperSonali M SmithMichael R BishopJustin KlinePublished in: Blood advances (2022)
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.
Keyphrases
- end stage renal disease
- ejection fraction
- chronic kidney disease
- newly diagnosed
- allogeneic hematopoietic stem cell transplantation
- prognostic factors
- multiple sclerosis
- acute myeloid leukemia
- stem cells
- bone marrow
- rheumatoid arthritis
- healthcare
- poor prognosis
- acute lymphoblastic leukemia
- early onset
- high dose
- patient reported outcomes
- systemic lupus erythematosus
- long non coding rna
- advanced non small cell lung cancer
- risk assessment
- cancer therapy
- high intensity
- drug delivery
- climate change
- cell therapy
- disease activity
- genome wide
- health insurance
- replacement therapy
- smoking cessation
- hematopoietic stem cell