Table 2.
Synopsis of current evidence and evolving role of checkpoint inhibitors in selected subtypes of T-cell NHL.
| Histologic subtype | Current level of evidence | |
|---|---|---|
| Alterations associated with an inflamed lymphoma environment | Clinical response to checkpoint inhibitors | |
| PTCL, NOS |
Weak
(i) A small subset of EBV-positive cases bears structural variations of PD-L1/PD-L2 [93]. |
Weak: studies with anti-PD-1 ICIs terminated due to cases with hyperprogression
(i) Disappointing ORR and DOR with anti-PD-1 ICIs in r/r disease [144, 145]. (ii) Hyperprogression in a third of cases; studies terminated. |
|
| ||
| ALCL |
Moderate
(i) PD-L1 upregulation in ALK-positive and ALK-negative cases [134, 135]. |
Moderate to strong
(i) Data on a limited number of patients originating from small studies and case reports show impressive responses and durable CRs with anti-PD-1 ICI monotherapy in both ALK-positive and ALK-negative cases [145–149]. (ii) Ongoing clinical trial to determine efficacy in r/r setting and as consolidative therapy in patients achieving CR. |
|
| ||
| NKTCL |
Moderate to strong
(i) Distinct molecular subtype with inflamed phenotype (PD-L1/PD-L2 SVs and JAK/STAT mutations) [136]. (ii) EBV-upregulated PD-L1 expression [37]. |
Strong
(i) High ORR and CR rates to anti-PD-1 ICIs in patients with r/r disease failing prior treatment with asparaginase [151–154]. (ii) Presence of mutated PD-L1 is a powerful predictive biomarker of response to anti-PD1 ICIs [155]. (iii) Ongoing clinical trials in upfront and r/r setting |
|
| ||
| ATLL |
Moderate
(i) Aberrant PD-L1 expression in one-third of cases [138]. (ii) High mutational burden of TCR and NF-κB genes [139]. |
Studies with anti-PD-1 ICIs terminated due to hyperprogression
(i) Hyperprogression developed in first 3 patients after a single dose of anti-PD-1 ICI [156]. (ii) Hyperprogression implies that PD-1 functions as a tumor suppressor in ATLL and other T-cell malignancies [163]. |
|
| ||
| MF and SS |
Moderate
(i) PD-1 expression more pronounced in early stages and PD-L1 in more advanced stages of disease [140]. (ii) Genomic alterations of PD-1 and PD-L1 [141, 142]. |
Moderate
(i) Responses to pembrolizumab in over one-third of patients with r/r MF or r/r SS [159]. (ii) Cutaneous flare reaction common in patients with SS; no cases of hyperprogression. (iii) Ongoing studies further assessing role of ICIs in cutaneous T-cell lymphomas. |
Abbreviations: ALCL: anaplastic large cell lymphoma; ALK: anaplastic lymphoma kinase; ATLL: adult T-cell leukemia/lymphoma; CR: complete remission; DOR: duration of response; EBV: Epstein-Barr virus; ICI: immune checkpoint inhibitor; IGH: immunoglobulin heavy chain; JAK: Janus kinase; MCI: macrophage checkpoint inhibition; ME: microenvironment; MF: mycosis fungoides; NF-κΒ: nuclear factor kappa-light-chain-enhancer of activated B cells; NKTCL: natural killer T-cell lymphoma; ORR: overall response rate; PD-1: programmed cell-death protein 1; PD-L1: programmed cell-death 1 ligand 1; PTCL, NOS: peripheral T-cell lymphoma, not otherwise specified; r/r: relapsed/refractory; SS: Sézary syndrome; STAT: signal transducer and activator of transcription proteins; SVs: structural variations; TCR: T-cell receptor.