T follicular helper phenotype predicts response to histone deacetylase inhibitors in relapsed/refractory peripheral T-cell lymphoma

Abstract

Histone deacetylase inhibitors (HDACi) are active agents for peripheral T-cell lymphoma (PTCL). Anecdotally angioimmunoblastic T-cell lymphoma (AITL) appears to respond better than PTCL–not otherwise specified (NOS) to HDACi. The new World Health Organization classification shows that a subgroup of PTCL carries similarities in phenotype and gene expression profiling to AITL, comparable to T follicular helper (TFH) cells. The disease might behave similarly to AITL when treated with HDACi. We analyzed 127 patients with AITL or PTCL-NOS treated with HDACi at relapse as a single agent or in combination. We re-reviewed the pathology of all PTCL-NOS to identify the TFH phenotype. Patients received HDACi at relapse as a single agent in 97 cases (76%, 59 TFH, 38 non-TFH) or in combination in 30 cases (24%, 18 TFH, 12 non-TFH) including duvelisib, lenalidomide, lenalidomide plus carfilzomib, and pralatrexate. Seven PTCL-NOS had TFH phenotype; 2 PTCL-NOS were reclassified as AITL. Overall response rate (ORR) was 56.5% (28.9% complete response [CR]) in TFH and 29.4% (19.6% CR) in non-TFH phenotype patients (P = .0035), with TFH phenotype being an independent predictor of ORR (P = .009). Sixteen patients sufficiently responded to HDACi or HDACi in combination with another agent to proceed directly to allogeneic transplantation; 1 of 16 responded to donor lymphocyte infusion (12 TFH, 4 non-TFH). Our results, although retrospective, support that HDACi, as a single agent or in combination, may have superior activity in TFH-PTCL compared with non-TFH PTCL. This differential efficacy could help inform subtype-specific therapy and guide interpretation of HDACi trials.

Comprehensive analysis of clinical, pathological, and genomic characteristics of follicular helper T-cell derived lymphomas

“…Paola et al already conducted a retrospective study to show the efficacy of histone deacetylase inhibitors (HDACi) in PTCL-NOS with TFH versus non-TFH phenotypes. The response rate to HDACi in PTCL-NOS with a TFH cell phenotype was about twice as high as that of the non-TFH phenotype (56.5% vs. 29.4%, p -value = 0.0035) [ 34 ]. Therefore, our data suggest that new target agents under development or research for AITL might also be promising treatment strategies in other TFH lymphomas.…”

Targeted Approaches to T-Cell Lymphoma

“…Perhaps unsurprising, the PTCL subtypes characterized by the T follicular phenotype and defined by hallmark mutations in epigenetic regulators, namely AITL and PTCL-TFH, have been shown to more responsive to HDAC inhibition. A retrospective cohort of 164 patients reported higher response rates in patients with TFH phenotype (ORR 56.5%) than those with and in non-TFH phenotype patients (ORR 56.5% vs. 29.4% p = 0.0035) [73].…”

Molecular understanding of peripheral T-cell lymphomas, not otherwise specified (PTCL, NOS): A complex disease category

“…70 Ghione et al reported that relapsed/refractory patients with PTCL who showed either AITL or nPTCL-Tfh phenotypes had higher response rate to histone deacetylase inhibitors (HDACi), including romidepsine and belinostat, than those without. 72 Gene mutations were examined in some samples included in this study. Intriguingly, patients responsive to HDACi more frequently exhibited AITL-specific mutational profiles (mutations in TET2, and/or DNMT3A, and/or RHOA) 33 than those without, although the relationship between clinical efficacy and mutational profiles must be confirmed in a larger cohort.…”

“…Intriguingly, patients responsive to HDACi more frequently exhibited AITL-specific mutational profiles (mutations in TET2 , and/or DNMT3A , and/or RHOA ) 33 than those without, although the relationship between clinical efficacy and mutational profiles must be confirmed in a larger cohort. 72 …”