Survival and response rates of histone deacetylase inhibitors in peripheral T-cell lymphoma: A comprehensive systematic review and meta-analysis of 67 studies.

Abstract Introduction: Peripheral T-cell lymphomas (PTCL) account for 5-15% of non-Hodgkin lymphomas. It has high relapses and unfavorable prognoses with first-line chemotherapy regimens (cyclophosphamide, doxorubicin, vincristine, and prednisone). Recently, histone deacetylase inhibitors (HDACi) have been investigated for their efficacy in both relapsed/refractory (R/R) and untreated (UT) PTCL. HDACi blocks the removal of the acetyl group from histones, leading to hyperacetylation, promotes tumor suppressor gene transcription, thus causing cell cycle arrest and apoptosis. Currently, romidepsin, vorinostat, and belinostat have US FDA approval for the treatment of relapsed/refractory PTCL, while chidamide is approved in China but is not approved in the US. In this meta-analysis, we assess the efficacy of different subtypes of HDACi used as combination treatment and monotherapy and their responses based on (UT) and (R/R) PTCL. Methods: A comprehensive search was conducted using PubMed, Cochrane Library, and ClinicalTrials.gov from inception to July 25th, 2025. Studies included for cumulative response rates such as objective response rate (ORR) and complete response (CR) from phase 1/2 trials and single-arm observational studies. While phase 3 randomized control trials (RCTs) and comparative studies are used for survival analysis using overall survival (OS) and progression-free survival (PFS). RevMan version 5.4.1 was used for statistical analysis. A random effect model with inverse variance as a statistical method was used to calculate risk difference (RD), hazard ratio (HR), and 95% confidence interval (CI). Results: A total of 67 studies met our inclusion criteria, of which 40 are phase 1/2 trials, 4 phase 3 RCTs, and 23 observational studies. The data comprises 4131 patients, predominantly male (62.3%) with an age range of 18 to 93 years, median age 60 years. PTCL subtypes included PTCL- not otherwise specified (NOS) (45.6%), angioimmunoblastic T-cell lymphoma (AITL) (28.4%), anaplastic large cell lymphoma (ALCL) (13.6%), extranodal natural killer T-cell lymphoma (6%). Bone marrow involvement was present in 58.6% patients. Both UT and R/R patients had significant outcomes. The CR was higher by 49% in the previous (UT), followed by 21% p-value = <0.00001 in R/R. From single-arm studies, in previous (UT) patients who received HDACi-based combination treatment. Pooled ORR was higher in chidamide, [75%; 95% CI: (0.65, 0.84), p-value = <0.00001, I2=81%], followed by romidepsin [63%; 95% CI: (0.56, 0.70), p-value = <0.00001, I2=0%]. Similarly, Pooled CR in chidamide, [51%; 95% CI: (0.41, 0.62), p-value = <0.00001, I2=80%], and romidepsin [42%; 95% CI: (0.30, 0.54), p-value = <0.00001, I2=75%] In R/R patients, who received HDACi-based combination treatment, he pooled ORR was significantly high in Chidamide [61 %; 95% CI: (0.46, 0.75), p-value = <0.00001, I2=93%], followed by romidepsin [59%; 95% CI: (0.49, 0.69), p-value = <0.00001, I2=72%], pabinostat [43%; 95% CI: (0.23, 0.63), p-value = <0.0001], natatinostat [40%; 95% CI: (0.25, 0.55), p-value = <0.00001]. The CR was significantly higher in romidepsin [34%; 95% CI: (0.29, 0.39), p-value = <0.00001, I2=73%], followed by chidamide [17%; 95% CI: (0.15, 0.20), p-value = <0.00001, I2=92%]. HDACi monotherapy in patients with R/R T cell lymphoma, demonstrated an ORR, with chidamide [42%; 95% CI: (0.148, 0.57), p-value = <0.00001, I2=85%] followed by romidepsin [30%; 95% CI: (0.25, 0.35), p-value = <0.00001, I2=35%], abexinostat [28%; 95% CI: (0.19, 0.37), p-value = <0.00001], belinostat [26%; 95% CI: (0.19, 0.33), p-value = <0.00001, I2=0%]. ORR in R/R patients based on PTCL subtypes is significant, with the highest in AITL 94% (p-value <0.00001), followed by ATLL =54% (p-value <0.0001), ALCL ALK negative = 41% (p-value 0.04), and PTCL-NOS = 32% (p-value <0.00001). Based on double arm studies, HDACi in (UT) and R/R PTCL has improved OS [HR 0.66; 95% CI (0.49-0.89), P-value= 0.006, I2 72%] and PFS [HR 0.64; 95% CI (0.51-0.79), P-value= <0.0001, I2 42%]. Conclusion: This meta-analysis demonstrates that HDACi has shown overall improved response rates and survival in PTCL patients. However, chidamide has higher response rates than romidepsin in previously treated (UT) patients. In R/R patients, complete remission is higher with romidepsin; however, chidamide was associated with higher overall response rates with meaningful tumor shrinkage, including both complete and partial remission.