Signal Transduction and Targeted Therapy | A single-arm phase II study of abexinostat as a histone deacetylase inhibitor in relapsed/refractory follicular lymphoma

This study provides a new treatment option for relapsed/refractory follicular lymphoma, demonstrating a significant objective response rate after failure of multiple lines of therapy, offering clinical evidence for the design of subsequent combination therapies.

 

Literature Overview

The article titled 'Abexinostat, a histone deacetylases inhibitor, for patients with relapsed or refractory follicular lymphoma: a multi-center, single-arm phase 2 study,' published in the journal Signal Transduction and Targeted Therapy, systematically investigates the efficacy and safety of the histone deacetylase (HDAC) inhibitor abexinostat in patients with relapsed or refractory follicular lymphoma (r/r FL). The study employed a multi-center, single-arm design, enrolling patients who had previously received at least two systemic therapies, with the primary endpoint being the objective response rate (ORR) of abexinostat. Results showed that abexinostat monotherapy achieved an ORR of nearly 70% in heavily pre-treated patients, highlighting its potential in epigenetic therapy. This study fills a critical gap in the current systemic data on HDAC inhibitors for third-line or later treatment regimens and provides key evidence for future research.

Background Knowledge

Follicular lymphoma (FL) is an indolent B-cell non-Hodgkin lymphoma. Although initial treatments yield favorable responses, most patients eventually relapse or progress to refractory disease. Despite the availability of anti-CD20 monoclonal antibodies (e.g., rituximab) combined with chemotherapy, patients with r/r FL face limited treatment options and poor prognoses after multiple lines of therapy. Epigenetic dysregulation, particularly inactivating mutations in histone acetyltransferases such as CREBBP and EP300, is highly prevalent in FL. These mutations lead to reduced histone acetylation, chromatin condensation, and silencing of tumor suppressor genes, providing a rationale for HDAC-targeted therapeutic strategies. However, existing HDAC inhibitors have shown limited efficacy and significant toxicity in r/r FL, restricting their clinical utility. Therefore, developing novel HDAC inhibitors such as abexinostat holds substantial clinical importance. Abexinostat, a pan-HDAC inhibitor, exhibits a prolonged pharmacodynamic window and a manageable toxicity profile, with preliminary activity demonstrated in phase I studies. This phase II study aims to validate its efficacy and safety in a larger cohort, offering a new therapeutic avenue for patients with r/r FL.

 

 

Research Methods and Experiments

The study adopted a single-arm, multicenter, phase II design, enrolling 90 patients with r/r FL who received abexinostat at 80 mg orally twice daily using a 7-days-on/7-days-off cycle. All patients had received a median of three prior lines of therapy and were previously exposed to anti-CD20 treatment. Efficacy was assessed by an independent review committee (IRC) according to the Lugano 2014 criteria, with ORR as the primary endpoint and DoR, PFS, OS, and safety as secondary endpoints. The study utilized Simon’s two-stage design, with a pre-specified null hypothesis of ORR ≤30%. Key experiments included IRC-based tumor response assessment, Kaplan-Meier survival analysis, and subgroup analyses, particularly exploratory evaluations of CREBBP and KMT2D expression status. Additionally, biomarker analyses were conducted using blood and tumor tissue samples to identify potential predictive factors.

Key Conclusions and Perspectives

• The IRC-assessed ORR was 69.5% (57/82), significantly exceeding the pre-specified threshold of 30%, indicating substantial antitumor activity of abexinostat in r/r FL and supporting its potential as a third-line or later therapy.
• The complete response (CR) rate was 14.6%, and the disease control rate (DCR) reached 91.5%, suggesting that abexinostat not only induces partial responses but also achieves deep remissions, guiding future research into its role in conversion therapy or minimal residual disease (MRD) eradication.
• The median PFS was 13.80 months, and median OS has not yet been reached (47.18 months), indicating durable clinical benefit from abexinostat and supporting the use of PFS as a key endpoint in future studies.
• Subgroup analyses revealed higher ORR in CREBBP(+) patients (76.9% vs 52.4%), suggesting that CREBBP inactivation may serve as a potential biomarker for abexinostat sensitivity, guiding future precision medicine strategies.
• The most common treatment-related adverse event was thrombocytopenia (85.6%), with only 42.2% being grade 3–4 and largely reversible, indicating manageable toxicity that supports long-term treatment and provides valuable reference for safety assessment in future combination regimens.

Research Significance and Prospects

This study confirms that abexinostat demonstrates significant efficacy and controllable safety in r/r FL, providing strong evidence for the application of epigenetic therapy in B-cell lymphomas. Mechanistically, abexinostat restores histone acetylation and reactivates tumor suppressor genes, potentially overcoming resistance caused by CREBBP inactivation. Future studies may explore combination regimens of abexinostat with immunomodulatory agents (e.g., lenalidomide) or anti-CD20 monoclonal antibodies to enhance antitumor immune responses. Moreover, CREBBP expression status may serve as a predictive biomarker for patient stratification, enabling personalized therapy.

From a clinical translation perspective, abexinostat offers a new treatment option for r/r FL patients who have failed multiple lines of therapy, especially when CAR-T or bispecific antibodies are unavailable. Its oral administration also improves patient compliance. However, the single-arm design lacks a control group, necessitating randomized controlled trials to confirm its advantages. Additionally, long-term follow-up data will further clarify its impact on overall survival.

 

 

Conclusion

This study establishes abexinostat as a new option for third-line or later treatment of relapsed/refractory follicular lymphoma, with its high response rate and manageable toxicity delivering significant clinical benefit to patients. By targeting HDAC, abexinostat restores epigenetic regulation disrupted by CREBBP inactivation, offering a novel approach to overcoming resistance mechanisms. The study not only validates the potential of monotherapy but also lays the foundation for future combination strategies, such as with immunotherapies. From bench to bedside, this work underscores the importance of epigenetic targets in lymphoma treatment and advances the field of precision medicine. Particularly for patients lacking effective treatment options, abexinostat provides an accessible and effective oral regimen that could become a key component of r/r FL care. Future research should focus on biomarker-driven patient selection and optimization of combination therapies to maximize clinical benefit.

 

Lin Gui, Haifeng Liu, Huaqing Wang, Wentao Wu, and Yuankai Shi. Abexinostat, a histone deacetylases inhibitor, for patients with relapsed or refractory follicular lymphoma: a multi-center, single-arm phase 2 study. Signal Transduction and Targeted Therapy.