Highlight
- Linperlisib (a PI3Kδ inhibitor) plus chidamide (a histone deacetylase inhibitor) showed a 59.1% objective response rate in relapsed/refractory CTCL patients.
- No dose-limiting toxic effects observed; treatment was generally well tolerated with manageable adverse events.
- Median progression-free survival was 5.4 months, demonstrating meaningful disease control in a difficult-to-treat population.
- All-oral regimen offers a convenient treatment option targeting complementary oncogenic pathways in advanced CTCL, particularly mycosis fungoides.
Study Background and Disease Burden
Cutaneous T-cell lymphoma (CTCL) is a rare heterogeneous group of non-Hodgkin lymphomas primarily involving the skin. Among its subtypes, mycosis fungoides and Sézary syndrome represent the most common and aggressive clinical variants. Advanced CTCL often presents with relapsed or refractory (r/r) courses, posing significant challenges to effective management. Therapeutic options for r/r CTCL remain limited, frequently providing suboptimal responses and associated with considerable toxicities. Improving outcomes in this patient population requires innovative approaches that target key oncogenic pathways involved in CTCL pathogenesis.
Recent insights into molecular drivers of CTCL have identified the phosphatidylinositol 3-kinase delta (PI3Kδ) pathway and epigenetic modifiers such as histone deacetylases (HDACs) as pivotal in disease progression and immune regulation. Linperlisib is a potent and selective oral PI3Kδ inhibitor, while chidamide is an oral selective HDAC inhibitor approved in some hematologic malignancies. Preclinical work suggested that dual targeting these pathways could synergistically inhibit tumor growth and enhance immune-mediated antitumor activity. Given these scientific rationales, investigating the combination of linperlisib and chidamide in r/r CTCL could fulfill an unmet clinical need.
Study Design
This was a prospective, single-arm, phase 1 nonrandomized clinical trial conducted at a tertiary referral hospital in China between May 1, 2023, and March 6, 2025. A 3 + 3 dose-escalation phase of linperlisib (40, 60, 80 mg once daily) in combination with fixed-dose chidamide (20 mg twice weekly) was completed, followed by a dose-expansion phase at the recommended phase 2 dose.
Eligible patients had histologically confirmed advanced CTCL, including mycosis fungoides or Sézary syndrome, with Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients had received a median of three prior systemic therapies (range, 1-7), reflecting a heavily pretreated, refractory population. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal.
Primary endpoints included dose-limiting toxic effects, maximum tolerated dose (MTD), and objective response rate (ORR) assessed by standardized criteria. Secondary endpoints included safety profile, progression-free survival (PFS), and disease control rate (DCR).
Key Findings
Twenty-two patients were enrolled (19 with mycosis fungoides and 3 with Sézary syndrome; 45.5% female; median age 44 years, range 27-71). No dose-limiting toxic effects emerged during escalation, establishing the MTD and recommended phase 2 dose of linperlisib at 80 mg daily combined with chidamide 20 mg twice weekly.
The safety profile was manageable. Common treatment-related adverse events included nausea (36.4%), pruritus (31.8%), and skin rash (27.3%), predominantly grade 1-2 in severity. Grade 3 adverse events occurred in 22.7% of patients but no grade 4 or 5 events were observed, underscoring acceptable tolerability.
Efficacy results were encouraging. The ORR was 59.1% (13 of 22 patients; 95% CI, 38.7%-76.7%), comprising 2 complete responses and 11 partial responses. Disease control rate, inclusive of stable disease, reached 86.4% (19 of 22 patients). Median progression-free survival was 5.4 months, suggestive of clinically meaningful disease stabilization in this refractory setting.
These outcomes highlight the potential synergy of targeting PI3Kδ and HDAC pathways to overcome resistance mechanisms in CTCL. Notably, patients with mycosis fungoides constituted the majority and appeared to derive substantial benefit, reinforcing this subtype as a key target population.
Expert Commentary
The combination of linperlisib plus chidamide represents a rational therapeutic innovation leveraging complementary molecular mechanisms. PI3Kδ inhibition disrupts critical survival and proliferation signals within malignant T cells, while HDAC inhibition modifies epigenetic regulation and immune surveillance, potentially enhancing antitumor response.
This phase 1 trial, although limited by single-arm design and modest sample size, provides important proof-of-concept for efficacy with acceptable tolerability. The absence of dose-limiting toxicities and manageable adverse events support feasibility of this all-oral regimen in outpatients. The PFS of 5.4 months notably compares favorably to historical outcomes with single-agent therapies in r/r CTCL.
Further randomized trials are warranted to confirm efficacy and better characterize long-term safety. Mechanistic studies exploring biomarker correlates may elucidate predictors of response and resistance. Additionally, head-to-head comparisons with current standard-of-care agents could clarify the clinical role of this combination.
Conclusion
Linperlisib plus chidamide demonstrated promising safety and efficacy in a heavily pretreated population with relapsed or refractory cutaneous T-cell lymphoma, particularly mycosis fungoides. The regimen’s all-oral administration and dual-pathway targeting offer a novel and potentially more effective therapeutic avenue. Pending validation in larger controlled trials, this combination may soon expand the armamentarium against advanced CTCL, addressing a significant unmet need in this challenging malignancy.
References
Pang Z, Wang Y, Liu Z, et al. Linperlisib Plus Chidamide in Relapsed or Refractory Cutaneous T-Cell Lymphoma: A Nonrandomized Clinical Trial. JAMA Dermatol. Published online July 02, 2025. doi:10.1001/jamadermatol.2025.1926
Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768-3785. doi:10.1182/blood-2004-09-3502
Kim YH, Plastaras JP, Hoppe RT. Cutaneous T-cell lymphoma: 2018 update on diagnosis, risk-stratification, and management. Am J Hematol. 2018 Mar;93(3): 467-475. doi:10.1002/ajh.25094
O’Connor OA, Lowenberg B, Pettengell R, et al. Phase 1 study of chidamide, an oral subtype-selective histone deacetylase inhibitor, in patients with advanced hematologic malignancies. J Hematol Oncol. 2015;8:1. doi:10.1186/s13045-014-0104-8
Mathews Griner LA, Guha R, Shinn P, et al. High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill diffuse large B-cell lymphoma cells. Proc Natl Acad Sci U S A. 2014;111(6):2349-2354. doi:10.1073/pnas.1315309111
