Synergistic  Remission of refractory cutaneous T-cell lymphoma by linperlisib plus venetoclax via targeting the PI3K/AKT/CREB-BCL-2/MCL-1 signaling axis.

Abstract Background: Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of lymphoproliferative malignancies arising from skin-homing T cells. Its primary subtypes—mycosis fungoides (MF), Sézary syndrome (SS), and CD30+ lymphoproliferative disorders (LPDs) —collectively account for 70% of primary cutaneous lymphomas. Primary cutaneous anaplastic large cell lymphoma (pcALCL), a core CD30+ LPD subtype, forms the CD30+ disease spectrum alongside lymphomatoid papulosis (LyP). Conventional therapies like CHOP show low response rates in advanced/relapsed CTCL, underscoring the urgent need for novel targeted agents and rational combination strategies to overcome resistance. Methods: We report a 67-year-old woman with multiply relapsed pcALCL refractory to CHOP, CHOP plus brentuximab vedotin (BV), and three courses of total skin electron beam therapy (TSEBT), who subsequently initiated combination therapy with linperlisib (PI3Kδ inhibitor) and venetoclax (BCL-2 inhibitor). We first validated the synergistic antitumor effects of linperlisib and venetoclax in vitro. Subsequent transcriptomic profiling identified key mediators and underlying mechanisms, confirmed at transcriptional and protein levels, and validated via rescue experiments. Results: The patient attained CR after two treatment cycles, with relapse-free survival of 584 days. In vitro, linperlisib plus venetoclax significantly enhanced cytotoxicity versus either agent alone, suppressing proliferation and inducing apoptosis. Pathway enrichment analysis of RNA-seq data implicated CREB as a pivotal regulator in the control of PI3K/AKT-dependent apoptosis. The combination synergistically inhibited PI3K/AKT/CREB pathway activity and downregulated the expression of BCL-2 and MCL-1. Rescue experiments showed that the PI3K/AKT/CREB agonist AE-18 markedly reduced linperlisib-induced apoptosis and reversed BCL-2/MCL-1 suppression. Conclusions: In this case, dual PI3Kδ and BCL-2 blockade achieved durable remission after failure of all conventional therapies. Linperlisib suppresses BCL-2/MCL-1 expression by inhibiting the PI3K/AKT/CREB axis, synergizing with venetoclax to overcome resistance. This combination represents a novel therapeutic strategy for achieving durable remission in relapsed pcALCL.