To the editor

Peripheral T-cell lymphoma (PTCL) comprises a heterogeneous group of hematological malignancies where relapsed or refractory (R/R) disease is common. Current standard treatments for R/R PTCL have limited efficacy, and new therapeutic methods are urgently needed [1, 2]. We summarize the latest updates on novel agents and regimens for R/R PTCL from the 2023 ASH Annual Meeting.

Novel agents in R/R PTCL

Valemetostat, a potent dual inhibitor of Enhancers of Zeste Homolog 1 and 2 (EZH1/2), is approved for the treatment of R/R adult T-cell leukemia/lymphoma in Japan. In a multinational pivotal phase II trial of R/R PTCL (VALENTINE-PTCL01), continuous administration of 200 mg/day valemetostat was well tolerated and displayed an objective response rate (ORR) of 43.7% (52/119) with 14.3% complete response (CR) and a median duration of response (DOR) of 11.9 months. Responses were observed across all PTCL subtypes. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months and 17.0 months, respectively [3]. Another exciting EZH1/2 dual inhibitor HH2853 was evaluated in a phase Ib trial. Among 28 R/R PTCL patients with assessable efficacy, HH2853 resulted in a 60.7% ORR with 21.4% CR. With a median follow-up duration of 2.79 months, the median DOR, PFS and OS were not achieved. The 3-month PFS rate and 6-month OS rate were 74.44% and 91.97%, respectively. Trentment-related adverse events (TRAEs) were manageable and consistent with other HH2853 studies [4].

Golidocitinib is the first JAK1 selective inhibitor to enter pivotal clinical development for R/R PTCL. In the global phase II trial (JACKPOT8 Part B), patients with R/R PTCL were given 150 mg/day of golidocitinib continuously and showed a 44.3% (39/88) ORR, including 24% CR, with a median DOR, PFS and OS of 20.7 months, 5.6 months and 19.4 months, respectively. The majority of treatment-emergent adverse events (TEAEs) were reversible and clinically manageable [5].

Linperlisib, a novel PI3Kδ-selective inhibitor, has received marketing approval in China for the treatment of R/R follicular lymphoma patients with 2 prior systemic therapies. In a pivotal phase II study of R/R PTCL, patients were consecutively administered linperlisib 80 mg/day, achieving 48% (42/88) ORR with 30% CR and median PFS and OS of 5.5 months and 14.2 months, respectively. Activity was demonstrated in all subtypes, and the median DOR was not reached at a median follow-up of 13.9 months. Linperlisib has a favorable safety profile, with lower levels of severe gastrointestinal and liver toxicity than other PI3K agents [6]. BR101801, a triple inhibitor of PI3Kγ/δ and DNA-PK, showed clinical benefit and a manageable safety profile in a phase I trial of R/R PTCL: 31.6% (6/19) ORR, 21.1% CR, and a median PFS of 7.5 months; median OS and DOR were not reached in a median follow-up duration of 12.9 months; grade 3–4 TRAEs included elevated transaminases and neutropenia [7].

Preliminary phase Ib data on the anti-KIR3DL2 mAb lacutamab in 10 patients with KIR3DL2-expressing R/R PTCL confirmed an acceptable safety profile for monotherapy, with the majority (90%) of TEAEs being of grade 1–2 severity [8]. The preclinical activity profile improved when assessed in combination with pralatrexate or CHOP. Two additional preclinical studies revealed superior antitumor activity against PTCL with the CD38/CD3xCD28 trispecific antibody SAR442257 monotherapy [9] and the CDK9 inhibitor AZD4573 monotherapy or in combination with CHOP [10].

Novel regimens in R/R PTCL

A multicenter retrospective study of 184 patients with R/R PTCL revealed that novel agent exposure with and without the use of stem cell transplantation (SCT) significantly improved OS and event-free survival [11]. For patients who respond after salvage therapy but are ineligible for autologous SCT or intensive consolidation chemotherapy, a multicenter phase II trial demonstrated that maintenance therapy with the immunomodulator lenalidomide 50 mg for 3 weeks in 4-week cycles was tolerable and produced promising responses, with a 1-year PFS of 49%, a median OS of 34.1 months and manageable TRAEs [12].

The histone deacetylase inhibitor chidamide combined with the hypomethylating agent azacitidine for injection was evaluated in a phase I trial for R/R PTCL. This pair was well tolerated and resulted in an ORR of 56.25% (9/16), with a median PFS and OS of 6.45 months and 17.5 months, respectively [13]. Chidamide has also been studied in combination with parsaclisib, a potent PI3Kδ-selective inhibitor, in a phase Ib/II trial of R/R PTCL. Preliminary results showed a favorable safety profile, with predominantly grade 1/2 hematologic toxicities and gastrointestinal reactions. Among the 9 efficacy evaluable patients, 5 (55.6%) achieved CR, and patients previously exposed to chidamide could still have durable responses [14].

An ongoing phase II study (LuminICE) was designed to explore the efficacy and safety of the CD30/CD16A bispecific antibody (AFM13) in combination with allogeneic natural killer cells (AB-101) in R/R Hodgkin lymphoma and CD30 + PTCL [15].

In conclusion, the 2023 ASH Annual Meeting showcased many notable advances in new agents and novel rational drug combinations targeting the epigenome, proliferative signaling pathways, tumor microenvironment and cell surface receptors for the treatment of R/R PTCL, as summarized in Tables 1 and 2. A deeper understanding of the molecular and genomic profiles will provide potential therapeutic targets for PTCL. Notably, with technological innovations, chimeric antigen receptor (CAR)-T cells targeting CD5, CD7, CD30, CD70 or TRBC1 have been developed and are being explored in clinical trials in selected patients with R/R PTCL.

Table 1 Outcomes of clinical trials of novel agents in relapsed or refractory PTCL from 2023 ASH Annual Meeting
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Table 2 Outcomes of novel regimens in relapsed or refractory PTCL from 2023 ASH Annual Meeting
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