S108 EXABS-217-TCL Novel Targeted Agents in T-Cell Lymphoma Alessandro Broccoli, MD, PhD1,2, and Pier Luigi Zinzani, MD, PhD1,2,* 1IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia “L. e A. Seràgnoli”, Bologna, Italy 2Dipartimento di Scienze Mediche e Chirurgiche, Università di Bologna, Bologna, Italy *Corresponding author: pierluigi.zinzani@unibo.it Keywords Duvelisib, golidocitinib, linperlisib, valemetostat Introduction Peripheral T-cell lymphomas (PTCL) represent a large and highly heterogeneous group of neoplasms: their classification is constantly evolving and being updated. Anaplastic large cell lymphoma (ALCL), angioimmunoblastic T-cell lymphoma (AITL), PTCL with a T-follicular helper phenotype, and PTCL not otherwise specified (PTCL-NOS) are the most significant entities with a nodal presentation. Treatment is challenging since initial presentation: first line approaches, mainly derived from the experience with the aggressive B-cell lymphoma counterparts, are in fact largely insufficient. A great proportion of patients frequently display disease recurrence or refractoriness to frontline treatment, and often fail to complete the planned program due to lymphoma progression while still on therapy. At this point, PTCL patients exhibit a very poor prognosis and are hard to be rescued with chemotherapy. Approved agents in relapsed and refractory disease, among which there are novel antifolates (pralatrexate) or histone deacetylase inhibitors (romidepsin, belinostat, chidamide), are effective in only 25%-40% of treated patients, with complete responses (CR) observed in less than 20% and mainly with short duration. The exception is represented by brentuximab vedotin, which has an indication in relapsed or refractory ALCL, however with much more disappointing results in other PTCL subtypes. New drugs leveraging on innovative or peculiar molecular mechanisms are therefore eagerly required. Four agents currently under evaluation in clinical trials are reviewed in this paper: the phosphatidylinositol-3 kinase (PI3K) inhibitors duvelisib and linperlisib; the Janus kinase (JAK) 1 inhibitor golidocitinib (DZD4205); the enhancer of zeste homologs 1 and 2 (EZH1/ EZH2) inhibitor valemetostat. Duvelisib The phase 2 PRIMO study of duvelisib (a PI3K gamma/delta inhibitor) in relapsed or refractory PTCL consisted of an initial dose-optimization phase, in which the drug was given at the dose of either 25 mg twice daily (cohort 1) or 75 mg twice daily (cohort 2), and of a subsequent expansion phase, when the dose of duvelisib was 75 mg twice daily for the first 2 cycles, then 25 mg twice daily for the following cycles. Patients enrolled in the doseoptimization phase achieved a response in 35% and 54% of the cases for cohort 1 and 2, respectively, with a CR in 25% and 31% of the cases, respectively. Among the initial 78 patients enrolled in the ongoing expansion phase, who received a median of 3 previous lines of therapy, the overall response rate was 50%, which included a CR in 32% of the cases and a partial response in 18%. Median time to response was 53 days, with a median duration of response (DOR) of 233 days. Forty-four percent of the patients on study discontinued the study drug due to disease progression, whereas an adverse event was the cause of withdrawal in 18% of the cases. Liver function tests elevation, along with neutropenia, infections and maculo-papular rash were the most relevant grade 3-4 drugrelated adverse events. In 6% of the treated patients, duvelisib represented an effective bridge therapy to a subsequent autologous or allogeneic transplantation. The combination of duvelisib with romidepsin showed to be highly active in a cohort of 55 patients with relapsed and refractory PTCL across several histotypes. Within a dose range of duvelisib between 25 mg and 75 mg twice daily (in combination with fixed-dose romidepsin, 100 mg/m2), the combination produced an overall response rate of 55%, with a CR in 34% of the cases. The median progression-free survival (PFS) was 7 months. Twenty eight percent of the patients treated had the opportunity to proceed to a subsequent consolidative transplantation phase. Linperlisib Linperlisib is an oral and highly selective inhibitor of PI3K delta now under evaluation in a phase 1b trial enrolling patients with relapsed and refractory PTCL who had received at least one prior systemic treatment. Given at the daily dose of 80 mg, it produced an overall response rate of 70% and a CR rate of 33% in a population of 30 evaluable patients, with PTCL-NOS and AITL being the most responsive disease subtypes. Most of the responses have been detected within the completion of the second month of therapy. Median PFS, overall survival and DOR have not yet been reached. The treatment was overall well tolerated; neutropenia represented the only significant grade 3 adverse event, occurring in nearly 11% of the patients. Golidocitinib (DZD4205) The JAK/STAT pathway plays an important role in PTCL oncogenesis, as JAK mutations are found in anaplastic large-cell lymphomas and STAT3 mutations in up to 40% across all PTCL subtypes. Therefore, JAK/STAT inhibition has a sound rationale in the treatment of relapsed and refractory PTCL. DZD4205 is an orally available selective JAK1 inhibitor now evaluated in a phase 1/2 trial at two dose levels (150 mg/day and 250 mg/day). In a population of 42 patients with previously treated PTCL,
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