Outcomes of second-line systemic therapy for relapsed or refractory peripheral T-cell lymphomas: A single-center, retrospective analysis

Abstract Purpose: Limited data exist detailing the outcomes with second-line (2L) systemic treatment of relapsed or refractory (R/R) peripheral T-cell lymphomas (PTCL) in contemporary practice. Previous series (Mak et al. 2013) demonstrated extremely poor outcomes for such patients (pts): median progression-free (PFS) and overall survival (OS) after relapse or progression were 3.1 and 5.5 months, respectively. However, advances have been made since then in developing targeted therapies including brentuximab-vedotin, HDAC, PI3K, EZH, and JAK inhibitors and others, and more frequent use of alloHCT. Data from newer cohorts with access to these agents would update our understanding of prognosis in this setting, redefine prognostic variables, and serve as a benchmark for future studies. Methods: We identified consecutive pts with PTCL treated with 2L systemic therapy at our center from 2012-2025; 1L therapy may have occurred elsewhere. We included common nodal subtypes of PTCL: anaplastic large cell lymphoma (ALCL), T follicular helper lymphomas (TFH), and PTCL, not otherwise specified (NOS); all pts had pathology reviewed at our center. We queried institutional databases and performed chart review to extract variables of interest and categorized 2L therapies as either conventional cytotoxic chemotherapy, non-chemotherapy, or combinations. Treatment may have occurred as standard-of-care or in a clinical trial. We calculated survival times starting from 2L initiation using Kaplan-Meier methods. We associated features of interest (age at 2L, disease subtype, prior HCT, primary refractory disease, and chemotherapy 2L treatment) with PFS/OS in univariable and multivariable Cox models. Results: 212 eligible pts were identified; most pts were male (57%) and most had TFH lymphomas (50%) followed by NOS (37%) and ALCL (13%). Regarding frontline therapy and outcome, most pts received anthracycline-based multiagent chemotherapy (83%) and most attained a response followed by subsequent relapse (64%), versus 36% that had primary refractory disease. Fifty-five pts (26%) had previously undergone HCT (54 autologous, 1 allogeneic). At time of R/R disease, the median age was 66 years (IQR, 57-74). 2L management was non-chemotherapy in 57% of pts, chemotherapy in 43% of pts, and combined in 1%; 40% of pts were treated in a clinical trial. Among 197 pts with response data, the overall response rate to 2L was 63% (42% CR, 21% PR): non-chemotherapy 66%, chemotherapy 59%; 29 pts (14%) underwent HCT immediately post-2L (8/29, 28% autologous, 21/29, 72% alloHCT). With a median follow-up among survivors of 44 months, the median PFS (medPFS) and OS after 2L are 4.7 (95% CI: 3.6-6.4) and 22.7 (95% CI: 13.4-34.3) months, respectively. The 12-month rates of PFS and OS were 32% (95% CI: 27-39) and 58% (95% CI: 51-65), respectively; 24- and 36-month OS rates were 49% (95% CI: 43-57) and 41% (95% CI: 35-49), respectively. NOS [vs. TFH/ALCL, adjusted HR (aHR) 1.8, 95% CI 1.3-2.5, P = 0.0002] and primary refractory disease (aHR 1.7, 95% CI: 1.2-2.3, P = 0.005) each conferred inferior PFS in multivariable analysis. Regarding OS, NOS (aHR: 2.0, 95% CI: 1.5-2.9, P <0.0001) and primary refractory disease (aHR 1.7, 95% CI: 1.1-2.4, P = 0.009) conferred inferior OS in univariable and multivariable analysis. Conclusions: We analyzed a large cohort of pts with R/R PTCL initiating 2L systemic therapy in an era with additional treatment options and increasing use of novel therapies. Since prior publications, we highlight improved OS, suggesting that recent therapeutic advances are improving longer-term outcomes. MedPFS to 2L appeared similar to prior series, suggesting that recent expansion of treatment options has allowed for more opportunities to identify an effective therapy for an individual patient. Increasing use of consolidative alloHCT for pts may also contribute to these improved OS outcomes. Pts with NOS (reflecting the lack of subtype-specific advances that have been attained for ALCL/TFH) and those with primary refractory disease fared relatively poorly. Even with these improvements, R/R PTCL remains an area of high unmet need; novel treatment approaches in clinical trials and translational efforts aimed at further elucidating the disease pathobiology of PTCL to identify new treatment targets are urgently needed.