Outcomes of relapsed or refractory mature T/NK-cell lymphomas in the era of novel agents: A nationwide observational Study in Japan

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Abstract Background: Mature T-cell and natural killer-cell lymphomas (MTNKLs) are often refractory to conventional treatment and associated with a poor prognosis. Between March 2014 and March 2024, nine novel agents were approved in Japan as single agents (SAs) for relapsed or refractory (R/R) MTNKL. However, the real-world treatment patterns and prognosis of patients with R/R MTNKL in this new treatment era remains unclear. This study aimed to elucidate the outcomes of 2nd-line therapy and treatment patterns in patients with R/R MTNKL, for whom nine SAs are available. Methods: This nationwide, retrospective observational study was conducted across 23 institutions in Japan (ClinicalTrials.gov, ID: NCT06422247). Key inclusion criteria included: age ≥ 18 years and initiation of 2nd-line therapy for R/R MTNKL between April 2018 and March 2023. Eligible diagnoses included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), nodal lymphomas of T follicular helper cell origin (TFHL), including angioimmunoblastic T-cell lymphoma, ALK-positive anaplastic large cell lymphoma (ALK+ALCL), ALK-negative ALCL (ALK-ALCL), breast implant-associated ALCL (BIA-ALCL), extranodal NK/T-cell lymphoma (ENKTL), and mycosis fungoides (MF) with large cell transformation (LCT), according to the revised 4th World Health Organization classification. The primary endpoint was overall survival (OS) after 2nd-line therapy initiation (OS-2L), and the secondary endpoints included time to next treatment (TTNT) and treatment patterns. Results: A total of 256 patients were analyzed. The median age was 66 years (range, 55–77 years), and 66% were male. The histological subtypes included PTCL-NOS (40%), TFHL (38%), ENKTL (11%), ALK+ALCL (6%), ALK-ALCL (3%), MF with LCT (2%), and BIA-ALCL (0%). Among all patients, 54% exhibited extranodal involvement, 41% had high International Prognostic Index scores (3–5), and 40% had disease refractory to 1st-line therapy. The overall median OS-2L (in months [mo], 95% confidence interval [CI]) was 18.3 (14.8–27.9), and by histological subtype, it was 14.9 (11.6–27.9) for PTCL-NOS; 19.7 (12.9–49.1) for TFHL; not reached (NR) (14.8–not estimable [NE]) for ALK+ALCL; 28.1 (4.6–NE) for ALK-ALCL; 15.9 (3.7–31.8) for ENKTL; and 22.9 (13.7–NE) for MF with LCT. Fifty-four percent and 12% of patients aged ≥ 65 and < 65 years, respectively, received SAs as 2nd-line therapy. Thirteen percent of patients underwent autologous hematopoietic stem cell transplantation (HSCT), and 18% underwent allogeneic HSCT during 2nd- or later-line therapies. OS-2L was significantly longer in patients who received HSCT after 2nd- or later-line therapies than in patients who did not receive HSCT (median OS [mo, 95% CI]: NR [28.3-NE] vs. 13.1 [9.6-16.8]). No difference in OS-2L or TTNT after 2nd-line treatment initiation (TTNT-2L) was observed between patients who received SAs and those who received conventional multiagent-chemotherapies (CCs) (median OS-2L [mo, 95% CI]: SAs, 16.8 [13.1-38.9]; CCs, 18.3 [13.7-28.3]; p=.99; median TTNT-2L: SAs, 5.9 [4.0-9.9]; CCs, 3.9 [2.7-5.1]; p=.25). It was consistent in different subgroups except for patients with refractory disease to 1st-line therapy or with Eastern Cooperative Oncology Group performance status ≥2, where SAs showed longer TTNT than CCs. The median TTNT of each SA after 2nd- or later-line therapies (mo, 95% CI) was 10.7 (3.9–17.3) for brentuximab vedotin (BV; n = 53, 21%), 5.0 (2.7–7.1) for tucidinostat (n = 36, 14%), 3.9 (2.6–4.8) for romidepsin (n = 80, 31%), 2.1 (0.4–5.2) for darinaparsin (n = 7, 3%), 1.8 (1.3–2.5) for pralatrexate (n = 58, 23%), 1.5 (0.6–NE) for forodesine (n = 8, 3%), 1.1 (0.4–2.4) for mogamulizumab (n = 22, 9%), 0.7 (0.4–3.5) for denileukin diftitox (n = 5, 2%), and NR (NE–NE) for alectinib (n = 1, 0.4%). In patients with TFHL, romidepsin (44%) and tucidinostat (18%) yielded median TTNTs (mo, 95% CI) of 4.0 (2.6–8.7) and 5.5 (1.9–7.8), respectively. Among the SAs, BV showed the longest median TTNT following 2nd- or later-line therapies in both TFHL (10.7 mo; 95% CI, 3.2–24.0) and PTCL-NOS (4.4 mo; 95% CI, 1.0–NE).Conclusion: To the best of our knowledge, this study reports the most recent treatment patterns and prognoses for patients with R/R MTNKL. No standard of care has been established, as diverse treatment patterns have been observed. SAs resulted in similar survival outcomes to CCs in 2nd-line therapy, despite distinctive clinical background of the groups.

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