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Romidepsinhas demonstrated comparable efficacy across the 3 most common PTCL subtypes. Although pralatrexate has general approval for the treatment of PTCL, based on results from the pivotal study in relapsed/refractory PTCL [20], National Comprehensive Cancer Network guidelines report that pralatrexate has demonstrated limited activity in AITL [8]. Brentuximab vedotin has demonstrated considerable activity in ALCL [21], and responses have also been seen in CD30+ cases of other NHL subtypes (including AITL) [23]; however, its utility in non-CD30+ PTCLs is unknown.

The results presented herein demonstrate that treatment with single-agent romidepsin leads to highly durable responses in patients with relapsed/refractory PTCL, including patients with the 3 major PTCL subtypes, patients who received several prior systemic therapies, patients with advanced disease, and, importantly, patients refractory to their last prior therapy. Patients with long-term responses to romidepsin can successfully continue on romidepsin, with or without reducing dose frequency, to maintain response at the discretion of the investigator. Whether combining romidepsin with regimens that induce higher initial response rates (eg, CHOP) will enhance the durability of these responses and lead to prolonged survival, both in relapsed/refractory patients and in those with newly diagnosed disease, warrants further investigation. Additionally, the potential for use of romidepsin as maintenance therapy after chemotherapy induction or after consolidation with high-dose chemotherapy followed by SCT should be examined, because long-term tolerability has been demonstrated.

This study is ongoing, but December 31, 2011, was the cutoff date for this analysis. Patients who withdrew without PD were to be followed every 2 months until PD, withdrawal from study, or start of alternate therapy. All descriptive statistical analyses were performed by using SAS statistical software version 9.2 (SAS Institute, Cary, NC). Time-to-event data were summarized by Kaplan-Meier methods.

The authors take full responsibility for the content of this manuscript, but thank Stacey Rose, PhD (MediTech Media), for providing medical editorial assistance. Financial support for medical editorial assistance was provided by Celgene Corporation.

BC interpreted the data, drafted the paper, and approved all versions including the final version. BB and JW acquired and analyzed the data, critically revised the paper, and approval all versions including the final version. BP, HMP, FF, LS, FM, LPB, SPI, AS, TN, JN, SH, CC, MG, MW interpreted the data, critically revised the paper and approved all versions including the final version. All authors are responsible for the accuracy and integrity of all aspects of the manuscript.

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Figure 1 GATA-3 expression is associated with dismal outcomes in PTCL, NOS. GATA-3 expression was determined by immunohistochemistry and patients were stratified by treatment. Among GATA-3 positive patients (n=28) that received first-line anthracycline-based chemotherapy, 86% received CHOP or CHOEP. Among GATA-3 negative patients (n=61), 87% were treated with CHOP/CHOEP. Consistent with prior studies, GATA-3 expression was associated with inferior event-free survival (EFS). Importantly, no significant improvement in EFS was observed for GATA-3+ patients treated with CHOP/CHOEP in comparison to PTCL, NOS patients (n=33) who received palliative or best supportive care alone (72% hospice care with or without corticosteroids), highlighting the futility of current therapies in this subset. [Data reprinted with permission from (39)].

Copyright 2023 Weiss, Reneau and Wilcox. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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With the exception of ALCL, in which brentuximab vedotin (BV)-CHP (cyclosphosphamide, doxorubicin, prednisone) is considered the new standard treatment, uncertainty remains regarding the optimal front-line therapeutic regimen and the role of consolidative high-dose chemotherapy and autologous stem cell transplant (auto-SCT). This is particularly apparent in TFHL in which sensitivity to epigenetic therapies has led to numerous studies evaluating chemotherapy-free, novel therapy combination treatment approaches, also in treatment-nave patients. Furthermore, as the genomic landscape is uncovered, evolving studies are targeting specific pathway vulnerabilities (e.g., Janus kinase [JAK]/signal transducer and activator of transcription [STAT], phosphatidyl inositol 3 kinase [PI3K]) as well as integrating biological correlates in an effort to understand biomarkers of response and resistance. As a follow-up to the nodal PTCL pathobiology paper by Bisig, Savage and de Leval in this issue, we review the history of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and transplant for nodal PTCL, highlight new treatment advances in the front-line and relapsed/refractory (R/R) settings as well as the promise of a more 'personalized' therapy approach.

The recently activated TRANSCRIPT trial will address the role of auto-SCT in patients with nodal PTCL (excluding ALK+ ALCL) in CR following induction therapy (NCT05444712) (Online Supplementary Table S1). Despite data limitations, consolidative auto-SCT should still be a strategy to consider with upfront treatment but guidelines differ about whether it should be performed exclusively in patients in CR.34,44 Further studies are needed, ideally by subtype, to identify lower-risk patients in whom auto-SCT may be omitted and, conversely, determine whether there are molecular markers, such as P53 or DNMT3A mutations, that identify cases in which auto-SCT is futile.

The risk of BIA-ALCL is exclusively associated with textured implants and the time from implant to development of ALCL is 7-11 years. The overall risk varies in series but is likely between 1:1,000 to 1:10,000.45 Peri-implant effusion is the most common presentation with 85% of patients having stage 1 disease limited to the seroma capsule. The effusion, preferably as a large volume, should be sent for cytology with cell block preparation and flow cytometry including CD30 in the panel. A positron electron tomography scan should be done before surgery as post-surgical inflammatory changes can complicate interpretation.45 As recently reviewed,45 the mainstay of treatment is implant removal and en-bloc complete capsulectomy, with bilateral removal if textured implants are used. Complete surgical excision in patients with stage 1 disease yields a 5-year disease-specific survival of 95%. For those presenting with stage 2 disease, there are limited data to guide recommendations. Surgery should include removal of the mass and sampling/removal of suspicious lymph nodes.45 With incomplete resection, radiation may be considered and in rare cases adjuvant BV has been administered although data supporting this approach are lacking. Although patients with BIA-ALCL were not included in ECHELON-2, BV-CHP would be reasonable in those with disease outside of the breast and lymph nodes, or with lymph node involvement.45

Unfortunately, despite advances in the front-line setting a large proportion of PTCL patients have lymphoma relapse or have primary refractory disease. The only established curative treatment is SCT, although rare long-term remissions have been observed following systemic therapy alone, which, in some cases, may reflect more indolent disease biology.46-48

With the emergence of genomic techniques, there is a greater understanding of underlying disease biology which has also helped to inform therapeutics. This is best shown in TFHL, which are typified by recurrent mutations in epigenetic modifiers,5 with growing evidence of sensitivity to a broad range of agents of this class (Tables 3-5). In a proportion of ALCL and other rarer PTCL subtypes, there is evidence of JAK/STAT pathway activation, leading to recent trials with JAK inhibitors.49 Although studies of PTCL-NOS have elucidated the GATA3 and TBX21 molecular subtypes, how this informs treatment decisions remains unknown. Here, we review the overall management of R/R nodal PTCL, highlighting situations in which biology can guide treatment options.

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