Romidepsin in peripheral T-cell lymphomas: current updates and treatment considerations

Peripheral T-cell lymphomas (PTCL) are a heterogeneous and rare group of lymphomas. The most common subgroups include nodal T-follicular helper cell lymphoma (nTFHL), systemic anaplastic T-cell lymphomas (ALCL), and not otherwise specified peripheral T-cell lymphoma (PTCL-NOS). nTFHL is characterized by the immunohistochemical co-expression of at least two THF markers along with CD4 and is further divided into nTFHL-angioimmunoblastic type (nTFHL-AI), nTFHL-follicular type (nTFHL-F), and nTFHL-not otherwise specified (nTFHL-NOS) (1).

Despite their rarity, PTCLs present a significant clinical challenge due to their aggressive nature and poor prognosis. Current treatments for PTCLs are often limited and non-specific, primarily relying on chemotherapy-based regimens. These treatments frequently yield unsatisfactory results, with a 5-year overall survival (OS) rate of around 30% (2,3). For patients younger than 65 years, first-line therapy is usually based on induction chemotherapy like cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (CHOEP) or CHOP, followed by autologous stem cell transplantation (ASCT). In the NLG-T-01 study, however, many patients did not tolerate dose-dense induction chemotherapy, with only 72% being able to proceed to ASCT. Moreover, more than 50% of patients experienced lymphoma relapse within three years after completing treatment (4). These findings underscore the pressing need for more effective therapeutic strategies in this difficult-to-treat population.

Although numerous targeted therapies have been explored in T-cell lymphomas, such as CD2 with siplizumab, CD4 with zanolimumab, and CD52 with alemtuzumab, these efforts have often been limited by either low efficacy, significant toxicity, or the risk of secondary malignancies such as Epstein-Barr virus lymphoproliferative disease (5). A notable advancement for some patients has been the introduction of the anti-CD30 monoclonal antibody brentuximab vedotin (BV), which, when added to cyclophosphamide, doxorubicin, and prednisone (CHP), showed particular success in ALCL lymphomas (6). These findings underscore the critical role of targeted therapy in T-cell lymphomas, similar to the progress seen in B-cell counterparts.

Mutational analysis studies in nTFHL-AI and nTFHL-F have demonstrated an increased prevalence of mutations in genes encoding for epigenetic regulatory factors such as TET2, RHOA, or DNMT3A (7). In line with these findings, drugs capable of inhibiting epigenetic factors, such as hypomethylating agents (HMAs) or histone deacetylase inhibitors (HDACi), have shown some efficacy.

HDACi can induce acetylation of histones and other proteins, leading to antitumor activity by increasing the expression of pro-apoptotic proteins, tumor suppressors, and inhibiting cell growth (8). Among the various HDACi, romidepsin has demonstrated its activity in a phase 2 study conducted on 130 PTCL patients, with an overall response rate (ORR) of 25% (15% complete response, CR). In responding patients, the median duration of response (DOR) was 17 months. Approximately two-thirds of the CRs were achieved in patients with angioimmunoblastic T-cell lymphoma (AITL) (9). Given the activity of romidepsin as monotherapy, various studies have sought to enhance its efficacy in relapsed/refractory PTCL patients by combining it with other drugs such as cisplatin, gemcitabine, pralatrexate, azacitidine, and liposomal doxorubicin, yielding encouraging results (10).

In light of the unsatisfactory results of the current standard first-line therapy and the activity of romidepsin, an international phase III study was conducted by Lymphoma Study Association (LYSA) between 2013 and 2017 on 421 untreated PTCL patients, randomizing them 1:1 to receive CHOP with or without romidepsin. The primary endpoint of the study was progression-free survival (PFS). Unfortunately, the study did not meet its primary endpoint (median PFS of Ro-CHOP was 12 vs. 10.2 months for CHOP, P=0.09). This was partly due to the higher toxicity of Ro-CHOP, which frequently required dose reductions as compared to the standard arm. Interestingly, a marginally greater benefit was observed in TFH-like histologies, in line with previous studies (11).

Similarly to this study, the Italian phase Ib/II PTCL13 study also did not demonstrate any benefit in adding romidepsin to first-line chemotherapy treatment. In the Italian experience, an attempt was made to improve the results obtained with the CHOEP regimen (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisone) from the NLG-T-01 study by adding romidepsin on days 1 and 8. In the phase Ib part, the dose of romidepsin was determined to be 14 mg/m² in combination with CHOEP. In the phase II part of the study, Ro-CHOEP was administered to 86 PTCL patients. As mentioned before, this study also failed to meet its primary endpoint with a PFS at the interim analysis of 48% at 18 months, leading to the study’s suspension due to inefficacy. Unlike Bachy’s study, in this experience, there did not seem to be differences between TFH-like histologies and other subgroups. However, the authors themselves emphasize the limited sample size for assessing potential differences (12).

In the accompanying article to this editorial, the authors update and re-analyze the results of the LYSA study in light of new biological evidence. In this new analysis, with a final follow-up of 72 months, no significant changes emerged regarding the efficacy and safety of the Ro-CHOP combination compared to the first analysis. This new analysis compared TFH lymphomas (nTFHL-AI, nTFHL-F and nTFHL-NOS) with non-TFH lymphomas, showing a significantly better PFS with Ro-CHOP as compared to CHOP in TFH lymphomas [PFS of 19.5 months in Ro-CHOP vs. 10.6 months in the CHOP arm, hazard ratios (HR) 0.703, 95% confidence interval (CI): 0.502 to 0.985; P=0.03], with a benefit particularly evident in high-risk patients with International Prognostic Index (IPI) 4 or 5. However, this PFS advantage did not translate into improved OS (13).

These findings underscore the importance of considering the heterogeneity of PTCL in therapeutic strategies, with treatment regimens that should account for the biological diversity observed in cases such as TFH-lymphomas and ALCL. However, this complexity increases the challenges in conducting specific studies due to the rarity of these diseases.

It is important to note that in relapsed and refractory PTCL, the prognosis remains highly unfavorable regardless of the treatment employed. This conclusion is underscored by the second analysis, which shows a dismal PFS of just 3.3 months and an OS of 11.5 months at relapse (13). These figures highlight the challenges in managing PTCL, where conventional therapies often fall short. However, there is emerging evidence suggesting that the introduction of brentuximab could offer a glimmer of hope. When used either as monotherapy or in combination with bendamustine, brentuximab appears to demonstrate superior efficacy compared to standard treatments, potentially improving outcomes for patients with PTCL (14,15). This advancement underscores the need for continued innovation and tailored approaches in the treatment of these difficult-to-manage lymphomas.

The heterogeneity of PTCL has long been underestimated and misunderstood, partly due to their relative rarity, which made trials design. Biological drugs such as HDACi and brentuximab seem to have greater efficacy in subgroups such as nTFHL or ALCL.

Similar to HDACs, HMAs such as azacitidine, guadecitabine, or oral azacitidine have also shown efficacy in PTCL. These epigenetic modifiers inhibit DNA methyltransferase and have been tested both as monotherapy and in combination with chemotherapy, demonstrating significant effectiveness, particularly in TFH-lymphomas (16-18).

Emerging research indicates the role of biological markers like TP53 mutations and other regulatory genes, along with specific rearrangements such as GATA3 and TBX21, which could identify subgroups that are more or less chemosensitive (19,20). However, current knowledge is insufficient to definitively guide the treatment of these lymphomas.

Given the complex nature and poor prognosis of PTCL, it is crucial to continue exploring targeted therapies and personalized treatment approaches. In the accompanying article, authors have updated the trial follow-up, and have reported important observations on the activity of Ro-CHOP in TFH lymphomas, underscoring the need for ongoing research to better understand the disease and improve patient outcomes. Similar promising results have been reported in a phase 2 study on the combination of oral 5-azacytidine and romidepsin in patients with relapsed/refractory PTCL, demonstrating prominent efficacy in TFH lymphomas. Additionally, patients with a higher mutation burden in genes encoding DNA methyltransferases showed higher response rates compared to other subgroups, although this was not statistically significant (21).

Unfortunately, a ground-breaking breakthrough in the treatment of these patients has not yet been achieved. However, with advancements in biological knowledge, new drugs in testing (NCT04803201 duvelisib; NCT06072131 belinostat or pralatrexate in combination with CHOP; NCT03240211 pembrolizumab with decitabine and pralatrexate; NCT04083495 CD30 CAR, and others) and therapeutic combinations are currently in development, introducing new elements to our understanding and treatment of these lymphomas.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, AME Clinical Trials Review. The article has undergone external peer review.

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-24-136/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-24-136/coif). C.V. reports payment or honoraria from AbbVie, BMS, Astra Zeneca, Servier, Incyte, Roche, Pfizer, Novartis, Gentili, Janssen, Kite-Gilead, Beigene, Lilly, Kyowa Kirin, Takeda. The other authors have no conflicts of interest to declare.

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