What's new in peripheral T‐cell lymphomas

Abstract Peripheral T‐cell lymphomas (PTCLs) are a rare, heterogeneous group of hematological malignancies with extremely poor prognosis for almost all subtypes. The diverse clinicopathological features of PTCLs make accurate diagnosis, prognosis, and choice of optimal treatment strategies difficult. Moreover, the best therapeutic algorithms are still under debate due to the extrapolated approaches developed for B‐cell lymphomas and to the absence of few treatment protocol specifically developed for PTCLs. Some advances have been made with CD30 monoclonal antibody, mainly for anaplastic large‐cell lymphomas, with improvements in progression‐free survival and overall survival. Several new drugs are under evaluation in clinical trials, although not all the results are as encouraging as expected. In this review, we briefly present the most updated information on diagnosis, prognostication, and treatment strategies in PTCLs.


| INTRODUCTION
Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous subgroup of rare hematological malignancies originating from postthymic lymphocytes. From different available data, PTCLs account for approximately 5%-15% of all lymphomas in Western countries, with an incidence of 0.5-2 per 100,000 people per year. 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. expression of GATA3 and those with an increased expression of TBX21. 3,5 The GATA3 group is associated with poor outcomes and has more loss or mutation of tumor suppressor genes including TP53, PTEN, PRDM1, and CDKN2A/B, and gains in STAT3, REL, and MYC oncogenes. 6 The TBX21 group is enriched with alterations of genes involved in DNA methylation. 7 These three groups are added to other previously characterized subtypes with specific cell of origin, which include ALCL, adult T-cell leukemia/lymphoma, and gamma-delta PTCL. The better characterization of the cell of origin in PTCL is advantageous in the classification of these lymphomas as it reduces the undefined basket of PTCL-NOS and provides a strong rationale for determining the most effective therapies in these lymphomas. Immunomodulatory agents and epigenetic modifiers are more suitable for TFH subtypes, while phosphatidylinositol 3-kinase (PI3K) inhibitors, hypomethylating agents, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) inhibitors might find a better role in GATA3 or TBX21 subtypes. 8

| Prognosis and staging
In the last two decades, many studies have been conducted to identify and validate clinical and biological factors that can be used to predict the heterogenous outcome of PTCL patients. Several of these studies have confirmed that a poor Eastern Cooperative Oncology Group Scale of Performance Status score, extranodal involvement, advanced disease, bulky, Ki67, and a high lactate dehydrogenase rate correlate with shorter overall survival (OS). [9][10][11] The International Prognostic Index (IPI) was formally validated in PTCL 1,12 but the lack of clearly defined risk groups prompted the search for PTCL-specific prognostic indexes. 9,11 The Fondazione Italiana Linfomi defined the first Prognostic Index for PTCL-NOS (PIT), which stratifies patients into four distinct groups; the PIT showed an independent correlation with OS. Subsequently, PIT was updated to modified PIT by replacing bone marrow involvement with Ki67 rate expression. 10 A new model, the T-cell score, has recently been defined by using the prospectively collected data registered in the T-cell Project. 13 More recently, novel prognostic indexes have been identified and validated for specific PTCL subtypes, including enteropathy-associated T-cell lymphoma (EATCL) and nasal-type extranodal NKTCL. As shown in Table 1 interim and end-of-treatment FDG-PET to predict outcomes. 15,16 Although promising, data regarding the role of metabolic response in PTCLs are very preliminary and thus need to be confirmed by larger studies.

| Treatment
The optimal management of patients with PTCL, which is disputed, is in any case limited to few options, all with unsatisfactory efficacy.
None of the currently available recommendations are based on highquality evidence, and few well-designed randomized clinical trials (RCTs) have been conducted to support therapeutic choices. The currently recommended treatment strategy for PTCLs derives mostly from B-cell lymphoma treatment strategies, with the recommended use of an aggressive approach with anthracycline-based polychemotherapy (i.e., CHOP or CHOEP) and with autologous stem cell transplant (autoSCT) to consolidate response to first-line therapy or to manage relapsed patients. 17 Regarding the role of anthracyclines in PTCL, while their role is still debated, anthracycline void regimens have so far failed to demonstrate their superiority to CHOP. 17 Based on a recent meta-analysis, the 5-year OS achieved with this approach was 36.6%. 18 Several attempts have been made to improve the poor results achieved with CHOP. These include the addition of novel agents and the intensification of therapy. Some clinical studies on etoposide intensification of standard CHOP have shown conflicting results. However, the addition of etoposide has shown better progression-free survival (PFS), especially in patients with ALCL, in those with favorable risk factors, and in patients age ≤ 60 years. 12,[19][20][21] The results of three randomized trials that evaluated the efficacy of adding a novel agent to the CHOP backbone are available.
One prospective trial combined alemtuzumab, an anti-CD52 monoclonal antibody, with CHOP; it failed to show improved outcomes compared to chemotherapy alone. 22  confidence interval: 0.63-1.04). Although this study was not able to confirm the initial hypothesis of the superiority of Ro-CHOP, the subgroup analysis seems to suggest that the novel combination acts differently in different PTCL subtypes, with relatively higher activity observed for AITLs. 24 In summary, even if associated with unsatisfactory results, CHOP chemotherapy should still be considered as the reference therapy for most PTCL subtypes with the main exception of ALCL for which BV-CHP is the preferred recommended option and of NKTCL. The use of CHOEP is supported by low quality of evidence but can be considered as a reasonable option in young and fit subjects with non-ALCL PTCLs.
The use of high-dose chemotherapy followed by autoSCT in first complete remission (CR1) is recommended by most of the available guidelines 17,25 (Table 2). Several groups have reported that achieving CR before autoSCT is a significant independent predictor of improved survival in patients with PTCL receiving upfront autoSCT. [26][27][28] However, there have been no RCTs specifically designed to evaluate upfront autoSCT in comparison with observation in CR1 for PTCL. [29][30][31] Several retrospective studies and prospective single-arm phase II trials have reported encouraging results with this approach ( Table 3). The largest prospective phase II study, published by the Nordic Group (NLG-T-01), included 160 patients with PTCLs; 72% of patients underwent autoSCT in first remission after six courses of CHOEP chemotherapy. 32 All nodal PTCL subtypes were included, with the exception of A.

| ALK-positive ALCLs
One hundred thirty patients achieved CR (63%) or partial response (PR; 37%), and 115 (88.5%) underwent ASCT. Overall, the 5-year OS and PFS for the intention-to-treat population were 51% and 44%, respectively. Considering subtype distribution, better outcomes were observed for ALK-negative ALCL than for other subtypes. 32 In a second study by Reimer et al., 33 B symptoms X X   was not able to confirm DHAP superiority over GDP in PTCLs. 45 In relapsed/refractory PTCLs, alloSCT is also a feasible option in almost all subtypes after failing prior autoSCT. 17,25,46 However, nonrelapse mortality varies from 8.2% to 40%. [47][48][49] These scatter data suggest that it is necessary to carefully select possible candidates for alloSCT.

Regional
Several new agents have been tested in the relapsed refractory Results achieved with these agents are very similar with CR rates of 10%-25% and with a median PFS of less than 1 year.

| Novel agents
Pharmacology research is very active in PTCL, and therapeutic development is mainly driven by advances in the understanding of the biology of the disease (Table 4). The same agent has been evaluated in combination with romidepsin, showing greater activity in AITL and PTCL-NOS (overall response rates 74% and 64%, respectively, CR rates 63% and 36%, respectively). 52 A promising therapeutic strategy in PTCL is represented by targeting of tumor microenvironment. Blocking the PD1 interaction with its ligand is justified by the finding of an increased expression of PD-L1 in both malignant and stromal cells of several PTCL subtypes.
Indeed, some activity of anti-PD1 agents in PTCL has been described by phase I studies, 53 and more convincing results have been achieved with NKTCL. The use of PD1 blockers, however, has also been associated with cases of hyperprogression, thus making further clarification of PD1 inhibition in PTCL urgently needed.
Finally, cellular therapy based on the concept of chimeric antigen receptor T cells is also being developed for T-cell lymphomas, 54 as is the use of bispecific antibodies targeting both CD30 and CD16A. 55

| CONCLUSIONS
Management of PTCL patients continues to be a real challenge for hematologist-oncologists. The oversimplified approach that has been used for many years, replicating the rules of B-cell lymphoma management, is clearly unsatisfactory and requires radical reassessment.
New insights into the biology of the disease and a renewed interest on the part of the scientific community in the management of PTCL have led to the identification of new targets and to confirming the activity of new agents, which are now moving PTCLs into the era of targeted therapy. Moreover, taking into account the different biology and unique behavior of PTCL subtypes, each with a different response to therapy, has become indispensable; these differences result in more difficulties in interpreting the available data and in designing future trials. PTCL remains a challenging disease which requires massive international cooperation.