Toward a Biology-Driven Treatment Strategy for Peripheral T-cell Lymphoma

Indolent disease

Patients with smoldering and chronic favorable presentations of ATLL often do not require multiagent chemotherapy at diagnosis. This is based on data which show that median OS is around 4 years post diagnosis. ²² More recently, a retrospective series has shown a 100% 5-year OS in this group of patients with antiviral therapy alone and this is described in further detail below. ²³

Aggressive disease

Patients with lymphomatous and acute presentations of ATLL are typically unwell at diagnosis (hypercalcemia, B symptoms, and organ infiltration) and have been treated with multiagent chemotherapy up front. The efficacy of CHOP-like regimes for this group of patients has been demonstrated in a number of retrospective analyses of PTCL/ATLL studies as well as control arms of randomized trials.^24–26

More recently, a Japanese trial has demonstrated the efficacy of VCAP-AMP-VECP (vincristine, cyclophosphamide, doxorubicin, and prednisolone; doxorubicin, ranimustine, and prednisolone; vindesine, etoposide, carboplatin, and prednisolone chemotherapy in this group of patients, albeit at the expense of considerably increased treatment toxicity. ²⁶

Mogamulizumab

C-C chemokine receptor type 4 is widely expressed on ATLL neoplastic cells as well as other helper T cell–derived lymphomas. The defucosylated, anti-CCR4 humanized monoclonal antibody mogamulizumab has been approved in Japan for the treatment of r/r ATLL, cutaneous T-cell lymphoma, and PTCL-NOS on the basis of phase 1/2 studies which demonstrated efficacy and acceptable toxicity. ²⁷ Removal of fucosyl groups provides the antibody with greater antibody-dependent cellular cytotoxicity. In the largest randomized study of mogamulizumab so far conducted, it has demonstrated efficacy in r/r ATLL (overall response rate [ORR] 23.4% by independent assessor (11/47), with PFS of 3 months, compared with 0/24 for investigator choice treatment). ²⁸ An earlier nonrandomized phase 2 study demonstrated 50% ORR in the r/r setting in a smaller group (28) of patients. ²⁹ This provides a clear example where an understanding of disease biology (in this case, CCR4 expression) has led to advances in treatment.

Antiviral therapy

Antiviral agents have been widely used as part of treatment regimens for ATLL, although without a plausible biological explanation for their efficacy. HTLV-1 infection in ATLL is believed to be in a latent phase, and it is unclear, therefore, how such an approach may potentially improve outcomes. Typically, the antiviral agent zidovudine plus interferon alfa have been used. ³⁰

The most comprehensive evaluation of antiviral agents in ATLL has been a retrospective meta-analysis involving 245 patients in France, United Kingdom, United States, and Martinique. ²³ This study included patients with smoldering, chronic, lymphomatous, and acute ATLL treated with antiviral therapy alone and antiviral therapy plus chemotherapy. For patients with indolent presentations of ATLL, antiviral therapy demonstrated apparent efficacy with 100% 5-year OS compared with 42% in patients treated with chemotherapy or chemotherapy plus antiviral therapy. Similarly, patients with acute (leukemic) ATLL antiviral therapy alone improved 5-year OS from 10% to 28% over treatments including chemotherapy. This benefit was not, however, noted for patients with lymphomatous ATLL where antiviral therapy alone resulted in considerably poorer 5-year OS compared with chemotherapy-based treatments (0% vs 18%). These data, while interesting, are derived from a retrospective study and should be translated cautiously into clinical practice, preferably in the context of prospective studies.

Nasal disease

The treatment of ENKTCL is dependent on the stage of the disease at presentation. Stage I or contiguous stage II disease can be treated with radiotherapy +/− multiagent chemotherapy with curative intent. More advanced disease carries a markedly shorter median duration of remission and is generally treated with multiagent chemotherapy. For limited-stage disease, adjuvant chemotherapy postradiotherapy probably does lead to improved OS. This has been demonstrated in retrospective studies. For example, a retrospective series of 136 cases of ENKTCL showed survival benefit for nasal cases receiving radiotherapy in addition to chemotherapy. ³³ Combined modality therapy has therefore become standard of care in this setting. ³⁴

Extranasal disease

For disseminated disease, there is no consensus as to the most effective form of multiagent chemotherapy and no relevant randomized trials exist. Extranodal NK/T-cell lymphoma frequently expresses high levels of P-glycoprotein that gives it a multidrug resistance phenotype. ³⁵ This may explain frequent resistance to anthracycline-based chemotherapy, although this remains unclear. ³⁶

Most recent studies have focused on the role of l-asparaginase, a drug which has activity that is not affected by P-glycoprotein expression due to its extracellular mode of action. It has demonstrated efficacy in newly diagnosed and relapsed disease.^37,38 This drug was incorporated into the LVP (l-asparaginase, vincristine, and prednisolone) regimen with radiotherapy where it produced an 81% complete response (CR) in newly diagnosed disease. ³⁹ The 5-year survival data from this study have now been published and show an OS and PFS both of 64%. ⁴⁰ Similarly, GELOX (gemcitabine, l-asparaginase, and oxaliplatin) elicited a 74.1% CR in a prospective phase I/II study with a 2-year PFS of 86%. ⁴¹ A subsequent retrospective study comparing GELOX with EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone), which lacks asparaginase, showed a superior CR, ORR, and PFS for GELOX. ⁴²

A more intense asparaginase-containing chemotherapy regimen SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) has also been assessed in newly diagnosed and r/r disease giving an OR response rate of 78%, with 47% PFS at a median follow-up of 31 months, which was similar for newly diagnosed and r/r disease, albeit at the expense of significant toxicities. ⁴³

Most recently, a Chinese randomized controlled study including 42 patients has compared safety and efficacy of DDGP (dexamethasone, cisplatin, gemcitabine, and polyethylene glycol-l-asparaginase) and SMILE regimens for newly diagnosed advanced NK/T-cell lymphoma. This was a randomized controlled, multicenter, and open-label clinical trial. ⁴⁴ This study demonstrated significant improvements in PFS, OS (74% compared with 45% for 2-year OS), and tolerability from DDGP compared with SMILE.

Brentuximab vedotin

Brentuximab vedotin is an antibody-drug conjugate (ADC) with specificity for CD30. The chemotherapy moiety is monomethyl auristatin E which is an antitubulin agent. It has demonstrated efficacy in classical Hodgkin lymphoma as well as ALCL. The original phase 2 study in r/r ALCL showed that it could induce CRs in more than half of the patients when used as monotherapy. The ORR rate was 86%. The median durations of ORR and CR were 12.6 and 13.2 months, respectively. ⁴⁶ ECHELON-2, a study comparing brentuximab vedotin + CHP with CHOP in newly diagnosed ALCL remains ongoing. Brentuximab is currently used in r/r disease, often as a bridge to consolidation with stem cell transplant.

ALK inhibitors

Crizotinib and ceritinib are inhibitors of ALK and have also been used in a limited fashion, in ALK-positive ALCL. Crizotinib has been used as monotherapy in a small series of patients with relapsed ALK-positive ALCL who were refractory to chemotherapy. 10 of 11 (90.9%) of patients responded by entering at least a partial remission, and there is evidence that these are durable remissions with 63.7% PFS at 2 years. ⁴⁷

In a phase 1 ceritinib trial for patients with advanced ALK-positive tumors, 3 of 304 patients had ALK-positive ALCL. All 3 patients achieved a response (2 CRs, 1 PR) with ongoing remissions of at least 20 months. ⁴⁸ Clearly, these data relate to very small groups of patients, but they do demonstrate potential therapies for the future.

Clinical features

Patients with AITL usually present with acute onset systemic symptoms, although, more rarely, they present with asymptomatic lymphadenopathy. About 90% of patients present with advanced (stage III-IV) disease. B symptoms, rash, ascites, and pleural effusions and autoimmune phenomena such as polyarthritis and positive direct antiglobulin test are common.

Morphological features

Involved lymph nodes show complete or partial effacement of the normal architecture by a paracortical infiltrate. This infiltrate consists of malignant T cells and numerous inflammatory cells, including plasma cells, histiocytes, eosinophils, B-immunoblasts, which are often positive for EBV. There is prominent neovascularization with high endothelial venules with thickened or hyalinized walls. Expanded networks of follicular dendritic cells (FDCs), best appreciated with immunostains for dendritic cell markers (eg, CD21, CD23, and CD35), surround these abnormal blood vessels.

Immunophenotypic characteristics

Angioimmunoblastic T-cell lymphoma cells express pan T-cell antigens (CD4+, CD3+, CD2+ with variable expression of CD5 and CD7) as well as cell surface markers that are usually expressed on follicular helper T (T_FH) cells: CD10, BCl6, PD-1, CXCL13, and ICOS.

Diagnostic uncertainty may still arise, however, because of the variable expression of these cell surface markers on other subtypes of PTCL and the similarity of the background milieu to an inflammatory state. T-cell receptor (TCR) rearrangement studies may clarify this to some extent but are hampered by the relatively low burden of neoplastic cells within the malignant lesion.

Gene expression profiling and T_FH derivation

Gene expression profile studies provide further diagnostic information and have confirmed the T_FH cell as the likely cell of origin of AITL. Gene expression profile analyses of an array of T-cell NHL samples and cell lines have shown that AITL cases have a signature that is distinct from other T-cell NHL subtypes.^50,51 The AITL signature has a strong imprint from the tumor microenvironment (overexpression of B-cell–related and FDC-related genes, chemokines, and genes implicated in angiogenesis), as well as overexpression of genes characteristic of normal T_FH cells, for example, CXC13, BCL6, PD-1, CD40L, and NFATC1. Oncogenic pathways including nuclear factor κB (NF-κB), interleukin (IL)-6, and transforming growth factor β were also identified.

Normal T_FH cells migrate to B-cell follicles and provide help to B cells for high-affinity antibody production. ⁵² The close interaction between T_FH and B cells may explain some of the clinical characteristics of AITL. For example, clonal IGHV rearrangements are seen in approximately 15% of AITL cases, and hypergammaglobulinemia and autoimmune phenomena are relatively common. There is also a recognized increased risk of developing diffuse large B-cell lymphoma. ⁵³ Epstein-Barr virus–positive polyclonal B cells are highly prevalent in AITL (95% cases are EBV-encoded small RNA positive). Most of the malignant T cells are, however, negative. This suggests against a primary role for EBV in AITL tumorigenesis and instead indicates that EBV-infected B cells may take advantage of the permissive T_FH-driven interactions. ⁵⁴

A proportion of cases that have been reported morphologically as PTCL-NOS, and lack some of the phenotypic hallmarks of AITL, share this T_FH—such as GEP signature, 20% in 1 case series. ⁵¹ This has led to their unification in the latest WHO classification system under a common subtype of PTCL with a T_FH phenotype. ⁴ This group comprises AITL, T_FH lymphoma, and nodal PTCL with T_FH phenotype. The WHO diagnostic criteria specify that they should express at least 2 to 3 T_FH-related markers, including PD-1, CD10, BCL6, CXCl13, ICOS, SAP, and CCR5. However, although AITL, T_FH lymphoma, and nodal PTCL with T_FH phenotype share a common GEP, they are maintained as separate disease entities because of their distinct clinical and pathological features.

Recurrent genetic mutations

In addition to this characteristic GEP profile, AITL and PTCLs with a T_FH phenotype share unifying recurrent genetic mutations. Using exome and transcriptome sequencing of AITL tumor samples, a specific RHOA mutation, encoding a p.Gly17Val substitution, was identified in 55.3% of AITL cases. ⁵⁵ It was also present in a lower proportion of PTCL-NOS (7.7%) and NK/T-cell lymphoma (15%) but absent in B-cell lymphomas. RHOA encodes a small guanosine triphosphatase protein in the RAS family: the p.Gly17Val mutation results in a loss of function. The group hypothesizes that this mutation is key to AITL tumorigenesis. It was shown to increase proliferation in cell lines, possibly by altering AKT kinase phosphorylation and signaling, downstream of the TCR.

IDH2 mutations are another potential driver mutation and have been identified in 20% to 45% of AITL cases. ⁵⁶ They were absent in other B-cell and T-cell lymphomas. IDH2 mutations are thought to alter enzymatic function, leading to accumulation of oncometabolites that affect hypoxia signaling and histone and DNA methylation.

TET2 mutations are also frequently identified in AITL (47%) as well as PTCL-NOS, particularly those expressing T_FH cell markers (58%). ⁵⁷ These are mainly frameshift and nonsense mutations similar to those seen in myeloid malignancies. However, unlike in myeloid malignancies in AITL, IDH2 and TET2 mutations may coincide. DNMT3A mutations have also been detected in 33% of patients and seem to coincide with TET2 mutations. ⁵⁸ DNMT3A and TET2 are involved in DNA and histone methylation, suggesting potential epigenetic pathways for tumorigenesis in AITL.

Several other less frequent but recurrent mutations identified in this group, including mutations in genes involved in DNA damage response (ATM), escape from immune surveillance mechanisms (B2M and CD58) and TCR signaling through SRC kinases (FYN). ⁵⁹

Clinical features

Approximately, 38% of patients have nodal disease alone, 49% have nodal and extranodal disease, and 13% have extranodal disease only. Circulating lymphoma cells may be seen, but leukemic presentation is rare. Some cases are associated with eosinophilia or hemophagocytosis.

Morphological features

Morphological heterogeneity within PTCL-NOS has long been recognized: diffuse small cleaved, mixed, large cell, immunoblastic subtypes are recognized. ⁶¹ There is usually effacement of the normal architecture by sheets of atypical lymphoid cells in a diffuse or paracortical distribution. There are typically a variety of admixed cells including eosinophils, plasma cells, B cells, and histiocytes.

Immunophenotypic characteristics

There is no characteristic immunophenotype for PTCL-NOS. T-cell–associated antigens, including CD2, CD3, CD5, and CD7, are variably expressed. Most of the cases express CD4 only but some tumors may be CD4−/CD8−, CD4−/CD8+, or CD4+/CD8+. T-cell receptor gene rearrangements may commonly be detected, although this has limitations as a diagnostic tool, as discussed previously.

GEP of PTCL-NOS

One large study that performed GEP on 372 cases of T cell-NHL was able to reclassify 37% of PTCL-NOS into other subgroups, including AITL, ALCL, and NK-cell NHLs. ⁶⁰ This still left 32% of cases in the PTCL-NOS group. These same GEP studies identified 2 meaningful subtypes within this PTCL-NOS group, with prognostic, and potentially therapeutic, relevance. About 33% of cases where categorized by high expression levels of GATA 3 and its target genes, CCR4, CXCR7, and IL18RA. There was enrichment of gene proliferation signals such as MYC and MTOR. This subtype was associated with worse outcomes, 19% OS at 5 years. The other subtype showed high expression of TBX21 and EOMES and their target genes, CXCR3, IL2RB, CCL3, and interferon gamma. This subtype showed enrichment of interferon gamma and NF-κB–induced signatures and was associated with a more favorable clinical prognosis, 38% 5-year OS. The 2 subtypes could be distinguished with 80% confidence according to these differences in GEP. No significant differences regarding immunophenotypic characteristics, specifically CD4 or CD8 positivity, or clinical characteristics could be identified.

Chemotherapy agents

In the phase 2 PROPEL (Pralatrexate in Patients With Relapsed or Refractory Peripheral T-cell Lymphoma) trial, which included 115 patients with r/r T-cell NHL who had received ≥1 line of chemotherapy, the antifolate drug, pralatrexate, had a 29% ORR and 11% CR rate, with median duration of response of 10.1 months. ⁶² Cell of origin may be important even in response to conventional chemotherapy agents: response rates in AITL were 8% versus 31% in PTCL-NOS. In the phase 2 BENTLY (Bendamustine in Patients With Refractory or Relapsed T-cell Lymphoma) trial, which included 60 patients with r/r PTCL treated with bendamustine, ORR was 50% with a CR of 28%. Progression-free survival was relatively short at 3.6 months. ⁶³

Monoclonal antibodies and antibody conjugates

Brentuximab vedotin has shown benefit in CD30+ ALCL: ORR 86% with 57% CR and median PFS of 12.6 months. ⁴⁶ It was also effective, although slightly less so, in CD30+ PTCL-NOS and AITL: ORR 43%, PFS: 6.7 months. ⁶⁴ Interestingly, response appeared to be independent of CD30 expression levels. Similarly, response rate appeared to be independent of CD25 (IL2 receptor) expression level in a trial of the IL-2-diphtheria toxin fusion protein, denileukin. ⁶⁵ Overall response rate was 61.5% in CD25-positive tumors and 45.5% in CD25-negative tumors, with a median PFS of 6 months. The anti-CD52 monoclonal antibody, alemtuzumab, has previously been tested in r/r PTCL and had a 36% ORR but with short lived responses and significant toxicity, in terms of infective complications. ⁶⁶

Immune modulators

Lenalidomide is an immune modulator and has antiangiogenic activity. It has some single agent activity in r/r T-cell NHL: 26% ORR, median PFS: 4 months. ⁶⁷ Response rates were slightly higher in PTCL-NOS (43%) and AITL (33%), which might fit with the importance of interactions with the microenvironment in T-cell NHL subtypes with a T_FH phenotype. The immune checkpoint inhibitors are being used with impressive results across an array of solid organ malignancies and B-cell lymphomas. They have not specifically tested in T-cell NHL to date. However, the expression of PD-1 on T_FH cells is associated with high-affinity antibody responses. ⁵² Abrogation of this cross talk by an immune checkpoint inhibitor may have therapeutic value.

Histone deacetylase inhibitors

The high frequency of TET2 mutations in PTCL-NOS and AITL suggests that aberrant epigenetic modifications may be important in pathogenesis. Histone deacetylase inhibitors, such as romidepsin, are therefore an exciting area of investigation. In particular, patients who respond to these agents tend to have more durable responses than to other investigational agents. A phase 2 clinical trial of romidepsin in r/r PTCL led to romidepsin’s approval by the Food and Drug Administration (it remains unlicensed in the United Kingdom and Europe). Overall response rate was 25%, including 15% of patients with CR. ⁶⁸ Median duration of response was 17 months.

Drugs targeting oncogenic pathways

Gene expression profile studies have shown increased activation of oncogenic pathways in association with specific T-cell NHL subtypes. These oncogenic pathways are also potential drug targets. For example, increased activity of NF-κB has been demonstrated in AITL and some PTCL-NOS subtypes. The NF-κB inhibitor bortezomib may therefore be of therapeutic benefit. In a small phase 2 trial of 15 patients with mycosis fungoides or PTCL with limited skin involvement, ORR was 67% with response duration of 7 to 14 months. ⁶⁹ Gene expression profile on ENKTCL samples demonstrated consistent enrichment of several distinct gene signatures, including upregulation of the NOTCH and AURKA signaling pathways. AURKA is involved in several well-characterized oncogenic pathways, including upregulation of C-MYC and inhibition of TP53. Molecular inhibitors of the NOTCH and AURKA pathways induced cell cycle arrest and apoptosis in ENKTCL lines, identifying these as promising candidates for therapeutic trials in ENKTCL lymphoma, a subtype that has historically been associated with very poor outcomes. ⁷⁰

Kinase inhibitors

Activating mutations of kinases can be seen in various T-cell NHL subtypes. Small-molecule inhibitors of these kinases, many of which are already available for other malignancies, may therefore be effective. The therapeutic potential of crizotinib in ALK-positive r/r ALCL has been discussed above. There is a high frequency of STAT3 mutations in hepatosplenic T-cell lymphoma ⁴⁹ and STAT5 B mutations in T-cell prolymphocytic leukemia, ⁷¹ which may be targetable by existing JAK2 inhibitors. Platelet-derived growth factor receptor α is overexpressed in PTCL-NOS, raising the possibility of efficacy for imatinib. ⁷² Dasatinib has been demonstrated to impair the growth of PTCL-NOS cell lines expressing the FYN kinase gene mutation, which is present in some PTCL-NOS tumors. ⁵⁹