Educational theme: Advances in T-cell lymphomas

Throughout May, the Lymphoma Hub will be focusing on a new educational theme of “Advances in T-cell lymphomas”. This article introduces the topic of T-cell lymphomas and summarizes some of the latest advances and key clinical trials in the field.

The newly designed Lymphoma Hub website also contains a wealth of information about T-cell lymphomas. Head to the “Mature T and NK cell neoplasm” section of the website to navigate through the available content.

Introduction

Tumors of mature T-cell origin are collectively known as peripheral T-cell lymphomas (PTCLs), which are non-Hodgkin lymphomas (NHLs) that account for approximately 15% of NHL cases.¹ There are over 25 different subsets based on the World Health Organization (WHO) classification. PTCLs are mainly subdivided based on a leukemic, extranodal or nodal presentation. Unfortunately, patients with PTCLs tend to have a poorer prognosis than B-cell NHL subtypes.²

The most frequent T-cell and natural killer (NK)-cell neoplasms are PTCL not otherwise specified (NOS) and angioimmunoblastic T-cell lymphoma (AITL). Other T-cell lymphomas include follicular helper T-cell PTCL (TFH-PTCL), extranodal PTCL, cutaneous T-cell lymphoma (CTCL) and anaplastic large cell lymphoma (ALCL).²

To read more about the molecular pathogenesis of T-cell lymphomas, click here, or watch Philippe Gaulard discuss this topic below.

At the International Conference on Malignant Lymphoma (ICML) meeting in 2019, the Lymphoma Hub also spoke to Stefano Luminari who discussed how the classification of PTCLs has changed with our increased understanding of the biology of the disease, including the creation of new entities.

Current standard-of-care (SOC) treatment

Frontline SOC treatment for T-cell lymphomas typically consists of chemotherapy followed by consolidation with autologous (auto) or allogeneic (allo) hematopoietic stem cell transplantation (HSCT). To learn more about the treatment pathway for patients with T-cell lymphoma, watch the interview below with Julie Vose, filmed during the Society of Hematologic Oncology (SOHO) meeting in 2019.

Frontline chemotherapy

The most commonly used frontline chemotherapy regimen is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). Despite being SOC, CHOP only provides modest efficacy in aggressive T-cell lymphomas and numerous studies are underway to identify more efficacious combination regimens. Results from a phase I trial combining CHOP therapy with alemtuzumab, an anti-CD52 antibody, showed response rates to the combination were modest and not overtly different to CHOP alone. In addition, there was a high therapy-associated toxicity rate. Another study, CHEMO-T (NCT01719835) evaluated whether gemcitabine, cisplatin and methylprednisolone (GEM-P) could induce superior responses to CHOP in patients with previously untreated PTCL. However, the results from CHEMO-T indicated that GEM-P was not more effective than CHOP, highlighting that more effective frontline therapies are urgently needed.

The addition of brentuximab vedotin to cyclophosphamide, doxorubicin and prednisone (A-CHP) was compared to SOC CHOP therapy in the phase III ECHELON-2 trial (NCT01777152). This study was conducted in patients with previously untreated CD30⁺ PTCL. The A-CHP regimen provided a superior survival benefit over SOC CHOP therapy, reducing the risk of an event by 29% with a comparable safety profile to SOC therapy. The authors of the ECHELON-2 study suggest that A-CHP should become the new SOC for patients with CD30⁺ PTCL. Brentuximab vedotin is approved by the United States Food & Drug Administration (FDA) for the frontline treatment of PTCL. The study investigators also looked at whether CD30 expression levels affect response to A-CHP. The results are discussed by Ranjana Advani below.

Consolidation with HSCT

The question of whether auto-HSCT or allo-HSCT should be used as first-line consolidation is also debated. The AATT study (2007-001052-39) sought to compare auto- to allo-HSCT as consolidation treatments in patients following first-line chemotherapy for naïve PTCL. The results, presented at the American Society of Clinical Oncology (ASCO) meeting in 2019, showed no statistically significant difference in event-free survival or overall survival (OS) between auto- or allo-HSCT. The authors concluded that allo-HSCT should be reserved for high-risk patients due to the higher treatment-related mortality, despite better tumor control.

Additionally, a retrospective analysis of patients treated in the phase II SWOG S9704 trial found that consolidative auto-HSCT following first-line therapy with rituximab + CHOP did not provide an additional survival benefit for patients with aggressive T-cell NHL. To learn more, watch Olivier Tournilhac discuss auto versus allo-HSCT as consolidation therapy with the Lymphoma Hub at the ICML in 2019.

Treatment of extranodal natural killer (NK) T-cell lymphoma (ENKTL)

For patients with ENKTL, a recent analysis of the clinical characteristics and outcomes of patients from the International T-cell Project found:

• The use of radiation therapy with chemotherapy is important to manage ENKTL as demonstrated by an improved OS and progression-free survival (PFS) in patients treated with this combined therapy
• Patients with advanced-stage disease, treated with L-asparaginase-based regimen showed a better response compared to patients treated with anthracycline-based or non-anthracycline/non-asparaginase regimens

Future directions for treatment

Improvements using traditional chemotherapeutic backbones such as CHOP have failed to improve efficacy significantly in the last two decades.¹ Advances in the understanding of the molecular pathogenesis of PTCLs has recently led to the discovery that epigenetic dysfunction appears to be a hallmark event of transformation in T-cell lymphomas. Therefore, drugs targeting this dysfunction may prove efficacious for these difficult-to-treat diseases. The use of immune epigenetic therapies has shown promising results in PTCLs, with these agents likely to form the backbone of new therapeutic combinations.

During the SOHO meeting in 2019, Owen A. O’Connor kindly provided the Lymphoma Hub with a thorough overview of treatments in the pipeline for PTCL, available below. In this video, Owen A. O’Connor discusses how the approval of novel agents has changed the treatment landscape in PTCL, and where the future of PTCL treatment may lead.

Histone deacetylase (HDAC) inhibitors

Romidepsin (ROMI) is an HDAC inhibitor that is being investigated in PTCL. Other HDAC inhibitors under investigation include belinostat and chidamide.³ ROMI is approved by the FDA for PTCL following one line of prior therapy and CTCL following one prior systemic therapy.⁴

Vorinostat is another HDAC inhibitor that is approved for CTCL that is progressive, persistent or recurrent following two systemic therapies, which is considered SOC in this setting.⁵

Hypomethylating agents (HMA)

HMAs such as azacitidine (AZA) address the hypomethylating defects commonly seen in T-cell lymphomas, such as mutations in TET2, IDH and DNMT3. Interestingly, HMAs have effects both on the PTCL, and also the microenvironment. Adding an HMA to an HDAC inhibitor is hypothesized to be efficacious in PTCLs; this concept is discussed later in the article.

Anti-folates

Pralatrexate is a novel anti-folate which received FDA approval for relapsed/refractory (R/R) PTCL.⁶ The phase II PROPEL study evaluated single-agent pralatrexate in patients with R/R PTCL. The results indicated an overall response rate (ORR) of 29% with a median OS of 14.5 months.³

Immune checkpoint inhibitors

Results from a phase II trial (NCT02535247) investigating pembrolizumab, a programmed cell death -1 (PD-1) inhibitor, in patients with R/R mature T-cell lymphoma, found pembrolizumab had modest efficacy with an expected safety profile, though studies with larger sample sizes are required to confirm the results.

Phosphoinositide 3-kinase (PI3K) inhibitors

Duvelisib is an oral inhibitor of two PI3Ks – PI3K-δ and PI3K-γ. The ongoing phase II PRIMO study (NCT03372057) is investigating duvelisib as a monotherapy in patients with R/R PTCL. Duvelisib has been granted both orphan drug designation and fast track designation by the FDA for R/R PTCL. Another PI3K inhibitor under investigation is copanlisib.³

Aurora A kinase inhibitors

Alisertib is an aurora A kinase inhibitor. The phase III LUMIERE trial (NCT01482962) sought to compare alisertib monotherapy, to investigator’s choice in patients with R/R PTCL. PTCL subtypes included PTCL-NOS, AITL and ENKTL. However, this study did not find a significant improvement in outcomes with alisertib compared to comparator drugs (such as gemcitabine, pralatrexate or ROMI).

Farnesyltransferase inhibitors

Tipifarnib is a selective inhibitor of farnesyltransferase that is being investigated in patients with R/R T-cell lymphomas. Results of a phase II trial (NCT02464228) were presented at the 61^st meeting of the American Society of Hematology (ASH). Tipifarnib was recently granted fast track designation by the FDA for R/R T-cell lymphomas including AITL and nodal PTCL with a TFH phenotype.

Dual SYK/JAK inhibitors

Cerdulatinib is a dual inhibitor of SYK and JAK that has previously been granted orphan drug designation by the FDA for R/R PTCL. In a phase IIa dose-expansion study patients with R/R PTCL or CTCL were treated with cerdulatinib monotherapy. The ORR in patients with PTCL was 35%, predominantly seen in patients with AITL/TFH subtype.⁷

Synthetic retinoids

For patients with CTCL, bexarotene, a synthetic retinoid related to vitamin A, was approved in 1999. Long-term follow-up data indicate it is well-tolerated and effective in both early and advanced CTCL.⁸

Immunotherapies

Immunotherapies are another class of novel agent that could provide a benefit to patients with PTCL. Some examples of these therapies are discussed below, including both approved and investigatory agents.

Monoclonal antibodies (mAbs)

Mogamulizumab is a mAb that targets chemokine receptor type 4 (CCR4).⁹ The phase III MAVORIC trial (NCT01728805), comparing vorinostat to mogamulizumab in patients with previously treated CTCL (R/R mycosis fungoides or Sézary syndrome), found mogamulizumab led to significant improvements in PFS and ORRs compared to vorinostat. Mogamulizumab was also found to have a comparable safety profile to vorinostat, indicating this novel therapy may have potential in R/R CTCL. Mogamulizumab is approved by the FDA for patients with mycosis fungoides or Sézary syndrome.¹⁰

Lacutamab is a first-in-class anti-killer cell immunoglobulin-like receptor 3DL2 (KIR3DL2) mAb being investigated in advanced T-cell lymphomas. The phase II TELLOMAK study (NCT03902184) is an open-label, multi-cohort study investigating  lacutamab as monotherapy and in combination with chemotherapy. The study was placed on a partial hold by the FDA in January 2020 due to Good Manufacturing Practice (GMP) deficiencies at a subcontractor site.

Antibody-drug conjugates

As discussed above, brentuximab vedotin is approved for the frontline treatment of PTCL by the FDA. Brentuximab vedotin is an antibody-drug conjugate that targets CD30. It is conjugated to the anti-microtubule agent monomethyl auristatin E which, upon binding, is released into the cell leading to cell cycle arrest and apoptosis.¹¹

Bispecific cell engagers

AFM13 is a first-in-class tetravalent bispecific innate cell engager that binds to CD30 on tumor cells and CD16A on NK cells. It is in development for the treatment of CD30⁺ lymphomas, including PTCL. An ongoing phase II study called REDIRECT (NCT04101331) is investigating AFM13 as monotherapy in patients with R/R CD30⁺ PTCL. AFM13 was recently granted orphan drug designation for the treatment of T-cell lymphomas including PTCL by the FDA.

Chimeric antigen receptor (CAR) T-cell therapy

CAR T-cell therapy products have been approved for B-cell NHLs such as diffuse large B-cell lymphoma. There is hope that these products may be effective in CD30⁺ T-cell lymphomas as well.¹

Generating a new backbone therapy

Whilst response rates with single-agent ROMI are in the mid 20% mark, using ROMI in combination with other agents has led to much higher ORRs. Using such epigenetic strategies as the backbone to subsequent combination therapies appears to be a promising strategy.

A phase I/II study (NCT01998035) is studying the combination of AZA, an HMA, and ROMI for newly diagnosed and R/R PTCL. Results from the phase I portion of the study were published in Blood in November 2019 and found patients with PTCL responded better than patients with non-T-cell lymphoma who were included in the study, with a 73% response rate. The phase II results were presented at the ICML in June 2019 and showed AZA + ROMI was particularly active in patients with AITL and PTCL-TFH. During ICML 2019, the Lymphoma Hub also spoke to Lorenzo Falchi about how AZA + ROMI might fit into the treatment pathway in T-cell lymphoma. Watch the interview below.

Another combination regimen of alisertib with ROMI has been tested in a phase I study (NCT01897012) in patients with R/R aggressive T-cell lymphomas. Whilst the safety profile was found to be as expected, the preliminary efficacy was low in the heavily pretreated population.

It is hypothesized that incorporating an immune checkpoint inhibitor, or PI3K inhibitor into these new combinations may show more promising results than single-agent therapy, and this is the approach that will be investigated in future clinical trials.

The Global T-Cell Lymphoma Consortium

Owen A. O’Connor, Won Seog Kim and Peir Luigi Zinzani recently established the Global T-Cell Lymphoma Consortium. These three experts represent the areas of the world most affected by T-cell lymphomas. The aim of the consortium is to create a comprehensive network of clinical cancer centers and investigators, to conduct quality clinical research to advance treatment in T-cell lymphomas. One of the key requirements to meet this aim is to recruit patients to clinical trials. Recruiting more patients will allow the identification of optimal treatments for individual subtypes, ultimately improving the outcomes of these patients.¹  

Conclusion

PTCLs are a largely heterogenous group of diseases with limited treatment options. Traditional therapies are based on studies in aggressive B-cell lymphomas, and efficacy of traditional therapeutic options such as CHOP, and HSCT, do not exhibit the same efficacy in PTCL. Increased understanding of the molecular pathogenesis of PTCLs has led to the development of epigenetic therapies, which are now being tested as the new backbone to treatment regimens. Targeting the underlying epigenetic dysfunction with combination regimens appears promising, though this work may only continue with the ongoing accrual of patients to clinical trials.