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CME Corner

Treatment Challenges in Peripheral T-Cell Lymphoma

Authored by

Jasmine M Zain, MD

Affiliation

City of Hope Cancer Center, Duarte, CA

Disclosures

Dr Zain reports that she has been a speaker for Kirowin Kyowa, Portola, Seattle Genetics, and Spectrum.

Citation

J Clin Pathways. 2020;6(3):32-34. doi:10.25270/jcp.2020.4.00005

This section called “CME Corner,” highlights, when available, relevant continuing medical education (CME) opportunities deemed to be of use to readers. Articles include an overview of a specific area where key opinion leaders have determined there to be an educational need and a link to the available CME program.

The CME program titled "Confronting the Challenges of Peripheral T-Cell Lymphoma: Genomic Profiling and the Future Treatment Landscape" is currently available on this topic until April 30, 2020.


Peripheral T-cell lymphoma (PTCL) is a diverse group of aggressive lymphomas that develop from mature T cells and natural killer (NK) cells and account for 12%-15% of all non-Hodgkin lymphomas worldwide. There are many subtypes as defined by the 2016 World Health Organization classification.1 In the United States and Europe, the most common subtypes are PTCL-not-otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALCL), and angioimmunoblastic T-cell lymphoma (AITL), while extranasal NK T cell lymphoma (ENKTL) and adult T-cell leukemia lymphoma (ATLL) associated with the HTLV1 virus is more common in Asian countries. ATLL also has a higher incidence in the Caribbean and parts of Central America. Most PTCL subtypes are aggressive lymphomas, including PTCL-NOS, AITL, ALCL, enteropathy-type T-cell lymphoma, and extranodal NK cell/T-cell lymphoma with 5-year survivals of less than 30% with the exception of anaplastic lymphoma kinase-positive ALCL.2 

The diagnosis and treatment of PTCL is challenging for a number of reasons. The rarity of these diseases and the various subtypes means that most hematologists/oncologists and hematopathologists see very few cases of these subtypes at any given time. The lack of specific diagnostic characteristics make it difficult to differentiate them from benign conditions or even other subtypes of lymphomas. A second opinion from an expert lymphoma hematopathologist may be needed to confirm a diagnosis. Most lymphoma therapies that have been developed have really been geared toward the more common B-cell lymphomas. There are very few treatments that are specific for T-cell lymphomas. Using paradigms borrowed from aggressive B-cell lymphomas, like the use of combination chemotherapy, may not be the best approach to treat PTCLs and may account for the poor outcomes that are seen with current treatment strategies.

This lack of specific treatment for PTCL may be explained by the challenges in performing clinical trials for PTCL. According to the Untied States Surveillance Epidemiology and End Registry (SEER), the incidence of PTCL is <1 case per 100,000 people in the United States.3 Multiple tumor types and the aggressive nature of these diseases makes it challenging to get adequate samples for basic research in the biology of these lymphomas and equally difficult to accrue patients to clinical trials. There is also reluctance in developing T-cell lymphoma directed therapies by big pharma as the focus remains on developing treatments for other more common malignancies. 

In recent years successful collaboration between major academic centers and clinical consortia has allowed success in this regard, and there has been progress both in the understanding of pathogenic mechanisms and therapeutic advances in the treatment of PTCL. 

Treatment Options and Standard of Care 

The standard upfront remains CHOP or CHOP-based therapy for most subtypes. The only upfront treatment that has shown superiority over CHOP, based on a randomized clinical trial, is the combination of brentuximab vedotin (Adcetris) plus cytoxan vincristine and prednisone (CHP) for CD30 expressing PTCL subtypes.This led to a category 1 recommendation for Adcetris +CHP as front-line therapy for CD30 PTCL by the National Comprehensive Cancer Network. Other combinations of CHOP with targeted agents have shown promising data based on phase 2 studies but none has been practice changing. 

Several single agents are now approved by the Food and Drug Administration for the treatment of relapsed or refractory PTCL. These include belinostat5 (overall response rate [ORR], 25%), romidepsin6 (ORR, 25%), and pralatrexate (ORR, 29%).7 Brentuximab vedotin is approved for relapsed ALCL with a response rate of 87%8 and can be used for other CD30 expressing PTCL histologies albeit with lower rates of response.9

NK/T-cell lymphomas, are unique lymphomas that belong on the T-cell lymphoma spectrum. A defining feature of all NK/T-cell lymphomas is the presence of Epstein-Barr virus in the tumor and plays a role in lymphomagenesis,1 and they have unique clinical behavior. They respond poorly to CHOP like chemotherapy due to the high expression levels of multidrug resistance glycoprotein. More effective agents include methotrexate and L-asparaginase.10 They are also sensitive to radiation and optimal treatment approaches for localized stage I and II diseases including a combination of chemotherapy and radiation.11 NK/T-cell lymphomas have been shown to be the only subtype of PTCL that has shown high response rates to immune checkpoint inhibitors in the setting of relapsed disease.12 

Prospective Treatments

A better understanding of the pathogenesis of PTCL has outlined several biologic mechanisms that can be exploited for therapies. Some of the promising pathways are as follows.

PI3 kinase pathway has been shown to be dysregulated in many hematologic malignancies, and there is promising clinical data to support the use of PI3-kinase inhibitors in the treatment of relapsed PTCL. Specific subtypes of PTCL may have higher response rates, but results of studies are awaited.13 JAK/STAT pathways has been shown to be dysregulated in several subtypes, and clinical trials of JAK Inhibtors are ongoing, backed by gene sequencing and other biomarker analysis to predict responses.14 Other pathways include the SYK pathway and mTOr pathways. Further lab and clinical data may show that combinations of these agents are synergistic or are needed to avoid resistance.

Epigenetic therapies. Histone deacetylase inhibitors have had selective activity in PTCL, but more recently there is an emerging interest in hypomethylating agents especially in subtypes with specific mutations, ie, TET2.15-17 Targeting the histone methylation pathway with EZH2 inhibitors is being evaluated with the expectation that higher responses will be seen in tumors that overexpress EZH2. Combination doublets are showing higher response rates than single agents and will likely be moved into an upfront setting to allow for more specific anti-T-cell therapies.16,17 

Antibody-based therapies are being explored either directed against tumor-specific antigens like CCR4 (targeted by Mogamulizumab) or by antibody conjugates. Brentuximab vedotin is an example of an antibody drug conjugate but there are others in trials as well including CD25 drug conjugate (ADC-301). Another approach is bispecific antibody engagers that are being evaluated in other hematologic malignancies and are now making their way into PTCL. One example is the AFM13 that targets CD30 and engages NK cells via CD16 receptor.18 

Immune checkpoint inhibitors have shown disappointing results as single agents in PTCL, and there is a fear of hyper progression noted in a few studies.19 The only exception being NK/T-cell lymphomas as described above. Combinations of checkpoint inhibitors and chemotherapy or targeted agents with direct cytotoxicity may help circumvent the issue of hyper progression and hold promise as trials are being conducted. 

Personalized Treatment and Biomarkers

Currently the only clinically useful biomarker is CD30 that can be selectively targeted for therapeutic purposes. Current data has failed to show a relationship with the degree of expression and the rate of response. This may have to do with the methodology of testing as well as the heterogeneity of CD30 expression in tumors. Nonetheless it is now recommended that all patients with PTCL have their tumors tested for CD30 expression at the time of diagnosis and at relapse. 

Next-generation sequencing, mutational analysis, and other molecular technologies are starting to get into the clinical setting for PTCL patients. The biggest challenge to this approach has been scarcity of tissue samples and tissue banks. These are now being addressed through large consortia and cooperative groups. Few mutations have been found to be recurrent in some subtypes of PTCL. One example is a TET2 mutation that in clinical trial has shown to be associated with a higher response rate to hypomethylating agents. Further confirmation is pending results of ongoing trials.15 It is important to note that current and future clinical trials should include biomarker analysis that predict response and allow us to better select patients for specific therapies and spare toxicities to those patients who are not likely to respond. 

On the Horizon

The future holds brighter for patients with PTCL. Targeted agents and biomarker-driven therapies hold promise for improved outcomes both as single agents and combinations.  Some combinations are already in clinical trials and have shown clinical synergy, ie, romidepsin and lenalidomide (ORR, 78%),20 and romidepsin and pralatrexate (ORR, 71%).21 When combined with biomarker data, it is likely that treatments will be based on tumor characteristics and molecular profiling thus optimizing the therapeutic effects and minimizing toxicities. 

Another promising approach is the development of chimeric antigen receptor (CAR) T-cell therapies for PTCL, a field that has lagged behind other hematologic malignancies. It is inherently difficult to develop a CAR-T therapy against T-cell lymphomas due to: (1) a lack of specific tumor targets with the exception of CD30 and possibly CCR4; (2) fratricide, which results in failure of expansion of CAR-T; (3) severe T-cell immunosuppression due to T-cell depletion by CAR-T; and (4) contamination of leukapheresis product with malignant T cells resulting in a tumor cell being engineered into a CAR.22 Attempts to overcome these challenges include CRISPR and other gene editing techniques to modify the TCR on CARs, delete CD5 or CD7 from CARs, or using non-T cells for CAR construction. CD30 CAR Ts are in trials.

While allogeneic stem cell transplantation can result in long-term remissions in PTCL through a graft vs lymphoma effect, it cannot be offered to all patients and comes at significant morbidity and mortality due to immunosuppression and graft-vs-host disease. There are several advances in the field of transplantation. Some of the practice-changing approaches have been the increasing use of haploidentical and cord blood as stem cell sources, improved treatments for graft-vs-host disease and better supportive care. These will continue to make transplants safer and more tolerable for patients with PTCL who absolutely need an allogeneic transplant for cure. 

Finally I want to touch upon the concept of molecular remission. As has been demonstrated in chronic myeloid leukemia, a state of molecularly undetectable disease results in improved survival and disease-free survival. We must strive toward that same goal in PTCL in spite of the heterogeneity. The hope is that we will have techniques of personalized medicine to select patients who will benefit from specific therapies and spare them toxicities of ineffective treatments at all stages of their disease with the goal of achieving a cure.


The CME program titled "Confronting the Challenges of Peripheral T-Cell Lymphoma: Genomic Profiling and the Future Treatment Landscape" is currently available on this topic until April 30, 2020.

References

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2. Vose JM. Peripheral T-cell non-Hodgkin’s lymphoma. Hematol Oncol Clin North Am. 2008;22(5):997-1005, x. doi:10.1016/j.hoc.2008.07.010

3. Morton LM, Wang SS, Devesa SS, Hartage P, Weisenburger DD, Linet MS. Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood. 2006;107(1):265-276. doi:10.1182/blood-2005-06-2508

4. Horwitz S, O’Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet. 2019;393(10168):229-240. doi:10.1016/S0140-6736(18)32984-2

5. O’Connor OA, Horwitz S, Masszi T, et al. Belinostat in patients with relapsed or refractory peripheral T-cell lymphoma: results of the pivotal phase II BELIEF (CLN-19) study. J Clin Oncol. 2015;33(23):2492-2499. doi:10.1200/JCO.2014.59.2782

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7. O’Connor OA, Pro B, Pinter-Brown L, et al. Pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma: results from the pivotal PROPEL study.
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10. Yamaguchi M, Kwong YL, Kim WS, et al. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: the NK-Cell Tumor Study Group study. J Clin Oncol. 2011;29(33):4410-4416. doi:10.1200/JCO.2011.35.6287

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12. Chan TSY, Li J, Loong F, Khong PL, Tse E, Kwong YL. PD1 blockade with low-dose nivolumab in NK/T cell lymphoma failing L-asparaginase: efficacy and safety. Ann Hematol. 2018;97(1):193-196. doi:10.1007/s00277-017-3127-2

13. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898. doi:10.1182/blood-2017-08-802470

14. Gomez-Arteaga A, Margolskee E, Wei MT, van Besien K, Inghirami G, Horwitz S. Combined use of tofacitinib (pan-JAK inhibitor) and ruxolitinib (a JAK1/2 inhibitor) for refractory T-cell prolymphocytic leukemia (T-PLL) with a JAK3 mutation. Leuk Lymphoma. 2019;60(7):1626-1631. doi:10.1080/10428194.2019.1594220

15. Delarue R, Dupuis J, Sujobert P, et al. Treatment with hypomethylating agent 5-azacytidine induces sustained response in angioimmunoblastic T cell lymphomas. Blood. 2016;128(22):4164-4164. doi:10.1182/blood.V128.22.4164.4164

16. Lue JK, Prabhu SA, Liu Y, et al. Precision targeting with EZH2 and HDAC inhibitors in epigenetically dysregulated lymphomas. Clin Cancer Res. 2019;25(17):5271-5283. doi:10.1158/1078-0432.CCR-18-3989

17. Otsuka Y, Nishikori M, Arima H, et al. EZH2 inhibitors restore epigenetically silenced CD58 expression in B-cell lymphomas. Mol Immunol. 2020;119:35-45. doi:10.1016/j.molimm.2020.01.006

18. Rothe A, Sasse S, Topp MS, et al. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. Blood. 2015;125(26):4024-4031. doi:10.1182/blood-2014-12-614636

19. Rauch DA, Conlon KC, Janakiram M, et al, Rapid progression of adult T-cell leukemia/lymphoma as tumor-infiltrating Tregs after PD-1 blockade. Blood. 2019;134(17):1406-1414. doi:10.1182/blood.2019002038

20. Cosenza M, Civallero M, Fiorcari S, et al. The histone deacetylase inhibitor romidepsin synergizes with lenalidomide and enhances tumor cell death in T-cell lymphoma cell lines. Cancer Biol Ther. 2016;17(10):1094-1106. doi:10.1080/15384047.2016.1219820

21. Amengual JE, Lichtenstein R, Lue J, et al, A phase 1 study of romidepsin and pralatrexate reveals marked activity in relapsed and refractory T-cell lymphoma. Blood. 2018;131(4):397-407. doi:10.1182/blood-2017-09-806737

22. Fleischer LC, Spencer HT, Raikar SS. Targeting T cell malignancies using CAR-based immunotherapy: challenges and potential solutions. J Hematol Oncol. 2019;12(1):141. doi:10.1186/s13045-019-0801-y

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