Diagnosis and Treatment of Non-Hodgkin T-Cell Lymphomas: Application of Biological Markers

FACULTY

GOAL

The goal of this activity is to educate clinicians about the diagnosis and treatment of T-cell lymphomas, using updated research on drug pharmacology and pharmacokinetics, biological markers, and diagnostic tools.

INTENDED AUDIENCE

The intended audience for this activity comprises academic and community hematologists and oncologists, oncology nurses, oncology nurse practitioners, oncology physician assistants and associates, oncology pharmacists, and radiologists.

EDUCATIONAL OBJECTIVES

After completing this activity, participants should be better able to:

1. Recognize the epidemiology of T-cell lymphomas, including symptoms and risk factors.
2. Differentiate among T-cell lymphoma subtypes using biological markers.
3. Evaluate methods of biomarker detection for limitations and reliability.
4. Identify which quantity of a biomarker indicates positive expression.
5. Assess first- and second-line treatment options with emerging technologies for various subcategories of T-cell lymphoma.

PHYSICIAN ACCREDITATION STATEMENT

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

PHYSICIAN CREDIT DESIGNATION

Global designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Global is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education with Commendation.

PHARMACIST CREDIT DESIGNATION

Global designates this continuing education activity for 1.0 contact hour (0.1 CEU) of the ACPE (Universal Activity Number 0530-9999-24-056-H01-P). This is a knowledge-based activity.

GLOBAL CONTACT INFORMATION

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To receive credit, participants must participate in the activity and complete and pass the post-test with a minimum score of 70%. Additionally, participants will need to complete the evaluation. CME certificates will be sent via email to those successfully completing the activity.

SYSTEM REQUIREMENTS

PC

• 1.4 GHz Intel Pentium 4 or faster processor (or equivalent)
• Windows 10, 8.1 (32-bit/64-bit); Windows 7 (32-bit/64-bit ) 512 MB of RAM (1 GB recommended)
• Microsoft Internet Explorer 11 or later, Windows Edge browser, Mozilla Firefox, and Google Chrome
• For HTML Client – Google Chrome (v70.0 and above), Mozilla Firefox (v65.0 and above), and Edge (v42.0 and above)

Mac

• 1.83 GHz Intel Core Duo or faster processor 512 MB of RAM (1 GB recommended)
• MAC OS X 10.12, 10.13, and 10.14
• Mozilla Firefox, Apple Safari, Google Chrome
• For HTML Client – Google Chrome (v70.0 and above), Apple Safari (v12.0 and above), and Mozilla Firefox (v65.0 and above)

FEE INFORMATION AND REFUND/CANCELLATION POLICY

There is no fee for this educational activity.

DISCLOSURES OF RELEVANT FINANCIAL RELATIONSHIPS

Global adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the ACCME and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scientifically rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all financial relationships with any ineligible company within the past 24 months to Global. All financial relationships reported are identified as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant financial relationships have been mitigated.

The faculty have the following relevant financial relationships with ineligible companies:

• Kieron M. Dunleavy: Consulting fees (eg, advisory boards): AbbVie, ADC Therapeutics, Astra Zeneca, Genmab, ONO Pharmaceuticals; contracted research (principal investigators must provide information, even if received by the institution): Allogene, ATARA, Genentech, Kymera Therapeutics, ONO Pharmaceuticals
• Francine M. Foss: Honoraria: Acrotech, Citius Pharma, Kyowa Kirin, Secura Biotech; speakers’ bureaus: Acrotech, Kyowa Kirin, Pfizer, Seattle Genetics

The planners and managers have the following relevant financial relationships with ineligible companies:

• The planners and managers at Global have no relevant financial relationships to disclose.
• The planners and managers at ACE have no relevant financial relationships to disclose.

DISCLOSURE OF UNLABELED USE

This educational activity may contain discussion of published and/or investigational uses of agents not indicated by the FDA. Global and ACE do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

This activity is jointly provided by Global Education Group and Applied Clinical Education.

This activity is distributed by CMEZone.com.

Introduction

The term lymphoma refers to a collection of rare blood cancers that involve the uncontrolled growth of lymphocytes, or white blood cells. Non-Hodgkin lymphomas (NHLs) represent the most common hematologic malignancy worldwide and are responsible for approximately 3% of cancer diagnoses and deaths.¹ T-cell lymphomas are NHLs that develop from T lymphocytes, which are found in lymph tissue. These cancers involve tumor cells that are morphologically distinct from those found in other NHLs. Lymphomas can be nodal (originating in the lymph nodes) or extranodal (originating outside the lymph nodes)² and can form in organs, such as the spleen, tonsils, bone marrow, intestines, or skin.³

More than 40 types of T-cell lymphomas have been identified,⁴ with incidence varying across countries and regions.^1,5 The most common is peripheral T-cell lymphoma (PTCL). It includes at least 30 subtypes⁶ and accounts for 10% of NHL cases in the United States and Europe, 22% in South Korea, 25% in Japan, and 33% in China.⁷ Survival rates also vary by subtype, but prognosis is poor for many subtypes,⁸ and refractory disease is common.

Diagnosis of T-cell lymphomas can be difficult due to the rarity of these diseases and a lack of standardization in biomarker measurement. As technology has advanced, however, a general understanding of molecular analysis has increased. Methods of identifying biological markers of lymphomas currently include immunohistochemistry (IHC) and flow cytometry (FCM).⁹ Several biological markers, including anaplastic lymphoma kinase (ALK) and CD30 positivity, are valuable for diagnosis, treatment, and prognosis.^4,6

This educational activity reviews the diagnosis and management of T-cell lymphomas, including epidemiology, symptoms, and risk factors; the identification and measurement of biological markers; and established and emerging treatment options.

Epidemiology, Classification, and Key Subtypes

The 2 most updated classification proposals for lymphoid neoplasms are the International Consensus Classification¹⁰ and World Health Organization Classification of Hematolymphoid Tumors 5th edition (WHO-HAEM5).¹¹ The WHO-HAEM5 includes additional categories, such as Epstein-Barr virus (EBV)-positive natural killer (NK)/T-cell lymphomas, hepatosplenic T-cell lymphoma, and primary cutaneous T-cell lymphoma (CTCL). The exact names of the categories vary between the 2 sets of classifications, so they have been simplified for the purposes of this activity. In addition, precursor T-cell neoplasms, exclusively childhood cancers, and certain leukemias have been excluded, as they are outside the scope of this initiative.

The most common subtypes of T-cell NHLs in Western populations include peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), T-follicular helper (TFH) lymphomas, and anaplastic large-cell lymphoma (ALCL).

PTCL-NOS is the most common T-cell lymphoma. It accounts for 30% to 50% of T-cell lymphomas in the United States⁶ and is more prevalent in men than women.² Onset typically occurs at around age 60, but it can also occur in younger adults and children.² PTCL-NOS is an aggressive cancer with a poor prognosis. Historical retrospective studies have demonstrated overall survival (OS) rates of 41% at 3 years and 32% at 5 years and progression-free survival (PFS) rates of 28% at 3 years and 23% at 5 years.⁸

ALCL accounts for 2% of all lymphomas and approximately 24% of all PTCLs in the United States.¹² ALCL is the most common type of T-cell lymphoma in children. Translocation of the ALK gene is a characteristic of a subgroup of ALCL called ALK-positive ALCL. This disease has a better outcome than ALK-negative ALCL, which lacks this translocation.^2,6,7

TFH lymphomas are a group of lymphomas that arise from follicular helper T cells and include angioimmunoblastic T-cell lymphoma (AITL), follicular-type, and NOS. TFH lymphomas express at least 2 markers characterized by normal TFH cells (CD10, BCL6, CXCL13, programmed death [PD]1, and inducible T-cell costimulatory [ICOS]). These lymphomas also share genetic aberrations in epigenetic genes such as Tet2 and DNMT3 and as such are sensitive to epigenetic modulatory agents including histone deacetylase inhibitors (HDACIs) and demethylating agents.¹³

Risk Factors

A variety of risk factors for non-Hodgkin T-cell lymphomas have been identified; however, they tend to differ among subtypes. Some lymphomas are associated with previous infection with viruses such as HIV, EBV, and human herpesvirus 6.¹⁴ The human T-lymphotropic virus, endemic in parts of Japan, the Caribbean basin, and the southern Mediterranean, is linked to adult T-cell leukemia/lymphoma.² Other risk factors include celiac sprue, which has been implicated in enteropathy-associated T-cell lymphomas (EATL),² and the use of immunosuppressive agents, which are often involved in the treatment of inflammatory bowel disease but have been linked to the development of hepatosplenic T-cell lymphomas. Most recently, textured breast implants have been associated with ALCL of the capsule surrounding the implant, termed breast implant-associated anaplastic large cell lymphoma (BIA-ALCL).¹⁵ A genetic component has also been suggested in NHLs, as a family history of lymphoma may be a risk factor. These genetic risks have not been well characterized. Finally, environmental exposures to chemicals and pesticides such as dioxin have also been associated with the development of lymphomas.¹⁴

Presentation and Diagnosis

Symptoms associated with T-cell lymphomas vary widely among subtypes but include swollen lymph nodes, anemia, thrombocytopenia, and liver or spleen enlargement (Figure 1).¹⁷ So-called Category B symptoms consist of fever, unexplained weight loss, and night sweats. Skin rashes and/or itching can occur and are characteristic of the cutaneous lymphomas such as mycosis fungoides and Sezary syndrome.² Patients also may be asymptomatic at presentation or exhibit atypical symptoms, often secondary to organ involvement or bone marrow infiltration.¹⁷

Figure 1. Key symptoms of lymphomas.¹⁷

ARF, acute renal failure; CNS, central nervous system; DVT, deep vein thrombosis; GI, gastrointestinal; MM, multiple myeloma; PE, pulmonary embolism; SVC, superior vena cava.

Used with permission from Paquin AR, et al. The diagnosis and management of suspected lymphoma in general practice. Eur J Haematol. 2023;110(1):3-13. Permission conveyed through Copyright Clearance Center, Inc.

Other patients may require immediate medical attention for a range of oncologic emergencies. For example, an enlarged tumor can cause vena cava syndrome, malignant epidural spinal cord compression, malignant pericardial effusion, or gastrointestinal obstruction.¹⁸ Paraneoplastic syndromes associated with cytokine release and hemophagocytic lymphohistiocytosis can occur and may require emergency treatment of the underlying lymphoma.¹⁷

Individuals with Category B symptoms should undergo a comprehensive lymph node exam. In the case of lymphadenopathy or splenomegaly, a further workup for lymphoma is warranted, regardless of patient age. When assessing probable lymphoma in general practice, routine laboratory studies are often helpful in identifying cytopenias, elevated lymphocyte counts due to circulating tumor cells, or metabolic abnormalities associated with hepatic involvement or organ injury (Table 1).¹⁷ Once the suspicion of lymphoma has been established, a multidisciplinary approach to diagnosis often involves collaboration among specialists in radiology, cytomorphology, immunophenotyping, hematopathology, oncology, and nursing.¹⁹

Positron emission tomography (PET) scanning is used to identify the location and staging of the most enlarged nodes for biopsy.¹⁴ 18F-fluorodeoxyglucose PET (FDG-PET) is a standard imaging modality for staging because the extranodal spread of T-cell lymphomas may not be captured by other imaging methods. This renders PET scans as a key instrument in the early detection of NHLs.²⁰ However, PET scans can only detect lymphomas that are avid for 18F-FDG, and PTCLs vary widely in their degree of FDG avidity. For example, nodal lymphomas frequently have an increased FDG uptake and CTCLs, such as mycosis fungoides and Sezary syndrome, typically have low to moderate FDG uptake.²¹

T-cell lymphomas are typically diagnosed through lymph node biopsy. Open surgical biopsy is the gold standard; however, physicians often use core needle biopsy or nodal excision.¹⁴ Fine-needle biopsies should not be done for diagnosis of lymphomas as they do not accurately reflect the underlying architecture or provide adequate sampling for diagnosis. IHC, FCM, and molecular studies should be performed on tissue from the biopsy to confirm diagnosis and subtype.⁹

The essential panels for T-/NK-cell lymphoma diagnosis include T- and B-cell markers, Ki-67, and EBV in situ hybridization. The National Comprehensive Cancer Network (NCCN) guidelines list several recommended panels for diagnosis and accurate subtyping of T-cell lymphomas, including CD4, CD8, CD56, CD30, ALK, TIA-1, granzyme B, PD-1, CXCL13, CD10, Bcl-6, ICOS, CD2, CD5, CD7, CD21, β-F1, and TCR-delta.^22,23 One limitation of IHC is the high variability in evaluation of IHC markers.²⁴ Discrepancies in the degree of staining can make confirming a diagnosis difficult in some cases.

FCM can be helpful in detecting CD30 expression due to its sensitivity.²⁵ A combination of IHC and FCM is best practice for consistent detection, although FCM is generally used as an adjunct test.⁹ Physicians may also consider the use of open-source software for digital pathology image analysis to streamline quantitative assessment.²⁴

Biological Markers

Several biomarkers that may have prognostic or diagnostic importance in T-cell lymphomas include ALK, CD30, GATA3, TBX21, and RHOA G17V. The degree of staining for each biomarker varies by subtype and affects diagnosis, treatment, and prognosis.²⁴

ALK is a protein that is expressed on surface of cells. Overexpression of ALK protein, or ALK positivity, is often demonstrated in ALCL.²⁶ ALK-positive ALCL has an overall favorable outcome with certain chemotherapy combinations, such as CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone)-type regimens.²⁷ ALK-negative ALCL, however, is associated with worse outcomes and requires more aggressive treatment. This may include stem cell transplantation as consolidation in first remission.⁶

AITL is associated with mutations in epigenetic genes such as TET2, RHOA, and IDH2. The RHOA G17V mutated subtype of AITL is associated with Category B symptoms, stronger PD-1 expression, and poor outcomes.²⁸ In patients with PTCL-NOS, GATA3 gene expression is associated with poorer prognosis, and TBX21 cases have better outcomes.⁸

CD30 is a protein and receptor of the tumor necrosis factor family that is expressed in a subset of T-cell lymphomas.⁷ CD30 is highly expressed in both ALK-positive and ALK-negative ALCL, including BIA-ALCL.^7,15 CD30 expression has also been found by IHC in 32% to 64% of PTCL-NOS cases, 50% to 100% of EATL cases, and 46% to 80% of AITL cases. Due to a lack of standardization, the cutoff percentage for CD30 positivity varies among studies and clinical trials, and in clinical practice. In a recent literature review, included studies used a wide range of cutoffs for CD30 positivity, from >10% to >80%. More recent studies use a 5-tiered scale with categories of <5%, 5% to 24%, 25% to 49%, 50% to 75%, and >75% (Table 2).^7,29-38

Current Treatment Options for PTCL-NOS, ALCL, and TFH Lymphomas

CHOP-based regimens have typically been associated with high response rates but primary treatment failure in up to 40% of patients with PTCL and 5-year OS rates of only 35%.³⁹ Responses to CHOP alone have not been durable, thus the recommendation for consolidation with autologous stem cell transplantation in responders.^39,40 Therefore, many efforts have been made to improve this regimen. For the purpose of this review, discussion of treatment strategies will focus on the 3 most common forms of T-cell lymphoma: PTCL-NOS, ALCL, and TFH lymphomas.

Chemotherapy Combinations

BV-CHP, a combination of brentuximab vedotin (BV ), cyclophosphamide, doxorubicin, and prednisolone (CHP), is now approved as a first-line treatment for ALCL, which commonly expresses CD30.^7,41 BV consists of a human chimeric immunoglobulin G1 antibody directed against CD30 that is covalently linked to the potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker.^42,43 The binding of BV to CD30 on the tumor cell membrane triggers a cascade of events that ultimately results in apoptotic death of the CD30-expressing tumor cell (Figure 2).⁴³

Figure 2. Mechanism of action of BV in a CD30+ tumor cell.⁴³

a) BV binds to the CD30 membrane receptor. b) The CD30–drug complex is internalized and traffics to a lysosome, where enzymes cleave the linker between the antibody and MMAE, a microtubule-disrupting agent. c) MMAE is released intracellularly, where it: d) binds to tubulin (leading to G2/M cell cycle arrest and concurrent induction of apoptosis), and extracellularly into the surrounding area, where MMAE may induce apoptosis in surrounding cells (bystander effect), irrespective of CD30 status.

BV, brentuximab vedotin; MMAE, monomethyl auristatin E.

Used with permission from Scott LJ. Brentuximab vedotin: a review in CD30-positive Hodgkin lymphoma. Drugs. 2017;77(4):435-445. Springer Nature.

In addition to its direct anti-tumor activity related to the apoptosis of CD30+ tumor cells, BV may also exert anti-tumor activity via other indirect mechanisms, based on in vitro and in vivo studies.⁴⁴ Because MMAE crosses the cell membrane and is released into the surrounding extracellular matrix, BV also potentially exerts cytotoxic activity on “bystander” tumor cells, irrespective of CD30 status. This may explain its activity in heterogeneous tumors such as Hodgkin lymphoma.

The ECHELON-2 study was a multicenter, randomized, phase 3 study that compared frontline therapy with CHOP vs CHOP plus BV for CD30-positive PTCLs.⁴⁵ Vincristine was dropped from the BV-CHP arm of the study due to avoid overlapping neurotoxicity with BV. The study was enriched for patients with ALCL by design, with 70% of patients enrolled having ALCL. Results from this trial showed that BV-CHP improved both PFS and OS without increasing toxicity compared with CHOP. The 5-year PFS rates in the BV-CHP and CHOP arms were 51.4% and 43%, respectively, and the 5-year OS rates were 70.1% and 61%, respectively.⁴⁶ Based on this study, BV-CHP is now recommended in the NCCN guidelines as the standard frontline therapy for ALCL and other CD30-positive T-cell lymphomas.²²

Although regulatory approval allows for the use of BV-CHP regardless of CD30 expression, use of BV-CHP in those with ≤10% CD30 expression remains controversial. Moreover, in ECHELON-2, the effect of BV-CHP was largely driven by the 70% of patients with ALCL, which uniformly expresses CD30 and is most sensitive to BV. The study was not powered to compare efficacy among individual histologic subtypes, but the benefit of BV-CHP was unclear in PTCL-NOS and AITL, in which CD30 expression is not uniform. Thus, BV-CHP is the standard of care in ALCL, but CHOP remains a standard treatment option for other subtypes. This has prompted interest in investigating other BV-containing frontline combinations in non-ALCL populations. In a phase 2 study of CD30-expressing PTCL (CD30 expression ≥1%), BV-CHP with the addition of etoposide with maintenance BV (with or without consolidative autologous stem cell transplantation) was tolerable and effective, with overall response rates (ORRs) of ~90% regardless of subtype or CD30 expression.⁴⁷

CHOEP is a variation of CHOP with the addition of etoposide. A study of ALK-positive ALCL, AITL, and PTCL-NOS found an OS rate of 61% after 3 years with this regimen. The benefits of etoposide appear to be in the treatment of ALK-positive ALCL, but not in ALK-negative AITL or PTCL-NOS.⁴⁸ In a comparison with CHOP, more adverse events (AEs) were noted in the CHOEP group, especially anemia and thrombocytopenia.

Epigenetic Modifying Agents

Romidepsin is an HDACI that selectively inhibits class I HDACs and was granted accelerated approval by the FDA in 2011 primarily based on a single-arm, international, phase 2 study in patients with relapsed or refractory PTCL.⁴⁹ A phase 3 study of CHOP ± romidepsin for frontline treatment of PTCL was meant to serve as a confirmatory study for romidepsin approval. However, it failed to meet its primary end point, leading to voluntary withdrawal of romidepsin for the indication of relapsed or refractory PTCL.⁵⁰ Nonetheless, the NCCN guidelines continue to list romidepsin as a potential treatment option for initial palliative-intent therapy and for relapsed or refractory disease.²² Romidepsin is administered on a weekly schedule at a dose of 14 mg/m² for 3 of 4 weeks and is associated with nausea, dysgeusia, and, in some cases, prolongation of the QTc interval.

Belinostat, a pan-HDACI with efficacy similar to romidepsin, received accelerated approval in 2014 based on an international, phase 2, single-arm study in 129 patients with relapsed or refractory PTCL. This study demonstrated an ORR of 25.8%, a complete response (CR) rate of 10.8%, and median duration of response (DOR) of 13.6 months.⁵¹ Belinostat is administered daily for 5 consecutive days on a 3-week schedule. AEs include nausea and thrombocytopenia. The confirmatory study for belinostat is an ongoing 3-arm, phase 3 study comparing belinostat-CHOP, pralatrexate-CHOP, and CHOP alone for patients with untreated PTCL (CRESCENDO/NCT06072131).

Azacytidine is a hypomethylating agent that was examined in the phase 3 Oracle study, which compared azacitidine with the investigator’s choice of bendamustine, gemcitabine, or romidepsin in patients with relapsed or refractory TFH lymphomas. The study failed to meet its primary end point, which required improvement in PFS with significance of P<0.025.⁵² With the modest activity of azacitidine observed in this trial, azacytidine may be more appropriate in combination with other agents.

ALK Inhibitors for ALK-Positive ALCL

ALK-positive ALCL is characterized by the activation of the ALK receptor tyrosine kinase by the t(2;5) chromosomal translocation. Crizotinib is a small-molecular inhibitor of several tyrosine kinases, including ALK. It demonstrated an ORR of 90% in pediatric patients with relapsed or refractory ALK-positive ALCL.⁵³ Crizotinib was also evaluated in combination with a standard frontline pediatric regimen for patients with untreated ALK-positive ALCL and demonstrated promising efficacy (2-year event-free survival of 76.8%) but a concerning rate of thromboembolic events (20% before anticoagulation medications were mandated).⁵⁴

In an open-label phase 2 trial of 10 patients (aged ≥6 years; median age, 19.5 years), treatment with alectinib (300 mg twice daily except in patients weighing <35 kg, who were given a reduced dose of 150 mg twice daily), resulted in an ORR of 80% with estimated 1-year PFS and OS rates of 58% and 70%, respectively.⁵⁵ Alectinib was approved in Japan for relapsed or refractory ALK-positive ALCL based on this study.

Brigatinib has shown efficacy in patients with relapsed or refractory ALK-positive ALCL after prior therapy with BV and crizotinib.⁵⁶ In a study of 15 patients with previously treated ALK-positive ALCL brigatinib was associated with an ORR of 93% (73% CR). After a median follow-up of 15 months, the 1-year PFS and OS rates were 72% and 85%, respectively.

PI3-Kinase Inhibition

Duvelisib is a PI3K-δ,γ inhibitor that was investigated in the multicenter phase 2 PRIMO study in patients with relapsed or refractory PTCL. This study demonstrated an ORR of 49% and a CR rate of 34%, with a median PFS of 3.6 months.⁵⁷ Although the study was not powered for subgroup analyses, duvelisib appeared to demonstrate preferential activity in certain subgroups (ORR of 67% in AITL and 48% in PTCL-NOS vs 13% in ALCL). Patients with AITL and PTCL-NOS also had significantly longer median PFS of 9.1 months and 3.5 months, respectively, compared with 1.5 months for ALCL.⁵⁷ Based on these data, treatment with duvelisib can now be considered, especially for TFH lymphomas, but it carriers risks for transaminitis, colitis, rash, and infection. The potential for frontline use of duvelisib is being evaluated in the ongoing randomized phase 2 Alliance study, in which duvelisib + CHOP is being compared with CHOEP (NCT04803201). Duvelisib combinations with chidamide (NCT05976997) and ruxolitinib (NCT05010005) are also ongoing.

Linperlisib, a PI3K-γ selective agent, has been studied in China, demonstrating a 48% ORR in relapsed or refractory PTCL with a relatively lower rate of diarrhea (14%) and transaminitis (20%–23%), and studies are ongoing in other countries.⁵⁸ Given the relatively high ORR and CR rates, PI3K inhibitors are promising in PTCL, where the effectiveness of other therapies is limited.

Hematopoietic Stem Cell Transplantation Consolidation

Hematopoietic stem cell transplantation (HSCT) has been used in consolidation of remissions after frontline therapy and should be considered for patients who are candidates for transplant (Figure 3).⁵⁹ For those who are not candidates or who have primary refractory disease, survival rates are low.^60,61 These patients may benefit from allogeneic transplantation if they respond to salvage therapies.

Figure 3. Current frontline treatment for common PTCLs.⁵⁹

AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; BV-CHP, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisolone; CHOEP, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisolone; CHOP, cyclophosphamide, doxorubicin, vincristine and prednisolone; CR, complete response; IPI, International Prognostic Index; NOS, not otherwise specified; PTCL, peripheral T-cell lymphoma; TFH, T-follicular helper

Used with permission from Moskowitz AJ, et al. Current and upcoming treatment approaches to common subtypes of PTCL (PTCL, NOS; ALCL; and TFHs). Blood. 2024;144(18):1887-1897. Permission conveyed through Copyright Clearance Center, Inc.

Treatment for Relapsed and Refractory Disease

The selection of second-line (2L) therapy (single agent vs combination regimen) should be based on the patient’s age and performance status, donor availability, agents’ AE profiles, and the goals of treatment. For instance, if the intent is to transplant, ORR or CR rates may be more important than the ability to give a medication in an ongoing or maintenance fashion without cumulative toxicity. For patients in whom autologous HSCT is imminent, combination chemotherapy before transplantation is often preferred.

Allogeneic HSCT is also a standard of care in eligible individuals with relapsed or refractory disease.²² OS in relapsed or refractory PTCL without allogeneic HSCT is <1 year.^62,63 Combination chemotherapy may be preferred for patients who are ready to proceed to allogeneic HSCT when a suitable donor has already been identified. However, if no donor is available, the use of intensive combination chemotherapy is not recommended due to the inability to maintain a response for longer periods with continuous treatment. For those who do not plan to pursue transplantation or treatment, palliative radiotherapy and/or best supportive care are recommended and should be suggested.²²

The median PFS in relapsed or refractory PTCL with existing therapies is short (3-4 months).⁶⁴ This underscores the need for novel approaches for patients with recurrence. 2L treatment for T-cell lymphomas often involves enrollment in clinical trials, as it provides access to cutting-edge pharmaceuticals. However, trials are not always a good fit for every patient, due to exclusion criteria and other factors.

BV

The safety and efficacy of BV in patients with relapsed or refractory systemic ALCL was initially established in a multicenter phase 2 study.⁶⁵ Long-term follow-up results confirmed the durability of clinical benefit with BV in relapsed or refractory systemic ALCL.⁶⁶ After a median follow-up of approximately 5 years, the ORR of 86% (66% CR and 21% PR) was similar to the previously reported ORR of 86% (57% CR) as evaluated by an independent review committee. The estimated 5-year OS and PFS rates were 60% and 39%, respectively. The 5-year OS rate was higher for patients who achieved a CR (79% vs 25% for those who did not achieve a CR). The median DOR for all patients was 26 months. The ORRs were similar for patients with ALK-negative ALCL (88%; 52% CR) and ALK-positive ALCL (81%; 69% CR). The estimated 5-year OS and PFS rates were 61% and 39%, respectively, for patients with ALK-negative ALCL. The corresponding survival rates were 56% and 37%, respectively, for those with ALK-positive ALCL. Among patients who achieved a CR, the 5-year PFS rate was 60% for those with ALK-negative ALCL and 50% for those with ALK-positive ALCL. Peripheral neuropathy was the most common AE, reported in 57% of patients, with resolution or improvement reported in the majority with long-term follow-up. In August 2011, based on the results from this study, BV was approved by the FDA for the treatment of patients with systemic ALCL after failure of at least one previous multiagent chemotherapy regimen.⁴¹

The planned subset analysis of a phase 2 multicenter study that evaluated the efficacy and safety of BV in relapsed or refractory CD30-positive NHL showed that this agent was also effective in other subtypes of relapsed PTCL, particularly AITL.⁶⁷ This analysis included 35 patients with PTCL (22 with PTCL-NOS and 13 with AITL); the ORR, median DOR, and median PFS for all patients with T-cell lymphoma were 41%, 7.6 months, and 2.6 months, respectively. The ORR (54% vs 33%) and the median PFS (6.7 vs 1.6 months) were better for patients with AITL than those with PTCL-NOS.

A retrospective study from the LYSA Research Network confirmed the efficacy of BV in combination with bendamustine in patients with relapsed or refractory PTCL (n=82), particularly as a bridge to allogeneic HCT. The ORR was 68%, with a 49% CR rate.⁶⁸ After a median follow-up of 22 months, the median PFS and OS were 8.3 months and 26.3 months, respectively. The outcomes were better for patients who underwent allogeneic HCT after achieving CR. In this group, the median PFS was 19.3 months, and the median OS was not reached.

In addition to BV, other CD30-directed therapies, including chimeric antigen receptor T-cell–based therapy and bispecific antibodies, are currently under investigation.

Chemotherapy

In patients with good performance status, 2L chemotherapy may be an option,⁶² and a variety of regimens are recommended in the NCCN guidelines. Selected combinations include²²:

• DHAP, consisting of dexamethasone, cytarabine, and platinum;
• ESHAP, consisting of platinum (cisplatin or oxaliplatin) in addition to etoposide, methylprednisolone, and cytarabine;
• ICE, which also leverages ifosfamide and carboplatin to target disease; and
• Gemcitabine-based approaches, including GemOx (gemcitabine and oxaliplatin), GDP (gemcitabine, dexamethasone, and cisplatin), GVD (gemcitabine, vinorelbine, and liposomal doxorubicin)

Single-agent chemotherapy has also been shown to be effective and may serve as a bridge to allogeneic transplantation. Active single agents listed in the NCCN guidelines include romidepsin, BV, belinostat, duvelisib, and pralatrexate.^22,69 Pralatrexate, an antifolate analogue, carries an ORR of 29% with a median PFS and OS of 3.5 and 14.5 months, respectively. The original study used dosing at 30 mg/m² weekly for 6 weeks of a 7-week cycle, although with high rates of rash, cytopenias, and mucositis.⁶⁹ Toxicities can be mitigated by dosing for 3 weeks of a 4-week cycle and utilizing leucovorin.

Novel Approaches

Novel targeted therapies in development for relapsed or refractory T-cell lymphomas are demonstrating efficacy in clinical trials. One new area involves the inhibition of este homolog 1 and 2 enhancers (EZH1/2s). Valemetostat, a medication with this mechanism of action, was recently approved in Japan.⁷⁰ In the pivotal phase 2 VALENTINE-PTCL01 trial, conducted in patients with relapsed or refractory adult T-cell leukemia/lymphoma, the ORR was 43.7%, the CR rate was 14.3%, OS was 17 months, and PFS was 5.5 months.⁷¹ Another dual EZH1/2 inhibitor, HH2853, is in early-stage development. It demonstrated an ORR of 60.7% and a CR rate of 21.4% in relapsed or refractory PTCL in a phase 1b study.⁷² A phase 3 confirmatory study of valemetostat in PTCL is in development. Given the efficacy and safety profile, EZH2 inhibitors are promising both as single-agents and in combination but are not currently approved for standard use outside of Japan.

Preclinical data show that activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway may mediate the pathogenesis of PTCL, making it a promising target. Ruxolitinib, a JAK1/2 inhibitor, was investigated in a phase 2 study involving patients with both relapsed or refractory PTCL and CTCL. Biomarker-driven cohorts were established based on the presence of activating mutations in the JAK/STAT pathway or overexpression of pSTAT3 by IHC. Among 45 patients with PTCL, ORRs were 37% and 36% in those with JAK/STAT-activating mutations or pSTAT3 overexpression, respectively, compared with only 7% in patients without JAK/STAT activation.⁷³

Golidocitinib is a selective JAK1 tyrosine-kinase inhibitor. In JACKPOT8 Part B, a single-arm, multinational, phase 2 study exploring the safety and efficacy of golidocitinib in relapsed or refractory PTCLs, the ORR was 44% and the CR rate was 24% after a median follow-up period of 13 months. Grade 3/4 treatment-related AEs occurred in 59% of participants.⁷⁴ Given its tolerability and efficacy, golidocitinib is an encouraging, well-tolerated agent with a potential use in PTCL.

Chidamide is an oral selective class I HDACI that was approved in China in 2014 based on a single-arm phase 2 study of 79 patients with relapsed or refractory PTCL. This trial demonstrated an ORR of 28% and a CR rate of 14% in intent-to-treat patients, with an ORR of 50% in patients with AITL.⁷⁵ Currently, chidamide is only available in China, and several studies examining chidamide-based regimens are ongoing.

Interleukin-2-inducible kinase (ITK) is an important mediator for T-cell receptor signaling. Studies have shown upregulation or aberrant activation of ITK in AITL and other nodal TFH lymphomas. One ITK inhibitor, soquelitinib, demonstrated tumor responses in heavily pretreated PTCLs in a phase 1/1b clinical trial, with a phase 3 study in development.⁷⁶

Combinations of Novel Agents

Whereas novel agents have primarily been studied as monotherapy, numerous studies have evaluated combinations of novel agents or the addition of novel agents to chemotherapy. Several romidepsin-based combinations have demonstrated efficacy in patients with PTCL (Table 3),^77-80 and thus, combinations of novel agents may represent important treatment options in the future.

Shared Decision Making in Oncology

Patients and providers are encouraged to engage in shared decision making (SDM) to determine optimal therapeutic approaches that can be based on a variety of complex, intermingling factors. Patients have different support needs; physicians who take a personalized approach to SDM can streamline the process and improve the patient experience. Patient-readiness aids are especially helpful for identifying individual needs.⁸¹

Once patient readiness is established, value clarification is critical to SDM, particularly where early-phase clinical trials are concerned. It is important to understand patients’ perspectives on a wide variety of principles and values. This ensures the incorporation of personal values in SDM, thus improving both the process itself and patient outcomes.⁸² Design-based, data-driven decision-support tools can also be used to encourage personalized care and empower patients to feel more in control of their treatment journey. These tools are underutilized in clinical practice.⁸³

Clinical Trials in Oncology

Patient participation in clinical trials forms the backbone of cancer clinical research. Clinical trials are the key step in advancing new treatments and improving outcomes. With greater participation, trials can be conducted more rapidly and efficiently, and novel therapies can be discovered more quickly, benefitting all patients with cancer. Additionally, trials offer patients the opportunity to access the newest available treatments, so access to trials should be equitable and easy for interested individuals.⁸⁴

Unfortunately, most adult patients with cancer do not participate in clinical trials. In fact, it is believed that enrollment rates in this population are only 2% to 3%,⁸⁵ despite the fact that most Americans have a favorable view of clinical trial involvement.⁸⁶ The gap between the willingness of patients to participate in trials and their actual participation rates suggests the presence of numerous barriers, many of which are modifiable (Figure 4).⁸⁴

Figure 4. Cancer clinical trial decision making framework.⁸⁴

Used with permission from Unger JM, et al. Systemic review and meta-analysis of the magnitude of structural, clinical, and physician and patient barriers to cancer clinical trial participation. JNCI: Journal of the National Cancer Institute. 2019;111(3):245-255. Open-access article. Creative Commons 4.0: http://creativecommons.org/licenses/by-nc-nd/4.0/

Conclusion

Non-Hodgkin T-cell lymphomas are a heterogeneous group of blood cancers that are associated with poor outcomes and frequent relapse. Clinicians can streamline diagnosis and treatment via thorough analysis of biomarkers and accurate subtyping by IHC. Consensus on optimal frontline approaches is lacking, but recent data show that the incorporation of BV with CHOP has improved PFS and OS in CD30-expressing T-cell lymphomas. Consolidation with autologous transplantation remains a standard for transplant-eligible patients in first remission, but there remains no consensus on the management of relapsed and refractory disease. Novel agents and targeting strategies are in development to address the underlying biology of the different subtypes of T-cell lymphoma and hopefully will be implemented in future treatment algorithms. Finally, the approach to aggressive T-cell lymphoma requires multispecialty collaboration for diagnosis and management of this complex group of diseases.

2. In the United States, T-cell lymphomas account for what percentage of cases of non-Hodgkin lymphoma?
   correct answer: b.

   More than 40 types of T-cell lymphomas have been identified, with incidence varying across countries and regions. The most common is peripheral T-cell lymphoma. It includes at least 30 subtypes and accounts for 10% of NHL cases in the United States and Europe, 22% in South Korea, 25% in Japan, and 33% in China.
3. Which of the following is the most common T-cell lymphoma subtype?
   correct answer: c.

   Peripheral T-cell lymphoma not otherwise specified is the most common T-cell lymphoma. It accounts for 30% to 50% of T-cell lymphomas in the United States and is more prevalent in men than women. Onset typically occurs at around age 60, but it can also occur in younger adults and children.
4. Which of the following is a potential risk factor for the development of T-cell lymphoma?
   correct answer: d.

   A variety of risk factors for non-Hodgkin T-cell lymphomas have been identified; however, they tend to vary among subtypes. Some lymphomas are associated with previous infection with viruses such as HIV, EBV, and human herpesvirus. The human T-lymphotropic virus, endemic in parts of Japan, the Caribbean basin, and the southern Mediterranean, is linked to adult T-cell leukemia/lymphoma. Other risk factors include celiac sprue, which has been implicated in enteropathy-associated T-cell lymphomas, and the use of immunosuppressive agents, which are often involved in the treatment of inflammatory bowel disease but have been linked to the development of hepatosplenic T-cell lymphomas. Most recently, textured breast implants have been associated with ALCL of the capsule surrounding the implant, termed breast implant-associated anaplastic large cell lymphoma. A genetic component has also been suggested in NHLs, as a family history of lymphoma may be a risk factor. These genetic risks have not been well characterized. Finally, environmental exposures to chemicals and pesticides such as dioxin have also been associated with the development of lymphomas.
5. Which of the following agents targets CD30 on T-cell lymphoma cells?
   correct answer: a.

   Brentuximab vedotin (BV) consists of a human chimeric immunoglobulin G1 antibody directed against CD30 that is covalently linked to the potent microtubule-disrupting agent, monomethyl auristatin E (MMAE) by a protease-cleavable linker. The binding of BV to CD30 on the tumor cell membrane triggers a cascade of events that ultimately results in apoptotic death of the CD30-expressing tumor cell.
6. In the ECHELON-2 study, what was the 5-year progression-free survival rate for patients with PTCL treated with BV-CHP (brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisolone)?
   correct answer: c.

   The ECHELON-2 study was a multicenter, randomized, phase 3 study that compared frontline therapy with CHOP vs CHOP plus BV for CD30-positive PTCLs. Vincristine was dropped from the BV-CHP arm of the study due to avoid overlapping neurotoxicity with BV. Results from this trial showed that BV-CHP improved both PFS and OS without increasing toxicity compared with CHOP. The 5-year PFS rates in the BV-CHP and CHOP arms were 51.4% and 43%, respectively, and the 5-year OS rates were 70.1% and 61%, respectively. Based on this study, BV-CHP is now recommended in the NCCN guidelines as the standard frontline therapy for ALCL and other CD30-positive T-cell lymphomas.
7. What is the 5-year overall survival (OS) rate with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) in patients with PTCL?
   correct answer: b.

   CHOP-based regimens have typically been associated with high response rates but primary treatment failure in up to 40% of patients with PTCL and 5-year OS rates of only 35%. Responses to CHOP alone have not been durable, thus the recommendation for consolidation with autologous stem cell transplantation in responders. Therefore, many efforts have been made to improve this regimen.
8. Your patient with relapsed ALCL is a candidate for single-agent treatment with BV. She asks about side effects that have been observed with this therapy in clinical trials. Which of the following should you tell her was the most common adverse event observed in a pivotal phase 2 study of single-agent BV in patients with relapsed or refractory ALCL?
   correct answer: d.

   In a multicenter, phase 2 study of BV in relapsed or refractory systemic ALCL, peripheral neuropathy was the most common AE, reported in 57% of patients, with resolution or improvement reported in the majority with long-term follow-up.
9. Ruxolitinib and golidocitinib are novel agents being investigated in patients with PTCL that target which of the following pathways?
   correct answer: a.

   Ruxolitinib is a JAK1/2 inhibitor, and golidocitinib is a selective JAK1 tyrosine-kinase inhibitor.
10. Which of the following is not an ALK inhibitor that has been investigated in patients with T-cell lymphoma?
    correct answer: b.

    Duvelisib is a PI3K-δ,γ inhibitor that was investigated in the multicenter phase 2 PRIMO study in patients with relapsed or refractory PTCL. This study demonstrated an ORR of 49% and a CR rate of 34%, with a median PFS of 3.6 months. Brigatinib, crizotinib, and alectinib are ALK inhibitors.