T-Cell Lymphomas — Approach and Management

Overview

T-cell lymphomas are a group of diseases that originate from mature (peripheral) T lymphocytes, constitute a relatively small proportion of all non-Hodgkin's lymphomas in Western countries, but are biologically and clinically extremely heterogeneous; this protocol primarily covers systemic (nodal and extranodal) peripheral T-cell lymphomas (PTCL), while cutaneous T-cell lymphomas (mycosis fungoides, Sézary syndrome) are managed differently as a separate entity. The most common subtypes are peripheral T-cell lymphoma (PTCL-NOS), angioimmunoblastic T-cell lymphoma, and anaplastic large cell lymphoma (ALCL), which cannot be classified otherwise.

In the World Health Organization's 2022 (WHO-HAEM5) classification, angioimmunoblastic lymphoma was grouped under the nodal TFH cell lymphoma family on the basis of common T-follicular helper (TFH) cell origin, and nodal TFH cell lymphoma was renamed angioimmunoblastic type; This family also includes the follicular type and the type that cannot be classified otherwise. Anaplastic large cell lymphoma is recognized by the strong CD30 expression of tumor cells and is divided into two groups based on the presence of anaplastic lymphoma kinase (ALK) protein:

ALK-positive ALCL occurs mostly in younger patients and has a markedly GOOD prognosis; ALK-negative ALCL occurs at an older age and progresses worse. The clinical picture is usually aggressive: diffuse lymphadenopathy, frequent extranodal involvement (skin, liver, spleen, bone marrow), B symptoms (fever, night sweats, weight loss) and autoimmune phenomena, rash, polyclonal hypergammaglobulinemia and immunodeficiency, especially evident in angioimmunoblastic/nodal TFH lymphoma.

The basis of diagnosis is an EXCISIONAL (or sufficient tissue) biopsy of the involved lymph node; Fine needle aspiration is insufficient for diagnosis as the diagnosis of T-cell lymphoma requires tissue architecture, detailed immunohistochemistry (T-cell markers, CD30, ALK, TFH markers), T-cell receptor clonality analysis, and, when necessary, molecular-cytogenetic examination. Additional serology and investigations are required to differentiate adult T-cell leukemia/lymphoma (HTLV-1 associated) and Epstein-Barr virus–associated T/NK-cell lymphomas in the appropriate clinical and geographical context.

Once the diagnosis is confirmed, staging is performed based on whole-body FDG-PET/CT using the Ann Arbor system and the 2014 Lugano adaptation, while bone marrow assessment contributes to the International Prognostic Index (IPI) risk determination. In general, PTCL responds less to standard chemotherapy compared to aggressive B-cell lymphomas and has worse long-term outcomes; therefore, treatment selection considers subtype, ALK status, CD30 expression, and risk group together.

Key considerations

• B-cell lymphomas (especially diffuse large B-cell lymphoma) similarly present with lymphadenopathy and B symptoms but carry B-cell markers (CD20) in immunophenotyping; differentiation is performed with excisional biopsy and immunohistochemistry, and treatment is entirely different (rituximab-based regimens).
• Hodgkin lymphoma can morphologically and immunophenotypically be confused particularly with CD30-positive ALCL; it is distinguished by Reed-Sternberg cells, CD15 expression, and the underlying reactive inflammation, whereas ALK and T-cell markers assist in diagnosing ALCL.
• Adult T-cell leukemia/lymphoma (ATLL) is associated with HTLV-1 virus, and is differentiated by endemic region/origin history, hypercalcemia, skin involvement, and characteristic leukocyte morphology; HTLV-1 serology confirms the diagnosis, and management is different.
• Extranodal NK/T-cell lymphoma (nasal type) is associated with Epstein-Barr virus, typically involves destructive midline facial/nasal structures, and is managed with asparaginase-based regimens; EBER positivity and clinical localization provide differentiation.
• Cutaneous T-cell lymphoma (mycosis fungoides, Sézary syndrome) presents with skin-limited patches/plaques or erythroderma and is managed with skin-directed and systemic treatments according to stage, different from systemic PTCL; this group is outside the scope of this protocol.
• Reactive/infectious lymphadenopathy and autoimmune lymphoproliferative conditions can particularly mimic the immune phenomena of angioimmunoblastic/nodal TFH lymphoma; lymphadenopathy that is persistent, growing, or accompanied by B symptoms must be evaluated with excisional biopsy.

Why it matters

The treatment of peripheral T-cell lymphomas is based on the combined evaluation of the subtype, ALK status, CD30 expression, and risk group; because this group responds less to standard chemotherapy compared to aggressive B-cell lymphomas and long-term outcomes are generally worse. The backbone of treatment is combination chemotherapy containing anthracyclines.

In most nodal PTCLs, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) is the basic regimen; however, due to inadequate results with CHOP, treatment intensity is increased in suitable patients. In a large analysis by the German DSHNHL group, it was shown that adding etoposide to CHOP (CHOEP) markedly improves event-free survival in patients aged sixty and under with normal lactate dehydrogenase levels; this benefit is most pronounced in ALK-positive anaplastic large cell lymphoma, while it is less clear in angioimmunoblastic lymphoma and PTCL-NOS, and in older patients, routine use is not recommended due to the additional toxicity of etoposide.

The most important advance in treatment has been in CD30-positive disease: In the ECHELON-2 randomized phase 3 trial, in patients with CD30-positive peripheral T-cell lymphoma (mostly systemic anaplastic large cell lymphoma), the BV-CHP regimen, in which the CD30-targeted antibody-drug conjugate brentuximab vedotin replaced vincristine, improved both progression-free and overall survival compared to standard CHOP (five-year progression-free survival approximately 51.4% vs.

43.0%). This result has made brentuximab vedotin part of first-line treatment in CD30-positive disease, especially in anaplastic large cell lymphoma; however, it should be kept in mind that the benefit is mainly supported by evidence in anaplastic large cell lymphoma, and is less clear in other subtypes with weak CD30 expression.

ALK status is prognostically determinant: ALK-positive anaplastic large cell lymphoma typically occurs in young patients and has a good prognosis (five-year overall survival approximately 70-90%), so routine autologous stem cell transplantation in first complete response is generally not recommended; in contrast, ALK-negative anaplastic large cell lymphoma and other nodal subtypes have a worse course.

Therefore, in most nodal peripheral T-cell lymphomas other than ALK-positive anaplastic large cell lymphoma, consolidation with high-dose chemotherapy and autologous stem cell transplantation is frequently considered in first complete response; however, the survival advantage of this approach over standard therapy has not been definitively proven in randomized studies, and the decision is individualized based on the patient's age, performance status, subtype, and response to treatment. In relapsed or refractory disease, the approach is shaped according to transplant eligibility: in transplant-eligible patients, autologous (and in selected cases, allogeneic) stem cell transplantation is aimed for after salvage chemotherapy; in transplant-ineligible patients, single-agent options are introduced.

In this group, pralatrexate, belinostat, and romidepsin have received accelerated approval based on response rates shown in single-arm phase 2 studies; however, the response rates are relatively low (e.g., approximately 29% for pralatrexate, approximately 26% for belinostat), and the role of these agents is temporary; brentuximab vedotin shows high efficacy as a single agent in CD30-positive relapsed anaplastic large cell lymphoma. In angioimmunoblastic/nodal TFH lymphoma, due to the epigenetic biology of the disease, hypomethylating agents and targeted therapies are being investigated in clinical trials, so participation in a clinical trial is strongly recommended for suitable patients.

Common mistakes include attempting to make the diagnosis with fine needle aspiration (insufficient for tissue architecture and immunophenotype), skipping determination of CD30 and ALK status (directly affects treatment and prognosis), and neglecting tumor lysis syndrome prophylaxis in bulky/rapidly proliferating disease.

Critical complications

• Aggressive course due to the disease itself: rapidly progressing mass, widespread extranodal involvement (skin, liver, spleen, bone marrow), and cytopenias due to bone marrow involvement can quickly worsen if treatment is delayed.
• Tumor lysis syndrome presents at the start of treatment in bulky or rapidly proliferating disease with hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and acute kidney injury; if not prevented, it can lead to arrhythmia and renal failure.
• Hemophagocytic lymphohistiocytosis (macrophage activation syndrome) can be seen especially in angioimmunoblastic/nodal TFH and Epstein-Barr virus–associated T-cell lymphomas and forms a life-threatening condition with fever, cytopenias, high ferritin, and organomegaly.
• Infections are common due to both disease-related immune deficiency (especially in angioimmunoblastic/nodal TFH lymphoma) and chemotherapy-induced neutropenia; febrile neutropenia requires urgent treatment, and opportunistic infections (including viral reactivation) may occur.
• Cumulative cardiotoxicity (cardiomyopathy, heart failure) due to doxorubicin is a common risk of CHOP/CHOEP/BV-CHP regimens and requires baseline and follow-up cardiac evaluation.
• Peripheral neuropathy (cumulative, mostly sensory) and neutropenia associated with brentuximab vedotin can be dose-limiting in BV-CHP treatment; neuropathy partially improves after treatment.
• Oncologic emergencies: superior vena cava syndrome and airway compression due to large mediastinal/cervical mass, spinal cord compression due to epidural involvement, and febrile neutropenia under chemotherapy require urgent diagnosis and treatment.
• Complications related to autologous/allogeneic stem cell transplantation (prolonged cytopenia, infection, graft-versus-host disease in allogeneic transplantation) occur in patients who undergo transplantation as consolidation or salvage therapy.

Special considerations

• A young patient with ALK-positive anaplastic large cell lymphoma, by definition, is a group with a good prognosis; high response and good long-term survival are achieved with CHOP/CHOEP-based treatment, routine autologous stem cell transplantation is generally not required at first complete response, and late effects (fertility, cardiotoxicity) are also considered in treatment choice.
• Elderly patients are challenging in terms of both disease biology and treatment tolerance; ALK-negative anaplastic large cell lymphoma and other subtypes are more common and have a worse prognosis in this group, and regimens are adapted to comorbidities due to etoposide and intensive regimen toxicity (especially cytopenia and infection) and anthracycline cardiotoxicity.
• Patients with angioimmunoblastic/nodal TFH lymphoma have pronounced immune deficiency, autoimmune phenomena, and infection tendency; infection prophylaxis and careful monitoring are important in this group, and due to the epigenetic biology of the disease, participation in clinical trials is strongly recommended for suitable patients.
• A patient suspected of adult T-cell leukemia/lymphoma (HTLV-1 associated) (endemic area/origin, hypercalcemia, skin involvement) should be evaluated as a separate entity and confirmed with HTLV-1 serology; management includes antiretroviral-interferon or intensive chemotherapy ± allogeneic transplantation according to the subtype and differs from standard PTCL regimens.
• In relapsed/refractory disease, the distinction between transplant-eligible and non-eligible patients determines management; in transplant-eligible patients, salvage chemotherapy and autologous (and in selected cases allogeneic) stem cell transplantation is targeted, while in non-eligible patients, single agents such as pralatrexate/belinostat/romidepsin and clinical trial options with brentuximab vedotin in CD30-positive disease are considered.

Follow-up plan

The initial phase of follow-up is the evaluation of treatment response: response is documented during and at the end of treatment with FDG-PET/CT and the Lugano 2014 criteria, with the goal of a complete metabolic response. During active treatment, complete blood count, organ functions, and toxicity are assessed before each cycle; for doxorubicin, cardiac symptoms and echocardiography if necessary, for brentuximab vedotin peripheral neuropathy, and for all regimens, cytopenia and infection are monitored; fever and neutropenia together are urgently managed as febrile neutropenia.

At the start of treatment and in the first cycles, kidney function, uric acid, potassium, phosphorus, and calcium are monitored for tumor lysis syndrome. In patients planned for autologous stem cell transplantation as consolidation, chemosensitivity and transplant eligibility are reassessed.

After treatment is completed, clinical follow-up, examination, and imaging when necessary are performed to detect relapse; since peripheral T-cell lymphomas have a relatively high tendency to relapse, close monitoring in the first years is important, but the frequency of routine imaging is determined according to guidelines and individual risk, and unnecessary radiation is avoided. Patients with angioimmunoblastic/nodal TFH lymphoma are monitored for infection and autoimmune complications.

In the long term, patients who have received anthracyclines and radiotherapy when necessary are managed for cardiovascular risk factors and cardiac monitoring is continued; in young patients, fertility and endocrine status are evaluated. Patients are educated about signs of relapse (new/enlarging lymph node, recurrent B symptoms), infection-fever, cardiac and neurological symptoms, and are instructed to seek care without delay in these situations.

Diagnosis, subtyping, staging, treatment selection, consolidation, and relapse management are the responsibility of hematology/medical oncology; the primary care physician plays an active role in monitoring for tumor lysis and febrile neutropenia, cardiovascular risk management, vaccination, and complication follow-up.