T-Cell Non-Hodgkin Lymphoma (NHL)

Introduction:

NHL is categorized into two groups of B-cell lymphomas and T/NK-Cell lymphomas:

• B-cell lymphomas (85–90%): (discussed in a separate post B-Cell Non-Hodgkin lymphoma)

  • Aggressive:

    • Diffuse large B-cell lymphoma (DLBCL)

    • High-grade B-cell lymphoma (HGBL)

      • Includes selected lymphomas with MYC and BCL2 rearrangements

      • Historically referred to as “double-hit” lymphoma when MYC and BCL2 rearrangements are present

    • Burkitt lymphoma (BL):

      • Highly aggressive

      • Derived from germinal center B cells

    • Mantle cell lymphoma (MCL):

      • Generally clinically aggressive, although behavior can be heterogeneous

      • Derived from mantle-zone B cells

  • Indolent:

    • Follicular lymphoma (FL):

      • Derived from germinal center B cells

    • Marginal zone lymphoma (MZL):

      • Subtypes: Extranodal, Nodal, Splenic

    • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

    • Lymphoplasmacytic lymphoma (LPL)

• T-cell lymphomas (10-15%):

  • Peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS):

    • One of the most common subtype of mature T-cell lymphomas

    • An aggressive mature T-cell lymphoma that does not meet criteria for another defined T-cell lymphoma entity.

  • Cutaneous T-cell lymphoma (CTCL):

    • Mycosis Fungoides

    • Sézary Syndrome

  • Anaplastic large cell lymphoma (ALCL):

    • Can be ALK-positive or ALK-negative

  • Enteropathy-associated T-cell lymphoma (EATL):

    • Rare, aggressive peripheral T-cell lymphoma of the small intestine

    • Strongly associated with celiac disease

  • Hepatosplenic T-cell lymphoma (HSTCL)

  • Adult T-cell leukemia/lymphoma (ATLL)

  • Extranodal NK/T-cell lymphoma (ENKTL)

  • T-cell large granular lymphocytic leukemia (T-LGLL):

    • indolent chronic lymphoproliferative disorder

    • Often with extranodal involvement (peripheral blood, bone marrow, spleen)

T-Cell Non-Hodgkin Lymphomas

Adult T-Cell Leukemia/Lymphoma (ATLL)

Background:

• Immunophenotype:

  • Positive CD2, CD3, CD4, CD5, CD25, CCR4

  • Negative CD7, CD8, cytotoxic markers (TIA-1, granzyme B, perforin)

  • Variable CD30

    • CD30 is a marker of activated/mature lymphocytes

  • Presence of > 5% T lymphocytes with abnormal immunophenotype is required for diagnosis

• Associated with HTLV-1

• Can have skin lesions or osteolytic bone lesions (which leads to hypercalcemia)

• Peripheral smear shows atypical lymphocytes with multilobulated “flower” cells

Treatment:

• BV-CHP

  • Brentuximab Vedotin + Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Prednisone

  • First-line treatment of CD30-positive peripheral T-cell lymphomas

• Dose adjusted EPOCH

• Zidovudine + interferon

Anaplastic Large-Cell Lymphoma (ALCL)

Background:

• Positive CD30

• Subtypes:

  • ALK-positive ALCL:

    • Systemic, often younger patients, better prognosis

  • ALK-negative ALCL:

    • Systemic, older patients, worse prognosis

  • Primary cutaneous ALCL:

    • Localized to skin, excellent prognosis

  • Breast implant–associated ALCL:

    • Localized to capsule/implant, distinct management

Treatment:

• Localized disease be cured with complete excision

  • Consider RT +/- systemic therapy if residual disease

• Systemic therapy:

  • First Line:

    • BV-CHP

      • First-line for systemic CD30+ ALCL

    • CHOP

    • EPOCH

  • Subsequent Lines:

    • Brentuximab

    • Bendamustine

    • Bortezomib

    • Cyclophosphamide

    • ALK inhibitors (alectinib, crizotinib, brigatinib, ceritinib, lorlatinib)

      • Only for relapsed/refractory ALK-positive ALCL

    • Clinical trial

Mycosis Fungoides (MF) /Sezary Syndrome (SS)

Background:

• Primary cutaneous Lymphoma that involves T cells

• MF generally affects the skin but may progress to affect the internal organs over time.

• SS is defined by blood involvement and having clonal rearrangement of TCR in the blood

  • Requires systemic treatment

Treatment:

• Skin directed therapies:

  • Local RT

  • Phototherapy

  • Topical corticosteroids

  • Topical Imiquimod

  • Topical Nitrogen Mustard

  • Topical Retinoids

  • Topical Mechlorethamine

• Systemic Therapies:

  • Mogalizumab

  • Romidepsin

  • Interferon alfa

  • Retinoids

  • Bexarotene

  • Brentuximab vedotin

  • Gemcitabine

  • Methotrexate

    
    

Extranodal NK/T-Cell Lymphoma (ENKTL)

Background:

• Very aggressive

• Typically difficult to diagnose due to necrosis

  • Typical phenotype of NK cell:

    • CD2+, CD7+, surface CD3- (may express cytoplasmic CD3ε), CD56+ (characteristic NK cell marker), CD4 and CD8 are usually absent.

  • Typical phenotype of T-Cell:

    • CD2+, CD7+, surface CD3+ (defining factor), EBER-, CD56 variable, rearranged TCR

      • T Helper: CD3+, CD4+, CD8-

      • T cytotoxic: CD3+, CD4-, CD8+

• EBV-encoded RNA (EBER) in situ hybridization is characteristically positive in ENKTL.

• May present with major GI bleed if involved

• Subtypes:

  • Nasal ENKTL

  • Extranasal ENKTL

  • Aggressive NK-cell leukemia

Treatment:

• ChemoRT:

  • RT concurrently with 3 cycles of DeVIC

    • DeVIC: Dexamethasone, Etoposide (VP-16), Ifosfamide, Carboplatin

  • SMILE x 2-4 cycles → RT

    • SMILE: Steroid (Dexa), Methotrexate, Ifosfamide, L-asparaginase, Etoposide

  • P-GEMOX x2 cycles → RT → P-GEMOX

    • P-GEMOX: Pegaspargase, Gemcitabine, Oxaliplatin

  • GELAD x2 cycles → RT → GELAD x 2 cycles

    • GELAD: Gemcitabine, Etoposide, Pegaspargase (a form of L-asparaginase), Dexamethasone

• If treated with chemo alone:

  • Modified SMILE → allo-HSCT consolidation

  • P-GEMOX → allo-HSCT consolidation

  • DDGP → allo-HSCT consolidation

    • DDGP: Dexamethasone, Cisplatin (DDP), Gemcitabine, Pegaspargase