T-cell and NK-cell lymphomas

Overview

• Heterogeneous group of mature post-thymic T-cell and NK-cell neoplasms; ~10 to 15% of NHL in Western countries, higher in Asia/Latin America. Incidence is increasing (reason unclear, possibly better recognition).
• Generally poorer prognosis than B-cell NHL (5-year OS ~30 to 40% for most aggressive PTCL subtypes), with notable exceptions (ALK+ ALCL, indolent CTCL). Many subtypes are hard to treat; new/novel agents are being developed.
• WHO 2022 / ICC 2022: classified as nodal vs extranodal vs leukemic; some entities renamed (e.g., AITL → nodal TFH lymphoma).

WHO Classification of PTCL (by compartment)

• Leukemic / blood-based: adult T-cell leukemia/lymphoma (ATLL).
• Nodal-based: PTCL, not otherwise specified; angioimmunoblastic T-cell lymphoma (AITL / nodal TFH); anaplastic large-cell lymphoma, primary systemic type.
• Other extranodal / organ-based: subcutaneous panniculitis-like T-cell lymphoma; cutaneous gamma-delta T-cell lymphoma; hepatosplenic T-cell lymphoma; extranodal NK/T-cell lymphoma, nasal type; enteropathy-type T-cell lymphoma.

Common Mature T-cell and NK-cell Neoplasms: Immunophenotype

Clinical Suspicion and Common Features of PTCL

• Presenting syndromes: typical nodal or extranodal lymphoma; hemophagocytic syndrome; pulmonary syndrome; facial/sinus syndrome; systemic illness with atypical organ infiltration.
• Common characteristics: male in 55 to 62%; prior immunological disorder in 25 to 32%; elevated LDH at diagnosis in 42 to 87%; B symptoms in 53 to 57%; stage IV in 50 to 55%; autoimmune arthritis in 4 to 7%.

Major Subtypes and Key Features

• PTCL-NOS (~25%): heterogeneous diagnosis of exclusion; nodal; aggressive. CD4+ > CD8+ with loss of CD5/CD7. Molecular profiling identifies cell-of-origin phenotypes: Th1/TBX21 vs Th2/GATA3 (GATA3 has worse survival than TBX21). Cases with a TFH phenotype are excluded from PTCL-NOS and classified separately as nodal TFH-cell lymphoma (WHO-HAEM5).
• Nodal TFH lymphoma (formerly AITL, ~20%): mature CD4+ PTCL of older adults. Presents with rash, EBV+ background B-blasts, fluid retention (effusions, ascites), generalized lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, eosinophilia, and fever; may have a positive Coombs test with hemolysis. TFH markers: PD-1, CXCL13, ICOS, BCL6, CD10. Mutations: TET2, DNMT3A, IDH2 (R172), RHOA (G17V). Prognosis similar to PTCL-NOS; may co-present with a concurrent DLBCL, so send EBV and appropriate IHC.
• ALCL, ALK+: NPM-ALK fusion t(2;5); younger patients; best prognosis of all T-cell lymphomas (5-year OS >70%). CD30+ uniform/strong, ALK+, EMA+.
• ALCL, ALK-: older; worse prognosis. DUSP22 rearrangement is prognostically favorable (better PFS than triple-negative ALK- ALCL) but outcomes are heterogeneous and not reliably ALK+-like; do not de-escalate therapy on this basis alone; TP63 rearrangement has very poor outcomes (data still needs validation).
• Breast implant-associated ALCL (BIA-ALCL): associated with textured implants; CD30+, CD4+, CD45+, ALK-. Usually contained within the capsule and/or seroma (stage IAE, ~72%); nodal involvement ~14%, extranodal ~3%. If a seroma is drained, send cytology. Localized disease needs only local control (capsulectomy curative for early stage); incomplete resection → RT +/- systemic therapy; extended stage II to IV → systemic therapy (brentuximab vedotin +/- CHP, or CHOP/CHOEP/DA-EPOCH).
• Adult T-cell leukemia/lymphoma (ATLL): HTLV-1-associated; Caribbean, Japan, sub-Saharan Africa. CD4+ CD25+ "flower cells"; hypercalcemia, lytic bone lesions, skin involvement. Subtypes: acute, lymphomatous, chronic, smoldering. Needs a distinct approach from other PTCL.
• Extranodal NK/T-cell lymphoma, nasal type: Asian/Latino predominance; EBV+ uniformly; nasal cavity/upper aerodigestive tract (also skin, GI, salivary gland); angioinvasive and necrotic. CD2+, cytoplasmic CD3ε+, CD56+, surface CD3-. Aggressive: treat with chemotherapy + RT (RT alone for unfit stage I nasal disease). See treatment below.
• Hepatosplenic T-cell lymphoma (HSTCL): rare, aggressive; usually gamma-delta TCR; young men; immunosuppression context (anti-TNF plus thiopurine in IBD). Hepatosplenomegaly, sinusoidal infiltration, pancytopenia. Median OS ~1 year.
• Enteropathy-associated T-cell lymphoma (EATL): type I celiac-associated (refractory celiac sprue); MEITL (monomorphic epitheliotropic intestinal T-cell lymphoma) is a separate entity, formerly called EATL type II, non-celiac, SETD2-inactivated with JAK-STAT (STAT5B, JAK3) mutations, Asian predominance.
• Subcutaneous panniculitis-like T-cell lymphoma (SPTCL): alpha-beta TCR, CD8+, indolent; HLH risk in a subset. Distinguish from cutaneous gamma-delta T-cell lymphoma, which is aggressive.
• Aggressive NK-cell leukemia: EBV+, fulminant, HLH-like; very poor prognosis.
• T-cell prolymphocytic leukemia (T-PLL): see dedicated section below.
• T-large granular lymphocyte leukemia (T-LGL): indolent; STAT3 mutations; cytopenias (especially neutropenia), associated with rheumatoid arthritis. Treatment: methotrexate, cyclosporine, cyclophosphamide.

Frontline Treatment: Aggressive Nodal PTCL

• Backbone: for PTCL-NOS and AITL/nodal TFH, give CHO(E)P (etoposide added in younger fit patients), or BV-CHP if CD30 ≥10% (systemic ALCL, including ALK-negative, gets BV-CHP, see below), and consolidate with autologous SCT in CR1. High-risk (IPI, stage IV, or elderly) respond poorly. Survival and PFS are better with CHOP-like regimens than with less intense treatment. CHOP/CHOEP alone remains inadequate (5-year OS ~30%).
• CHOEP vs CHOP (Schmitz Blood 2010): CHOEP improved EFS in younger patients (18 to 60), no advantage over 60.
• ECHELON-2 (Horwitz Lancet 2019; PMID 30522807): brentuximab vedotin + CHP (BV-CHP) vs CHOP in CD30+ PTCL (≥10% CD30, i.e., most ALCL and ~50% of other PTCLs). PFS HR 0.71, OS HR 0.66; BV-CHP became the FDA standard first line for CD30+ PTCL in Nov 2018. (Earlier phase 1 BV-CHP, Fanale Blood 2018: 5-year PFS 52%, OS 80%.)
• ALK+ ALCL: BV-CHP standard (high CD30); excellent outcomes. ALK- ALCL: BV-CHP with auto-HSCT consolidation in CR1 (especially TP63+).
• ASCT in CR1: prospective data support consolidation. Reimer JCO 2009 (CHOP x 4 to 6 then ASCT): 66% (55/83) transplanted; ITT ORR after myeloablative therapy 66%; 3-year OS 48%, DFS 53%, PFS 36%. Nordic Lymphoma Group (CHOEP x 6 → ASCT): 5-year OS 51%, PFS 44%, treatment-related mortality 4%.
• Adding drugs to CHOP that did NOT help: CHOP +/- alemtuzumab (no difference; d'Amore ASH 2018); lenalidomide + CHOP in AITL (no difference; Lemonnier ASH 2018). Romidepsin-CHOP (phase 1b/2), belinostat-CHOP (phase 1), and CEOP alternating with pralatrexate (phase 2) showed activity but did not establish superiority (Ro-CHOP later failed to improve PFS or OS in the randomized setting, contributing to romidepsin's US withdrawal, see below).

Extranodal NK/T-cell Lymphoma: Treatment

• Principle: conventional anthracycline-containing regimens are ineffective and should be replaced by non-anthracycline regimens, preferably including L-asparaginase. Combine chemotherapy with RT (RT alone for unfit stage I nasal disease).
• SMILE (steroid, methotrexate, ifosfamide, L-asparaginase, etoposide): better than CHOP. In 38 patients with newly diagnosed stage IV (n=20) or relapsed/refractory (n=18) nasal NK/T (Yamaguchi JCO 2011): ORR after 2 cycles 79%, CR 45%; 19 went to stem-cell transplant; 1-year OS 55%.
• DDGP (dexamethasone, cisplatin, gemcitabine, pegaspargase) vs SMILE (Wang, ASH 2019): DDGP may be better than SMILE.

Cutaneous T-cell Lymphoma (CTCL): Mycosis Fungoides and Sezary Syndrome

• Mycosis fungoides (MF): the most common CTCL, with many clinicopathologic variants; usually indolent (patches → plaques → tumors → erythroderma). Extracutaneous spread (nodes, blood, less often other organs) occurs in advanced stages. CD4+, CD7-/dim; epidermotropism with Pautrier microabscesses. Thought to arise from skin-resident effector memory T cells.
• Sezary syndrome (SS): rare (<5% of cutaneous lymphomas), older patients; erythroderma plus significant blood involvement by atypical T cells (Sezary cells with cerebriform nuclei). Defined by B2 blood involvement plus a clonal TCR rearrangement in the blood matching the skin clone. Thought to arise from circulating central memory T cells, so SS is considered distinct from MF (overlap cases exist).
• Diagnosis / immunophenotype: CD2+, CD3+, CD4+, CD5+, CD7-, CD8- (rarely CD8+), CD30-/+, cytotoxic granule proteins negative. Clonal TCR rearrangement alone is not sufficient (also seen in benign conditions).

CTCL Staging: TNMB

• Tumor (skin): T1 <10% BSA; T2 ≥10% BSA; T3 tumor(s) ≥1 cm; T4 erythema ≥80% BSA. TNMB (tumor, node, metastasis, blood) staging is the most important prognostic factor.

CTCL Management

• Early stage (IA to IIA, patch/plaque): skin-directed therapy. First line: topical steroids, mechlorethamine (nitrogen mustard), bexarotene, PUVA, narrowband UVB, localized RT. Second line: total skin electron beam therapy (TSEBT, 12 to 36 Gy), interferon-alpha, methotrexate.
• Advanced stage (IIB to IV): systemic therapy. First line adds methotrexate, extracorporeal photopheresis (ECP), and chemotherapy (HDAC inhibitors, gemcitabine, liposomal doxorubicin). Second line: brentuximab vedotin, mogamulizumab, alemtuzumab, pembrolizumab.
  • ALCANZA (Prince Lancet 2017): brentuximab vedotin vs methotrexate/bexarotene significantly improved PFS; now approved for CD30+ disease.
  • MAVORIC (Kim Lancet Oncol 2018): mogamulizumab (anti-CCR4) vs vorinostat improved PFS; FDA approved Aug 2018.
  • Pembrolizumab in R/R MF/SS (Khodadoust JCO 2020): single-arm phase 2 (n=24), ORR 38%, durable responses (median DOR not reached).
  • Denileukin diftitox-cxdl (Lymphir): IL-2/diphtheria-toxin fusion; FDA approved Aug 7, 2024 for R/R stage I to III CTCL after ≥1 prior systemic therapy (Pivotal Study 302; ORR 36%, CR 9%); boxed warning for capillary leak syndrome.
  • HDAC inhibitors: vorinostat and romidepsin (romidepsin remains FDA-approved for CTCL; only its PTCL indication was withdrawn in 2021). Other (non-HDAC) systemic agents: gemcitabine, liposomal doxorubicin.
• Sezary / erythrodermic disease: combine skin-directed and systemic therapy. Skin-directed: phototherapy (UVB, NB-UVB, PUVA, UVA1), topical steroids, topical mechlorethamine or imiquimod/retinoids (bexarotene, tazarotene), TSEBT. Systemic combinations include mogamulizumab, romidepsin, ECP, interferon, and retinoids in various pairings; other options include alemtuzumab, bexarotene, brentuximab, gemcitabine, liposomal doxorubicin, methotrexate, pembrolizumab, pralatrexate, vorinostat.
• Allo-HSCT: the only curative option; reserved for advanced/refractory disease.

ALK-Targeted Therapy

• Crizotinib: FDA approved (Jan 2021) for pediatric patients ≥1 year and young adults with R/R systemic ALK+ ALCL (off-label in older adults). Kids/AYA ORR 88%, CR 81%; adults ORR 83.3%, CR 58%. Phase 2 monotherapy in R/R ALK+ ALCL (11 patients): ORR 91%, CR 82%, 3-year PFS 62% (also off-label in R/R).
• Ceritinib: ORR ~75% in children.
• Alectinib: good response in R/R ALK+ ALCL.

T-cell Prolymphocytic Leukemia (T-PLL)

• Presentation: rare (only ~2% of mature lymphocytic leukemias in adults over 30); leukocytosis (often WBC >100,000/µL), hepatosplenomegaly, generalized lymphadenopathy, skin lesions, serous effusions. Aggressive relative to B-PLL.
• Diagnosis: peripheral smear shows prolymphocytes. Classic IHC: CD1a-, TdT-, surface CD3+/-, CD2+, CD5+, CD7 strongly +, CD52 strongly + (alemtuzumab target), TCR alpha-beta+, usually CD4+/CD8- (~21% variant patterns). TCL1 rearrangement is characteristic. HTLV-1 PCR is negative (distinguishes from ATLL). Clonal TCR rearrangement alone is nonspecific.
• Treatment: 10 to 20% are inactive/indolent → observe (will slowly progress). Most have active disease and are resistant to conventional chemotherapy (historical median survival ~7 months). Alemtuzumab (anti-CD52)-based therapy, alone or with chemotherapy, is standard: ORR ~76% (CR ~60%), median DOR ~7 months. Check for CMV reactivation by PCR during alemtuzumab, and give antiviral and PJP prophylaxis. Consolidate with allogeneic SCT if there is a good response.

Relapsed / Refractory PTCL Therapies

• Pralatrexate (targeted antifolate): PROPEL trial (n=115), ORR 29% (median PFS 3.5 months, OS 14.5 months); key toxicity mucositis. FDA 2009 for R/R PTCL (O'Connor JCO 2011).
• Romidepsin (HDAC inhibitor): phase 2 (n=131) ORR 25%, DOR 17 months, similar across PTCL-NOS/AITL/ALCL (Coiffier JCO 2012). FDA accelerated approval withdrawn 2021 after the confirmatory Ro-CHOP phase 3 failed its primary endpoint (PFS), with no OS benefit.
• Belinostat (pan-HDAC inhibitor): BELIEF trial (n=129), ORR 26% (CR 10%), median DOR 8.3 months. FDA 2014 for R/R PTCL.
• Duvelisib (dual PI3K-delta/gamma inhibitor): 35 patients (PTCL and CTCL), ORR 42% overall, 50% in PTCL (Horwitz Blood 2018).
• Lenalidomide (EXPECT trial, n=54): ORR 22%, 31% in AITL; median PFS 2.5 months.
• Bendamustine (BENTLY trial, n=60): ORR 50% (CR 28%), median PFS 3.6 months (Damaj JCO 2013).
• Brentuximab vedotin: CD30+ disease, including BIA-ALCL. Phase 2 in CD30+ ALCL (n=58): ORR 86% (CR 57%); phase 2 in CD30+ PTCL (n=34): ORR 41% (no correlation between CD30 level and response).
• Mogamulizumab (anti-CCR4): ATLL ORR ~50% (median OS 13.7 months), PTCL ORR ~35%; CTCL (FDA Aug 2018) and ATLL (Japan). Frequent infusion reactions and rash.
• Crizotinib / alectinib: ALK+ ALCL (see ALK-targeted therapy).
• Valemetostat (Ezharmia): dual EZH1/EZH2 inhibitor. VALENTINE-PTCL01 (Horwitz Lancet Oncol 2024): ORR 43.7%, CR 14.3% in R/R PTCL. Approved in Japan for R/R ATL (Sept 2022) and R/R PTCL (June 2024); investigational/not yet FDA-approved in the US as of May 2026 (FDA orphan-drug designation for PTCL Dec 2021).
• Allo-HSCT: curative potential in R/R PTCL.

High-Yield Pearls

• ALK+ ALCL: NPM-ALK t(2;5); younger; best prognosis among PTCLs.
• ALK- ALCL: DUSP22 (favorable) vs TP63 (worst).
• BIA-ALCL: textured implants; CD30+, ALK-; capsulectomy curative for early stage.
• HTLV-1 + hypercalcemia + lytic bones + flower cells = ATLL.
• Nasal mass + EBV+ + necrosis = extranodal NK/T-cell, nasal type; use L-asparaginase regimens (SMILE/DDGP), not anthracyclines.
• Gamma-delta HSTCL: young IBD patients on anti-TNF plus thiopurine.
• Refractory celiac sprue → EATL.
• BV-CHP (ECHELON-2): first line for CD30+ PTCL (≥10%).
• Sezary triad: erythroderma + circulating Sezary cells (B2) + clonal TCR matching skin.
• STAT3 mutation + RA + neutropenia = T-LGL.
• TCL1 rearrangement, CD52++, HTLV-1 negative = T-PLL (alemtuzumab).
• Mogamulizumab: anti-CCR4 for CTCL/Sezary.
• Romidepsin PTCL indication withdrawn 2021 (Ro-CHOP failed PFS/OS); still approved for CTCL.
• Denileukin diftitox-cxdl (Lymphir): FDA Aug 2024 for R/R CTCL; capillary-leak boxed warning.
• Valemetostat (EZH1/2 inhibitor): Japan-approved R/R PTCL (2024); US still investigational.