45  Aggressive Non-Hodgkin & Burkitt Lymphomas

Key Points
  • DLBCL: most common aggressive NHL (~30%); COO (GCB vs ABC); R-CHOP × 6 standard
  • Double-hit: MYC + (BCL2/BCL6) = poor prognosis; DA-EPOCH-R preferred
  • Burkitt: t(8;14) MYC; Ki-67 ~100%; hyperCVAD or CODOX-M/IVAC; TLS risk high
  • PMBCL: young ♀; anterior mediastinum; DA-EPOCH-R ± RT; 70% 5-yr PFS
  • MCL: t(11;14) cyclin D1; MIPI score; BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib)
  • CNS prophylaxis: essential all aggressive NHL; HD-MTX or IT-MTX during induction
  • R/R DLBCL: CAR-T (axi-cel, liso-cel, tisa-cel) or salvage chemo → ASCT

45.1 Aggressive B-Cell Lymphomas: Overview

Heterogeneous neoplasms from mature B-cells w distinct genetics & clinical features; classified per WHO 2022 - Rapid progression, systemic involvement, high CNS relapse risk - Spectrum: DLBCL variants, MCL, Burkitt, high-grade B-cell (DHL/THL), PMBCL, PCNSL

45.2 Diffuse Large B-Cell Lymphoma (DLBCL)

Most common aggressive NHL (~30%); median age 55 yrs; ♂ > ♀

45.2.1 Diagnostics & Classification

  • Histology: Large B-cells w round nuclei, prominent nucleoli, abundant cytoplasm
    • CD20+, CD5– (vs CLL), high mitotic rate, apoptotic figures
    • Mutations: TP53, MYD88, CDKN2A
  • COO (cell-of-origin): GCB vs ABC subtypes
    • ABC = worse prognosis; high-grade w MYC & BCL2/BCL6 now distinct entity
  • IPI score (5 factors): age, LDH, PS, stage, extranodal sites
    • Low (0–1), IRL (2), IRH (3), high (4–5)

45.2.2 Frontline Treatment

  • R-CHOP × 6–8 cycles (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)
    • 5-yr PFS 50–60%; consolidation RT for limited stage (IPI <3) optional
  • DA-EPOCH-R (etoposide-based)
    • Superior PFS vs R-CHOP in retrospective series; higher toxicity
    • Consider: CNS involvement, high-risk features

45.2.3 Relapsed/Refractory DLBCL

  • Salvage chemo (GDP, DHAP) → ASCT if chemosensitive
  • CAR-T (axi-cel, liso-cel, tisa-cel): FDA-approved; ↓ OS vs historical ASCT controls
  • Venetoclax + obinutuzumab: elderly/unfit; good tolerability
  • Selinexor + dexamethasone: TP53 mutations

45.3 High-Grade B-Cell Lymphoma, NOS

45.3.1 Double-Hit & Triple-Hit Lymphomas

5–10% DLBCL w MYC + BCL2 translocations (FISH/karyotype) - Reclassified 2022 WHO as high-grade B-cell lymphoma w MYC & BCL2 rearrangements - Poor prognosis: advanced stage, extranodal involvement, median OS ~2 yrs w conventional Rx - Preferred regimen: DA-EPOCH-R (inadequate data; conventional Rx insufficient)

Triple-Hit (MYC + BCL2 + BCL6): rare, dismal outcomes - Consult experienced lymphoma specialist; limited treatment data

45.4 Primary Mediastinal B-Cell Lymphoma (PMBCL)

Young adult ♀; median age 35 yrs; anterior mediastinal mass

  • Presentation: SVC syndrome, effusions; distant spread uncommon
  • Histology: sclerosis, distinct from nodal DLBCL
  • Standard Rx: DA-EPOCH-R ± consolidative RT (↑ outcomes vs R-CHOP)
    • 5-yr PFS 70% (R-CHOP); 20% primary induction failure
    • RT to residual mass post-chemo improves PFS
  • R/R PMBCL: DA-EPOCH-H superior; salvage chemo → ASCT, CAR-T

45.5 Primary CNS Lymphoma (PCNSL)

Rare; brain, spinal cord, eye, leptomeninges w/o systemic involvement (~95% DLBCL)

45.5.1 Diagnostics

  • Age: typically 60+ yrs w focal neuro symptoms, mental status change, ↑ ICP
  • Imaging: contrast-enhanced MRI essential
  • Biopsy: stereotactic; mutations CD79B, MYD88, IGHV common
  • Staging: MRI + CSF examination

45.5.2 Management

  • Preferred Rx: HD-MTX (3.5–8 g/m²) ± HD-ara-C (HDAC)
    • ± rituximab + MTX; superior CNS penetration vs R-CHOP
    • WBRT: 0.6–3.4% 5-yr CNS relapse, but neurocognitive toxicity limits use
  • R/R PCNSL: salvage options limited; consider ASCT, CAR-T w R-CHOP

45.5.3 Secondary CNS Involvement

  • Incidence: ~4% DLBCL; ↑ w testicular, adrenal, bone marrow involvement
  • Risk model: CNS-IPI (low/intermediate/high)
    • High-risk (elevated LDH, stage III/IV, extranodal) → HD-MTX prophylaxis

45.6 Burkitt Lymphoma (BL)

Highly aggressive; rapid onset, bulky disease; t(8;14) MYC; Ki-67 ~100%

45.6.1 Presentation & Risk Stratification

  • Histology: medium-sized cells, “starry sky” appearance
    • CD20+, CD19+, BCL6+, CD10+; nearly 100% mitotic rate
    • Endemic (African ♂ jaw masses, EBV+); sporadic (Western)
  • High-risk features: bulky abdominal mass, CNS involvement, incomplete resection
    • ~20% low-risk BL
  • Tumor lysis syndrome (TLS) risk: very high w bulk disease
    • Prophylaxis: allopurinol or rasburicase, aggressive IV hydration, consider pre-Rx glucocorticoids

45.6.2 Chemotherapy Regimens

  • HyperCVAD (hyperfractionated CHOP alternating w HD-MTX/ara-C)
    • 2-yr PFS 80%, 5-yr OS ≥85% w rituximab consolidation
  • CODOX-M/IVAC (cyclophosphamide, vincristine, doxorubicin, HD-MTX alternating w ifosfamide, etoposide, ara-C)
    • 2-yr EFS >90% in many series
  • R-CHOP: less favored; ↓ efficacy vs HyperCVAD/CODOX-M

45.6.3 CNS Prophylaxis & Relapse

  • Essential: IT-MTX or HD-systemic MTX during induction (standard practice)
  • Up to 50% relapse: HD-MTX in prior responders reasonable if durable response
    • R/R BL: salvage options limited; ifosfamide, sequential ASCT if responsive (not well-studied)

45.7 Mediastinal Grey Zone Lymphoma (MGZL)

Overlap features PMBCL & cHL; young ♂, median age 20–40 yrs

  • Diagnostic challenge: intermediate features, requires expert hematopathology review
  • Clinical course: mirrors PMBCL
  • Rx: PMBCL/DLBCL-type regimens preferred over ABVD
    • Brentuximab vedotin ± AVD or ± rituximab for select cases

45.8 Mantle Cell Lymphoma (MCL)

5–8% NHL; historically poor prognosis; now improved w novel Rx (median OS ≥5 yrs)

45.8.1 Diagnostics & Prognosis

  • Genetics: t(11;14) cyclin D1, SOX11 var
  • MIPI score (3 risk groups): age, PS, LDH, WBC
    • Incorporates Ki-67 proliferation index & TP53 mutations
  • Management approach: personalize to age, comorbidities, fitness for HDC/ASCT
    • Observation suitable for asymptomatic indolent MCL; most require Rx

45.8.2 Newly Diagnosed MCL: Age-Based Approach

Younger (<65 yrs, HDC/ASCT candidates) - R-HyperCVAD alternating cycles → HDC/ASCT - Superior outcomes vs R-CHOP alone; rituximab maintenance post-ASCT ↑ OS - R-CHOP w induction: alternative; less intensive

Older (≥65 yrs, comorbidities) - R-CHOP + rituximab maintenance (standard) - BTK inhibitor + R: ibrutinib ± rituximab shows ↑ outcomes vs R-CHOP alone - Venetoclax + R-CHOP: emerging, favorable tolerability - Lenalidomide + R: ORR 75–92%

45.8.3 Relapsed/Refractory MCL

MCL incurable; relapsing-remitting course w progressive PFS shortening; duration first remission <12 mo → poor prognosis

BTK Inhibitor-Based Approaches - Ibrutinib: ORR 68–80%, median PFS 2.6 yrs - Acalabrutinib (2nd-gen): ORR 80%, 2-yr PFS 50% (phase 3) - Zanubrutinib: ORR 84%, median DoR 27.3 mo

Other Options - Venetoclax + R: ORR 87%, 2-yr PFS 53%; superior vs comparators - Selinexor + dexamethasone: ORR 55% (vs 42% dex alone); emerging for BTK-resistant - R-CHOP ± BTK/venetoclax: alternative if BTK-naive

45.9 Immunodeficiency-Associated Lymphomas

WHO-HAEMS recognizes primary immunodeficiencies (“inborn errors of immunity”) w distinct histology & oncogenic drivers - Syndromes: Wiskott-Aldrich, ataxia-telangiectasia, CVID, X-linked lymphoproliferative - Pediatric-predominant; EBV-associated - Tx: varies by underlying disorder & lymphoma subtype - Transplantation curative option; CAR-T, novel immunomodulators emerging (limited data)

45.10 Clinical Pearls

Pearl 1: CNS Prophylaxis Essential - All aggressive B-cell NHL: IT-MTX (12 mg/dose) or HD-systemic MTX (≥1 g/m²) during induction - High-risk: CNS-IPI score, ↑ LDH, stage III/IV → more intensive regimens

Pearl 2: R/R DLBCL Now Increasingly Salvageable - CAR-T (tisa-cel, axi-cel, liso-cel) after R-CHOP progression - ↓ OS vs historical ASCT; ensure adequate bridging Rx & disease control before referral

Pearl 3: Burkitt Requires Rapid Intensive Therapy - HyperCVAD or CODOX-M/IVAC standard; CNS prophylaxis essential - TLS risk very high w bulky disease → prophylaxis w allopurinol/rasburicase, aggressive hydration, consider pre-Rx steroids

Aggressive B-Cell NHL: Comparative Features
Lymphoma Type Median Age (yr) Typical Presentation 5-yr PFS w Standard Rx
DLBCL 55 Advanced stage, ↑ LDH, mediastinal mass 50–60% (R-CHOP)
PMBCL 35 Anterior mediastinal mass, SVC syndrome 70–80% (DA-EPOCH-R)
Burkitt 20–50 Bulky disease, CNS involvement 75–85% (HyperCVAD)
MCL 65 Advanced stage, splenomegaly 50–75% (Rx-dependent)
DHL 60–70 Poor prognosis, MYC/BCL2 20–30% (inadequate data)
PCNSL 60 Focal neuro symptoms, ↑ ICP 30–50% (HD-MTX-based)
Treatment Algorithms for Aggressive NHLs
Lymphoma First-Line Therapy Relapsed/Refractory Options
DLBCL R-CHOP (or DA-EPOCH-R) Salvage chemo → ASCT; CAR-T; venetoclax
PMBCL DA-EPOCH-R ± RT Salvage chemo → ASCT; CAR-T
Burkitt HyperCVAD or CODOX-M/IVAC + R Limited options; ASCT if chemosensitive
MCL R-CHOP ± maint (older) or R-HyperCVAD → ASCT (younger) BTK inhibitor ± R; venetoclax ± R
PCNSL HD-MTX ± HD-ara-C Salvage limited; ASCT, CAR-T w R-CHOP