44  Indolent Non-Hodgkin B-Cell Lymphoma

Key Points
  • FL: t(14;18) → BCL2 overexpression; CD5−, CD10+, BCL6+; 75% stage III-IV at diagnosis
  • MZL: CD5− extranodal; MALT (gastric → H. pylori eradication), nodal, splenic subtypes
  • LPL/WM: MYD88 L265P (90%); IgM monoclonal; BTK inhibitors (ibrutinib, acalabrutinib)
  • HCL: BRAF V600E (>95%); monocytic; TRAP+; purine analogs or vemurafenib 1st-line
  • Mgmt: Limited stage (I-II) → curative intent (RT ± R-CHOP); advanced → watch-wait vs. rituximab ± chemo per FLIPI
  • Transformation (2-3%/yr FL): TP53, MYC, EZH2 mutations → aggressive NHL

44.1 Follicular Lymphoma

44.1.1 Epidemiology & Pathology

  • 20-30% of all NHL; median age 60 yr; 75% stage III-IV at presentation
  • Pathology: germinal center B cells; follicular architecture; t(14;18) → BCL2/BCL6 overexpression
  • Grading: Grade 1-2 (low, <15 centroblasts/hpf); Grade 3A (high, 15-75); Grade 3B (high diffuse, treat as DLBCL)
  • CD profile: CD5−, CD10+, BCL2+, BCL6+

44.1.2 Staging & Prognosis

  • FLIPI score (Table 44-4): 5 variables
    • Age >60 yr, Stage III-IV, Hb <12 g/dL, LDH ↑, >4 nodal sites
    • Low (0-1): 36%, 5-yr OS 91%, 10-yr OS 71%
    • Intermediate (2): 37%, 5-yr OS 78%, 10-yr OS 51%
    • High (≥3): 27%, 5-yr OS 53%, 10-yr OS 36%
  • Prognostic markers: TP53, EZH2, MYC mutations; FISH for t(14;18); POI24 (proliferation index)

44.1.3 Localized FL (Stage I-II, ~10%)

  • Involved-field radiation alone: curative in ~50%; excellent OS >15 yr
  • Observation then deferred Tx: median wait 3 yr before therapy; 7-yr OS 15 yr
  • R-CHOP + RT (SWOG 0014): 10-yr OS 89% vs. 86% w/ RT alone; no OS benefit from chemo
  • Approach: Single-modality RT preferred in selected pts; rituximab monotherapy may defer chemo

44.1.4 Advanced FL (Stage III-IV)

Watch-&-wait (asx, low tumor burden) - RESORT trial: immediate R (4 cycles) vs. observation; median time to chemo 3 yr (obs arm); no OS diff - ~50% asx at diagnosis suitable for observation - Imaging q 3 mo initially; beyond 6 mo w/ stable disease may defer if <5% change - Defers toxicity; cumulative survival similar

Rituximab monotherapy - Single-agent R (375 mg/m² weekly × 4): CR 40-50%, median TTP 3 yr - Use: elderly/unfit or chemo-declining - Maintenance R (q 2 mo × 2 yr, PRIMA): median PFS 4 mo → 3 yr; limited OS benefit

Chemoimmunotherapy (CIT) - R-CHOP (gold standard): ORR 92%, CR 91%, median PFS 36 mo - R-CVP: alternative (cardiac CI to anthracyclines); ORR 80%, CR 60% (inferior) - Bendamustine-R (BR): ORR 94%, median PFS ≥50 mo (StiL); less hematotox/alopecia/infxn vs. R-CHOP - Maintenance R (post-R-CHOP): PRIMA → median PFS 2.8 → 3.2 yr (HR 0.65); OS benefit less robust

44.1.5 Relapsed/Refractory FL

Rituximab-sensitive (resp to prior R, ≥2 yr from completion) - Re-induction w/ prior regimen: option if long interval - Lenalidomide + R: ORR 90%, median PFS 3 yr; favorable toxicity - Venetoclax-R: ORR 94%; FDG-PET neg CRs - BR: ORR ~80%, median PFS 3-4 yr (durable) - Maintenance R: standard post-induction

Rituximab-refractory (progressive on/within 6 mo of R) - Bendamustine monotherapy (GADOLN): ORR 75%, median PFS 9 mo - BTK inhibitors (ibrutinib, acalabrutinib): ORR 63-93%, CR 21-40%; durable; off-label - Venetoclax + R: ORR 94% - CAR-T (lisocabtagene, axicabtagene): ~90% response post-≥2 lines; durable; toxicity (CRS, neuro) - Anti-CD20 mAbs: obinutuzumab, ublituximab, ofatumumab - Radioimmunoconjugates (ibritumomab tiuxetan): radio-labeled; myelosuppression - Low-intensity chemo (FND): median PFS 2-3 yr - ASCT: historical; less used w/ novel agents

44.2 Marginal Zone Lymphomas

44.2.1 General Features

  • ~7% of NHL; CD5−, typically extranodal; 3 subtypes: MALT, nodal, splenic
  • Distinct from CLL/FL: extranodal origin; RF: infectious agents, autoimmunity, genetic abnormalities

44.2.2 MALT Lymphomas

  • ~70% of MZL; 90% gastric; rest ocular, salivary, thyroid, lung
  • Pathology: monocytoid B cells; CD5−, CD10−; may harbor t(11;18) (API2-MALT1), t(14;18), t(3;14)
  • MALT IPI (Table 44-6): stage, LDH, ECOG
    • Low: EFS 70%, PFS 95%, OS 100%
    • Intermediate: EFS 56%, PFS 93%, OS 98%
    • High: EFS 29%, PFS 33%, OS 84%

Gastric MALT (stage I) - H. pylori−positive: antibiotic eradication → ~75% response; median time to resp 2-4 mo; LT remission ~90% - H. pylori−negative or t(11;18)+: antibiotic resistance likely; rituximab or CIT - Upper endoscopy: confirms erythema, erosions, ulcers, masses; biopsy mandatory - Advanced disease (III-IV): R monotherapy, CIT, or observation - Transformation risk: low (~10% to DLBCL); median OS post-transform ~6 mo - Surveillance: Upper GI endoscopy; biopsy if relapse suspected

Nongastric MALT: excellent prognosis limited-stage; 1/3 stage 4 at dx; OS >10 yr if early

44.2.3 Nodal MZL

  • ~5% of indolent lymphomas; marginal zone B-cell origin
  • Prognosis: stage I-II favorable; stage III-IV less favorable (but better than other B-cell NHL)
  • Hepatitis C: ~10% cases; DAA eradication may improve prognosis
  • Mgmt: similar to FL (R monotherapy, BR, or CIT first-line); observation option if asx

44.2.4 Splenic MZL

  • 5-10% of MZL; CD5−, CD10−; w/ or w/o villous lymphocytes
  • Presentation: splenomegaly (80%), cytopenias (anemia, leukopenia), hepatomegaly (rare)
    • Autoimmune cytopenia (AIHA, ITP) reported; lymphadenopathy rare
  • Diagnosis: BM & PB involvement common; splenectomy or BM biopsy (distinctive morphology)
  • vs. other splenic B-cell: unlike CLL/MCL (CD5+); unlike HCL (CD11c+, TRAP+)
  • Prognosis: variable; median OS >10 yr; transform to DLBCL rare (~5%)
  • Mgmt: observation (asx, no cytopenias); R monotherapy, CIT, or splenectomy (symp, cytopenias)
    • Splenectomy effective ~40% cytopenias (esp. ITP); IVIG pre-op for ITP
    • BTK inhibitors (ibrutinib) also active

44.3 Lymphoplasmacytic Lymphoma/Waldenström Macroglobulinemia

  • ~2% of NHL; ~50% w/ Waldenström macroglobulinemia (IgM M-protein)
  • Pathogenesis: MYD88 L265P (~90% LPL, >95% WM) → NF-κB activation; therapeutic target
  • CD profile: CD5−, CD10−, CD19+, CD20+
  • Prognosis: IPI applicable; median OS >10 yr

Management - Asx: observation reasonable - Symp: R monotherapy, CIT (R-CHOP, BR), or BTK inhibitors (ibrutinib, acalabrutinib) - BTK inhibitors (ibrutinib approved): durable resp; preferred 1st-line (NCCN WM) - Bortezomib (proteasome inhibitor): w/ R + dexamethasone; ORR ~90%; comparable to BTK inhibitor - Transformation risk: low (3-5% to DLBCL); MYD88 monitoring less predictive

44.4 Hairy Cell Leukemia

44.4.1 Features

  • ~2% of leukemias; monocytic origin; monocyte infiltration w/ “hairy” cytoplasm
  • Pathology: TRAP+ (tartrate-resistant acid phosphatase); BM fibrosis common
  • CD profile: CD5−, CD10−, CD11c+, CD19+, CD20+, CD25+; CD13+, CD14−; FMC7+
  • BRAF V600E: >95% of cases; pathognomonic; therapeutic target

44.4.2 Management

  • Purine analogs (pentostatin, cladribine): 1st-line
    • Pentostatin: 4 cycles over 6 mo; CR ~90%; sustained remissions
    • Cladribine: comparable efficacy
  • + Rituximab: adds to purine analog CR rates & PFS
  • BRAF inhibitors (vemurafenib): ORR 93% monotherapy; combo w/ R (sustained resp)
    • Alternative to purine analogs (better AE profile in select pts, e.g., immunocompromised)
  • Infection monitoring: high risk post-Tx (fungal, mycobacterial, viral) due to monocytopenia
    • Prophylaxis considered early post-Tx
  • Response: BM biopsy confirms CR; cytopenia resolution marks improvement

44.5 Additional Considerations

  • HBV monitoring: baseline serology (HBsAg, anti-HBc) for all on CD20 therapy
    • HBsAg+ w/ occult hepatitis → prophylactic antivirals before CD20 Tx (reactivation risk)
  • Transformation: biopsy-confirmed before retreatment decision (low-grade vs. DLBCL)
    • Molecular: FISH, TP53, MYC, EZH2 mutations if transformation suspected
Clinical Pearls
  1. Limited-stage FL: Involved-field RT alone curative ~50%; OS >15 yr; combined modality (R-CHOP → RT) no OS benefit vs. RT alone
  2. R-refractory advanced FL: CAR-T offers durable remissions post-≥2 lines; venetoclax + R, BTK inhibitors, anti-CD20 bispecific antibodies increasingly used; early non-chemo intervention reduces cumulative toxicity
  3. Gastric MALT: H. pylori eradication sole intervention sufficient ~75% stage I; LT remission >10 yr; t(11;18) API2-MALT1 predicts antibiotic resistance; R or CIT if recurrence/failure