Waldenström 巨球蛋白血症

Buzzwords → Dx

Diagnostic Criteria

• Lymphoplasmacytic lymphoma (LPL) in marrow + IgM monoclonal protein (any quantity) = WM.
• MYD88 L265P testing on marrow (positive ~95 %).
• IgM MGUS = IgM monoclonal protein <3 g/dL + BMPC <10 % LPL + no symptoms — progresses to WM ~1–2 %/yr.
• Smoldering WM = bone marrow ≥10 % LPL + IgM monoclonal but no symptoms.

Workup

• CBC + smear + reticulocyte; CMP, LDH, β2M.
• SPE + IFE + sFLC + IgM/IgG/IgA quantitation + serum viscosity.
• Marrow aspirate + biopsy with MYD88 L265P + CXCR4 testing.
• CT C/A/P for adenopathy; consider PET-CT in suspected transformation.
• Cryoglobulin + cold agglutinin titer + direct Coombs.
• Anti-MAG antibody if peripheral neuropathy.
• Renal workup if proteinuria (cast nephropathy, light-chain).
• Slit-lamp for retinal hemorrhages if hyperviscosity suspected.

Treatment indications (any one)

• Hyperviscosity symptoms
• Symptomatic anemia (Hb <10 g/dL) or thrombocytopenia (<100 ×10⁹/L)
• B-symptoms
• Symptomatic adenopathy / splenomegaly / hepatomegaly
• Symptomatic peripheral neuropathy
• Cold agglutinin disease / cryoglobulinemia
• Renal involvement (cast nephropathy, light-chain disease)
• AL amyloidosis
• Bing-Neel syndrome (CNS WM)

Treatment Algorithm

flowchart TD
  A[Confirmed WM] --> B{Asymptomatic vs symptomatic?}
  B -- asymptomatic --> C[Watch and wait<br>q3-6 mo SPE + CBC + symptom review]
  B -- hyperviscosity --> D[Plasmapheresis IMMEDIATELY<br>removes IgM mechanically]
  B -- other indications --> E[Initiate systemic therapy]
  D --> E
  E --> F{Genotype}
  F -- MYD88+ CXCR4-WT --> G[Zanubrutinib OR ibrutinib<br>ASPEN — zanu lower AF + bleeding]
  F -- MYD88+ CXCR4-mutated --> H[Zanubrutinib<br>or BR<br>or BR + ibrutinib]
  F -- MYD88-WT (rare) --> I[BR or DRC<br>BTKi response poor]
  F -- chemo preference --> J[BR or DRC dexamethasone-rituximab-cyclophosphamide]
  G --> K{Response?}
  H --> K
  I --> K
  J --> K
  K -- relapse --> L[Switch class: BTKi <-> chemo<br>or auto-HCT in fit pts<br>or carfilzomib / venetoclax / proteasome]
  L --> M{Bing-Neel CNS WM?}
  M -- yes --> N[Ibrutinib (penetrates CNS)<br>or HD-MTX-based regimen]

Pearls / Pitfalls

• DON'T transfuse RBCs in hyperviscosity before plasmapheresis — adding viscosity-contributing RBCs without removing IgM can worsen symptoms (stroke, blindness). Plasmapheresis first, then RBC if anemic.
• Ibrutinib + warfarin/DOAC → high bleeding risk; consider zanubrutinib (lower bleeding) or alternate anticoagulation.
• CXCR4 WHIM-like mutation decreases ibrutinib response — ASPEN showed zanubrutinib superior in CXCR4-mutated WM.
• Bing-Neel syndrome (CNS WM): suspect with new neurologic symptoms in WM patient → MRI + LP. Ibrutinib penetrates CNS; HD-MTX-based regimen alternative.
• Type I cryoglobulinemia from WM → avoid cold exposure; warm IV fluids; don't use refrigerated blood products.
• IgM peripheral neuropathy with anti-MAG antibodies → typically distal sensory; treat with rituximab + BTKi; nerve damage often partial recovery.
• Cold agglutinin disease (CAD) from WM → avoid cold; rituximab + bendamustine; transfusions warmed, avoid IVIG (can worsen hyperviscosity).
• AL amyloidosis can complicate WM — screen with NT-proBNP/troponin/urine albumin if symptoms.
• Auto-HCT in WM is rarely used; reserved for chemo-sensitive relapsed disease in young pts.
• Avoid live vaccines; PCV20 + influenza + RZV recommended.

Cross-references

• Hyperviscosity — emergency plasmapheresis
• Cytogenetics Atlas — MYD88 L265P, CXCR4
• Drug Regimens — zanubrutinib, ibrutinib, BR, DRC
• AIHA — cold agglutinin disease
• IgM MGUS — precursor

相關題目

• Q-070 — Waldenström — symptomatic hyperviscosity emergency
• Q-071 — Waldenström — CXCR4 mutation impact on BTKi choice
• Q-072 — Waldenström — Bing-Neel syndrome
• Q-178 — Hyperviscosity — IgM threshold and clinical features

Sources