NCCN 2024-2025
Clinical Pearls
- Malignant accumulation of IgM-secreting lymphoplasmacytic cells (B-cell and plasma cells) in the bone marrow and other organs. Goal of therapy is palliative.
- Epidemiology: ~25% are asymptomatic (median time to symptom onset >10 years). Median age at diagnosis is 70 years.
- Genomics:
| Mutation | Prevalence | Outcome | Therapy |
| MYD88L265P somatic mutation | 95% Recommend to test | Activate several pathways (NF-κB, JAK/STAT3, BTK), leading to increase B-cell survival, proliferation, cytokines | BTK inhibitors |
| CXCR4 mutation | 30%, useful to test if BTKi will be used | Poor prognosis: slow time to response, less response depth, shorter PFS with ibrutinib monotherapy; varying resistance levels to Bendamustine and bortezomib | Zanubrutinib > Ibrutinib (ASPEN trial), Ibrutinib±R Investigational: Mavorixafor+Ibrutinib, Ulocuplumab+Ibrutinib |
- Prognostic tool: Both tools use labs only and exclude molecular/genetic data.
- IPSSWM (3 groups): age, β2-microglobulin, hemoglobin, platelet count, IgM level.
- rIPSSWM (5 groups): age, β2-microglobulin, LDH, albumin.
- Clinical indications for therapy initiation: recurrent fevers, night sweats, weight loss, hyperviscosity, symptoms of bulky lymphadenopathy, disease-related peripheral neuropathy, and/or symptomatic splenomegaly, hepatomegaly, or other organomegaly.
- Laboratory indications for therapy initiation: symptomatic cryoglobulinemia, symptomatic cold agglutin anemia, autoimmune hemolytic anemia (AIHA) or thrombocytopenia, disease-related nephropathy, anemia, or thrombocytopenia. Monoclonal IgM level alone doesn’t indicate treatment initiation.
- Plasmapheresis (temporary/immediate IgM reduction) if hyperviscosity, symptomatic cryoglobulinemia, severe hemolysis. However, systemic treatment should be initiated as soon as possible. Hyperviscosity symptoms include headache, blurry vision, epistaxis.
- CD20 expression on WM cells: Rituximab-based therapies (Rituximab monotherapy, BR). Rituximab monotherapy produces a slow response. “IgM flare” occur in 80% with antiCD20 mAb, worsening hyperviscosity and IgM-related complications. Avoid rituximab in IgM >4000 mg/dL. Rituximab lysis the lymphoplasmacytic cells (B-cell and plasma cells) dumping intracellular IgM into the bloodstream.
- First-line therapy:
- Preferred: BR, DR+Bortezomib, Ibrutinib±R, Zanubrutinib.
- Other recommendations: Bendamustine, DR+Carfilzomib, DR+Ixazomib, Rituximab alone, DRC, R-CP.
- Relapse/refractory (limited data):
- Preferred: BR, DR+Bortezomib, Ibrutinib±R, DRC, Zanubrutinib.
- Other recommendations: Acalabrutinib, Bendamustine, DR+Ixazomib, Rituximab alone, DRC, Venetoclax.
- Useful in certain circumstances: Cladribine±R, Everolimus, Fludarabine±R, FCR, Ofatumumab (antiCD20; if rituximab intolerant), R-CHOP.
- Cellular therapy: auto-SCT, allo-SCT.
- Supportive Care Considerations for Oncology Pharmacists
- Infusion-reaction (Rituximab): APAP + diphenhydramine ± steroids + H1/H2 blocker (with Tafasitamab only)
- Febrile Neutropenia ppx (age≥65): G-CSF (filgrastim 5mcg/kg SC daily D6+ until ANC >0.5 x109/L of nadir). Use broad-spectrum antibiotics if febrile.
- Cardiotoxicity (Doxorubicin): monitor LVEF by ECHO/MUGA at baseline, then when needed. Use DA-R-EPOCH (if LVEF >35%),
R-CEOP (if anthracycline is contraindicated).
- Neuropathy (Vincristine): dose reduction/interruption if severe. Gabapentin 300mg/day (adjust dose per response)
- Nephrotoxicity/hemorrhagic cystitis (Cyclophosphamide): aggressive hydratin, mesna (Ifosfamide, cyclophos >1200mg/m2)
- Anticoagulation prophylaxis (Lenalidomide)
- HBV/HCV reactivation (Rituximab): screen at baseline, treat when needed. Entecavir or Tenofovir ppx if receiving rituximab.
- PJP Prophylaxis (Bendamustine, prolonged steroids): TMP-SMX or Dapsone.
- HSV ppx (Bendamustine, prolonged steroids): acyclovir 400mg PO BID; Acyclovir/Valacyclovir in rituximab-regimen.
| Regimens | Medications |
| BR | Bendamustine, Rituximab |
| DR-Bortezomib | Dexamethasone, Rituximab, Bortezomib |
| DRC | Dexamethasone, Rituximab, Cyclophosphamide |
| R-CP | Rituximab, Cyclophosphamide, Prednisone |
| FCR | Fludarabine, Cyclophosphamide, Rituximab |
| R-CHOP | Rituximab, Cyclophosphamide, doxorubicin (Hydroxydaunorubicin), vincristine (Oncovin), Prednisone |
Epidemiology
Approximately 25% of patients have asymptomatic disease and may not require immediate therapy as their median time to symptom is >10 years. Median age at diagnosis is 70 years (benefit vs risk in therapy).
Genomics
CD20 is uniformly expressed on WM cells.
| Gene | Prevalence | Function | Therapy |
| MYD88L265P somatic mutation | 95% | Cell survival | BTK inhibitors |
| CXCR4 mutation | 30% | Poor prognosis (develop symptomatic hyperviscosity; associated with slower time to response, less depth of response, and shorter PFS with ibrutinib monotherapy; varying resistance level to Bendamustine and Bortezomib) | Zanubrutinib > Ibrutinib (ASPEN trial), Ibrutinib±R Investigational: Mavorixafor+Ibrutinib, Ulocuplumab+Ibrutinib |
Wild-type MYD88 (MYD88WT): need therapy earlier in the disease course, higher risk of transforming into an aggressive lymphoma, lower responses to BTK inhibitors, and shorter OS.
Guidelines recommends testing for MYD88L265P, may be useful to test CXCR4 mutation if BTK inhibitors is to be used.
Prognosis
IPSSWM (3 groups; age, β2-microglobulin, hemoglobin, platelet count, IgM level), and rIPSSWM (5 groups; age, β2-microglobulin, LDH, albumin). Both scores use labs only and exclude molecular/genetic data.
Management
Clinical indications for therapy initiation: recurrent fevers, night sweats, weight loss, hyperviscosity, symptoms of bulky lymphadenopathy, disease-related peripheral neuropathy, and/or symptomatic splenomegaly, hepatomegaly, or other organomegaly.
Laboratory indications for therapy initiation: symptomatic cryoglobulinemia, symptomatic cold agglutin anemia, autoimmune hemolytic anemia (AIHA) or thrombocytopenia, disease-related nephropathy, anemia, or thrombocytopenia. Monoclonal IgM level alone doesn’t indicate treatment initiation.
Goal of therapy:
Treatment options
- Plasmapheresis (if high IgM)
- Chemoimmunotherapy ()
- Targeted therapy: BTK inhibitor
- Cellular therapy: auto-SCT, allo-SCT
Initial Treatment (First-Line)
Plasmapheresis (temporary IgM reduction) is indicated if immediate reduction of IgM is required, like in hyperviscosity, symptomatic cryoglobulinemia, severe hemolysis. However, the reduction in IgM is only temporary, and systemic treatment should be initiated as soon as possible.
Rituximab-based regimens (CD20 consistently overexpressed).
AntiCD20 mAb: Rituximab monotherapy produces a slow response. “IgM flare” can occur in 80% with antiCD20 mAb, worsening hyperviscosity and other IgM-related complications. Avoid rituximab in IgM >4000 mg/dL.
| Preferred regimens | BR, DR+Bortezomib, Ibrutinib±R (category 1), Zanubrutinib (category 1). |
| Other recommendations | Bendamustine, DR+Carfilzomib, DR+Ixazomib, Rituximab alone, DRC, R-CP |
Relapse/Refractory
Limited studies/data, and most recommendations are per clinician preference and/or small studies. If the initial response lasted >4 years, reusing the same regimen may be reasonable, though definitions vary. For shorter intervals, use a non-cross-resistant salvage regimen.
| Preferred regimens | BR, DR+Bortezomib, Ibrutinib±R (category 1), Zanubrutinib (category 1), DRC |
| Other recommendations | Acalabrutinib, Bendamustine, DR+Ixazomib, Rituximab alone, DRC, Venetoclax |
| Useful in certain circumstances | Cladribine±R, Everolimus, Fludarabine±R, FCR, Ofatumumab (if rituximab intolerant), R-CHOP |
Cellular therapy: auto-SCT, allo-SCT
Medication Summary for Waldenström Macroglobulinemia
| Medication | Class/MOA | Clinical Pearls |
| Rituximab IV Rituxan Hycela® SC (with hyaluronidase human; enhance absorption) | Anti-CD20 mAb. B-cell lysis via CDC, ADCC, apoptosis. | ADE: Infusion reactions (1st dose 12-77%, less with repeated doses), HBV reactivation (screen), neutropenia, rare PMLPremeds (infusion-rxn): APAP, diphenhydramine ± glucocorticoid (dexa/MP).Start slow infusion then increase rate if tolerated (5-6h initially). If tolerated, can consider SC (with hyaluronidase).For rigors (infusion-rxn): Meperidine (DEMEROL®) 12.5 mg IV over 5 min PRN; may repeat once after 15 min. Max 2 doses.Rituxan Hycela® SC (~5-7 min) only after 1+ dose of rituximab IV tolerated. With premeds, monitor for injection site-reaction. |
| Ofatumumab IV (Arzerra) | AntiCD20 mAb (fully human) | ADE: Infusion reactions, cytopenias, HBV reactivation.Premeds: APAP + antihistamine ± corticosteroid before infusion.HBV screening required prior to use. |
| Cyclophosphamide IV/PO (prodrug to 5-FU) | Alkylating agent (nitrogen mustard). Forms adduct with DNA. | Hemorrhagic cystitis (use Mesna if dose >1200 mg/m2).Delayed CINV, myelosuppression, SIADH, alopecia, secondary malignancy, fertility. Dose adjust in renal/hepatic dysfunction. |
| Bendamustine IV (BENDEKA®) | Alkylating agent (nitrogen mustard). | CINV mod: Palonosetron, dexamethasone.PJP prophylaxis and HSV/shingles prophylaxis (acyclovir (ZOVIRAX) 400 mg/day PO BID).ADE: myelosuppression, rash. Secondary malignancy (MDS/leukemia 0.3-0.5% in 5-7yr). Dose adjust in renal/hepatic dysfunction. |
| Cladribine IV (Leustatin) | Antimetabolite (Purine analog). Inhibits DNA synthesis. | ADE: Myelosuppression, immunosuppression (CD4/CD8 ↓), infection risk.Prophylaxis: PJP and antiviral if prolonged lymphopenia.REMS: Yes (for MS formulation – Mavenclad®)Monitor for delayed cytopenias. |
| Fludarabine IV/PO (Fludara) | Antimetabolite (Purine analog). Inhibits DNA polymerase. | ADE: Profound myelosuppression, immunosuppression (T-cell), neurotoxicity (high dose). Avoid in renal dysfunction.Prophylaxis: PJP ± antiviral (especially in combo regimens). |
| Vincristine IV | Microtubule-targeting agents (Vinca Alkaloids). Inhibits microtubule function. | ADE: constipation (senna, docusate). Limited myelosuppression. DLT neuropathy (peripheral, autonomic constipation, cranial), P-gp substrate. CINV minimal.Max dose 2mg, no intrathecal administration (fatal). Vesication or extravasation (CVC line needed). Eliminated from liver (hepatotoxicity). |
| Doxorubicin IV (Adriamycin®, Hydroxydaunorubicin HCl) | Anthracycline. Blocks topoisomerase function. | Cardiotoxicity: Lifetime dose 550mg/m2 (peds 425), monitor LVEF (echo). Dexrazoxane (chelating agent, immediately before doxo) to minimize cardiotoxicity, given to most peds for long-term safety, chance for future use.IV vesicant (use central line). Red urine, erythematous streaking of veins.ADE: Diarrhea, radiation recall. Liposomal DOX cause HFS (like 5-FU). CINV: Dose-dependent mod-high. Liposomal low. |
| Everolimus PO (Afinitor) | mTOR inhibitor. Inhibits cell growth and angiogenesis | ADE: Stomatitis, hyperglycemia, hyperlipidemia, interstitial lung disease.CYP3A4 substrateTake consistently (with or without food)Monitor: lipids, glucose, pulmonary symptoms. |
| Dexamethasone or Prednisone PO/IV | Corticosteroid. Lympholytic, anti-inflammatory | ADE: high glucose, HTN, insomnia, mood swings/irritability, wt. gain, increase appetite, fluid retention, osteoporosis and adrenal insufficiency.Dexamethasone in <10y (due to avascular necrosis), prednisone in >10y.Take with food (reduce GI upset), in the morning (reduce insomnia). |
| Bortezomib IV/SC (Velcade®) | Proteasome inhibitor (reversible). Cell cycle arrest/apoptosis. | ADE: peripheral neuropathy (IV>SC; similar efficacy), thrombocytopenia, neutropenia, fatigue, GI (NVCD).HSV/shingles prophylaxis (acyclovir 400 mg PO BID). TLS ppx in high tumor burden. Avoid in same day IT chemo (fatal cases).DDI (CYP3A4 substrate); avoid in hepatic impairment |
| Carfilzomib IV (Kyprolis) | Proteasome inhibitor (irreversible) | ADE: Cardiopulmonary (↑ heart failure), hypertension, thrombocytopenia.Premeds (infusion-reaction): Dexamethasone. Short t½, rapid clearance.HSV/VZV prophylaxis (acyclovir (ZOVIRAX) 400 mg/day PO BID) |
| Ixazomib PO (Ninlaro) | Proteasome inhibitor (reversible) | ADE: GI upset, thrombocytopenia, peripheral neuropathy.Take on empty stomach (≥1 hr before or 2 hrs after food).HSV/VZV prophylaxis (acyclovir (ZOVIRAX) 400 mg/day PO BID) |
| Venetoclax PO (Venclexta) | BCL-2 inhibitor; promotes apoptosis in BCL-2–dependent cells | ADE: TLS, neutropenia, thrombocytopenia, anemia, GI upset, infectionsTLS ppx (hydration, allopurinol), step-up dosing (20, 50, 100, 200, 400)DDI (CYP3A4 substrate). Take with food. (to improve absorption) |
| Ibrutinib PO(Imbruvica) | BTKi (1st gen, irreversible). Blocks BTK → block BCR pathway → B-cell apoptosis | ADE: AF, HTN, bleeding (avoid anticoagulants, hold 7d before/after surgery), rash, infection, diarrhea, myelosuppression. Avoid in patients with cardiac history. DDI (CYP3A4 substrate). Take on empty stomach (≥1h before or 2h after).Monitor ECG, BP, CBC. |
| Acalabrutinib PO (Calquence) | BTK inhibitor (2nd gen, irreversible, more selective > ibrutinib; fewer cardiac ADE) | ADE: Headache, fatigue, anemia, thrombocytopenia, diarrhea, bleeding, infection.DDIs: CYP3A4 substrate. Avoid PPIs (↓ absorption); separate H2 blockers/antacids.Administer with or without food, take with water only.Hold before/after surgery as with ibrutinib. Less AF than ibrutinib (but still monitor). |
| Zanubrutinib PO (Brukinsa) | BTKi (2nd gen, irreversible, highly selective): Block BCR signaling → apoptosis. | Preferred in higher CV risk due to lower AFib incidence vs ibrutinib.ADE (well tolerated): neutropenia, thrombocytopenia, bleeding, HTN, AF (< ibrutinib), infections, diarrhea, rash. Monitor CBC, infections, bleeding, cardiac symptoms. DDI (CYP3A4 substrate). Consider viral/microbial ppx in prolonged neutropenia. With/without food. |