HemOncRx

Marginal Zone Lymphomas (MZL)

NCCN 2024-2025

MZL are indolent B-cell NHL (but can progress) from post-germinal center MZ B-cells. It consists of extranodal MZL (EMZL) stomach (MALT, H.pylori), EMZL noncutaneous, EMZL cutaneous, nodal MZL (NMZL), splenic MZL (SMZL), histological transformation to DLBCL. Goal of therapy is palliative.

EMZL Stomach (MALT, H.Pylori; most common 50-70%)

  • Evaluation: endoscopic biopsy (stomach; FNA is inadequate), H.pylori, Ig gene rearrangement, PE, PS, CBC, CMP, LDH, HBV/HCV, PET/CT (if ISRT), pregnancy, bone marrow biopsy, ECHO/MUGA (if anthracycline), SPEP.
  • Differential diagnosis (CD5+, cyclin D1): MCL [FISH t(11;14)]
  • Genetics (CD20): MALT1 rearrangement [t(11;18); locally advanced, lack tumor response to antibiotic (<5%)], MYD88 (10%; 90% in WM), CD10-, CD5-, cyclin D1-, BCL2- follicle
  • Histological transformation to LBCL: treat as DLBCL
  • Stage I1-2, II1: antibiotic (if H.pylori+ for eradication), ISRT [if t(11;18) H.pylori±], Rituximab (if ISRT ineligible, H.pylori±)
    • Involvement of submucosa, regional LN, or both t(11;18) and t(1;14) BCL10 have less response to antibiotic therapy.
    • H.pylori eradication therapies (ACG 2024, 1st line):
      • PPI BID + bismuth subsalicylate 300mg QID + metronidazole 500mg TID/QID + tetracycline 500mg QID 14 days
      • If local clarithromycin resistance <15% and no prior macrolide: PPI BID + clarithromycin 500mg BID + amoxicillin 1g BID (or metronidazole 500mg BID if PCN allergy) 14 days
  • Stage II2-E, Stage IV (distant nodal, advanced stage): clinical trial (incurable; first line)
    • Asymptomatic, no indication: active surveillance
    • Indication for therapy: clinical trial, symptoms, GI bleed, threatened end-organ function, bulky, steady/rapid progression
    • First line therapy: BR, R-CHOP, R-CVP, R2 (chemo-free regimen, category 2B), Rituximab alone (if multifocal, low tumor burden; 375 mg/m2/wk x4 doses), palliative ISRT, surgical resection (limited, life-threatening hemorrhage)
    • First-line for elderly or firm: Rituximab alone (375 mg/m2/wk x4 doses), Chlorambucil±R, Cyclophosphamide±R.
      • IELSG-19 (R-Chlorambucil vs Chlorambucil vs Rituximab): higher EFS, PFS; well tolerated
    • First-line extended dosing: Rituximab (375 mg/m2 q8-12wk x2yrs)
  • Refractory/relapse
    • Second-line and subsequent therapy: BR or BG (avoid if prior Bendamustine), BTKi (Acalabrutinib, Zanubrutinib ≥1 antiCD20, Pirtobrutinib ≥cBKi), R-CHOP, R-CVP, R2, Ibrutinib, G-Lenalidomide, Rituximab (if longer remission duration)
      • Acalabrutinib and Zanubrutinib (vs Ibrutinib) has more favorable toxicity with same efficacy
      • ACE-LY-003 (Acalabrutinib 100mg BID): ORR 53%, CR 13%, tumor reduction 90%, time to response 2.9mo, PFS 27.4mo; G3+ ADE neutropenia, anaemia, dyspnoea, fatigue, thrombocytopenia; HTN, AFib/flutter, bleed; ttt DC 7%
      • GADOLIN (BG vs Benda): longer PFS; G3+ ADE cytopenia, infusion-rxn; lower treatment-related death (25% vs 42%)
      • AUGMENTIN (R2 vs R-placebo): improved PFS (HR 0.46), DOR 39.4mo; ADE infection, neutropenia, cutaneous rxn (lena); G3+ neutropenia, leukopenia
      • BRUIN (Pirto, previous cBTKi): ORR 57.8%, CR 20%, DOR 21.6mo; ADE (fatigue, diarrhea, dyspnea; less bleed, AF)
      • MAGNOLIA (Zanubrutinib 160mg BID): ORR 68.2%, 24moDOR 72.9%, 24moPFS 70.9%, 24moOS 85.9%; G3+ neutropenia; less AFib/flutter, HTN
    • Second-line and subsequent for elderly/infirm: BTKi (Acalabrutinib, Zanubrutinib ≥1 antiCD20, Pirtobrutinib ≥cBKi),
      R2, Rituximab (375 mg/m2/wk x4 doses), Chlorambucil±R, Cyclophosphamide±R, Ibrutinib
      • GADOLIN (Benda+Obinu vs Benda): longer PFS; G3+ ADE neutropenia, thrombocytopenia, anemia, infusion-related reactions; lower treatment-related death (25% vs 42%)
    • Second-line extended (CR or PR): Obinutuzumab (after BG if Rituximab refractory; 1g q8wk x12 doses)
    • Second-line consolidation: HD+autoSCT.
    • Third-line and subsequent: 2L (if not used), CAR T-cell (Yescarta)
      • ZUMA-5 (Yescarta): ORR 96%, CR 74%; G3+ cytopenia, infections, CRS 7%, ICANS 19%, serious ADE 50%,death 3%
    • Third-line consolidation: allo-SCT (if stem cell mobilization failures and persistent bone marrow involvement)
  • Histological transformation: treat as DLBCL
  • CR may be achieved as early as 3 months after initial therapy, but can take longer to achieve (up to 18 months) (category 2B).
  • Follow-up/restaging (at 6mo): endoscopy, biopsy (rule out LBCL). Active surveillance (if asymptomatic nonprogressive, slowly responding disease)
  • Fertility preservation: sperm banking, semen cryopreservation, IVF, ovarian tissue or oocyte cryopreservation.
  • Supportive Care Considerations (for all MZL)
    • Infusion reaction (Rituximab, Obinutuzumab): APAP, dexamethasone, diphenhydramine
    • TLS Prophylaxis (high tumor burden): Hydration, allopurinol (low-intermediate risk), Rasburicase 3-6mg (G6PD test; if uric acid >8mg/dL, bulky disease, PO intolerant)
    • Cardiotoxicity (Doxorubicin): monitor LVEF by ECHO/MUGA at baseline, then when needed.
    • Neuropathy (Vincristine): dose reduction/interruption if severe.
    • CRS (CAR T): premeds of APAP, diphenhydramine, dexamethasone
    • Anticoagulation prophylaxis (Lenalidomide)
    • HSV prophylaxis (Bendamustine, prolonged steroids): acyclovir 400mg PO BID.
    • PJP Prophylaxis (Bendamustine, prolonged steroids): TMP-SMX or Dapsone.
    • HBV/HCV reactivation (Rituximab, Obinutuzumab): screening at baseline (sAg, HBc; eAg if high risk factor; viral load if positive and GI consult), treat when needed. Entecavir or Tenofovir ppx if receiving rituximab.
RegimensMedications
BRBendamustine, Rituximab
BGBendamustine, Obinutuzumab (Gazyva)
R-CHOPRituximab, Cyclophosphamide, doxorubicin (Hydroxydaunorubicin), vincristine (Oncovin), Prednisone
R-CVPRituximab, Cyclophosphamide, Vincristine, Prednisone
R2 or LRLenalidomide (Revlimid), Rituximab

EMZL Nongastric (Noncutaneous)

  • Nongastric sites: bowel (small/large), breast, head/neck, lung, dural, ocular adnexa, ovary, parotid, prostate, salivary gland. Infectious organisms were associated with many nongastric sites (reports), but testing is not required for management in the US.
  • Evaluation: consider upper GI endoscopy (if head/neck, lungs), PE, PS, CBC, CMP, LDH, HBV/HCV, PET/CT (if systemic therapy), pregnancy, bone marrow biopsy, ECHO/MUGA (if anthracycline), MRI+contrast (neurological or CT CI), neck CT (if RT for SI-II), autoimmune evaluation (Sjogren’s), SPEP
  • Genetics (CD20): CD10-, CD5-, CD23±, CD43±, cyclin D1-, with BCL2- follicles, MYD88 (10%; 90% in WM)
  • Stage IE, IIE contiguous: ISRT, surgery (lung, breast [lumpectomy], thyroid, colon/small bowel), Rituximab (in specific cases), active surveillance (if excisional biopsy, or RT-induced morbidity).
    • In surgery: consider locoregional ISRT (if positive margins), or active surveillance (if negative margins)
  • Stage IV: ISRT, active surveillance (if excisional biopsy, or RT-induced morbidity, no indication), systemic therapy (1-3L below).
    • Empiric doxycycline may be trialed in noncutaneous EMZL based on anecdotal responses seen in ocular and cutaneous MZL.
  • Systemic Therapy (also used in EMZl, NMZL and SMZL):
    • Indication: clinical trial candidate, symptomatic, GI bleeding, threatened end-organ function, bulky, steady/rapid progression
    • 1L: BR, R-CHOP, R-CVP, R2, Rituximab (375mg/m2/wk x4 doses)
    • 1L old/infirm: Rituximab (375mg/m2/wk x4 doses), Chlorambucil±R, Cyclophosphamide±R
    • 1L extended (optional if CR/PR): Rituximab (375mg/m2 q8-12wk upto 2y)
    • 2L: BR, BG, cBTKi (Acalbrutinib, Zanubritinib [≥1 antiCD20]), noncBTKi (Pirtobrutinib [after cBTKi]), R-CHOP, R-CVP, R2, Ibrutinib, G-lenalidomide, Rituximab (if longer duration of remission)
    • 2L old/infirm: cBTKi (Acalbrutinib, Zanubritinib [≥1 antiCD20]), noncBTKi (Pirtobrutinib [after cBTKi]), R2, Rituximab (375mg/m2/wk x4 doses), Chlorambucil, Cyclophosphamide±R, Ibrutinib
    • 2L extended (optional if CR/PR): Obinutuzumab (1g q8wk x12doses if BG)
    • 2L consolidation (optional if CR/PR): HDT/AutoSCT
    • 3L: 2L if not given, CAR-T (axi-cel)
    • 3L consolidation: AlloSCT (if SC mobilization failure, persistent BM involvement)
  • R/R (local recurrence): ISRT (if not given previously), systemic therapy
  • R/R (systemic recurrence; check indication): 1L (if treatment-naïve), 2L (if prior Rituximab), active surveillance (if no indication)
  • Histological transformation: rebiopsy (FDG-PET guided) and treat as LBCL (suspect if PD, high LDH, single site growing disproportionately, extranodal, new B symptoms)
  • Follow-up: every 3-6mo for 5y then annually or clinically indicated (tests, imaging).
  • Fertility preservation: sperm banking, semen cryopreservation, IVF, ovarian tissue or oocyte cryopreservation.

Nodal MZL (NMZL)

  • Rare (10%), mostly spread from extranodal sites.
  • Distinguish (differential diagnosis) from nodal FL, MCL, LPL, CLL. Ped NMZL should be considered if localized disease in young pts.
  • Evaluation: Ig gene rearrangement, PE, ECOG, CBC, CMP, LDH, HBV/HCV, PET/CT+contrast (if systemic tx, RT in SI-II), BM biopsy (in SI-II ISRT, to explain cytopenia), rule out extranodal primary sites (neck [ocular, parotid, thyroid, salivary], axillary [lung, breast, skin], mediastinal hilar [lung], abdominal [spleen, GI], inguinal, iliac [GI, skin]), pregnancy (if chemo, RT), ECHO/MUGA (if anthracycline), SPEP
  • Genetics (CD20+): CD10-, CD50, CD23±, CD43±, cyclin D-, BCL2- follicle, MYD88 (90% WM, 10% MZL)
  • Stage I, II contiguous: ISRT, ISRT+antiCD20±chemo (1L, high FFS but not OS), antiCD20±chemo (1L, high FFS but not OS; if bulky intraabdominal, SI mesenteric)
    • If NR: 1L (if prior ISRT), 2L (if prior antiCD20±chemo), 3L (if prior 2L), histological transformation
  • Stage II noncontiguous: antiCD20±chemo±ISRT (1L, local palliation), active surveillance (if ISRT toxicity>benefit)
    • If NR: ISRT (if not given previously), 3L, histological transformation
  • Stage III/IV: active surveillance (category 1, if no indication), clinical trial, palliative ISRT, systemic therapy (1L, 2L, 3L)
    • Indication (GELF): clinical trial candidate, symptomatic, threatened end-organ function, bulky, steady/rapid progression
    • If CR/PR (PET PR showed shorter PFS): consolidation/extended therapy  follow-up  systemic therapy (if relapse, progressive, histological transformation; if indicated)
    • If NR/PD: rebiopsy  3L (CAR-T axi-cel) or histological transformation
  • Histological transformation: rebiopsy (FDG-PET guided) and treat as LBCL (suspect if PD, high LDH, single site growing disproportionately, extranodal, new B symptoms)
  • Follow-up: H&P and labs q3-6mo x5y then annually; imaging q6mo x2y then annually
  • Fertility preservation: sperm banking, semen cryopreservation, IVF, ovarian tissue or oocyte cryopreservation.

Splenic MZL (SMZL)

  • SMZL are small lymphoid cells with Ig light chain restriction (CD5-, CD10-, cyclin D1-). Mostly diagnosed at splenectomy because immunophenotype is nonspecific and morphological features on BM may not be diagnosed
  • Differential diagnosis: LPL (if plasmacytoid differentiation with cytoplasmic Ig detectable on paraffin sections)
  • Evaluation: PR, CBC, CMP, LSH, HBV/HCV, CT (PET, C/A/P), SPEP, pregnancy (if chemo/RT), BM biopsy±aspirate, immunofixation of blood (if high Ig or SPEP+), cryoglobulin, direct Coombs test, Ig gene rearrangement
  • Genetics (CD20+): annexin A1, IgM, IgD, CD10-, CD5-, CD23±, CD43±, BRAF- and CD103- (vs HCL), NOTCH2 mutation, KLF2 mutation, MYD88 (90% WM, MZL 10%)
  • Asymptomatic, no progressive cytopenia, no splenomegaly: active surveillance (q3-6mo x5y then annually)
  • Splenomegaly with HCV: consult hepatology + antiHCV regimen (regress lymphoma)
    • AntiHCV (AASLD–IDSA Guideline): Epclusa 1 tab/d x12wk, Mavyret 3 tab/d x8-12wk, Harvoni (gen1,4-6) 1 tab/d x12wks
    • If NR or antiHCV is CI: active surveillance (if asymptomatic), Rituximab or splenectomy (if symptomatic, cytopenia)
    • Splenectomy (category 2B) requires vaccination for pneumococcal, meningococcal, H.influenza, HBV
  • Splenomegaly without HCV: active surveillance (if asymptomatic), Rituximab or splenectomy (if symptomatic, cytopenia)
  • Recurrent: active surveillance (no indication), 1L (if ttt-naïve), 2L (if prior Rituximab), splenectomy (+vaccines), palliative ISRT
    • Indication (GELF): clinical trial candidate, symptomatic, threatened end-organ function, bulky, steady/rapid progression

Medication Summary of Marginal Zone Lymphomas (MZL)

MedicationClass/MOAClinical 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.
Obinutuzumab IV (Gazyva®)Anti-CD20 mAbADE: infusion-reaction (stepwise titration), neutropenia, TLS, infection.Premeds (infusion-rxn): APAP, diphenhydramine, glucocorticoid (dexa/MP).TLS prophylaxis: antihyperuricemics + adequate hydration in high TLS risk. Consider holding antiHTN 12h before to 1h after Obinut (benefit vs risk).Consider holding blood thinners (especially during cycle 1).G3+ neutropenia >1wk: recommend antimicrobial (until G≤2); consider antiviral, antifungal prophylaxis. HBV reactivation (screen).
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 ppx and HSV/shingles ppx (acyclovir (ZOVIRAX) 400 mg/day PO BID).ADE: myelosuppression, rash, secondary malignancy (MDS/leukemia 0.3-0.5% in 5-7y).Dose adjust in renal/hepatic dysfunction. Not recommended if CrCl <40.
Chlorambucil PO (Leukeran)Alkylating agent (nitrogen mustard). DNA crosslinker.ADE: Myelosuppression, secondary malignancies, seizures (rare).Avoid in severe hepatic dysfunction.
Vincristine IVMicrotubule-targeting agents (Vinca Alkaloids). Inhibits microtubule fxn.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 and chance to use in future.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.
Prednisone PO/IVCorticosteroid. Lympholytic, anti-inflammatoryADE: 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).
Ibrutinib PO (Imbruvica)BTK Inhibitor (1st gen, irreversible). Blocks BTK → block BCR pathway → B-cell apoptosisADE: 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®) more selective > ibrutinibBTKi (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, bleed (avoid anticoagulants, hold 7d before/after surgery),, HTN, AF (< ibrutinib; EKG), infections, diarrhea, rash, high uric acid; lymphocytosis (≥50% baseline during 1st few weeks but resolves over weeks-months), secondary malignancy (skin; avoid sun exposure, apply sunscreen). Monitor CBC, infections, bleeds, cardiac symptoms; DDIDDI (CYP3A4 substrate). Consider viral/microbial ppx in prolonged neutropenia. With/without food.
Pirtobrutinib PO (Jaypirca) 200 mg/dayBTKi (3rd gen, reversible). Active even in C481S mutations (ibrutinib resistance).Useful in BTKi–relapsed/refractory disease.ADE: fatigue, MSK pain, cytopenia, diarrhea, bruising, cough, infectionDDI (CYP3A4 substrate). With/without food
Lenalidomide IV (Revlimid)Immunomodulator. antiangiogenic, enhances T-cell/NK function.REMS program (fetal-embryonic toxicity).Anticoagulation prophylaxis (high thrombosis risk)ADE: dizzy/fatigue, tumor flare, TLS (in high tumor burden), lower CD34+ stem cells (if ≥4 cycles), HF, death (in CML, MM), hepatotoxicity, secondary malignancy (AML, MDS), lactose intolerance, hypersensitivity [immediate (anaphylaxis, angioedema), delayed (rash, urticaria, SJS/TEN, myocarditis, pneumonitis)], Monitor CBC (neutro-/thrombocytopenia). Adjust dose in renal impairment.

H.pylori and HCV Medication Summary of Marginal Zone Lymphomas (MZL)

Pantoprazole, Esomeprazole POPPI. Inhibit H+/K+ ATPase gastric cells →
↓gastric acid secretion → improves antibiotic stability & efficacy		ADE: HA, diarrhea, nausea, B12 deficiency (long-term), ↑ fracture risk, low MgMonitoring: electrolytes (if long-term), symptom reliefDDI: ↓absorption of drugs needing acidic pH (atazanavir, erlotinib);
esomeprazole inhibits CYP2C19 (↓clopidogrel activation)Counseling: Take 30-60min before meals; avoid long-term use unless needed
Bismuth subsalicylate PO (Pepto-Bismol)Coats ulcers/erosions; binds toxins; bactericidal against H. pyloriADE: Black tongue/stool, constipation, tinnitus (rare), neurotoxicity (high doses)Monitoring: Salicylate toxicity (especially in renal impairment or with aspirin [])DDI: Avoid with other salicylates (↑ toxicity)Contraindication: ASA allergy, children (Reye’s syndrome risk), pregnancyCounseling: Temporary dark stool is harmless; take with food
Metronidazole PONitroimidazole antibiotic. Disrupts DNA structure → cell death (anaerobes, protozoa, H. pylori)ADE: Metallic taste, nausea, peripheral neuropathy (high dose/long term), disulfiram-like reaction with alcoholMonitoring: CNS effects, avoid >14 days if neuropathyDDI: Alcohol (disulfiram-like reaction), ↑ warfarin effect (↑ INR)Counseling: Avoid alcohol during & x3 days after; take with food to ↓ GI upset
Tetracycline POTetracycline antibiotic. Binds 30S ribosomal subunit → inhibits protein synthesisADE: Photosensitivity, GI upset, tooth discoloration, esophagitisMonitoring: Renal function, GI side effectsDDI: ↓ absorption with calcium, iron, antacids; avoid with retinoids (↑ ICP)Contraindications: Pregnancy, children <8 yearsCounseling: sunscreen, empty stomach +water, avoid lying down immediately
Doxycycline POTetracycline antibiotic. Same as tetracycline (30S ribosome inhibition)Use: Alternative to tetracycline in bismuth quadruple therapyADE: Photosensitivity, esophagitis, tooth discoloration, GI upsetMonitoring: Liver function in long-term useDDI: Same as tetracycline (antacids, iron, dairy ↓ absorption)Counseling: Take with full glass of water, avoid lying down after; sunscreen
Clarithromycin POMacrolide antibiotic. Inhibits 50S ribosomal subunit → inhibits protein synthesisADE: Taste changes (bitter), QT prolongation, GI upset, LFTs elevationMonitoring: QT interval (especially if other QT-prolonging drugs), LFTsDDI: Major CYP3A4 inhibitor (↑ statins, CCBs, carbamazepine, etc.); avoid with lovastatin/simvastatinCounseling: bitter taste; inform if any palpitations or muscle pain (if on statins)
Amoxicillin POBeta-lactam antibiotic (aminopenicillin) Binds PBP → inhibits bacterial cell wall synthesisADE: GI upset, rash, anaphylaxis, diarrheaMonitoring: Allergic reactionsDDI: May ↓ efficacy of OCPs (controversial); ↑ rash with allopurinolCounseling: Take with food to reduce GI upset
Sofosbuvir/Velpatasvir PO (Epclusa®)
1 tabs/day		Sofosbuvir: NS5B polymerase inhibitor → chain termination Velpatasvir: NS5A inhibitor → disrupts viral replication and assemblyUse: Pan-genotypic (genotypes 1–6); preferred option ADE: HA, fatigue, nausea, insomnia, anemia (rare), ALT/AST elevationsMonitoring: HCV RNA, LFTs, renal. HCV RNA at 12wk post-ttt (SVR12 = cure)Screen for HBV reactivation (HBsAg, anti-HBc) before startingDDI: Antacids/PPI (reduce velpatasvir absorption/efficacy; space 4h), amiodarone (severe bradycardia; avoid), statins (↑statin levels, rhabdomyolysis risk), enzyme inducers (rifampin, carbamazepine; ↓efficacy)
Glecaprevir/Pibrentasvir PO (Mavyret®)
3 tabs/day		Glecaprevir: NS3/4A protease inhibitor Pibrentasvir: NS5A inhibitor → inhibits viral replicationUse: Pan-genotypic (1–6); 8wk course for non-cirrhotic patients; safe in renal impairment (including dialysis)ADE: Headache, fatigue, nausea, diarrhea, elevated bilirubin/ALT (transient)Monitoring: Baseline HCV RNA, LFTs, renal function. HCV RNA at 12 weeks post-treatment (SVR12). Screen for HBV reactivationDDI: Strong CYP3A/P-gp inducers (contraindicated), statins (dose limit or avoid), anticonvulsants (carbamazepine, phenytoin; avoid)Counseling: Take with food (↑absorption). Take missed dose if <18h.
Sofosbuvir/Ledipasvir PO (Harvoni®)
1 tabs/day		Sofosbuvir: NS5B polymerase inhibitor Ledipasvir: NS5A inhibitorUse: HCV genotypes 1,4-6 (especially genotype 1).ADE: Fatigue, headache, nausea, diarrhea, insomniaMonitoring: HCV RNA, SVR12. LFTs, HBV reactivation, renal (if +tenofovir)DDI: antacids (space by ≥4h), amiodarone (serious bradycardia risk; avoid), tenofovir (TDF, ↑ nephrotoxicity risk), PPI (limit dose [omeprazole ≤20 mg])