NCCN 2025
- Incidence: ~2-3% per year (FL) and less with MZL (mostly with NMZL, SMZL); associated with poor prognosis
- Minimal or no prior therapy (ISRT, Rituximab):
- HGBL with MYC/BCL2: treat as HGBL (double-hit or triple-hit; majority are GCB-like lymphoma)
- HGBL MYC/BCL2±BCL6, DLBCL/HGBL MYC/BCL2: clinical trial, consolidative ISRT (if localized), induction
(DA-EPOCH-R, RCHOP [if IPI<2], R-mini-CHOP [if old/frail], R-HyperCVAD [toxic], R-CODOX-M/R-IVAC [toxic])
- HGBL with MYC/BCL6: manage as DLBCL, DA-EPOCH-R, still uncertain optimal therapy
- HGBL-NOS (blastoid, intermediate betweel DLBCL and BL, lack MYC/BCL2; poor prognosis with high LDH, high IPI score, BM/CNS involvement): clinical trial, consolidative ISRT (if localized), induction (DA-EPOCH-R, Pola-R-CHP [category 2B], R-CHOP, R-mini-CHOP [if old/frail], R-HyperCVAD [toxic], R-CODOX-M/R-IVAC [toxic])
- HGBL MYC/BCL2±BCL6, DLBCL/HGBL MYC/BCL2: clinical trial, consolidative ISRT (if localized), induction
- DLBCL or HGBL MYC/BCL6: chemoimmunotherapy (anthracycline preferred; 1st line) ± ISRT (if localized, bulky, limited osseous disease)
- SI-II: R-CHOP, Pola-R-CHP (if smIPI>1, category 1)
- SII with extensive mesenteric, SIII-IV: R-CHOP, Pola-R-CHP (if smIPI≥2, category 1), DA-EPOCH-R
- Poor LVEF (all stages): DA-EPOCH-R, R-CDOP, R-CEOP, R-GCVP, R-CEPP (category 2B)
- Very frail/old (>80yo) with comorbidities (all stages): R-CDOP, R-mini-CHOP, R-GCVP, R-CEPP (category 2B)
- If CR (PET-, 5PS 1-3): clinical trial, active surveillance if relapse: repeat biopsy (PET+ may represent post-ttt inflammation), follow multiple line management below
- If PR (PET+, 5PS 4), NR/PD (PET+, 5PS 5): CAR-T cell (axi-cel, liso-cel, tisa) ± bridging therapy (if eligible), systemic therapy
- HGBL with MYC/BCL2: treat as HGBL (double-hit or triple-hit; majority are GCB-like lymphoma)
- Multiple lines (≥2 chemoimmunotherapy like BR, R-CHOP prior HT): check MYC/BCL6; clinical trial, systemic therapy±ISRT, ISRT, best supportive care (pain, dyspnea, anorexia, cachexia, N/V, constipation, diarrhea, malignant bowel obstruction, insomnia, delirium, malignant wounds)
- If CR (PET-, 5PS 1-3): active surveillance, HDT/autoSCT±ISRT (if txp eligible), alloSCT±ISRT (if txp eligible).
- ISRT is considered if not previously given, localized, bulky, limited osseous disease.
- AutoSCT is not recommended after CAR T-cell therapy, but alloSCT could be considered. AlloSCT if SC mobilization failure or persistent BM involvement
- If PR (PET+, 5PS 4): CAR T-cell therapy (axi-cel, liso-cel, tisa-cel; if not previously given, after ≥1 anthracycline-regimen), alloSCT±ISRT
- AutoSCT is not recommended after CAR T-cell therapy, but alloSCT could be considered. AlloSCT if SC mobilization failure or persistent BM involvement, ISRT (if localized residual or residual FDG-avid disease not previously irradiated), active surveillance
- If NR/PD (PET+, 5PS 5): systemic therapy, T-cell engager (CAR-T, BiTE), best supportive care
- If CR (PET-, 5PS 1-3): active surveillance, HDT/autoSCT±ISRT (if txp eligible), alloSCT±ISRT (if txp eligible).
- Systemic therapy
- If transplant eligible: R-CHOP (if not previously given), DHAP±R, GDP, ICE±R
- If transplant ineligible: R-CHOP (if not previously given), PV±Bendamustine±R, Tafasitamab-cxix+Lenalidomide, CEOP±R, GDP±R, GemOx±R, Loncastuximab tesirine-lpyl, Selinexor (transformed FL, ≥2 systemic therapy txp or CAR-T)
- Use bendamustine with caution in CAR T and BiTE (CD3xCD20), delay bendamustine until after CAR-T leukapheresis.
- Unclear if tafasitamab, loncastuximab tesirine, other CD19 therapy have negative impact on efficacy CAR T-cell (CD19).
- T-cell Engager Therapy:
- CAR T-cell therapy (axi-cel, liso-cel, tisa-cel; after ≥1 anthracycline regimen)
- BiTE (Epcoritamab-bysp, Glofitamab-gxbm; after ≥2 systemic therapy including txp or CAR-T)
| Regimens | Medications |
| R-CHOP | Rituximab, Cyclophosphamide, doxorubicin (Hydroxydaunorubicin), vincristine (Oncovin), Prednisone |
| Pola-R-CHP | Polatuzumab vedotin, Rituximab, Cyclophosphamide, doxorubicin (Hydroxydaunorubicin), Prednisone |
| DA-R-EPOCH [HGBL (DHL/THL), aggressive DEL] | Dose-Adjusted Rituximab, Etoposide, Prednisone, vincristine (Oncovin), Cyclophosphamide, doxorubicin (Hydroxydaunorubicin) |
| R-HyperCVAD | Rituximab, Hyperfractionated (smaller doses but more frequent), Cyclophosphamide, Vincristine, doxorubicin (Adriamycin), Dexamethasone Alternating with rituximab, high-dose methotrexate and cytarabine |
| R-CODOX-M/R-IVAC | Rituximab, Cyclophosphamide, vincristine (Oncovin), DOXorubicin, Methotrexate (high-dose) Alternating with rituximab, ifosfamide, etoposide, cytarabine |
| R-CDOP | Rituximab, Cyclophosphamide, liposomal Doxorubicin, vincristine (Oncovin), Prednisone |
| R-CEOP | Rituximab, Cyclophosphamide, Etoposide, vincristine (Oncovin), Prednisone |
| R-GCVP | Rituximab, Gemcitabine, Cyclophosphamide, Vincristine, Prednisone. |
| R-mini-CHOP (elderly and frail) | Rituximab 375 mg/m² D1, Cyclophosphamide 400 mg/m² D1, Doxorubicin 25 mg/m² D1 (Hydroxydaunorubicin), Vincristine 1 mg D1 (Oncovin), Prednisone 40 mg/m² D1–5 |
| R-CEPP (category 2B) | Rituximab, Cyclophosphamide, Etoposide, Procarbazine, Prednisone |
| DHAP | Dexamethasone, cytarabine (High-dose Ara-C), Platinum (carboplatin, cisplatin, oxaliplatin) |
| GDP | Gemcitabine, Dexamethasone, Platinum (carboplatin, cisplatin) |
| ICE | Ifosfamide, Carboplatin, Etoposide |
| GemOx | Gemcitabine, Oxaliplatin |