B-Cell Lymphomas: Diffuse Large B-Cell Lymphoma

B-Cell Lymphomas: Diffuse Large B-Cell Lymphoma

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced health care team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are provided only to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data become available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶Primary Mediastinal Large B-Cell Lymphoma (PMBL)11

REGIMEN

DOSING

First-Line Therapy

Dose-adjusted EPOCH-R (Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin) + Rituximab2-7,a-g,u,gg

Days 1-4 (Cycle 1): Etoposide 50mg/m2 IV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4 (Cycle 1): Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4 (Cycle 1): Doxorubicin 10mg/m2 IV continuous infusion over 24 hours dailya, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours daily

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Day 1: Rituximab 375mg/m2 IV

Days 1-5: Prednisone 60mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 6 cycles.

RCHOP (Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisone) +/- ISRT (Category 1)5-8,b,d-g,h,i,u,gg

Day 1: Cyclophosphamide 750 mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Day 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles (followed by radiation).

RCHOP (Cyclophosphamide + Doxorubicin + Vincristine + Prednisone) + Rituximab followed by ICE (Ifosfamide + Carboplatin + Etoposide)5-7,9,b-g,j,u,gg

Day 1: Cyclophosphamide 1,000mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (uncapped) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks for 4 cycles, followed by:

Day 2: Ifosfamide 5,000mg/m2 IV continuous infusion over 24 hours, with:

Day 2: Mesna 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 2 week for 3 cycles

RCHOP (Cyclophosphamide + Doxorubicin + Vincristine + Prednisone) + Rituximab followed by ICE (Ifosfamide + Carboplatin + Etoposide) + Rituximab5-7,9,b-g,j,u,gg

Day 1: Cyclophosphamide 1,000mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (uncapped) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks for 4 cycles, followed by:

Day 2: Ifosfamide 5,000mg/m2 IV continuous infusion over 24 hours, with:

Day 2: Mesna 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks for 3 cycles.

Relapsed/Refractory Therapy

Pembrolizumab10-12

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks up to 2 years of therapy.

OR

Day 1: Pembrolizumab 400mg IV over 30 minutes.

Repeat cycle every 6 weeks up to 2 years of therapy.

Nivolumab (Category 2B)13-15

Day 1: Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 3 weeks.

Nivolumab + Brentuximab Vedotin (CD30-positive disease) (Category 2B)13,14,16,k,u

Day 1: Brentuximab Vedotin 1.8mg/kg (maximum dosing weight is 100 kg) IV over 30 minutes, followed by:

Day 8 (Cycle 1): Nivolumab 240mg IV over 30 minutes, followed by:

Day 1 (Cycle 2 and beyond): Nivolumab 240mg IV over 30 minutes.

Repeat cycle every 3 weeks.

▶Diffuse Large B-Cell Lymphoma1

First-Line Therapy

Preferred Regimens

RCHOP (Cyclophosphamide + Doxorubicin + Vincristine + Prednisone) + Rituximab (Category 1)5-8,17,b,d-i,u,gg

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Day 1-5: Prednisone 100mg orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 3 cycles (stage I,II) nonbulky disease (<7.5 cm) followed by radiation or 6 cycles (stage I,II) nonbulky disease (<7.5 cm) or bulky disease (≥7.5 cm) with or without subsequent radiation or 6 cycles (stage III-IV) with interim restaging after 2-4 cycles.

Other Recommended Regimens

Dose-adjusted EPOCH (Etoposide + Prednisone + Vincristine + ­Cyclophosphamide + Doxorubicin) + Rituximab2,3,5-7,18,a-g,u,gg

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4: Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4 (Cycle 1): Doxorubicin 10mg/m2 IV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours dailya

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Days 1-5: Prednisone 60mg/m2 orally twice daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

First-Line Therapy for Patients with Poor Left Ventricular Functionl-n

Other Recommended Regimens (No Preferred Regimens)

Dose-adjusted EPOCH (Etoposide + Prednisone + Vincristine + ­Cyclophosphamide + Doxorubicin) + Rituximab2,3,5-7,18,a-g,o,u,gg

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4: Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4: (Cycle 1) Doxorubicin 10mg/m2 IV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours dailya

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Days 1-5: Prednisone 60mg/m2 orally twice daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

RCDOP (Rituximab + Cyclophosphamide + Liposomal Doxorubicin + Vincristine + Prednisone)5-7,19,20,b-g,i,u,gg

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Liposomal Doxorubicin 30mg/m2 IV over 60 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

RCEOP (Rituximab + Cyclophosphamide + Etoposide + Vincristine + Prednisone)5-7,21,b,d-g,u,gg

Day 1: Cyclophosphamide 750 mg/m2 IV over 30 minutes

Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 50mg/m2 IV over 60 minutes daily, OR Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 100mg/m2 orally once daily.

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

RCEPP (Rituximab + Cyclophosphamide + Etoposide + Prednisone + Procarbazine)5-7,22,b,d-g,gg

Days 1,8: Cyclophosphamide 600mg/m2 IV over 30 minutes

Days 1-3: Etoposide 70mg/m2 IV over 60 minutes daily

Days 1-10: Procarbazine 60mg/m2 orally once daily

Days 1-10: Prednisone 60mg/m2orally once daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

RGCVP (Rituximab + Gemcitabine + Cyclophosphamide + Vincristine + Prednisone)5-7,23,b-g,u,gg

Days 1,8 (Cycle 1): Gemcitabine 750mg/m2 IV over 30 minutes, if tolerated, followed by:

Days 1,8 (Cycle 2):  Gemcitabine 875mg/m2 IV over 30 minutes, if tolerated, followed by:

Days 1,8 (Cycles 3-6): Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 10mg orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

First-Line Therapy For Very Frail Patients and Patients >80 Years Of Age With Comorbiditiesm,n

Other Recommended Regimens

RCDOP (Rituximab + Cyclophosphamide + Liposomal Doxorubicin + Vincristine + Prednisone)5-7,19,20,b,d-i,u,gg

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Liposomal Doxorubicin 30mg/m2 IV over 60 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

RCEPP (Rituximab + Cyclophosphamide + Etoposide + Prednisone + Procarbazine)5-7,22,b,d-g,u,gg

Days 1,8: Cyclophosphamide 600mg/m2 IV over 30 minutes

Days 1-3: Etoposide 70mg/m2 IV over 60 minutes daily

Days 1-10: Procarbazine 60mg/m2 orally daily

Days 1-10: Prednisone 60mg/m2orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

R-mini-CHOP (Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisone)5-7,24,b,d-i,u,gg

Day 1: Cyclophosphamide 400mg/m2 IV over 30 minutes

Day 1: Doxorubicin 25mg/m2 IV push

Day 1: Vincristine 1mg IV over 5-10 minutes

Days 1-5: Prednisone 40mg/m2 orally daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

RGCVP (Rituximab + Gemcitabine + Cyclophosphamide + Vincristine + Prednisone)5-7,23,b-g,u,gg

Days 1,8 (Cycle 1): Gemcitabine 750mg/m2 IV over 30 minutes, if tolerated followed by:

Days 1,8 (Cycle 2):  Gemcitabine 875mg/m2 IV over 30 minutes if tolerated, followed by:

Days 1,8 (Cycles 3-6): Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Cyclophosphamide 750mg/m2 IV over 30 minutes

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 10mg orally daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

First-Line Consolidation (Optional)

Lenalidomide Maintenance (Category 2B)

(for patients 60–80 years of age)25,26

Days 1-21: Lenalidomide 25mg orally daily.

Repeat cycle every 4 weeks for 2 years.

Concurrent Presentation With CNS Disease

Parenchymal Disease

High-Dose Methotrexate on Day 15 of 3-week RCHOP cycle27.c.p,q

Day 15 of each 3-week R-CHOP cycle: Methotrexate 3,000-3,500mg/m2 IV over 4 hours

Day 16: Leucovorin 25 mg IV over 15 minutes OR orally starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until methotrexate serum concentration is <0.05 micromol/L).

Leptomeningeal Disease

IT Methotrexate + Cytarabine (CNS Prophylaxis)28,29

Day 1: Cytarabine 50-100mg intrathecal, with:

Day 1: Methotrexate 12-15mg intrathecal, with:

Day 1: Hydrocortisone 50-100mg (preservative-free) intrathecal.

Frequency and duration are dependent on risk of patient and CNS status.

High-Dose Methotrexate in combination with RCHOP or as consolidation after RCHOP + IT Methotrexate + Cytarabine27,b-g,p,q

Dependent on chemotherapy regimen given and count recovery for 1-8 cycles.

Day 1 on alternate cycles of chemotherapy regimen: Methotrexate 3,000-3,500mg/m2 IV over 4 hours.

Day 2 starting 24 hours from initiation of Methotrexate infusion and continuing every 6 hours (until methotrexate serum concentration is <0.05 micromol/L): Leucovorin 25mg IV over 25 minutes or orally.

Second-Line And Subsequent Therapy (Intention to Proceed To Transplant)l,r,s

Preferred Regimens

DHAP (Dexamathasone + Cisplatin + Cytarabine)30,c,t,u

Days 1-4: Dexamethasone 40mg orally OR IV daily

Day 1: Cisplatin 100mg/mIV continuous infusion over 24 hours

Day 2: Cytarabine 2,000mg/m(age ≤70 years) IV over 3 hours every 12 hours for 2 doses, OR:

Day 2: Cytarabine 1,000mg/m(age >70 years) IV over 3 hours every 12 hours for 2 doses.

Repeat cycle every 3 or 4 weeks for 6-10 cycles.

DHAP (Dexamathasone + Cisplatin + Cytarabine) + Rituximab5-7,30,31,c-g,t,u

Day 1: Rituximab 375mg/mIV

Days 1-4: Dexamethasone 40mg orally OR IV daily

Day 1: Cisplatin 100mg/mIV continuous infusion over 24 hours

Day 2: Cytarabine 2,000mg/m(age ≤ 70 years) IV over 3 hours every 12 hours for 2 doses, OR:

Day 2: Cytarabine 1,000mg/m(age >70 years) IV over 3 hours every 12 hours for 2 doses.

Repeat cycle every 3 or 4 weeks for 6-10 cycles.

DHAX (Dexamethasone + Cytarabine + Oxaliplatin)32,33,c,t,u

Days 1-4: Dexamethasone 40mg IV OR orally

Day 2: Cytarabine 2,000mg/m2 (age ≤70 years) IV over 3 hours every 12 hours for 2 doses, OR:

Day 2: Cytarabine 1,000mg/m2 (age >70 years) IV over 3 hours every 12 hours for 2 doses

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours.

Repeat cycle every 3 weeks for 2-6 cycles.

DHAX (Dexamethasone + Cytarabine + Oxaliplatin) + Rituximab33,34,c-g,t,u

Days 1-4: Dexamethasone 40mg IV OR orally

Day 2: Cytarabine 2,000mg/m2 (age ≤70 years) IV over 3 hours every 12 hours for 2 doses, OR:

Day 2: Cytarabine 1,000mg/m2 (age >70 years) IV over 3 hours every 12 hours for 2 doses

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours

Day 1: Rituxumab 375mg/m2 IV.

Repeat cycle every 3 weeks for 2-6 cycles.

Gemcitabine + Dexamethasone + Carboplatin35,h,i,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Repeat cycle every 3 weeks for 4 cycles.

Gemcitabine + Dexamethasone + Carboplatin + Rituximab5-7,35,d-I,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles.

GDP (Gemcitabine + Dexamethasone + Cisplatin)36,h,i,t,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks for 6 cycles.

GDP (Gemcitabine + Dexamethasone + Cisplatin) + Rituximab5-7,36,37,d-i,t,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

ICE (Ifosfamide + Carboplatin + Etoposide)38,c,j,u

Day 2: Ifosfamide 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Mesna 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Carboplatin AUC 5 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes daily.

Repeat cycle every 2 weeks for 3 cycles.

ICE (Ifosfamide + Carboplatin + Etoposide) + Rituximab5-7,39,c-g,j,u

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes

Day 2: Ifosfamide 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Mesna 5,000mg/m2 IV continuous infusion over 24 hours

Day 2: Carboplatin AUC 5 IV over 30 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks for 3 cycles.

Other Recommended Regimens

ESHAP (Etoposide + Methylprednisolone + Cytarabine + Cisplatin)40,c,t,u

Days 1-4: Etoposide 40mg/m2 IV over 60 minutes daily

Days 1-5: Methylprednisolone 50 mg IV over 15 minutes daily

Day 5: Cytarabine 2,000mg/m2 IV over 3 hours

Days 1-4: Cisplatin 25mg/m2 IV continuous infusion over 24 hours daily

Repeat cycle every 3 or 4 weeks for 6-8 cycles.

ESHAP (Etoposide + Methylprednisolone + Cytarabine + Cisplatin) + Rituximab5-7,40,41,c-g,t,u

Days 1-4: Etoposide 40mg/mIV over 60 minutes daily

Days 1-5: Methylprednisolone 500mg IV over 15 minutes daily

Day 5: Cytarabine 2,000mg/mIV over 3 hours

Days 1-4: Cisplatin 25mg/mIV continuous infusion over 24 hours daily

Day 1: Rituximab 375mg/mIV.

Repeat cycle every 3 or 4 weeks for 6-8 cycles.

GemOX (Gemcitabine + Oxaliplatin)42-44,u

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks (preferred) for 6 cycles or every 3 weeks for 6 cycles.

GemOX (Gemcitabine + Oxaliplatin) + Rituximab5-7,d-g,u

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks (preferred) for 6 cycles or every 3 weeks for 6 cycles.

MINE (Mesna + Ifosfamide + Mitoxantrone + Etoposide)45,c,j,u

Days 1-3: Mesna 400mg/m2 IV over 15 minutes three times daily (before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose)

Days 1-3: Ifosfamide 2,000mg/m2 over 3 hours daily

Day 1: Mitoxantrone 8mg/m2 IV over 30 minutes.

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks for 3 cycles.

MINE (Mesna + Ifosfamide + + Mitoxantrone + Etoposide) + Rituxumab5-7,45,c-g,j,u

Days 1-3: Mesna 400mg/m2 IV over 15 minutes three times daily (before Ifosfamide, then at 4 and 8 hours from the start of each Ifosfamide dose)

Days 1-3: Ifosfamide 2,000mg/m2 over 3 hours daily

Day 1: Mitoxantrone 8mg/m2 IV over 30 minutes

Days 1-3: Etoposide 100mg/m2 IV over 60 minutes

Day 1 (Cycles 1-3): Rituximab 375mg/mIV, followed by:

Day 7 (Cycle 3): Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 3 cycles.

Second-Line and Subsequent Therapy (non-candidates for transplant)l,r,s

Preferred Regimens

GemOX (Gemcitabine + Oxaliplatin)42-44,u

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours.

Repeat cycle every 2 weeks (preferred) for 6 cycles or every 3 weeks for 6 cycles.

GemOX (Gemcitabine + Oxaliplatin) + Rituximab5-7,42-44,d-g,u

Day 1: Gemcitabine 1,000mg/m2 IV over 30 minutes

Day 1: Oxaliplatin 100mg/m2 IV over 2 hours

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 2 weeks (preferred) for 6 cycles or every 3 weeks for 6 cycles.

Polatuzumab Vedotin-piiq46-49,i,u,v

Day 1: Polatuzumab Vedotin-piiq 1.8mg/kg IV over 90 minutes

Repeat cycle every 3 weeks for 6 cycles.

Polatuzumab Vedotin-piiq + Bendamustine + Rituximab5-7,48-51,d-g,i,u,v,w,x

Days 1-2: Bendamustine 90mg/m2 IV over 10-60 minutes daily

Day 1: Polatuzumab Vedotin-piiq 1.8mg/kg IV over 90 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Polantuzumab Vedotin-piiq + Rituximab5-7,46,48,50,d-g,i,u,v,w,u

Day 1: Polatuzumab Vedotin-piiq 1.8mg/kg IV over 90 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Other Recommended Regimens

CEPP (Cyclophosphamide + Etoposide + Prednisone + Procarbazine)22,b,u

Days 1,8: Cyclophosphamide 600mg/m2 IV over 30 minutes

Days 1-3: Etoposide 70mg/m2 IV over 60 minutes daily

Days 1-10: Procarbazine 60mg/m2 orally daily

Days 1-10: Prednisone 60mg/m2 orally daily. 

Repeat cycle every 4 weeks for 6 cycles.

RCEPP (Rituximab + Cyclophosphamide + Etoposide + Prednisone + Procarbazine)5-7,22,b,d-g,u,gg

Days 1,8: Cyclophosphamide 600mg/m2 IV over 30 minutes

Days 1-3: Etoposide 70mg/m2 IV over 60 minutes daily

Days 1-10: Procarbazine 60mg/m2 orally once odaily

Days 1-10: Prednisone 60mg/m2orally once daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 4 weeks for 6 cycles.

CEOP (Cyclophosphamide + Etoposide + Vincristine + Prednisone)21,b,u

Day 1: Cyclophosphamide 750 mg/m2 IV over 30 minutes

Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 50mg/m2 IV over 60 minutes daily, OR

Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 100mg/m2 orally once daily.

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally daily.

Repeat cycle every 3 weeks for 6 cycles.

RCEOP (Rituximab + Cyclophosphamide + Etoposide + Vincristine + Prednisone)5-7,21,b,d-g,u,gg

Day 1: Cyclophosphamide 750 mg/m2 IV over 30 minutes

Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 50mg/m2 IV over 60 minutes daily, OR

Day 1: Etoposide 50mg/m2 IV over 60 minutes, followed by:

Days 2-3: Etoposide 100mg/m2 orally once daily.

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Days 1-5: Prednisone 100mg orally daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Dose-adjusted EPOCH (Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin3,18,19,a-g,u

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4 (Cycle 1): Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4 (Cycle 1): Doxorubicin 10mg/m2 continuous infusion over 24 hours dailya, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours daily

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Days 1-5: Prednisone 60mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 6 cycles.

Dose-adjusted EPOCH (Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin) + Rituximab2,3,5-7,18,a-g,u,gg

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4: Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4: (Cycle 1) Doxorubicin 10mg/m2 continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours dailya

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Days 1-5: Prednisone 60mg/m2 orally twice daily

Day 1: Rituximab 375 mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Gemcitabine + Dexamethasone + Carboplatin35,h,i,u

Days 1,8: Gemcitabine 1,000mg/mc IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Repeat cycle every 3 weeks for 4 cycles.

Gemcitabine + Dexamethasone + Carboplatin + Rituximab5-7,35,d-i,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Carboplatin AUC 5 IV over 30 minutes.

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles.

GDP (Gemcitabine + Dexamethasone + Cisplatin)36,h,i,u,t

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks for 6 cycles.

GDP (Gemcitabine + Dexamethasone + Cisplatin) + Rituximab5-7,36,37,d-i,u,t

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1-4: Dexamethasone 40mg orally OR IV

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Gemcitabine + Vinorelbine (Category 3)52,h,i,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1,8: Vinorelbine 30mg/m2 IV over 5-10 minutes.

Repeat cycle every 3 weeks for a maximum of 6 cycles.

Gemcitabine + Vinorelbine + Rituximab (Category 3)5-7,52,53,d-i,u

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1,8: Vinorelbine 30mg/m2 IV over 5-10 minutes

Day 1: Rituximab 375mg/mIV.

Repeat cycle every 3 weeks for a maximum of 6 cycles.

Rituximab5-7,54,d-g,u

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every week for 8 weeks.

Tafasitamab-cxix + Lenalidomide26,55,56,i,y,z

Days 1,4,8,15,22 (Cycle 1): Tafasitamab-cxix 12mg/kg IV, followed by:

Days 1,8,15,22 (Cycles 2-3): Tafasitamab-cxix 12mg/kg IV, followed by:

Days 1,15 (Cycle 4 and beyond: Tafasitamab-cxix 12mg/kg IV, with:

Days 1-21 (Cycles 1-12): Lenalidomide 25mg orally daily.

Repeat cycle every 4 weeks for 12 cycles, followed by:

Days 1,15: Tafasitamab-cxix 12mg/kg IV.

Repeat cycle every 4 weeks.

Useful In Certain Circumstances

Brentuximab vedotin (for CD30-positive disease)16,57,k,u

Day 1: Brentuximab vedotin 1.8mg/kg (maximum 180 mg) IV over 30 minutes.

Repeat cycle every 3 weeks.

Bendamustine (Category 2B)49,58,u

Days 1-2: Bendamustine 120mg/m2 IV over 10-60 minutes.

Repeat cycle every 3 weeks for 6 cycles.

Bendamustine + Rituximab (Category 2B)5-7,49,59,60,d-g,u

Days 1-2: Bendamustine 120mg/m2 IV over 10-60 minutes

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Ibrutinib (non-GCB-like DLBCL)61,62,h,aa

Days 1-28: Ibrutinib 560mg orally daily.

Repeat cycle every 4 weeks.

Lenalidomide (non-GCB-like DLBCL)26,63,64,h,u

Days 1-21: Lenalidomide 25mg orally daily.

Repeat cycle every 4 weeks.

Lenalidomide + Rituximab (non-GCB-like DLBCL)5-7,26,65,d-h,u

Days 1-21: Lenalidomide 20mg orally daily

Days 1,8,15,22: Rituximab 375mg/m2 IV.

Administer for one 4-week cycle, followed by:

Days 1-21: Lenalidomide 20mg orally daily.

Repeat cycle every 4 weeks.

Consolidation After Alternate Second-Line Therapy

Allogeneic hematopoietic cell transplant (Nonmyeloablative or Myeloablative) for CR/PR following alternative second-line therapy.h

Third-Line And Subsequent Therapy (only after ≥2 lines of systemic therapy)

Anti-CD19 CAR T-cell therapy (only after ≥2 prior chemoimmunotherapy regimens)h,x

• Axicabtagene ciloleucel

• Lisocabtagene maraleucel

• Tisagenlecleucelbb

Loncastuximab Tesirine66,67,u,z,cc

Day 1: Loncastuximab Tesirine-Ipyl 0.15 mg/kg IV over 30 minutes.

Repeat cycle every 3 weeks for 2 cycles, followed by:

Day 1: Loncastuximab tesirine-Ipyl 0.075 mg/kg IV over 30 minutes.

Repeat cycle every 3 weeks.

Selinexor (only after ≥2 lines of systemic therapy, including patients with disease progression after transplant or CAR-T therapy)68,69,dd

Days 1,3,8,10,15,17,22,24: Selinexor 60mg orally.

Repeat cycle for 4 weeks.

▶High-Grade B-Cell Lymphomas with Translocations of MYC and BCL2 and/or BCL6 (Double-/Triple-Hit Lymphoma)z

Dose-adjusted EPOCH-R (Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin) + Rituximab2-7,a-g,u,gg

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4 (Cycle 1): Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4 (Cycle 1): Doxorubicin 10mg/m2 IV continuous infusion over 24 hours dailya, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours daily

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Day 1: Rituximab 375mg/m2 IV

Days 1-5: Prednisone 60mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 6 cycles.

R-HyperCVAD (Rituximab + Cyclophosphamide + Vincristine + Doxorubicin, + Dexamethasone) alternating with High-dose Methotrexate and Cytarabine5-7,70,71,b-g,p,u

Cycle A

Days 1-3: Cyclophosphamide 300mg/m2 IV over 3 hours every 12 hours for 6 doses

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours starting 1 hour before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide

Days 4,11: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Day 4: Doxorubicin 50mg/m2 IV push

Days 1-4,11-14: Dexamethasone 40mg IV OR orally

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles (A1, A2, A3 and A4), alternating with Cycle B course.

Cycle B

Day 1: Methotrexate 200mg/m2 IV over 2 hours, followed by:

Day 1: Methotrexate 800mg/m2 IV over 22 hours

12 hours after completion of Methotrexate Infusion: Leucovorin 50mg IV over 15 minutes OR orally, followed by:

Every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.5micormol/L): Leucovorin 15mg IV over 15 minutes OR orally

Days 2-3: Cytarabine (age ≤60 years) 3,00mg/m2 IV over 3 hours every 12 hours for 4 doses OR

Days 2-3: Cytarabine (age >60 years) 1,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles (B1, B2, B3, B4), alternating with Cycle A course for a total of 8 cycles (A1, B1, A2, B2, A3, B3, A4, B4).

R-CODOX-M/R-IVAC (Rituximab-Cyclophosphamide + Vincristine + Doxorubicin with Methotrexate/Ifosfamide + Etoposide + Cytarabine)5-7,72-74,b-g,j,u

Cycle A

Days 1-2: Cyclophosphamide 800mg/m2 IV over 30 minutes daily

Days 1,15: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Day 1: Doxorubicin 50mg/m2 IV push

Day 15: Methotrexate 3,000mg/m2 IV over 4 hours.

Day 11: Leucovorin 200mg/m2 IV over 15 minutes starting 24 hours from the initiation of Methotrexate infusion, followed by:

Leucovorin 15mg/m2 IV over 15 minutes OR orally every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)

Day 1: Rituximab 375mg/m2 IV

Days 1,3: Cytarabine 50mg intrathecal.

Day 1: Methotrexate 12mg intrathecal

Repeat cycle every 4 weeks (or when post-nadir ANC is ≥1000 cells/mm2) for 2 cycles (A1, A2) alternating with Cycle B.

Cycle B

Days 1-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily, with:

Days 1-5: Mesna 500mg/m2 IV over 15 minutes three times daily (before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose)

Days 1-5: Etoposide 60mg/m2 IV over 60 minutes daily

Days 1-2: Cytarabine 2,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 1: Rituximab 375mg/m2 IV

Day 5: Methotrexate 12 mg intrathecal.

Repeat cycle every 4 weeks (or when post-nadir ANC is ≥1000 cells/mm2) for 2 cycles (B1, B2) alternating with Cycle A for a total of 4 cycles (A1, B1, A2, B2).

▶High-Grade B-Cell Lymphomas, NOSee

RCHOP (Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisone)5-8,b,d-g

Day 1: Cyclophosphamide 750 mg/m2 IV over 30 minutes

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Vincristine 1.4mg/m2 (maximum 2 mg) IV over 5-10 minutes

Day 1-5: Prednisone 100mg orally once daily

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 6 cycles.

Dose-adjusted EPOCH-R (Etoposide + Prednisone + Vincristine + Cyclophosphamide + Doxorubicin) + Rituximab2-7,a,b,d-g

Days 1-4 (Cycle 1): Etoposide 50mg/mIV continuous infusion over 24 hours daily, followed by:

Days 1-4 (Cycle 2 and beyond): Etoposide IV continuous infusion over 24 hours dailya, with:

Days 1-4 (Cycle 1): Vincristine 0.4mg/m2 IV continuous infusion over 24 hours daily, with:

Days 1-4 (Cycle 1): Doxorubicin 10mg/m2 IV continuous infusion over 24 hours dailya, followed by:

Days 1-4 (Cycle 2 and beyond): Doxorubicin IV continuous infusion over 24 hours daily

Day 5 (Cycle 1): Cyclophosphamide 750mg/m2 IV over 30 minutes, followed by:

Day 5 (Cycle 2 and beyond): Cyclophosphamide IV over 30 minutesa

Day 1: Rituximab 375mg/m2 IV

Days 1-5: Prednisone 60mg/m2 orally twice daily.

Repeat cycle every 3 weeks for 6 cycles.

R-HyperCVAD (Rituximab + Cyclophosphamide + Vincristine + Doxorubicin, + Dexamethasone) alternating with High-dose Methotrexate and Cytarabine5-7,70,71,b-g,p,ff

Cycle A

Days 1-3: Cyclophosphamide 300mg/m2 IV over 3 hours every 12 hours for 6 doses

Days 1-3: Mesna 600mg/m2 IV continuous infusion over 24 hours starting 1 hour before the first dose of Cyclophosphamide and completing 12 hours after the last dose of Cyclophosphamide

Days 4,11: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes

Day 4: Doxorubicin 50mg/m2 IV push

Days 1-4,11-14: Dexamethasone 40mg IV OR orally

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles (A1, A2, A3 and A4), alternating with Cycle B course.

Cycle B

Day 1: Methotrexate 200mg/m2 IV over 2 hours, followed by:

Day 1: Methotrexate 800mg/m2 IV over 22 hours

12 hours after completion of Methotrexate Infusion: Leucovorin 50mg IV over 15 minutes OR orally, followed by:

Every 6 hours for at least 8 doses (until Methotrexate serum concentration is <0.5­micormol/L): Leucovorin 15mg IV over 15 minutes OR orally

Days 2-3: Cytarabine (age ≤60 years) 3,00mg/m2 IV over 3 hours every 12 hours for 4 doses OR

Days 2-3: Cytarabine (age >60 years) 1,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 1: Rituximab 375mg/m2 IV.

Repeat cycle every 3 weeks for 4 cycles (B1, B2, B3, B4), alternating with Cycle A course for a total of 8 cycles (A1, B1, A2, B2, A3, B3, A4, B4).

R-CODOX-M/R-IVAC (Rituximab-Cyclophosphamide + Vincristine + Doxorubicin with Methotrexate/Ifosfamide + Etoposide + Cytarabine)5-7,72-74,b-g,j,ff

Cycle A

Days 1-2: Cyclophosphamide 800mg/m2 IV over 30 minutes daily

Days 1,15: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5-10 minutes.

Day 1: Doxorubicin 50mg/m2 IV push

Day 15: Methotrexate 3,000mg/m2 IV over 4 hours.

Day 11: Leucovorin 200mg/m2 IV over 15 minutes starting 24 hours from the initiation of Methotrexate infusion, followed by:

Leucovorin 15mg/m2 IV over 15 minutes OR orally every 6 hours (until Methotrexate serum concentration is <0.05micromol/L)

Day 1: Rituximab 375mg/m2 IV

Days 1,3: Cytarabine 50mg intrathecal.

Day 1: Methotrexate 12mg intrathecal

Repeat cycle every 4 weeks (or when post-nadir ANC is ≥1000 cells/mm2) for 2 cycles (A1, A2) alternating with Cycle B.

Cycle B

Days 1-5: Ifosfamide 1,500mg/m2 IV over 3 hours daily, with:

Days 1-5: Mesna 500mg/m2 IV over 15 minutes three times daily (before Ifosfamide, then at 4 and 8 hours from start of each Ifosfamide dose)

Days 1-5: Etoposide 60mg/m2 IV over 60 minutes daily

Days 1-2: Cytarabine 2,000mg/m2 IV over 3 hours every 12 hours for 4 doses

Day 1: Rituximab 375mg/m2 IV

Day 5: Methotrexate 12 mg intrathecal.

Repeat cycle every 4 weeks (or when post-nadir ANC is ≥1000 cells/mm2) for 2 cycles (B1, B2) alternating with Cycle A for a total of 4 cycles (A1, B1, A2, B2).

  a Dosing for cycle 2 and beyond based on absolute neutrophil count and platelet nadir measurements during the previous cycle.

  b Oral hydration is strongly encouraged with Cyclophosphamide; poorly hydrated patients may need supplemental IV hydration. Patients should attain combined oral and IV hydration of 2,000-3,000 mL/day on day of chemotherapy.

  c Supportive care includes myeloid growth factor support with filgrastim or pegfilgrastim.

  d Rituximab and hyaluronidase human for subcutaneous injection may be substituted for Rituximab in patients who have received one full dose of a Rituximab product by intravenous route without experiencing severe adverse reactions. Dose: Rituximab and hyaluronidase human 1,400 mg subcutaneous.7

  e Initiate treatment with Rituximab and hyaluronidase human only after a patient has received at least one full dose of a Rituximab product by intravenous infusion.

  f An FDA-approved biosimilar is an appropriate substitute for Rituximab.

  g For Rituximab, premedication for infusion reactions is required. The recommended dosing is: diphenhydramine 12.5-50mg IV OR oral 30-40 minutes pre-Rituximab AND acetaminophen 650mg orally 30-40 minutes pre-Rituximab.

  h CAR, chimeric antigen receptor; CNS, central nervous system; CR, complete response; CSFs, colony-stimulating factors; DLBCL, diffuse large b-cell lymphoma; FDA, U.S. Food and Drug Administration; GCB, Germinal Center B-cell; HGBL, high-grade B-cell lymphoma; ISRT, involved site radiation therapy; IT, intrathecal; NOS, not otherwise specified; PR, partial response.

  i CSFs may be considered for primary prophylaxis based on the febrile neutropenia risk of the chemotherapy regimen.

  j Hydration is required pre-and post-administration of Ifosfamide.

  k For Brentuximab Vedotin: Consider premedication for hypersensitivity. Acetaminophen 650-1000mg orally 30-40 minutes pre-Brentuximab Vedotin AND diphenhydramine 12.5-50mg IV or orally 30-60 minutes pre-Brentuximab Vedotin with or without corticosteroid per institutional protocol 30-40 minutes pre-Brentuximab Vedotin (consider for subsequent infusions if prior reaction).

  l Inclusion of any anthracycline or anthracenedione in patients with impaired cardiac functioning should have more frequent monitoring.

  m There are limited published data regarding use of these regimens; however, they are used at NCCN Member institutions for the first-line treatment of DLBCL for patients with poor left ventricular function, very frail patients, and patients >80 years of age with comorbidities

  n There are limited data for treatment of early-stage disease with these regimens; however, short-course chemotherapy + RT for stage I-II disease is practiced at NCCN Member Institutions.

  o If upward dose adjustment is necessary, Doxorubicin should be maintained at base dose and not increased.

  p Alkaline hydration is required pre- and post-administration of high-dose Methotrexate.

  q Concurrent high-dose Methotrexate with dose adjusted EPOCH can result in unacceptable toxicities.

  r If additional anthracycline is administered after a full course of therapy, careful monitoring is essential. Dexrazoxane may be added as a cardioprotectant.

  s Rituximab should be included as second-line therapy if there is a relapse after a reasonable remission (>6 months); however, Rituximab should often be omitted in patients with primary refractory disease.

  t Hydration with supplemental electrolytes is required pre-and post-administration of Cisplatin.

  u This regimen may be associated with a risk of tumor lysis syndrome with the first cycle. Tumor lysis prophylaxis and/or treatment may be indicated.

  v For Polatuzumab Vedotin-piiq: Premedication for infusion reactions is required. The recommended dosing is: diphenhydramine 12.5-50mg IV OR orally 30-40 minutes pre-Polatzumab Vedotin-piiq AND acetaminophen 650mg orally 30-40 minutes pre-Polatuzumab Vedotin-piiq.

  w Premedication for Polatuzumab Vedotin-piiq may be omitted if already premedicated for Rituximab within the chemotherapy regimen.

  x Bendamustine, Rituximab, and Polatuzumab Vedotin-piiq is indicated for the treatment of adult patients with relapsed or refractory DLBCL or HGBL, with translocations of MYC and BCL2 and/or BCL6.

  y For Tafasitamab-cxix: Premedication for infusion reaction is required. The recommended dosing is: Famotidine 20mg IV or orally (or equivalent H2 blocker) 30 minutes pre-Tafasitamab-cxix AND H1 antagonist (diphenhydramine 25-50mg IV or orally 30 minutes pre-Tafasituamb-cxix AND acetaminophen 650-1,000mg orally 30 mintues pre-Tafasitamab-cxix AND/OR glucocorticoids may be considered 30 minutes pre-talasitamab-cxix. For patients not experiencing infusion-related reactions during the first 3 infusions, premedication is option for subsequent infusions.

  z It is unclear whether Tafasitamab or Loncastuximab Tesirine or if any other CD-19 directed therapy would have a negative impact on the efficacy of subsequent anti-CD19 CAR T-cell therapy.

  aa This agent has multiple drug-drug interactions.

  bb Tisagenlecleucel is not FDA-approved for relapsed/refractory primary mediastinal large B-cell lymphoma.

  cc For Loncastuximab Teserine-lpyl: premedication with dexamethasone for fluid retention is required. Dexamethasone 4mg orally or IV twice daily for 3 days beginning the day before administration. If dexamethasone administration does not begin the day before, dexamethasone should begin at least 2 hours prior to administration.

  dd Selinexor is FDA approved only for DLBCL and transformed DLBCL arising from follicular lymphoma.

  ee While the standard of care has not been established, the following induction regimens have been used at NCCN Member Institutions.

  ff Potentially toxic regimen; performance status and comorbidities should be considered.

  gg There may be an increased risk of CNS events in selected cases (4-6 factors according to prognostic model to assess risk of CNS disease, HIV-associated lymphoma, testicular lymphoma, high-grade B-cell lymphomas (HGBLs) with translocations of MYC and BCL2 and/or BCL6 (Double/Triple Hit Lymphoma), HGBLs not otherwise specified, Primary cutaneous DLBCL, leg type, stage IE DLBCL of the breast, or kidney or adrenal involvement). CNS prophylaxis can be considered (4- 8 doses of intrathecal methotrexate and/or cytarabine, or high-dose systemic methotrexate) during or after the course of treatment.

References

1. Referenced with permission from the NCCN Clinical Practice Guidelines in OncologyTM B-Cell Lymphomas Version 4.2021. Available at: https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf. Accessed September 17, 2021.

2. Purroy N, Bergua J, Gallur L, et al. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma. A phase II study conducted by the Spanish PETHEMA Group. Br J Haematol. 2015;169:188-198.

3. Wilson WH, Grossbard ML, Pittaluga S, et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002;99(8):2685-2693.

4. Dunleavy K, Pittaluga S, Maeda LS, et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013;368:1408-1416.

5. Rituximab (Rituxan) [package insert]. South San Francisco, CA: Biogen and Genentech, Inc.; June 2021.

6. Rituximab and Hyaluronidase Human (Rituxan Hycela) [package insert]. South San Francisco, CA; Genentech, Inc.: June 2021.

7. Assouline S, Buccheri V, Delmer A, et al. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomized controlled non-inferiority trial. Lancet Haematol. 2016;3(3):e128-138.

8. Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242.

9. Moskowitz C, Hamlin PA, Jr., Maragulia J, et al. Sequential dose-dense RCHOP followed by ICE consolidation (MSKCC protocol 01-142) without radiotherapy for patients with primary mediastinal large B-cell lymphoma [abstract]. Blood. 2010;116:Abstract 420.

10. Pembrolizumab (Keytruda) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; August 2021.

11. Zinzani PL, Ribrag V, Moskowitz CH, et al. Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary mediastinal large B-cell lymphoma. Blood. 2017;130:267-270.

12. Lala M, Li TR, de Alwis DP, et al. A six-weekly dosing schedule for pembrolizumab in patients with cancer based on evaluation using modelling and simulation. Eur J Cancer. 2020;131:68-75.

13. Nivolumab (Opdivo)[package insert]. Princeton, NJ: Bristol-Myers Squibb Company. 2014.

14. Zinzani P, Santoro A, Gritti G, et al. Nivolumab combined with brentuximab vedotin for relapsed/refractory primary mediastinal large b-cell lymphoma: efficacy and safety from the phase II Checkmate 436 study. J Clin Oncol. 2019;37:3081-3089.

15. Lesokhin A, Ansell S, Armand P, et al. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol. 2016;34(23):2698-704.

16. Brentuximab vedotin (Adcetris) [package insert]. Bothell, WA: Seagen Inc.; October 2019.

17. Coiffier B, Thieblemont C, Van Den Neste E, et al. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood. 2010;116:2040-2045.

18. Wilson WH, Dunleavy K, Pittaluga S, et al. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008;26:2717-2724.

19. Zaja F, Tomadini V, Zaccaria A, et al. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2006;47:2174-2180.

20. Martino R, Perea G, Caballero MD, et al. Cyclophosphamide, pegylated liposomal doxorubicin Caelyx),vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: Results from a prospective phase II study. Haematologica. 2002;87:822-827.

21. Moccia A, Schaff K, Hoskins P, et al. R-CHOP with etoposide substituted for doxorubicin (R-CEOP):Excellent outcome in diffuse large B cell lymphoma for patients with a contraindication to anthracyclines [abstract]. Blood. 2009;114: Abstract 408.

22. Chao NJ, Rosenberg SA, and Horning SJ. CEPP(B): An effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin’s lymphoma. Blood. 1990;76:1293-1298.

23. Fields PA, Townsend W, Webb A, et al. De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United Kingdom National Cancer Research Institute trial. J Clin Oncol. 2014;32:282-287.

24. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460-468.

25. Thieblemont C, Tilly H, Gomes da Silva M, et al. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017;35:2473-2481.

26. Lenalidomide (Revlimid) [package insert]. Summit, NJ; Celegene Corp.; October 2019.

27. Abramson JS, Hellmann M, Barnes JA, et al. Intravenous methotrexate as central ­nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010;116:4283-4290.

28. Arkenau HT, Chong G, Cunningham D, et al. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. Ann Oncol. 2007;18(3):541-5.

29. Kovacs CS, Sweetenham JW, Earl M, et al. Intrathecal chemotherapy prophylaxis for CNS relapse of DLBCL In the RCHOP era: A single center analysis [abstract]. Blood. 2010;116(21):Abstract 2804.

30. Velasquez WS, Cabanillas F, Salvador P, et al. Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP). Blood. 1988;71 (1):117-122.

31. Moy UJM, Orlopp KS, Flieger D, et al. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin’s lymphoma. Cancer Invest. 2006;24(6):593-500.

32. Machover D, Delmas-Marsalet B, Misra SC, et al. Dexamethasone, high-dose cytarabine, and oxaliplatin (DHAOx) as salvage treatment for patients with initially refractory or relapsed non-Hodgkin’s lymphoma. Ann Oncol. 2001;12(10):1439-43.

33. Rigacci L, Fabbri A, Puccini B, et al. Oxaliplatin-based chemotherapy (dexamethasone, high-dose cytarabine, and oxaliplatin)+/-rituximab is an effective salvage regimen in patients with relapsed or refractory lymphoma. Cancer. 2010;116:4573-4579.

34. Lignon J, Sibon D, Madelaine I, et al. Rituximab, dexamethasone, cytarabine, and oxaliplatin (R-DHAX) is an effective and safe salvage regimen in relapsed/refractory B-cell non-Hodgkin lymphoma. Clin Lymphoma Myeloma Leuk. 2010;10:262-269.

35. Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010;51:1523-1529.

36. Crump M, Kuruvilla J, Couban S, et al. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014;32:3490-3496.

37. Hou Y, Wang H, Ba Y, et al. Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed aggressive B-cell lymphoma. Med Oncol. 2012;29(4):2409-2416.

38. Zelenetz AD, Hamlin P, Kewalramani T, et al. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non_Hodgkin’s lymphoma. Ann Oncol. 2003;14(Suppl_1):i5-i10.

39. Kewalramani T, Zelenetz AD, Nimer SD, et al. Rituximab and ICE (RICE) as ­second-line therapy prior to autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004;103:3684-3688.

40. Velasquez WS, McLaughlin P, Tucker S, et al. ESHAP – an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994;12:1169-1176.

41. Martin A, Conde E, Arnan M, et al. R-ESHAP as salvage therapy for patients with ­relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008;93:1829-1836.

42. Corazzelli G, Capobianco G, Arcamone M, et al. Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-­ineligible patients with refractory/relapsing B-cell lymphoma. Cancer Chemother Pharmacol. 2009;64:907-916.

43. Lopez A, Gutierrez A, Palacios A, et al. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008;80:127-132.

44. Mounier N, El Gnaoui T, Tilly H, et al. Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not ­candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica. 2013;98:1726-1731.

45. Joyce RM, Regan M, Ottaway J, et al. A phase I-II study of rituximab, ifosfamide, ­mitoxantrone and etoposide (R-IME) for B cell non-Hodgkin’s lymphoma prior to and after high-dose chemotherapy and autologous stem cell transplantation (HDC-ASCT). Ann Oncol. 2003;14 Suppl1:i2-7.

46. Morschhauser F, Flinn IW, Advani R, et al. Polatuzumab vedotin or pinatuzumab vedotin plus rituximab in patients with relapsed or refractory non-Hodgkin lymphoma: final results from a phase 2 randomised study (ROMULUS). Lancet Haematol. 2019;6:e254-e265.

47. Palanca-Wessels MC, Czuczman M, Salles G, et al. Safety and activity of the anti-CD79B antibody-drug conjugate polatuzumab vedotin in relapsed or refractory B-cell non-Hodgkin lymphoma and chronic lymphocytic leukaemia: a phase 1 study. Lancet Oncol. 2015;16(6):704-715.

48. Polatuzumab vedotin-piiq (Polivy) [package insert]. South San Francisco, CA: Genetech, Inc.;2020.

49. Bendamustine Hydrochloride (Bendeka) [package insert]. North Wales, PA:Teva Pharamceuticals USA, Inc.;2017.

50. Sehn LH, Herrera AF, Flowers CR, et al. Polatuzumab vedotin in relapsed or refractory diffuse large B-cell lymphommeya. J Clin Oncol. 2020;38:155-165.

51. Sehn LH, Herrera AF, Matasar MJ, et al. Polatuzumab vedotin (POLA) plus bendmustine (B) with rituximab ® or obinutuzumab (G) in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): updated results of a phase (PH) IB/II study [abstract]. Blood. 2018;132(suppl_1):1683.

52. Papageorgiou ES, Tsirigotis P, Dimopoulos M, et al. Combination chemotherapy with gemcitabine and vinorelbine in the treatment of relapsed or refractory diffuse large B-cell lymphoma: a phase-II trial by the Hellenic Cooperative Oncology Group. Eur J Hematol. 2005;75:124-129.

53. Xiros N, Economopoulos T, Valsami S, et al. Rituximab in combination with vinorelbine/gemcitabine chemotherapy in patients with primary refractory or early relapsed T cell rich B cell lymphoma. A pilot study. Leuk Res. 2003;27:1097-1099.

54. Coiffier B, Haioun C, Ketterer N, et al. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998;92(6):1927-1932.

55. Salles G, Duell J, Gonzales Barca E, et al. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020;21:978-988.

56. Tafasitamab-cxix (Monjuvi) [package insert]. Boston, MA: Morphosys US Inc.; June 2021.

57. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates ­objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015;125(9);1394-1402.

58. Weidmann E, Kim SZ, Rost A, et al. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2002;13:1285-1289.

59. Vacirca JL, Acs PI, Tabbara IA, et al. Bendamustine combined with rituximab for ­patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014;93(3):403-409.

60. Ogura M, Ando K, Taniwaki M, et al. Feasibility and pharmacokinetic study of bendamustine hydrochloride in combination with rituximab in relapsed or refractory aggressive B cell non-Hodgkin’s lymphoma. Cancer Sci. 2011;102(9):1687-1692.

61. Ibrutinib (Imbruvica) [package insert]. Horsham, PA: Janssen Biotech, Inc. December 2020.

62. Wilson WH, Young RM, Schmitz R, et al. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015;21:922-926.

63. Witzig TE, Vose JM, Zinzani PL, et al. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Ann Oncol. 2011;22(7):1622-1627.

64. Wiernik PH, Lossos IS, Tuscano JM, et al. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. J Clin Oncol. 2008;26(30):4952-4957.

65. Wang M, Fowler N, Wagner-Bartak N, et al. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular, and transformed lymphoma: a phase II clinical trial. Leukemia. 2013;27:1902-1909.

66. Caimi PF, Ai, Alderuccio JP, et al. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021;22(6):790-800.

67. Loncastuximab tesirine-lpyl (Zynlonta) [package insert]. Murray Hill, NJ: ADC Therapeutics US: April 2021.

68. Selinexor (Xpovio) [package insert]. Newton, MA: Karyopharm Therapeutics Inc.; April 2021.

69. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7:e511-e522.

70. Tsai J, Greer J, Morgan D, et al. Role of aggressive chemotherapeutic regimens in double hit lymphoma- can alternate aggressive induction regimens overcome the poor prognosis of diffuse large B cell lymphoma? Blood. 2013;12:4361.

71. Oki Y, Westin JR, Vega F, et al. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013;163:611-620.

72. LaCasce A, Howard O, Lib S, et al. Modified magrath regimens for adults with Burkitt and Burkitt-like lymphoma: preserved efficacy with decreased toxicity. Leuk Lymphoma. 2004;45:761-767.

73. Sun H, Savage KJ, Karsan A, et al. Outcome of Patients With Non-Hodgkin Lymphomas With Concurrent MYC and BCL2 Rearrangements Treated With CODOX-M/IVAC With Rituximab Followed by Hematopoietic Stem Cell Transplantation. Clin Lymphoma Myeloma Leuk. 2015;15:341-348.

74. Noy A, Lee JY, Cesarman E, et al. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma. Blood. 2015;126:160-166.

(Revised 10/2021; NCCN B-Cell Lymphomas Guidelines. V4.2021) © 2021 Haymarket Media, Inc.

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