Non-Hodgkin Lymphoma: Pharmacologic Management

Non-Hodgkin lymphoma (NHL) consists of a diverse group of lymphomas that originate in the lymphoid tissues and spread throughout the body. According to the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, an estimated 80,550 new cases of NHL will be diagnosed in the United States in 2023, accounting for 4.1% of all new cancer cases.¹ 

Approximately 90% of NHL cases in adults are B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. Other, less frequently seen types of B-cell lymphoma include Burkitt lymphoma, mantle cell lymphoma (MCL), and mucosa-associated lymphoid tissue (MALT) lymphoma.^2,3 

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Treatment of Adult B-Cell Lymphomas

The following treatment recommendations — established by the National Comprehensive Cancer Network (NCCN) — offer guidance on induction therapy, maintenance therapy, and treatment for relapsed or refractory disease for the most common types of B-cell lymphoma.³ 

Burkitt Lymphoma

Burkitt lymphoma is a rare form of B-cell lymphoma that is often the most aggressive, often spreading to extranodal sites. It may be associated with Epstein-Barr virus or HIV infections.³ 

Cure is possible for a significant number of patients with Burkitt lymphoma by using dose-intensive multiagent chemotherapy regimens. Between 60% and 90% of children and young adults with Burkitt lymphoma achieve durable remission with proper treatment.⁴ However, the prognosis for older adults tends to be less favorable.⁵ 

Treatment recommendations from the NCCN involve chemotherapy and central nervous system (CNS) prophylaxis with intrathecal chemotherapy.³ Induction therapy recommendations for patients with low-risk Burkitt lymphoma include:

• 3 cycles of CODOX-M (cyclophosphamide, doxorubicin, and vincristine with intrathecal methotrexate and cytarabine, then high-dose systemic methotrexate)
• 3 cycles of DA-EPOCH-R (dose-ascending etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab)
• Hyper-CVAD + rituximab (cyclophosphamide, vincristine, doxorubicin, and dexamethasone)
• CODOX-M/IVAC (cyclophosphamide, doxorubicin, and high-dose methotrexate alternating with ifosfamide, etoposide, and high-dose cytarabine) with or without rituximab

The NCCN treatment guidelines do not recommend CHOP as adequate therapy for Burkitt lymphoma. 

Patients with relapsed or refractory Burkitt lymphoma are recommended to join a clinical trial or be treated with multiagent chemotherapy regimens, such as:

• High-dose cytarabine
• R-IVAC (ifosfamide, etoposide, and cytarabine + rituximab)
• DA-EPOCH-R
• R-GDP (gemcitabine, dexamethasone, and cisplatin + rituximab)
• R-ICE (ifosfamide, carboplatin, and etoposide + rituximab)

Diffuse Large B-Cell Lymphoma

As the most common type of lymphoma seen in adults, DLBCL accounts for approximately 30% of NHL cases.⁶ Other types of NHL managed with the same treatment guidelines as DLBCL include:³

• DLBCL not otherwise specified
• DLBCL coexistent with any kind of low-grade lymphoma 
• Anaplastic lymphoma kinase-positive DLBCL
• Epstein-Barr virus-positive DLBCL in older patients
• Grade 3 follicular lymphoma
• Intravascular large B-cell lymphoma
• DLBCL associated with chronic inflammation
• T-cell/histiocyte-rich large B-cell lymphoma 

First-line treatment recommendations for stage I-II DLBCL include:

• 3 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by radiation therapy
• 6 cycles of R-CHOP with or without radiation therapy
• 4 to 6 cycles of R-CHOP-14 with or without radiation therapy

Patients newly diagnosed with stage III or IV DLBCL are recommended to receive 21-day cycles of R-CHOP per clinical trial results from several studies. The NCCN recommends a preferred regimen of 6 cycles in total. For patients with primary mediastinal large B-cell lymphoma or those with high-grade B-cell lymphomas with MYC or BCL2 translocations, DA-EPOCH-R may be preferred. Very frail or old patients who cannot tolerate intense chemotherapy regimens are recommended to receive R-mini-CHOP. 

Outcomes for patients with relapsed or refractory DLBCL depend on response to the initial therapy. Patients who undergo high-dose therapy with autologous stem cell rescue (HDT/ASCR) tend to have better outcomes than those who were not initially candidates for this treatment regimen. If a patient is still sensitive to chemotherapy but did not initially achieve complete response (CR), they may be a candidate for HDT/ASCR to treat their relapsed or refractory disease. 

Effective regimens recommended by the NCCN for second-line therapy for DLBCL in candidates for HDT/ASCR include:

• R-DHAX (rituximab, dexamethasone, cytarabine, and oxaliplatin)
• R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin)

• R-ICE
• R-GDP

The NCCN currently does not offer recommendations for treating patients who are not candidates for HDT/ASCR. Instead, these patients are advised to enroll in a clinical trial to receive optimal care and monitoring. Standard treatment options also include chemoimmunotherapy such as gemcitabine-based treatments ± rituximab, bendamustine ± rituximab, or polatuzumab vedotin monotherapy or in combination with bendamustine ± rituximab. Non-chemotherapy options include ibrutinib, lenalidomide ± rituximab, or tafasitamab. For patients with CD30-positive DLBCL, brentuximab vedotin is also a treatment option. 

The US Food and Drug Administration (FDA) has recently approved several new monotherapies and treatment regimens for treating relapsed/refractory DLBCL after at least 2 prior lines of therapy. They include:

• Polatuzumab vedotin in combination with bendamustine and rituximab
• Tafasitamab + lenalidomide
• Loncastuximab tesirine
• Selinexor
• Chimeric antigen receptor (CAR) T-cell therapy

Primary Mediastinal Large B-Cell Lymphoma

Primary mediastinal large B-cell lymphoma is similar to DLBCL but is still a distinct subtype of NHL.³ The NCCN recommends treating patients with primary mediastinal large B-cell lymphoma with the following combinations, which have been shown to significantly improve progression-free survival rates in clinical trials:

• 6 cycles of R-CHOP + radiation therapy
• 4 cycles of R-CHOP followed by ICE ± rituximab
• 6 cycles of DA-EPOCH-R 

Treatment recommendations for relapsed or refractory primary mediastinal large B-cell lymphoma follow those listed for DLBCL. Pembrolizumab is another treatment option approved by the FDA for treating relapsed or refractory primary mediastinal large B-cell lymphoma after at least 2 prior lines of therapy. 

Follicular Lymphoma

Follicular lymphoma is the most common type of indolent (slow-growing) NHL, accounting for approximately 22% of new NHL cases.⁶ The recommended first-line treatment for follicular lymphoma is chemoimmunotherapy with CHOP or CVP (cyclophosphamide, vincristine, and prednisone). The NCCN guidelines also recommend combining this regimen with obinutuzumab or rituximab and lenalidomide + rituximab. 

Patients with low-burden follicular lymphoma may be treated with first-line rituximab as a single agent. The combination of lenalidomide + rituximab is the preferred treatment for patients with category 2A follicular lymphoma. 

Following completion of first-line therapy, patients may be observed or treated with additional extended or consolidation therapy:

• Rituximab maintenance (dosing every 8 weeks for up to 2 years)
• Obinutuzumab maintenance
• Consolidation with rituximab following single-agent rituximab as a first-line therapy
• Ibritumomab tiuxetan for category 2B follicular lymphoma

For patients with relapsed or refractory follicular lymphoma, the following treatments are recommended:

• Bendamustine + rituximab (BR regimen) if it was not previously used as a first-line treatment
• Single-agent rituximab
• Lenalidomide ± rituximab
• CAR T-cell therapy
• PI3K inhibitors, including copanlisib, duvelisib, and umbralisib
• Tazemetostat

Mantle Cell Lymphoma

Accounting for approximately 3% of NHL cases, mantle cell lymphoma (MCL) is characterized by unfavorable properties of both indolent and aggressive NHL disease. It can be a difficult cancer to treat as many cases are not diagnosed until they have progressed to an advanced stage.^6,7 

Therefore, aggressive induction therapy is the preferred first-line treatment. This includes treatment with rituximab, dexamethasone, cytarabine, and platinum-based therapy (cisplatin, carboplatin, or oxaliplatin). The NCCN treatment guidelines also recommend:

• Alternating R-CHOP and R-DHAP
• A dose-intensified R-CHOP regimen alternating with high-dose cytarabine
• HyperCVAD (cyclophosphamide, vincristine, doxorubicin, methotrexate, cytarabine, and dexamethasone) + rituximab

Less aggressive induction therapy options include:

• Bendamustine + rituximab
• R-CHOP
• Lenalidomide + rituximab
• VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone)
• Modified Hyper-CVAD + rituximab

Following induction therapy, maintenance therapy with rituximab has been shown to significantly improve overall survival in patients with MCL. It is the preferred treatment for patients who are not candidates for HDT/ASCR.

Currently, the NCCN has yet to define an optimal treatment approach for relapsed or refractory MCL. Patients who experience relapse within 12 months of completing treatment have a poor prognosis. Recommended second-line therapies include:

• Ibrutinib ± rituximab
• Lenalidomide with rituximab
• Acalabrutinib
• Zanubrutinib
• CAR T-cell therapy with brexucabtagene autoleucel

Marginal Zone Lymphoma

Marginal zone lymphoma (MZL) is categorized into 3 types: MALT lymphoma, nodal MZL, and splenic MZL.⁶ The NCCN provides treatment guidelines for first-line and second-line therapies for these conditions.

First-line preferred treatments for MALT lymphoma include chemoimmunotherapy regimens with an anti-CD20 monoclonal antibody. Clinical trials have confirmed that these regimens are effective for treating MZL specifically. They include:

• Bendamustine + rituximab
• R-CHOP
• R-CVP
• Single-agent rituximab (preferred treatment for splenic MZL)

The NCCN does not recommend obinutuzumab-containing chemoimmunotherapy as a first-line treatment for MZL. Other recommended regimens from the NCCN include lenalidomide + rituximab and ibritumomab tiuxetan, an antibody-drug conjugate that delivers a conjugated radioisotope. Both have been shown to improve objective response rates in clinical trials of MZL. 

For patients with relapsed/refractory MZL, treatment guidelines recommend:

• Bendamustine + obinutuzumab 
• Bruton tyrosine kinase (BTK) inhibitors (zanubrutinib, ibrutinib)
• Umbralisib 
• Lenalidomide + rituximab  
• Ibritumomab tiuxetan

Pharmacotherapy Recommendations for Non-Hodgkin Lymphoma

The following tables detail chemotherapy and combination regimens, small molecule inhibitors, and CAR T-cell therapies used to treat NHL. 

Table 1. Management Guidelines for Chemotherapy/Combination Therapy Regimens for Non-Hodgkin Lymphoma

Combination name	Dose	Treatment Duration
BR	Bendamustine 90 mg/m2 on days 1 and 2; rituximab 375 mg/m2 on day 1	4-wk cycles for a total of 6 cycles
CHOP	Cyclophosphamide 750 mg/m2 on day 1; doxorubicin 50 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1 (maximum 2-mg dose); prednisone 100 mg orally on days 1-5	3-6 cycles depending on the cancer type
CVP	Cyclophosphamide 750 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; prednisone 40 mg/m2 orally on days 1-5	21-day cycles for a maximum of 8 cycles
CODOX-M	Cyclophosphamide 800 mg/m2 on day 1; cyclophosphamide 200 mg/m2 on days 2-5; doxorubicin 40 mg/m2 on day 1; vincristine 1.5 mg/m2 on days 1 and 8 (cycle 1 and cycle 3); methotrexate loading dose of 100 mg/m2 (>65 y) or 300 mg/m2 (<65 y) on day 10, followed by 900 mg/m2 or 2700 mg/m2 administered over 23 hours Intrathecal medications: Cytarabine 70 mg on days 1 and 3; methotrexate 12 mg on day 15; leucovorin 15 mg orally on day 16 (24 h after methotrexate)	3 cycles total
CODOX-M/IVAC (May be combined with rituximab)*	Cycles 1 & 3: Follow CODOX-M dosing listed above Cycles 2 & 4: Ifosfamide 1000 mg/m2 (>65 y) or 1500 mg/m2 on days 1-5; etoposide 60 mg/m2 on days 1-5; cytarabine 1 g/m2 (>65 y) or 2 g/m2 (<65 y) every 12 h on days 1 and 2 Intrathecal medications; Methotrexate 12 mg; leucovorin 15 mg orally on day 6, (24 h after methotrexate) *375 mg/m2 of rituximab on day 1	4 cycles total
DA-EPOCH-R	Etoposide 50 mg/m2/d on days 1-4; doxorubicin 10 mg/m2/d on days 1-4; vincristine 0.4 mg/m2/d on days 1-4; cyclophosphamide 750 mg/m2/d on day 5; prednisone 60 mg/m2 orally twice daily on days 1-5; G-CSF 5 µg/kg/d on day 6 to ANC > 5 × 109/L past nadir	21-d cycles for a maximum of 8 cycles
High-dose cytarabine	3 g/m2 every 12 h; combined with other chemotherapy regimens	Total of 4 doses
Hyper-CVAD	Cycle A (days 1, 3, 5, & 7): Cyclophosphamide 300 mg/m2 every 12 h on days 1-3; mesna 600 mg/m2 continuous IV infusion starting 1 h before cyclophosphamide and ending 12 h after; vincristine 2 mg on days 4 and 11; doxorubicin 50 mg/m2 on day 4; dexamethasone 40 mg/d orally or IV for 8 doses on days 1-4 and 11-14 Cycle B (days 2, 4, 6, & 8): Methotrexate 1000 mg/m2 continuous IV infusion over 24 h on day 1; cytarabine 3000 mg/m2 every 12 h for 4 doses on days 2-3; calcium leucovorin 50 mg IV infusion 12 h after methotrexate infusion is completed	4 cycles of A and 4 cycles of B (8 cycles total)
R-CHOP	Cyclophosphamide 750 mg/m2 on day 1; doxorubicin 50 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1 (maximum 2-mg dose); prednisone 100 mg orally on days 1-5; rituximab 375 mg/m2 on day 1
R-CVP	Cyclophosphamide 750 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; prednisone 40 mg/m2 orally on days 1-5; rituximab 375 mg/m2 on day 1	Up to 8 cycles
R-DHAP	Dexamethasone 40 mg on days 1-4; cisplatin 100 mg/m2 on day 1; cytarabine 2 g/m2 on day 2; rituximab 375 mg/m2 on day 1	21- to 28-d cycles for a total of 2 cycles (relapsed/refractory), 6 cycles for patients who are ineligible for transplant; 3 cycles for MCL
R-DHAX	Dexamethasone 40 mg on days 1-4; oxaliplatin 130 mg/m2 on day 1; cytarabine 2000 mg/m2 on d 2; rituximab 375 mg/m2 on day 1	21-d cycles for 2-6 cycles
R-GDP	Rituximab 375 mg/m2 on day 1; gemcitabine 1000 mg/m2 on days 1 and 8; cisplatin 75 mg/m2 on day 1; dexamethasone 40 mg IV or orally on days 1-4	21-d cycles for up to 6 cycles
R-ICE	Carboplatin AUC 5 (cannot exceed 800 mg per dose) on day 1; etoposide 100 mg/m2 on days 1-3; ifosfamide 5 g/m2 on day 2; rituximab 375 mg/m2 on day 1
R-mini-CHOP	Cyclophosphamide 400 mg/m2 on day 1; doxorubicin 25 mg/m2 on day 1; vincristine 1 mg on day 1; prednisolone 40 mg orally on days 1-5; rituximab 375 mg/m2 on day 1	21-d cycles for 6 cycles total
Rituximab + lenalidomide	Cycle 1: Rituximab 375 mg/m2 on days 1, 8, 15, and 22; lenalidomide 20 mg once daily  Cycles 2-5: rituximab on d 1 and lenalidomide once daily Cycles 6-12: lenalidomide once daily	21-d cycles for up to 12 cycles total
VR-CAP	Rituximab 375 mg/m2 on day 1; cyclophosphamide 750 mg/m2; doxorubicin 50 mg/m2; bortezomib 1.3 mg/m2; prednisone 100 mg/m2 orally	21-d cycles for 6 or 8 cycles total

ANC = absolute neutrophil count; AUC = area under the curve; G-CSF = granulocyte colony-stimulating factor; IV = intravenous.

From NCCN Treatment Guidelines and clinical trials.^3,8-15

Table 2. Treatment Guidelines for Monoclonal Antibody Drugs for Non-Hodgkin Lymphoma

Treatment name	Dose	Administration	Treatment Duration
Brentuximab vedotin	1.8 mg/kg	IV infusion over 30 min	Every 3 wk
Ibritumomab tiuxetan	Rituximab 250 mg/m2, ibritumomab tiuxetan 0.4 mCi/kg for patients with a normal platelet count or ibritumomab tiuxetan 0.3 mCi/kg for relapsed/refractory disease with normal platelet count	IV infusion over 10 min	Day 1: Rituximab Days 7, 8, or 9: Rituximab followed by ibritumomab tiuxetan
Loncastuximab tesirine	First 2 cycles: 0.15 mg/kg Subsequent cycles: 0.075 mg/kg	IV infusion over 30 min	Treat on day 1 of 21-d cycle
Obinutuzumab	First dose: 100 mg Second dose: 900 mg  Subsequent doses: 1000 mg	First dose (day 1): IV infusion at 25 mg/h over 4 h Second dose (day 2): IV infusion at 50 mg/h Subsequent doses (days 8 and 16): IV infusion at 100 mg/h	Repeat dose of 1000 mg on day 1 for 6 cycles total
Pembrolizumab	200 mg	IV infusion of 200 mg every 3 wk or 400 mg every 6 wk	Treat up to 2 y or until unacceptable toxicity occurs or disease progresses
Polatuzumab vedotin	1.8 mg/kg	Administer acetaminophen and antihistamine prior to IV infusion	Treat on day 1 of 21-d cycle with chemotherapy for 6 cycles
Tafasitamab-cxix	12 mg/kg	Cycle 1: days 1, 4, 8, 15, and 22 Cycle 2 and 3: days 1, 8, 15, and 22 Cycle 4 and beyond: days 1 and 15	Treat for a maximum of 12 cycles

IV = intravenous.

From NCCN Treatment Guidelines and FDA-approved prescribing information.^3,16-22

Table 3. Management Guidelines for Small Molecule Inhibitors for Non-Hodgkin Lymphoma

Drug	Dose	Administration	Treatment Duration
Acalabrutinib	100 mg twice daily (every 12 h)	Orally with or without food	Take until unacceptable toxicity occurs or disease progresses
Bortezomib	1.3 mg/m2	IV infusion twice weekly for 2 wk as part of VR-CAP	21-d cycles for 6 total cycles
Copanlisib	60 mg	IV infusion over 1 h on days 1, 8, and 15 on an intermittent schedule	28-d cycle
Duvelisib	25 mg twice daily	Orally with or without food	Take until unacceptable toxicity occurs or disease progresses
Ibrutinib	560 mg once daily	Orally with water	Take until unacceptable toxicity occurs or disease progresses
Pirtobrutinib	200 mg once daily	Orally with or without food	Take until unacceptable toxicity occurs or disease progresses
Selinexor	60 mg	Orally with water	Take on days 1 and 3 each wk until unacceptable toxicity occurs or disease progresses
Tazemetostat	800 mg twice daily	Orally with or without food	Take until unacceptable toxicity occurs or disease progresses
Umbralisib	800 mg once daily	Orally with food	Take until unacceptable toxicity occurs or disease progresses
Zanubrutinib	160 mg twice daily or 320 mg twice daily	Orally with or without food	Take until unacceptable toxicity occurs or disease progresses

From NCCN Treatment Guidelines and FDA-approved prescribing information^{3, 23-32}

Table 4. Management Guidelines for CAR T-Cell Therapy for Non-Hodgkin Lymphoma

Drug	Dose	Administration	Treatment Duration
Axicabtagene ciloleucel	Autologous CAR-positive T-cell treatment, target dose is 2 × 106 T cells/kg body weight	Administer acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV 1 h before infusion IV infusion over 30 min	One-time treatment following 3 d of lymphodepleting therapy
Brexucabtagene autoleucel	Autologous CAR-positive T-cell treatment, target dose is 2 × 106 T cells/kg body weight	Administer acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV 30-60 min before infusion	One-time treatment following 3 d of lymphodepleting therapy
Lisocabtagene maraleucel	Autologous CAR-positive T-cell treatment, target dose is 50 to 110 × 106 T cells	Administer acetaminophen 650 mg orally and diphenhydramine 12.5 mg IV 30-60 min before infusion	One-time treatment following 3 d of lymphodepleting therapy
Tisagenlecleucel	Autologous CAR-positive T-cell treatment, target dose is 0.6 to 6.0 × 106 T cells	Administer acetaminophen and diphenhydramine 30-60 min before infusion	One-time treatment following 4 d of lymphodepleting therapy

CAR=chimeric antigen receptor.

From NCCN Treatment Guidelines and FDA-approved prescribing information^{3, 33-36}

Side Effects, Adverse Events, and Drug-Drug Interactions Associated With Treatment for Non-Hodgkin Lymphoma

Patients should be closely monitored throughout treatment for adverse events and toxicities. The following tables detail the most common adverse events reported in clinical trials for the recommended pharmacotherapies, drug-drug interactions to be aware of, and special population considerations for patients undergoing treatment for non-Hodgkin lymphoma. 

Table 5. Side Effect Profiles of Chemotherapy Drugs for Non-Hodgkin Lymphoma

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Bendamustine	Fatigue, nausea, vomiting, pyrexia, diarrhea Warnings: Infections, PML, myelosuppression, infusion reaction, skin reactions, TLS, extravasation injury, hepatotoxicity, other malignancies	CYP1A2 inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; do not use in patients with moderate to severe hepatic impairment and those with creatinine clearance <40 mL/min, use caution in those with lesser degrees of renal impairment
Cisplatin	Nausea, vomiting, peripheral neuropathy, myelosuppression, pyrexia, increased risk of infection Warnings: Infusion reaction or anaphylaxis, ocular toxicity, ototoxicity, secondary leukemia, nephrotoxicity	Ototoxic and nephrotoxic drugs	Do not use in pregnant or breastfeeding individuals; use with caution in patients with renal impairment
Cyclophosphamide	Pyrexia, alopecia, nausea, vomiting, diarrhea, neutropenia, febrile neutropenia Warnings: Immunosuppression and myelosuppression, serious infections, pulmonary toxicity, cardiotoxicity, renal and urinary tract toxicity, veno-occlusive liver disease	Protease inhibitors, pentostatin, azathioprine, cytarabine, zidovudine, natalizumab, ACE inhibitors, trastuzumab, G-CSF/GM-CSF, busulfan, amiodarone, indomethacin, thiazide diuretics, anthracyclines	Do not use in pregnant or breastfeeding individuals; use with caution in patients with hepatic and renal impairment
Cytarabine	Nausea, vomiting, constipation, headache, confusion, fatigue, pyrexia, weakness, abnormal gait,  back pain Warnings: Neurotoxicity, chemical arachnoiditis, convulsions	Use caution when administering other cytotoxic agents intrathecally	Do not use in pregnant or breastfeeding individuals
Doxorubicin	Pyrexia, fatigue and weakness, nausea, vomiting, anorexia, constipation, diarrhea, stomatitis (oral mucositis), rash, decreased blood cell count, hand-foot syndrome (palmer-planter erythrodysesthesia) Warnings: Thrombocytopenia or neutropenia, cardiomyopathy	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in patients with hepatic impairment
Etoposide	Neutropenia, nausea, abdominal pain, constipation, vomiting, dysphagia, pyrexia Warnings: Myelosuppression, anaphylaxis, secondary leukemias, optic neuritis	Warfarin	Do not use in pregnant or breastfeeding individuals
Gemcitabine	Nausea, vomiting, cytopenias, proteinuria, dyspnea, rash, elevated liver enzymes Warnings: Hepatic, pulmonary, radiation, and renal toxicities; infusion reaction	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in patients with renal or hepatic impairment
Ifosfamide	Alopecia, nausea, vomiting, cytopenias, hematuria, infection Warnings: Myelosuppression, serious infections, urotoxicity, neurotoxicity, pulmonary toxicity, cardiotoxicity, secondary malignancies, veno-occlusive liver disease, CNS toxicity	CYP3A4 inhibitors and inducers	Do not use in pregnant or breastfeeding individuals; adjust dosing and monitor with geriatric patients; use with caution in patients with renal or hepatic impairment
Lenalidomide	Fatigue, nausea, peripheral edema, diarrhea, cytopenias, pyrexia, cough, rash, constipation Warnings: Myelosuppression, serious infections, infusion reaction, tumor flare reaction, TLS, hepatotoxicity, secondary malignancies, venous thromboembolism	Estrogen therapies, erythropoietin-stimulating agents, digoxin	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients and those with renal impairment
Methotrexate	Ulcerative stomatitis, nausea, abdominal distress, infection, fatigue, pyrexia, chills, leukopenia, dizziness Warnings: Myelosuppression, hypersensitivity; gastrointestinal, renal, neurological, pulmonary and hepatic toxicity; skin reactions; serious infections; TLS; secondary malignancies; infertility	Oral antibiotics (neomycin, penicillin, sulfonamide), antifolate drugs, proton pump inhibitors, protein-bound drugs, probenecid, sulfa drugs, anticoagulants, nephrotoxic products, weak acids, hepatotoxic drugs, aspirin, NSAIDs, nitrous oxide, folic acid	Do not use in pregnant or breastfeeding individuals; monitor patients with renal or hepatic impairment
Oxaliplatin	Cytopenias, nausea, diarrhea, emesis, stomatitis, fatigue, elevated liver enzymes Warnings: Peripheral sensory neuropathy, hypersensitivity, pulmonary and hepatic toxicity, severe myelosuppression, PRES, hemorrhage, rhabdomyolysis	Nephrotoxic drugs, anticoagulants, drugs that prolong QT interval	Do not use in pregnant or breastfeeding individuals; reduce dosing in patients with renal impairment
Vincristine	Nausea, constipation, pyrexia, fatigue, diarrhea, anemia, insomnia, decreased appetite, febrile neutropenia, peripheral neuropathy Warnings: Myelosuppression, hepatic toxicity, extravasation tissue injury, neurotoxicity, TLS, severe constipation and bowel obstruction	Strong CYP3A inhibitors or inducers, P-gp inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; use with caution in patients with hepatic impairment

ACE = angiotensin-converting enzyme; CNS = central nervous system; G-CSF = granulocyte colony-stimulating factor; GM – CSF = granulocyte-macrophage colony-stimulating factor; NSAID = non-steroidal anti-inflammatory drug; P-gp = P-glycoprotein; PRES = posterior reversible encephalopathy syndrome; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^38-48

Table 6. Side Effect Profiles of Monoclonal Antibody Drugs for Non-Hodgkin Lymphoma

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Brentuximab vedotin	Infections, cytopenias, fatigue, nausea, diarrhea, vomiting, rash, cough,  Warnings: Peripheral sensory neuropathy, hematologic toxicities, infusion reaction, TLS, renal impairment, hepatotoxicity, serious infections, pulmonary toxicity, hyperglycemia, gastrointestinal complications	Strong CYP3A4 inducers or inhibitors, P-gp inhibitors, contraindicated for use with bleomycin due to pulmonary toxicity	Not recommended in people with moderate to severe hepatic impairment or severe renal impairment
Ibritumomab tiuxetan	Nausea, abdominal pain, diarrhea, pyrexia, asthenia, nasopharyngitis, cough Warnings: Severe cytopenias; infusion reaction; skin reaction; increased risk of leukemia, MDS, and other cancers	Additional testing may be needed in patients taking medications that interfere with coagulation or platelet function	Do not use in pregnant or breastfeeding individuals
Obinutuzumab	Fatigue, neutropenia, upper respiratory tract infection, infusion reaction, cough, musculoskeletal pain Warnings: PML, HBV reactivation, infusion reaction, hypersensitivity, infections, TLS, cytopenias, disseminated intravascular coagulation	None indicated	Do not use in pregnant or breastfeeding individuals
Pembrolizumab	Pyrexia, fatigue, rash, dyspnea, cough, decreased appetite Warnings: Immune-related reactions, infusion-related reaction	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Rituximab	Pyrexia, chills, infusion reactions, lymphopenia, infection, asthenia Warnings: HBV reactivation, infections, constipation leading to bowel obstruction and perforation, TLS, PML, infusion reaction	None indicated	Do not use in pregnant or breastfeeding individuals

HBV = hepatitis B virus; P-gp = P-glycoprotein; MDS = myelodysplastic syndrome; PML = progressive multifocal leukoencephalopathy; TLS  =  tumor lysis syndrome.

From FDA-approved prescribing information.^16-22

Table 7. Side Effect Profiles for Small Molecule Inhibitors for Non-Hodgkin Lymphoma

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Acalabrutinib	Cytopenias, upper respiratory tract infection, musculoskeletal pain, diarrhea, headache Warnings: Serious infections, cytopenias, hemorrhage, atrial fibrillation, second primary malignancies	Moderate or strong CYP3A inhibitors or inducers, agents that reduce gastric acid	Do not use in pregnant or breastfeeding individuals; avoid treatment in patients with severe hepatic impairment
Bortezomib	Cytopenias, nausea, vomiting, diarrhea, constipation, decreased appetite, neuralgia, peripheral neuropathy, fatigue, pyrexia, hyperglycemia Warnings: Cardiac, pulmonary, and gastrointestinal toxicity, thrombotic microangiopathy, hypotension, peripheral neuropathy, PRES, cytopenias, TLS	Strong CYP3A4 inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; lower the starting dose in patients with moderate to severe hepatic impairment
Copanlisib	Hyperglycemia, cytopenias, fatigue, asthenia, nausea, vomiting, diarrhea, stomatitis, hypertension, skin rash, infections Warnings: Hyperglycemia, infections, skin reactions, neutropenia, hypertension, noninfectious pneumonia	Strong CYP3A4 inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; reduce dose to 45 mg or 30 mg in patients with moderate or severe hepatic impairment, respectively
Duvelisib	Infection, pneumonia, pneumonitis, diarrhea or colitis, rash Warnings: Severe diarrhea or colitis, infections, pneumonitis, skin reactions, neutropenia, hepatotoxicity	Strong CYP3A4 inhibitors or inducers, CYP3A4 substrates	Do not use in pregnant or breastfeeding individuals
Ibrutinib	Cytopenias, fatigue, peripheral edema, upper respiratory tract infections, musculoskeletal pain, nausea, vomiting, constipation, decreased appetite, dyspnea, bruising, rash Warnings: Infection, hemorrhage, hypertension, cardiotoxicity, cytopenias, TLS, second primary malignancies	Moderate or strong CYP3A inducers or inhibitors	Do not use in pregnant or breastfeeding individuals; avoid treating patients with severe hepatic impairment; adjust the dose in patients with mild to moderate hepatic impairment
Pirtobrutinib	Cytopenias, bruising, diarrhea, fatigue, musculoskeletal pain Warnings: Hemorrhage, cytopenias, infections, atrial fibrillation, second primary malignancy	Moderate or strong CYP3A inducers or inhibitors, may interfere with sensitive CYP2C8, CYP3A4, CYP2C19, P-gp, or BCRP substrates	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients; reduce dose in patients with severe renal impairment
Selinexor	Pyrexia, weight loss, decreased appetite, nausea, vomiting, constipation, diarrhea, fatigue Warnings: Neutropenia, thrombocytopenia, hyponatremia, infections, gastrointestinal and neurological toxicity, cataracts	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Tazemetostat	Abdominal pain, nausea, fatigue, upper respiratory tract infection, musculoskeletal pain Warnings: Secondary malignancies	Moderate or strong CYP3A inhibitors or inducers, CYP3A substrates	Do not use in pregnant or breastfeeding individuals
Umbralisib	Fatigue, nausea, abdominal pain, vomiting, decreased appetite, diarrhea or colitis, elevated liver enzymes, cytopenias, rash Warnings: Neutropenia, infections, skin reactions, allergic reaction to FD&C Yellow No. 5, hepatotoxicity, diarrhea or colitis	None indicated	Do not use in pregnant or breastfeeding individuals
Zanubrutinib	Neutropenia, thrombocytopenia, hemorrhage, musculoskeletal pain, upper respiratory tract infection Warnings: Infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies	Moderate or strong CYP3A inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with severe hepatic impairment

BCRP = breast cancer resistance protein; P-gp = P-glycoprotein; PRES = posterior reversible encephalopathy syndrome; TLS = tumor lysis syndrome

From FDA-approved prescribing information^23-32

References 

1. Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Non-Hodgkin Lymphoma. National Cancer Institute. Accessed May 6, 2023. https://seer.cancer.gov/statfacts/html/nhl.html 
2. Thandra KC, Barsouk A, Saginala K, Padala SA, Barsouk A, Rawla  P. Epidemiology of non-Hodgkin’s lymphoma. Med Sci (Basel). 2021;9(1):5. doi:10.3390/medsci9010005
3. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (NCCN Guidelines®), B-Cell Lymphomas. National Comprehensive Cancer Network. Updated May 11, 2023. Accessed May 6, 2023. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf
4. Perkins AS, Friedberg JW. Burkitt lymphoma in adults. Hematology Am Soc Hematol Educ Program. 2008:341-348. doi:10.1182/asheducation-2008.1.341
5. Kelly JL, Toothaker SR, Ciminello L, et al. Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens. Clin Lymphoma Myeloma. 2009;9:307-310. doi:10.3816/CLM.2009.n.060.
6. Al-Hamadani M, Habermann TM, Cerhan JR, Macon WR, Maurer MJ, Go RS. Non-Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: a longitudinal analysis of the National Cancer Data Base from 1998 to 2011. Am J Hematol. 2015;90:790-795. doi:10.1002/ajh.24086
7. Teodorovic I, Pittaluga S, Kluin-Nelemans JC, et al. Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin’s lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group. J Clin Oncol. 1995;13:2819-2826. doi:10.1200/JCO.1995.13.11.2819
8. Marcus R, Imrie K, Blech A, et al. CVP chemotherapy plus rituximab compared with CVP as a first-line treatment for advanced follicular lymphoma. Blood. 2005;105(4):1417-1423. doi:10.1182/blood-2004-08-3175
9. Barnes JA, LaCasce AS, Feng Y, et al. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt’s lymphoma: a retrospective analysis.  Ann Oncol. 2011;22(8):1859-1864. doi:10.1093/annonc/mdq677
10. Magrath I, Adde M, Shad A, et al. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996;14:925-934. doi:10.1200/JCO.1996.14.3.925 
11. 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. doi:10.1182/blood.v99.8.2685.
12. Kanbar AH, Sacher RA. Burkitt Lymphoma and Burkitt-Like Lymphoma Treatment & Management. Updated July 5, 2022. Accessed May 6, 2023. https://emedicine.medscape.com/article/1447602-treatment#d12
13. Lacout C, Orvain C, Seegers V, et al. R-DHA-oxaliplatin (R-DHAOx) versus R-DHA-cisplatin (R-DHAP) regimen in B-cell lymphoma treatment: an eight-year trajectory study. Eur J Haematol. 2020;105(2):223-230. doi:10.1111/ejh.13429
14. Peyrade F, Jardin F, Gisselbretch C, et al. Rituximab and reduced dose CHOP (R-mini-CHOP) for patients over 80 years with diffuse large B-cell lymphoma (DLBCL) – Groupe d’Etude Des Lymphomes De l’Adulte (GELA) Study LNH03-7B. Blood. 2010;116(21):853. doi:10.1182/blood.V116.21.853.853
15. Robak T, Pylypenko H, Verhoef G, et al; LYM-3002 Investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018;19(11):1449-1458. doi:10.1016/S1470-2045(18)30685-5
16. Adcetris. DailyMed. Updated November 14, 2022. Accessed May 10, 2023. 
17. Zevalin. DailyMed. Updated April 25, 2023. Accessed May 10, 2023. 
18. Zynlonta. DailyMed. Updated April 25, 2023. Accessed May 10, 2023. 
19. Gazyva. DailyMed. Updated July 19, 2022. Accessed May 10, 2023. 
20. Keytruda. DailyMed. Updated April 3, 2023. Accessed May 10, 2023. 
21. Polivy. DailyMed. Updated April 24, 2023. Accessed May 10, 2023. 
22. Monjuvi. DailyMed. Updated November 22, 2022. Accessed May 10, 2023. 
23. Calquence. DailyMed. Updated March 23, 2022. Accessed May 10, 2023. 
24. Velcade. DailyMed. Updated October 25, 2022. Accessed May 10, 2023. 
25. Aliqopa. DailyMed. Updated March 30, 2023. Accessed May 10, 2023. 
26. Copiktra. DailyMed. Updated December 28, 2021. Accessed May 10, 2023. 
27. Imbruvica. DailyMed. Updated August 1, 2022. Accessed May 10, 2023. 
28. Jaypirca. DailyMed. Updated January 27, 2023. Accessed May 10, 2023. 
29. Xpovio. DailyMed. Updated July 25, 2022. Accessed May 10, 2023. 
30. Tazverik. DailyMed. Updated July 31, 2020. Accessed May 10, 2023. 
31. Ukoniq. DailyMed. Updated December 15, 2022. Accessed May 10, 2023. 
32. Brukinsa. DailyMed. Updated April 21, 2023. Accessed May 10, 2023. 
33. Yescarta. DailyMed. Updated November 9, 2022. Accessed May 10, 2023. 
34. Tecartus. DailyMed. Updated September 19, 2022. Accessed May 10, 2023. 
35. Breyanzi. DailyMed. Updated July 29, 2022. Accessed May 10, 2023. 
36. Kymriah. DailyMed. Updated May 27, 2022. Accessed May 10, 2023. 
37. Treanda. DailyMed. Updated October 27, 2023. Accessed May 11, 2023. 
38. Cisplatin. DailyMed. Updated December 31, 2019. Accessed May 11, 2023. 
39. Cyclophosphamide. DailyMed. Updated September 8, 2021. Accessed May 11, 2023. 
40. Cytarabine. DailyMed. Updated June 3, 2021. Accessed May 11, 2023. 
41. Adriamycin. DailyMed. Updated December 20, 2022. Accessed May 11, 2023. 
42. Etoposide. DailyMed. Updated June 2, 2022. Accessed May 11, 2023. 
43. Gemcitabine. DailyMed. Updated January 4, 2020. Accessed May 11, 2023. 
44. Ifosfamide. DailyMed. Updated April 19, 2023. Accessed May 11, 2023. 
45. Revlimid. DailyMed. Updated March 24, 2023. Accessed May 11, 2023. 
46. Trexall. DailyMed. Updated April 30, 2021. Accessed May 11, 2023. 
47. Oxaliplatin. DailyMed. Updated July 12, 2022. Accessed May 11, 2023. 
48. Vincristine Sulfate. Daily Med. Updated February 3, 2023. Accessed May 11, 2023. 

Author Bio

Emily Wagner, MS, earned a Bachelor of Science in biotechnology from the Rochester Institute of Technology in 2018 and a Master of Science in biomedical sciences with a focus in pharmacology from the University of Colorado Anschutz Medical Campus in 2020. During her thesis work, she studied non-small cell lung cancer and how the immune system plays a role in response to different treatments. Emily currently lives in Colorado where she enjoys the mountains, spending time with her dog, baking, and reading a good book.