Approach

Treatment for non-Hodgkin's lymphoma (NHL) varies depending on the histological subtype and stage. Symptom severity informs decisions about when to start therapy.

Prognostic tools can be used for risk-stratification to help guide treatment decisions for certain subtypes.

Enrolment in a clinical trial should be considered for all patients where possible, particularly those with aggressive lymphomas and those with relapsed or refractory disease.

Aggressive B-cell lymphoma: diffuse large B-cell lymphoma (DLBCL)

Initial treatment depends on stage and risk stratification (e.g., using the International Prognostic Index [IPI] or stage-modified IPI [smIPI]). See Criteria.

Stages I-II (excluding stage II with extensive mesenteric disease), non-bulky (<7.5 cm), and low-risk disease (i.e., smIPI 0-1)

The recommended treatment is 3 cycles of R-CHOP-21 (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone given on day 1 of a 21-day cycle), followed by interim restaging with positron emission tomography/computed tomography (PET/CT) scan.[48]​

Depending on response, further cycles of R-CHOP-21 (to a total of 4-6 cycles) with or without involved-site radiotherapy (ISRT), or ISRT alone, or a repeat biopsy (to guide further treatment) is indicated.[48] For young women in whom radiation to the breast carries potential risk of breast cancer, R-CHOP-21 alone may be preferred.[88]

Stages I-II (excluding stage II with extensive mesenteric disease), bulky (≥7.5 cm), and low-risk disease (i.e., smIPI 0-1)

The recommended treatment is 3-4 cycles of R-CHOP-21, followed by interim restaging with PET/CT scan.[48] Depending on response, further cycles of R-CHOP-21 (to a total of 6 cycles) with or without ISRT, or repeat biopsy (to guide further treatment), is indicated.[48]

Stages I-II (excluding stage II with extensive mesenteric disease), non-bulky or bulky, and high-risk disease (i.e., smIPI >1)

The recommended treatment is R-CHOP-21 or Pola-R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) for 2-4 cycles, followed by interim restaging with PET/CT or CT scan.[48] Depending on response, further cycles of the initial regimen (to a total of 6 cycles), or repeat biopsy (to guide further treatment) is indicated.[48]

Stage II with extensive mesenteric disease, or stages III-IV

The recommended treatment is R-CHOP-21 or Pola-R-CHP (IPI ≥2) for 2-4 cycles, followed by interim restaging with PET/CT or CT scan.[48] Depending on response, further cycles of the initial regimen (to a total of 6 cycles), or repeat biopsy (to guide further treatment) is indicated.[48]

Other recommended treatment regimens include rituximab plus dose-adjusted etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH). Dose-adjusted R-EPOCH should be considered for patients with a poor prognosis (e.g., those with MYC translocations and BCL2 and/or BCL6 rearrangements [i.e., 'double-hit' or 'triple-hit']) or those with HIV infection.[48][89][90]

Alternative first-line regimens are recommended for certain patients (e.g., those with poor left ventricular function; those who are very frail; those aged >80 years with comorbidities).[48][51]​​​​​​​​

DLBCL: central nervous system (CNS) prophylaxis

CNS relapse occurs in approximately 5% of patients with DLBCL following initial treatment, and is associated with a poor prognosis.[91]

The use of CNS prophylaxis is controversial and it is not routinely recommended. CNS prophylaxis can be considered for patients with high-risk disease, including those with the following:[48][87][92]​​​[93]

  • High-risk score on the CNS-International Prognostic Index (i.e., CNS-IPI 4-6)

  • Kidney or adrenal gland involvement

  • Testicular lymphoma

  • Primary cutaneous DLBCL, leg type

  • Stage IE DLBCL of the breast

The optimal approach to CNS prophylaxis is unclear. Typically, high-dose systemic methotrexate and/or intrathecal methotrexate and/or intrathecal cytarabine are given during or after treatment.[48][93]​ In DLBCL patients receiving CNS prophylaxis, CNS relapse rates are similar regardless of route of administration (intrathecal vs intravenous) and timing (during vs. after treatment).[94][95]​​​​

Refractory or relapsed DLBCL

Approximately 40% of patients with DLBCL will have refractory disease or relapse, most of whom will ultimately die from their lymphoma.[96][97]​​​​ Relapse should be confirmed by biopsy before proceeding with treatment.

Treatment for refractory or relapse DLBCL can be guided by response to initial treatment, time of relapse (i.e., early vs. late), and intention to proceed to autologous stem cell transplant (ASCT).

Refractory or relapsed DLBCL: primary refractory disease or early relapse (<12 months)

Chimeric antigen receptor (CAR) T-cell therapy is recommended for patients who have primary refractory disease or early relapse.[48] Options include:

  • Axicabtagene ciloleucel

  • Lisocabtagene maraleucel

Patients should receive bridging therapy (e.g., with chemotherapy) as clinically indicated, while waiting for administration of CAR T-cell therapy.[48]

Patients should be carefully assessed for suitability for CAR T-cell therapy. Toxicities include cytokine release syndrome, neurotoxicity, and prolonged cytopenias, which may limit feasibility of use to younger or fit older patients. In the US, CAR T-cell therapy is only available through a Risk Evaluation and Mitigation Strategies (REMS) programme.

Patients unsuitable for CAR T-cell therapy can be considered for a clinical trial or salvage chemotherapy.[48] Salvage chemotherapy regimens include:

  • Dexamethasone and cytarabine (DHA) and a platinum agent (cisplatin, carboplatin, or oxaliplatin) ± rituximab

  • Gemcitabine plus dexamethasone and a platinum agent (cisplatin or carboplatin) ± rituximab

  • Ifosfamide plus carboplatin and etoposide (ICE) ± rituximab

Relapsed DLBCL: late relapse (>12 months) and intention to proceed to ASCT

Salvage chemotherapy regimens are recommended for patients with late relapse, who are eligible for intensive consolidation and intended for ASCT.[48]​​

If a complete or partial response is achieved following salvage chemotherapy, then consolidation therapy with ASCT (with or without ISRT) is recommended, if suitable (e.g., based on age, general fitness, comorbidities).[48]

CAR T-cell therapy (e.g., axicabtagene ciloleucel; tisagenlecleucel; lisocabtagene maraleucel) is an option if a partial response is achieved following salvage chemotherapy.[48]

Relapsed DLBCL: late relapse (>12 months) and no intention to proceed to ASCT

CAR T-cell therapy, monoclonal antibody therapy, and second-line chemotherapy regimens can be considered for patients with late relapse who are not intended for ASCT.

Options include:[48][98][99][100][101]

  • Lisocabtagene maraleucel

  • Polatuzumab vedotin ± bendamustine ± rituximab

  • Tafasitamab plus lenalidomide

  • Second-line chemotherapy

    • CEOP (cyclophosphamide, etoposide, vincristine, prednisolone) ± rituximab

    • Dose-adjusted EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin) ± rituximab

    • GemOx (gemcitabine plus oxaliplatin) ± rituximab

    • Gemcitabine plus dexamethasone and a platinum agent (cisplatin or carboplatin) ± rituximab, if not used first-line

Refractory or relapsed DLBCL: treatment following ≥2 lines of systemic therapy

Subsequent treatment options include:[48][102][103][104][105]​​​​

  • CAR T-cell therapy (axicabtagene ciloleucel; tisagenlecleucel; lisocabtagene maraleucel) if not used previously

  • Bispecific antibody therapy (epcoritamab, glofitamab)

  • Loncastuximab tesirine

  • Selinexor (including patients with disease progression after transplant or CAR T-cell therapy)

Aggressive B-cell lymphoma: primary mediastinal large B-cell lymphoma (PMBCL)

First-line treatment options for PMBCL include:[48]

  • Dose-adjusted R-EPOCH (for 6 cycles)

  • R-CHOP-21 (for 6 cycles) ± ISRT to the mediastinum

  • R-CHOP-14 (for 4-6 cycles)

R-EPOCH is the preferred regimen in fit patients (who can tolerate more intensive chemotherapy), and in younger patients (as it avoids the need for radiotherapy which is associated with long-term complications).[106]​ 

Patients treated with 4 cycles of R-CHOP-14 (given on a 14-day cycle) who achieve a complete response receive consolidation therapy with ICE (ifosfamide, carboplatin, and etoposide) with or without rituximab.[48][107]

Patients achieving only a partial response with initial treatment, or who have progressive, relapsed, or refractory disease (confirmed by biopsy) can be considered for second-line treatment, which includes:[48]

  • Pembrolizumab

  • Nivolumab with or without brentuximab vedotin

Treatment options for relapsed or refractory DLBCL can also be considered in these patients.

Aggressive B-cell lymphoma: primary CNS lymphoma (PCNSL)

PCNSL is an aggressive form of NHL that arises in and is confined to the brain, leptomeninges, spinal cord, retina, vitreous humour, and occasionally the optic nerve. Although most PCNSL tumours are clinical stage IE (1 extranodal site) and systemic spread is uncommon, the response rate to chemotherapy is much lower than in other high-grade B-cell lymphomas that are stage IE.

If the patient is HIV positive, antiretroviral therapy (ART) should be administered concurrently with systemic therapy.[53]

Optimal treatment for PCNSL involves two phases: induction and consolidation.

PCNSL: induction therapy

All patients who are clinically fit should be treated with high-dose methotrexate-based induction therapy.[53]

Induction therapy regimens include:[53][108]​​

  • High-dose methotrexate plus rituximab (with or without temozolomide)

  • High-dose methotrexate plus vincristine, procarbazine, and rituximab (R-MPV)

  • High-dose methotrexate plus cytarabine, thiotepa, and rituximab

Whole-brain radiotherapy (WBRT) may be used as part of induction therapy (depending on the regimen and methotrexate dose), or used for palliative treatment of older and clinically unfit patients who are not candidates for systemic therapy.[53]​​ While PCNSL is sensitive to WBRT, response is usually short-lived and neurotoxicity may occur (particularly in older patients).[108]

PCNSL: consolidation therapy

Patients achieving a complete response to induction therapy can be considered for consolidation therapy. Options include:[108][109][110][111]​​

  • High-dose chemotherapy (e.g., thiotepa plus cytarabine and carmustine; or thiotepa plus busulfan and cyclophosphamide) with autologous stem cell rescue

  • High-dose cytarabine with or without etoposide

Low-dose WBRT may be considered for consolidation if systemic consolidation therapy is not an option.[112]

Aggressive B-cell lymphoma: primary effusion lymphoma (PEL)/body cavity lymphoma

Treatment includes EPOCH or CHOP.[48]

Rituximab is not indicated because most cases of PEL are CD20-negative.

PEL occurs most commonly in immunocompromised patients (e.g., those with HIV infection). ART is important (along with chemotherapy) in treating HIV-positive PEL patients. For detailed information on ART, see HIV infection.

Aggressive B-cell lymphoma: Burkitt's lymphoma

Burkitt's lymphoma is a highly aggressive NHL that requires treatment with intensive multiagent chemotherapy regimens.

Treatment is based on age and risk-stratification (i.e., low risk or high risk).[48] Patients with normal serum lactate dehydrogenase (LDH), or stage I disease and completely resected abdominal lesion, or single extra-abdominal mass <10 cm, are considered low risk.[48] All other patients are considered high risk.

Initial treatment for patients aged <60 years with low-risk disease includes:[48]

  • R-CODOX-M (rituximab plus cyclophosphamide, doxorubicin, vincristine, and methotrexate)

  • R-EPOCH

  • R-hyper-CVAD (rituximab plus cyclophosphamide, vincristine, doxorubicin, and dexamethasone, alternating with methotrexate and cytarabine)

Initial treatment for patients aged <60 years with high-risk disease includes:[48]

  • R-CODOX-M alternating with R-IVAC (rituximab plus ifosfamide, etoposide, and cytarabine)

  • R-hyper-CVAD

  • R-EPOCH (for those not able to tolerate aggressive regimens)

Initial treatment for patients aged ≥60 years with low-risk or high-risk disease is R-EPOCH.[48]

A clinical trial (if available) or palliative ISRT is recommended for patients who do not achieve a complete response after initial treatment.[48]

Burkitt's lymphoma: CNS prophylaxis

Burkitt's lymphoma has a propensity to spread to the CNS. CNS prophylaxis (with high-dose systemic methotrexate and intrathecal methotrexate and/or cytarabine) is typically included in chemotherapy regimens for Burkitt's lymphoma.

Relapsed Burkitt's lymphoma

Optimal treatment for relapsed Burkitt's lymphoma is unclear.

If relapse occurs >6-18 months after initial treatment, the following regimens can be considered for second-line treatment (if not previously used):[48]

  • R-EPOCH

  • R-ICE (rituximab, ifosfamide, carboplatin, and etoposide)

  • R-IVAC

Consolidation therapy with ASCT (with or without ISRT) should be considered after second-line treatment, depending on response.[48] Allogeneic stem cell transplantation (with or without ISRT) may be considered for consolidation therapy in select patients (if a donor is available).

Patients with relapse occurring <6 months after initial therapy, or who do not respond to second-line treatment, should be considered for a clinical trial or supportive/palliative care.[48]

Aggressive B-cell lymphoma: mantle cell lymphoma (MCL)

Treatment for MCL should be individualised based on disease stage, disease characteristics (e.g., TP53 mutation status), symptoms, and patient factors (e.g., age, performance status, comorbidities, desire/eligibility for aggressive therapy).

A small proportion of patients with MCL (10% to 15%) have indolent disease and can be observed if asymptomatic, but most have rapidly progressing advanced disease and need treatment at the time of diagnosis.[48][96]

Enrolment in a clinical trial should be considered, particularly for patients with advanced disease and those with TP53 mutation.

Localised MCL (stage I or stage II [non-bulky])

Less aggressive induction therapy (with or without ISRT) is recommended for patients with localised disease.[48] Options include:[48]

  • Bendamustine plus rituximab

  • VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone)

  • R-CHOP

  • Lenalidomide plus rituximab

  • Acalabrutinib plus rituximab

ISRT alone is also an option for patients with stage I or contiguous stage II (non-bulky) disease.[48]

Select patients (e.g., those with good performance status) with asymptomatic noncontiguous stage II (non-bulky) disease can be observed.[48]

Advanced MCL (stage II [bulky, noncontiguous]; stage III-IV): suitable for aggressive induction therapy and stem cell transplant

Aggressive induction therapy is recommended for patients with advanced disease.[48] Options include:[48]

  • LyMA regimen: R-DHA (rituximab, dexamethasone, and cytarabine) plus a platinum agent (carboplatin, cisplatin, or oxaliplatin) followed by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone)

  • NORDIC regimen: dose-intensified induction immunochemotherapy with rituximab plus cyclophosphamide, vincristine, doxorubicin, prednisolone (known as maxi-CHOP) alternating with rituximab plus high-dose cytarabine

  • Rituximab plus bendamustine followed by rituximab plus high-dose cytarabine

  • TRIANGLE regimen: R-CHOP plus a covalent Bruton's tyrosine kinase (BTK) inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) alternating with R-DHA plus a platinum agent (carboplatin, cisplatin, or oxaliplatin)

  • R-hyper-CVAD

  • RBAC500 regimen (rituximab, bendamustine, plus cytarabine)

Maintenance therapy with a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) plus rituximab is recommended if patients achieve a complete response after aggressive induction therapy.[48] 

Consolidation therapy with ASCT (followed by maintenance therapy with a covalent BTK inhibitor plus rituximab) is also an option if patients achieve a complete response after aggressive induction therapy.[48] Clinical trials are under way to address which patients with MCL are most likely to benefit from ASCT.

Advanced MCL (stage II [bulky, noncontiguous]; stage III-IV): not suitable for aggressive induction therapy and stem cell transplant

Less aggressive induction therapy is recommended for patients with advanced disease who are not suitable for aggressive induction therapy.[48] Options include:[48]

  • Bendamustine plus rituximab

  • VR-CAP

  • R-CHOP

  • Lenalidomide plus rituximab

  • Acalabrutinib plus rituximab

Maintenance therapy with rituximab is recommended for patients who are in remission, and who are not candidates for ASCT, following less aggressive induction.[48]

TP53-mutated MCL

Patients with TP53-mutated MCL treated with conventional therapy (including transplant) have a poor prognosis. Consolidative ASCT is not recommended for these patients. Enrolment in a clinical trial is strongly recommended.[48]

The following options can be considered (followed by maintenance therapy):[48]

  • Zanubrutinib plus obinutuzumab plus venetoclax

  • TRIANGLE regimen: R-CHOP plus a covalent BTK inhibitor (ibrutinib, acalabrutinib, or zanubrutinib) alternating with R-DHA plus a platinum agent (carboplatin, cisplatin, or oxaliplatin) followed by maintenance therapy with a covalent BTK inhibitor plus rituximab

  • Less aggressive induction therapy if not suitable for aggressive induction therapy

Relapsed or refractory MCL

Although MCL is initially responsive to chemotherapy, the disease inevitably relapses.[113][114][115][116]

Preferred second-line treatments include:[48][117][118][119]​​​

  • Covalent BTK inhibitors (acalabrutinib; zanubrutinib)

  • Lenalidomide plus rituximab

For patients with relapsed or refractory disease after two or more lines of systemic therapy (including a covalent BTK inhibitor), options include:[48][120][121]

  • CAR T-cell therapy (brexucabtagene autoleucel, lisocabtagene maraleucel)

  • Pirtobrutinib (a non-covalent [reversible] BTK inhibitor​)

High-grade B-cell lymphoma, not otherwise specified (NOS); double-hit lymphoma; triple-hit lymphoma

High-grade B-cell lymphomas NOS appear blastoid or are intermediate between DLBCL and Burkitt's lymphoma, but lack an MYC and BCL2 and/or BCL6 rearrangement.

High-grade B-cell lymphomas with rearrangements of MYC and BCL2 or BCL6 are known as 'double-hit' lymphomas; if all three are rearranged, they are referred to as 'triple-hit' lymphomas.

The optimal treatment approach for patients with high-grade B-cell lymphoma (NOS, double-hit, or triple-hit) has not been established. Enrolment in a clinical trial is recommended.[48]

A rituximab-based chemotherapy regimen (e.g., R-dose-adjusted EPOCH) is recommended.[48][122]​ R-CHOP-21 is an option for low-risk patients and those who are older or less fit.

High-grade B-cell lymphomas: CNS prophylaxis

Patients are at high risk for CNS involvement. CNS prophylaxis can be considered in select patients with careful balancing of risk versus benefit. However, there are no robust data to support routine CNS prophylaxis, even among high-risk patients, and it is unclear if any prophylactic therapies effectively reduce the risk of CNS relapse. The optimal method of CNS prophylaxis is unclear.

CNS prophylaxis may include high-dose systemic methotrexate and/or intrathecal methotrexate and/or cytarabine, given during or after treatment.

Aggressive T-cell lymphoma: enteropathy-associated T-cell lymphoma [EATL]/intestinal T-cell lymphoma; peripheral T-cell lymphoma, not otherwise specified (PTCL NOS); systemic anaplastic large cell lymphoma (systemic ALCL); angioimmunoblastic T-cell lymphoma (AITL)

Treatment for peripheral T-cell lymphomas (including EATL, PTCL NOS, systemic ALCL, AITL) is based on histology (CD30 expression), stage, and patient factors (e.g., age, fitness, comorbidities).[123] Many patients are unsuitable for chemotherapy because of poor performance status.[124]

Enrolment in a clinical trial should be considered.[49]

Preferred first-line treatments include:[49]

  • Brentuximab vedotin (an anti-CD30 antibody-drug conjugate) plus CHP (cyclophosphamide, doxorubicin, and prednisolone) if CD30+ histology confirmed

  • CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, prednisolone)

  • CHOP

  • Dose-adjusted EPOCH

ISRT may be combined with first-line treatment regimens in certain patients (e.g., those with localised [stage I-II] disease).[49]

Peripheral T-cell lymphoma: consolidation therapy

Eligible patients in complete remission following initial therapy may be considered for consolidation therapy with ASCT.[49][125]​​ However, the benefits of ASCT in peripheral T-cell lymphoma are unclear, and may be limited to certain subtypes.[126][127][128][129]​​​

Relapsed or refractory peripheral T-cell lymphoma

Recommended second-line and subsequent treatments for patients with relapsed or refractory disease include:[49]

  • Belinostat

  • Brentuximab vedotin (if not used previously and CD30+ histology confirmed)

  • Duvelisib

  • Pralatrexate

  • Romidepsin

Aggressive T-cell lymphoma: subcutaneous panniculitis-like peripheral T-cell lymphoma (SPTCL)

Optimal management of SPTCL is unclear due to lack of evidence. Treatment can be guided by the presence of haemophagocytic lymphohistiocytosis (HLH) and tumour burden.[49]

The following regimens can be considered for first-line treatment of patients with HLH, systemic disease, or high tumour burden:[49]

  • Ciclosporin with or without prednisolone

  • Pralatrexate with or without prednisolone

  • Romidepsin with or without prednisolone

  • CHOEP

  • Dose-adjusted EPOCH

  • ESHA (etoposide, methylprednisolone, and cytarabine) plus a platinum agent (cisplatin or oxaliplatin)

  • ICE

The following options can be considered for first-line treatment of patients without HLH who have low tumour burden (localised or limited subcutaneous disease):[49]

  • Ciclosporin with or without prednisolone

  • Methotrexate with or without prednisolone

  • Bexarotene with or without prednisolone

  • Local therapy (ISRT or intralesional corticosteroid)

Indolent B-cell lymphoma: classic follicular lymphoma (cFL)

Treatment for cFL is based on stage, indications for treatment (including symptoms; threatened end-organ function; clinically significant/progressive cytopenia secondary to lymphoma; clinically significant bulky diseases; steady/rapid progression), and patient factors (e.g., age, fitness, comorbidities).[48]

Prognostic tools (e.g., Follicular Lymphoma International Prognostic Index [FLIPI]) can help guide treatment. See Criteria.

Localised disease (stage I or II)

  • Initial therapy includes ISRT and/or rituximab (with or without chemotherapy).[48][130]​

  • Observation may be considered for some patients (e.g., those with noncontiguous stage II disease in whom toxicity of treatment outweighs benefit).

Advanced-stage disease (stage III or IV): with no indication for treatment

  • Observation is recommended.[48]

Advanced-stage disease (stage III or IV): with indication for treatment

  • Preferred first-line treatment regimens for those with high tumour burden include: CHOP plus obinutuzumab or rituximab; bendamustine plus rituximab or obinutuzumab; CVP (cyclophosphamide, vincristine, and prednisolone) plus obinutuzumab or rituximab; or lenalidomide plus rituximab.[48][131][132][133][134]

  • Preferred first-line treatment for patients with low tumour burden is rituximab alone.[48]

  • In older patients and/or those with significant comorbidities, rituximab alone may be a good palliative choice.[48] Chlorambucil (with or without rituximab) or cyclophosphamide (with or without rituximab) may also be considered for these patients.

Consolidation and maintenance therapy for cFL

Consolidation with rituximab may be considered for patients who respond to initial treatment with rituximab alone.[48]

Maintenance therapy with rituximab or obinutuzumab may be considered for patients who respond to chemoimmunotherapy (depending on the initial regimen used and response achieved).[48]

Relapsed, progressive, or refractory cFL

Patients with relapsed or progressive disease who have no indications for treatment can be observed.[48]

Patients with relapsed, progressive, or refractory disease who have indications for treatment can be considered for second-line treatments. Options include (if not used previously):[48]

  • CHOP plus obinutuzumab or rituximab

  • CVP plus obinutuzumab or rituximab

  • Bendamustine plus rituximab or obinutuzumab

  • Lenalidomide with or without rituximab

  • Lenalidomide plus obinutuzumab

  • Obinutuzumab alone

  • Rituximab alone

In patients previously exposed to chemotherapy and monoclonal antibody therapy, lenalidomide plus monoclonal antibody therapy would be standard second-line therapy.

Rituximab alone may be a good palliative choice for older patients and/or those with significant comorbidities.[48] Tazemetostat, or cyclophosphamide with or without rituximab, may also be considered for these patients.

Maintenance therapy with rituximab or obinutuzumab, or consolidation therapy with ASCT, may be considered for those who respond to second-line treatment.[48]

Third-line and subsequent treatment options include:[48]

  • Bispecific antibody therapy (epcoritamab; mosunetuzumab)

  • CAR T-cell therapy (axicabtagene ciloleucel; lisocabtagene maraleucel; tisagenlecleucel)

  • Tazemetostat

  • Zanubrutinib plus obinutuzumab

Second-line treatments can also be considered for third-line use if not previously used.

Indolent B-cell lymphoma: marginal zone lymphoma (MZL); gastric mucosa-associated lymphoid tissue (MALT) type

MZL is usually indolent and often a consequence of chronic antigenic stimulation from a pathogen (e.g., Helicobacter pylori, hepatitis C virus).[135] 

Marginal zone lymphoma (MZL)

  • Nodal MZL: initial treatment options include ISRT, ISRT plus rituximab (with or without chemotherapy), or rituximab (with or without chemotherapy).[48]​ Recommended chemotherapy regimens include bendamustine, CHOP, CVP, or lenalidomide.[48]

  • Splenic MZL: initial treatment options include hepatitis C treatment (if hepatitis C positive), rituximab, splenectomy, or observation (e.g., if asymptomatic and/or without splenomegaly).[48][136][137]

  • Second-line treatment options for MZL include (if not used previously): bendamustine plus obinutuzumab (not recommended if treated with prior bendamustine); bendamustine plus rituximab (not recommended if treated with prior bendamustine); acalabrutinib; zanubrutinib (after at least one prior anti-CD20 monoclonal antibody-based regimen); pirtobrutinib (after prior covalent BTK inhibitor therapy); CHOP plus rituximab; CVP plus rituximab; lenalidomide plus rituximab.

  • Axicabtagene ciloleucel is a third-line therapy for patients with MZL.[48]

Gastric MALT lymphoma

Commonly associated with H pylori infection.

  • H pylori-positive gastric MALT lymphoma: initial treatment is with antibiotics to eradicate H pylori.[48] ​​​​

Patients who have the t(11;18) translocation are often H pylori-negative, and have antibiotic-resistant tumours.[138]

  • Antibiotic-resistant gastric MALT lymphoma (i.e., H pylori-negative or t(11;18)-positive): initial treatment options include ISRT (preferred) or rituximab (if ISRT is contraindicated).[48]

  • Patients who are t(11;18)-positive and H pylori-positive can be treated with antibiotics (in addition to ISRT or rituximab) to eradicate the underlying H pylori infection.[48]

See MALT lymphoma.

Primary cutaneous B-cell lymphomas

These B-cell lymphomas are relatively rare (approximately 20% of all primary lymphomas of the skin) and heterogeneous.

Subtypes include primary cutaneous follicle centre lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous DLBCL, leg type (PCDLBCL, leg type).

Primary cutaneous follicle centre lymphoma and marginal zone lymphoma

Treatment options for localised PCFCL and PCMZL include:[54]

  • Local ISRT

  • Surgical resection (for small isolated lesions)

Patients with generalised disease or cosmetically disfiguring lesions may require systemic treatment (e.g., rituximab with or without CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone]).[54]

Primary cutaneous DLBCL, leg type

PCDLBCL, leg type is associated with an aggressive clinical course and poor survival.

Recommended first-line treatments for younger and fit older patients with PCDLBCL, leg type include.[48]

  • R-CHOP plus ISRT (for localised disease)

  • R-CHOP with or without ISRT (for generalised disease)

In older patients or patients with significant comorbidities, palliative radiotherapy for localised lesions can be utilised.[48][139]

CNS prophylaxis may be considered for patients with PCDLBCL, leg type due to the increased risk for CNS relapse with this subtype.[48]

Indolent T-cell lymphoma: primary cutaneous anaplastic large cell lymphoma (PC-ALCL)

Treatments for localised PC-ALCL (solitary or grouped lesions) include:

  • ISRT

  • Surgical excision with or without ISRT (for small local lesions)

Brentuximab vedotin is the preferred initial treatment for PC-ALCL patients with multifocal lesions or regional lymph node involvement.[54]

If patients have regional lymph node involvement, ISRT may be combined with brentuximab vedotin, or used alone in select patients.[54]

Indolent T-cell lymphoma: breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

Treatment for localised disease (i.e., confined to the fibrous scar capsule) is complete surgical resection of the breast implant, capsule, and associated mass.[49]​ Suspicious lymph nodes detected during explantation should be biopsied.

Removal of the contralateral breast implant can be considered because bilateral disease is reported in approximately 4.6% of cases.[49][140]

​Re-excision surgery alone (without systemic therapy) may be possible for local disease relapse.[49]

Systemic therapy (e.g., brentuximab vedotin with or without CHP; CHOP; CHOEP; dose-adjusted EPOCH) may be considered for advanced-stage disease.[49]

The FDA recommends that cases of BIA-ALCL should be reported to a national disease registry (e.g., PROFILE Registry).[141]​​

Supportive therapy

Consider supportive care measures for all patients, at all stages of treatment, to prevent or manage complications.

  • Tumour lysis syndrome (TLS): an oncological emergency, particularly among patients with Burkitt's lymphoma. Vigorous hydration (with intravenous fluids), phosphate-binding agents, and hypouricaemic agents (e.g., allopurinol or rasburicase) should be used to prevent or treat TLS. TLS is characterised by hyperkalaemia, hyperphosphataemia, hyperuricaemia, hypocalcaemia, and/or elevated serum LDH, which can occur following treatment for NHL (or spontaneously in rare cases). See Complications.

  • Treatment-related neutropenia: older patients receiving curative chemotherapy (e.g., R-CHOP) should be considered for prophylactic G-CSF.[142][143]​ Patients receiving salvage regimens should receive G-CSF concomitantly with chemotherapy.[1]

  • Infection: antibiotic prophylaxis is indicated for patients with severe neutropenia (absolute neutrophil count <500 cells/microlitre [<0.5 × 10⁹/L]).

  • Haemorrhagic cystitis: mesna should be used to manage haemorrhagic cystitis in patients receiving high-dose cyclophosphamide or ifosfamide. Mesna is not required for less intensive cyclophosphamide-containing regimens (e.g., CHOP, CHOEP).

  • Methotrexate-related toxicity: folinic acid prophylaxis can minimise toxicity associated with methotrexate (e.g., myelosuppression, gastrointestinal toxicity, hepatotoxicity). All patients receiving high-dose methotrexate should receive folinic acid rescue therapy.[48]

Safety considerations

R-CHOP is relatively well tolerated, with the main toxicities being haematological (from bone marrow suppression), infection (from neutropenia), cardiac (from doxorubicin), alopecia, infusion-related respiratory symptoms (with or without bronchospasm), chills, fever, and hypotension from rituximab.[144]

Cardiac arrhythmias may occur with BTK inhibitors, particularly in patients with cardiac risk factors (e.g., hypertension and diabetes mellitus).[145][146][147][148][149]​​​​​ Clinical evaluation of cardiac history and function should be performed prior to initiating BTK inhibitors. Patients should be carefully monitored during treatment for cardiac arrhythmias and signs of deterioration of cardiac function, and clinically managed as appropriate. The risks and benefits of initiating or continued treatment with BTK inhibitors should be carefully assessed; alternative treatment may need to be considered. 

In 2023, the manufacturer of ibrutinib (a covalent BTK inhibitor) voluntarily withdrew the US indication for MCL after a confirmatory phase 3 trial in patients with untreated MCL failed to demonstrate significant improvement in overall survival and complete response rate compared with placebo (despite meeting its primary endpoint of progression-free survival).[150]​ The US NCCN guidelines include ibrutinib as an option for patients with MCL (e.g., as part of the TRIANGLE regimen).[48]​ In Europe, ibrutinib continues to be approved for use in patients with relapsed or refractory MCL.

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