Approach

Treatment for non-Hodgkin's lymphoma (NHL) varies depending on the histological subtype, location of lymphoma, and disease 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.

DLBCL: 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.[70]​ Depending on metabolic response (assessed using the Deauville criteria; see Criteria), further cycles of R-CHOP-21 (to a total of 4-6 cycles) with or without involved-site radiotherapy (ISRT), or ISRT alone, or repeat biopsy (to guide further treatment) is indicated.[70] For young women in whom radiation to the breast carries potential risk of breast cancer, R-CHOP-21 alone may be preferred.[125]

DLBCL: 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.[70] Depending on metabolic 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.[70]

DLBCL: 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.[70] Depending on metabolic response, further cycles of the initial regimen (to a total of 6 cycles), or repeat biopsy (to guide further treatment) is indicated.[70]

DLBCL: stage II with extensive mesenteric disease, or stages III-IV

The recommended treatment is R-CHOP-21 or Pola-R-CHP (for patients with IPI ≥2) for 2-4 cycles, followed by interim restaging with PET/CT or CT scan.[70] Depending on metabolic response, further cycles of the initial regimen (to a total of 6 cycles), or repeat biopsy (to guide further treatment) is indicated.[70]

Other recommended treatment regimens include dose-adjusted R-EPOCH (rituximab plus etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin).[70] 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.[70][126]

DLBCL: patients unsuitable for standard first-line regimens

Alternative first-line regimens are recommended for patients (all stages) with poor left ventricular function (e.g., R-CEOP [rituximab, cyclophosphamide, etoposide, vincristine, prednisolone]; R-GCVP [rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone]), and those who are very frail or >80 years of age with comorbidities (e.g., R-mini-CHOP [rituximab plus reduced-dose CHOP]).[70]​​​​​​​​​​

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.[127]

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:[70][121][128]​​​​[129]

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

  • 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, systemic high-dose methotrexate and/or intrathecal methotrexate and/or intrathecal cytarabine are given during or after treatment.[70][129]​​​ 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).[130][131]​​​​​​

Refractory or relapsed DLBCL

Approximately 40% of patients with DLBCL will have refractory or relapsed disease, most of whom will ultimately die from their lymphoma.[132][133]​​​​​​

Refractory and relapsed disease should be confirmed by repeat biopsy before proceeding with salvage treatment.[70][134]​​​

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.[70] 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.[70]

Patients should be carefully assessed for suitability for CAR T-cell therapy. Toxicities include cytokine release syndrome (CRS), neurotoxicity, secondary malignancies (e.g., T-cell malignancies), and cardiovascular complications, which may limit use of CAR T-cell therapy.[135][136][137][138][139]

Patients with primary refractory disease or early relapse (<12 months) who are unsuitable for CAR T-cell therapy can be considered for a clinical trial or an alternative salvage regimen (if not previously given).[70] 

  • Epcoritamab plus GemOx (gemcitabine plus oxaliplatin)

  • Glofitamab plus GemOx

  • Polatuzumab vedotin with or without bendamustine plus rituximab

  • Polatuzumab vedotin plus mosunetuzumab

  • Tafasitamab plus lenalidomide (excluding primary refractory disease)

  • Salvage chemotherapy (e.g., DHA [dexamethasone plus cytarabine] plus a platinum agent [cisplatin, carboplatin, or oxaliplatin]; gemcitabine plus dexamethasone and a platinum agent [cisplatin or carboplatin]; ICE [ifosfamide, carboplatin, etoposide]) with or without rituximab

Palliative ISRT or best supportive care is also an option for patients with primary refractory disease or early relapse who are unsuitable for CAR T-cell therapy.[70] 

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

Salvage chemotherapy is recommended for patients with late relapse (>12 months) who are eligible for intensive consolidation, and intended for ASCT (based on age, general fitness, comorbidities).[70] ​​Preferred salvage chemotherapy regimens include:

  • DHA plus a platinum agent (cisplatin, carboplatin, or oxaliplatin) with or without rituximab

  • Gemcitabine plus dexamethasone and a platinum agent (cisplatin or carboplatin) with or without rituximab

  • ICE with or without rituximab

If a complete or partial response is achieved following salvage chemotherapy, then consolidation (high-dose) therapy with ASCT (with or without ISRT) is recommended for suitable candidates.[70]​ Allogeneic SCT (with or without ISRT) may be considered for consolidation therapy in select patients (e.g., those with stem cell mobilisation failure and persistent bone marrow involvement) if a donor is available.[70]

CAR T-cell therapy (e.g., axicabtagene ciloleucel; tisagenlecleucel; lisocabtagene maraleucel) is an option if a partial response is achieved following salvage chemotherapy.[70]

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

Salvage therapy for patients with late relapse (>12 months) who are not intended for ASCT include (if not previously given):[70]

  • Lisocabtagene maraleucel (with bridging therapy as needed)

  • Epcoritamab plus GemOx

  • Glofitamab plus GemOx

  • Polatuzumab vedotin with or without bendamustine plus rituximab

  • Polatuzumab vedotin plus mosunetuzumab

  • Tafasitamab plus lenalidomide

  • Second-line chemotherapy (e.g., CEOP [cyclophosphamide, etoposide, vincristine, prednisolone]) with or without rituximab

Palliative ISRT or best supportive care is also an option for patients with late relapse who are not intended for ASCT.[70]

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

Subsequent treatment options include (if not used previously):[70]​​​​​

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

  • Epcoritamab

  • Glofitamab

  • Brentuximab vedotin plus lenalidomide plus rituximab (for CD30-positive disease)

  • Loncastuximab tesirine

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

Palliative ISRT or best supportive care is also an option if patients are unsuitable for subsequent treatment following ≥2 lines of systemic therapy.[70]

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

First-line treatment options for PMBCL include:[70]

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

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

  • R-CHOP-14 (for 4-6 cycles)

Intensive regimens (e.g., dose-adjusted R-EPOCH or R-CHOP-14) are usually preferred in fit patients, and in younger patients (as it avoids the need for radiotherapy which is associated with long-term complications).[70][140]​ 

Patients treated with 4 cycles of R-CHOP-14 (given on a 14-day cycle) who achieve a complete response can receive consolidation therapy with 3 cycles of ICE with or without rituximab.[70][141]

Patients achieving 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:[70]

  • ISRT (if a partial response is achieved and confirmed by biopsy)

  • 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)

Patients with PCNSL have disease confined to the CNS (i.e., stage IE); systemic involvement is rare.[142] Prognosis is poor compared with other lymphomas that are stage IE.[142]​​

PCNSL is commonly associated with HIV infection.[65] If the patient is living with HIV, antiretroviral therapy (ART) should be administered concurrently with systemic therapy.[79]​ For detailed information on ART, see HIV in adults.

PCNSL: induction therapy

All patients who are clinically fit should be treated with high-dose methotrexate-based induction therapy.[79]

Induction therapy regimens include:[79][143]​​​

  • 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 with palliative intent in patients who are not candidates for systemic therapy.[79]​​ While PCNSL is sensitive to WBRT, response is usually transient and neurotoxicity may occur (particularly in older patients).[143]

Patients with ocular involvement may be considered for ocular radiotherapy (if unresponsive to systemic therapy) or referred to a specialist ophthalmologist for intraocular methotrexate therapy.[79]

PCNSL: consolidation therapy

Patients achieving a complete response to induction therapy can be considered for consolidation therapy. Options include:[79][143][144][145][146]​​​

  • High-dose chemotherapy (e.g., cytarabine plus thiotepa followed by carmustine plus thiotepa; 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.[147]

Patients with residual disease after induction therapy can be considered for treatment with the following:[79]

  • High-dose cytarabine with or without etoposide

  • Temozolomide (after WBRT)

  • WBRT

  • Best supportive care

Relapsed or refractory PCNSL

Optimal treatment for relapsed or refractory PCNSL is unclear. Treatment is typically based on prior treatments received and time to relapse (i.e., early [<12 months] vs. late [≥12 months]).[79]

Systemic therapy options include an alternative chemotherapy regimen if relapse is early, or retreatment with high-dose methotrexate-based therapy if relapse is late.[79]

Targeted therapies can also be considered for relapsed or refractory PCNSL, including ibrutinib (a covalent Bruton's tyrosine kinase [BTK] inhibitor), lenalidomide, or pomalidomide.[79]

Enrolment in a clinical trial should be encouraged.

Aggressive B-cell lymphoma: primary effusion lymphoma (PEL)

The optimal management of PEL is unclear. Treatment options include:[70]

  • EPOCH (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin)

  • CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)

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

PEL occurs most commonly in immunocompromised patients (e.g., those living with HIV).[1]​ ART is important (along with chemotherapy) in treating patients with HIV-positive PEL. For detailed information on ART, see HIV in adults.

Aggressive B-cell lymphoma: Burkitt's lymphoma

Burkitt's lymphoma is a highly aggressive NHL that requires treatment with intensive multiagent chemotherapy regimens.[70] CHOP is not an adequate regimen.

Treatment is based on age and risk-stratification (i.e., low risk or high risk).[70]

Patients with normal serum lactate dehydrogenase (LDH) and stage I disease (single extra-abdominal mass <10 cm) or a completely resected abdominal lesion are considered low risk.[70] 

Patients with stage I disease and an abdominal mass or extra-abdominal mass >10 cm, or with stage II to IV disease, are considered high risk.[70]

Initial treatment for patients aged <60 years with low-risk disease includes:[70]

  • R-CODOX-M (rituximab plus cyclophosphamide, doxorubicin, and vincristine with intrathecal methotrexate and cytarabine followed by high-dose systemic methotrexate)

  • Dose-adjusted R-EPOCH for 2 cycles followed by interim PET/CT scan (depending on metabolic response, additional cycles of dose-adjusted R-EPOCH with or without intrathecal methotrexate are indicated)

  • 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:[70]

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

  • R-hyper-CVAD

  • Dose-adjusted R-EPOCH plus intrathecal methotrexate (for those not able to tolerate aggressive regimens)

Initial treatment for patients aged ≥60 years with low-risk disease is dose-adjusted R-EPOCH for 2 cycles followed by interim PET/CT scan (depending on metabolic response, additional cycles of dose-adjusted R-EPOCH with or without intrathecal methotrexate are indicated).[70]

Initial treatment for patients aged ≥60 years with high-risk disease is dose-adjusted R-EPOCH plus intrathecal methotrexate (for those presenting with symptomatic CNS disease).[70]

A clinical trial (if available) or palliative ISRT is recommended for patients who do not achieve a complete response after initial treatment.[70]

Burkitt's lymphoma: CNS prophylaxis/therapy

Adequate CNS prophylaxis/therapy with high-dose systemic methotrexate and intrathecal methotrexate and/or cytarabine is recommended with all regimens for Burkitt's lymphoma due to the high risk for CNS involvement.[70]

Relapsed or refractory Burkitt's lymphoma

Optimal treatment for relapsed or refractory Burkitt's lymphoma is unclear. Patients should be treated in a clinical trial where available.

If relapse occurs >6-18 months after initial treatment, the following regimens can be considered for second-line treatment and beyond (if not previously used):[70]

  • Dose-adjusted R-EPOCH plus intrathecal methotrexate

  • R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) plus intrathecal methotrexate (if not received previously)

  • R-IVAC plus intrathecal methotrexate (if not received previously)

Consolidation therapy with ASCT (with or without ISRT) should be considered after second-line treatment, depending on response.[70] Allogeneic SCT (with or without ISRT) may be considered for consolidation therapy in select patients (e.g., those with stem cell mobilisation failure and persistent bone marrow involvement) if a donor is available.

Patients with relapse occurring <6 months after initial therapy, or who do not respond to second-line treatment or have progressive disease, should be considered for a clinical trial or best supportive care (including palliative ISRT).[70]

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).[70][134]​​[148]

A small proportion of patients with MCL (10% to 15%) have indolent disease and can undergo active surveillance if asymptomatic.[70][132]​ Typical characteristics of indolent MCL include: IGHV-mutated; SOX11-negative; leukaemic or non-nodal MCL with splenomegaly; gastrointestinal, blood, or bone marrow involvement; low tumour burden; and Ki-67 proliferation fraction <10%.[70]

Most patients with MCL have rapidly progressing advanced-stage disease and need treatment at the time of diagnosis.[70][132]

Enrolment in a clinical trial should be considered, particularly for patients with advanced-stage disease and those with TP53 mutation.[70]

Initial treatment is typically given in phases (induction, consolidation, maintenance).

Localised MCL (stage I or stage II [non-bulky]) without TP53 mutations

Less aggressive induction therapy is recommended for patients with localised disease.[70] Options include:

  • Acalabrutinib plus bendamustine plus rituximab

  • Bendamustine plus rituximab

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

  • R-CHOP

  • Lenalidomide plus rituximab

  • Acalabrutinib plus rituximab

ISRT alone or combined with a less aggressive induction regimen is also an option for patients with stage I or contiguous stage II (non-bulky) disease.[70]

Select patients (e.g., those with good performance status) with asymptomatic noncontiguous stage II (non-bulky) disease may undergo active surveillance.[70]

Advanced MCL (stage II [bulky]; stage III-IV) without TP53 mutations: suitable for aggressive induction therapy and stem cell transplant

Aggressive induction therapy is recommended for patients with advanced disease.[70] Options include:​

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

  • NORDIC regimen: dose-intensified R-CHOP (known as R-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 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, and 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.[70] 

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.[70] Interim analysis of results from a phase 3 randomised trial suggest that patients who achieve complete remission with undetectable minimal residual disease after induction therapy may be less likely to benefit from consolidation ASCT in first remission.[149]

Advanced MCL (stage II [bulky]; stage III-IV) without TP53 mutations: 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.[70] Options include:​

  • Acalabrutinib plus bendamustine plus rituximab

  • 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 after induction therapy with bendamustine plus rituximab or R-CHOP, and who are not candidates for ASCT.[70]

TP53-mutated MCL

Patients with TP53-mutated MCL treated with conventional MCL therapy (including ASCT) have a poor prognosis.[150][151] Enrolment in a clinical trial is strongly recommended.[70]

The following options can be considered (followed by maintenance therapy) in the absence of a suitable clinical trial:[70]

  • Zanubrutinib plus obinutuzumab plus venetoclax (for all patients)

  • 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 (for patients suitable for aggressive induction therapy)

  • Less aggressive induction therapy (for patients not suitable for aggressive induction therapy)

Relapsed or refractory MCL

Although MCL is initially responsive to chemotherapy, the disease inevitably relapses.[152][153][154][155]

Preferred second-line treatments include:[70][156][157][158]​​​

  • Covalent BTK inhibitors (acalabrutinib; zanubrutinib)

  • Lenalidomide plus rituximab

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).[159]​ In Europe, ibrutinib continues to be approved for use in patients with relapsed or refractory MCL.

For patients with relapsed or refractory disease after two or more lines of systemic therapy (including a covalent BTK inhibitor), options include:[70][160][161]

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

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

  • Glofitamab (if progressive disease occurs after CAR T-cell therapy and pirtobrutinib, or if ineligible for CAR T-cell therapy)

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

High-grade B-cell lymphoma NOS appears blastoid or is intermediate between DLBCL and Burkitt's lymphoma, and lacks MYC and BCL2 rearrangements with or without BCL6 rearrangements.

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.[70]

The following rituximab-based chemotherapy regimens may be used for induction therapy:[70]

  • Dose-adjusted R-EPOCH

  • R-CHOP-21 (for patients with low risk or limited-stage disease [IPI <2])

  • R-mini-CHOP (for patients who are frail or older)

Consolidative ISRT is preferred for localised disease.[70]

High-grade B-cell lymphomas: CNS prophylaxis

Patients are at risk for CNS involvement.[162][163]​​ 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 systemic high-dose methotrexate and/or intrathecal methotrexate and/or cytarabine, given during or after treatment.

Aggressive T-cell lymphoma: peripheral T-cell lymphomas

Peripheral T-cell lymphomas (PTCLs) comprise: PTCL not otherwise specified (PTCL NOS); nodal T-follicular helper cell lymphomas (nTFHLs); systemic anaplastic large cell lymphoma (systemic ALCL); enteropathy-associated T-cell lymphoma (EATL); monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL).

Treatment for PTCLs is based on histopathology (e.g., CD30 expression), stage, and patient factors (e.g., age, fitness, comorbidities).[164]

Patients with PTCL (except those with ALK-positive ALCL) are often unsuitable for chemotherapy and have a poor prognosis because of older age and poor performance status at diagnosis.[165][166]​​ 

A clinical trial is preferred for most patients with PTCL. In the absence of a suitable clinical trial, or if a patient has ALK-positive ALCL, the following regimens can be used for first-line treatment:[71]

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

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

  • CHOP

  • Dose-adjusted EPOCH

ISRT may be combined with first-line treatment regimens.[71] Chemotherapy alone is, however, recommended for patients with stage III-IV ALK-positive ALCL.​

Peripheral T-cell lymphoma: consolidation therapy

Eligible patients in complete remission following initial therapy may be considered for consolidation therapy with ASCT.[71][167]​​​ However, the benefits of ASCT in peripheral T-cell lymphoma are unclear, and may be limited to certain subtypes.[168][169][170][171]​​​​

Relapsed or refractory peripheral T-cell lymphoma

Recommended second-line and subsequent treatments for patients with relapsed or refractory disease include:[71]

  • Belinostat

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

  • Duvelisib

  • Pralatrexate

  • Romidepsin

  • ALK inhibitors for ALK-positive ALCL (e.g., alectinib, brigatinib, ceritinib, crizotinib, lorlatinib)

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

Optimal management of SPTCL is unclear. Treatment can be guided by the presence of haemophagocytic lymphohistiocytosis (HLH) and tumour burden.[80]

The following regimens can be considered for first-line treatment of patients with HLH, systemic disease, or high tumour burden:[80]

  • 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):[80]

  • 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 (FL)

Treatment for classic FL is based on stage, indications for treatment (including symptoms; threatened end-organ function; clinically significant/progressive cytopenia secondary to lymphoma; clinically significant bulky disease; steady/rapid progression), and patient factors (e.g., age, fitness, comorbidities).[70]

Prognostic tools (e.g., Groupe d'Etude des Lymphomes Folliculaires [GELF] criteria or Follicular Lymphoma International Prognostic Index [FLIPI]) can help guide treatment. See Criteria.

Classic FL: localised disease (stage I or II)

Initial therapy includes ISRT and/or rituximab (with or without chemotherapy depending on tumour burden).[70]

Active surveillance may be considered for some patients (e.g., those with noncontiguous stage II disease in whom toxicity of treatment outweighs benefit).[70]

Classic FL: advanced-stage disease (stage III or IV)

Active surveillance is recommended for patients with no indication for treatment.[70]

Preferred first-line treatment regimens for those with high tumour burden and indications for treatment include:[70][172][173][174][175]

  • CHOP plus obinutuzumab or rituximab

  • Bendamustine plus rituximab or obinutuzumab

  • CVP (cyclophosphamide, vincristine, and prednisolone) plus obinutuzumab or rituximab

  • Lenalidomide plus rituximab

Preferred first-line treatment for patients with low tumour burden and indications for treatment is rituximab alone.[70]

Preferred first-line treatment for patients who are older or who have significant comorbidities is rituximab alone.[70] Chlorambucil (with or without rituximab) or cyclophosphamide (with or without rituximab) may also be considered for these patients.

First-line consolidation and maintenance therapy for classic FL (advanced-stage disease)

Consolidation with rituximab may be considered for patients with stage III or IV disease who respond to initial treatment with rituximab alone.[70]

Maintenance therapy with rituximab or obinutuzumab may be considered for patients with stage III or IV disease who respond to chemoimmunotherapy (depending on the initial regimen used and response achieved).[70]

Relapsed, progressive, or refractory classic FL

Patients with relapsed or progressive disease who have no indications for treatment can undergo active surveillance.[70]

Second-line treatments can be considered for patients with relapsed, progressive, or refractory disease who have indications for treatment.[70] Options include (if not used previously):​

  • CHOP plus obinutuzumab or rituximab

  • CVP plus obinutuzumab or rituximab

  • Bendamustine plus obinutuzumab or rituximab

  • Tafasitamab plus lenalidomide plus rituximab (if the patient has received ≥1 prior systemic therapy including anti-CD20 monoclonal antibody therapy [e.g., rituximab, obinutuzumab])

  • Lenalidomide with or without rituximab

  • Lenalidomide plus obinutuzumab

  • Obinutuzumab alone

  • Rituximab alone

Preferred second-line treatment for patients who are older or who have significant comorbidities is rituximab alone or tazemetostat.[70] 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.[70]

Third-line and subsequent treatment options include:[70]

  • Bispecific antibody therapy (epcoritamab; mosunetuzumab)

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

  • Tazemetostat

  • Zanubrutinib plus obinutuzumab

  • Loncastuximab tesirine plus rituximab

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

Indolent B-cell lymphoma: nodal and splenic marginal zone lymphoma (MZL)

Treatment for nodal MZL is based on stage, indications for treatment, and patient factors. The treatment approach and treatment options for nodal MZL are broadly the same as classic FL.[70]

Splenic MZL

Treatment is informed by the presence of splenomegaly, indications for treatment (e.g., symptoms; threatened end-organ function; cytopenias [including autoimmune cytopenia]; clinically significant bulky disease; steady or rapid progression), hepatitis C status, and patient factors.[70]

Patients who are asymptomatic with no splenomegaly or progressive cytopenias can be observed until indications for treatment develop.[70]

Patients with splenomegaly should be treated according to hepatitis C status.[70] Options include:

  • Hepatitis C treatment (if hepatitis C positive)

  • Active surveillance (if hepatitis C negative and asymptomatic)

  • Rituximab (if hepatitis C negative, and cytopenias or symptoms are present)

  • Splenectomy (in select hepatitis C-negative patients with cytopenias or symptoms or who are not responsive to rituximab)

For detailed information on hepatitis C treatment, see Hepatitis C topic.

Relapsed splenic MZL

Patients who relapse should undergo active surveillance if they have no indications for treatment.[70]

Systemic therapy, splenectomy, or palliative ISRT is recommended for patients who relapse and have indications for treatment.[70] 

Systemic therapy includes (if not used previously):[70] 

  • Rituximab

  • Bendamustine plus obinutuzumab

  • Bendamustine plus rituximab

  • Acalabrutinib

  • Zanubrutinib (after at least one prior anti-CD20 monoclonal antibody-based regimen)

  • Ibrutinib

  • Pirtobrutinib (after prior covalent BTK inhibitor therapy)

  • R-CHOP

  • R-CVP

  • Lenalidomide plus rituximab

  • Lenalidomide plus obinutuzumab

Axicabtagene ciloleucel can be considered for subsequent systemic therapy.[70]

For management of extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma) see MALT lymphoma.

Primary cutaneous B-cell lymphomas

Comprise primary cutaneous follicle centre lymphoma (PCFCL), primary cutaneous marginal zone lymphoma (PCMZL), and primary cutaneous DLBCL, leg type (PCDLBCL, leg type).[1][2]

Primary cutaneous follicle centre lymphoma and marginal zone lymphoma

Treatment options for localised PCFCL and PCMZL include:[80]

  • Local ISRT (preferred)

  • Surgical resection (for small isolated lesions)

  • Observation (if ISRT or surgical resection is neither feasible nor desired)

Patients with generalised disease or cosmetically disfiguring lesions may be managed with the treatment options recommended for localised PCFCL and PCMZL. Observation is appropriate for asymptomatic patients with generalised disease. Consider systemic treatment (e.g., rituximab with or without CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisolone]) for patients with extensive generalised disease.[80]

Primary cutaneous DLBCL, leg type

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

Recommended first-line treatments for patients with PCDLBCL, leg type include.[70]

  • R-CHOP plus local ISRT (for localised disease)

  • Local ISRT alone (for localised disease if unable to tolerate chemoimmunotherapy)

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

CNS prophylaxis may be considered for patients with PCDLBCL, leg type due to the increased risk for CNS relapse with this subtype.[70][176]

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

Treatments for localised PC-ALCL (solitary or grouped lesions) include:[80]

  • 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.[80]

ISRT may be combined with brentuximab vedotin, or used alone, in select patients with regional node involvement.[80]

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.[71]​ Suspicious lymph nodes detected during explantation should be biopsied.

Removal of the contralateral breast implant can be considered; bilateral disease is reported in approximately 4.6% of cases.[71][177]

Systemic therapy (e.g., brentuximab vedotin with or without CHP; CHOP; CHOEP; dose-adjusted EPOCH) should be considered for patients with BIA-ALCL who present with an unresectable breast mass, or those with extended disease (stage II to IV).[71]

Debulking surgery before systemic therapy may be considered for patients with disseminated stage IV disease, but this should be discussed with a multidisciplinary team.[178]

​Re-excision surgery alone (without systemic therapy) may be possible for local disease relapse.[71]

The US Food and Drug Administration (FDA) recommends that cases of BIA-ALCL should be reported to a national disease registry (e.g., PROFILE Registry).[179]​​

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, and hypocalcaemia, which can occur following treatment for NHL (or spontaneously in rare cases).

  • Treatment-related neutropenia: patients receiving curative chemotherapy (e.g., R-CHOP) should be considered for prophylactic granulocyte colony-stimulating factor (G-CSF).[180]​​[181][182]​​​​ All patients receiving salvage chemotherapy should receive a G-CSF concomitantly to prevent treatment-related neutropenia.[181][183]​​​

  • Infection: antibiotic prophylaxis should be considered for patients with severe neutropenia (absolute neutrophil count <500 cells/microlitre [<0.5 × 10⁹/L]).[184]

  • Haemorrhagic cystitis: mesna should be used to manage haemorrhagic cystitis in patients receiving high-dose cyclophosphamide or ifosfamide.[185]​ 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.[70]​ Glucarpidase should be used to reduce toxic plasma methotrexate concentration in patients with significant renal dysfunction who are receiving high-dose methotrexate.[70]

  • Chemoimmunotherapy-related toxicity: R-CHOP is relatively well tolerated, with the main toxicities being haematological (bone marrow suppression), infection (neutropenia), cardiac (from doxorubicin), alopecia, infusion-related respiratory symptoms (with or without bronchospasm), chills, fever, and hypotension (from rituximab).[186]

  • CAR T-cell-related toxicity: cytokine release syndrome (CRS), neurotoxicity, and T-cell malignancies may occur with CAR T-cell therapy, and can be fatal or life-threatening.[135][136][137]​ Tocilizumab is recommended for the management of patients with prolonged or severe CAR T-cell-associated CRS.[135] Cardiovascular complications (including myocardial ischaemia, venous thromboembolism, decreased left ventricular systolic function, and cardiogenic shock) may also occur with CAR T-cell therapy.[138][139]

  • BTK inhibitor-related toxicity: cardiovascular complications (including hypertension; atrial fibrillation; and ventricular arrhythmias, with related sudden cardiac death) may occur with BTK inhibitor therapy.[187][188][189][190][191]​ These events have occurred particularly in patients with cardiac risk factors (e.g., hypertension and diabetes mellitus) or a previous history of cardiac arrhythmias, and in patients with acute infections. Clinical evaluation of cardiac history and function should be performed prior to initiating BTK inhibitors. Patients should be carefully monitored for cardiac arrhythmias and signs of deterioration of cardiac function during treatment, 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.

See Complications for further detail.

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