Jun Zhu,Jun Ma,Union for China Lymphoma Investigators of Chinese Society of Clinical Oncology

1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing),Department of Lymphoma,Peking University Cancer Hospital &Institute,Beijing 100142,China;2 Department of Hematology &Oncology,Harbin Institute of Hematology &Oncology,Harbin 150010,China

1.General guidelines

2.Diagnosis

3.Staging

4.Treatment

4.1 Diffuse large B-cell lymphoma (DLBCL)

4.2 Follicular lymphoma (FL)

4.3 Mantle cell lymphoma (MCL)

4.4 Marginal zone lymphoma (MZL)

4.5 Burkitt lymphoma (BL)

4.6 CLL/Small lymphocytic lymphoma (SLL)

4.7 Extra-nodal natural killer/T-cell lymphoma(ENKTCL),nasal type

4.8 Peripheral T-cell lymphoma (PTCL)

4.9 HL

4.10 Primary central nervous system lymphoma

5.Prognosis

Lymphomas are a group of heterogeneous diseases,which is divided into two main categories:Hodgkin lymphoma(HL) and non-Hodgkin lymphoma (NHL).There is an estimated 75,400 incidence cases and 40,500 deaths annually in China,of which NHL accounts for about 90%of lymphoma burden (1,2).

1.General guidelines

Pre-treatment evaluation includes clinical evaluation,physical examination,laboratory examination,imaging examination and histological examination. Clinical evaluation includes age,sex,tumor-related symptoms such as fatigue and pruritus.B symptom (fever to more than 38.3 °C,drenching night sweats,or unexplained weight loss of more than 10% of body mass over 6 months) is recorded.Physical examination includes measurement of palpable lymph nodes and hepatosplenomegaly.Hepatitis B virus(HBV) surface antigen (HBsAg) and anti-hepatitis B core antibody (anti-HBc) are examined,and HBV DNA is examined once HBsAg or anti-HBc is positive.Prophylactic anti-HBV therapy is administered during chemotherapy or anti-CD20 antibody-based immunotherapy if HBsAg or HBV DNA is positive.Imaging examination including computed tomography (CT) or positron emission tomography (PET)-CT is employed for staging and response assessment.

Chemotherapy-based mode is preferred for most aggressive lymphomas.Anthracyclines-based regimens are commonly used,of which rituximab is used for CD20-positive lymphomas.Indication-oriented individualized strategies should be considered for most indolent lymphomas.“Watch and wait” approach is used for patients without therapeutic indication,and chemotherapy or target therapy is used for those who are suitable for initialization of therapy.

2.Diagnosis

Pathological types are based on the 2016 revision of the World Health Organization classification of lymphoid neoplasms (3). Pathological diagnosis,based on morphology,immunohistochemistry,flow cytometry and cytogenetics,is vitally important for comprehensive diagnosis.Complete or partial resection of lesion is the preferred biopsy method,which provides a basis of accurate pathological diagnosis.Core needle biopsy is an alternative method for those unresectable masses.However,fine needle biopsy is not recommended.Of note is that clinical,laboratory,and imaging data are equally important.Thus,multidisciplinary team (MDT) is emphasized in both diagnosis and treatment procedure.

3.Staging

The staging criteria recommended in the Lugano classification are applicable for nearly all types of lymphoma (Table 1) (4).In addition,chronic lymphocytic leukemia (CLL),primary gastrointestinal tract lymphoma and primary cutaneous lymphoma have their unique staging systems.

4.Treatment

4.1 Diffuse large B-cell lymphoma (DLBCL)

As shown inTable 2,the strategy for newly-diagnosed patients with DLBCL depends on age,tumor size,cardiac function and prognostic scores such as international prognostic index (IPI) and age-adjusted international prognostic index (aaIPI).Both anthracycline and anti-CD20 monoclonal antibody are crucial for the treatment of DLBCL (5).The most common regimen is R-CHOP(rituximab,cyclophosphamide,doxorubicin,vincristine and prednisone).Radiotherapy is applied for patients who have bulky disease (≥7.5 cm) or extranodal invasion at baseline,and for those who can’t achieve complete remission at the end of induction chemotherapy.Central nervous system(CNS) prophylaxis with intrathecal or intravenous methotrexate is recommended for patients with high risk according to CNS-IPI (6).

Salvage chemotherapy with individualized regimens such as ICE (ifosfamide,carboplatin and etoposide),GDP(gemcitabine,dexamethasone and cisplatin) or DHAP(dexamethasone,high-dose cytarabine and cisplatin) is recommended for relapsed/refractory patients.Autologous stem cell transplantation (ASCT) consolidation is recommended for transplant-eligible patients who achieved remission from salvage therapy (7).Clinical trials including chimeric antigen receptor T-cell immunotherapy (CAR-T)are options,especially for patients who are ineligible for ASCT or resistant to salvage therapy.

4.2 Follicular lymphoma (FL)

The Chinese Society of Clinical Oncology (CSCO)guidelines for FL is applicable for patients with grade FL1-3a.Patients with grade FL3b and histologicallytransformed lymphoma should be treated according to clinical practice guidelines for DLBCL.

As shown inTable 3,involved-site radiotherapy (ISRT) is appropriate for patients with stage I or contiguous stage II disease,while anti-CD20 monoclonal antibody-based immunotherapy with or without chemotherapy and ISRT is preferred for those with non-contiguous stage II disease.For stage III-IV disease,“watch and wait” approach is applicable for patients without treatment indication,while chemotherapy with or without immunotherapy is an option for those with treatment indication (8).The common front-line chemotherapy regimens include R-CHOP,RCVP (rituximab,cyclophosphamide,vincristine and prednisone),BR (bendamostine and rituximab) and R2(lenalidomide and rituximab).Rituximab maintenance can be chosen for those responders for rituximab-based therapy who have high tumor burden at baseline (9,10).

Table 1 Staging criteria for lymphoma according to Lugano classification

Table 2 Treatment strategies for newly-diagnosed diffuse large B-cell lymphoma

Table 3 Treatment strategies for newly-diagnosed follicular lymphoma

The choice of salvage treatment depends on age,physical condition,pathological type and previous treatment efficacy.Original or alternative front-line regimens can be used for patients with long-term remission (＞12 months)after front-line treatment,while non-cross-resistance regimens can be used for those who had early relapse (＜12 months) or refractory diseases.ASCT can be used for thosetransplant-eligible patients who are sensitive to salvage chemotherapy.

4.3 Mantle cell lymphoma (MCL)

For newly-diagnosed MCL,treatment selection is based on age and fitness.Intensive therapies are preferred for young and fit patients,and non-intensive approaches are appropriate for elderly or frail patients (Table 4).Immunochemotherapy is required for stage I-II disease with large tumor burden or adverse prognostic features and stage III-IV disease.The regimens based on rituximab and high-dose cytarabine,including R-CHOP alternating with R-DHAP (rituximab,dexamethasone,high-dose cytarabine and cisplatin),dose-intensified R-CHOP alternating with high-dose cytarabine,R-hyper-CVAD/MA (rituximab,cyclophosphamide,vincristine,doxorubicin,dexamethasone,methotrexate and cytarabine) are preferred.For patients with stage I-II disease,ISRT can be chosen for limited non-bulky diseases,and consolidation radiotherapy after systemic chemotherapy may be considered for diseases with large tumor burden.For transplant-eligible patients,consolidation ASCT followed by rituximab maintenance is preferred (11).For elderly or frail patients,rituximab combined with less aggressive regimens such as CHOP or bendamustine can be used as induction chemotherapy,and rituximab maintenance may be used for those responders.

Non-cross-resistant approaches such as bendamustinecontaining regimens are preferred as salvage treatment.Lenalidomide and venetoclax,Bruton tyrosine kinase(BTK) inhibitors such as ibrutinib,zanubrutinib,and orelabrutinib,can be considered,especially for patients with early relapsed or refractory diseases (12).ASCT or allogeneic stem cell transplantation (allo-SCT) should be a consolidation option for transplant-eligible patients.

4.4 Marginal zone lymphoma (MZL)

The front-line therapy of MZL refers to the primary site and disease stage (Table 5).For primary gastric disease,Helicobacter pylori(H.pylori) eradication is preferred forH.pylori-positive stage I disease,and radiotherapy is chosen for primary gastric stage II disease,bulky tumor,translocation with t(11;18) and no-responders for anti-H.pyloritherapy. For non-gastric stage I-II disease,radiotherapy is an option for most patients while rituximab can be applied to radiotherapy-ineligible patients.Splenectomy is the diagnostic and therapeutic approach for spleen MZL,and anti-HCV therapy is considered when HCV is positive.For stage III-IV disease,“watch and wait”approach is used for patients without treatment indication,and rituximab combined with cytotoxic drugs such as chlorambucil,bendamustine,CHOP and CVP regimens is the common therapeutic approach for those who need initiation of treatment (13,14).

For salvage treatment,prior regimens can be re-used if the duration of response exceeded 2 years.BTK inhibitors including ibrutinib or zanubrutinib are reasonable choices,especially for early relapsed or refractory diseases (15).In addition,the clinical trial is a reasonable option.

4.5 Burkitt lymphoma (BL)

As shown inTable 6,dose-intensive multi-agent chemotherapy with CNS prophylaxis is preferred for newly-diagnosed BL.Dose-intensive regimens including CODOX-M-R (cyclophosphamide,vincristine,doxorubicin,methotrexate and rituximab),CODOXM/IVAC-R (CODOX-M/IVAC-R,cyclophosphamide,vincristine,doxorubicin,methotrexate,ifosfamide,etoposide,cytarabine and rituximab),R-hyper-CVAD/MA,and DA-EPOCH-R (dose-adjusted etoposide,prednisone,vincristine,cyclophosphamide,doxorubicin and rituximab)are commonly used,while R-CHOP regimen is not adequate (16,17).CNS prophylaxis is applied with systemic and/or intrathecal chemotherapy with methotrexate and/or cytarabine.

Table 4 Treatment strategies for newly-diagnosed mantle cell lymphoma

Table 5 Treatment strategies for newly-diagnosed marginal zone lymphoma

Table 6 Treatment strategies for newly-diagnosed Burkitt lymphoma

For relapsed or refractory disease,clinical trials are preferred treatment options.When clinical trials are not suitable,non-cross-resistance chemotherapy with ICE,GDP,EPOCH (rituximab,etoposide,prednisone,vincristine,cyclophosphamide and doxorubicin) and IVAC(ifosfamide,etoposide and cytarabine) regimens can be used.Consolidation ASCT or allo-SCT is applied for patients who achieve remission (18).

4.6 CLL/Small lymphocytic lymphoma (SLL)

Rai (19) and Binet (20) staging system are applied for CLL while Lugano staging system is applied for SLL.For newly-diagnosed CLL/SLL,“watch and wait” approach is applied when a patient has no treatment indications including progressive marrow failure,massive or progressive or symptomatic splenomegaly,massive or progressive or symptomatic lymphadenopathy,progressive lymphocytosis,autoimmune complications,symptomatic or functional extranodal involvement,and disease-related symptoms.As shown inTable 7,front-line therapy choice is based onTP53status and comorbidities when treatment indications are present.For patients without del(17p)/TP53mutation,BTK inhibitors,venetoclax,bendamustine and FCR (fludarabine,cyclophosphamide and rituximab)regimens can be used.For patients with del(17p)/TP53mutation,BTK inhibitors are preferred (21-23).

For patients who have a relapse within 3 years,refractory disease,del(17p)/TP53mutation,individualized strategy including BTK inhibitors (i.e.ibrutinib,zanbrutinib,orelabrutinib),venetoclax,lenalidomide and high-dose methylprednisolone with rituximab can be applied.For patients who relapse 3 years after induction therapy and have no del(17p)/TP53mutation,repeat of first-line regimen can be considered.The clinical trial is a treatment option.

4.7 Extra-nodal natural killer/T-cell lymphoma(ENKTCL),nasal type

For newly-diagnosed ENKTCL,treatment models are based on stage and risk stratification (24).As shown inTable 8,combined radio-chemotherapy is preferred for stage I-II disease,and chemotherapy with asparaginasecontaining regimens is often used for stage III-IV disease(25-27). Risk stratification is recommended for the treatment of early-stage ENKTCL,in which radiotherapy alone with an optimal dose of 50 Gy can be chosen as primary therapy for low-risk patients,while sequential chemotherapy and radiotherapy are mostly used for intermediate-and high-risk patients.Asparaginase-based or pegaspargase-based chemotherapy with SMILE(dexamethasone,methotrexate,ifosfamide,L-asparaginase and etoposide),P-GemOx (pegaspargase,gemcitabine and oxaliplatin),DDGP (dexamethasone,cisplatin,gemcitabline,and pegaspargase),COEP-L (cyclophosphamide,vincristine,etoposide,prednisone and L-asparaginase),AspaMetDex (L-asparaginase,methotrexate and dexamethasone) regimens are used for stage III/IV disease.ASCT is used for transplant-eligible patients.

Table 7 Treatment strategies for newly-diagnosed chronic lymphocytic leukemia

Table 8 Treatment strategies for newly-diagnosed extra-nodal natural killer/T-cell lymphoma,nasal type

For relapsed or refractory diseases,clinical trials such as anti-PD-1 antibody and chidamide are treatment options.In absence of suitable clinical trials,salvage chemotherapy with non-cross-resistance regimens can be used.Although it is controversial,ASCT can be considered for patients who achieved a complete remission after salvage treatment (28).

4.8 Peripheral T-cell lymphoma (PTCL)

For newly-diagnosed PTCL,there are limited data to support a specific treatment model.As shown inTable 9,CHOEP regimen is commonly used for ALK-positive anaplastic large cell lymphoma (ALCL,ALK+),while clinical trials are optimal for other PTCL subtypes including PTCL-not otherwise specified (PTCL-NOS),angioimmunoblastic T-cell lymphoma (AITL) and ALKnegative anaplastic large cell lymphoma (ALCL,ALK-).Consolidation ASCT is applied for transplant-eligible patients achieving remission (29-31).

For relapsed or refractory diseases,participation in a clinical trial is preferred.In the absence of suitable clinical trials,salvage therapy with single agents such as pralatrexate (32),chidamide (33),and bendamustine or with multiagent regimens such as ICE,DHAP,GDP,ESHAP(etoposide,methylprednisolone,cytarabine and cisplatinum),and GemOx (gemcitabine and oxaliplatin) are considered.Brentuximab vedotin can be used for systemic ALCL.Crizotinib can be used for ALCL,ALK+.ASCT or allo-SCT is applied for transplant-eligible patients.

4.9 HL

For newly-diagnosed classic Hodgkin lymphoma (CHL),treatment strategy is based on stage and prognosis risk stratification.PET-guided adjustment strategy is preferred.As shown inTable 10,the combined chemoradiotherapy with ABVD (doxorubicin,bleomycin,vinblastine anddacarbazine) or BEACOPP (bleomycin,etoposide,doxorubicin,cyclophosphamide,vincristine,procarbazine and prednisone) regimen is preferred for stage I-II disease,while chemotherapy with or without radiotherapy is commonly applied to stage III-IV disease.For nodular lymphocyte-predominant HL,stage IA disease without unfavorable factors can be treated with radiotherapy alone,other conditions refer to the treatment principles of CHL.

Table 9 Treatment strategies for newly-diagnosed peripheral T-cell lymphoma

For relapsed or refractory disease,salvage chemotherapy followed by ASCT is preferred (34,35).Immune checkpoint inhibitors (i.e.sintilimab,tislelizumab,camrelizumab,nivolumab,pembrolizumab,and zimberelimab) and brentuximab vedotin can be considered to integrate into salvage regimens (36-38).

4.10 Primary central nervous system lymphoma

For newly-diagnosed patients with primary central nervous system lymphoma,high-dose methotrexate-based chemotherapy is preferred (Table 11). Whole brain radiotherapy (WBRT) with a dose of 45 Gy can be utilized for patients who could not tolerate systemic chemotherapy.Both ASCT and WBRT are considered as consolidation therapy,but the long-term neurotoxicity of WBRT should be paid attention (39,40).

Table 10 Treatment strategies for newly-diagnosed classic Hodgkin lymphoma

Table 11 Treatment strategies for newly-diagnosed primary central nervous system lymphoma

For relapsed or refractory diseases,clinical trials are preferred.In the absence of suitable clinical trials,highdose methotrexate can be reused for patients who achieve＞1 year of duration of remission,while non-cross-resistance chemotherapy and WBRT can be used for other conditions.BTK inhibitors including ibrutinib,zanbrutinib and orelabrutinib can be considered.ASCT can be conducted as consolidation strategy for patients who achieved complete remission after salvage therapy.

5.Prognosis

Pathological type plays a crucial role in the prognosis of lymphoma (41-43). Moreover,multiple clinical and laboratory data further determined prognosis.Of note is iteration of prognosis model over time.For example,IPI is widely used for most aggressive lymphomas in the pretarget therapy era,and the revised IPI (R-IPI) and the National Comprehensive Cancer Network IPI (NCCNIPI) are developed for DLBCL in the target therapy era(44).In addition,some pathological types such as FL and MCL have unique prognosis assessing systems (45,46).