• Adverse prognostic factors in early primary HL: different study groups on early
  

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, and accounts for about 60% of adult NHL in Europe and the United States.

30 to 40 , with China accounting for 35 ~50. The median age of onset of DLBCL is 50 to 70 years, with slightly more men than women.

and Ki-67, but also markers needed for differential diagnosis, such as CD23, CD5, and cyclin D1 for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and MCL. FL often has t(14;18) translocations and resulting Bcl2 protein overexpression, but there is varying degrees of loss with increasing grade, making it difficult to confirm the diagnosis, and FISH BCL2 testing can be performed when necessary.

Pediatric-type follicular lymphoma (PTFL) is a type of lymph node disorder that occurs primarily in children and young adults.

The 2017 edition of the WHO Classification of Tumors of the Hematopoietic and Lymphoid Tissues newly introduced “duodenal follicular lymphoma,” which has a good prognosis and needs to be distinguished from FL in other gastrointestinal anatomic sites; the newly introduced “large B-cell lymphoma with IRF4 gene rearrangement,” which occurs in the pharyngeal lymphatic ring and cervical lymph nodes and is common in children and young adults. The newly proposed “large B-cell lymphoma with IRF4 gene rearrangement”, which occurs in the pharyngeal lymphatic ring and cervical lymph nodes, is more common in children and young adults, and has a histologic presentation consistent with classic high-grade FL, with IHC showing IRF4+/CD10+/BCL6+ and FISH showing IRF4 rearrangement. In addition, the previous in situ follicular lymphoma was changed to in situ follicular neoplasm. Bone marrow cytology: When the tumor cells involve the bone marrow, nucleated cell proliferation can be significantly active, mainly with an increase in FL cells, which are larger than normal lymphocytes, with round or irregular nuclei, fine nuclear chromatin, faintly visible nucleoli, abundant cytoplasm and light blue color, and some FL cells with vacuolar degeneration. The diagnosis of FL is based on pathologic histology.

• Treatment: Grade 1 to 2 FL is an inert lymphoma, and depending on the stage, the treatment strategy is as follows. Grade 3 FL is treated as DLBCL.
  

  Stage I/II FL: Patients with stage I/II have a potential cure with radiotherapy. In stage I and stage II patients with limited lesions and no large masses, radiotherapy is the mainstay. Treatment is preferred to ISRT, or ISRT + CD20 monoclonal antibody ± chemotherapy; in special cases where radiotherapy is not possible, CD20 monoclonal antibody ± chemotherapy can be chosen. Stage I with a large mass or

Stage II patients with extensive lesions, refer to the treatment strategy of stage III/IV, and recommend mainly medical treatment with CD20 monoclonal antibody±chemotherapy±palliative ISRT, or in the absence of treatment indications observational follow-up.

②Stage III/IV FL: Stage III/IV FL is considered to be an incurable disease. In stage III/IV FL with low tumor load, there is no difference in patient OS when treated immediately after diagnosis versus observational follow-up and treatment when indicated.

Patients without indication for treatment may have a physical or laboratory examination every 3 to 6 months for 5 years and once a year after 5 years, and a CT examination ≥6 months for 2 years and ≥1 year after 2 years.

Patients with indications for treatment need to be treated. Indications for treatment include availability for appropriate clinical trials, high tumor load, symptomatic, organ function threatening, secondary hematocrit, large masses, and persistent lesion progression.

FL’s recommended first-line regimens include R-B (rituximab, bendamustine), R-CHOP or G-CHOP (otuzumab, cyclophosphamide, adriamycin, vincristine, prednisone), R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) monoclonal, cyclophosphamide, vincristine, prednisone) or G-CVP (otuzumab, cyclophosphamide, vincristine, prednisone) and R-R (rituximab, lenalidomide). Rituximab monotherapy is an option for some patients with low tumor load. In elderly and frail patients, single agent rituximab, or single agent alkylating agents (e.g., nitrogen mustard phenylbutyrate, cyclophosphamide) ± rituximab, etc. are recommended. In patients with primary, high tumor load, rituximab maintenance therapy may prolong PFS after induction chemotherapy to achieve CR or PR.

③ Treatment of relapsed refractory FL: Watchful follow-up remains preferred for relapsed FL when

Treatment is indicated before starting rescue therapy. The histologic transformation should be highly suspected when the standard uptake values on PET-CT are significantly higher.

Rituximab therapy can be continued if relapse progression occurs more than 6 months after the last dose of rituximab. Depending on the first-line regimen, recommended second-line regimens include R-B, R-CHOP, R-CVP, or R-R. For patients with progression of disease (POD) within 24 months of the start of first-line treatment with R-CHOP or R-CVP regimens, lenalidomide-based regimens, participation in clinical trials, or HDT/ASCT are recommended as consolidation therapy. Rituximab maintenance therapy is also an option after remission with second-line induction chemotherapy. Anti-CD19 CAR-T therapy is an option for patients who fail second-line and above.

About 15Histologic conversion to DLBCL can occur in about 15 of FL, with an annual conversion rate of

2 ~3 . Risk factors associated with histologic transformation include late stage, high follicular lymphoma international prognostic index (FLIPI), increased LDH, and B symptoms. Active treatment and follow-up have no significant impact on the rate of conversion. The prognosis of transformed FL is usually poor, and factors such as staging at the time of transformation, whether the patient has received chemotherapy or rituximab prior to transformation, and whether the patient is transformed to double- or triple-hit DLBCL are associated with prognosis. Treatment of transformed FL is referenced to DLBCL.

④Prognosis: FLIPI has two scoring systems, FLIPI1 and FLIPI2, with a score of

containing 5 independent poor prognostic factors, both of which classify patients into 3 risk groups.

The FLIPI1 scoring system score of 0 to 1 was the low risk group, 2 was the intermediate risk group, and ≥3 was the high risk group; the FLIPI2 scoring system score of 0 was the low risk group, 1 to 2 was the intermediate risk group, and 3 to 5 was the high risk group (Appendix 4.3). event-free survival after POD24 or first-line immunochemotherapy was An event-free survival time of ≤12 months after POD24 or first-line immunochemotherapy is indicative of a poor prognosis. In one study, the 5-year overall survival rate for POD24 and non-POD24 patients after first-line treatment with R-CHOP regimen was 50 and 90.

Marginal zone lymphoma is a B-cell lymphoma that originates from the marginal zone and is an inert lymphoma. There are three subtypes according to the site of origin: extra-nodal marginal zone lymphoma [also known as mucosa-associated lymphoid tissue (MALT) lymphoma], lymph node marginal zone lymphoma, and splenic marginal zone lymphoma. Of these, MALT lymphoma is the most common.

The etiology of marginal zone lymphoma is associated with persistent immune stimulation due to chronic infection or inflammation. For example, gastric MALT lymphoma is associated with chronic infection with Hp, thyroid MALT lymphoma is associated with Hashimoto’s thyroiditis, parotid MALT lymphoma is associated with desiccation syndrome, and hepatitis C virus infection is associated with marginal zone lymphoma of the lymph nodes and splenic marginal zone lymphoma.

The pathologic diagnosis of marginal zone lymphoma is more of an exclusionary approach, with nonspecific immunomarkers that require the exclusion of other types of small B-cell lymphomas, and CD21 and CD23 often showing an expanded FDC network. The pathology often shows clonal proliferation of small lymphocytes, causing widening of the marginal zone, atrophy of the germinal center, follicular “implantation” and lymphoepithelial lesions.

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• MALT lymphoma: The most common primary site of MALT lymphoma is the stomach. primary site is the stomach
  

Intestinal tract, with gastric primary accounting for about 80~85 . About 2/3 of patients have limited stage, 1/3 have extensive stage, and the percentage of bone marrow invasion is about 10 to 15 .

1) Gastric primary MALT lymphoma: clinical features: symptoms include dyspepsia, acid reflux, abdominal pain and weight loss, B symptoms are uncommon, and gastric bleeding is about

20 to 30 , perforation ratio of about 5 ~10 . Stage I and II patients account for 80to

90 , 90 , 90 of patients are Hp-positive. Gastroscopy may show erythema, erosion, and ulceration of the gastric mucosa.

Pathologic diagnosis: Gastric MALT lymphoma requires gastroscopic biopsy for pathologic diagnosis and routine Hp staining. MALT lymphoma typically has a dense proliferation of small lymphocytes that in most cases infiltrate and disrupt the mucosal epithelium, forming a lymphoepithelial lesion. IHC markers include CD3, CD5 MALT lymphoma can be diagnosed after excluding FL, CLL/SLL and MCL, in combination with morphology and B-cell phenotype. In a few cases, PCR-Ig assay was required to obtain monoclonal evidence to confirm the diagnosis. To determine whether a gastric MALT lymphoma is Hp-dependent, t(11;18) translocations can be detected by FISH or PCR, and t(11;18) translocations are indicative of poor anti-Hp therapy. The diagnosis of DLBCL with MALT lymphoma should be made when bulky transformed lymphocytes show solid or sheet-like hyperplasia.

Treatment principles: Stage I/II: anti-Hp therapy is recommended for Hp-positive, t(11;18)-negative or unknown patients; anti-Hp therapy in combination with ISRT is preferred for Hp-positive, t(11;18)-positive patients; anti-Hp in combination with ISRT is also preferred if radiotherapy is contraindicated. Anti-Hp therapy in combination with rituximab is also an option if radiotherapy is contraindicated. For patients who are not responding to anti-Hp therapy or are Hp-negative, ISRT is recommended, and for patients who are not candidates for radiotherapy, rituximab alone may be chosen.

Drug therapy. After anti-Hp therapy, the first gastroscopy review can be done after 3 months, and if the gastroscopy suggests remission of the lesion, gastroscopy can be performed every 3-6 months thereafter. stage IIE, III/IV: Those without indications for treatment can opt for observation and follow-up, and those with indications for treatment refer to the principles of treatment for stage III/IV FL, and surgical treatment is limited to exceptional cases such as the occurrence of hemorrhage and perforation.

②Non-gastric primary MALT lymphoma: Clinical features: Non-gastric primary MALT lymphoma presents an inert course with a prognosis similar to that of gastric primary MALT lymphoma. Common sites of non-gastric primary MALT lymphoma include salivary glands, lung, head and neck, ocular appendages, skin, thyroid, and breast.

Treatment principles: ISRT or surgery is preferred for stage I/II. Those who may have serious complications due to treatment may also be treated with observational follow-up or rituximab monotherapy. For stage III/IV, refer to the treatment strategy for stage III/IV FL.

• Lymphoma of the lymph node marginal zone: clinical features: 1.5 of all lymphomas~1.8 , with a median age at presentation of 60 years and similar proportions of men and women, and a prevalence of advanced lesions. It mainly involves the lymph nodes, but occasionally the bone marrow and peripheral blood. Most patients present with painless multiple lymph node enlargement, with the exception of patients with MALT lymphoma or splenic marginal zone lymphoma with lymph node involvement.
  

  Pathologic diagnosis: Similar structural features to splenic marginal zone lymphoma, non-specific immunophenotype, similar to other subtypes of marginal zone lymphoma.

  Treatment principles: refer to the treatment principles of FL.

  Prognosis: 5-year overall survival rate of 60 to 80 , prognosis can be determined by referring to FLIPI.

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  • Lymphoma of the splenic marginal zone: clinical features: accounts for 2, in
    

  The median age of onset is 50 years, with equal proportions of men and women. The spleen and splenic hilar lymph nodes are often involved.

It also frequently involves the bone marrow, peripheral blood, and liver. The main manifestation is splenomegaly, which may be accompanied by autoimmune thrombocytopenia, anemia, and hair cells seen in the peripheral blood. Laboratory tests must include testing for hepatitis C virus.

Pathologic diagnosis: The histology is similar to that of lymph node marginal zone lymphoma, and the immunophenotype is nonspecific. The diagnosis can be based on the presence of abnormal small lymphocytes in the bone marrow or peripheral blood with clinical manifestations of splenomegaly, after exclusion of FL, CLL/SLL, MCL, etc.

Treatment principles: Patients with asymptomatic, non-progressive hematocrit and no splenomegaly can be followed up. For patients with splenomegaly and positive hepatitis C virus, if there is no contraindication to treatment, anti-hepatitis C virus treatment can be given. Patients with splenomegaly and negative for hepatitis C virus may be followed up if they are asymptomatic; for patients with symptoms, rituximab monotherapy is preferred, and splenectomy is recommended for patients for whom rituximab therapy is not effective. For patients who progress after these treatments, refer to the treatment strategy for stage III/IV FL.

CLL/SLL are inert B-cell lymphomas, and CLL and SLL are different presentations of the same disease with the same treatment. The main difference between the two is that CLL presents with a large, abnormal number of lymphocytes in the peripheral blood, whereas in SLL the tumor load is mainly located in the lymph nodes. SLL is defined by the International Working Group on Chronic Lymphocytic Leukemia as having enlarged lymph nodes and/or splenomegaly, no hematocrit due to bone marrow invasion, and a peripheral blood clonal B-cell count <5×109/L. SLL requires histopathological confirmation by lymph node biopsy, whereas flow cytology is usually is sufficient to diagnose

Determination of CLL, with lymph node biopsy and bone marrow biopsy required when diagnosis is difficult. The diagnosis of CLL requires the following criteria: peripheral blood clonal B-cell count ≥5×109/L; clonal B-cell phenotype confirmed by flow cytometry; typical immunophenotype is CD19

(+), CD5(+), CD23(+), CD200(+), CD20(weak+), CD79b

(weak+), FMC-7 (-), CD10 (-), CyclinD1 (-). If the peripheral blood clonal B-cell count does not reach 5×109/L, but there is hematocrit due to bone marrow invasion, CLL is still diagnosed.

CLL/SLL accounts for approximately 7 percent of NHL in Europe and the United States to 10 , and is the most common type of adult leukemia. The incidence of CLL/SLL in Asia and China is low, accounting for about 1to 3 of NHL src=”https://www.kiraspecialist.com/wp-content/uploads/2022/06/062222_1008_202268.png” alt=””/>. The median age of onset is 65 years, and the male to female ratio is 1.5:1 to 2:1.

• Clinical manifestations: The lesions usually involve peripheral blood, bone marrow, lymph nodes, and liver and spleen. The clinical manifestations are varied, with most patients being asymptomatic and some presenting with malaise, autoimmune anemia, infection, and hepatosplenomegaly and lymph node enlargement.
  
• Pathologic diagnosis: typical CLL/SLL cells are monolithic, diffusely infiltrating with pseudofollicular formation （IHC phenotype: CD5(+), CD23(+), CD43
  

  (+) or (-), CD10 (-), CD19 (+), CD20 (weakly +), LEF1 (+). When MCL needs to be identified, other markers such as Cyclin D1, SOX11 can be added. the presence of proliferative foci is easily misdiagnosed as reactive hyperplasia. All have monoclonal B-cell hyperplasia in the anterior phase.

  Blood counts: persistently elevated white blood cells and lymphocytes, often >50 when classified as better differentiated CLL cells and can reach 80 to 90 , with a form similar to

Normal lymphocytes, but with irregularly shaped nuclei, deep cuts or nuclear fissures, irregularly aggregated nuclear chromatin, low cytosolic mass, and gray-blue color without granules. Ruptured cells (basket cells) are more common; a small number of naïve lymphocytes are seen, usually <

2 . When peripheral blood naïve lymphocytes are >55 , the diagnosis is B-CLL/juvenile lymphocytic leukemia. Thrombocytopenia is seen in advanced stages.

Bone marrow cytology: markedly active or extremely active proliferation of nucleated cells in the bone marrow. The lymphatic lineage is highly proliferative, with predominantly abnormal mature small lymphocytes accounting for 40

or more, even up to 90. The cells are basically the same size and morphology as the peripheral blood, with inconspicuous morphological abnormalities. The nuclei may have deep cuts or fissures, irregular aggregation of nuclear chromatin, no or inconspicuous nucleoli, a small amount of cytoplasm, and no granules. Some medium to large lymphocytes may also be interspersed. Primitive, naive lymphocytes are generally <5 . Increased numbers of naïve lymphocytes correlate with disease progression. The triad of granulocytes, erythrocytes and megakaryocytes is significantly reduced. Nucleated erythrocytes may be significantly increased when the patient has concomitant hemolysis.

• Staging: SLL according to Ann-Arbor staging system, CLL according to Rai and Binet staging system (see Appendix 2.2).
  
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  • Treatment.
    

  ①SLL: Stage I patients are treated with local radiotherapy; Stage II-IV patients can be observed and followed up if no treatment is indicated, and the treatment principles of CLL are referred to when treatment is indicated.

  ②CLL: Low- and intermediate-risk patients in Rai 0-II can be followed up if no treatment is indicated; patients in Rai 0-II, patients with treatment indication, or patients in Rai III-IV with persistent hematocrit, according to del(17p) and/or TP53 mutation by FISH, immunoglobulin heavy chain mutable areas

  (immunoglobulin heavy chain variable region, IGHV)

Mutation status, patient’s general status and co-morbidities are factors that should be taken into account in selecting the appropriate treatment regimen. The treatment of supportive therapy for CLL, such as management of tumor lysis syndrome, infection, and autoimmune hemocytopenia, should be addressed.

③ Indications for treatment: suitability for clinical trials; significant disease-related symptoms, such as severe malaise, night sweats, weight loss, and noninfectious fever; threatening organ function; persistently enlarging large masses, such as splenomegaly more than 6 cm below the left costal margin and lymph nodes >10 cm in diameter; progressive anemia and progressive thrombocytopenia; failure of hormonal therapy. The patient’s condition is not a major one.

④ Choice of first-line treatment regimen.

• No del(17p)/TP53 mutation: frail patients with severe concomitant disease (intolerant to purine analogs) or age ≥65 years and age <65 years with severe concomitant disease (creatinine clearance ＜Other recommended regimens include: bendamustine + CD20 monoclonal antibody (not recommended for frail patients), high-dose methylprednisolone + rituximab, azacitidine phenybutyrate, and rituximab.
  

  Patients <65 years of age without severe co-morbidities, recommended regimens include: ibrutinib, bendamustine + CD20 monoclonal antibody, FCR (fludarabine, cyclophosphamide, rituximab) (preferable in patients with CLL with IGHV mutations), FR

  (fludarabine, rituximab), high-dose methylprednisolone + rituximab, and ibrutinib + rituximab.

  Maintenance therapy after first-line therapy: for high-risk patients (peripheral blood microscopic residual tumor cells ≥ 10-2 or IGHV non-mutant peripheral blood microscopic residual tumor cells ≥ 10-4 and <10-2) can be considered for lenalidomide maintenance therapy.

• with del(17p)/TP53 mutation: Ibrutinib is the preferred recommendation. Other recommended regimens include: high-dose methylprednisolone + rituximab.
  

  ⑤ Treatment options for patients with relapsed drug resistance.

• No del(17p)/TP53 mutation: frail patients with severe concomitant disease or age ≥65 years and age <65 Bruton's tyrosine kinase inhibitors (ibrutinib, zebutinib, obutinib) are recommended first for patients with severe concomitant disease (creatinine clearance <70 ml/mim), and veneclare
  

  (venetoclax) + rituximab, other recommended regimens include: bendamustine + rituximab, reduced-dose FCR, high-dose methylprednisolone + rituximab, lenalidomide ± rituximab, venetoclax, increased-dose rituximab rituximab, bendamustine + rituximab + ibrutinib.

  Patients <65 years of age without severe co-morbidities are first recommended for treatment with Bruton's tyrosine kinase inhibitors (ibrutinib, zebutinib, obutinib), and other recommended regimens include: bendamustine + rituximab, FCR, high-dose methylprednisolone + rituximab, lenalidomide ± rituximab, Vinecla, bendamustine + rituximab + ibrutinib.

  Maintenance therapy after second-line therapy: Lenalidomide maintenance therapy may be considered for patients who have achieved CR or PR after second-line therapy.

• with del(17p)/TP53 mutation: the preferred recommendation for second-line or higher treatment options: Bruton tyrosine kinase inhibitors ( Ibrutinib, Zebutinib, Obutinib), Vinecla + Rituximab, Vinecla; other recommended regimens include: high-dose methylprednisolone + Rituximab, Lenalidomide ± Rituximab.
  

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• Prognosis: Adverse prognostic factors include: IGHV without mutation, del(17p)
  

/TP53 mutation, del (11q), complex karyotype (≥3 chromosomal abnormalities); flow cytometry detection of tumor cells positive for CD38 ≥30, ZAP-70 positive ≥20, CD49d positive ≥30. Elevated β2 microglobulin and late staging, etc.

MCL accounts for approximately 3 to 10 percent of the NHL. 10 , with a male-to-female ratio of 2:1 to 3:1 and a median age of onset of about 65 years. The natural course can be aggressive or inert, but most have aggressive growth characteristics. The response to treatment is similar to that of inert lymphoma and is not curable with conventional chemotherapy. The survival period of previous multidrug combination chemotherapy is about 3-5 years, but it has been significantly extended in recent years with the introduction of HDT/ASCT, cytarabine and targeted drugs. A small proportion of inert MCL, called leukemia-like non-lymphoid MCL, has a lesser molecular genetic variation, no del(17p)/TP53 mutations, and no or low expression of SOX11, with a course similar to inert lymphoma and a better prognosis.

(1) Clinical features: Most often involves lymph nodes, bone marrow, gastrointestinal tract, spleen, and pharyngeal lymphatic rings, and at diagnosis 70for stage IV. Bone marrow invasion rate can be 50to

100 , with a high rate of invasion of the lower gastrointestinal tract, often presenting endoscopically as multiple polypoid lesions.

• Pathologic diagnosis: The tumor cells of MCL are small to medium to large lymphocytes with a consistent morphology and a slightly irregular nuclear surface. The tumor cells in MCL are small to medium to large lymphocytes with uniform morphology, slightly irregular nuclei, and diverse growth patterns, including nodular, nodular and diffuse. IHC marker selection includes CD20, PAX5, CD3, Cyclin D1, CD10, CD23, and CD24.
  

MUM-1, CyclinD1, SOX11, and CD138. The typical immunophenotype is CD19

(+), CD5(+), CD23(-), CD200(weak+), CD20(+), CD79b

(+), FMC-7 (+), CD10 (-), CyclinD1 (+). Most patients have CD5(+), Cyclin D1(+) expression, and in the case of Cyclin D1(-), FISH for CCND2 and CCND3 and IHC for SOX11 can be added for a comprehensive diagnosis. Confirmation of the diagnosis is difficult and additional evidence needs to be sought, and the FISH test t(11;14) is highly sensitive and specific for the diagnosis of MCL. In addition, the 2017 WHO Classification of Hematopoietic and Lymphoid Tissue Neoplasms classifies MCL into two types: classical MCL, which presents with SOX11 positivity and no mutation in IGHV, and is clinically aggressive with a poor prognosis, and can also present with more aggressive variant maternal cell and polymorphic phenotypes, often with TP53 mutations; and leukemic extranodal MCL, which often involves peripheral blood, bone marrow and spleen, and presents with SOX11. The other is leukemic extranodal MCL, often involving peripheral blood, bone marrow, and spleen, which is SOX11-negative with IGHV mutations, clinically inert, and has a better prognosis.

Bone marrow cytology: When the tumor cells involve the bone marrow, a variable number of abnormal lymphocytes are seen in the bone marrow smear, with varying cell sizes and round or mildly irregular nuclei, mostly with a large, malformed nucleolus. The cytoplasm is abundant and pale blue in color.

• Treatment: Patients with MCL should be examined thoroughly and staged accurately to guide the choice of treatment. For patients with maternal cell transformation or CNS symptoms, cerebrospinal fluid and brain MRI should be performed, and for patients with a proposed stage I or II diagnosis, endoscopy should be performed to exclude gastrointestinal invasion.
  

  1) Treatment strategy: Stage I or limited Stage II without large masses is recommended for either ISRT alone or conventional dose-intensity immunochemotherapy ± ISRT.

For extensive stage II without a large mass, conventional-dose intensity immunochemotherapy is recommended. Some patients with inert clinical features, such as leukemia-like non-lymphoid MCL with splenomegaly, SOX11-negative [IGHV mutant], no TP53 mutation or deletion, and low tumor load, Ki-67 proliferation index <10, etc., can be observed for follow-up.

Patients with stage II with large masses and stage III/IV with aggressive clinical features are recommended for sequential HDT/ASCT after high-dose intensity induction chemotherapy if HDT/ASCT is appropriate; patients who are not suitable for HDT/ASCT are recommended to participate in clinical trials or conventional dose intensity. Patients with inert features who are asymptomatic or have no indication for treatment may be observed for follow-up. Those with symptoms or indications for treatment need to be selected accordingly based on the presence or absence of TP53 mutations.

First-line regimens: high-dose intensity regimens: R-DHA (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin), alternating R-CHOP/R-DHAP, NORDIC (intensified dose of R-CHOP [maxi-CHOP] alternating with rituximab + high-dose cytarabine) regimen, HyperCVAD, rituximab, bendamustine sequential rituximab and high-dose cytarabine; other recommended regimens: bendamustine + rituximab.

Conventional dose-intensity regimens: recommended bendamustine + rituximab, VR-CAP (bortezomib, rituximab, cyclophosphamide, adriamycin, and prednisone), R-CHOP, lenalidomide + rituximab; other recommended regimens. Modified R-HyperCVAD regimen (for patients <60 years of age), RBAC500 (rituximab, bendamustine, adriamycin).

Consolidation therapy: HDT/ASCT can be considered.

Maintenance therapy: rituximab.

③ Second-line regimens: regimens or drugs not used in first-line regimens may be chosen. Recommended preferred regimens include: BTK inhibitors (ibrutinib, zebutinib, obrutinib); lenalidomide + rituximab; other recommended regimens include: bendamustine + rituximab, bendamustine + rituximab + cytarabine, bortezomib ± rituximab; R-DHAP, R-DHAX (dexamethasone, cytarabine, oxaliplatin), R-GemOx , BTK inhibitor + lenalidomide + rituximab, BTK inhibitor + vinecla, vinecla ± rituximab, etc.

Consolidation therapy after second-line therapy: allogeneic hematopoietic stem cell transplantation.

Sporadic and immunodeficiency-associated variants. Burkitt’s lymphoma accounts for approximately 3 to 5 and accounts for about 40 percent of childhood NHL.

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• Clinical features: Epidemic Burkitt’s lymphoma occurs mainly in Africa
  

Equatorial region and northeastern Brazil, with peak age of onset between 4 and 7 years, male to female ratio of 2:1, mostly involving the jaws, and EBV positivity rate >95. Sporadic Burkitt’s lymphoma is scattered throughout the world, mainly in children and young adults, with a male to female ratio of 2:1 to 3:1. Abdominal involvement is common, with an EBV positivity rate of <30. The immunodeficiency-associated type occurs mostly in patients with AIDS and often involves lymph nodes and bone marrow. Burkitt’s lymphoma is the tumor with the shortest cell multiplication cycle and grows rapidly. Extra-nodal invasion of Burkitt’s lymphoma is common, with the head and neck, abdomen, bone marrow, and central nervous system being the most frequently involved sites.

• Pathologic diagnosis: Classic Burkitt’s lymphoma morphology shows diffuse proliferation of moderately large tumorigenic B cells in a homogeneous pattern, with marked nuclear schizophrenia and apoptosis. The apoptosis is obvious, and starry sky phenomenon is common. The tumor cells originate from the germinal center, and the IHC immunophenotype often shows sIgM(+), single light chain(+), CD19(+), CD20
  

  (+), CD22 (+), c-Myc (+), CD10 (+), Bcl6 (+), Bcl2

  (- or weakly +), CD5 (-), CD23 (-), MUM-1 (-), and TdT (-). The proliferation index was very high, with Ki-67 nearly 100. Even though the morphology and immunophenotype were typical of Burkitt’s lymphoma, FISH MYC testing was performed, where t

  (8;14) accounted for about 80, t(2;8) and t(8;22) accounted for 15. The differential diagnosis includes morphology, immunophenotype are typical of Burkitt’s lymphoma, but those without MYC abnormalities are classified as high-grade B-cell lymphoma, non-specific. EBER testing is mandatory for Burkitt’s lymphoma, but more sporadic patients in our country, EBER

(-) is more common.

Bone marrow cytology: markedly active or extremely active bone marrow proliferation. The typical Burkitt’s lymphoma cells are medium to large lymphocytes of varying size and easily distributed in piles; the nuclei of leukemic cells are large, mostly round or irregular, with coarse granular nuclear chromatin and one to several distinct nucleoli of varying size; the cytosolic mass is variable, strongly basophilic and contains lipid vacuoles of varying size and number in a chisel-like pattern, and vacuoles are also seen in the nuclei. The smear showed many degenerated cells, and the proliferation of granulocytes and erythrocytes was inhibited.

• Treatment: chemotherapy is the mainstay, but the CHOP regimen is not effective, and high-dose intensive therapy and combination with rituximab may improve the outcome. The central nervous system should be treated prophylactically and tumor lysis syndrome should be adequately prevented. The chemotherapy options for Burkitt’s lymphoma include CODOX-M + rituximab, CODOX-M/IVAC regimen, DA-EPOCH-R or R-HyperCVAD/HD-MA regimens.
  

  protocols, etc. For low-risk patients with low tumor load, 3 cycles of treatment to CR followed by one cycle of consolidation therapy can end the treatment. In patients with existing brain parenchymal invasion at diagnosis, the first cycle of therapy should begin with a regimen that includes drugs that can cross the blood-brain barrier. The DA-EPOCH-R regimen should be chosen in combination with intrathecal MTX, which is not appropriate for patients with parenchymal invasion.

  There is no clearly recommendable second-line rescue regimen; consider R-ICE, R-GDP, R-IVAC, high-dose cytarabine + rituximab, and HDT/ASCT or allogeneic hematopoietic stem cell transplantation for patients who achieve CR after rescue therapy.

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  • Prognosis: age >40 years, poor general condition, late staging, LDH
    

increased, bone marrow and CNS invasion, and human immunodeficiency virus positivity have a poor prognosis.

lymphoblastic lymphoma (LBL) accounts for 3 percent of adult NHL~4% of NHL in adults and about 40% of NHL in children. It is a highly aggressive lymphoma. It can be divided into T-cell-derived (T-LBL) and B-cell-derived (B-LBL), with T-LBL accounting for 80% of LBLand above, B-LBL accounts for about 80% of LBL

10 ~15. LBL is associated with acute LBL and acute lymphocyte leukemia (ALL) are the same disease with different clinical manifestations and different stages of development, and the 2017 edition of WHO Hematopoietic and Lymphoid Tissue Neoplasms defines the ratio of primitive and naive lymphocytes in the bone marrow as ≥20 Defined as ALL.

• Clinical manifestations: The typical clinical manifestations of T-LBL are cough and shortness of breath due to a large anterior mediastinal mass, which may be accompanied by pleural effusion, and bone marrow and central nervous system invasion. B-LBL often presents with enlarged lymph nodes, and skin or bone invasion is common.
  
• Pathologic diagnosis: In terms of cell morphology, LBL mainly presents with diffuse growth of medium-sized tumor cells with round, non-circular nuclei. The immunophenotype of LBL is characterized by TdT(+), but CD99, CD34, CD10 can also be added to assist in the determination of maternal cell differentiation. The immunophenotype of B-LBL is sIg(-), cIg
  

  (+), CD10(+), CD19(+), CD20(-) or (+), CD79(+), PAX5(+); the immunophenotype of T-LBL is CD3ε(+) or (-), CD2(+), CD4(+), CD8 （CD7, CD43, CD4 (+), CD4 (+), CD8 (+), CD1a (+) or (-), and CD7 (+).

Cannot be used as a marker for T lymphocytes alone. When cells are naive, additional assays for CD34, CD117, MPO, and Lys are required to identify AML. Because LBL originates from immature stage lymphocytes, it is not uncommon and particularly important to note that tumor cells may express markers of B or T lymphocytes, or even molecular markers of NK or myeloid cells. B-LBL is often associated with specific genetic abnormalities, such as BCR-ABL1, ETV6-RUNX1, and KMT2A rearrangements, and molecular genetic testing is recommended when available. The following is a list of the genes that are associated with specific genetic abnormalities

Bone marrow cytology: The bone marrow nucleated cell proliferation is mostly extremely active or markedly active, with predominantly primitive and naive lymphocytes, often with abnormal morphology; primitive lymphocytes are round, oval, or caudate in shape; nuclei are mostly round, with large nuclei and unevenly coarse and fine nuclear chromatin. The nuclei were mostly round, oval or with caudate protrusions. The nuclei were mostly round, with a large nucleus, a thick and thin nuclear chromatin, and a regular arrangement. Granulocyte proliferation was significantly inhibited, and granulocytes were significantly reduced or even absent. Erythrocyte proliferation was also significantly suppressed, and young red blood cells were rare or absent. The majority of megakaryocytes were significantly reduced or absent, and platelets were rare. Degenerated cells are significantly increased. Nuclear schwannoma cells are easily seen. In T acute lymphoblastic lymphoma, eosinophilic infiltration around the lymphoma cells was found, requiring exclusion of eosinophilia and myeloid hyperplasia with 8p11.2 cytogenetic abnormalities of the FGFR1 gene.

Blood count: leukocytes are mostly elevated, a few up to 100×109/L.