Guidelines for the Treatment of Diffuse Large B-Cell Lymphoma (2022 Edition)

Diffuse Large B-Cell Lymphoma Guidelines

(2022 Edition)

I. Overview

Diffuse large B cell lymphoma (DLBCL) is an aggressive tumor derived from mature B cells and is the most common type of non-Hodgkin’s lymphoma. DLBCL is clinically heterogeneous and the following subtypes of large B-cell lymphoma are listed in the 2016 WHO classification.

1. Non-specific type.

(1) Hair growth center B-cell subtype.

(2) Activated B-cell subtype.

2. Large B-cell lymphoma with T/histiocyte-rich cells.

3. Primary diffuse large B-cell lymphoma of the central nervous system.

4. Primary diffuse large B-cell lymphoma of the skin, leg type.

5. EBV-positive diffuse large B-cell lymphoma, non-specific type.

6. EBV-positive mucosal ulcer.

7. Diffuse large B-cell lymphoma associated with chronic inflammation.

8. Lymphoma-like granuloma

9. Primary mediastinal large B-cell lymphoma.

10. Intravascular large B-cell lymphoma.

11. ALK-positive large B-cell lymphoma.

12. Plasmacytoid lymphoma.

13. Primary exudative lymphoma.

14. Herpesvirus 8 positive diffuse large B-cell lymphoma, non-specific. 15. Burkitt’s lymphoma

16. Burkitt-like lymphoma with 11q abnormality

17. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements. 18. High-grade B-cell lymphoma, non-specific.

19. High-grade B-cell lymphoma that cannot be typed, between DLBCL and classical Hodgkin’s lymphoma.

Due to the differences in prognosis and management of each subtype, this article will discuss the management guidelines mainly for diffuse large B-cell lymphoma, a non-specific type.

Diagnosis and Differential Diagnosis

(a) Clinical manifestations. 1.

Lymph nodes (involvement of lymph nodes) or extranodal (involvement of organs or tissues outside the lymphatic system) Symptoms: any extranodal site may be involved. Patients usually present with progressively enlarged, painless masses, most often in the neck or abdomen. Symptoms may occur outside the lymph nodes, depending on the site of involvement, including the gastrointestinal tract, central nervous system, and bones. They may also occur in rare sites such as the liver, lungs, kidneys, or bladder. A disease- or treatment-related tumor lysis syndrome, in which tumor cell contents are spontaneously released or released into the bloodstream in response to chemotherapy, can occur, causing electrolyte and metabolic imbalances with progressive systemic toxicity.

Tumor lysis syndrome is a condition in which tumor cell contents are spontaneously released or released from the blood as a result of chemotherapy, causing electrolyte and metabolic imbalance with progressive systemic toxicity, accompanied by cardiac arrhythmias, multi-organ failure, seizures, and death. 2. Physical examination.

Massive lymph nodes (usually in the neck, axilla, or groin) or masses may be palpable in appropriate areas; liver enlargement and/or splenomegaly may be present. B symptoms may be present, including: unexplained persistent fever (>38°C); unexplained weight loss Weight loss over 6 months>10%; night sweats.

3.

Confirming the diagnosis of DLBCL requires a pathologic biopsy of the lesion, either by surgical excision or by coarse needle aspiration of the lymph nodes or extra-nodal tissue to obtain a specimen. Microscopic morphologic and immunohistochemical analysis of the tumor is performed to identify diffuse large B-cell lymphoma and to classify.

(1) Immunohistochemistry: germinal center B-cell-derived (GCB), non-germinal center B-cell-derived (non-GCB) identification, such as CD10, MUM-1, and BCL-6; molecules that contribute to risk assessment The following molecules have been identified as risk assessment, such as C-MYC, BCL-2, CD5, TP53, Ki-67, etc.; potential therapeutic targets, such as CD20, CD19, CD30, etc., and other molecules that can help in differential diagnosis, such as CD23, CD138, SOX11, PAX5, κ/λ, etc.

(2) Fluorescence in situ hybridization (FISH): EBV in situ hybridization; FISH for MYC, BCL-2, and BCL-6 rearrangements should be performed in all DLBCL patients to rule out double/ triple hit lymphoma. /For the purpose of health care resource conservation, double/triple-hit lymphoma screening should be clinically refined for patients with ≥40% C-MYC expression.

4.

Full blood count for initial assessment of bone marrow function; serum lactate dehydrogenase; assessment of liver function, renal function; human immunodeficiency virus and hepatitis B virus infections, etc.

Related tests; monitoring uric acid levels to detect tumor lysis syndrome. Bone marrow examination: bone marrow cytology, flow cytology, chromosome, bone marrow biopsy and immunohistochemistry (specimens should be >1.6 cm) along with bone marrow aspiration, bone marrow cytology and immunophenotyping, except for DLBCL involvement. Patients at high risk for CNS lymphoma require a lumbar puncture to complete the cerebrospinal fluid examination. Cranial enhancement MRI and flow cytometry is recommended for detection of lymphoma cells in the cerebrospinal fluid if available.

Laboratory manifestations of tumor lysis syndrome.

(1) Hyperuricemia (uric acid level > 8 mg/dL or 475.8 μmol/L).

(2) Hyperkalemia (potassium level > 6 mmol/L).

(3) Hyperphosphatemia (phosphorus level > 4.5 mg/dL or 1.5 mmol/L).

(4) Hypocalcemia (corrected calcium ion < 7 mg/ dL or 1.75 mmol/L; calcium ion < 1.12 mg/dL or 0.3 mmol/L).

5. Imaging.

Patients are advised to undergo whole-body PET/CT before, during and at the end of treatment. If PET/CT is not available, enhanced CT examinations of the neck, chest, abdomen, and pelvis can be performed. This is to clarify disease staging and assess outcomes (Table 1).

Table 1 Ann Arbor staging of primary lymphoma in lymph nodes

Note: PET/CT as a staging method, unconditionally applied Patients with PET/CT can also choose CT, MRI or B ultrasound. The tonsils, Wechsler’s ring, and spleen are not extra-junctional organs.

(ii) Diagnosis and differential diagnosis.

1. Diagnosis.

Histopathologic analysis of diffuse large B-cell lymphoma features: diffuse proliferation of tumorigenic large B lymphocytes with complete or partial destruction of normal tissue architecture. Immunophenotypic analysis is performed to clarify the diagnosis and to distinguish between germinal center B-cell sources and non-germinal center B-cell sources. Immunohistochemical tests need to include: CD20, PAX5, CD3, CD5, CD10, CD45, BCL2, BCL6, Ki-67, IRF4/MUM-1, P53, and MYC.

The Hans system is commonly used clinically for classification according to immunohistochemistry: germinal center B-cell type and activated B-cell type or non-germinal center B-cell type (Figure 1)

The Hans system is used clinically for classifying the cell type according to immunohistochemistry.

Figure 1 Hans system

Other immunohistochemical tests that can help identify lymphoma subtypes and facilitate the selection of targeted therapies include CD79a, Cyclin D1, SOX11, CD19, CD30, CD138, EBER-ISH, ALK, HHV8, P53, PD-1 and PD-L1. Further, MYC, BCL2, BCL6, IRF4 and other breakage recombination was examined by fluorescence in situ hybridization.

2. Differential diagnosis.

In addition to differentiating from non-neoplastic diseases such as: mononucleosis, nodular disease, etc.

Other mature B-cell tumors such as follicular lymphoma, marginal zone lymphoma, condyloma

cellular lymphoma, aggressive (high-grade) lymphoma subtypes (about 7% of all lymphomas), and Burkitt’s lymphoma.

III. Risk Assessment

(i) International Prognostic Index.

1. international prognostic index (IPI).

(1) Risk factors.

(2) Hazard stratification.

3. NCCN-IPI.

(1) Risk factors.

*Vital organs: including bone marrow, central nervous system, liver/gastrointestinal organs, lungs

(2) Risk stratification.

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(ii) Major adverse prognostic factors in patients treated with other standard chemotherapy. 1. Non-germinal center B-cell subtypes (activated B-cell subtypes). 2. MYC and BCL-2 and/or BCL-6 rearrangements.

3. High expression of MYC and BCL2.

4. TP53 mutation.

5. EBV-related disease.

IV. Treatment

(i) Treatment goals.

Long-lasting complete remission with a view to eradication.

(ii) Induction therapy.

The treatment of diffuse large B-cell lymphoma is selected based on patient age, Ann Arbor staging and IPI, and the immunologic and molecular phenotypic characteristics of the tumor The appropriate regimen.

1. Limited-stage diffuse large B-cell lymphoma [Ann Arbor stage I and II non-large mass (<7.5 cm) disease]: first-line therapy Includes three courses of chemotherapy with R-CHOP regimen and radiotherapy to the involved site; or 4 courses of chemotherapy with R-CHOP regimen plus 2 courses of rituximab (IPI=0 score); or 6 courses of chemotherapy with R-CHOP regimen ± radiotherapy to the involved site.

2. Limited-stage diffuse large B-cell lymphoma [Ann Arbor stages I and II with large

Large diffuse B-cell lymphoma [Ann Arbor stages I and II with a large mass (≥ 7.5 cm)]: 6 courses of chemotherapy on the R-CHOP regimen as first-line therapy and radiation therapy in some patients; initial Large mass (>7.5 cm) site radiotherapy.

3. Advanced diffuse large B-cell lymphoma (Ann Arbor stages III-IV): first-line therapy includes chemotherapy with the R-CHOP regimen or the R-DA-EPOCH regimen. The initial large mass (>7.5 cm) is treated with radiotherapy.

4. For patients of advanced age or who are not candidates for standard chemotherapy, R-GemOx, R-miniCHOP, R-CDOP, R-CEPP, R-GCVP, etc. or targeted therapy-based regimens may be considered.

5. Double/triple strike lymphoma: Prefer high-dose regimens: R-DA-EPOCH, R- hyperCVAD/MA, or R-CODOX/MA regimens, and patients who obtain complete patients may be considered for autologous peripheral blood stem cell transplantation.

6. Maintenance therapy: Lenalidomide maintenance therapy may be considered after induction therapy in older patients (≥60 years).

7. Central nervous system lymphoma prophylaxis.

For patients with the following high-risk factors.

(1) High-risk patients with a CNS-IPI score of 4 to 6 consisting of 5 risk factors in the IPI score and adrenal/renal involvement.

( 2) Involvement of the following organs: testis, breast, sinus, dura mater, etc.

(3) Human immunodeficiency virus-associated lymphoma.

(4) Double-hit and dual-expression lymphomas.

(5) Primary cutaneous DLBCL, leg type.

Currently, common clinical methods of central prophylaxis include triple intrathecal injection and high-dose methotrexate

pteridine, but the optimal method has not been established.

8. Management of tumor lysis syndrome.

Identify risk factors including large masses, lactate dehydrogenase two times above the upper limit of normal, spontaneous tumor lysis syndrome, elevated leukocyte levels, involvement of bone marrow, hyperuricemia, failure of allopurinol therapy, and involvement of the kidneys.

Treatment includes pre-chemotherapy hydration, uric acid-lowering therapy, and monitoring of blood uric acid, creatinine, and electrolytes.

9. Hepatitis B or C infection.

For patients with positive HBsAg, prophylactic antiviral therapy is required. For HBcAb-positive/HBsAg-negative patients, ongoing monitoring of HBV DNA or prophylactic antiviral therapy is required. The choice of antiviral therapy is recommended for low resistance rates of entecavir or tenofovir. Radical anti-HCV therapy may be considered for patients with concomitant hepatitis C virus infection.

(iii) Efficacy assessment. 1. PET/CT 5-point scale.

(1) No higher than background uptake.

(2) Uptake ≤ mediastinal blood pool.

(3) Uptake > mediastinal blood pool, but ≤ hepatic blood pool.

(4) Uptake of moderate > hepatic blood pools (mild).

( 5) Uptake of significant> hepatic and/or neoplastic lesions.

( 6) Areas of neoplastic uptake not associated with lymphoma.

2. Efficacy criteria.