Diffuse large B-cell lymphoma (DLBCL) is the most common type of adult lymphoma and is a group of malignancies with great heterogeneity in terms of clinical presentation and prognosis. Its incidence accounts for 31-34% of non-Hodgkin’s lymphoma (NHL) and is generally greater than 40% in Asian countries. A 2011 analysis conducted by a consortium of 24 centers in China with a total of 10,002 case samples reported that DLBCL accounted for 45.8% of all NHL and 40.1% of all lymphomas in China.
As an aggressive NHL, the natural course of DLBCL is relatively short, but a certain percentage of patients can be cured with appropriate treatment. Previously, the treatment of DLBCL was dominated by chemotherapy, and patients survived for more than 5 years after receiving combination chemotherapy containing anthracyclines in about 1/3 of patients. The advent of rituximab in combination with chemotherapy regimens has further increased the long-term survival rate of DLBCL patients significantly. The introduction of PET-CT into the disease assessment system can more accurately guide the clinical treatment and determine the prognosis of the disease.
I. Definition
DLBCL is a diffuse growth of tumorigenic large B lymphocytes with nuclei similar to or larger than the nuclei of normal tissue cells, usually two times larger than normal lymphocytes.
In the WHO 2008 classification, DLBCL is classified into central blastocytic type, immunoblast type and interstitial type according to histomorphologic changes, and special rare pressure types such as mediastinal large B-cell lymphoma, intravascular large B-cell lymphoma and T-cell/histiocyte rich type.
Diagnosis, staging and prognosis
1. Diagnosis: DLBCL relies on biopsy histopathology and immunohistochemical analysis to clarify the diagnosis. Tests for CD20, CD3, CD5, CD10, BCL-2, BCL-6, GCET1, FOXP1, IRF4/MUMI, Ki-67 and CD21 are required. CyclinD1, k/r, CD138, EBV, ALK, HTLV1, etc. are optional in some cases.
Lymph nodes suspected of having lesions should be excised as completely as possible for pathological examination. Fine needle aspiration or coarse needle aspiration biopsy is generally not indicated for the diagnosis of incipient lymphoma. In specific cases where resection biopsy of the suspected lymph nodes is not possible, fine or coarse needle aspiration biopsy combined with other complementary techniques (immunohistochemistry, flow cytometry, PCR for amplification of clonal immunoglobulin light and heavy chain genes (IgL, IgH) and T-cell receptor* (TCR) gene rearrangement, FISH for t(14;18), t(8;14), t(3;v) etc.) can be performed for the diagnosis of lymphoma (refer to the recommendations of the 2012 Rebel NCCN guidelines). If the tissue taken and its findings do not help the clinician to make a diagnosis of the disease, another biopsy should be performed.
DLBCL is a polygenic tumor that shows genetic heterogeneity. With the advent of DNA microarray technology, DLBCL has been classified into germinal center B-cell-like lymphoma, activated B-cell-like lymphoma, and third-pressure DLBCL based on different gene expression patterns.
DLBCL can be classified into GCB-pressure type and non-GCB-pressure type by detecting B-cell markers in the germinal center (CD10, BCL-6, GCET1) and non-germinal center B-cell markers (FOXP1, MUM1). Although the guiding significance of this pathological typing by applying immunohistochemistry for clinical prognosis is still controversial, it is still recommended to keep this pathological typing for further accumulation of data.
2. Staging and prognosis: The Ann Arbor/Cotswords staging system is currently used for staging patients with DLBCL. Through comprehensive staging examination, the scope of tumor invasion and the organism condition of patients can be accurately understood. However, its clinical value in determining the prognosis of patients is less than that of the International Prognostic Index (IPI), and therefore it is not recommended as the main reference factor when formulating the best treatment plan.
IPI is the currently accepted prognostic index for DLBCL. Poor prognosis includes: age > 60 years, stage III/IV lesions, LDH > upper limit of normal value, ECOG physical status score >= 2 and extra-nodal invasion sites >= 2. The 5-year overall survival rates were 70-80%, 50-60%, 40-50% and 20-30% for patients in the low (0-1 score), low-intermediate risk (2 score), high-intermediate risk (3 score) and high risk (4-5 score) groups, respectively. The age-adjusted IPI was based on the lesion being stage III/IV, LDH greater than the upper limit of normal, and physical status ECOG score greater than or equal to 2 as the scoring criteria for patients older than 30 years of age.
III. Treatment
1, pre-treatment evaluation: the following examination items must be performed before treatment (1) medical history including B is. (2) Physical examination: including general condition, general skin, superficial lymph nodes (especially Wechsler’s ring), liver and spleen and abdominal masses. (3) Physical status. (4) Laboratory examination: routine blood, urine and stool, liver and kidney function, ECG, LDH, β2 microglobulin. (5) In addition to routine examinations, all DLBCL patients should undergo bone marrow aspiration and biopsy before treatment to clarify the presence of bone marrow invasion. The bone marrow biopsy sample should be at least 37.5px or higher. (6) Testing for HBV surface antigen/antibodies and core antigen/antibodies, HBV DNA copy number, and HIV. Testing for hepatitis C indicators is only required in high-risk individuals. (7) Imaging examinations: a. CT examination of the neck, chest, abdomen and pelvis should be performed in all patients; b. PET-CT has been widely used internationally for accurate diagnosis and efficacy evaluation of lymphoma patients and is recommended; c. Cardiac ultrasonography; d. Gastrointestinal endoscopy in case of gastrointestinal tract invasion; e. Lumbar puncture in case of central nervous system (CNS) invasion and magnetic resonance imaging ( MRI examination.
2. First-line treatment options: Before the introduction of rituximab, the traditional anthracycline-based CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) regimen was the first-line treatment for DLBCL. With the application of rituximab, the long-term survival rate of DLBCL patients has been significantly improved, which makes DLBCL a malignancy with the potential for long-term disease-free survival. The currently recommended first-line treatment options are.
(1) Young (age < 60 years) low-risk (aaIPI score 0-1) patients: standard treatment is 6-8 courses of R-CHOP21. The results of the subgroup analysis of the MInT study suggest that patients with aaIPI score 1 have an overall lower response level to standard aaIPI treatment than patients with aaIPI score 0, thus necessitating further treatment stratification. aaIPI score Patients with aaIPI score of 0 can be considered for 6 courses of R-CHOP21, while patients with aaIPI score of 1 can be considered for 8 courses of R-CHOP21. If the patient also has a large mass (>=187.5px), 8 courses of R-CHOP21 can be added to the affected field radiotherapy (RT) or directly to the high-intensity R-CVBP regimen.
(2) Young high-risk (aaIPI >= 2 points) patients: there is no standard regimen, and it is recommended to increase the drug or dosing density on top of R-CHOP to improve the efficacy. Autologous hematopoietic stem cell transplantation (AHSCT) is also recommended as consolidation therapy for high-risk patients who have achieved complete remission (CR) after treatment.
(3) Elderly (age >60 years) patients: consider 8R-6CHOP21 treatment. For the ultra-advanced (age >80 years) patients among them, a 6-course R-minniCHOP21 regimen is recommended if there is no cardiac insufficiency, and adriamycin should be used with caution if cardiac insufficiency is present. In case of testicular DLBCL, contralateral testicular radiotherapy is recommended after receiving chemotherapy.
3. CNS prophylaxis: Patients with intermediate to high risk and high risk of CNS recurrence, especially for patients with extra-nodal involvement at more than 1 site or elevated LDH. CNS prophylaxis is mandatory for these patients. Patients with testicular and breast lymphoma should receive CNS prophylaxis.
4. Treatment options for relapsed, refractory patients: other drugs that are not cross-resistant to CHOP can be chosen i.e. second-line regimen chemotherapy + rituximab or individualized regimen. If patients are eligible for transplantation and achieve CR or partial remission (PR), they will undergo hematopoietic stem cell transplantation (HSCT) + local RT (30-40 Gy) after chemotherapy or enter clinical trials, if patients are not eligible for transplantation or the disease status is still stable or progressive after treatment, enter clinical trials or perform best supportive care.
5. Treatment of complications.
(1) Prevention and treatment of CNS invasion: Patients with paranasal sinus, testicular and stock market involvement or elevated LDH with involvement of two or more extra-nodal sites may be at higher risk of CNS invasion in lymphoma. 4-8 intrathecal methotrexate (MTX) + cytarabine (ARA-C) or 3-3.5 g/m2 MTX intravenous infusion may be considered as prophylaxis, and if the patient also has If the patient also has CNS parenchymal involvement then systemic MTX should be considered to be added to the treatment regimen, and if the patient also has soft meningeal involvement then 4-8 intrathecal injections of MTX + Ara-C 3-3.5g/m2 MTX intravenously should be considered.
(2) Prevention and control of cardiac adverse reactions: mainly control the total amount of anthracyclines accumulated, especially important for elderly patients, Adriamycin at 450-550mg/m2 and Epirubicin below 900mg/m2.
(3) HBV reactivation: The rate of HBV carriage is high in patients with DLBCL in China, and the use of chemotherapeutic drugs or rituximab may cause reactivation of HBV, leading to serious consequences such as fulminant hepatitis. According to the recommendations of the American Academy of Liver Diseases (AASLD), the European Association for the Study of the Liver (EASL) and the Asia Pacific Association for the Study of the Liver (APASL) on the management of HBV reactivation, all patients planning to receive chemotherapy or rituximab treatment should be tested for hepatitis B virus surface antigen (HBSAg) first, and if positive, viral load must be tested and appropriate antiviral therapy initiated before tumor initiation. antiviral therapy. If the HBV DNA is less than or equal to 2000 IU or if the chemotherapy course is less than 1 year, lamivudine or telbivudine can be used for antiviral therapy. Conversely, antiviral therapy with entecavir or tenofovir is preferred. During chemotherapy and/or rituximab treatment, changes in HBV indicators should be closely monitored. It is necessary to maintain antiviral therapy for at least six months after completion of oncologic therapy, and patients who are eligible should continue antiviral therapy until the endpoint of liver disease treatment (HBeAg seroconversion in hepatitis B virus e antigen (HBeAg)-positive patients, persistent undetectable levels of HBV DNA, and disappearance of HBsAg in HBeAg-negative patients) is reached.
IV. Follow up
1. Time: once every 3 months in the first year after completion of treatment; once every 6 months in the second year, and once a year for more than 3 years.
2. Content: Blood routine, liver and kidney function, LDH, β2 microglobulin, EKG, ultrasound of abdomen (liver, pancreas, retroperitoneum), X-ray chest film (front and side) or CT, and other necessary examinations.
V. Efficacy criteria
Efficacy assessment is recommended to be performed 8 weeks after the completion of treatment, and the specific criteria are shown in Tables 1 and 2. International clinical studies suggest that there is some prognostic value of PET/CT-based midterm efficacy assessment, which can be considered after the completion of 2-4 courses of treatment. Patients with a CR assessment result should continue to complete the established treatment regimen, patients with a PR assessment result and a high degree of tumor volume reduction may also be considered to continue the established treatment regimen or add RT for focal masses, patients with a PR assessment result but a suboptimal degree of tumor volume reduction may be considered to move directly to the second-line regimen, while patients with a stable or progressive disease assessment result should be immediately transferred to second-line therapy .
Summary of treatment options
1. First-line regimen: R-CHOP21: rituximab + cyclophosphamide + adriamycin + vincristine + prednisone (class 1); R-dose adjusted EPOCH: rituximab + etoposide + prednisone + vincristine + cyclophosphamide + adriamycin (class 2B); R-minniCHOP21: rituximab + reduced dose of CHOP21 (dose reduced to one-half to one-third of standard one-half to one-third of the standard dose).
2. First-line treatment regimen for patients with left heart insufficiency: R-CHOP: rituximab + cyclophosphamide + etoposide + vincristine + prednisone; R-CHOP: rituximab + cyclophosphamide + liposomal adriamycin + vincristine + prednisone.
3.First-line consolidation therapy: High-risk patients who achieve CR after treatment can be considered for high-dose chemotherapy + autologous hematopoietic stem cell transplantation.
4.Second-line treatment plan: (consider high-dose chemotherapy + autologous HSCT): DHAP (dexamethasone + cisplatin + cytarabine) + rituximab; ESHAP (etoposide, methylprednisolone, cisplatin, cytarabine) + rituximab; GDP (gemcitabine + dexamethasone + cisplatin) + rituximab; GemOX (gemcitabine + oxaliplatin) + rituximab anti; ICE (isocyclophosphamide + carboplatin + etoposide) + rituximab; MINE (mesylate/isocyclophosphamide, mitoxantrone and etoposide) + rituximab; dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + adriamycin) + rituximab.
5. Second-line treatment regimen (not considering high-dose chemotherapy + autologous HSCT): clinical trials; CEPP + rituximab; EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + adriamycin) + rituximab.