Diffuse large B-cell lymphoma C83.3

Diffuse large B-cell lymphoma (DLBCL) is the most common neoplasm of all non-Hodgkin lymphomas(NHL). It is classified as an aggressive B-cell non-Hodgkin's lymphoma (B-NHL) and originates from mature B cells. Diffuse large B-cell lymphoma (DLBCL) is characterized by rapidly progressive lymph node enlargement and/or extranodal manifestations, and also variably by general symptoms (B-symptomatology), and is rapidly fatal without treatment.

According to the current WHO classification, a distinction is made between:

diffuse large B-cell lymphoma, not further specified (NOS)

other mature aggressive/blastic B-cell lymphomas (see below differential diagnosis).

According to their definition, the subtypes of aggressive B-cell lymphomas mentioned in the WHO classification are defined and differentiated from each other by clinical parameters (e.g. localization), histological features, immunophenotype, their characteristic association with infectious agents or their genetic aberrations. Within the group of diffuse large B-cell lymphomas, NOS, the individual subtypes can be subdivided according to:

morphological criteria

• centroblastic
• immunoblastic
• anaplastic

gene expression

• germinal-center B-cell (GCB)-like
• activated B-cell (ABC)-like

immunohistochemical parameters

of importance are: CD5, CD30, MYC, BCL2, BCL6, GCB-like, non-GCB-like)

after genetic anomalies:

v.a. translocation of MYC-, BCL2- and/or BCL6

Other large B-cell lymphomas treated according to the same principles as diffuse large B-cell lymphoma, NOS, include large lmyphoma variants (see differential diagnosis below).

Aggressive mature B-cell lymphomas with simultaneous MYC and BCL2 and/or BCL6 translocation (so-called 'double-hit' or 'triple-hit' lymphomas) are distinguished from diffuse large B-cell lymphoma, NOS as a separate entity with the name 'high-grade B-cell lymphoma' (Swerdlow SH et al.).

DLBCL is the most common type of non-Hodgkin's lymphoma, accounting for approximately 30 to 40% of all lymphomas. The incidence of diffuse large B-cell lymphoma is approximately 7 cases per 100,000 population per year. In recent decades, the number of new cases has increased. Men are affected more frequently than women. The disease is more common in Caucasians than in Africans or Asians.

Diffuse large B-cell lymphoma is a heterogeneous disease. Based on similarities with the presumed cell of origin ('cell oforigin', COO), the subgroups ofgerminal center B-cell-like ('GCB') andactivated B-cell-like('ABC') diffuse largeB-cell lymphomas can be distinguished on the basis of gene expression. In 10-15% of DLBCL, a clear assignment to the subtypes mentioned above is not possible. The clinical significance of the genetic classifications is unclear.

At diagnosis, rapidly progressive lymph node enlargement and/or extranodal manifestations are usually present. The symptoms are determined by the localization of the manifestations. In 10-25% there is bone marrow infiltration, which may be large cell (concordant) or small cell (discordant). Some of the patients suffer from fever, night sweats and/or weight loss (B symptoms).

Laboratory tests include a blood count with differential blood count, clinical chemistry parameters such as: bilirubin, GOT, GPT, alkaline phosphatase, gamma-GT; creatinine. Serum LDH gives information about cell proliferation, uric acid about cell decay. Before starting therapy: perform hepatitis and HIV serology.

Further examinations: electrocardiogram; echocardiography.

For diagnosis, a sufficiently large tissue sample is required, preferably as a sampling of the entire lymph node, on which histological, immunohistochemical, cytogenetic and molecular genetic examinations are performed. Morphology is of particular importance for the diagnosis and differentiation of differential diagnoses. The following analyses must be performed:

CD20 expression and, if necessary, other B-cell markers; testing for MYC translocations in order to differentiate from 'high-grade B-cell lymphomas' according to the WHO classification. The prognostic relevance of MYC translocations seems to depend on the translocation partner (Rosenwald A et al. 2019).

Parallel testing for expression of MYC and BCL2: If both markers are expressed, a so-called 'double expressor' status is present. Patients with 'double expressor' lymphoma showed a worse prognosis in retrospective analyses (Johnson NA et al 2012). However, the presence of a 'double expressor' status has currently no therapeutic relevance.

Determination of COO subtype, although the choice of method is optional. COO subtyping currently has no clinical relevance but is part of the WHO classification.

Staging

The Ann Arbor classification is used for staging (Lister TA et al. 1989). This requires a history (B symptoms), physical examination (tonsils, lymph nodes, liver, spleen, effusions, visible or palpable space-occupying lesions), computed tomography (CT) scans with contrast of the neck, thorax, and abdomen, and a bone marrow biopsy (unilateral; aspiration and trephination of at least 2 cm).

Ann Arbor classification (Lister TA et al. 1989)

I: Nodal involvement in a single lymph node region.

IE: Presence of a single extralymphatic localized focus

II: involvement of several lymph node regions on one side of the diaphragm

IIE: Presence of a single extralymphatic focus and involvement of one or more lymph node regions on one side of the diaphragm.

III: involvement of lymph node regions on both sides of the diaphragm

IIIE: Presence of a single extralymphatic focus and involvement of one or more lymph node regions on both sides of the diaphragm.

IV: Diffuse involvement of one or more extralymphoid organs (multiple local manifestations in one extranodal site and involvement of the liver and/or bone marrow are considered diffuse).

Suffix S

Involvement of the spleen (counts as lymph node)

Suffix A/B

A: None of the general symptoms defined under B

B: One or more of the following three general symptoms:

fever not otherwise explicable above 38°C

night sweats with change of clothes not otherwise explained

weight loss of more than 10 % of body weight within 6 months, not otherwise explained

Other large B-cell non-Hodgkin's lymphomas that are treated according to the same principles as DLCBL include.

• T-cell/histiocyte-rich large B-cell lymphoma
• primary cutaneous diffuse large B-cell lymphoma leg type
• Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma
• primary mediastinal large B-cell lymphoma
• intravascular large B-cell lymphoma
• Plasmoblastic lymphoma
• follicular lymphoma grade 3b

In addition, there are some rarer forms of large B-cell non-Hodgkin's lymphoma.

The therapy claim is curative. First-line therapy is 6 - 8 cycles of the R-CHOP protocol. In early stages a reduction of the therapy cycles is possible. The role of radiotherapy has not been finally clarified. Other unresolved issues such as prognosis- or response-driven therapy, the value of more intensive treatment protocols, or the efficacy of new agents are the subject of prospective clinical trials. The cure rate of patients with diffuse large B-cell lymphoma is approximately 60-70%.

First-line therapy:

• Immunochemotherapy: 6 - 8 cycles of the CHOP protocol and 8 doses of rituximab (R-CHOP protocol). The CHOP protocol is equivalent to more complex therapy regimens with better tolerability. The addition of rituximab improved treatment outcomes in all subgroups studied (Coiffier B et al.(2010).
• Maintenance therapy: Maintenance therapy with rituximab is not indicated in diffuse large B-cell lymphoma as it does not improve treatment outcomes. Similarly, maintenance therapies with other agents such as lenalidomide did not improve overall survival.
• Radiation: The place of radiotherapy in the treatment regimen of diffuse large B-cell lymphoma is not supported by randomized trials. Radiotherapy has moved from the former sole curative modality of therapy to consolidative therapy in the sense of "involved site" irradiation of the initial attack (Campbell BA et al 2012).

Complex therapy protocols: In patients below the age of 60 with intermediate prognosis (aaIPI 1), the R-ACVBP protocol proved significantly superior to the R-CHOP protocol (Récher C et al 2011). The therapeutic approach is similar to that commonly used in acute lymphoblastic leukemia in that induction with 4 cycles of a dose-intensified R-CHOP variant is followed by consolidation with 2 cycles of high-dose methotrexate, 4 cycles of rituximab/ifosfamide/etoposide, and 2 cycles of cytarabine. New CD20 antibodies such as obinutuzumab or ofatumumab failed to improve the treatment results achieved in diffuse large B-cell lymphoma with rituximab in randomized trials.

Vitamin D: Because patients with diffuse large B-cell lymphoma and a serum vitamin D concentration below the normal range would have a less favorable disease course than patients with normal vitamin D concentration, vitamin D supplementation is recommended (Bittenbring JT et al 2014).

Recurrence:

• Conventional salvage therapy followed by high-dose therapy with autologous hematopoietic stem cell transplantation is considered the standard therapy for relapse in patients below the age of 60 but also in older patients without therapy-limiting comorbidities (Philip T et al (1995). Maintenance therapy with rituximab is not indicated. CAR-T cell treatments are available from the 2nd relapse onwards. Currently, two CAR T-cell products are approved for the treatment of patients with at least 2 prior therapies and are the current standard of care in this setting (axicabtagen ciloleucel and tisagenlecleucel) (Neelapu SS et al 2017).
• Elderly patients: In patients who are not eligible for autologous or allogeneic hematopoietic stem cell transplantation or CAR T-cell therapy due to age or comorbidity, the treatment goal is often palliative.

International Prognostic Index (IPI): Prognosis can be estimated using the International Prognostic Index, which includes age (≤ vs. > 60 years), general condition (ECOG 0 - 1 vs. ≥ 2), Ann Arbor stage (I, II vs. III, IV), involvement of extranodal organs (0 - 1 vs. ≥ 2 extranodal organs) and LDH (≤ vs. > upper normal limit) in favorable vs. unfavorable expression (0 vs. 1 point). Based on the expression, four risk groups are distinguished: 0 - 1 points: low risk (overall survival at 3 years: 91%); 2 points: low intermediate (81%); 3 points: high intermediate (65%); 4 - 5 points: high.

The age-adjusted International Prognostic Index (aaIPI) is a prognostic score reduced to the factors general condition, Ann Arbor stage, and LDH, in which the above four risk groups are defined by 0, 1, 2, or 3 unfavorable factor expressions. In contrast to the IPI, the aaIPI allows survival prognosis independent of age.

The National Comprehensive Cancer Network (NCCN) is a further development of the IPI. Here, age and LDH activity are divided into 4 and 3 subgroups, respectively, and only a few extranodal manifestations are considered risk factors (Zhou Z et al. (2014).

Bone marrow involvement: Large cell (concordant) bone marrow infiltration is a risk factor independent of the International Prognostic Index. This is not true for small-cell (discordant) infiltration, which may reflect an indolent lymphoma component (Sehn LH et al 2011).

Bulk: A very large lymphoma manifestation represents a risk factor independent of the International Prognostic Index (Pfreundschuh M et al (2008).

Comorbidities: An assessment of comorbidities should always be performed before starting therapy. Both the Charlson Comorbidity Score and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) can be used, whereby the HCT-CI is more accurate with regard to cardiovascular and nephrological comorbidities. Both 'scores' are predictive and prognostic factors. In addition, a comparison of comorbidities at diagnosis and at relapse can be helpful for therapy decisions in case of a later intensification of therapy in case of relapse or refractoriness (Charlson ME et al. 1987; Artz AS et al. 2006).

The purpose of follow-up is to support reintegration into family, work and society, to detect disease recurrence and to detect and minimise long-term complications, in particular infertility, secondary malignancies and cardiovascular disorders.

Comment: In patients below the age of 45 years, secondary malignancies are frequently observed following successful treatment with CHOP-type therapy protocols (Moser EC et al. 2006). In addition to myelodysplasias and acute myeloid leukaemias, there are increased incidences of bronchial carcinomas (increased risk due to concomitant nicotine use), colorectal carcinomas, prostate carcinomas, cyclophosphamide-induced bladder carcinomas and Hodgkin's lymphomas.

After treatment with anthracyclines, the risk of developing heart failure is increased compared with the normal population, especially if chemotherapy was given before 55 years of age. Influenceable cofactors are arterial hypertension and nicotine consumption.

Pregnancy and fertility: In the presence of aggressive lymphoma in the first trimester, termination of pregnancy is recommended because chemotherapy administered during the phase of organogenesis carries a high risk of malformations. In the second and third trimesters, the risk is low. The R-CHOP protocol is suitable as a standard therapy regimen. Antimetabolites (e.g. methotrexate) must not be used because of the risk of fetal CNS damage. If the lymphoma occurs in late pregnancy and is not very aggressive, treatment may be postponed until after delivery. If the patient wishes to have children, sperm should be preserved before chemotherapy.

1. Artz AS et al. (2006) Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 12:954-964.
2. Bittenbring JT et al. (2014) Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab. J Clin Oncol 32:3242-3248.
3. Campbell BA et al. (2012) Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy. Cancer 118:4156-4165.
4. Charlson ME et al. (1987) A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 40:373-383.
5. Coiffier B et al.(2010) Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood 116:2040-204
6. Johnson NA et al (2012) Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol 30:3452-3459.
7. Lister TA et al. (1989) Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin's disease: Cotswolds Meeting. J Clin Oncol 7:1630-1636.
8. Moser EC et al. (2006) Risk of second cancer after treatment of aggressive non-Hodgkin's lymphoma; an EORTC cohort study. Haematologica 91:1481-148
9. Neelapu SS et al (2017) Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med 377:2531-2544.
10. Pfreundschuh M et al. (2008) Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol 9:435-444.
11. Philip T et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med 333:1540-1545.
12. Récher C et al (2011) Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet 378:1858-1867.
13. Rosenwald A et al. (2019) Prognostic significance of MYC rearrangement and translocation partner in diffuse large B-cell lymphoma: A Study by the Lunenburg Lymphoma Biomarker Consortium. J Clin Oncol 37:3359-3368.
14. Sehn LH et al (2011) Impact of concordant and discordant bone marrow involvement on outcome in diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol 29:1452-1457.
15. Swerdlow SH et al. (2017) WHO classification of tumours of haematopoietic and lymphoid tissue. Revised 4th ed. Lyon: IARC; 2017.
16. Zhou Z et al. (2014) An enhanced International Prognostic Index (NCCN-IPI) for patients with diffuse large B-cell lymphoma treated in the rituximab era. Blood 123:837-842.