Diffuse large B-cell lymphoma

Type of blood cancer

Diffuse large B cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non Hodgkin lymphoma among adults,) or, in rare cases termed Richter's transformation, chronic lymphocytic leukemia. An underlying immunodeficiency is a significant risk factor for development of the disease. Infections with the Epstein–Barr virus (EBV), Kaposi's sarcoma associated herpesvirus, human immunodeficiency virus (i. e. HIV),

Diagnosis of DLBCL is made by removing a portion of the tumor through a biopsy, and then examining this tissue using a microscope. Usually a hematopathologist makes this diagnosis. Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments. However, the usual treatment for most subtypes of DLBCL is chemotherapy combined with a monoclonal antibody drug that targets the disease's cancerous B cells, usually rituximab. Through these treatments, more than half of all patients with DLBCL can be cured; The remaining DLBCL cases consist of relatively rare subtypes that are distinguished by their morphology, (i. e. microscopic appearance), immunophenotype, (i. e. expression of certain marker proteins), clinical findings, and/or association with certain pathogenic viruses.

DLBCL cases that do not fit the distinctive clinical presentation, tissue morphology, neoplastic cell phenotype, and/or pathogen associated criteria of other DLBCL subtypes are termed Diffuse large B cell lymphoma, not otherwise specified: DLBCL, NOS, while representing 80–85% of all DLBCL cases, is a diagnosis of exclusion. In general, DLBCL, NOS is an aggressive disease with an overall long term survival rate in patients treated with standard chemotherapy regimens of ~65%. However, this disease has many variants that differ not only in the just cited parameters but also in their aggressiveness and responsiveness to treatment.

About 70% of DLBCL, NOS cases present primarily with lymph node disease. In these cases, the most typical presenting symptom at the time of diagnosis is a mass that is rapidly enlarging and located in a part of the body with multiple lymph nodes such as the groin, arm pits, or neck. In the remaining ~30% of other cases, the disease begins as an extranodal lymphoma, most commonly in the stomach, The presenting signs and symptoms in these cases reflect the presence of a rapidly expanding tumor or infiltrate that produces symptoms specific to the organ of involvement such as increased size, pain, and/or dysfunction.

The International Prognostic Index and more recently, the Index's age adjusted variant use age >60 years, elevated serum lactate dehydrogenase levels, low performance status, and involvement in more than one extranodal site as contributors to a poor prognosis in patients with DLBCL, NOS. EZH2: This gene's product, the EZH2 protein, is a histone lysine N methyltransferase. It thereby regulates the expression of other genes which control lymphocyte maturation. As a consequence of these gene changes and possibly other changes that have not yet been identified, the neoplastic cells in DLBCL, NOS exhibit pathologically overactive NF κB, PI3K/AKT/mTOR, JAK STAT0, MAPK/ERK, B cell receptor, toll like receptor, and NF κB signaling pathways and thereby uncontrolled pro malignant behaviors. IHC analyses measure the cellular expression of specific proteins using a panel of fluorescent antibodies that bind to and therefore stain a set of key proteins. For example, one commercially available panel uses three antibodies to detect CD10, BCL6, and MUM1 proteins; GBC express whereas ABC and unidentified cells do not express these proteins; accordingly, this as well as other IHC panels classify ABC and undetermined neoplastic cell types together as non GBC. Individuals with the ABC, unclassifiable, and non GBC variants have significantly worse prognoses than individuals with the GBC variant: These lymphomas, termed high grade B cell lymphoma with MYC, BL2, and/or BL6 rearrangements or, more simply, DH/THL, are regarded as borderline DLBCL, NOS. These cells, which typically have a centroblast like morphology, infiltrate one or, in ~6% of cases, both testicles. PT DLBCL is an aggressive disease that often spreads to the central nervous system Relapses generally occur within the first 3 years of diagnosis with few cases doing so after 5 years. Patients who are refractory to, relapse within 1 year of diagnosis before starting, relapse within 6 months after completing, or progress within 2 years of starting R CHOP have poorer prognoses. as well as the antigens chosen to be their targets and the hemophagocytic lymphohistiocytosis/macrophage activation syndrome (i. e. a form of Hemophagocytic lymphohistiocytosis). Individual studies within and outside of this meta analysis have reported remissions lasting >2 years but also lethal cytokine release syndrome and neurotoxicity responses to this therapy. The Committee for Orphan Medicinal Products of the European Medicines Agency recommends tisagenlecleucel retain its orphan drug designation. Monoclonal antibodies directed against CD19, CD22, CD30, and PD L1 have been developed for use as immunotherapeutic agents in other hematological malignancies and are being or plan to be tested for their usefulness in DLBCL, NOS. In April 2021, the FDA approved the CD19 directed antibody drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy. Glofitamab (Columvi) is a bispecific monoclonal antibody that was approved for medical use in Canada in March 2023.

Neoplastic cell expression of CD30 in DLBCL, NOS is a favorable prognostic indicator; in these cases, brentuximab vedotin may be a useful addition to chemotherapy treatment protocols. This agent is a CD30 targeting antibody that delivers a toxin, monomethyl auristatin E, to CD30 expressing cells, has therapeutic efficacy against other CD30 expressing lymphomas, and may prove useful in treating the 10–15% of DLBCL, NOS cases expressing this protein. The neoplastic cells in the GBC variant of DLBCL, NOS often have mutations in the EZH2, BCL2 and CREBBP genes and overactive PI3K/AKT/mTOR and JAK STAT signaling pathways while neoplastic cells in the ABC variant often have mutations in the MYD88, CD79A and CD79B (polatuzumab vedotin) genes and overactive B cell receptor, toll like receptor, and NF κB signaling pathways. for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene. GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the MYC gene and is undergoing a phase I clinical trial for the treatment of high grade B cell lymphoma with MYC, BL2, and/or BL6 rearrangements (i. e. DH/THL). RO6870810, another BET inhibitor, in combination with Venetoclax, an inhibitor of the Bcl 2 protein, is likewise in a phase I clinical trial for the treatment of DH/THL. Combined therapy using MCL 1 inhibitor (S63845) or BCL XL inhibitor (A 1331852) in addition to Venetoclax can be a solution to overcome this issue.

DLBCL subtypes have been sorted into groups based on their distinctive morphology or immunophenotype, distinctive clinical issues, and distinctive virus driven etiology. The prognoses and treatment of these subtypes varies with their severity. Most subtypes are aggressive diseases and consequently treated in a manner similar to DLBCL, NOS. Further details on these subtypes, including their treatments, can be found in their respective main article linkages.

T cell/histiocyte rich large B cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic B cells embedded in a background of reactive T cells and histiocytes develop in the liver, spleen, bone marrow and/or, rarely other sites. Patients usually present with advanced disease; their overall 3 year survival rates in different studies range between 46% and 72%. and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV).

Large B cell lymphoma with IRF4 rearrangement (LBCL with IRF4 rearrangement) is a DLBCL in which tissue infiltrates containing intermediate or large sized neoplastic B cells strongly express a chromosomal translocation involving the IRF4 gene on the short arm of chromosome 6. These cells form follicular, follicular and diffuse, or entirely diffuse infiltrates