Diffuse large B-cell lymphoma

Source: Wikipedia, the free encyclopedia.
Diffuse large B cell lymphoma
Other namesDLBCL or DLBL
Micrograph (Field stain) of a diffuse large B cell lymphoma.
SpecialtyHematology, oncology, dermatology

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,[1] with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK.[2][3] This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years,[3] although it can occur in young adults and, in rare cases, children.[4] DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy.[5] The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.[6]

The causes of diffuse large B-cell lymphoma are not well understood. Usually DLBCL arises from normal B cells, but it can also represent a

human immunodeficiency virus (i.e. HIV),[12] and the Helicobacter pylori bacterium[7] are also associated with the development of certain subtypes of diffuse large B-cell lymphoma. However, most cases of this disease are associated with the unexplained step-wise acquisition of increasing numbers of gene mutations and changes in gene expression that occur in, and progressively promote the malignant behavior of, certain B-cell types.[14]

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.[15] Numerous subtypes of DLBCL have been identified which differ in their clinical presentations, biopsy findings, aggressive characteristics, prognoses, and recommended treatments.[16] 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.[17] Through these treatments, more than half of all patients with DLBCL can be cured;[18] the overall cure rate for older adults is less than this but their five-year survival rate has been around 58%.[19]

Subtypes of diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma encompasses a biologically and clinically diverse set of disease subtypes,

bacterium, Helicobacter pylori.[23]

Diffuse large B-cell lymphoma, not otherwise specified

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.[24]

Presenting signs and symptoms

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,

lactic acid dehydrogenase and beta-2 microglobulin in many cases; malignant cells infiltrating their bone marrow in 10–20% of cases; and/or localized Stage I or II disease in up to 50% of cases and disseminated Stage III or IV disease in the remaining cases.[12] Bone marrow involvement may be due to DLBCL, NOS cells or low grade lymphoma cells; only DLBCL, NOS cell infiltrates indicate a worse prognosis.[22] Uncommonly, DLBCL may arise as a transformation of marginal zone lymphoma (MZL) in individuals who have been diagnosed with this indolent cancer 4–5 years (median times) previously.[26]

Prognostic indicators based on clinical presentation

The

adrenal glands, ovaries, or bone marrow has a high rate of spreading to other organs, including the central nervous system. All of these cases as well as cases initially involving the central nervous system have relatively poor to very poor prognoses. Cases initially involving the stomach, thyroid, or a single bone site have relatively good prognoses.[25]

Pathophysiology

Most cases of DLBCL, NOS appear to result at least in part from the step-wise development of

mutations, altered expressions, amplifications (i.e. increases in the number of copies of specific genes), and tranlocations from normal sites to other chromosomal sites. These changes often result in gains or loses in the production or function of the product of these genes and thereby the activity of cell signaling pathways that regulate the maturation, proliferation, survival, spread, evasion of the immune system, and other malignant behaviors of the cells in which they occur. While scores of genes have been reported to be altered in DLBCL, NOS many of these may not contribute to DLBCL, NOS. Changes in the following genes occur frequently in, and are suspected of contributing to, this disease's development and/or progression.[14]

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.[27]

Diagnosis

Microscopic examinations of involved tissues reveal large neoplastic cells that are typically classified as B-cells based on their expression of B-cell marker proteins (e.g.

histiocytes that have a reactive morphology.[22]

Variants of DLBCL, NOS

The World Health Organization, 2016, requires that the neoplastic cells in DLBCL, NOS be further defined based on whether they are derived from germinal center B-cells (i.e. GBC) or activated B-cells (i.e. ABC) as identified by gene expression profiling (GEP) or are GBC or non-GBC as identified by immunohistochemical (IHC) analyses. As identified by GEP, which measures all cellular messenger RNAs, GBC and ABC represent about 50 and ~35% of DLBCL, NOS cases, respectively, with ~15% of cases being unclassifiable.[30] 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.[27] Individuals with the ABC, unclassifiable, and non-GBC variants have significantly worse prognoses than individuals with the GBC variant:[24] respective 5 year progression-free and overall survival rates have been reported to be 73–80% for GBC variants and 31–56% for ABC variants. Clinically, however, most DLBCL, NOS cases are analyzed by IHC and therefore classified as either GBC or non-GBC variants with non-GBC variants having progression-free and overall survival rates similar to those of the ABC variants.[22]

Gene and protein

testicles. PT-DLBCL is an aggressive disease that often spreads to the central nervous system[32] and has median overall survival and progression-free survival times of 96 and 49 months, respectively.[12]

The neoplastic cells in almost all cases of DLBCL, NOS express CD20. Commercially available anti-CD20 antibody agents such as rituximab or Obinutuzumab (which is sometimes used in place of rituximab) kill cells that express high levels of CD20 by binding to this cell-surface protein and thereby targeting them for attack by the hosts adaptive immune system. The addition of one of these immunotherapy agents to chemotherapy protocols has greatly improved the prognosis of most DLBCL, NOS variants.[22] Neoplastic cell expression of CD30, found in 10–15% of DLBCL, NOS cases is a favorable prognostic indicator. As indicated in the following Treatments and prognoses section, expression of the CD20 and CD30 proteins as well as the CD19, CD20 CD22, CD30, CD79A, CD79B, and D-L1 proteins, expression of the MYC, BCL2, MYD88nd, and CREBBP genes, and expression of the PI3K/AKT/mTOR, JAK-STAT, B-cell receptor, toll-like receptor, and NF-κB signaling pathways are being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC DLBCL, NOS cases.[14][22]

Treatments and prognoses

First-line therapy

First-line therapy for patients with the GBC variant of DLBCL, NOS is

adriamycin, cyclophosphamide, vindesine, bleomycin, and cytarabine followed by sequential consolidation therapy with systemic methotrexate, ifosfamide, and etoposide, and then cytarabine) achieved significantly better response rates than R-CHOP in ABC/NGC variant cases lymphoma.[27] In DLBCL, NOS variants which trend to spread or to the central nervous system, methotrexate has been recommended to be added to regimens not containing it for use as prophylaxis to reduce the incidence of this complication.[31] The role of Autologous stem-cell transplantation as an addition to first-line therapy in the treatment of DLBCL, NOS, including cases with a poor prognosis, is unclear.[14]

A phase I clinical research trial found that the addition of lenalidomide to the R-CHOP regimen produce an ~80% complete response rate in GBC as well as non- GBC DLBCL, NOS variants.[14] Two phase III clinical research trials are underway to confirm these results and determine if the R-CHOP + lenalidomide regimen is superior to R-CHOP in the up-front treatment of GBC and/or non-GBC variants.[14]

Treatment of recurrent and refractory DLBCL, NOS

Patients with DLBCL, NOS who relapse or progress following first-line therapy have been treated with "salvage regimens" consisting of high-dose (also termed high-intensity) chemotherapy conditioning drugs followed by autologous stem cell transplantation. This regimen has attained 3-year progression-free survival rates of 21–37%.[14] Relapse following this treatment carries a very poor prognosis with median overall survival times of ~10 months.[31] Patients who have failed or because of health issues are ineligible for autologous stem cell transplantation have been treated with low-dose (i.e. low-intensity) chemotherapy conditioning regimens followed by allogeneic stem cell transplantation. This regimen has achieved 3 year progression-free and overall survival rates of 41% and 52%, respectively.[33] Further studies are underway to determine the best treatment regimens for these cases.[14][33] Patients refractory to first-line therapy or who relapse within 12 months of receiving salvage therapy (including bone marrow transplant) for recurrent disease have had poor prognoses with median overall survival rates of 3.3 and 6.3 months, respectively.[14] The prognosis of these patients appears to be improved by using CAR-T therapy.

Chimeric antigen receptor T cell (i.e. CAR-T)

T-cells; genetically engineering these cells to express an artificial T-cell receptor designed to bind an antigen expressed on the surface of their neoplastic B-cells; and infusing these cells back into the donor patient. The targeted antigen has usually been CD19, a surface membrane protein expressed on virtually all B-cells including the neoplastic cells in DLBCL, NOS.[31] However, design of CARs[34] as well as the antigens chosen to be their targets [31]
are constantly being changed in order to improve the efficacy of this therapeutic strategy.

CAR-T therapy for DLBCL, NOS has been used on patients who are refractory to and/or have progressed on first-line as well as salvage (including autologous stem cell transplantation) treatment regimens. Patients are treated first with a conditioning chemotherapy regimen, usually cyclophosphamide and

antibody-drug conjugate loncastuximab tesirine as a treatment for adult patients with relapsed or refractory DLBCL after systemic therapy.[40]

Glofitamab (Columvi) is a bispecific monoclonal antibody that was approved for medical use in Canada in March 2023.[41]

Emerging therapies

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.[22] These different gene mutations and dysregulated signaling pathways are also being studied as potential therapeutic targets for the individualized treatment of GBC and ABC/non-GBC cases.[14] CUDC-907, an inhibitor of PI3K and histone deacetylases, is being evaluated in two separate clinical trials[42][43] for the treatment of refractory and/or relapsed DLBCL, NOS including cases with alterations in the MYC gene.[44] GSK525762, an inhibitor of the BET family of proteins, suppresses expression of the MYC gene and is undergoing a phase I clinical trial[45] 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[46] for the treatment of DH/THL.[44] Pharmacological inhibition of BCL-2 is effective in most B cell lymphomas, but often leads to acquired resistance due to the expression of other major anti-apoptotic BCL-2 family proteins like BCL-XL and MCL-1.[47] 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.[48]

Subtypes of diffuse large B-cell lymphoma

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.[citation needed]

DLBCL with a distinctive morphology or immunophenotype

T cell/histiocyte-rich large B-cell lymphoma
Main article: T cell/histiocyte-rich large B-cell lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a DLBCL in which tumors containing small numbers of usually large neoplastic

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%.[12]

ALK+ large B-cell lymphoma
Main article: ALK+ large B-cell lymphoma

ALK+ large B-cell lymphoma (ALK+ LBCL) is a DLBCL in which neoplastic lymphocytes that express the

lymph nodes as well as extranodal sites, e.g. the mediastinum, bones, bone marrow, nasopharynx, tongue, stomach, liver, spleen, and skin. About 60% of these individuals present with advanced disease. ALK+ LBCL has an overall 5 year survival rate of ~34%.[12]

Plasmablastic lymphoma
Main article: Plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a DLBCL in which neoplastic immunoblastic or plasmablastic cells embedded in a background of other cell types infiltrate the oral/nasal cavity or much less often the gastrointestinal tract.[12] Some 70% of individuals with PBL are infected with EBV[49] and/or (particularly those with oral/nasal cavity disease) human immunodeficiency virus (HIV).[12] PBL is an aggressive disease with a median survival time of ~15 months.[12]

Intravascular large B-cell lymphoma
Main article:
Intravascular large B-cell lymphoma

Intravascular large B-cell lymphoma (IVLBCL) is a DLBCL in which medium- to large-sized neoplastic B-cells infiltrate small- to medium-sized blood vessels and sinusoids in the liver, spleen, and/or bone marrow. IVLBCL may be associated with the hemophagic syndrome (i.e. excessive cytokine secretion and systemic inflammation). Patients with the latter syndrome have very short survival times.[12] The poor prognosis of this disease has been significantly improved by rituximab or similar immunochemotherapy drugs but significant proportions of these responding cases relapse, often with central nervous system involvement.[50]

Large B-cell lymphoma with IRF4 rearrangement
Main article: IRF4

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[12] in Waldeyer's tonsillar ring or other regions of the head and neck. The disease, which represents ~0.05% of all DLBCL, occurs primarily in children and young adults and typically has a good prognoses.[24] Cases with a follicular pattern of tissue infiltrates often have indolent disease and an excellent prognosis following excision and may not need chemotherapy. Cases with a purely diffuse tissue infiltrate pattern, in contrast, often do require chemotherapy.[12]

DLBCL with distinctive clinical issues

Primary mediastinal large B-cell lymphoma
Main article:
Primary mediastinal large B-cell lymphoma

Primary mediastinal large B-cell lymphoma (PMBL), also termed primary mediastinal (thymic) large B-cell lymphoma, is a DLBCL in which neoplastic B-cells infiltrates are commonly located in

mediastinal lymph nodes. The disease represents 6–10% of all DLBCL cases, presents with early stage disease in ~80% of cases, and has an overall survival rate at 5 years of 75–85%.[12]

Primary cutaneous diffuse large B-cell lymphoma, leg type
Main article: Primary cutaneous diffuse large B-cell lymphoma, leg type

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a DLBCL in which diffuse patterns of immunoblastic and/or centroblastic B-cells infiltrate the dermis and/or subcutaneous tissue principally, but not exclusively, of the legs. This disease's 5-year overall survival rate is 50–60%.[12]

Primary diffuse large B-cell lymphoma of the central nervous system
Main article: Primary central nervous system lymphoma

Primary diffuse large B-cell lymphoma of the central nervous system (DLBCL-CNS, also termed primary central nervous system lymphoma [PCNSL]) is a DLBCL in which diffuse patterns of neoplastic B-cells with centroblastic, immunoblastic, or poorly

leptomeninges, or eye.[24] The disease usually presents as a single lesion with a predilection for the supratentorial region of the brain but may involve the eye in 15–25% of cases, the cerebrospinal fluid in 7–42% of cases, and the spinal cord in ~1% of cases. The disease has a 5-year overall survival rate of ~30%.[12]

Diffuse large B-cell lymphoma associated with chronic inflammation
Main articles: Diffuse large B-cell lymphoma associated with chronic inflammation and Fibrin-associated diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is an

pulmonary tuberculosis that had progressed to a pyothorax (i.e. pus in the pleural cavity). Fibrin-associated large B-cell lymphoma (FA-DLBCL), often considered a sub-type of DLBCL-CI, is an infiltration of large neoplastic B-cells and fibrin affix to a prosthesis (e.g., cardiac valve, orthopaedic device) or accumulate within a hydrocele, pseudocyst, cardiac myxoma, or chronic subdural hematoma. The B-cells in these lesions are often but not always infected with the Epstein–Barr virus.[12] DLBCL-CI occurring in cases of pleural empyema (sometimes termed pyothorax-associated lymphoma, i.e. PAL) is an aggressive lymphoma with a five-year overall survival rate of 20–35%; FA-DLBCL, when involving the heart (e.g. occurring on myxommas or prosthetic valves) or vasculature structures (e.g. on thrombus-laden vascular grafts), may involve life-threatening cardiovascular complications, particularly strokes. Outside of these complications, however, DLBCL-CI usually has a highly favorable outcome.[24]

Lymphomatoid granulomatosis
Main article: Lymphomatoid granulomatosis

Lymphomatoid granulomatosis (LYG) is a DLBCL in which large, atypical B-cells with immunoblastic or

microvasculature. Lymphomatoid granulomatosis almost always involves the lung but may concurrently involve the brain, peripheral nervous system, skin, kidneys, liver, gastrointestinal tract, and/or upper respiratory tract; LYG has an increased incidence in persons with Wiskott–Aldrich syndrome or HIV or who are immunosuppression due to chemotherapy or organ transplantation.[12] The disease's prognosis is highly variable: patients with low grade disease often require no therapy except watchful waiting while patients with high grade disease usually require chemotherapy.[51]

Primary effusion lymphoma
Main article: Primary effusion lymphoma

Primary effusion lymphoma (PEL) is a DLBCL in which neoplastic B cells that resemble immunoblasts, plasmablasts, or Reed–Sternberg cells infiltrate the pleural, pericardial, or peritoneal membranes that surround the lungs, heart, and abdominal organs, respectively. This infiltration leads to the seeping of fluid into the cavities which are encased by these membranes, i.e. it leads to pleural effusions, pericardial effusions, and abdominal ascites. Some cases of PEL also involve the gastrointestinal tract and lymph nodes. The disease occurs primarily in people who are immunosuppressed or test positive for HIV[12] and are also latently infected with Kaposi's sarcoma-associated herpesvirus;[13] PEL is an aggressive disease with an overall 1 year survival rate of ~30%.[13]

DLBCL driven by viruses

Epstein–Barr virus-positive diffuse large B-cell lymphoma, not otherwise specified
Main article:
Epstein–Barr virus-associated lymphoproliferative diseases § Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified

Epstein–Barr virus-positive diffuse large B cell lymphoma, not otherwise specified (EBV+ DLBCL, NOS) is a B-cell lymphoma in which neoplastic B-cells that are infected with the Epstein-Barr virus cause a disease that does not fit into other subtypes of DLBCL. In EBV+ DLBCL, small neoplastic B-cells, other lymphocyte typess, plasma cells, histiocytes and epithelioid cells interspersed with Reed–Sternberg-like cells[24] infiltrate, almost exclusively, lymph nodes.[11] Elderly patients with the disease have median survival times of ~2 years while young patients have long-term treatment-related remissions in >80% of cases.[24]

HHV8-positive diffuse large B-cell lymphoma, NOS
Main articles: HHV8-positive diffuse large B-cell lymphoma and HHV-8-associated MCD

HHV8-positive diffuse large B-cell lymphoma, NOS (HHV8+ DLBCL, NOS; also termed HHV8-positive diffuse large B-cell lymphoma [HHV8+ DLBCL]) is a DLBCL in which

Kaposi sarcoma in rare cases. HHV8+ DLBCL commonly takes an aggressive course and has a poor prognosis.[12]

Related disorders

Helicobactor pylori associated diffuse large B-cell lymphoma

See also: Helicobacter pylori § Diffuse large B-cell lymphoma

Rare cases of DLBCL are associated with the presence of the bacterium, Helicobacter pylori, in the neoplastic B-cells.

proton pump inhibitors directed at killing the bacterium.[52][23] Perhaps because of these features of the disease, H. pylori+ DLBCL has not been classified as a DLBCL by the World Health Organization, 2016.[23]

Recent studies suggest that localized, early-stage H. pylori+ DLBCL, when limited to the stomach, is successfully treated with H. pylori eradication protocols consisting of two or more antibiotics plus a proton pump inhibitor.[53][52][54][23] However, these studies also agree that patients treated with one of these H. pylori eradication regimes need to be carefully followed: those unresponsive to, or worsening on, these regimens should be switched to a chemotherapy regimen (e.g. R-CHOP) and/or, for complicated bulky disease, surgery and/or local radiotherapy.[52][23]

Epstein–Barr virus-positive mucocutaneous ulcer

Main articles:
Epstein–Barr virus-associated lymphoproliferative diseases § Epstein–Barr virus-positive mucocutaneous ulcer

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) was first described as a lymphoproliferative disorder in which Epstein–Barr virus-infected B-cells proliferate and cause

mucous membranes and skin of immunosuppressed individuals. Its lesions consist of Epstein–Barr virus-positive, variable-sized, atypical B-cells that by conventional histopathologic criteria indicate the lesions are a form of DLBCL. Since these lesions regress spontaneously without anti-cancer treatment, EBVMCU is now considered a pseudo-malignant disorder.[55] Elderly individuals that evidence the disease but have no other cause for immunosuppression may exhibit a relapsing and remitting course with their ulcers worsening but then regressing spontaneously.[56] Persistent and/or severely symptomatic cases have had excellent responses to rituximab.[57] Individuals developing these ulcers as a consequence of immunosuppressive therapy generally have a remission after the dosage of the drugs used in their immunosuppressive treatments are reduced. Most of these patients do not relapse.[56]

See also

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External links

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