DLBCL current standards of care and future paradigms 2026

Diffuse large B cell lymphoma

Diffuse large B cell lymphoma (or DLBCL) is a type of non-Hodgkin lymphoma, which is a cancer of the lymphatic system. 

It develops when the body makes abnormal B lymphocytes. These lymphocytes are a type of white blood cell that normally help to fight infections.  When you have a lymphoma, the abnormal lymphocytes build up in lymph nodes or other body organs. 

DLBCL grows quickly and your treatment starts soon after diagnosis.

The lymphatic system

The lymphatic system is an important part of our immune system. It has tubes that branch through all parts of the body.

These tubes are called lymph vessels or lymphatic vessels and they carry a straw-coloured liquid called lymph. This liquid circulates around the body tissues. It contains a high number of white blood cells (lymphocytes) which fight infection.

The lymph organs include the bone marrow, thymus, spleen, and lymph nodes. These help to fight infection throughout the body. The organs of the lymphatic systems are connected by a network of lymphatic and blood vessels, through which lymphatic fluid flows.

There are two primary types of lymphocytes: B cells and T cells. Diffuse large B cell lymphoma (DLBCL) is a cancer of B lymphocytes. Almost all lymphocytes begin growing in the bone marrow or lymph nodes. T cells leave the bone marrow before they are completely matured, and finish maturing in the thymus gland. B cells instead continue to develop and mature in the bone marrow and lymph nodes. In DLBCL, the abnormal B cell lymphocytes are larger than normal, and they have stopped responding to signals that usually limit the growth and reproduction of cells.

When you have lymphoma, some of your white blood cells (lymphocytes) don't work properly. They start to divide constantly but don't develop fully. So they can't fight infection as normal white blood cells do.

There are several different types of Non-Hodgkin Lymphoma:

These include:

• Diffuse large B-cell lymphoma.

• Anaplastic large-cell lymphoma.

• Burkitt lymphoma.

• Lymphoblastic lymphoma.

• Mantle cell lymphoma.

• Peripheral T-cell lymphoma.

The type you have depends on several factors including the type of cell it starts in and how fast it grows.

There are two main types of lymphocytes – B cells and T cells. They both help us fight infections but in slightly different ways.

DLBCL affects the B cells and so is called a B cell lymphoma.

Types of diffuse large B cell lymphoma (DLBCL)

As the name suggests, diffuse large B cell lymphoma (DLBCL) means this type of lymphoma has:

• abnormal and enlarged B cells 

• cancer cells that have spread out ( or diffused)

Subclassification of DLBCL

Under the WHO classification of lymphoid malignancies, the following histological variants are considered clinical and/or pathological distinct subtypes of DLBCL:

• DLBCL not otherwise specified (NOS)

  T-cell/histiocyte-rich large B-cell lymphoma

• Primary DLBCL of the central nervous system (CNS)

• Primary cutaneous DLBCL, leg type

• Epstein-Barr virus–positive (EBV+) DLBCL, NOS

• EBV+ mucocutaneous ulcer

• DLBCL associated with chronic inflammation

• Lymphomatoid granulomatosis

• Primary mediastinal (thymic) large B-cell lymphoma

• Intravascular large B-cell lymphoma

• ALK-positive B-cell lymphoma

• Plasmablastic lymphoma

• Primary effusion lymphoma

• Human herpesvirus 8 (HHV8)-positive DLBCL

The WHO classification also contains the following entities:

• High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements

• High-grade B-cell lymphoma, NOS

• B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma

DLBCL is curable in about two-thirds of patients. Research has focused on determining which patients have less favorable prognoses so that they can be considered for novel targeted-treatment strategies. In 2000, gene expression profiling was used to define two principal DLBCL molecular subtypes, germinal center B-cell-like (GCB) and activated B-cell-like (ABC). Patients with GCB DLBCL have more favorable outcomes than those with ABC DLBCL when treated with standard immunochemotherapy. 

https://www.genome.gov/Multimedia/Slides/TCGA2/03_Staudt.pdf

How common is it?

Non-Hodgkin lymphoma (NHL) has an annual incidence of about 24 cases per 100,000 persons in the United States and accounts for an estimated 4.3% of all newly diagnosed cancers.¹ 

The prevalence of NHL increases with age. For men this range starts from 0.05% at the age of 40, to 1.3% at 75 years of age. In women this range is 0.03% at 40 to 0.96% after 75 years old.

DLBCL is the most common type of Non-Hodgkin Lymphoma, accounting for approximately 31% of all non-Hodgkin lymphomas in Western countries and 37% of B-cell-tumors worldwide.² 

The median age at presentation is 66, however, DLBCL can occur at any age.

5-year survival rates decrease by age from 78% for those aged < 55 years to 54% for those aged ≥ 65 years.¹

Causes of DLBCL:

Doctors don't know what causes DLBCL and other non-Hodgkin's lymphomas. They do know that you are more likely to get them if you're:

Middle-aged or older (on average, people are diagnosed with DLBCL at 64 years old) 

A man

Not Asian or African-American

Your chances of getting DLBCL may also go up if you have an autoimmune disease, or your immune system is weakened in another way.

If you've been treated with both radiation and chemotherapy before, or you've been exposed to higher levels of radiation or certain chemicals, your odds are higher, too.

Clinical presentation:

The clinical presentation of DLBCL is diverse and depends on the site of disease involvement. Extranodal involvement is common and is seen in up to one-third of patients at the time of diagnosis.⁴ 

The most common extranodal presentation is in the gastrointestinal tract, followed by the bone, testis, spleen, salivary gland, thyroid, liver, kidney, and adrenal gland. 

DLBCL is an aggressive disease, with tumors showing a rapid growth rate and patients presenting with large masses that infiltrate tissues or obstruct organs. 

Symptoms

The first sign of DLBCL is often a lump in your groin, armpit, or neck. It's likely to grow quickly and may or may not be painful. In about 40 percent of cases, the cancer does not begin in the lymph nodes, but instead develops elsewhere. This is called extranodal disease. The most common site of extranodal involvement is the stomach or gastrointestinal tract, but the disease can arise in virtually any normal organ.

Most people (about 60 percent) are not diagnosed with DLBCL until the disease is advanced (stage III or IV). In the remaining 40 percent of people, the disease is confined to one side of the diaphragm (above or below the diaphragm). This is called localized disease. 

Common symptoms upon presentation include:

• Fever

• Drenching night sweats

• Weight loss

• Belly or chest pain or pressure

• Shortness of breath or cough

• Itching

Getting a Diagnosis

The doctor will ask:

• Do you have swelling in your groin, armpits, neck, or another part of your body?

• If you do have swelling, when did it start and is it painful?

• Have you noticed anything else that you're concerned about?

• Do you tend to get a lot of infections?

• Have you had any infections lately?

• Have you ever been diagnosed with lymphoma?

• Do you have other medical conditions?

• What medications do you take for them?

Pathology

Pathological evaluation is extremely important in the diagnosis of diffuse large B-cell lymphoma (DLBCL). 

Sufficient biopsy material and formal consultation by an experienced hematopathologist is mandatory.

The preferred diagnostic procedure is an excisional biopsy, unless contraindicated because of significant comorbid conditions, the clinical scenario (eg, rapidly growing nodal masses requiring urgent treatment), or the location of nodal/extranodal-involved sites.

In cases in which excisional biopsy cannot be performed, multiple core biopsies are acceptable. 

Fine-needle aspiration (FNA) has a high yield of false-negative results and is not recommended in the workup and diagnosis of patients with a suspected diagnosis of DLBCL or any other forms of lymphoma.

Biopsy

Bone marrow aspiration and biopsy is performed as part of the staging process to help rule out involvement with lymphoma. Bilateral iliac crest bone marrow biopsies are also performed as part of the staging.

Lymph node biopsy is required to establish a definitive diagnosis of non-Hodgkin lymphoma (NHL); this should be an excisional biopsy rather than a needle biopsy, because nodal architecture is often difficult to assess when small amounts of tissue are used.

Because bone marrow involvement increases the likelihood of lymphomatous involvement of the meninges, in patients with advanced-stage disease, a lumbar puncture for cytologic and chemical analysis of the cerebrospinal fluid may be necessary. 

Histology/cytology

DLBCL is clinically, morphologically, and genetically a highly heterogeneous lymphoid malignancy, this means it consists of different, distinguishable parts or elements.

DLBCL can arise from mature B cells at different stages of differentiation.

 Gene mutations promote changes in B cells, thus changing their gene expression and promoting neoplastic transformation. These lymphoid cells have a nuclear size equal to or exceeding normal macrophage nuclei or more than twice the size of a normal lymphocyte.⁵ 

Biomarkers are used to analyse a patient’s possible response to chemotherapy or help identify a patient for a targeted therapy or immunotherapy. 

Some of the many biomarkers identified (but not always expressed) in the malignant B-cells include CD19, CD79a, CD20, PAX5, and CD22; other markers that may be expressed with variable frequency include CD38 and CD138, CD30 (associated with anaplastic morphology), and CD5.⁶ 

DLBCL may arise as primary or de novo, or may result from the progression or transformation of other B-cell neoplasms such as chronic lymphocytic leukaemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, follicular lymphoma, and lymphocyte-predominant Hodgkin lymphoma.²

Morphological, biological, and clinical studies have allowed the subdivision of DLBCL into morphological variants, molecular and immunophenotypic subgroups, and distinct disease entities. However, a large number of cases still remain biologically heterogeneous for which there are no clear and accepted criteria for subclassification: these are collectively termed DLBCL not otherwise specified (DLBCL NOS).²

According to the 2016 World Health Organization (WHO) classification, DLBCL can be subdivided into morphological and immunological variants:

• Centroblastic variant: a predominant population of medium to large lymphoid cells with oval to round nuclei

• Immunoblastic variant: > 90% immunoblasts and large cells with large nuclei

• Anaplastic variant: large to very large cells and pleomorphic nuclei

  
  

Other variants include primary cutaneous DLBCL, Epstein-Barr virus positive DLBCL, and primary central nervous system DLBCL.⁵ Additionally, subgroups of DLBCL can be classified based on gene expression profiling, including the germinal centre B-cell (GCB) and the activated B-cell (ABC) types, which are associated with specific genetic alterations, different molecular pathways and clinical outcomes.⁷ 

Further subgroups included in the WHO classification that do not strictly fit into the GCB or ABC subtypes include those with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 translocations, termed double-/triple-hit lymphomas, respectively.⁷ 

These mutations confer a prognostic relevance as patients with double-/triple-hit mutations often demonstrate inferior outcomes to standard chemotherapy (rituximab, cyclophosphamide, vincristine doxorubicin, and prednisolone; better known as R-CHOP).⁸

The diagnosis of diffuse large cell lymphoma is usually confirmed after positive findings are obtained from a lymph node biopsy specimen. Pathology findings should be reviewed by an expert hematopathologist, because lymphomas can be difficult to classify.

Diffuse large B-cell lymphomas are more or less composed of equal numbers of small and large cells. The small cells are usually slightly larger than normal lymphocytes, and they have a cleaved or indented nucleus and coarse chromatin.

The large cells can be cleaved or noncleaved. The cytoplasm of these cells is pale, and the cells have an irregular, central, indented nucleus with inconspicuous nucleoli. A subset of the large cells has rounded nuclei with 1 or more nucleoli; these are the noncleaved large cells and are somewhat larger than the cleaved cells.

Here you can see a H & E and touch prep smear of DLBCL.

A H&E (or Hematoxylin and eosin) stain is one of the principal tissue stains used in histology.

A touch prep method consists of touching the corresponding margin onto a glass slide. The principle of this technique is that if cancer cells are present, they will stick to the slide, while fat cells will not.

In both images you can see the enlarged cleaved cells.

In this table you can see common immunophenotyping markers used to identify and classify DLBCL.

When using fresh tissue for flow cytometric immunophenotyping, the predominant populations are lymphoid. These can be stratified as large and small lymphocytes (CD45 positive). 

This gating dot plot identifies both a small (in red) and large (in green) subset of lymphocytes. DLBCL would fall in the large lymphocyte region.

Staging

Clinical staging of patients with diffuse large B-cell lymphoma (DLBCL) is fundamental in order to

• Define the treatment plan (i.e., combined-modality vs systemic therapy plus/minus CNS prophylaxis),

• Determine risk stratification according to the International Prognostic Index (IPI) score system, and

• Predict the likelihood of survival following frontline therapy.

The staging of lymphoma patients provides information necessary for treatment planning and has prognostic significance, especially in Hodgkin lymphoma (HL). Currently the R-IPI score (revised- international prognostic score) is the preferred staging system for DLBCL.

After histologic and immunologic findings confirm the diagnosis of diffuse large cell lymphoma, a pretreatment staging evaluation should be performed.

At minimum, patients should have routine blood counts and blood chemistries, particularly a lactate dehydrogenase (LDH) level, which is a prognostic parameter. Carefully examine the peripheral blood smear for any abnormal lymphoid cells.

Note that tumor lysis syndrome manifests as a rapid rise in potassium, phosphorus, and uric acid and a drop in calcium; this can lead to a sudden death from electrolyte abnormalities.

Radiologic staging studies include chest radiography and computed tomography (CT) scanning of the chest, abdomen, and pelvis. Bone, gallium, and PET scans, as well as plain films, may be helpful in selected patients.

Ann Arbor staging system

The Ann Arbor staging system, originally designed for Hodgkin disease, is traditionally used to assess the extent of disease involvement in patients with non-Hodgkin lymphoma (NHL). The stages are characterized as follows:

• Stage I - Involvement of a single lymph node region (I) or localized involvement of a single extralymphatic organ or site (IE)

• Stage II - Involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extralymphatic organ or site and its regional lymph nodes, with or without involvement of other lymph node regions on the same side of the diaphragm (IIE)

• Stage III - Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an associated extralymphatic organ or site (III E ), by involvement of the spleen (IIIs), or by both (IIIE+S)

• Stage IV - Disseminated (multifocal) involvement of one or more extra lymphatic organs, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (nonregional) nodal involvement

  
  

• A symptoms - No systemic symptoms present

• B symptoms - Unexplained fever ≥ 38º C; drenching night sweats; weight loss ≥ 10% body weight

The Cotswold’s modifications are as follows:

• X = bulky disease - Bulky disease is defined as a mass of nodes with one diameter of >10 cm or a mediastinal mass larger than one third of the transthoracic (mediastinal) width

• Number or anatomic regions involved - The number of anatomic regions involved should be indicated by a subscript (eg, II3).

The Revised-International Prognostic Index: 

The original International Prognostic Index (IPI) was developed and validated prior to the addition of rituximab to curative anthracycline-based chemotherapy. Clinical trials have confirmed that rituximab improves the survival of individuals with diffuse large B-cell lymphoma.

The revised International Prognostic Index (R-IPI) was developed to predict the outcome of individuals receiving rituximab with chemotherapy. The score is able to differentiate patients into three groups (very good, good, poor), all of who have survival >50% in the new era.

The R-IPI includes:

a) Age if they are 60+. 

b) Ann Arbor stage III-IV (III: Involvement on both sides of the diaphragm, IV: Involvement of extranodal sites).

c) ECOG (Eastern Cooperative Oncology Group)/WHO (World Health Order) performance status ≥2 (describes a patient's level of functioning, ability to self-care, daily activity, and physical ability). Score from 0-5, with 0=active, 5=dead. 

d) Serum LDH (lactate dehydrogenase) level >1× normal (normal levels of LDH in the blood usually range between 140 units per liter (units per litre) to 280 (units per litre) for adults). 

e) >1 extranodal site (Bone marrow, GI tract, liver, lung, central nervous system, skin, testes and Waldeyer’s ring).

f) Hemoglobin, bilirubin, creatinine levels (normal, upper normal, elevated, and high).

g) Charlson Comorbidity Index (CCI): Second solid tumor (non-metastatic), diabetes with end organ damage, diabetes (without complication), chronic pulmonary disease, peripheral vascular disease, connective tissue disease, ulcer disease, congestive heart failure, cerebrovascular disease (except hemiplegia), myocardial infarction, and moderate or severe liver disease.

h) Comorbidity factors affecting utilization of hematopoietic stem cell transplantation (HSCT): including previous solid tumor, cardiovascular comorbidity, renal comorbidity, diabetes, arrhythmia, rheumatologic comorbidity.

The International Prognostic Index, gives one point for each of the above characteristics, for a total score ranging from zero to five, representing three risk groups:

• Low risk – IPI score of 0 or 1 (91 percent of people in this risk group are still alive at three years)

• Low to intermediate risk – IPI score of 2 (81 percent of people in this risk group are still alive at three years)

• High to intermediate risk – IPI score of 3 (65 percent of people in this risk group are still alive at three years)

• High risk – IPI score of 4 or more (59 percent of people in this risk group are still alive at three years)

DIFFUSE LARGE B CELL LYMPHOMA TREATMENT

The treatment of DLBCL depends upon whether the disease is localized (early stage) or advanced (stage 3 or 4).

Localized disease — Localized DLBCL is defined as Ann Arbor stage I or II nonbulky disease. The management of such patients requires an abbreviated course of combined systemic chemoimmunotherapy with R-CHOP, typically followed by involved-site radiation therapy (ISRT) or involved-field radiation therapy (IFRT). 

The most common chemotherapy regimen for front line DLBCL is called R-CHOP. R-CHOP includes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. The first four drugs are given into a vein (IV) over the course of one day, while prednisone is taken by mouth for five days. In the United States, this regimen is generally given every three weeks for six to eight cycles. R-CHOP achieves cures in approximately two thirds of patients with DLBCL.

In patients with an absolute contraindication to anthracyclines, etoposide can be substituted for doxorubicin (ie, R-CEOP rather than R-CHOP). A long-term study found that R-CEOP is a valid alternative to R-CHOP in this setting, offering a potential for cure. 

A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the effects. Thus, eight cycles of treatment would last 24 weeks (approximately five months). 

While also recommending R-CHOP for patients with low-risk disease, European guidelines include the use of rituximab with doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone R-ACVBP) for 6 cycles as an option for patients aged 60 years or younger with bulky low-risk or low-intermediate risk DLBCL.  An open-label phase III trial in patients aged 18-59 years with low-intermediate risk DLBCL reported significantly improved survival with R-ACVBP compared with standard R-CHOP; however, hematologic toxicity is greater with R-ACVBP, and vindesine is not commercially available in the United States.

The use of monoclonal antibodies, particularly rituximab, changed the treatment paradigm of patients with B-cell non-Hodgkin lymphoma, including DLBCL. Rituximab is a chimeric monoclonal antibody that targets the CD20 antigen present on normal and most malignant B-cells. The mechanisms by which rituximab elucidates its antitumor activity has been characterized and includes antibody-dependent cellular cytotoxicity (ADCC), complement-mediated cytotoxicity (CMC), and activation of intracellular pathways leading to apoptosis. Preclinical models demonstrated that rituximab potentiates the effect of several chemotherapeutic agents.  The addition of rituximab to standard doses of chemotherapy in DLBCL resulted in improved clinical outcomes without adding significant toxicity. 

Various protocols are in use. It is important to stress that the approach to early-stage DLBCL should be tailored according to site of disease involvement (eg, mediastinum, stomach), disease response, and patient comorbid conditions, in an attempt to optimize the achievement of a complete response, which can translate into improved survival. For example, in patients with DLBCL who are older than 80 years but have a good performance status, the use of rituximab with reduced doses of chemotherapy agents—so-called R-mini-CHOP—has proved effective.

For early-stage DLBCL, a 21-day R-CHOP cycle is typically used, involving different numbers of chemoimmunotherapy cycles. One recommended approach for stage I-II nonbulky disease consists of three 21-day cycles of R-CHOP followed by radiation therapy (RT); four cycles and six cycles are also used. Tomita et al demonstrated that in limited-stage DLBCL, three cycles of R-CHOP followed by involved-field radiation therapy (IFRT) could be effectively replaced by six cycles of R-CHOP alone, with IFRT used only in patients with a partial response to R-CHOP. In this retrospective study, which included 190 previously untreated patients with limited-stage DLBCL (5 of whom received IFRT), the 5-year progression-free survival (PFS) and overal survival (OS) were 84% and 90%, respectively. 

Imaging studies to determine response to R-CHOP can guide the decision whether to use RT. In a National Clinical Trials Network (NCTN) study, 128 patients with nonbulky (< 10 cm) stage I/II untreated DLBCL received three cycles of standard R-CHOP therapy, then underwent an interim positron emission tomography/computed tomography (PET/CT) scan. Those patients with a negative scan received one additional cycle of R-CHOP, whereas those with a positive scan received IFRT followed by radioimmunotherapy with ibritumomab tiuxetan. radioimmunotherapy. On median follow-up of almost 5 years, the estimated 5-year PFS was 87%  and the estimated OS estimate was 89%, with similar outcomes in patients with positive and negative PET/CT scans.

Radiation therapy — Radiation therapy (RT) refers to the exposure of a tumor to high-energy X-rays in order to slow or stop its growth. Exposure to X-rays damages cells. Unlike normal cells, cancer cells cannot repair the damage caused by exposure to X-rays over several days. This prevents the cancer cells from growing further and causes them to eventually die.

RT for lymphoma is usually given as external-beam RT, meaning that the radiation beam is generated by a machine that is outside the body. Exposure to the beam typically takes only a few seconds (similar to having an X-ray). In general, RT is given daily, five days per week, for approximately three to four weeks.

During this time, the person is closely monitored for signs of drug toxicity and side effects.

Side effects of chemotherapy — Most people who are treated with R-CHOP develop side effects, with the most common including:

●Fever and low blood counts – A potentially life-threatening side effect of chemotherapy is fever and lowered levels of a type of white blood cell, called neutrophils (the condition is called febrile neutropenia).

Anyone who is getting chemotherapy and who develops a temperature higher than 100.4°F (38°C) should immediately call his or her healthcare provider. This condition is a medical emergency and requires prompt treatment, usually with admission to a hospital and antibiotics by vein (IV).

Treatment may also be associated with low red blood cell count (anemia; causing weakness, fatigue, and other symptoms) and low platelet counts (causing easy bruising/bleeding). 

●Nausea and vomiting – Between 30 and 90 percent of people develop nausea and vomiting after R-CHOP. Several medications may be given before and after chemotherapy to reduce its severity. This often includes dexamethasone and aprepitant (sample brand name: Emend), and a 5-HT3 receptor antagonist such as ondansetron (brand name: Zofran), and granisetron (sample brand names: Kytril, Sancuso, Sustol).

●Hypersensitivity reaction – Hypersensitivity reactions may occur the first time a chemotherapy or immunotherapy drug is given, causing flushing; itching; chest, back, or abdominal pain; fever; nausea; dizziness; and other symptoms. It is not clear why this type of reaction occurs. Several medications are usually given before chemotherapy to reduce the severity of these symptoms, including acetaminophen (sample brand name: Tylenol), diphenhydramine (sample brand name: Benadryl), hydrocortisone (a steroid), and a stomach-acid-reducing medication, such as famotidine (brand name: Pepcid).

●Tumor lysis syndrome – Tumor lysis syndrome is a serious, potentially life-threatening condition that can occur after beginning treatment with chemotherapy. It happens because the tumor cells die quickly and release toxic break-down products into the bloodstream. Symptoms can include nausea, vomiting, diarrhea, lack of appetite, lethargy, blood in the urine, heart problems, seizures, muscle cramps, and others. Preventive treatments are usually given before chemotherapy to reduce the risk of developing tumor lysis syndrome, including IV fluids and medications. In addition, blood tests are often done during and after treatment to monitor for the condition.

●Other potential complications – Other potential complications of chemotherapy include damage to the heart (called cardiotoxicity) or the nerves (called neurotoxicity), loss of the ability to have children (infertility), and increased risk of some types of cancer. These risks, as well as ways to manage or monitor for them, should be discussed with a healthcare provider before beginning treatment.

Because multiple chemotherapy cycles are usually administered, patients need to consult a surgeon regarding implantation of a venous access device, which is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

Side effects of radiation therapy:

Common side effects include:

• Headaches.

• Hair loss.

• Nausea.

• Vomiting.

• Extreme tiredness (fatigue)

• Hearing loss.

• Skin and scalp changes.

• Trouble with memory and speech.

Patient monitoring

Patients are monitored very carefully while they are receiving chemotherapy. Frequent complete blood count (CBC) and chemistries are ordered for outpatient monitoring, to see if patients have developed any chemotherapy-related adverse effects.

Red blood cell transfusions or administration of hematopoietic growth factors (eg, erythropoietin, epoetin alfa, darbepoetin alfa) may be required for patients with persistently low hemoglobin values due to disease or chemotherapy.

Treatment of Advanced-Stage Disease

Historical perspective

The use of systemic chemotherapy to successfully eradicate DLBCL was first described in the early 1970s. After these original reports, CHOP (given every 21 days—ie, CHOP-21) became the standard of care for aggressive lymphomas in the United States.

In the late 1990s, results from clinical trials evaluating rituximab as monotherapy in aggressive lymphomas and the results reported by Czuczuman et al in patients with follicular lymphomas prompted research into the combination of rituximab and CHOP (R-CHOP) for aggressive B-cell lymphomas.  This yielded practice-changing results.

The landmark study validating the addition of rituximab to CHOP chemotherapy was conducted by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) and presented by Coiffier et al. It enrolled patients with newly diagnosed stage I-IV aggressive B-cell lymphomas who were older than 60 years and randomized them to receive eight cycles of either CHOP or R-CHOP at 21-day intervals. Compared with CHOP, R-CHOP chemotherapy resulted in higher response rates (76% vs 63%, respectively, P = 0.005) and, on 18-month follow-up, significantly better PFS and OS (P < 0.001 and P = 0.007, respectively).

Analysis of the study after 5 and 10 years of follow-up continued to show a clear benefit of R-CHOP in DLBCL. On 10-year follow-up, the PFS rate following therapy with R-CHOP or CHOP was 36.5% and 20%, respectively, and OS rates were 43.5% versus 27.6%. 

Similarly, a study by Habermann et al in untreated DLBCL patients who were 60 years or older found that the 3-year failure-free survival rate was 53% with R-CHOP versus 46% for CHOP. However, no benefit was seen with maintenance rituximab after R-CHOP. A study by the MabThera International Trial (MInT) group in 824 young patients with good-prognosis DLBC reported that after a follow-up period of 3 years, patients randomized to receive R-CHOP had higher event-free survival (79% vs 59%, P< 0.0001) and OS (93% vs 84%; P = 0.0001) than patients assigned to chemotherapy alone. The benefit of adding rituximab in high-intermediate and high-risk DLBCL patients younger than 60 years had been extrapolated from the results of the GELA and MInT studies. 

A 14-day (so-called dose dense) R-CHOP cycle has been studied for its potential to improve the worse prognosis in elderly patients with advanced-stage DLBCL. The RICOVER-60 trial conducted by the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) demonstrated the benefit of six cycles of R-CHOP-14 in elderly patients with DLBCL. On the other hand, in the randomized LNH03-6B trial by the GELA group in elderly patients with untreated DLBCL and at least one adverse prognostic factor, R-CHOP-14 did not improve efficacy compared with R-CHOP-21. However, that trial was criticized for high treatment-related mortality and low dose intensities in the R-CHOP-14 arm. 

Additional clinical trials have explored the combination of rituximab with other chemotherapy regimens. Wilson et al, from the National Cancer Institute, studied dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone in combination with rituximab (DA-EPOCH-R) in previously untreated DLBCL. [98] In this regimen, the  EPOCH doses are adjusted with each cycle to achieve an absolute neutrophil count nadir of 500 cells/µL. The study enrolled 72 consecutive patients with untreated DLBCL who were aged at least 18 years and had stage II or higher disease. Patients received 6-8 cycles of DA-EPOCH-R. IFRT was not permitted. At 5 years, PFS and OS were 79% and 80%, respectively. [98, 99]

In a randomized Alliance/Cancer and Leukemia Group B (CALGB) phase III study comparing R-CHOP-21 with DA-EPOCH-R in previously untreated DLBCL, DA-EPOCH-R was more toxic and did not improve PFS or OS compared with R-CHOP. However, while the trial design assumed a 55% 3-year PFS rate with R-CHOP, the observed 3-year PFS rate in the study was significantly better, at 72% The authors concluded that the more favorable results with R-CHOP may reflect more favorable patient characteristics, so the study results may not be generalizable to specific risk subgroups. [100]

Current practice

R-CHOP remains the regimen of choice for advanced-stage DLBCL. It may be given for six or eight cycles, and both 14-day and 21-day cycles are used. [73, 75]  R-CHOP can usually be used in fit patients up to 80 years of age in fit patients, but modulation of treatment according to geriatric assessment is recommended. In elderly patients who are unfit or frail or have cardiac dysfunction, other agents can be substituted for doxorubin (eg, gemcitabine, etoposide, liposomal doxorubicin). More intensive regimens (eg, R-CHOP plus etoposide) may be considered in selected patients.

https://www.eviq.org.au/haematology-and-bmt/lymphoma/non-hodgkin-lymphoma/70-r-chop21-rituximab-cyclophosphamide-doxorubici#evidence

FOLLOW-UP AFTER TREATMENT OF DIFFUSE LARGE B CELL LYMPHOMA

Response evaluation — After finishing the planned course of treatment, the person will have a medical history, physical examination, and laboratory testing to gauge his or her response to treatment.

A radiologic imaging test (PET/CT) is recommended, either six to eight weeks after finishing chemotherapy or 12 weeks after finishing radiation therapy.

A complete response has been achieved if all of the following criteria are met:

●There is no evidence of disease or disease-related symptoms on history and physical examination.

●The spleen and liver cannot be felt during the physical examination.

●Any abnormalities seen on the CT scan do not "light up" on the PET scan.

●If a pretreatment bone marrow biopsy was positive, a repeat bone marrow biopsy must be negative.

People who do not have a complete response are treated for refractory disease.

Surveillance for relapse — People who achieve a complete response must be evaluated on a regular basis after treatment. The visits usually include a medical history and physical examination, blood tests, and may include a radiologic imaging test, such as a CT scan. The purpose of these visits is to monitor for treatment complications and possible relapse. If there are new signs of a relapse, a biopsy must be done to confirm the diagnosis.

The frequency of these visits depends upon the comfort of both the person and physician. When deciding how often these visits should occur, the person and physician must consider the following:

●The majority of relapses occur during the first two years after finishing treatment.

●Relapses usually cause the person to have symptoms and are rarely found solely on the basis of routine radiologic imaging tests.

●If a relapse is picked up a few weeks earlier because of more intense monitoring, it is unlikely to improve outcome.

●The number of CT scans should be limited, particularly in younger individuals, to limit radiation exposure and the risk for second cancers

There is no role for routine PET or PET/CT imaging in the long-term follow-up of people who do not have any symptoms. There is limited data to support performing CT scans periodically to monitor for relapse. Whether or not to use CT scans in a person without symptoms should be determined on an individual basis.

RECURRENT OR REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA TREATMENT 

Recurrent disease is the term used to describe disease that returns after an initial remission. Refractory disease is the term used to describe disease that does not fully respond to treatment in the first place. 

Depending upon the person's age and underlying medical problems, treatment may include one or more chemotherapy medications given over several days. Sometimes people with refractory disease choose management with supportive care and no active therapy.

If the person responds to chemotherapy and is healthy enough, high-dose chemotherapy and a specific kind of bone marrow transplant called "autologous hematopoietic stem cell transplantation" (auto-HSCT) may be recommended. This type of transplant uses a person's own cells to "rescue" his or her bone marrow from intensive chemotherapy.  

An alternative for auto-HSCT is allogeneic HSCT (allo-HSCT). An autologous transplant uses a person's own stem cells. An allogeneic transplant uses stem cells from a donor whose human leukocyte antigens (HLA) are acceptable matches to the patient's (matched donor or unmatched donor). You can see the efficacy of auto vs allo-HSCT in the table below, showing event free survival and overall survival rates.

 Allo-HSCT is still being trialed but is showing good promise as an alternative option in DLBCL.

Relapse therapy

Options for relapsed disease continue to make progress. Second-line chemotherapy regimens vary, depending on whether stem cell transplantation (HSCT) is being considered, and if there is a matched donor or unmatched donor.

Options for relapsed or refractory disease include the following:

Chemoimmunotherapy

The past several years have seen the advent of the following novel agents for treatment of relapsed or recurrent DLBCL:

Polatuzumab vedotin (Polivy)

Selinexor (Xpovio)

Tafasitamab (Monjuvi)

Loncastuximab tesirine (Zynlonta)

Polatuzumab vedotin

In June 2019, polatuzumab vedotin, a CD79b-directed antibody-drug conjugate, gained accelerated approval from the FDA for adults with relapsed or recurrent DLBCL in combination with bendamustine and a rituximab product (ie, rituximab or a biosimilar) after at least 2 prior therapies. 

Accelerated approval of polatuzumab was based on a study in which 40% of patients (16/40) treated with polatuzumab vedotin plus bendamustine and rituximab (BR) achieved a complete response (CR) compared with 18% (7/40) of those receiving BR alone. The study also showed an OR of 45% with polatuzumab plus BR at the end of treatment compared with 18% for BR alone. Of patients who achieved a complete or partial response, duration of response was at least 6 months in 64% (16/25) of those receiving polatuzumab plus BR, compared with 30% (3/10) for BR alone. Additionally, response lasting at least 1 year was observed in 48% (12/25) of patients receiving polatuzumab plus BR compared with 20% (2/10) for BR alone. 

Selinexor

Selinexor is the first oral selective inhibitor of nuclear export (SINE) compound. In June 2020, the FDA granted selinexor accelerated approval for relapsed or refractory DLBCL, including DLBCL arising from follicular lymphoma, in patients previously treated with at least 2 lines of systemic therapy.

Tafasitamab 

In July 2020, the FDA granted accelerated approval to tafasitamab, a humanized Fc-modified cytolytic CD19-targeting monoclonal antibody, in combination with lenalidomide for the treatment of relapsed or refractory DLBCL not otherwise specified, including DLBCL arising from low-grade lymphoma, in adults who are ineligible for ASCT. Approval was based on data from the phase II L-MIND study, an open label, multicenter, single-arm trial that showed an overall response rate (ORR) of 55%, including a CR rate of 37% and a partial response (PR) rate of 18%. The median duration of response (mDOR) was 21.7 months. 

Loncastuximab tesirine

Loncastuximab tesirine, a CD19 antibody-drug complex, gained accelerated approval from the FDA in April 2021 for adults with relapsed/refractory large-B-cell lymphoma following 2 or more lines of systemic therapy. The indication includes DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma. Approval was based on results from the phase II, single-arm, open-label LOTIS-2 trial (n = 145). The trial demonstrated an ORR of 48.3% (70/145 patients), which included a CR rate of 24.1% (35/145 patients) and a PR rate of 24.1% (35/145 patients). Median time to response was 1.3 months and median duration of response for the 70 responders was 10.3 months. 

Because multiple chemotherapy cycles are usually administered, consult a surgeon regarding implantation of a venous access device, which is helpful for chemotherapy infusions and for the repeated blood samples required to monitor treatment toxicity.

CNS Prophylaxis in DLBCL

Central nervous system (CNS) relapse is a rare but significant complication in the management of patients with diffuse large B-cell lymphoma (DLBCL). The probability of CNS relapse after 1 year of diagnosis is estimated to be 2.3-4.5%. The risk of CNS relapse appears to be higher in subsets of DLBCL (4- to 15-fold increase in risk), and identification of such patients is imperative in an attempt to implement prophylactic therapy.  

Patients with elevated risk for CNS relapse are those with the following:

• Elevated lactate dehydrogenase (LDH) level at diagnosis

• Testicular, adrenal/kidney, or uterine involvement

• More than 2 extranodal sites involved by disease

• MYC translocation, particularly if occurring with a BCL2 translocation (classic double-hit lymphoma) or MYC/BCL2 with a  BCL6 translocation (triple-hit lymphoma) and,

• Concomitant infection with human immunodeficiency virus (HIV)

  
  

CNS prophylaxis has most often been performed with intrathecal methotrexate. However, in most studies of CNS prophylaxis in DLBCL, intrathecal prophylaxis has not been protective. Some evidence supports the use of intravenous methotrexate, and ongoing clinical trials are evaluating this strategy.

CAR-T therapy

In some cases, newer forms of immunotherapy, such as Chimeric antigen receptor "CAR-T" therapy, may be effective for relapsed DLBCL. CAR-T therapy involves genetically modifying specific cells from a person's immune system; this enables the cells to directly target the cancer cells

In October 2017, FDA approved axicabtagene ciloleucel (Yescarta) for treatment of large B-cell lymphoma after at least two other kinds of therapy have failed. Approved uses include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma. Axicabtagene ciloleucel is not indicated for the treatment of patients with primary central nervous system lymphoma. 

Approval was based on the results from the ZUMA-1 study, an open-label, multicenter trial enrolling of 111 patients from 22 institutions. Patients in ZUMA-1 received the target dose of axicabtagene ciloleucel (2 x 106 cells/kg) after low-dose conditioning with cyclophosphamide and fludarabine for 3 days. The modified intention-to-treat population involved 101 patients who received axicabtagene ciloleucel. In adults with relapsed/refractory DLBCL, the response rates were approximately 60-80%, with complete responses seen in 40-70% of patients. At 6-month follow-up, 40% of patients had maintained their complete response. The trial had a median survival follow-up of 8.7 months. 

In May 2018, tisagenlecleucel gained approval for adults with relapsed or refractory large B-cell lymphoma, including DLBCL not otherwise specified, high-grade B-cell lymphoma, and DLBCL arising from follicular lymphoma after ≥ 2 lines of systemic therapy. 

Approval was based on the single-arm, open-label, multicenter, phase 2 JULIET trial in adults with relapsed or refractory DLBCL and DLBCL after transformation from follicular lymphoma. Eligible patients must have been treated with at least 2 prior lines of therapy, including an anthracycline and rituximab, or relapsed following ASCT. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy.

The ORR for the 68 evaluable patients was 50% (95% CI: 37.6, 62.4) with a CR rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response (DOR) was longer in patients with a best overall response of CR, as compared to a best overall response of partial response (PR). Among patients achieving CR, the estimated median DOR was not reached (95% CI: 10.0 months, not estimable [NE]). The estimated median response duration among patients in PR was 3.4 months (95% CI: 1.0, NE). 

Lisocabtagene maraleucel (Breyanzi) is a CD19-directed CAR T-cell therapy for adults with R/R large B-cell lymphoma (LBCL) after two or more lines of systemic therapy, including DLBCL not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. It is not indicated for h primary CNS lymphoma.

In the chart below you can see the complete response, progression free survival and overall survival of CAR-T vs any other type of third line therapy (chemotherapy, immunotherapy, targeted therapy or allo/auto-HSCT). There is a marked improvement in endpoints. 

However, in the ZUMA-1 trial, approximately 60% of responding patients ultimately progressed, and median progression-free survival was only 5.9 months. Furthermore, the median duration of response for those with incomplete responses was only 1.9 months.

 In the JULIET trial, median PFS and OS were approximately 3 and 12 months, respectively. 

Safety and efficacy were evaluated in the TRANSCEND trial, an open-label, multicenter, single-arm trial. Patients (n=268) with R/R large B-cell non-Hodgkin lymphoma after at least 2 lines of therapy. Study patients received a single infusion of lisocabtagene maraleucel following completion of lymphodepleting chemotherapy. Of these patients, 54% achieved CR (95% CI: 47%-61%) and 19% achieved PR (95% CI:14%-26%). Median duration of response for all responders was 16.7 months (CR was not reached; PR: 1.4 months [95% CI: 1.1-2.2 months). Among all responders, 65% had remission for at least six months and 62% had remission lasting at least nine months.

Among patients in the TRANSCEND trial, the most common adverse reactions were as follows:

• Fatigue

• Cytokine release syndrome

• Musculoskeletal pain

• Nausea

• Headache

• Encephalopathy

• Infections (pathogen unspecified)

• Decreased appetite

• Diarrhea

• Hypotension

• Tachycardia

• Dizziness

• Cough

• Constipation

• Abdominal pain

• Vomiting

• Edema

CLINICAL TRIALS

A clinical trial is an approved research study that is designed to determine the best treatment for a particular disease. Clinical trials are especially important in DLBCL, since there no treatment program capable of curing all people with this disease.

Enrollment in a clinical trial, if available, is always recommended in DLBCL.

There are trials involving venetoclax: a potent, selective inhibitor of B-cell lymphoma-2 (BCL-2).

Polatuzumab vedotin combinations.

And Mosunetuzumab (an anti-CD20/CD3 BiTE therapy). BiTE therapy is a strategy to activate exhausted T cells induced by long-term exposure to tumor antigens.

Palliative care

Patients whose condition relapses after multiple treatment regimens or who have poor performance status and who are therefore not candidates for further chemotherapy should be considered for palliative management and hospice care. The following services can be sought in appropriate clinical situations:

Pain management service

Nursing home

Terminal care facility (hospice)

Home care with specialized nursing support for pain management

Rehabilitative centers

Guidelines summary

Guidelines on diffuse large B-cell lymphoma (DLBCL) have been published by the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO). 

Diagnosis

Treatment

References:

1. Sarkozy C, Sehn LH. Management of relapsed/refractory DLBCL. Best Pract Res Clin Haematol. 2018;31:209‐216. - PubMed

2. Boslooper K, Kibbelaar R, Storm H, et al. Treatment with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone is beneficial but toxic in very elderly patients with diffuse large B‐cell lymphoma: a population‐based cohort study on treatment, toxicity and outcome. Leuk Lymphoma. 2014;55:526‐532. - PubMed

3. Lugtenburg PJ, Lyon AR, Marks R, Luminari S. Treatment of aggressive non‐Hodgkin's lymphoma in frail patients: cardiac comorbidities and advanced age. Future Oncol. 2019;15:1197‐1205. - PubMed

4. Shi X, Liu X, Li X, et al. Risk stratification for diffuse large B‐cell lymphoma by integrating interim evaluation and International Prognostic Index: a multicenter retrospective study. Front Oncol. 2021;11:754964. - PMC - PubMed

5. Chiappella A, Crombie J, Guidetti A, Vitolo U, Armand P, Corradini P. Are we ready to treat diffuse large B‐cell and high‐grade lymphoma according to major genetic subtypes? HemaSphere. 2019;3:e284. - PMC - PubMed

6. Bartlett NL, Wilson WH, Jung S‐H, et al. Dose‐adjusted EPOCH‐R compared with R‐CHOP as frontline therapy for diffuse large B‐cell lymphoma: clinical outcomes of the phase III intergroup trial Alliance/CALGB 50303. J Clin Oncol. 2019;37:1790‐1799. - PMC - PubMed

7. Sehn LH, Martelli M, Trněný M, et al. A randomized, open‐label, phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B‐cell lymphoma: final analysis of GOYA. J Hematol Oncol. 2020;13:1‐9. - PMC - PubMed

8. Récher C, Coiffier B, Haioun C, et al. 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. 2011;378:1858‐1867. - PubMed

9. Peyrade F, Jardin F, Thieblemont C, et al. Attenuated immunochemotherapy regimen (R‐miniCHOP) in elderly patients older than 80 years with diffuse large B‐cell lymphoma: a multicentre, single‐arm, phase 2 trial. Lancet Oncol. 2011;12:460‐468. - PubMed

10. Peyrade F, Bologna S, Delwail V, et al. Combination of ofatumumab and reduced‐dose CHOP for diffuse large B‐cell lymphomas in patients aged 80 years or older: an open‐label, multicentre, single‐arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017;4:e46‐e55. - PubMed

11. Younes A, Sehn LH, Johnson P, et al. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non‐germinal center B‐cell diffuse large B‐cell lymphoma. J Clin Oncol. 2019;37:1285‐1295. - PMC - PubMed

12. Denker S, Bittner A, Frick M, et al. Ibrutinib‐ and bortezomib‐extended R‐CHOP induction in elderly higher‐risk patients newly diagnosed with diffuse large B‐cell lymphoma – first analysis of toxicity and efficacy signals. Leuk Lymphoma. 2022;63:84‐92. - PubMed

13. Davies AJ, Caddy J, McLaughlin K, et al. Durable responses from acalabrutinib in combination with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R‐CHOP) as first line therapy for patients with diffuse large B‐cell lymphoma (DLBCL): the Accept phase Ib/II single arm study. Blood. 2022;140:9478‐9479.

14. Morschhauser F, Feugier P, Flinn IW, et al. A phase 2 study of venetoclax plus R‐CHOP as first‐line treatment for patients with diffuse large B‐cell lymphoma. Blood. 2021;137:600‐609. - PMC - PubMed

15. Tilly H, Morschhauser F, Sehn LH, et al. Polatuzumab vedotin in previously untreated diffuse large B‐cell lymphoma. New Engl J Med. 2022;386:351‐363. - PMC - PubMed

16. Nowakowski GS, Hong F, Scott DW, et al. Addition of lenalidomide to R‐CHOP improves outcomes in newly diagnosed diffuse large B‐cell lymphoma in a randomized phase II US intergroup study ECOG‐ACRIN E1412. J Clin Oncol. 2021;39:1329‐1338. - PMC - PubMed

17. Nowakowski GS, Chiappella A, Gascoyne RD, et al. ROBUST: a phase III study of lenalidomide plus R‐CHOP versus placebo plus R‐CHOP in previously untreated patients with ABC‐type diffuse large B‐cell lymphoma. J Clin Oncol. 2021;39:1317‐1328. - PMC - PubMed

18. Gini G, Tani M, Tucci A, et al. Lenalidomide plus rituximab for the initial treatment of frail older patients with DLBCL: the FIL_ReRi phase 2 study. Blood. 2023;142:1438‐1477. - PubMed

19. Kuzume A, Chi S, Yamauchi N, Minami Y. Immune‐checkpoint blockade therapy in lymphoma. Int J Mol Sci. 2020;21:1‐15. - PMC - PubMed

20. Tamma R, Ranieri G, Ingravallo G, et al. Inflammatory cells in diffuse large B cell lymphoma. J Clin Med. 2020;9:2418. - PMC - PubMed

21. Ansell SM, Stenson M, Habermann TM, Jelinek DF, Witzig TE. Cd4+ T‐cell immune response to large B‐cell non‐Hodgkin's lymphoma predicts patient outcome. J Clin Oncol. 2001;19:720‐726. - PubMed

22. Fangazio M, Ladewig E, Gomez K, et al. Genetic mechanisms of HLA‐I loss and immune escape in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2021;118:e2104504118. - PMC - PubMed

23. Rimsza LM, Roberts RA, Miller TP, et al. Loss of MHC class II gene and protein expression in diffuse large B‐cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow‐up study from the Leukemia and Lymphoma Molecular. Blood. 2004;103:4251‐4258. - PubMed

24. Miller JS, Lanier LL. Natural killer cells in cancer immunotherapy. Annu Rev Cancer Biol. 2019;3:77‐103.

25. Gentles AJ, Newman AM, Liu CL, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21:938. - PMC - PubMed

26. Deng J, Fleming JB. Inflammation and myeloid cells in cancer progression and metastasis. Front Cell Dev Biol. 2022;9:759691. - PMC - PubMed

27. Sterner RC, Sterner RM. CAR‐T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11:69. - PMC - PubMed

28. Jacobson C, Locke FL, Ghobadi A, et al. Long‐term (≥4 year and ≥5 year) overall survival (OS) by 12‐ and 24‐month event‐free survival (EFS): an updated analysis of ZUMA‐1, the pivotal study of axicabtagene ciloleucel (Axi‐Cel) in patients (pts) with refractory large B‐cell lymphoma (LBCL). Blood. 2021;138:1764.

29. Neelapu SS, Jacobson CA, Ghobadi A, et al. Five‐year follow‐up of ZUMA‐1 supports the curative potential of axicabtagene ciloleucel in refractory large B‐cell lymphoma. Blood. 2023;141:2307‐2315. - PMC - PubMed

30. Schuster SJ, Tam CS, Borchmann P, et al. Long‐term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B‐cell lymphomas (JULIET): a multicentre, open‐label, single‐arm, phase 2 study. Lancet Oncol. 2021;22:1403‐1415. - PubMed

31. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B‐cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020;396:839‐852. - PubMed

32. Westin JR, Kersten MJ, Salles G, et al. Efficacy and safety of CD19‐directed CAR‐T cell therapies in patients with relapsed/refractory aggressive B‐cell lymphomas: observations from the JULIET, ZUMA‐1, and TRANSCEND trials. Am J Hematol. 2021;96:1295‐1312. - PMC - PubMed

33. Sehgal A, Hoda D, Riedell PA, et al. Lisocabtagene maraleucel as second‐line therapy in adults with relapsed or refractory large B‐cell lymphoma who were not intended for haematopoietic stem cell transplantation (PILOT): an open‐label, phase 2 study. Lancet Oncol. 2022;23:1066‐1077. - PubMed

34. Abramson JS, Solomon SR, Arnason JE, et al. Lisocabtagene maraleucel as second‐line therapy for large B‐cell lymphoma: primary analysis of phase 3 TRANSFORM study. Blood. 2022;141:1675‐1684. - PMC - PubMed

35. Locke FL, Miklos DB, Jacobson CA, et al. Axicabtagene ciloleucel as second‐line therapy for large B‐cell lymphoma. N Engl J Med. 2022;386:640‐654. - PubMed

36. Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first‐line therapy in high‐risk large B‐cell lymphoma: the phase 2 ZUMA‐12 trial. Nat Med. 2022;28:735‐742. - PMC - PubMed

37. Westin J, Jacobson CA, Chavez JC, et al. ZUMA‐23: a global, phase 3, randomized controlled study of axicabtagene ciloleucel versus standard of care as first‐line therapy in patients with high‐risk large B‐cell lymphoma. J Clin Oncol. 2023;41:TPS7578.

38. Deng Q, Han G, Puebla‐Osorio N, et al. Characteristics of anti‐CD19 CAR T‐cell infusion products associated with efficacy and toxicity in patients with large B‐cell lymphomas. Nat Med. 2020;26:1878‐1887. - PMC - PubMed

39. Zurko J, Nizamuddin I, Epperla N, et al. Peri‐CAR‐T practice patterns and survival predictors for all CAR‐T patients and post‐CAR‐T failure in aggressive B‐NHL. Blood Adv. 2023;7:2657‐2669. - PMC - PubMed

40. Lee DW, Santomasso BD, Locke FL, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2019;25:625‐638. - PMC - PubMed

41. Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T‐cell therapy — assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47‐62. - PMC - PubMed

42. Hawkins ER, D'Souza RR, Klampatsa A. Armored CAR T‐cells: the next chapter in T‐cell cancer immunotherapy. Biol Theory. 2021;15:95‐105. - PMC - PubMed

43. Yeku OO, Brentjens RJ. Armored CAR T‐cells: utilizing cytokines and pro‐inflammatory ligands to enhance CAR T‐cell anti‐tumour efficacy. Biochem Soc Trans. 2016;44:412‐418. - PMC - PubMed

44. Asmamaw Dejenie T, Tiruneh G, Medhin M, et al. Current updates on generations, approvals, and clinical trials of CAR T‐cell therapy. Hum Vaccin Immunother. 2022;18:e2114254. - PMC - PubMed

45. Han X, Wang Y, Wei J, Han W. Multi‐antigen‐targeted chimeric antigen receptor T cells for cancer therapy. J Hematol Oncol. 2019;12:128. - PMC - PubMed

46. ClinicalTrials.gov . Study of IMPT‐314 in R/R aggressive B‐cell NHL [Internet]. Accessed September 2, 2024. https://www.clinicaltrials.gov/study/NCT05826535

47. Depil S, Duchateau P, Grupp SA, Mufti G, Poirot L. “Off‐the‐shelf” allogeneic CAR T cells: development and challenges. Nat Rev Drug Discov. 2020;19:185‐199. - PubMed

48. Khurana A, Lin Y. Allogeneic chimeric antigen receptor therapy in lymphoma. Curr Treat Options Oncol. 2022;23:171‐187. - PMC - PubMed

49. Locke FL, Malik S, Tees MT, et al. First‐in‐human data of ALLO‐501A, an allogeneic chimeric antigen receptor (CAR) T‐cell therapy and ALLO‐647 in relapsed/refractory large B‐cell lymphoma (R/R LBCL): ALPHA2 study. J Clin Oncol. 2021;39:2529.

50. Salvaris R, Ong J, Gregory GP. Bispecific antibodies: a review of development, clinical efficacy and toxicity in B‐cell lymphomas. J Pers Med. 2021;11:355. - PMC - PubMed

51. Falchi L, Vardhana SA, Salles GA. Bispecific antibodies for the treatment of B‐cell lymphoma: promises, unknowns, and opportunities. Blood. 2023;141:467‐480. - PMC - PubMed

52. Sehn LH, Chamuleau M, Lenz G, et al. Phase 3 trial of subcutaneous epcoritamab + R‐CHOP versus R‐CHOP in patients (pts) with newly diagnosed diffuse large B‐cell lymphoma (DLBCL): EPCORE DLBCL‐2. Hematol Oncol. 2023;41:849‐850.

53. ClinicalTrials.gov . A study of TNB‐486 in subjects with relapsed or refractory B‐cell non‐Hodgkin lymphoma [Internet]; 2020. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT04594642

54. González BE. Role of bispecific antibodies in relapsed/refractory diffuse large B‐cell lymphoma in the CART era. Front Immunol. 2022;13:909008. - PMC - PubMed

55. Lu H, Oka A, Coulson M, et al. PIT565, a first‐in‐class anti‐CD19, anti‐CD3, anti‐CD2 trispecific antibody for the treatment of B cell malignancies. Blood. 2022;140:3148.

56. ClinicalTrials.gov . A study of JNJ‐80948543, a T‐cell redirecting CD79b x CD20 x CD3 trispecific antibody, in participants with non‐Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [Internet]. Accessed March 13, 2024. https://www.clinicaltrials.gov/study/NCT05424822

57. Dickinson MJ, Carlo‐Stella C, Morschhauser F, et al. Glofitamab for relapsed or refractory diffuse large B‐cell lymphoma. N Engl J Med. 2022;387:2220‐2231. - PubMed

58. Abramson JS, Palomba ML, Gordon LI, et al. Two‐year follow‐up of Transcend NHL 001, a multicenter phase 1 study of lisocabtagene maraleucel (liso‐cel) in relapsed or refractory (R/R) large B‐cell lymphomas (LBCL). Blood. 2021;138:2840. - PubMed

59. Johnson NA, Boyle M, Bashashati A, et al. Diffuse large B‐cell lymphoma: reduced CD20 expression is associated with an inferior survival. Blood. 2009;113:3773‐3780. - PMC - PubMed

60. Prevodnik VK, Lavrenčak J, Horvat M, Novakovič BJ. The predictive significance of CD20 expression in B‐cell lymphomas. Diagn Pathol. 2011;6:33. - PMC - PubMed

61. Horton HM, Bernett MJ, Pong E, et al. Potent in vitro and in vivo activity of an Fc‐engineered anti‐CD19 monoclonal antibody against lymphoma and leukemia. Cancer Res. 2008;68:8049‐8057. - PubMed

62. Katz BZ, Herishanu Y. Therapeutic targeting of CD19 in hematological malignancies: past, present, future and beyond. Leuk Lymphoma. 2014;55:999‐1006. - PubMed

63. Salles G, Długosz‐Danecka M, Ghesquières H, Jurczak W. Tafasitamab for the treatment of relapsed or refractory diffuse large B‐cell lymphoma. Expert Opin Biol Ther. 2021;21:455‐463. - PMC - PubMed

64. Her JH, Pretscher D, Patra‐Kneuer M, et al. Tafasitamab mediates killing of B‐cell non‐Hodgkin's lymphoma in combination with γδ T cell or allogeneic NK cell therapy. Cancer Immunol Immunother. 2022;71:2829‐2836. - PMC - PubMed

65. Awan FT, Lapalombella R, Trotta R, et al. CD19 targeting of chronic lymphocytic leukemia with a novel Fc‐domain‐engineered monoclonal antibody. Blood. 2010;115:1204‐1213. - PMC - PubMed

66. Duell J, Maddocks KJ, González‐Barca E, et al. Long‐term outcomes from the phase II L‐MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B‐cell lymphoma. Haematologica. 2021;106:2417‐2426. - PMC - PubMed

67. Duell J, Abrisqueta P, Andre M, et al. Tafasitamab for patients with relapsed or refractory diffuse large B‐cell lymphoma: final 5‐year efficacy and safety findings in the phase II L‐MIND study. Haematologica. 2024;109:553‐566. - PMC - PubMed

68. Chu Y, Lamb M, Cairo MS, Lee DA. The future of natural killer cell immunotherapy for B cell non‐Hodgkin lymphoma (B cell NHL). Curr Treat Options Oncol. 2022;23:381‐403. - PMC - PubMed

69. Liu E, Marin D, Banerjee P, et al. Use of CAR‐transduced natural killer cells in CD19‐positive lymphoid tumors. N Engl J Med. 2020;382:545‐553. - PMC - PubMed

70. Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR‐NK cells: a promising cellular immunotherapy for cancer. EBioMedicine. 2020;59:102975. - PMC - PubMed

71. Sabbah M, Jondreville L, Lacan C, et al. CAR‐NK cells: a chimeric hope or a promising therapy? Cancers (Basel). 2022;14:3839. - PMC - PubMed

72. Nieto Y, Banerjee PP, Kaur I, et al. Innate cell engager AFM13 combined with preactivated and expanded cord blood‐derived NK cells for patients with double refractory CD30+ lymphoma. Blood. 2022;140:415‐416.

73. Eladl E, Tremblay‐Lemay R, Rastgoo N, et al. Role of CD47 in hematological malignancies. J Hematol Oncol. 2020;13:1‐14. - PMC - PubMed

74. Tun AM, Ansell SM. Immunotherapy in Hodgkin and non‐Hodgkin lymphoma: innate, adaptive and targeted immunological strategies. Cancer Treat Rev. 2020;88:102042. - PubMed

75. Chao MP, Alizadeh AA, Tang C, et al. Anti‐CD47 antibody synergizes with rituximab to promote phagocytosis and eradicate non‐Hodgkin lymphoma. Cell. 2010;142:699‐713. - PMC - PubMed

76. Klichinsky M, Ruella M, Shestova O, et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat Biotechnol. 2020;38:947‐953. - PMC - PubMed

77. Kennedy GA, Tey SK, Cobcroft R, et al. Incidence and nature of CD20‐negative relapses following rituximab therapy in aggressive B‐cell non‐Hodgkin's lymphoma: a retrospective review. Br J Haematol. 2002;119:412‐416. - PubMed

78. Belada D, Kopeckova K, Bergua Burgues JM, et al. Safety and efficacy of tafasitamab ± lenalidomide added to first‐line R‐CHOP for DLBCL: phase 1b first‐MIND study. Blood. 2023;142:1348‐1358. - PMC - PubMed

79. ClinicalTrials.gov . A multicentre, parallel arm, open‐label trial of frontline R‐CHOP/pola‐RCHP and glofitamab in younger, higher risk patients with diffuse large B cell lymphoma (DLBCL) (COALITION) [Internet]; 2021. Accessed. April 19; 2023. https://clinicaltrials.gov/ct2/show/NCT04914741

80. Sehn LH, Hertzberg M, Opat S, et al. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022;6:533‐543. - PMC - PubMed

81. Westin J, Olszewski AJ, Fogliatto L, et al. SUNMO: a phase III trial evaluating the efficacy and safety of mosunetuzumab in combination with polatuzumab vedotin vs rituximab plus gemcitabine and oxaliplatin in patients with relapsed/refractory aggressive B‐cell non‐Hodgkin lymphoma. J Clin Oncol. 2023;41:TPS7586.

82. Nakamura A, Grossman S, Song K, et al. The SUMOylation inhibitor subasumstat potentiates rituximab activity by IFN1‐dependent macrophage and NK cell stimulation. Blood. 2022;139:2770‐2781. - PMC - PubMed

83. ClinicalTrials.gov . Subcutaneous epcoritamab with or without lenalidomide as first line therapy for diffuse large B‐cell lymphoma [Internet]; 2022. Accessed April 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05660967

84. Westin JR, Steiner R, Feng L, et al. Smart Stop: a phase II study of lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with chemotherapy in patients with newly diagnosed DLBCL. Blood. 2021;138:3572.

85. Westin J, Davis RE, Feng L, et al. Smart Start: rituximab, lenalidomide, and ibrutinib in patients with newly diagnosed large B‐cell lymphoma. J Clin Oncol. 2023;41:745‐755. - PMC - PubMed

86. Westin J, Burke JM, Chapman AE, et al. A phase 2, open‐label study of loncastuximab tesirine in combination with rituximab (lonca‐R) in previously untreated unfit/frail patients with diffuse large B‐cell lymphoma (DLBCL) (LOTIS‐9). Blood. 2022;140:6638‐6639.

87. ClinicalTrials.gov . A phase II trial of mosunetuzumab, polatuzumab, tafasitamab, and lenalidomide in patients with relapsed B‐cell NHL [Internet]; 2022. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05615636

88. Sakemura R, Horvei P, Manriquez‐Roman C, et al. Poster 2412: the impact of prior treatment with a CD19 targeting monoclonal antibody on subsequent treatment with CD19 targeting CART cell therapy in preclinical models. Blood. 2021;138:2412.

89. Sakemura RL, Manriquez‐Roman C, Horvei P, et al. CD19 antigen occupancy on cancer cells with the CD19 monoclonal antibody tafasitamab improves the activation, antitumor efficacy, and safety profile of CART19 cell therapy. Blood. 2022;140:2362‐2364.

90. ADC Therapeutics SA . ADC Therapeutics announces plan to discontinue the phase 2 LOTIS‐9 clinical trial of ZYNLONTA® (loncastuximab tesirine‐lpyl) and rituximab in unfit or frail previously untreated DLBCL patients [Internet]. Accessed February 9, 2024. https://ir.adctherapeutics.com/press‐releases/press‐release‐details/2023...

91. ADC Therapeutics SA . ADC Therapeutics announces voluntary pause of enrollment in the phase 2 LOTIS‐9 clinical trial of ZYNLONTA® (loncastuximab tesirine‐lpyl) and rituximab in unfit or frail previously untreated DLBCL patients [Internet]. Accessed February 9, 2024. https://ir.adctherapeutics.com/press‐releases/press‐release‐details/2023...

92. Chavez JC, Nastoupil LJ, Morschhauser F, et al. Efficacy and safety of golcadomide, a novel cereblon E3 ligase modulator (CELMoD) agent, combined with rituximab in a phase 1/2 open‐label study of patients with relapsed/refractory non‐Hodgkin lymphoma. Blood. 2023;142:4496.

93. Nastoupil LJ, Kuruvilla J, Chavez JC, et al. Phase Ib study of avadomide (CC‐122) in combination with rituximab in patients with relapsed/refractory diffuse large B‐cell lymphoma and follicular lymphoma. EJHaem. 2022;3:394‐405. - PMC - PubMed

94. Davoodi‐Moghaddam Z, Jafari‐Raddani F, Noori M, Bashash D. A systematic review and meta‐analysis of immune checkpoint therapy in relapsed or refractory non‐Hodgkin lymphoma; a friend or foe? Transl Oncol. 2023;30:101636. - PMC - PubMed

95. ClinicalTrials.gov . A phase I clinical study of HLX53 in advanced/metastatic solid tumors or lymphoma [Internet]; 2022. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05394168

96. ClinicalTrials.gov . Efficacy and safety of IBI110 single agent and in combination with sintilimab in patients with relapsed or refractory diffuse large B cell lymphoma (r/r DLBCL) [Internet]; 2022. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05039658

97. ClinicalTrials.gov . A safety and tolerability study of INCAGN02385 in select advanced malignancies [Internet]; 2020. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT03538028

98. ClinicalTrials.gov . Sym023 (anti‐TIM‐3) in patients with advanced solid tumor malignancies or lymphomas [Internet]; 2021. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT03489343

99. ClinicalTrials.gov . To evaluate the safety and efficacy of TQB2618 injection combined with penpulimab in the treatment of patients with relapsed and refractory lymphoma [Internet]; 2023. Accessed May 19, 2023. https://clinicaltrials.gov/ct2/show/NCT05400876

100. ClinicalTrials.gov . A study to evaluate the safety, tolerability, and efficacy of relatlimab in relapsed or refractory B‐cell malignancies [Internet]; 2023. Accessed May 19, 2023. https://www.clinicaltrials.gov/ct2/show/NCT02061761

101. Advani R, Flinn I, Popplewell L, et al. CD47 blockade by Hu5F9‐G4 and rituximab in non‐Hodgkin's lymphoma. N Engl J Med. 2018;379:1711‐1721. - PMC - PubMed

102. Advani R, Bartlett NL, Smith SM, et al. The first‐in‐class anti‐CD47 antibody HU5F9‐G4 + rituximab induces durable responses in relapsed/refractory DLBCL and indolent lymphoma: interim phase 1B/2 results. Hematol Oncol. 2019;37:89‐90.

103. Mangelberger D, Augsberger C, Landgraf K, Heitmüller C, Steidl S. Blockade of the CD47/SIRPα checkpoint potentiates the anti‐tumor efficacy of tafasitamab. Blood. 2020;136:11‐12.

104. Biedermann A, Mangelberger‐Eberl D, Mougiakakos D, et al. Blocking the CD47‐Sirpa axis enhances tafasitamab‐mediated phagocytosis. Blood. 2022;140:9292‐9293.

105. Ng WL, Ansell SM, Mondello P. Insights into the tumor microenvironment of B cell lymphoma. J Exp Clin Cancer Res. 2022;41:362. - PMC - PubMed

106. Kline J, Godfrey J, Ansell SM. The immune landscape and response to immune checkpoint blockade therapy in lymphoma. Blood. 2020;135:523‐533. - PubMed

107. Liu Y, Zhou X, Wang X. Targeting the tumor microenvironment in B‐cell lymphoma: challenges and opportunities. J Hematol Oncol. 2021;14:125. - PMC - PubMed

108. Ennishi D, Jiang A, Boyle M, et al. Double‐hit gene expression signature defines a distinct subgroup of germinal center B‐cell‐like diffuse large B‐cell lymphoma. J Clin Oncol. 2019;37:190‐201. - PMC - PubMed

109. Vivier E, Raulet DH, Moretta A, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44‐49. - PMC - PubMed

110. Liu S, Nguyen K, Park D, Wong N, Wang A, Zhou Y. Harnessing natural killer cells to develop next‐generation cellular immunotherapy. Chronic Dis Transl Med. 2022;8:245‐255. - PMC - PubMed

111. Gumber D, Wang LD. Improving CAR‐T immunotherapy: overcoming the challenges of T cell exhaustion. EBioMedicine. 2022;77:103941. - PMC - PubMed

112. Wherry E. T Cell exhaustion. Nat Immunol. 2011;12:492‐499. - PubMed

113. Chen BJ, Dashnamoorthy R, Galera P, et al. The immune checkpoint molecules PD‐1, PD‐L1, TIM‐3 and LAG‐3 in diffuse large B‐cell lymphoma. Oncotarget. 2019;10:2030‐2040. - PMC - PubMed

114. Josefsson SE, Beiske K, Blaker YN, et al. TIGIT and PD‐1 mark Intratumoral T cells with reduced effector function in B‐cell non‐Hodgkin lymphoma. Cancer Immunol Res. 2019;7:355‐362. - PMC - PubMed

115. Catakovic K, Klieser E, Neureiter D, Geisberger R. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15:1‐16. - PMC - PubMed

116. Chandrasekaran S, Funk CR, Kleber T, Paulos CM, Shanmugam M, Waller EK. Strategies to overcome failures in T‐cell immunotherapies by targeting PI3K‐δ and ‐γ. Front Immunol. 2021;12:718621. - PMC - PubMed

117. Profitós‐Pelejà N, Santos JC, Marín‐Niebla A, Roué G, Ribeiro ML. Regulation of B‐cell receptor signaling and its therapeutic relevance in aggressive B‐cell lymphomas. Cancers (Basel). 2022;14:860. - PMC - PubMed

118. Morin RD, Arthur SE, Hodson DJ. Molecular profiling in diffuse large B‐cell lymphoma: why so many types of subtypes? Br J Haematol. 2022;196:814‐829. - PubMed

119. Mondello P, Ansell SM, Nowakowski GS. Immune epigenetic crosstalk between malignant B cells and the tumor microenvironment in B cell lymphoma. Front Genet. 2022;13:826594. - PMC - PubMed

120. Ennishi D, Takata K, Béguelin W, et al. Molecular and genetic characterization of MHC deficiency identifies ezh2 as therapeutic target for enhancing immune recognition. Cancer Discov. 2019;9:546‐563. - PubMed

121. Hu M, Li Y, Lu Y, et al. The regulation of immune checkpoints by the hypoxic tumor microenvironment. Peer J. 2021;9:e11306. - PMC - PubMed

122. Henze AT, Mazzone M. The impact of hypoxia on tumor‐associated macrophages. J Clin Invest. 2016;126:3672‐3679. - PMC - PubMed