Seminar

B-cell non-Hodgkin lymphomas

Elisabeth Silkenstedt, Gilles Salles, Elias Campo, Martin Dreyling

B-cell lymphomas occur with an incidence of 20 new cases per 100 000 people per year in high-income countries. Lancet 2024; 403: 1791–807
They can affect any organ and are characterised by heterogeneous clinical presentations and courses, varying from Published Online
asymptomatic, to indolent, to very aggressive cases. Since the topic of B-cell non-Hodgkin lymphomas was last April 10, 2024
https://doi.org/10.1016/
reviewed in The Lancet in 2017, a deeper understanding of the biological background of this heterogeneous group of
S0140-6736(23)02705-8
malignancies, the availability of new diagnostic methods, and the development and implementation of new targeted
Department of Medicine III,
and immunotherapeutic approaches have improved our ability to treat patients. This Seminar provides an overview of LMU Hospital, Munich,
the pathobiology, classification, and prognostication of B-cell non-Hodgkin lymphomas and summarises the current Germany (E Silkenstedt,
knowledge and standard of care regarding biology and clinical management of the most common subtypes of mature Prof M Dreyling); Lymphoma
Service, Memorial Sloan-
B-cell non-Hodgkin lymphomas. It also highlights new findings in deciphering the molecular background of disease
Kettering Cancer Center,
development and the implementation of new therapeutic approaches, particularly those targeting the immune New York, NY, USA
system. (Prof G Salles); Department of
Pathology, Hospital Clinic,
Introduction stage of normal B-cell development, but most originate Institute for Biomedical
Research August Pi i Sunyer,
B-cell non-Hodgkin lymphomas (B-NHL) occur with an from the germinal centre, including Burkitt lymphoma, University of Barcelona,
incidence of 20 new cases per 100 000 per year in high- germinal centre B-cell-like (GCB)-type diffuse large Barcelona, Spain (Prof E Campo)
income countries and are characterised by heterogeneous B-cell lymphoma (DLBCL), and follicular lymphoma.2 Correspondence to:
pathogenic mechanisms and clinical courses. CD20- During the germinal centre reaction, two distinct Prof Martin Dreyling,
Department of Medicine III, LMU
directed antibody therapy in combination with a modifications of B-cell DNA alter the B-cell receptor:
Hospital, Munich 81377,
conventional chemotherapy backbone is still considered somatic hypermutation and class-switch recombination. Germany
standard of care in most B-NHL subtypes, achieving long- These processes are essential for the generation of [email protected]
lasting responses in most patients. However, patients with antibody diversity and normal immune response, but muenchen.de
high-risk disease often have early relapses with very poor they are error-prone and can cause DNA damage
clinical outcomes. Since the last Seminar in The Lancet in supporting lymphomagenesis.3,4 Most mantle cell
2017,1 understanding of the biological background and lymphomas are derived from B cells that have not arisen
genetic profile of the heterogeneous group of B-NHLs has from the germinal centre and which carry unmutated
substantially improved. This improvement has paved the immunoglobulin heavy chain variable (IGHV) genes.
way for numerous new developments in diagnosis, However, studies have shown that 15–40% of
prognostication, and therapeutic management of B-NHL, mantle cell lymphomas carry IGHV hypermutations,
allowing for better and individualised disease manage- suggesting an origin from cells that have already
ment. The most important breakthroughs in the past undergone the germinal-centre transit.5 Marginal zone
5 years include the implementation of revised lymphomas are mostly derived from post-germinal
classifications for the diagnosis of malignant lymphoma, centre cells, but a subset of cases in both nodal and
the identification of prognostically relevant genetic splenic marginal zone lymphomas have unmutated or
variants, and the approval of therapies that use the minimally mutated IGHV suggesting that such
immune system to target tumours, mostly with adoptive lymphomas might derive from cells that are independent
T-cell therapy, thus expanding the therapeutic landscape of the germinal centre.6
and improving outcomes especially for relapsed disease. The biological profiles of malignant B-NHL cells
This Seminar provides an overview of the pathobiology, usually reflect the equivalent healthy origin cell from
classification, and prognostication of B-NHL and where the lymphoma derived. Additionally, distinct
summarises the current knowledge and standard of care
regarding the biology and clinical management of the
most common subtypes of mature B-cell non-Hodgkin Search strategy and selection criteria
lymphomas, highlighting new findings in deciphering Data for this Seminar were identified by searches of PubMed
the molecular background of disease development and using the search terms “B-NHL”, “B-NHL classification”,
the implementation of new therapeutic approaches such “DLBCL”, “mantle cell lymphomas”, “follicular lymphoma”,
as chimeric antigen receptor (CAR) T-cell therapy and “marginal zone lymphoma”, “Waldenström”, and “Burkitt”.
bispecific antibodies. Papers referenced were selected by publication date, impact
factor of the journal, and authors known to be appreciated
Pathobiology and classification experts in the specific field. Abstracts and reports from
Non-Hodgkin lymphomas include a diverse group of meetings were included only when they related directly to
malignant tumours of the lymphoid tissues, deriving previously published work. Only articles published in English
from the clonal expansion of B cells (85–90%), T cells, between January, 1971, and the time of writing were included.
or natural killer cells.1 B-cell lymphomas can arise at any

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Panel: Mature B-NHL subtypes as classified by the International Consensus Classification and WHO Classification 5th edition
(selection including those discussed in this Seminar)
Small B-cell lymphomas • Primary cutaneous follicle centre lymphoma
International Consensus Classification • Paediatric-type follicular lymphoma
• Chronic lymphocytic leukaemia and small lymphocytic • Testicular follicular lymphoma†§
lymphoma • Large B-cell lymphoma with IRF4 rearrangement (listed
• Monoclonal B-cell lymphocytosis with follicular lymphoma)†§‡
• B-cell prolymphocytic leukaemia*† • Mantle cell lymphoma
• Splenic marginal zone lymphoma • In situ mantle cell neoplasia
• Hairy cell leukaemia • Leukaemic non-nodal mantle cell lymphoma
• Splenic B-cell lymphoma or leukaemia, unclassifiable‡ WHO Classification
• Splenic diffuse red pulp small B-cell lymphoma‡ • Extranodal marginal zone lymphoma of mucosa-associated
• Hairy cell leukaemia-variant†‡ lymphoid tissue (MALT lymphoma)
• Lymphoplasmacytic lymphoma • Primary cutaneous marginal zone lymphoma†§
• Waldenström macroglobulinaemia • Nodal marginal zone lymphoma
• IgM MGUS • Paediatric nodal marginal zone lymphoma
• IgM MGUS, plasma cell type*†§ • Follicular lymphoma
• IgM MGUS, NOS*†§ • Classic follicular lymphoma†§
• Primary cold agglutinin disease§ • Follicular large B-cell lymphoma†§
WHO Classification • In situ follicular B-cell neoplasm
• Chronic lymphocytic leukaemia or small lymphocytic • Duodenal-type follicular lymphoma
lymphoma • Testicular follicular lymphoma†
• Monoclonal B-cell lymphocytosis • Follicular lymphoma with uncommon features†§
• B-cell prolymphocytic leukaemia deleted • Follicular lymphoma with blastoid or large
• Splenic marginal zone lymphoma centrocytes†§
• Hairy cell leukaemia • Diffuse follicular lymphoma†§
• Splenic diffuse red pulp small B-cell lymphoma • Primary cutaneous follicle centre lymphoma
• Splenic B-cell lymphoma or leukaemia with prominent • Paediatric-type follicular lymphoma
nucleoli.†§ Encompasses hairy cell leukaemia-variant and • Mantle cell lymphoma
some cases of B-cell prolymphocytic leukaemia • In situ mantle cell neoplasm
• Lymphoplasmacytic lymphoma • Leukaemic non-nodal mantle cell lymphoma
• Waldenström macroglobulinaemia
Large B-cell lymphomas
• IgM monoclonal gammopathy of undetermined
International Consensus Classification
significance
• DLBCL, NOS
• Cold agglutinin disease§
• Germinal centre B-cell subtype
Nodal and extranodal neoplasms • Activated B-cell subtype
International Consensus Classification • Large B-cell lymphoma with 11q aberration†§
• Extranodal marginal zone lymphoma of mucosa-associated • Nodular lymphocyte predominant B-cell lymphoma (no
lymphoid tissue (MALT lymphoma) longer considered a Hodgkin subtype of lymphoma)†§
• Primary cutaneous marginal zone lymphoproliferative • T-cell or histiocyte-rich large B-cell lymphoma
disorder†§ • Primary DLBCL of the CNS†
• Nodal marginal zone lymphoma • Primary DLBCL of the testis†§
• Paediatric nodal marginal zone lymphoma • Primary cutaneous DLBCL, leg type
• Follicular lymphoma • Intravascular large B-cell lymphoma
• Grade 1–2 and 3A • HHV-8 and EBV-negative primary effusion-based
• Grade 3B lymphoma†§‡
• In situ follicular neoplasia • EBV-positive mucocutaneous ulcer
• Duodenal-type follicular lymphoma • EBV-positive DLBCL, NOS
• BCL2-R negative, CD23-positive follicle centre lymphoma • DLBCL associated with chronic inflammation
(related but not equivalent to the diffuse variant of follicular • Fibrin-associated DLBCL
lymphoma in the WHO classification)*†‡§ • Lymphomatoid granulomatosis
(Continues on next page)

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(Panel continued from previous page)

• EBV-positive polymorphic B-cell lymphoproliferative • EBV-positive mucocutaneous ulcer
disorder, NOS*†§ • EBV-positive DLBCL
• ALK-positive large B-cell lymphoma • DLBCL associated with chronic inflammation
• Burkitt lymphoma • Fibrin-associated large B-cell lymphoma
• High-grade B-cell lymphoma, with MYC and BCL2 • Lymphomatoid granulomatosis
rearrangements†§ • ALK-positive large B-cell lymphoma
• High-grade B-cell lymphoma with MYC and BCL6 • Burkitt lymphoma
rearrangements†§‡ • Diffuse large B-cell lymphoma or high-grade B-cell
• High-grade B-cell lymphoma, NOS lymphoma with MYC and BCL2 rearrangements†§
• Primary mediastinal large B-cell lymphoma • Cases with MYC and BCL6 rearrangements are classified
• Mediastinal grey-zone lymphoma§ either as a subtype of DLBCL NOS, or high-grade B-cell
• Plasmablastic lymphoma lymphoma NOS, according to their cytomorphological
• HHV-8-associated lymphoproliferative disorders features†§
• Multicentric Castleman disease • High-grade B-cell lymphoma, NOS
• HHV-8-positive germinotropic lymphoproliferative • Primary mediastinal large B-cell lymphoma
disorder • Mediastinal grey-zone lymphoma§
• HHV-8-positive DLBCL, NOS • Plasmablastic lymphoma
• Primary effusion lymphoma • KSHV or HHV-8-associated B-cell lymphoid proliferations
WHO Classification and lymphomas
• Diffuse large B-cell lymphoma, NOS • KSHV or HHV-8-associated multicentric Castleman
• Germinal centre B-cell subtype disease
• Activated B-cell subtype • KSHV or HHV-8-positive germinotropic
• High-grade B-cell lymphoma with 11q aberration†§ lymphoproliferative disorder
• T-cell or histiocyte-rich large B-cell lymphoma • KSHV or HHV-8-positive DLBCL
• Large B-cell lymphoma with IRF4 rearrangement (listed • Primary effusion lymphoma
with large B-cell lymphomas)†§ Adapted from Campo et al.7 B-NHL=B-cell non-Hodgkin lymphomas. DLBCL=Diffuse large
• Primary large B-cell lymphoma of immune-privileged sites B-cell lymphoma. EBV=Epstein–Barr virus. HHV-8=human herpesvirus-8. KSHV=Kaposi
sarcoma associated herpesvirus. MALT=mucosa-associated lymphoid tissue.
(includes CNS, testis, and vitreoretinal)†§ MGUS=monoclonal gammopathy of undetermined significance. NOS=not otherwise
• Primary cutaneous DLBCL, leg type specified. *Entities only present in the International Consensus Classification. †Entities
• Intravascular large B-cell lymphoma that differ between the International Consensus Classification and WHO 5th edition.
‡Provisional entities from the International Consensus Classification. §Entities that
• Fluid overload-associated large B-cell lymphoma†§ introduce substantial changes compared with the WHO 4th edition revised classification.

biological features of the different lymphoma others. Both classifications have many aspects in common
subtypes result from recurrent genetic, epigenetic, and but also some differences in terminology, diagnostic
other molecular aberrations. Specific characteristics criteria, and consideration of specific subtypes (panel).
regarding the pathobiology of the most common B-NHLs
will be discussed separately in the respective sections. Clinical presentation, staging, and
Two updated classifications of B-NHL were published in prognostication
2022: the International Consensus Classification (ICC) of People with B-NHL typically present with painless
Mature Lymphoid Neoplasms, which represents a joint lymphadenopathy, sometimes combined with consti-
effort of the Society for Hematopathology and the European tutional symptoms such as fever, night sweats, weight
Association for Hematopathology together with loss, or fatigue.9 However, because lymphoma
haematologists, oncologists, and scientists (clinical manifestations can occur in any organ other than the
advisory committee)7; and the WHO-2022 classification of lymphoid and haematopoietic system, a wide range of
haematopoietic and lymphoid tumours, which clinical presentations is possible.
was promoted by the WHO International Agency For an accurate diagnosis a biopsy sample, preferably
for Research on Cancer.8 Both proposals include from an excisional biopsy of an involved lymph node or a
modifications to the nomenclature for some subtypes, tumour in another organ, should be assessed by a
refinement of diagnostic criteria, and recognition of new haematopathologist using standardised diagnostic
subtypes. Moreover, both proposals recognise the procedures. Further diagnostic investigations to define
increasing importance of molecular and genomic data in the stage of the disease and estimate prognosis should
the diagnosis of and clinical decision making in some include a precise medical history, physical examination,
subtypes, but it was considered not sufficiently validated in and laboratory and imaging studies.

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PET-CT is considered to be the most accurate multicentre, multi-trial cohort of patients with follicular
instrument to precisely define disease stage and is lymphoma did not detect additional value of a bone
widely used for pretreatment assessment.10 Compared marrow biopsy in assessing response or predicting
with CT scans, PET-CT improves staging accuracy progression-free survival or overall survival.16 Therefore,
leading to downstaging or, more often, upstaging in bone marrow biopsy at first diagnosis should only be
10–30% of people.11 Furthermore, staging with PET-CT recommended in cases where it could influence
allows direct comparison with end-of-treatment management, including confirmation of limited stage
assessment, for which PET-CT is standard. Therefore, and assessment of cytopenias. For end-of-treatment
according to the consensus of the International evaluation, PET-CT and the use of the Deauville Score
Conference on Malignant Lymphomas Imaging Working proved to be a very sensitive tool for the prediction of
Group, PET-CT should be considered the gold standard disease-free survival, especially in DLBCL, and should
for routine staging of fluorodeoxyglucose (FDG)-avid therefore be considered standard of care.11 The Deauville
nodal lymphomas (all histologies except cutaneous Score is a five-scale scoring system based on visual
marginal zone lymphoma, chronic lymphocytic interpretation of FDG uptake, with a score of 3 or less
leukaemia/small lymphocytic lymphoma, Waldenström considered as complete remission, indicating a
macroglobulinaemia, and mycosis fungoides, unless favourable long-term prognosis.12,17
there is a suspicion of aggressive transformation).12 The most used staging systems are the Ann Arbor and
Moreover, PET-CT is a sensitive modality to assess bone the Lugano classifications. The Ann Arbor staging system
marrow involvement.13 In DLBCL, a PET-CT-positive was originally established for Hodgkin lymphoma and
bone marrow signal is considered sufficient to designate has been subsequently extended to B-NHL. This staging
advanced-stage disease, making an additional bone system defines four stages and is based on the location
marrow biopsy redundant.14 In follicular lymphoma, and number of involved sites, as well as the presence or
combined PET and bone marrow biopsy showed greater absence of systemic symptoms.18 The Lugano classification
accuracy for identifying bone marrow involvement than reclassifies patients as limited (stage I and II) or advanced
either test alone.15 Yet, whether bone marrow biopsy (stage III or IV) disease for treatment purposes, taking
provides crucial information to determine the choice of into account that stages III and IV are almost always
therapy remains debated.15 Results from a large treated similarly.10
The International Prognostic Index (IPI) was the first
international consensus system established to predict
IPI (DLBCL) NCCN-IPI FLIPI (follicular MIPI (simplified; prognosis in patients with aggressive B-NHL. This index
(DLBCL) lymphoma) MCL)
incorporates the following risk factors: age over 60 years,
Age >60 years=1 40–60 years=1; >60 years=1 50–59 years=1; stage III or IV disease, serum lactate dehydrogenase
61–74 years=2; 60–69 years=2;
above the upper limit of normal, performance status
≥75 years=3 ≥70 years=3
equal to or greater than two on the Eastern Cooperative
Lactate dehydrogenase >1 ULN=1 ≤3 ULN=1; >1 ULN=1 0·67–0·99 ULN=1; Oncology Group (ECOG) scale, and involvement of two
>3 ULN=2 1–1·49 ULN=2;
≥1·5 ULN=3 or more extranodal sites.19 For several subtypes of
Eastern Cooperative 1 1 ·· 1 indolent lymphomas, adjusted prognostic indices have
Oncology Group Performance been developed: for clinical risk stratification with
status ≥2 rituximab-based therapy, the National Comprehensive
Ann Arbor stage 3–4 1 1 1 ·· Cancer Network International Prognostic Index (NCCN-
Extranodal disease presence* 1 1 ·· ·· IPI) proved to be superior to the IPI in discriminating
>1
between low-risk and high-risk (defined as a <50%
Haemoglobin concentration ·· ·· <12= 1 ·· chance of 5-year overall survival) patients with DLBCL.20
(g/dL)
The Follicular Lymphoma International Prognostic
Number of nodal sites ·· ·· >4=1 ··
Index (FLIPI), a five-factor risk model based on age,
White blood cells (g per L) ·· ·· ·· 6·7–9·9=1;
10–14·9=2; ≥15=3 stage, serum lactate dehydrogenase, haemoglobin levels,
Risk categories and the number of involved nodal areas, has been
Low 0–1 0–1 0–1 0–3
validated following the introduction of CD20-directed
(Low-) Intermediate 2 2–3 2 4–5
antibody rituximab treatment.21,22 In mantle cell
(High-) Intermediate 3 4–5 ·· ··
lymphomas, the Mantle Cell Lymphomas International
High 4–5 3–5 6–11
Prognostic Index (MIPI) defines three risk groups based
≥6
on four independent prognostic factors: age,
DLBCL=diffuse large B-cell lymphoma. FLIPI=Follicular Lymphoma International Prognostic Index. IPI=International performance status, serum lactate dehydrogenase, and
Prognostic Index. MCL=mantle cell lymphoma. MIPI=Mantle Cell Lymphomas International Prognostic Index.
leukocyte count.23 Table 1 compares the subtype-specific
NCCN-IPI=National Comprehensive Cancer Network International Prognostic Index. ULN=upper limit of normal.
*Including bone marrow, gastrointestinal tract, liver, lung, CNS, and other sites. IPI scores.
The definition of more sophisticated scores integrating
Table 1: Subtype-specific risk scores and their relation to risk categories on each measure clinical-genetic factors is currently under investigation. For

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First-line approved First-line off-label Relapse approved Relapse off-label

Waldenström macroglobulinaemia
BTK inhibitor Ibrutinib or ·· Ibrutinib or zanubrutinib with or Acalabrutinib
zanubrutinib with or without rituximab
without rituximab*
Proteasome inhibitor ·· Bortezomib plus rituximab ·· Bortezomib plus rituximab
Others ·· ·· ·· Venetoclax
Marginal zone lymphoma
BTK inhibitor ·· ·· Ibrutinib; zanubrutinib Acalabrutinib
Immune modulator ·· ·· Rituximab plus lenalidomide† ··
Follicular lymphoma
BTK inhibitor ·· Rituximab plus lenalidomide Rituximab plus lenalidomide ··
Immunotherapy ·· ·· Axicabtagene ciloleucel‡; Glofitamab; epcoritamab
tisagenlecleucel‡; mosunetuzumab‡
Others ·· ·· Tazemetostat§ ··
Mantle cell lymphoma
BTK inhibitor ·· Rituximab plus ibrutinib§ Ibrutinib¶; zanubrutinib§; ··
acalabrutinib§; pirtobrutinib||§
Immune modulator ·· ·· Lenalidomide with or without ··
rituximab||
Immunotherapy ·· ·· Brexucabtagene autoleucel|| Glofitamab
Others ·· ·· ·· Venetoclax
Diffuse large B-cell lymphoma
BTK inhibitor ·· Ibrutinib (plus R-CHOP; ·· ··
molecular subtype)
Proteasome inhibitor ·· Bortezomib (plus R-CHOP; ABC ·· ··
subtype)
Immune modulator ·· ·· Tafasitamab plus ··
lenalidomide
Immunotherapy ·· ·· Axicabtagene ciloleucel; lisocabtagene ··
maraleucel; tisagenlecleucel‡;
glofitamab‡§ ; epcoritamab‡§
Others ·· ·· Selinexor||; loncastuximab tesirine Venetoclax (ViPOR)

BTK inhibitor. ABC=activated B cell. BTK=Bruton tyrosine kinase. R-CHOP=rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone or prednisolone.
ViPOR=venetoclax, ibrutinib, prednisone, obinutuzumab, and revlimid. *For patients not qualifying for immunochemotherapy. †Only USA. ‡For higher relapse. §For patients
with indolent forms. ¶Only EU. ||After previous BTK inhibitor.

Table 2: Recommended targeted therapies

example, the m7-FLIPI adds the mutational status of seven infiltration by small lymphoplasmacytic cells and the
genes (EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, presence of a detectable serum monoclonal IgM.29 If
and CARD11) to the commonly used FLIPI score, leading bone marrow infiltration is absent and the IgM level is
to a more precise estimation of 5-year failure-free survival less than 3 g/dL, an IgM monoclonal gammopathy of
in patients treated with immunochemotherapy.24 Further- unknown significance should be diagnosed. The MYD88
more, a robust 23-gene expression-based predictor of (L265P) mutation is considered the hallmark of
progression-free survival for similar patients, applicable to Waldenström macroglobulinaemia and is present in over
formalin-fixed, paraffin-embedded tumour biopsies, was 95% of cases.30 CXCR4 mutations can be found in
also developed.25 However, these scores are not yet ready 30–40% of patients with Waldenström macroglobuli-
for routine clinical use. naemia and are usually associated with a worse response
Circulating tumour DNA has also been found to be a to therapy and outcome compared to those without
promising candidate for the estimation of prognosis in CXCR4 mutations.31
high-risk DLBCL,26 post-allogeneic stem cell Although most patients are asymptomatic at the
transplantation,27 and after CAR T-cell therapy.28 time of diagnosis, some patients might develop
lymphadenopathy, splenomegaly, anaemia, neuropathy,
Specific subtypes of non-Hodgkin lymphomas or cryoglobulinaemia.32 In about 10–15% of patients,
Waldenström macroglobulinaemia signs of hyperviscosity syndrome such as headache,
Waldenström macroglobulinaemia is a rare low-grade blurred vision, confusion, and mucosal bleeding,
B-cell lymphoma that is defined by bone marrow associated with highly elevated IgM monoclonal protein,

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can be observed.32 About 1% of patients are diagnosed zanubrutinib, reporting high effectiveness of both BTK
with Bing-Neel syndrome, a rare presentation of inhibitors.42 However, zanubrutinib has a better toxicity
Waldenström macroglobulinaemia affecting the CNS.33 profile than ibrutinib, so should be preferably used. For
Treatment should be initiated in symptomatic patients. patients who relapse after BTK inhibitor treatment, the
Elevated IgM levels alone in asymptomatic patients should B-cell-lymphoma 2 (BCL2)-inhibitor venetoclax might
not be a reason to start treatment except in cases with IgM offer an effective salvage option;43 however this treatment
levels over 60 g/L.34 In such cases, patients are expected to is not yet approved. Recommended targeted therapies are
be at a considerably higher risk of developing symptomatic summarised in table 2.
hyperviscosity, which might support the decision to treat
asymptomatic patients before irreversible damage Marginal zone lymphoma
occurs.35 Alkylating drugs (bendamustine or cyclo- Marginal zone lymphomas represent approximately
phosphamide) in combination with rituximab are 5–15% of all B-NHL in high-income countries. Three
established first-line therapy options.36 The first-generation subtypes are recognised: extranodal marginal zone
Bruton’s tyrosine kinase (BTK)-inhibitor ibrutinib is an lymphomas (>60% of cases); splenic marginal zone
approved treatment for patients with symptomatic lymphoma (20%); and nodal marginal zone lymphoma
Waldenström macroglobulinaemia, and proved to be (<10%). The pathogenesis of extranodal marginal zone
effective in treatment-naive as well as pretreated lymphomas seems to be initiated by chronic
patients.37,38 However, patients with mutated CXCR4 have inflammation due to autoimmune or infectious diseases
lower response rates to ibrutinib.38 The combination of (figure 1). Several gene translocations including t(11;18)
ibrutinib and rituximab versus placebo and rituximab was (p21;q21) in BIRC3-MALT1, the rarer t(14;18)(p32;q21) in
evaluated in a randomised phase 3 study of 150 patients IGH-MALT1, and t(1;14)(p22;q32) in BCL10-IGH have
with previously treated or untreated Waldenström been identified in extranodal marginal zone lymphomas
macroglobulinaemia, and treatment with ibrutinib and but not in nodal marginal zone lymphomas or splenic
rituximab significantly improved median progression-free marginal zone lymphomas.45,46 The mutational profiles of
survival compared with rituximab and placebo in both the nodal marginal zone lymphomas and splenic marginal
previously treated and untreated groups,39 leading to its zone lymphomas share common alterations in KMT2D,
approval. This benefit was independent of MYD88 and NOTCH2, PTPRD, TNFAPI3, and KLF2.47
CXCR4 mutational status.39 Although effective, treatment Extranodal marginal zone lymphomas can occur at any
with ibrutinib was associated with some toxic effects.40 extranodal site, with the stomach being the most
Next-generation BTK inhibitors acalabrutinib and common site, followed by the ocular adnexa, lung, and
zanubrutinib have also been evaluated for the treatment salivary glands. Involvement of regional lymph nodes
of Waldenström macroglobulinaemia.41,42 Although and bone marrow infiltration might be present at
acalabrutinib is not yet approved, zanubrutinib was diagnosis and is associated with worse prognosis.48,49 To
approved in 2021 in the USA and Europe for adult patients estimate prognosis, the extranodal marginal zone
with Waldenström macroglobulinaemia who have lymphomas-specific prognostic index has been
received at least one previous therapy, or as first-line developed, distinguishing three risk groups (age
treatment for patients unsuitable for immuno- ≥70 years, Ann Arbor stage III or IV, and elevated lactate
chemotherapy. This approval was based on the ASPEN dehydrogenase) with 5-year event-free survival rates of
study, a randomised phase 3 trial comparing ibrutinib and 29–70%.50
All patients diagnosed with gastric marginal zone
lymphoma with confirmation of Helicobacter pylori
Chronic infection infection should initially receive H pylori eradication
by T lymphocytes therapy, irrespective of stage, which will often lead to
Helicobacter pylori
clinical remission.51 However, gastric marginal zone
lymphoma with the translocation t(11;18)(p21;q21),
Low-grade Low-grade
occurring in approximately 25% of patients with gastric
Normal mucosa Autoimmune lymphoma, lymphoma, High-grade marginal zone lymphoma, is known to be resistant to
gastritis MALT H pylori H pylori lymphoma antibiotic treatment.52 These patients also have a
dependent independent
significantly lower progression-free survival (26%) at
10 years compared with those without this translocation
(57%; p=0·004).53
Antigen-driven proliferation
In patients who do not have lymphoma regression as
Autonomous growth confirmed by repeated endoscopy assessment, involved-
t(11;18)
field radiation leads to excellent disease control in
localised stages,54 even with reduced doses of 24 Gy.55 For
Figure 1: Pathogenesis of gastric MALT lymphoma symptomatic patients with advanced-stage disease,
Reproduced from Fischbach.44 MALT=mucosa-associated lymphoid tissue. systemic therapy with rituximab as a single agent or in

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combination with either chlorambucil56 or bendamustine57 however acalabrutinib is still awaiting approval.
has shown convincing efficacy and is recommended.45 In Recommended targeted therapies are summarised in
asymptomatic patients, watchful waiting might be table 2.
preferred.
Splenic marginal zone lymphomas typically involve the Follicular lymphoma
spleen, hilar lymph nodes, bone marrow, and the blood. Follicular lymphoma accounts for around 25% of all
In approximately 20% of patients splenic marginal zone B-NHL cases and is the most common indolent
lymphomas, autoimmune manifestations, such as lymphoma in western Europe and the USA. Some major
autoimmune haemolytic anaemia, immune thrombo- changes have been made to the histological definition of
cytopenia, cold agglutinin disease, or acquired von follicular lymphoma subgroups in the updated
Willebrand disease, among others, have been observed.45 classification: although the ICC 2022 classification
Treatment of splenic marginal zone lymphomas should retains the grading of follicular lymphoma (1, 2, 3A,
be initiated if splenomegaly becomes symptomatic or is and 3B) according to the number of centroblasts as
rapidly progressive, or if any progressive cytopenias defined in the WHO 2016 edition,29 the new WHO-2022
(haemoglobin <10 g/dL, platelets <80 g/L, or neutrophils classification replaced this classic grading with biological
<1 g/L) are observed.45 However, splenectomy is no longer grouping.8 The majority of follicular lymphomas (85%),
considered the treatment of first choice and has widely so-called classic follicular lymphomas, are characterised
been replaced by monotherapy with rituximab,58 leading by a mostly follicular growth pattern, a composition of
to prolonged responses.59 centrocytes and centroblasts, and presence of the t(14;18)
Many patients with nodal marginal zone lymphomas (p32;q21) translocation. Two related subtypes, follicular
present with disseminated lymphadenopathy and large B-cell lymphoma and follicular lymphoma with
advanced-stage disease, with 10–20% of patients uncommon features, have also been defined. Follicular
reporting B symptoms. Treatment in these cases should large B-cell lymphoma largely complies with follicular
follow the principles of therapy for follicular lymphoma lymphoma grade 3B; this subtype is biologically distinct
(outlined in the following sections).45 with the frequent absence of t(14;18), but the expression
For relapsed or refractory mucosa-associated lymphoid of CD10 and increased p53 and IRF4/MUM1 expression.64
tissue (MALT) lymphoma, the most recent European Follicular large B-cell lymphoma is expected to behave
Society for Medical Oncology guidelines recommend the more like DLBCL clinically, and should be treated
combination of rituximab and the immunomodulatory accordingly.65 Follicular lymphoma with uncommon
drug lenalidomide as a potential treatment option.45 This features includes two different subtypes: one with so-
recommendation is based on the results of the phase 3 called blastoid or large centrocyte cytological features and
AUGMENT trial (rituximab plus lenalidomide vs one with a predominantly diffuse growth pattern. The
rituximab plus placebo),60 which led to the approval of latter, named BCL2-R negative CD23-positive follicle
rituximab plus lenalidomide by the US Food and Drug centre lymphoma, is considered in the ICC as a specific
Administration (FDA). However, in the subcohort of 63 follicular lymphoma subtype that lacks BCL2-R and
patients with either MALT lymphoma, splenic marginal carries STAT6 mutations, leading to overexpression of
zone lymphoma, or nodal marginal zone lymphoma, no CD23. Patients with this subtype frequently present with
differences in median progression-free survival were inguinal or pelvic large masses and might have diffuse or
observed between the two treatments. Recommended nodular histological patterns.7,8,66,67
targeted treatment alternatives in relapsed marginal zone Besides the classical t(14;18)(p32;q21) translocation,
lymphoma are BTK inhibitors; ibrutinib showed an epigenetic alterations and disrupted chromatin biology
overall response rate of 58% and a progression-free have been shown to drive follicular lymphoma
survival of 15·7 months in 63 patients with marginal zone pathogenesis.68,69 Mutations of KMT2D or other histone
lymphoma and was approved in 2017 for the treatment of modifiers (CREBBP, EZH2, MEF2B, and EP300) are
patients who require systemic therapy and have received found in the vast majority of follicular lymphoma
at least one previous anti-CD20-based therapy.61 cases.68,69
Zanubrutinib was evaluated in the phase 2 MAGNOLIA A small proportion of patients with follicular lymphoma
trial in patients with pretreated, relapsed, marginal zone are diagnosed with localised low tumour burden
lymphoma who had received at least one CD20-directed (stages I–II). In these cases, involved-site radiotherapy
regimen. Zanubrutinib showed even higher efficacy than with 24–30 Gy, optionally in combination with rituximab,
ibrutinib with an overall response rate of 68·2% (95% CI provides a potentially curative treatment strategy.70,71 In
55·56–79·11) and an estimated 15-month progression- patients for whom radiotherapy is not feasible, or in
free survival of 82·5%, leading to its approval by the advanced cases with low tumour burden, rituximab as a
FDA.62 In a phase 2 trial acalabrutinib had an overall single agent is a recommended option.72 In these cases, a
response rate of 53% and a progression-free survival of 2-year maintenance strategy with rituximab was not
27·4 months (12-month progression-free survival rate superior to a retreatment schedule with rituximab
67%) in patients with relapsed marginal zone lymphoma;63 monotherapy at time of progression.73 The majority of

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patients with follicular lymphoma present with advanced- approved in 2019 showing improved response rates and
stage III and IV disease. As no curative treatment strategy could be considered as salvage treatment.60 Consolidation
is available yet and clinical courses are often indolent with therapy with high-dose chemotherapy and autologous
spontaneous regressions in 10–20%,74,75 treatment stem cell transplantation (ASCT) might be considered,
initiation should only be based on the presence of especially for younger patients with suspected
B-symptoms, haematopoietic impairment, bulky disease, transformed histology.85,86
vital organ compression, ascites, pleural effusion, or rapid New targeted treatment approaches are being
lymphoma progression. When therapy is required, evaluated, but are yet to be confirmed in randomised
rituximab or the glycoengineered type 2 anti-CD20 phase 3 trials. CD19-directed CAR T-cell therapy with
monoclonal antibody obinutuzumab should be combined axicel or tisacel led to durable remissions in patients with
with one of the various chemotherapy regimens such as refractory follicular lymphoma, leading to FDA approval
CHOP (cyclophosphamide, doxorubicin, vincristine, and of both axicel and tisacel for relapsed follicular lymphoma
prednisone), bendamustine, or CVP (cyclophosphamide, after two or more lines of systemic therapy, including the
vincristine, and prednisone).75 A randomised phase 3 trial combination of an anti-CD20 monoclonal antibody and
comparing rituximab plus lenalidomide versus rituximab an alkylating agent.87,88 The bispecific antibody
plus chemotherapy in patients with advanced treatment- mosunetuzumab was evaluated in a single-arm phase 2
naive follicular lymphoma showed similar efficacy in both study in patients with relapsed or refractory follicular
arms.76 However, this combination is not approved for lymphoma who had received two or more previous lines
first-line treatment of follicular lymphoma. Maintenance of treatment, including an anti-CD20 therapy and an
therapy with rituximab or obinutuzumab (every 2 months) alkylating agent. Complete responses were observed in
should be considered for 2 years, as this was shown to 60% of patients with a tolerable safety profile.89 Based on
improve progression-free survival after various induction these results, mosunetuzumab was conditionally
regimens.77 However, there was no effect on overall approved in the EU for the treatment of relapsed or
survival rates.77 The FOLL12 study compared standard refractory follicular lymphoma. Two other bispecific
rituximab maintenance with a response-adapted antibodies, glofitamab and epcoritamab, are under
postinduction approach on the basis of metabolic response current investigation in clinical trials with encouraging
and molecular assessment of minimal residual disease results and are awaiting approval.90,91 The EZH2 inhibitor
using three types of postinduction therapies.78 The results tazemetostat is the first approved epigenetic-directed
showed significantly inferior 3-year progression-free therapy in follicular disease. Tazemetostat was effective
survival when applying a metabolic and molecular both in patients with activating mutations in the EZH2
response-adapted therapy compared to standard rituximab gene (overall response rate 69%) and in those with
maintenance.78 However, the application of an antibody wildtype EZH2 (overall response rate 35%).92
maintenance therapy should be evaluated critically.79,80 Tazemetostat could therefore be offered to patients with
Recommended targeted therapies are summarised in relapsed follicular lymphoma who have had at least two
table 2. previous treatments and who carry EZH2 mutations, or
A short duration of first remission (progression of to patients with relapsed or refractory follicular
disease within 2 years [POD24]) after a standard lymphoma who have no other therapeutic options.
immunochemotherapy induction is a strong predictor of Recommended targeted therapies are summarised in
a worse clinical outcome.81 A poor prognosis for early table 2.
relapse was also reported for patients treated with non-
chemotherapy rituximab-based doublets or rituximab as Mantle cell lymphoma
a single agent.82,83 Mantle cell lymphoma accounts for 5–7% of malignant
In relapse or progression, a new biopsy should be lymphomas in high-income countries. The clinical
obtained to exclude transformation to aggressive B-cell course is heterogeneous, ranging from indolent cases
lymphoma. Salvage treatment should be chosen that do not require therapy for years to highly aggressive
considering previous therapies, duration of response, mantle cell lymphomas with a poor short-term
and stage at relapse. In case of early progression (POD24), prognosis.93 The WHO 2016 update of lymphoid
a non-cross-resistant chemotherapy backbone regimen malignancies differentiates two distinct subtypes of
in combination with rituximab can be selected. In mantle cell lymphomas.29 Nodal mantle cell lymphomas
rituximab-refractory cases or patients with duration of (80–90% of cases) are characterised by unmutated IGHV,
response less than 6 months, obinutuzumab plus overexpression of the transcription factor sex-
bendamustine (plus obinutuzumab maintenance) was determining region Y-box 11 (SOX11), and a generally
shown to improve median progression-free survival and more aggressive clinical course (figure 2). Leukaemic
overall survival in patients not previously exposed to non-nodal mantle cell lymphomas (10–20% of cases)
these agents.84 Alternatively, in patients with short typically display mutated IGHV, SOX11 negativity, and
remissions after chemotherapy, a chemotherapy-free present with indolent biological behaviour (figure 2).
regimen combining rituximab with lenalidomide was Peripheral blood involvement is noted in almost all cases

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of nodal mantle cell lymphomas by flow cytometry; For patients 65 years or younger with advanced-stage
gastrointestinal polyposis is another common disease, a dose-intensified regimen comprising an
presentation. Thus, nodal mantle cell lymphomas immunochemotherapy induction followed by a high-
frequently have extranodal components to their dose consolidation regimen and ASCT was, until 2023,
presentation. Histologically, besides classical mantle cell the current standard of care.93 However, patients with
lymphomas (which have small to intermediate sized cells TP53 mutations did not benefit from this intensified
with irregular, cleaved nuclei and dense chromatin), therapeutic concept.108 Thus, TP53 status should be
pleomorphic and blastoid variants can also be evaluated at first diagnosis to stratify patients accordingly,
distinguished. Mantle cell lymphomas with blastoid and patients with TP53 mutations should be considered
morphology are characterised by neoplastic cells for experimental front-line trials. In Europe, alternating
resembling lymphoblasts and high proliferation, and application of R-CHOP and the cytarabine-containing
also have a more aggressive clinical course (figure 2).29,94 R-DHAP regimen (rituximab, dexamethasone, high-dose
Mantle cell lymphomas are genetically characterised by cytarabine, and cisplatin) or the sequential Nordic
the chromosomal t(11;14)(p13;q32) translocation that regimen (rituximab with dose-intensified CHOP and
results in cyclin D1 overexpression and dysregulation of high-dose cytarabine, followed by high-dose
the cell cycle at the G1–S phase transition.95,96 Detection chemotherapy and ASCT) are commonly used induction
of this translocation or cyclin D1 overexpression by strategies. Yet, in the era of targeted therapies, the added
immunohistochemistry is crucial to confirm the value of ASCT could be diminishing. The addition of
diagnosis. Furthermore, detection of SOX11 over- ibrutinib to first-line and maintenance therapy results in
expression, which is present in more than 90% of mantle an improved failure-free survival compared with
cell lymphomas cases, could help to confirm the intensive high-dose consolidation followed by ASCT.109
diagnosis.97 For patients with indolent forms of mantle cell
Next-generation sequencing approaches have begun to lymphomas, a front-line combination of ibrutinib and
unravel the genetic background of mantle cell rituximab proved to be a promising chemotherapy-free
lymphomas and identified numerous recurrent somatic regimen achieving a high rate of complete remission and
mutations, including genes involved in genotoxic stress undetectable minimal residual disease;110 however, this
pathways (ATM, TP53, or CDKN2A), epigenetic regimen is not yet approved.
regulators (NSD2, KMT2D, MEF2B, KMT2C, or Patients over 65 years who are ineligible for trans-
SMARCA4), and genes regulating cell homoeostasis, cell plantation present with variable clinical characteristics.
growth, and cell death (CCND1, TP53, CDKN2A, BIRC3,
CARD11, TRAF2, RB1, POT1, or NOTCH1/2).98–102 Progression
However, apart from TP53, the clinical relevance of most (TP53 and other
oncogenic
mutations is not clearly defined.
abnormalities)
Important clinical and serological factors associated
Classical MCL Blastoid MCL
with a worse clinical outcome include age greater than
Unmutated or
60 years, poor performance status, advanced stage of minimally mutated IG Lymph node
disease (Ann Arbor stage III or IV), splenomegaly, SOX11 + B cell extranodal
anaemia, high serum levels of β2-microglobulin and In situ MC neoplasia
lactate dehydrogenase, blastoid or pleomorphic cytology,
CCND1-R
extranodal presentation, and constitutional symptoms. A Mantle Pleomorphic MCL
zone
subset of patients with a favourable outcome suitable for Germinal
watchful waiting have been characterised based on centre
Pre-B cell
asymptomatic presentation, good performance status,
non-nodal disease, normal serum lactate dehydrogenase,
and low Ki67.103 Current evidence indicates that the most Naive
B cell
important prognostic markers independent of clinical Hypermutated IG PB, BM,
features are the proliferation rate, TP53 mutations, or Cyclin
SOX11–B cell spleen
high expression of TP53. High TP53 expression and Ki67 D1 neg
greater than 30%, together with blastoid morphology,
were reported to define high-risk biology with significantly
shorter failure-free survival and overall survival.104 In the
clinical setting, immunohistochemical determination of
Ki67 expression is a reliable prognostic marker and, in Leukaemic
combination with the MIPI (MIPI-c), is a useful tool to non-nodal MCL
estimate individual risk profile and identify high-risk Figure 2: Pathogenesis of mantle cell lymphoma
patients (Ki67 >30%) who might qualify for more Reproduced from Dreyling et al.93 BM=bone marrow. MC=mantle cell. MCL=mantle cell lymphoma. PB=peripheral
aggressive therapeutic approaches.94,105–107 blood.

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Healthy patients over 65 years should receive conventional Diffuse large B-cell lymphoma
immunochemotherapy. The combination of bortezomib, DLBCL is the most common and most aggressive B-NHL
rituximab, cyclophosphamide, doxorubicin, and subtype, accounting for 30–40% of cases in high-income
prednisone (VR-CAP) proved to be superior to R-CHOP in countries. DLBCL arises from the clonal proliferation of
a large international phase 3 trial and should be considered the germinal centre or activated B cells and can be
especially in more aggressive cases.111 Bendamustine plus subdivided according to the cell-of-origin (COO)
rituximab is also widely used in patients who do not qualify subtyping into GCB-like DLBCL, activated B-cell-like
for more intensive regimens. The addition of ibrutinib to (ABC) DLBCL, and the unclassified subtype, with the
this combination was evaluated in the phase 3 SHINE trial, GCB type displaying a more favourable outcome after
which reported a significant improvement of median standard chemotherapy (figure 3A).123 Gene expression
progression-free survival from 52·9 months to profiling identifies distinct signatures of the DLBCL
80·6 months compared with bendamustine plus subtypes that resemble the referred COO. Subsequently,
rituximab. However, no effect on overall survival was the immunohistochemical Hans classifier was
observed.112 Based on randomised studies, rituximab established to distinguish GCB and non-GCB subtypes,
maintenance has shown benefits in both younger and based on CD10, BCL6, and IRF4/MUM1 expression.126
older patients with mantle cell lymphomas and should Immunohistochemistry-based methods are still the most
thus be recommended.113,114 Other recommended targeted widely applied approach to identify the DLBCL cell of
therapies are summarised in table 2. origin in clinical routine, with approximately 80%
For relapsed mantle cell lymphomas, several targeted concordance in predicting the gene expression profiling
treatment approaches have been investigated with subtype or the prognostic molecular subgroups.127
promising results. The BTK inhibitor ibrutinib, targeting Genetic rearrangement of MYC can be detected by
the B-cell receptor pathway, was approved in 2013 for fluorescent in-situ hybridisation in approximately
relapsed mantle cell lymphomas, achieving remarkable 10–15% of patients with newly diagnosed DLBCL.
response rates and is currently being evaluated as part of Cases with both MYC and an additional rearrangement
upfront therapy. Furthermore, two other next-generation of the anti-apoptotic BCL2 are referred to as high-grade
BTK inhibitors (acalabrutinib and zanubrutinib) were B-cell lymphomas in the ICC and WHO-2022 and have
approved for relapsed or refractory mantle cell been associated with a poor response to standard
lymphomas.115,116 Venetoclax monotherapy has achieved immunochemotherapy. Double-hit lymphomas are
convincing response rates in patients who are high-risk usually detected in GCB-type DLBCL (figure 3A).123,128,129
and relapse after ibrutinib treatment117,118 and is awaiting Cases with MYC and BCL6 translocations are considered
approval. The combination of venetoclax with a BTK a provisional category of high-grade B-cell lymphomas in
inhibitor to treat relapsed or refractory mantle cell the ICC, but not in the WHO-2022 classification.
lymphomas is currently being evaluated in clinical trials. Lymphomas overexpressing the proteins BCL2 and MYC
Regarding immunotherapy approaches, promising but without translocations of the respective genes are
results were reported for the autologous CD19 CAR T-cell termed double expresser lymphomas; such lymphomas
construct brexucabtagene autoleucel. After a median occur in approximately 30% of newly diagnosed cases,
follow-up of 35·6 months, brexucabtagene autoleucel are usually of activated B-cell origin, and have an
was reported to induce durable overall response rates of intermediate outcome (figure 3A).123,128,130 Studies have
91% and a median progression-free survival of identified a specific gene expression signature of high-
25·8 months in patients with relapsed or refractory grade lymphomas, particularly with MYC and BCL2 but
mantle cell lymphomas who were previously treated with not BCL6 translocations, that could be useful in the
BTK inhibitors,119 and was approved for this indication in differential diagnosis of these tumours.131,132
2022. A second CD19-directed CAR T-cell product The use of in-depth genetic analyses, such as whole-
(lisocel) for relapsed or refractory mantle cell lymphomas exome sequencing and copy number alterations, has
is currently being evaluated in the ongoing phase 1 further improved the molecular characterisation of DLBCL
TRANSCEND B-NHL001 study (NCT02631044). (figure 3B).125 Similar molecular subsets have been
Bispecific antibodies are currently under investigation identified by different research groups: Schmitz and
in B-cell malignancies and reported results for colleagues initially defined four genetic subtypes of DLBCL
small numbers of patients with mantle cell lymphomas associated with different responses to upfront
treated with these agents in early-phase trials immunochemotherapy.133 These subtypes include the
are encouraging.91,120,121 Glofitamab, evaluated as a prognostically poor MCD (co-occurrence of MYD88L267P
monotherapy after pretreatment with obinutuzumab and CD79B mutations) and N1 (NOTCH1 mutations)
(1000 mg or 2000 mg) in a phase 1–2 trial in 37 heavily subtypes, as well as the prognostically favourable BN2
pretreated patients with mantle cell lymphomas, induced (BCL6 fusions and NOTCH2 mutations) and EZB (EZH2
high and durable complete remission rates of 73%.122 and BCL2 translocations) subtypes.133 Chapuy and
Recommended targeted therapies are summarised in colleagues reported five DLBCL subsets (C1–C5): a low-
table 2. risk DLBCL (C1 associated with MYD88 [non-L265P]

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mutations and perturbation of NOTCH and BCL6 A

signalling), a poor-risk ABC-DLBCL (C5 with MYD88
GCB ABC
[L265P] mutations), two subsets of GCB-DLBCLs with
different outcomes and targetable lesions (BCL2, PI3K,
High BCL2
EZH2, and CREBBP in C3; JAK/STAT and BRAF/MEK1 expression
in C4); and an ABC-GCB-independent group with biallelic
inactivation of TP53, CDKN2A loss, and associated BCL2-R
genomic instability (C2).134 The DLBCL taxonomy defined
by the LymphGen algorithm125 expanded these groups and
provided a unifying view of these two studies (figure 3B).
This classification divides DLBCL into seven genetic
High MYC
subtypes differing in oncogenic pathway engagement, Double-hit MYC-R
expression Double
gene expression phenotype, tumour microenvironment, lymphomas expresser
MYC and BCL2 lymphomas
survival rates, and potential therapeutic targets.125 However,
these genetic subtypes are not yet applied diagnostically in
B
routine clinical practice, and even with these sophisticated
approaches, a substantial proportion (about 40%) of MCD
DLBCL remains unassigned to these genetic subtypes.
DLBCL most often responds very well to initial therapy
and is curable for two-thirds of patients. Patients who do N1

not relapse within the first 24 months have a very good

ABC
prognosis and are expected to have a similar life A53
expectancy to the general population, albeit late relapses
are sometimes observed.135,136
For clinical risk stratification in the current era BN2
Unclassified
of rituximab-based therapy, the NCCN-IPI was superior to
the IPI in discriminating between low-risk and
high-risk (5-year overall survival <50%) patients ST2
with DLBCL.20 Refined categorisation of age, serum lactate
dehydrogenase, and disease involvement at specific
GCB MYC+
extranodal sites identified four risk groups of low
(0–1 point), low-intermediate (2–3 points), high- EZB
intermediate (4–5 points), and high (≥6 points) risk MYC–
patients.20
For most patients with advanced-stage DLBCL one cycle
of R-CHOP administered every 3 weeks for six total cycles Figure 3: DLBCL: Double-hit and double-expresser lymphomas and genetic
was considered standard of care, and dose intensification subtyping
with 14-day cycles did not prove to be superior.137 In (A) Reproduced from Dunleavy.124 (B) Reproduced from Wright et al.125
ABC=activated B cell-like. GCB=germinal centre B cell. All elements of the right
the Alliance/CALGB 50303 phase 3 intergroup trial, the
side and EZB are the names of the subtypes as defined by the LymphGen
dose-intensified regimen DA-EPOCH-R, containing dose- algorithm.
adjusted etoposide, prednisone, vincristine, cyclophos-
phamide, doxorubicin, and rituximab, was more toxic but modification resulted in a significantly improved
did not significantly improve 2-year progression-free progression-free survival after 2 years compared to the
survival or overall survival compared with R-CHOP.138 In R-CHOP arm (76·7% [72·7–80·8] vs 70·2% [65·8–74·6];
the FLYER trial, limited-stage DLBCL (stages I–II, non- p=0·02), whereas overall survival remained similar in
bulky disease, normal lactate dehydrogenase, and ECOG both arms. Subgroup analysis suggested a pronounced
performance status of 0–1) was sufficiently treated with benefit especially for high-risk patients (age <60 years,
only four cycles of R-CHOP followed by two cycles of IPI 3–5, or ABC subtype). Polatuzumab vedotin combined
rituximab alone, reporting a similar progression-free with R-CHP was approved by the FDA in April, 2023, for
survival to six cycles of R-CHOP at 3 years.139 However, first-line treatment of DLBCL.
almost 20 years after the first report on R-CHOP,140 the End-of-treatment response is monitored with PET-CT,
POLARIX study is the first phase 3 trial to successfully and PET-positive residues in combination with a
challenge this chemotherapy standard.141 Instead of Deauville score of 5 indicate therapeutic failure; these
vincristine patients received polatuzumab vedotin, a patients might require systemic salvage therapy. In the
humanised anti-CD79b antibody conjugated to case of a Deauville score of 4, rebiopsy should be
monomethyl auristatin E (already approved in relapsed considered, and salvage therapy or tight controls are
DLBCL), in combination with R-CHP.142,143 This adequate options.

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Multiple efforts have been made to improve first-line axicabtagene ciloleucel (axicel),152 lisocabtagene maraleucel
therapies for the treatment of DLBCLs with high-risk (lisocel),153 and tisagenlecleucel (tisacel).154 These products
biological features as defined by pathobiology (non-GCB have recently been compared to the current standard of
subtype, double-hit lymphomas) or patients who are care (salvage therapy followed by high-dose chemotherapy
expected to not respond to R-CHOP on the basis of and ASCT) in transplant-eligible patients with early
adverse clinical characteristics. relapses (within 12 months of R-CHOP completion).
The addition of ibrutinib to R-CHOP versus R-CHOP Event-free survival was significantly improved in patients
alone (PHOENIX trial) did not improve event-free receiving axicel (41% vs 16% after 2 years; p<0·001), and
survival, progression-free survival, or overall survival in response rates were also significantly higher compared to
patients with non-GCB DLBCL due to increased toxic patients receiving current standard of care.155 Similarly,
effects in patients aged 60 years or older, leading to lisocel also achieved a significantly improved event-free
compromised R-CHOP administration.144 Another phase 3 survival (44·5% vs 23·7% after 12 months; p<0·0001) as
trial (ROBUST) evaluated the addition of lenalidomide to well as higher response rates compared with the current
standard R-CHOP in patients with non-GCB DLBCLs, standard of care.156 In contrast, tisacel did not achieve any
showing slightly improved progression-free survival, but benefit in comparison to ASCT.157 However, this finding
not overall survival.145 The addition of bortezomib to was probably due to clinical trial design and delayed
R-CHOP also failed to significantly improve outcomes availability of CAR T-cell products and not due to different
over R-CHOP alone in patients with previously untreated product activity. Nevertheless, as two out of three studies
non-GCB DLBCL.146 showed the superiority of CAR T-cell products in first
For high-grade B-cell lymphomas with MYC and relapse, this treatment strategy represents the new
rearrangements of BCL2, BCL6, or both, DA-EPOCH-R standard of care for transplantation-eligible DLBCL
might be the preferred immunochemotherapeutic patients in early first relapse. Recommended targeted
regimen for inducing durable remissions.147 For this therapies are summarised in table 2.
aggressive subtype of DLBCL, the multicentre, open-label, Novel immunotherapeutic treatment alternatives
single-arm ZUMA-12 trial investigated the efficacy of the currently challenge the therapeutic algorithm of relapsed
CD19 CAR T-cell product axicel as first-line therapy for or refractory DLBCL. Bispecific T-cell engager therapies,
patients with high-risk DLBCL, reporting a complete such as antibodies targeting CD20 and CD3, are also
response rate of 78%.148 under investigation. Using step-up dosing to mitigate
The use of CNS prophylaxis in patients with newly side-effects encountered during the first infusions,
diagnosed DLBCL is increasingly questioned. Two large mosunetuzumab,121 epcoritamab (subcutaneous),91 as well
retrospective studies analysed the optimal timing and as glofitamab (two to one format with two CD20-binding
application of CNS prophylaxis.149,150 Even though these motifs and obinutuzumab pretreatment),90 all showed
studies did not aim to evaluate the effect of CNS encouraging results as single agents and are being
prophylaxis in general, they failed to show benefit evaluated in combinations with other agents. Glofitamab
regarding relapse rates compared with historical CNS is now approved in Canada and the USA, and epcoritamab
relapse rates. However, the authors consider high-dose in the USA, for third or later line of treatment. Antibody–
methotrexate prophylaxis adequate in ultra-high-risk drug conjugates provide another promising alternative
patients with testis and renal involvement. If indicated, treatment approach for relapsed or refractory DLBCL.
high-dose methotrexate should be applied at the end of These constructs selectively deliver cytotoxic agents to
treatment for at least two cycles. Recommended targeted tumour cells via conjugation to a monoclonal antibody
therapies are summarised in table 2. directed to a target tumour cell surface antigen.
Until recently, salvage chemotherapy followed by ASCT Loncastuximab tesirine, an anti-CD19 antibody conjugated
was considered the standard of care for transplantation- to a pyrrolobenzodiazepine dimer, proved to be effective
eligible patients with relapsed or refractory DLBCL. For in heavily pretreated patients with relapsed or refractory
patients who are not eligible for transplantation, several DLBCL as evaluated in the phase 2 LOTIS-2 study.158
approved alternative treatment options were shown to be
effective: polatuzumab in combination with rituximab Burkitt lymphoma
and bendamustine led to a significantly higher complete Burkitt lymphoma is a highly aggressive B-cell lymphoma
remission rate and reduced the risk of death by 58% of germinal centre origin that can be categorised into
compared with rituximab and bendamustine alone.143 The endemic, sporadic, and immunodeficiency-associated
anti-CD19 monoclonal antibody tafasitamab in subtypes. The B cells usually express CD45, CD20, CD79a,
combination with lenalidomide resulted in a high CD10, and BCL6 and are BCL2-negative with a very high
proportion of transplantation-ineligible patients having a proliferation rate (Ki67 index up to 100%). Burkitt
complete response.151 Three autologous CAR T-cell lymphoma is genetically characterised by the
products are currently FDA approved for the treatment of chromosomal translocation t(8;14) leading to constitutive
patients with relapsed or refractory DLBCL who have activation of MYC.159 Additional mutations involve the
received at least two previous lines of systemic therapy: transcription factor TCF3 or its negative inhibitor ID3 in

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40–70% of cases with the t(8;14) translocation, as well as care for relapsed disease in several lymphoma subtypes
CCND3 and inactivating alterations in TP53 or including DLBCL (CAR T-cells) as well as indolent
CDKN2A.160–162 Burkitt lymphoma has a gene expression lymphomas (bispecific antibodies). This knowledge could
profile that includes high expression of MYC target and lead to more risk-based and individualised treatment
germinal centre-associated B-cell genes that might help to strategies that benefit patients.
distinguish this lymphoma more reliably from DLBCL.163 Contributors
Considering the fast doubling time of Burkitt All authors contributed to the writing and review of the manuscript.
lymphoma, patients most often present with large tumour Declaration of interests
masses, bone marrow involvement, high serum lactate GS has received financial compensations for participating on advisory
dehydrogenase levels, and sometimes signs of boards and consulting from AbbVie, Beigene, Bristol Myers Squibb,
Epizyme, Roche, Genmab, Incyte, Janssen, Gilead, Loxo, Miltenyi,
spontaneous tumour lysis syndrome. As this lymphoma Molecular Partners, Morphosys, Nordic Nanovector, Novartis, Rapt, Takeda,
subtype tends to disseminate to the CNS, a staging lumbar Debiopharm, Ipsen, and Merck; has received hororaria from AbbVie, Bayer,
puncture should be performed at initial diagnosis.164 Incyte, Gilead, Morphosys, Novartis, and Regeneron; and is shareholder at
Immediate treatment initiation is of great importance, Owkin. EC has been a consultant for Takeda, NanoString Technologies, and
Illumina; has received honoraria from EusPharma, Takeda, and Janssen for
should mitigate the tumour lysis risk, and should include speaking at educational events; and is an inventor on a Lymphoma and
CNS prophylaxis. Excellent response rates are being Leukaemia Molecular Profiling Project patent (PCT/US2014/064161).
achieved with intensive immunochemotherapy regimens, MD has received research support from AbbVie, Bayer, Bristol Myers
such as cyclophosphamide, vincristine, doxorubicin, Squibb, Gilead, Janssen, and Roche; has received financial compensation
for participating at advisory boards from AstraZeneca, Beigene, Bristol
methotrexate, ifosfamide, etoposide, and cytarabine Myers Squibb, Gilead, Janssen, Lilly, Novartis, and Roche; and has received
(CODOX-M/IVAC).165 Addition of rituximab to a short honoraria from Amgen, AstraZeneca, Gilead, Janssen, Lilly, Novartis, and
intensive chemotherapy programme improved event-free Roche. ES declares no competing interests.
survival and overall survival in adults with Burkitt Acknowledgments
leukaemia or lymphoma.166 The infusional regimen DA- This research was funded in part through the National Institutes of
Health (NIH) and National Cancer Institute Cancer Centre support grant
EPOCH plus rituximab proved to be highly effective, with
P30 CA008748. EC is an academia researcher with the Catalan
a tolerable toxicity profile in adults with sporadic or Institution for Research and Advanced Studies, and is funded by the
immunodeficiency-associated Burkitt lymphoma.167 A Spanish Ministry of Science and Innovation (PID2021–123054OB-I00),
European phase 3 study comparing R-CODOX-M/IVAC and the NIH (1P01CA229100).
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