Sehn Laurie H Diffuse Large B Cell Lymphoma

The n e w e ng l a n d j o u r na l of m e dic i n e
Review Article
Dan L. Longo, M.D., Editor
Diffuse Large B-Cell Lymphoma

Laurie H. Sehn, M.D., M.P.H., and Gilles Salles, M.D., Ph.D.
L
From the BC Cancer Centre for Lymphoid arge B-cell lymphomas, with an estimated 150,000 new cases
Cancer and the University of British Co- annually worldwide, represent almost 30% of all cases of non-Hodgkin’s
lumbia, Vancouver, Canada (L.H.S.); and
the Lymphoma Service, Department of lymphoma. Patients typically present with progressive lymphadenopathy,
Medicine, Memorial Sloan Kettering Can- extranodal disease, or both and require therapy. Despite the advanced stage at
cer Center, New York (G.S.). Address re- presentation in the majority of patients, more than 60% can be cured with R-CHOP
print requests to Dr. Sehn at the BC Can-
cer Centre for Lymphoid Cancer, 600 W. (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) immuno-
10th Ave., Vancouver, BC V5Z 4E6, Canada, chemotherapy (Fig. 1A). Patients with treatment failure after R-CHOP often have a
or at lsehn@bccancer.bc.ca. poor outcome — in particular, those with disease that is refractory to frontline or
This article was updated on March 4, subsequent therapies — although some patients can have a durable remission and
2021, at NEJM.org. be cured after secondary therapies. Over the past two decades, improved insights
N Engl J Med 2021;384:842-58. into large B-cell lymphomas, in terms of epidemiology, prognostic factors, and
DOI: 10.1056/NEJMra2027612 biologic heterogeneity, have led to a refinement of disease classification and the
Copyright © 2021 Massachusetts Medical Society.
development of new therapeutic approaches.
Pathol o gic a l Fe at ur e s a nd Mol ecul a r Cl a ssific at ion

Diagnosis of large B-cell lymphomas relies on a detailed examination of tumor
tissue, best achieved with an excisional biopsy specimen evaluated by an expert
hematopathologist.5 In addition to morphologic characteristics, an accurate lym-
phoma classification requires specialized tests, including immunohistochemistry,
flow cytometry, fluorescence in situ hybridization (FISH), and molecular testing.
Biopsy specimens obtained by fine-needle aspiration are inadequate for patho-
logical assessment. Although specimens from core biopsy are frequently used, they
are often insufficient for a complete evaluation, and core biopsy should be per-
formed only if excisional biopsy is not feasible.
The updated World Health Organization (WHO) classification has refined the
categorization of large B-cell lymphomas, which are a heterogeneous collection of
clinicopathological entities (Table 1),6 of which diffuse large B-cell lymphoma, not
otherwise specified (DLBCL, NOS), is the most common. A detailed review of each
disorder is beyond the scope of this article, and thoughtful management often
requires consultative review.
This review focuses primarily on DLBCL, NOS (henceforth referred to simply as
DLBCL), which is also highly heterogeneous. Gene expression profiling has delin-
eated two distinct molecular subtypes of DLBCL, the germinal center B-cell–like
(GCB) subtype and the activated B-cell–like (ABC) subtype; 10 to 15% of cases are
unclassifiable.1 These subtypes are believed to arise from different stages of lym-
phoid differentiation (cell of origin), relying on separate oncogenic mechanisms,
with the ABC subtype having an inferior outcome (3-year progression-free sur-
vival, approximately 40 to 50%, vs. 75% with the GCB subtype).8,9 The ABC subtype
of DLBCL is characterized by chronic B-cell receptor signaling and activation of
nuclear factor κB, whereas the GCB subtype expresses genes commonly detected
in germinal center B cells, including BCL6 and EZH2 (Fig. 1C). This phenotypic
842 n engl j med 384;9 nejm.org March 4, 2021
The New England Journal of Medicine

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Copyright © 2021 Massachusetts Medical Society. All rights reserved.
distinction is relevant because targeted agents may In contrast to the relative rarity of double- or
be preferentially active in one subtype. Although triple-hit high-grade B-cell lymphoma detected
gene expression profiling is rarely performed in by FISH, overexpression of MYC protein as mea-
clinical practice, platforms suitable for routine care sured by immunohistochemical analysis occurs
may soon be available.9 Alternatively, immuno- in approximately 45% of cases and overexpres-
histochemistry-based algorithms, such as the Hans sion of BCL2 protein occurs in approximately
algorithm (Table 2), can be used to dichotomize 65% of cases (in the absence of dual rearrange-
cases as GCB and non-GCB (the latter compris- ment of MYC and BCL2).12 The overexpression of
ing the ABC subtype and the majority of unclas- both MYC and BCL2, occurring in approximately
sified cases), although these algorithms provide 30% of cases of DLBCL, termed double-expres-
only an approximation of gene expression profil- sor lymphoma, is associated with a worse prog-
ing, with a risk of misclassification.10 nosis than single or no overexpression of either
Detailed analyses of molecular aberrations (in- MYC or BCL2.14 Double-expressor lymphoma is
cluding gene mutations and copy-number gains not a discrete biologic entity, since it can occur
or losses) have led to proposals of new taxono- in both the GCB and ABC subtypes as a result of
mies for DLBCL, yielding unique, genetically de- varied underlying molecular mechanisms, but it
fined subtypes beyond the cell of origin2,3 (Fig. 1C). is more common in the ABC subtype, which may
These newly proposed classification schemes may in part mediate the prognostic implications.
better delineate distinct biologic entities, provid-
ing greater potential for individualized thera- Epidemiol o gic Fe at ur e s
peutic interventions. However, further validation
and development of reproducible molecular assays The median age at diagnosis of DLBCL is in the
will be required before clinical application is mid-60s; 30% of patients are older than 75 years
feasible. of age. Although the majority of patients present
In addition to the molecular heterogeneity without a history of lymphoma, DLBCL can arise
of DLBCL described above, recurrent genetic re- as a transformation from an underlying known
arrangements of clinical significance can be de- or occult low-grade B-cell lymphoma. Epidemio-
tected by FISH. A MYC rearrangement is seen in logic studies support a complex and multifacto-
12% of cases, whereas a MYC rearrangement rial cause of DLBCL, with risk factors including
concurrent with a rearrangement in BCL2, BCL6, genetic features, clinical characteristics, and im-
or both occurs in 4 to 8% of cases with morpho- mune dysregulation, as well as viral, environmen-
logic features of DLBCL, the majority of which tal, or occupational exposures15 (Fig. 1B). Although
are the GCB subtype, in which BCL2 rearrange- DLBCL is not considered a heritable disease,
ments occur exclusively.11,12 These cases are now genomewide association studies have identified
classified as “high-grade B-cell lymphoma with multiple genetic susceptibility loci, implicating
MYC and BCL2 and/or BCL6 rearrangements,” pathways involved with immune function.16
commonly referred to as double- or triple-hit Screening procedures are not available.
lymphoma, and are associated with a poor out-
come after R-CHOP.6,11 Data suggest that the ad- S taging a nd R e sp onse
verse outcome associated with double- or triple-hit A sse ssmen t
high-grade B-cell lymphoma is primarily evident
when MYC is translocated with an immuno- Staging and response assessment should be per-
globulin gene partner (rarely assessed in clinical formed in accordance with Ann Arbor staging
practice) and that concurrent rearrangements and the Lugano classification criteria5,17,18 (see
involving BCL2 or BCL6 have similar prognostic Tables S1 and S2 in the Supplementary Appen-
significance.11 Retrospective series suggesting that dix, available with the full text of this article at
R-CHOP may be insufficient in such cases NEJM.org). In recent years, because of its higher
prompted the use of more intensive therapies, sensitivity, 18F-fluorodeoxyglucose positron-emis-
such as dose-adjusted etoposide, prednisone, vin- sion tomography with computed tomography
cristine, cyclophosphamide, and doxorubicin with (PET-CT) has replaced CT.17 The total metabolic
rituximab (DA-EPOCH-R), which may be associ- tumor volume at diagnosis may also be prognos-
ated with improved outcomes and are currently tic.19 Staging bone marrow biopsy is positive in
recommended in appropriate cases.13 15 to 20% of cases and, when concordant large
n engl j med 384;9 nejm.org March 4, 2021 843

A Outcomes of Patients with DLBCL B Risk Factors for Development of DLBCL

1.00
Family history; genetic susceptibility
loci (TNF/LTA; 6p25.3; 6p21.33;
2p23.3; 8q24-21)
Probability of Survival
0.75 Viruses: EBV, HIV, HHV8,

hepatitis B, hepatitis C
Solid-organ transplantation
Increased B-cell–activating autoimmune
0.50 Risk disorders (SLE, Sjögren’s syn-
drome, celiac disease)
Time to progression Immunodeficiency
0.25 Progression-free survival Increased body-mass index
(in young adults)
Overall survival
Agricultural pesticides
Ionizing radiation
0.00
0 1 2 3 4 5 6 7 8 9 10 Allergies (including hay fever)
Blood transfusion
Years Decreased
Alcohol consumption
Risk Vegetable consumption
No. at Risk
Time to progression 3082 2133 1775 1446 1236 1048 830 700 585 468 391 Sun exposure
Progression-free 3082 2132 1774 1445 1235 1047 829 699 584 467 390 No Significant
survival Type 2 diabetes
Effect
Overall survival 3082 2336 1900 1558 1338 1140 911 767 647 519 437
C Biologic Features of DLBCL

Germinal Center B-Cell–Like Activated B-Cell–Like
Germinal center regulatory program Early plasmacytic regulatory program
reminiscent of light zone germinal center reminiscent of plasmablasts
Cell of Origin centrocytes Enhanced BCR signaling
Unclassifiable
Classification Immunoglobulin somatic hypermutation Genetic lesions: CARD11, CD79A/B,
Genetic lesions: t(14;18), BCL2, PTEN, TNFAIP3 (constitutive NF-κB
miR-17-92, GNA13, EZH2, KMT2D, CREBBP, activation), PRDM1, BCL2 (gain),
EP300 (chromatin modifiers)… CDKN2A, MYD88…
Potential correspondences
LymphGen
EZB ST2 BN2 A53 N1 MCD
Classification
HGBCL-
Potential correspondences DH/TH
DLBCL Clusters C3 C4 C1 C2 C5
TET2, SGK1, MYD88, CD79B,

BCL6,
BCL2, EZH2, TNFSFR14, DUSP2, PIM1, HLA-B,
NOTCH2, TP53, NOTCH1,
Genetic Hallmarks CREBBP, KMT2D ZFP36L1, BTG1, CDKN2A,
TNFAIP3, aneuploidy IRF2BP2
(and MYC in DH/TH cases) ACTG1, ACTB, ETV6, SPIB,
DTX1
ITPKB, NFKBIA OSBPL10
NOTCH2 Genetic
Epigenetic; PI3K signaling; B-cell receptor
Biologic Pathways JAK/STAT signaling; instability; NF-κB
cell migration; immune cell and NF-κB
Deregulated interactions
signaling immune immune activation
signaling
evasion evasion
Favorable; poor if EZB-MYC+ Poor or Poor or
Patient Prognosis Favorable Intermediate Unknown
or HGBCL-DH/TH intermediate intermediate
Nodular Primary
lymphocyte extranodal
predominant (CNS, testis,
Chronic
Genetic Similarities with Marginal zone HL skin)
Follicular lymphoma lymphocytic
Other Lymphoma Entities lymphoma T-cell or histio-
leukemia
Lymphoplas-
cyte-rich macytic
B-cell lymphoma
lymphoma

Figure 1 (facing page). Outcomes of Diffuse Large B-Cell B cells are present, is associated with a poor
Lymphoma (DLBCL), Risk Factors, and Biologic Features. prognosis.20 Bone marrow biopsy is no longer
Panel A shows Kaplan–Meier survival estimates for all mandatory in patients who have undergone PET-
patients with newly diagnosed DLBCL treated with R-CHOP CT staging, although low-volume disease or dis-
(rituximab, cyclophosphamide, doxorubicin, vincristine, cordant indolent lymphoma (which does not al-
and prednisone) in British Columbia, Canada (2001–2019).
Time to progression (TTP) is measured from the date
ter the outcome) may occasionally be missed.5,21
of diagnosis to the date of disease progression or death End-of-treatment response evaluation is best per-
from lymphoma, with deaths from unrelated causes cen- formed by means of PET-CT, with interpretation
sored. This curve highlights that the risk of DLBCL pro- according to the Deauville five-point scale (Table
gression is highest within the first 2 years, followed by a S3), with uptake in the mediastinum and liver
lower risk of progression for up to 10 years. Progression-
free survival (PFS) is measured from the date of diagno-
used as reference points. A score of 1 or 2 and
sis to the date of progression or death from any cause. probably 3 is considered to indicate a complete
Given that the median age of patients with DLBCL is in metabolic response.17
the mid-60s, the difference between the TTP and PFS The response during therapy can be assessed
curves reflects the competing risk of death from unre-
with the use of CT to detect nonresponding or
lated causes. The marginal difference between the PFS
and overall survival (OS) curves reflects the limited num- progressive disease. Studies evaluating the merit
ber of patients cured with secondary therapies, although of interim PET-CT have yielded conflicting re-
new therapies may improve overall survival. Panel B shows sults, although PET-CT after two to four cycles
reported risk factors for the development of DLBCL. of treatment appears to be prognostic, particu-
Panel C shows the heterogeneous biologic features that
larly when the response is assessed with the use
reflect insights gained over the past 20 years. Gene ex-
pression profiling originally delineated two molecular sub- of quantitative methods.22 However, treatment
types, germinal center B-cell–like and activated B-cell– modification based solely on interim PET-CT
like, which are believed to arise from different stages of findings has not been shown to alter the out-
B-cell lymphoid differentiation (cell of origin), with gene come and thus is not recommended outside of
expression resembling their normal B-cell counterparts.1
Distinct functional profiles and genetic aberrations have
clinical trials.17 Recently, circulating tumor DNA
been identified within the two subtypes, but heteroge- has shown promise as an interim response-assess-
neity within these subtypes has also been recognized. ment tool and is being actively investigated.23
On the basis of the results of in-depth genomic analy- Although data are limited, routine post-treat-
ses, new taxonomies for DLBCL have been proposed, ment surveillance imaging has not been shown
designated as the LymphGen classification2 and DLBCL
clusters.3 These taxonomies further refine DLBCL genom-
to affect the outcome and is generally discour-
ic classification and may better delineate distinct biolog- aged.5 Patients should be clinically monitored
ic entities. The postulated associations between cell-of- every 3 months for 2 years, then every 6 to 12
origin molecular subtypes and these new genomic entities months.5 Patients who remain event-free for
are denoted by solid arrows, indicating robust associa-
2 years from the time of diagnosis have an ex-
tions; dashed arrows indicate weaker associations or un-
certain associations. Genetic hallmarks based on recur- pected overall survival that is almost similar to
ring genomic aberrations and resultant deregulated survival in the general, age-matched population.24
genetic pathways have been identified within entities, However, physicians should monitor patients for
which are associated with varied prognoses. DLBCL with long-term risks, including late infectious com-
a MYC rearrangement and a concurrent rearrangement
in BCL2, BCL6, or both (double-hit [DH] or triple-hit [TH]
plications, autoimmune disorders, secondary can-
lymphoma) is currently classified as a high-grade B-cell cers, and cardiovascular events.
lymphoma (HGBCL-DH/TH). HGBCL-DH/TH cases, to-
gether with cases with an EZB subtype with a MYC DH
gene signature (EZB-MYC+),2,4 largely cluster with the Pro gnos t ic Fac t or s
EZB subtype and harbor biologic features associated with
a poor clinical outcome. BCR denotes B-cell receptor, CNS
The International Prognostic Index (IPI) remains
central nervous system, EBV Epstein–Barr virus, HHV8 the primary clinical tool for predicting outcomes
human herpesvirus 8, HIV human immunodeficiency and for stratifying patients in clinical trials.25
virus, HL Hodgkin’s lymphoma, miR-17-92 microRNA The IPI has been validated and refined in the
cluster 17-92, NF-κB nuclear factor κB, PI3K phosphati-
modern era, with the National Comprehensive
dylinositol 3-kinase, SLE systemic lupus erythematosus,
and TNF/LTA, tumor necrosis factor/lymphotoxin alpha. Cancer Network IPI (NCCN-IPI) allowing great-
er discrimination among high-risk patients26-28

846
Table 1. Pathological and Clinical Characteristics of Large B-Cell Lymphomas According to the World Health Organization (WHO) Classification.*
WHO Denomination Diagnostic Features Clinical Features and Outcome

Diffuse large B-cell lymphoma, NOS
Diffuse large B-cell lymphoma, NOS (accounts for Diffuse proliferation of medium or large lymphoid B cells typi- Median age: 65–70 yr, nodal presentation most common, 30–40%
>80% of cases of large B-cell lymphomas) cally expressing CD19, CD20, CD22, CD79a, PAX5, and of cases are primary extranodal; ABC subtype overrepresented
Molecular subtypes: GCB subtype, about 60%; surface or cytoplasmic immunoglobulin; molecular tech- among patients with primary extranodal lymphoma and elderly
ABC subtype, about 25–30%; unclassifiable, niques (e.g., GEP) or IHC-based algorithms recommended patients; prognosis varies
about 10–15%; new molecular entities recently to classify subtypes
characterized
Other large B-cell lymphomas
T-cell/histiocyte-rich large B-cell lymphoma (rare) Few large B cells embedded in a background of T cells and his- Commonly found in middle-aged men, advanced stage with extrano-
tiocytes; distinguish from nodular lymphocyte-predominant dal involvement (liver, spleen, bone marrow); poor prognosis
The
Hodgkin lymphoma
Primary diffuse large B-cell lymphoma of the CNS Typically ABC subtype; frequent loss of HLA class I/II; frequent Exclusively in CNS or intraocular region, rare systemic involvement;
(rare) mutation of MYD88 poor prognosis; specialized treatment with CNS-penetrating
agents, with or without radiation therapy, required; targeted
therapies under investigation
Primary cutaneous diffuse large B-cell lymphoma, Typically ABC subtype; frequent mutation of MYD88; distin- Typically in elderly patients and women; presents with skin nodules
leg type (rare) guish from other cutaneous B-cell lymphoma in lower legs; 10–15% of cases arise in other sites; poor
n engl j med 384;9

prognosis
EBV-positive diffuse large B-cell lymphoma, NOS Variable histologic features, including Hodgkin-like lesions, Typically in patients older than 50 yr; more frequent in Asia and
(rare) monomorphic to polymorphic patterns; EBV detectable in Latin America than elsewhere; extranodal involvement common;
tumor and frequently in serum prognosis varies
nejm.org
n e w e ng l a n d j o u r na l
EBV-positive mucocutaneous ulcer (rare) Polymorphic infiltrate with frequent Hodgkin-like cells; EBV Presents as localized, ulcerated lesions in oral mucosa, intestine, or

of
detectable in tumor skin; dissemination is rare; commonly occurs as iatrogenic or

age-related disease in immunocompromised patients; favorable
prognosis; consider reduction of immunosuppressive therapy
March 4, 2021
Diffuse large B-cell lymphoma associated with Morphologically similar to DLBCL, NOS but strongly associ- Occurs in context of chronic inflammation, involving pleural cavity
chronic inflammation (rare) ated with EBV; also called pyothorax-associated lymphoma, or other sites such as bone and joints; male predominance; poor

when associated with chronic pyothorax prognosis
m e dic i n e
Lymphomatoid granulomatosis (rare) EBV-driven angiocentric and angiodestructive lymphoprolifera- Commonly involves extranodal sites (lung >90%); often in context
tion with reactive T cells; grade based on proportion of EBV- of immunodeficiency; prognosis varies; no standard therapy
positive B cells and cytologic features
Large B-cell lymphoma with IRF4 rearrangement Strong expression of IRF4/MUM1, usually with IRF4 rearrange- Commonly in children and young adults; typically involves Waldeyer’s
(rare) ment; diffuse-to-follicular morphologic features; distinguish ring or cervical lymph nodes; favorable prognosis
from pediatric-type follicular lymphoma
Primary mediastinal (thymic) large B-cell Putative thymic B-cell origin; medium-to-large B cells, frequently Typically in young adults, female predominance; mediastinal promi-
lymphoma (around 6% of large B-cell cases) with sclerosis; distinctive phenotype (CD30, CD23, PDL1, nence with local invasion; can involve other nodal or extranodal
PDL2) and unique GEP signature; frequent 9p21 amplifica- sites (kidney and liver); prognosis varies; DA-EPOCH-R an
tion, genomic alterations of CIITA option
WHO Denomination Diagnostic Features Clinical Features and Outcome
Intravascular large B-cell lymphoma (rare) Lymphoma cells exclusively within lumina of small or interme- Wide intravascular dissemination (lung, bone marrow, skin, CNS,
diate vessels; bone marrow and skin biopsy may be useful kidney), often associated with fever of unknown origin or neuro-
to establish diagnosis logic or cutaneous symptoms; poor prognosis
ALK-positive large B-cell lymphoma (rare) ALK-positive large B cells, immunoblastic features and plasma- Typically in young men with generalized lymphadenopathy; progno-
cell phenotype, typically CD20-negative sis varies
Plasmablastic lymphoma (rare) Immunoblastic or plasmablastic B cells, plasma-cell phenotype Often associated with HIV infection or immunosuppression;
(CD138-positive, CD20-negative), often EBV-positive; dis- frequently extranodal; poor prognosis; consider more intensive
tinguish from multiple myeloma regimens
HHV8-positive diffuse large B-cell lymphoma (rare) HHV8-positive IgM lambda plasmablasts; often associated Often associated with HIV infection; lymphadenopathy and spleno-
with HHV8-positive multicentric Castleman disease megaly are common; poor prognosis; no standard therapy
Primary effusion lymphoma (rare) Immunoblastic or plasmablastic B cells, HHV8-positive and Often associated with HIV infection or immunosuppression; pres-
usually EBV-positive; plasma-cell phenotype lacking usual ents as pleural, pericardial, or peritoneal serous effusions, often
B-cell markers; CD20-negative without detectable tumor mass; poor prognosis; DA-EPOCH an
option
High-grade B-cell lymphoma
High-grade B-cell lymphoma with MYC and BCL2 Variable morphology, including DLBCL, B-cell lymphoma un- Frequently aggressive clinical presentation; higher risk of CNS
and/or BCL6 rearrangements or both (double- classifiable (with features intermediate between DLBCL and involvement; poor prognosis; consider more intensive immuno-
n engl j med 384;9

hit or triple-hit lymphoma) (4–8% of large B-cell Burkitt lymphoma), and blastoid features; MYC and BCL2 chemotherapy regimens, such as DA-EPOCH-R
cases) and/or BCL6 rearrangements, detected by FISH
High-grade B-cell lymphoma, NOS (rare) Heterogeneous category; often has morphologic features inter- Frequently aggressive clinical presentation; increased risk of CNS
mediate between DLBCL and Burkitt lymphoma; lacks MYC involvement; poor prognosis; consider more intensive immuno-
nejm.org
and BCL2 and/or BCL6 rearrangements chemotherapy regimens
B-cell lymphoma, unclassifiable
B-cell lymphoma, unclassifiable, with features inter- Overlapping morphologic or immunophenotypic features, or Male predominance, younger age (20–40 yr); mediastinal presenta-
mediate between diffuse large B-cell lymphoma both, between DLBCL and classic Hodgkin lymphoma tion most common (80% of cases) but can occur in other sites;
March 4, 2021
and classic Hodgkin lymphoma (grey-zone prognosis varies; no standard therapy, consider therapy suitable

lymphoma) (rare) for DLBCL or Hodgkin lymphoma
* Data are based on the updated WHO classification, and the terminology adheres to that of the WHO.6 For most rare entities, confirmation of the diagnosis by a hematopathologist with
expertise in lymphoma is highly recommended. Also, since clinical management of these rare entities may evolve rapidly, with new therapies under investigation in clinical trials, con-
sultation with a hemato-oncologist specializing in lymphoid cancer is recommended. The standard regimen for many of these entities continues to be R-CHOP (rituximab, cyclophos-

phamide, doxorubicin, vincristine and prednisone), although rituximab would be omitted in patients with lymphomas that are CD20-negative. Follicular lymphoma grades 3A and 3B
also contain a variable but substantial proportion of large B cells; although treatment for follicular lymphoma grade 3B is commonly the same as treatment for DLBCL, it is not included
in this table. Post-transplantation lymphoproliferative disorders may also present as large B-cell lymphoma but are beyond the scope of this review and generally require individualized
management.7 Finally, transformed indolent lymphoma may present as various forms of large B-cell lymphoma; the presence of the indolent lymphoma component (follicular, marginal-
zone, lymphoplasmacytic, chronic lymphocytic leukemia), when known, is usually noted in the pathological report, together with the diagnosis of the large B-cell lymphoma entity.
Treatment of transformed lymphoma is generally directed at the large B-cell lymphoma but must take into account the underlying indolent disease, as well as likely prior therapies. ABC
denotes activated B-cell–like, CNS central nervous system, DA-EPOCH-R dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin with rituximab, DLBCL
diffuse large B-cell lymphoma, EBV Epstein–Barr virus, FISH fluorescence in situ hybridization, GCB germinal center B-cell–like, GEP gene expression profiling, HHV8 human herpesvi-
rus 8, HIV human immunodeficiency virus, IHC immunohistochemistry, and NOS not otherwise specified.
847
Table 2. Biologic Factors Associated with Outcomes in Patients with DLBCL.*
Biomarker Methodology Prognostic Significance Other Implications

Cell-of-origin molecular Various technologies (gene array, ABC subtype is associated with ABC subtype may be associated
classification digital expression profiling, mul- poor prognosis with an increased risk of CNS
tiplex RT-PCR–based methods) relapse
Cell-of-origin IHC-based Various IHC-based algorithms to Non-GCB subtype is associated Dichotomizes patients into GCB
algorithms assign molecular subtype; most with poor prognosis, although and non-GCB subgroups and
commonly the Hans algorithm† this is not confirmed in some represents an approximation of
studies molecular subtype as assessed
by GEP
Double- or triple-hit FISH is used primarily in clinical Double- or triple-hit cases are as- Now classified by the WHO as high-
rearrangement involving practice; the use of break-apart sociated with poor prognosis; grade B-cell lymphoma with
MYC and either BCL2 or probes is recommended; GEP- poor prognosis may be limited MYC and BCL2 and/or BCL6 re-
BCL6 or both based assays may identify to cases in which the MYC arrangements; majority of cases
additional cases with double-hit translocation partner is an are GCB subtype; may benefit
signature undetected by FISH immunoglobulin gene locus from more intensive therapies
with similar biologic features
and outcome‡
MYC and BCL2 protein IHC measurement to estimate the Double expression of MYC and May have prognostic significance
expression percentage of cells expressing BCL2 or expression of BCL2 mainly in GCB-type DLBCL;
MYC or BCL2 protein or both; alone is associated with worse MYC-BCL2 double expression
40% cutoff threshold for MYC prognosis may be associated with an
and 50% for BCL2 increased risk of CNS relapse
Proliferation index IHC measurement of proliferation Higher proliferation may be asso High proliferation rate (>80%) may
marker Ki67; no established ciated with poorer prognosis, increase suspicion that patient
cutoff threshold although it has not consistently has high-grade B-cell lymphoma
been shown to be an indepen- (with or without double- or
dent prognostic marker triple-hit rearrangements)
TP53 PCR, NGS, or gene array for detec- TP53 mutations in the DNA-binding May cluster with a genetic subset
tion of mutation or deletion of domain are associated with of DLBCL
TP53 poor prognosis
CDKN2A Gene array, FISH, or PCR for detec- Deletion of the CDKN2A locus or May cluster with some genetic sub-
tion of deletion of the CDKN2A loss of the 9p21 is associated sets of DLBCL
locus or loss of the 9p21 region with poor prognosis
MHC class II IHC measurement of partial or Loss of expression of MHC class II Primarily observed in primary medi-
complete loss of MHC class II may be associated with a poor astinal B-cell lymphoma and in
expression prognosis (more frequent in tumors with EZH2 mutations
non-GCB subtype)
Lymphocyte count and Measured in peripheral blood; low Low lymphocyte count or low May have implications for immune-
lymphocyte:monocyte lymphocyte count (<1 × 109/liter) lymphocyte:monocyte ratio is based therapies
ratio or low lymphocyte:monocyte associated with poor prognosis
ratio (various cutoff thresholds)
Host genetics Single nucleotide variation in 5q23.2 Single nucleotide variation in Further investigation is needed
or 6q21 (PCR or single nucleo- 5q23.2 or 6q21 is associated
tide polymorphism array) with poor prognosis
* The list of select biologic factors correlated with outcomes in patients with DLBCL is based on reproducible observations, including valida-
tion in independent patient cohorts. NGS denotes next-generation sequencing, and RT-PCR reverse-transcriptase polymerase chain reaction.
† The Hans algorithm is as follows: GCB: CD10+ or CD10−BCL6+MUM1−; non-GCB: CD10−BCL6−MUM1+ or CD10−BCL6+MUM1+ or CD10−
BCL6−MUM1−.
‡ The information on methods for detecting additional cases with the use of a double-hit gene-expression signature is from Ennishi et al.4
(Table 3). However, these clinical indexes cannot Pr im a r y M a nagemen t

be used to identify patients at very high risk or
to discern biologic heterogeneity. Numerous bio- Advanced-Stage Disease
logic factors have been correlated with outcomes Treatment of DLBCL relies on systemic therapy.
(Table 2). However, they have yet to be integrated Most patients (approximately 70%) present with
into a validated prognostic index. advanced-stage disease, and historically, eight

Table 3. Clinical Indexes for Predicting Outcomes in Patients with DLBCL.*
Proportion of Estimated 5-yr Estimated 5-yr

Prognostic Index, Clinical Factors, and Risk Categories Patients PFS OS
percent
IPI
Age, >60 yr; LDH, >ULN; Ann Arbor stage III or IV; ECOG perfor-
mance status, >1; no. of extranodal sites of disease, >1
Risk categories
Low (0 or 1 factor) 34 81 88
Low-intermediate (2 factors) 23 67 76
High-intermediate (3 factors) 23 58 67
High (4 or 5 factors) 20 46 54
R-IPI
Age, >60 yr; LDH, >ULN; Ann Arbor stage III or IV; ECOG perfor-
mance status, >1; no. of extranodal sites of disease, >1
Risk categories
Very good (0 factors) 9 87 93
Good (1 or 2 factors) 48 74 81
Poor (3–5 factors) 43 53 61
NCCN-IPI
Age, >40 to ≤60 yr (1 point), >60 to ≤75 yr (2 points), >75 yr
(3 points); LDH ratio, >1 to ≤3 (1 point), >3 (2 points);
Ann Arbor stage III or IV (1 point); ECOG performance-
status score, ≥2 (1 point); extranodal disease: lymphoma
involvement in bone marrow, CNS, liver or GI tract, or lung
(1 point)
Risk categories
Low (0 or 1 point) 13 86 92
Low-intermediate (2 or 3 points) 41 75 84
High-intermediate (4 or 5 points) 36 54 63
High (6–8 points) 10 43 49
* The three commonly used clinical prognostic indexes established over the past 30 years are based on the most dis-
criminating clinical variables.25,27,28 The 5-year progression-free survival (PFS) and overall survival (OS) estimates are
derived from a large international collaboration involving 2124 patients with DLBCL who were treated between 1998
and 2009 with frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or a vari-
ant in seven multicenter, randomized clinical trials.26 An age-adjusted International Prognostic Index (IPI), for patients
who are 60 years of age or younger, has been designed that has only three factors: stage, lactate dehydrogenase (LDH)
level, and performance status.25 A stage-modified IPI, designed for patients with limited-stage disease, has four factors:
age (>60 years), stage (I or II), LDH level, and performance status.29 Other clinical factors associated with a poor out-
come have been identified, but many have not retained prognostic significance in multivariable models including the
presence of B symptoms, largest tumor diameter (≥7.5 cm or, more commonly, ≥10 cm used as a threshold), elevated
serum β2-microglobulin level, low hemoglobin and serum albumin levels, and bone marrow involvement (although
concordant bone marrow involvement with large B cells present has been shown to be an independent factor in some
studies20). Recently, baseline total metabolic tumor volume, assessed with 18F-fluorodeoxyglucose positron-emission
tomography and computed tomography, has been identified as a potentially independent prognostic measure.19 ECOG
denotes Eastern Cooperative Oncology Group, GI gastrointestinal, NCCN-IPI National Comprehensive Cancer Network
IPI, R-IPI Revised IPI, and ULN upper limit of the normal range.
cycles of CHOP was established as the preferred overall survival.30 A dose-intensive regimen of
chemotherapeutic regimen. The addition of the rituximab combined with doxorubicin, cyclophos-
anti-CD20 monoclonal antibody rituximab sub- phamide, vindesine, bleomycin, and prednisone
sequently led to a significant improvement in (R-ACVBP) has been the only regimen providing

a survival advantage over R-CHOP in patients the proteasome inhibitor bortezomib showed no
with an age-adjusted IPI score of 1 (on a scale of benefit,37,38 the addition of the Bruton tyrosine
0 to 3, with higher scores indicating greater kinase inhibitor ibrutinib yielded mixed find-
risk).31 However, clinically significant toxic effects ings. A phase 3 trial comparing ibrutinib and
curtailed its use. Attempts to improve outcomes R-CHOP with R-CHOP alone in patients with non-
by intensifying chemotherapy, with or without GCB DLBCL (selected on the basis of immuno-
stem-cell transplantation, or by decreasing the histochemical testing) showed no significant
interval between R-CHOP cycles to 14 days have difference in outcomes between groups in the
not yielded a survival benefit (Table S4). In a intention-to-treat population, but a secondary
randomized trial involving unselected patients analysis suggested a survival benefit with the
with DLBCL, DA-EPOCH-R was associated with addition of ibrutinib for patients younger than
greater toxic effects and did not improve pro- 60 years of age; toxic effects in older patients
gression-free or overall survival in the overall impeded treatment with R-CHOP.39 The use of
cohort, as compared with R-CHOP.32 It is note- ibrutinib with R-CHOP requires further validation.
worthy that high-risk patients were underrepre- A randomized phase 2 trial evaluating the
sented in this trial, and on post hoc analysis, addition of lenalidomide to R-CHOP (R2-CHOP)
patients with an IPI score of 3 to 5 (on a scale of in unselected patients suggested an improvement
0 to 5, with higher scores indicating greater in progression-free and overall survival,40 but the
risk) had improved progression-free survival with definitive phase 3 trial involving patients with
DA-EPOCH-R, although there was no significant the ABC subtype of DLBCL (selected by means of
difference in overall survival between the two gene expression profiling) showed no added
regimens. Although treatment with DA-EPOCH-R value of lenalidomide.41 Several phase 3 trials
has shown encouraging outcomes in patients with failed to show a survival benefit of maintenance
double- or triple-hit high-grade B-cell lymphoma therapy after R-CHOP, with agents such as ritux-
and those with primary mediastinal B-cell lym- imab,42 enzastaurin,43 everolimus,44 or lenalido-
phoma, its use for patients with high-risk DLBCL mide,45 adding to prior negative studies of main-
remains investigational. A study of the anti-CD20 tenance chemotherapy.
monoclonal antibody obinutuzumab did not show Outside of clinical trials, R-CHOP has pre-
that it provided an additional benefit, as com- vailed as the standard of care for DLBCL, regard-
pared with rituximab.33 This study showed no less of the immunohistochemical profile or mo-
added value of eight cycles of CHOP as compared lecular subtype. However, the negative findings
with six cycles, thereby confirming six cycles of in recent trials should be interpreted in the con-
R-CHOP every 3 weeks as the standard of care.34,35 text of numerous limitations. Delays incurred by
The value of consolidative radiation therapy biomarker testing probably led to selection bias,
after immunochemotherapy has not been proved. with underrepresentation of higher-risk patients
Patients with a complete metabolic response on that were in need of immediate treatment,46 limit-
post-treatment PET-CT have a favorable outcome ing the statistical power to detect a benefit. Most
without the use of radiation therapy.33,36 Whereas important, biologic heterogeneity due to the
biopsy and further systemic therapy may be war- molecular complexity of DLBCL, despite enrich-
ranted in patients with a positive finding on ment for cell of origin, may have limited the
PET-CT, consolidative radiation therapy may be ability to detect a benefit within more discrete
considered in some patients without evidence of subgroups of patients. Future trials will need to
disease progression who have residual positive have adaptive designs in order to maximize the
sites on PET-CT that are amenable to radiation likelihood of success.
therapy.36
Evaluating new therapies for patients with Limited-Stage Disease
disease that is resistant to chemotherapy is a Approximately 30% of patients present with
priority. However, in view of the biologic hetero- limited-stage disease, commonly defined as stage
geneity of DLBCL, targeted agents may benefit I or II disease that is nonbulky (largest mass,
only select subgroups of patients, requiring bio- <7.5 to 10 cm) and anatomically localized, with-
marker assessment. Several large, randomized out systemic symptoms. These patients tend to
trials have evaluated the addition of new agents have low-risk clinical features and a favorable
to R-CHOP (Table S4). Whereas the addition of outcome, although a pattern of delayed relapse

has been recognized.47 Before the introduction of geriatric assessment or simple functional testing
rituximab, the standard treatment consisted of may be useful to identify patients for whom a
three cycles of CHOP and involved-field radiation modified approach is warranted. For such pa-
therapy, since it improved overall survival, as tients, dose-reduced versions of R-CHOP, such as
compared with eight cycles of CHOP.29 However, R-mini-CHOP, may be used with curative intent.52
this survival advantage was lost with longer A short prephase of glucocorticoids, with or
follow-up as a result of late relapses and second without vincristine, may improve the side-effect
cancers probably related to the radiation therapy, profile associated with treatment.53 In patients
suggesting that chemotherapy alone may be ap- with a contraindication to anthracycline, substi-
propriate.47 With a 5-year overall survival rate in tution with gemcitabine or etoposide may pro-
the range of 85 to 95% for patients with limited- vide satisfactory results, whereas trials of alter-
stage disease, recent efforts have focused on native anthracyclines or cardioprotective agents
limiting the number of chemotherapy cycles or have not provided convincing evidence of safety
omitting radiation therapy (Table S4). or efficacy.54,55
A randomized trial has confirmed that treat-
ment with four cycles of R-CHOP alone is suffi- Central Nervous System Prophylaxis
cient for patients 60 years of age or younger Recurrence of disease in the central nervous
with nonbulky stage I or II disease (largest mass, system (CNS), occurring in 3 to 5% of patients,
<7.5 cm) who have no age-adjusted IPI risk fac- is a devastating event, with median overall sur-
tors (Eastern Cooperative Oncology Group [ECOG] vival of less than 6 months.56-58 CNS recurrence
performance status score of 0 or 1, on a scale of is often manifested early after the completion of
0 to 5, with higher numbers indicating greater therapy, suggesting the presence of occult CNS
disability; and a normal lactate dehydrogenase involvement at diagnosis. The CNS-IPI risk model,
level).48 PET-CT tailored therapy has been ex- which includes the five IPI risk factors and the
plored in patients with broader inclusion crite- presence of renal or adrenal involvement, strati-
ria. In a phase 3 trial, patients who had a com- fies patients into risk categories, with 12% of
plete metabolic response as indicated by PET-CT patients having a high risk of CNS recurrence
assessment after four cycles of R-CHOP did not (10 to 12% risk).58 Other factors may augment
benefit from the addition of radiation therapy, this risk, including ABC subtype, double expres-
although patients with at least one IPI risk factor sion of MYC and BCL2, and testicular involvement
received six cycles of R-CHOP.49 Results from a at presentation.56-58 The role of CNS prophylaxis
phase 2 trial and a population-based analysis that incorporates systemic CNS-penetrating agents
have shown that treatment with four cycles of remains unproved and controversial.59,60 Prophy-
R-CHOP alone appears to be sufficient in patients lactic intrathecal chemotherapy is no longer rec-
who have a complete metabolic response as indi- ommended for patients with DLBCL.61
cated by PET-CT after three cycles of R-CHOP.50,51
Optimal management has not been fully defined M a nagemen t of R el a psed
for patients with a positive interim PET-CT assess- or R efr ac t or y Dise a se
ment or for those with a high stage-modified IPI
score or disease that has high-risk biologic fea- Approximately 10 to 15% of patients treated
tures (few of whom have been included in recent with R-CHOP have primary refractory disease
trials). (i.e., an incomplete response or a relapse within
6 months after treatment), and an additional 20 to
Patients for Whom Standard Therapy 25% will have a relapse after an initial response,
Is Not Feasible typically within the first 2 years.24 Outcomes
Approximately 20 to 25% of patients are not remain poor for patients in whom frontline
candidates for treatment with standard frontline treatment fails, particularly patients with refrac-
therapy such as R-CHOP because of poor fitness tory disease, for whom the median overall sur-
related to age, coexisting medical conditions, or vival is approximately 6 months.62 Patients with
cardiac dysfunction. Patients with a good base- late relapses (>2 years after treatment) have
line performance status whose functional status somewhat better outcomes, although relapse with
has been compromised by lymphoma may be indolent lymphoma can occur, underscoring the
considered for standard therapy. Comprehensive need for repeat biopsy.63

Transplantation-Eligible Patients gene maraleucel have been associated with over-

Treatment with high-dose chemotherapy and all and complete response rates in the range of
autologous stem-cell transplantation (ASCT) of- 52 to 82% and 40 to 54%, respectively, among
fers the best chance of cure in patients with patients with relapsed or refractory aggressive
chemotherapy-sensitive relapsed or refractory dis- B-cell lymphoma67-69 (Table 4). Updated follow-up
ease, but because of advanced age and coexisting of the pivotal study of axicabtagene ciloleucel
medical conditions, only half of such patients are showed that 37% of patients had ongoing com-
considered to be candidates for transplantation. plete responses at a median follow-up of 27
The commonly used platinum-based salvage regi- months.88 However, the reports of outcomes are
mens (rituximab with dexamethasone, high-dose likely to be optimistic because of patient selec-
cytarabine, and cisplatin [R-DHAP], rituximab tion. These CAR T-cell products have received
with ifosfamide, carboplatin, and etoposide regulatory approval for patients with relapsed or
[R‑ICE], and rituximab with gemcitabine, dexa- refractory aggressive B-cell lymphoma who have
methasone, and cisplatin [R-GDP]) have shown received at least two lines of systemic therapy,
similar efficacy in randomized trials, and the and randomized studies are evaluating the possi-
choice of regimen may depend on institutional bility of replacing ASCT with CAR T-cell therapy.
preference or the side-effect profile.64,65 Approxi- Treatment with CAR T-cell therapy is associ-
mately 50% of patients have a response to initial ated with distinct toxic effects and may not be
salvage therapy and then undergo ASCT, with an appropriate for all patients. The reported rate of
overall cure rate in the range of 25 to 35%.64,65 grade 3 to 4 cytokine release syndrome and neu-
Allogeneic transplantation may also be curative; rologic toxic effects has ranged from 2 to 22%
however, the advantage of graft-versus-tumor and 10 to 28%, respectively.67-69 Currently, use of
effect is offset by higher treatment-related mor- CAR T-cell therapy remains impeded by potential
tality. In light of the availability of new agents, toxic effects, inadequate bridging therapy for pa-
the role of allogeneic transplantation in patients tients with rapidly evolving disease, the require-
in whom ASCT has failed is unclear. ment for specialized care, and economic consid-
erations, with cost-effectiveness analyses placing
Transplantation-Ineligible Patients it at a level that may not be feasible in some
Patients who are not candidates for ASCT be- clinical settings.89 Ongoing development, includ-
cause of poor fitness due to age or coexisting ing evaluation of constructs directed at alterna-
medical conditions, those who do not have a tive or multiple targets, as well as allogeneic
response to salvage therapy, and those who have “off-the-shelf” products, is likely to expand op-
a relapse after ASCT are classified as transplan- tions in the future.
tation ineligible. Ultimately, the majority of pa-
tients with relapsed or refractory DLBCL fall into Novel Therapies
this category, and sequential single-agent chemo- Despite the advance of CAR T-cell therapy, novel
therapy or a multiagent regimen with an accept- therapies are needed for relapsed or refractory
able side-effect profile, such as rituximab, gem- DLBCL. Numerous agents are undergoing evalu-
citabine, and oxaliplatin (R-GemOx), has frequently ation, and selected drugs of interest are listed in
been used with palliative intent.66 However, the Table 4.
availability of novel agents, including chimeric Antibody–drug conjugates allow selective de-
antigen receptor (CAR) T-cell therapy, has pro- livery of cytotoxic agents to tumor cells with the
vided alternatives with the potential for durable use of targeted antibodies. Polatuzumab vedotin
disease control and an apparent survival advan- is an antibody–drug conjugate targeting CD79b,
tage, as compared with conventional therapy. a component of the B-cell receptor complex.74 The
combination of polatuzumab vedotin and benda-
CAR T-Cell Therapy mustine–rituximab has received regulatory ap-
CAR T-cell therapy, a gene-modified cellular treat- proval on the basis of a randomized phase 2 trial
ment, represents a major paradigm shift in the involving transplantation-ineligible patients that
management of relapsed or refractory DLBCL. showed a significant improvement in the rates of
The first approved products involve autologous complete metabolic response, progression-free
T cells targeting CD19. In pivotal trials, axicabta- survival, and overall survival, as compared with
gene ciloleucel, tisagenlecleucel, and lisocabta- bendamustine–rituximab alone.75 A phase 3 trial

Table 4. Select Agents in Development for the Treatment of DLBCL.*
Clinical Trial Overall Response Complete

Class and Agent Target Phase Rate Response Rate Study
percent
CAR T-cell therapy†
Axicabtagene ciloleucel CD19 1 82 54 Neelapu et al.68
Tisagenlecleucel CD19 2 52 40 Schuster et al.69
Lisocabtagene maraleucel CD19 1 73 53 Abramson et al.67
Monoclonal antibodies
Tafasitamab CD19 2a 26 6 Jurczak et al.70
Tafasitamab plus lenalidomide CD19 2 60 43 Salles et al.71
Antibody–drug conjugates
Loncastuximab tesirine CD19 1 42 23 Hamadani et al.72
Brentuximab vedotin CD30 2 44 17 Jacobsen et al.73
Polatuzumab vedotin CD79b 1 52‡ 13‡ Palanca-Wessels et al.74
Polatuzumab vedotin plus BR CD79b 2, randomized 45 vs. 17.5 40 vs. 17.5 Sehn et al.75
vs. BR
Bispecific antibodies
Blinatumomab CD19–CD3 2 43 19 Viardot et al76
Mosunetuzumab CD20–CD3 1/1b 35§ 19§ Schuster et al.77
Glofitamab CD20–CD3 1/1b 41 29 Hutchings et al.78
Odronextamab CD20–CD3 1 42¶ 35¶ Bannerji et al.79
Epcoritamab CD20–CD3 1/2 76‖ 32‖ Hutchings et al.80
NF-κB and BCR modifiers
Ibrutinib BTK 1/2 37 ABC, 5 GCB 16 ABC, 0 GCB Wilson et al.81
Lenalidomide vs. investigator’s Multiple, NF-κB 2, randomized 28 vs. 12 10 vs. 2 Czuczman et al.82
choice
Agents with other targets
Venetoclax BCL2 1 18 12 Davids et al.83
Selinexor XPO1 2b 28 12 Kalakonda et al.84
Checkpoint inhibitors
Nivolumab PD-1 2 ≤10 ≤3 Ansell et al.85
Magrolimab CD47 1b 40 33 Advani et al.86
Epigenetic modifiers
Tazemetostat EZH2 2 17 EZH2 mt, 3 EZH2 mt, Ribrag et al.87
17 EZH2 wt 9 EZH2 wt
* Results from early clinical trials involving patients with relapsed or refractory DLBCL are shown. BCL2 denotes B-cell lymphoma 2, BCR
B-cell receptor, BR bendamustine plus rituximab, BTK Bruton’s tyrosine kinase, EZH2 enhancer of zeste homologue 2, mt mutant, NF-κB
nuclear factor κB, PD-1 programmed cell death protein 1, wt wild type, and XPO1 exportin 1.
† The three CD19-specific chimeric antigen receptor (CAR) T-cell products differ in the nature of the CAR construct and in the manufacturing
processes (axicabtagene ciloleucel comprises bulk T cells retrovirally transduced with a receptor containing the CD28 costimulatory domain;
tisagenlecleucel comprises bulk T cells lentivirally transduced with a receptor containing the 4−1BB costimulatory molecule; and lisocabta-
gene maraleucel comprises a 1:1 mix of CD4+ and CD8+ T cells separately transduced with a lentiviral vector coding for a receptor with the
4−1BB costimulatory domain). The bispecific CD3–CD20 antibodies present several differences in the antigen recognition domains of the
antibodies and the number of binding sites to CD20, as well as in the route of administration (intravenous vs. subcutaneous). For these
bispecific antibodies, early data from dose-escalation studies are presented.
‡ Results pertain to patients receiving a dose of 1.8 mg per square meter of body-surface area or higher.
§ Results pertain to the aggressive non-Hodgkin’s lymphoma cohort.
¶ Results pertain to patients receiving a dose of 80 mg or higher.
‖ Results pertain to patients receiving a dose of 12 mg or higher.

Pathological Review of Biopsy

• H&E staining; IHC profile (e.g., COO, DEL); FISH (MYC, BCL2, BCL6)
• Consider molecular testing for COO and viral testing as required
• Integrate clinical factors to identify unique WHO clinicopathological entities
~5–10% ~80–85% ~10–15%
High-Grade B-Cell Lymphoma Diffuse Large B-Cell Lymphoma, NOS Other Large B-Cell Lymphomas
With or without DH or TH Unique entities may require
rearrangements alternative treatment
Consider intensive therapy,
such as DA-EPOCH-R
Staging Investigation
• Routine labs (CBC, LDH, LFTs, Cr) and viral (HBV, HCV, HIV) testing
• 18FDG PET-CT imaging and dedicated investigations as clinically
indicated
• Bone marrow biopsy (optional)
• If high CNS risk: head MRI and lumbar puncture (flow cytometry)
~30% ~70%
If Standard Therapy Not Feasible or If
Anthracycline Contraindicated: dose reduction
or drug substitution with curative intent
Limited-Stage Advanced-Stage
• 3 Cycles of R-CHOP+XRT • 6 Cycles R-CHOP considered standard of care
• 4 Cycles of R-CHOP (bulk <7.5 cm, age-adjusted IPI=0) • New regimens to be considered in clinical trials
• PET-guided 4–6 cycles R-CHOP with or without XRT • High CNS risk: role of systemic prophylaxis unclear
~5% ~95% ~85% ~15%
Primary Refractory Complete Response Primary Refractory

Persistent disease or progression Determined by PET-CT and clinical assessment Persistent disease or progression
within 6 mo Clinical monitoring every 3 mo for 2 yr, then every 6–12 mo within 6 mo
5–10% 20–25%
Limited-Stage Relapse Advanced-Stage Relapse
Relapsed or Refractory Disease

Repeat biopsy recommended and
staging as outlined above
~50% ASCT Eligible ~50% Not Candidates for ASCT
Platinum-Based Salvage Therapy Second-Line Therapy Available Options for

ASCT-Ineligible Patients
• Immunochemotherapy
~50% Response ~50% Refractory • CAR T-cell therapy
• Polatuzumab vedotin+BR
• Selinexor
ASCT • Tafasitamab–lenalidomide
• Investigational agent
or regimen
~50% Response ~50% Relapse • Allogeneic stem-cell trans-
No ASCT plantation
Third-Line Therapy
• Best supportive care
or More (including XRT)
~25–35% of ASCT-Eligible After ASCT
Patients Are Cured

Figure 2 (facing page). Algorithm for the Management evaluating polatuzumab vedotin as a replacement
of Large B-Cell Lymphomas. for vincristine in R-CHOP in previously untreat-
Diagnostic confirmation is based on careful pathological ed patients has been completed, and the results
review of biopsy material (preferably from an excisional are pending. Additional antibody–drug conjugates
biopsy). Clinical and pathological features should be used are undergoing clinical evaluation.72,73
to categorize patients according to the World Health
Organization (WHO) classification for lymphoid cancers
Selinexor, a selective inhibitor of the nuclear
in order to identify patients with large B-cell lymphomas export protein XPO1, leading to nuclear accumu-
who may require alternative therapies. Routine staging lation of tumor suppressor proteins, has also
investigations should be performed to distinguish pa- received regulatory approval for patients with
tients with limited-stage disease (typically defined as Ann
relapsed or refractory DLBCL who have received
Arbor stage I or II, with nonbulky mass <7.5 to 10 cm,
without systemic symptoms and with disease that can at least two lines of therapy, on the basis of a
be encompassed by a radiation field) from those with phase 2 study showing modest single-agent ac-
advanced-stage disease. Evaluation of patients with a tivity.84 Tafasitamab is a humanized anti-CD19
high risk of CNS involvement should include magnetic monoclonal antibody providing a modest benefit
resonance imaging (MRI) of the brain and cytologic eval-
uation of cerebrospinal fluid, with flow cytometry to rule
as a single agent,70 but results from a phase 2
out occult CNS involvement. Patients with limited-stage study of tafasitamab in combination with lenali
disease may be treated with an abbreviated course of domide showed efficacy, leading to regulatory
immunochemotherapy, with or without radiation therapy. approval for patients with DLBCL who are trans-
Standard therapy for patients with advanced-stage dis-
plantation-ineligible.71 Since this agent has the
ease is six cycles of R-CHOP (rituximab, cyclophospha-
mide, doxorubicin, vincristine, and prednisone) immuno- same target as CD19-directed CAR T-cell ther-
chemotherapy, regardless of the immunohistochemical apy, appropriate sequencing of these options
(IHC) profile (e.g., double-expressor lymphoma [DEL]) needs to be assessed.
or molecular subtype. Outcomes in patients with high- Various other immunotherapeutic approaches
risk DLBCL remain unsatisfactory with R-CHOP, and
clinical trials should strongly be considered. Although
are under investigation. Despite efficacy in pri-
CNS-penetrating systemic therapy, such as high-dose mary mediastinal B-cell lymphoma, programmed
methotrexate with R-CHOP, can be considered for pa- cell death protein 1 (PD-1) inhibitors have failed
tients at high risk for CNS recurrence, the value of this to show a benefit in patients with DLBCL.85
approach remains unproven. Response should be as-
Magrolimab, a macrophage immune checkpoint
sessed with 18F-fluorodeoxyglucose positron-emission
tomography and computed tomography (18F-FDG PET-CT), inhibitor blocking the “don’t eat me” molecule
according to the Lugano classification criteria, with inter- CD47, appears to synergize with rituximab, en-
pretation according to the Deauville five-point scale.5,17,18 hancing macrophage cellular phagocytosis, and
Patients with evidence of relapsed or refractory disease has shown encouraging activity in an early clini-
should undergo repeat biopsy and staging to optimize
further therapy. Patients who are eligible for autologous cal trial.86
stem-cell transplantation (ASCT eligible) should receive By targeting antigens on both tumor cells and
platinum-based salvage therapy, with those who have a T cells, bispecific antibodies induce T-cell activa-
response proceeding to ASCT. Patients who do not have tion, leading to cell-mediated cytotoxicity. Bispe-
a response to salvage therapy or who have a relapse after
ASCT, as well as those who are not candidates for ASCT
cific antibodies have shown potential in relapsed
because of age and coexisting medical conditions, are or refractory DLBCL, with durable remissions
considered to be ASCT ineligible. There are numerous observed. Blinatumomab, a bispecific T-cell en-
treatment alternatives for these patients, and selection gager directed against CD3 and CD19, is active
of therapy should be individualized on the basis of dis- in DLBCL, but the development of this agent is
ease and clinical characteristics of the patient. Based
on regulatory approvals, some options may be indicated hindered by a continuous infusion schedule and
only for third-line therapy and beyond (e.g., CAR T-cell associated neurotoxicity.76 Several full-length bi-
therapy at present) and therefore thoughtful sequencing specific antibodies targeting CD3 and CD20,
of available therapies is instrumental. Clinical trials in- which are in development, have a longer half-life,
corporating new agents should strongly be considered
at all phases of therapy. CBC denotes complete blood
allowing for administration every 3 to 4 weeks,
count, COO cell of origin, Cr creatinine, DA-EPOCH-R including the possibility of subcutaneous deliv-
dose-adjusted etoposide, prednisone, vincristine, cyclo- ery. An ongoing phase 1–1b study of mosunetuzu
phosphamide, and doxorubicin with rituximab, FISH mab has shown promising response rates among
fluorescence in situ hybridization, H&E hematoxylin
patients with relapsed or refractory DLBCL, in-
and eosin, HBV hepatitis B virus, HCV hepatitis C virus,
LDH lactate dehydrogenase, LFTs liver-function tests, cluding patients in whom CAR T-cell therapy
NOS not otherwise specified, and XRT radiation therapy. had failed, with durable responses observed.77
Additional agents targeting CD3 and CD20 that

are in development and have shown preliminary A decision tree for management of large B-cell
efficacy are glofitamab, odronextamab, and ep- lymphomas is provided in Figure 2.
coritamab.78-80 Dr. Sehn reports receiving advisory board fees from AbbVie,
Other agents targeting apoptosis (the BCL2 AstraZeneca, Gilead, Genentech, Janssen, Merck, Takeda, Apo-
biologix, Acerta, Celgene, Kite, Karyopharm, Morphosys, Lund
inhibitor venetoclax), the B-cell receptor pathway beck, TG Therapeutics, Verastem, Sandoz, Incyte, Novartis,
(the Bruton tyrosine kinase inhibitor ibrutinib, Genmab, and Debiopharm, grant support and advisory board
fees from Teva, and advisory board fees and lecture fees from
as well as lenalidomide), and epigenetic regula- Roche and Seattle Genetics; and Dr. Salles, receiving honoraria
tors (the EZH2 inhibitor tazemetostat) have from Amgen, BMS, Acerta, AbbVie, Janssen, Merck, Gilead/Kite,
shown limited single-agent activity and are be- Morphosys, Servier, Celgene, Roche/Genentech, and Takeda,
honoraria and consulting fees from Novartis and Epizyme,
ing explored in various combinations.81-83,87 As ad- advisory board fees from Pfizer, Autolus, Allogene, Beigene,
ditional agents become available, the sequencing Debiopharm, Genmab, and Velosbio, and consulting fees from
of rational synergistic combinations, guided by Miltenyi and IPSEN. No other potential conflict of interest rel-
evant to this article was reported.
patient characteristics and underlying biologic Disclosure forms provided by the authors are available with
features that are based on validated molecular the full text of this article at NEJM.org.
We thank Drs. Joseph M. Connors, David W. Scott, and Ahmet
assays and predictive biomarkers, would be the Dogan for their helpful comments on an earlier version of the
desired goal. manuscript.
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The n e w e ng l a n d j o u r na l of m e dic i n e

Dan L. Longo, M.D., Editor

Diffuse Large B-Cell Lymphoma

Pathol o gic a l Fe at ur e s a nd Mol ecul a r Cl a ssific at ion

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A Outcomes of Patients with DLBCL B Risk Factors for Development of DLBCL

0.75 Viruses: EBV, HIV, HHV8,

C Biologic Features of DLBCL

TET2, SGK1, MYD88, CD79B,

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WHO Denomination Diagnostic Features Clinical Features and Outcome

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The New England Journal of Medicine

detectable in tumor skin; dissemination is rare; commonly occurs as iatrogenic or

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

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The New England Journal of Medicine

Copyright © 2021 Massachusetts Medical Society. All rights reserved.

Table 2. Biologic Factors Associated with Outcomes in Patients with DLBCL.*

Biomarker Methodology Prognostic Significance Other Implications

(Table 3). However, these clinical indexes cannot Pr im a r y M a nagemen t

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Table 3. Clinical Indexes for Predicting Outcomes in Patients with DLBCL.*

Proportion of Estimated 5-yr Estimated 5-yr

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Transplantation-Eligible Patients gene maraleucel have been associated with over-

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Table 4. Select Agents in Development for the Treatment of DLBCL.*

Clinical Trial Overall Response Complete

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Pathological Review of Biopsy

~5–10% ~80–85% ~10–15%

~5% ~95% ~85% ~15%

Primary Refractory Complete Response Primary Refractory

Relapsed or Refractory Disease

~50% ASCT Eligible ~50% Not Candidates for ASCT

Platinum-Based Salvage Therapy Second-Line Therapy Available Options for

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