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

C. Corey Hardin, M.D., Ph.D., Editor

Mantle-Cell Lymphoma
James O. Armitage, M.D., and Dan L. Longo, M.D.​​

F
or many years, pathologists were aware of a lymphoma of small From the Department of Internal Medi-
lymphocytes that did not fit into existing classifications. Early names pro- cine, Division of Oncology and Hematol-
ogy, University of Nebraska, Omaha
posed for this lymphoma with a diffuse growth pattern were intermediate ( J.O.A.). Dr. Armitage can be contacted
lymphocytic lymphoma and centrocytic lymphoma.1,2 Mantle-zone lymphoma was at ­joarmita@​­unmc​.­edu or at the Univer-
the name for the same lymphoma in expanded mantle zones3; in addition to a sity of Nebraska Medical Center, 986840
Nebraska Medical Center, Omaha, NE
typical morphologic appearance, this lymphoma had a characteristic immunophe- 68198-6840.
notype (i.e., CD5+, CD10−, Bcl-2+, Bcl-6−, CD20+), with the t(11;14)(q13;q32) chro-
N Engl J Med 2022;386:2495-506.
mosomal translocation, and expression of cyclin D1. In 1990, t(11;14) was shown DOI: 10.1056/NEJMra2202672
to be associated with intermediate lymphocytic lymphoma and centrocytic lym- Copyright © 2022 Massachusetts Medical Society.
phoma.4,5 In 1991, Raffeld and Jaffe first proposed the term mantle-cell lympho-
ma.6 Previously, mantle-cell lymphomas were given a variety of names based on CME
at NEJM.org
the then-extant criteria for histologic classification; often they were confused with
small lymphocytic lymphoma or were named diffuse small-cleaved-cell lymphoma.
Other names they were given include lymphoblastic lymphoma, diffuse large-B-
cell lymphoma, or follicular lymphoma. Initial studies of survival among patients
treated for mantle-cell lymphoma showed a poor outcome after standard chemo-
therapy with cyclophosphamide, vincristine, and prednisone (CVP) and cyclophos-
phamide, doxorubicin, vincristine, and prednisone (CHOP), with a median survival
of approximately 3 years, and long-term disease-free survival was rare.7,8 However,
with the development of rituximab and regimens specific for this disorder, sur-
vival has improved.

Epidemiol o gic Fe at ur e s a nd R isk Fac t or s

Mantle-cell lymphoma accounts for approximately 5 to 7% of all lymphomas, and
in North America and Europe, the frequency is similar to that of noncutane-
ous, peripheral T-cell lymphomas. The median age of patients is between 60 and
70 years, which is similar to the median age of patients with diffuse large-B-cell
lymphoma. However, mantle-cell lymphoma has a striking sex imbalance, with
approximately 70% of all cases in men.7
Less is known about risk factors for the development of mantle-cell lymphoma
than about risk factors for the other types of non-Hodgkin’s lymphoma. Factors
that are important for the development of other lymphomas, such as familial risk,
immunosuppression, other immune disorders, chemical and occupational expo-
sures, and infectious agents, have not been convincingly identified as predisposing
factors for mantle-cell lymphoma, with the possible exception of family history.9-12

Pathol o gic a l Fe at ur e s
The diagnosis of mantle-cell lymphoma is reproducible among expert hemato-
pathologists. In a study that used only morphologic features and immunopheno-
typing for diagnosis, the reproducibility was 87%, which was the same as the diag-

n engl j med 386;26  nejm.org  June 30, 2022 2495

The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

C D

E F

Figure 1. Photomicrographs of Cytologic Features and Patterns of Growth of Mantle-Cell Lymphoma.

Panel A (hematoxylin and eosin) shows a diffuse pattern at low power. The tissue is effaced, without any discernible
nodular architecture. Panel B (hematoxylin and eosin) shows a diffuse pattern at high power. Classic cytologic features
include monotonous, intermediate-size lymphocytes with irregular nuclei and intermediate-density chromatin. Pan-
el C shows the mantle-zone pattern; immunohistochemical staining is positive for cyclin D1. In this subset of nodu-
lar mantle-cell lymphoma, cyclin D1 nuclear expression shows the expansion of the lymphoma cells in the mantle zone
around benign germinal centers. Panel D (hematoxylin and eosin) shows pleomorphic cytologic features. The nuclei
vary in size and shape, with some large, cleaved forms. In the blastoid subtype, shown in Panel E (hematoxylin and
eosin), the nuclei are round, with fine chromatin, and some contain visible nucleoli. Panel F (hematoxylin and eosin)
shows a nodular pattern. A large nodule is present at the center of the image, without any visible germinal center.

nostic reproducibility for diffuse large-B-cell
lymphoma, extranodal marginal-zone lympho-
ma, and small lymphocytic lymphoma.13 The
neoplastic cells are small-to-medium-size lym-
phocytes with scant cytoplasm, clumped chro-
matin, inconspicuous nucleoli, and prominent
nuclear clefts. Growth patterns of mantle-cell
lymphoma include diffuse, nodular (though the
nodularity is more vague and less discrete than
that found in follicular lymphomas), mantle-
zone lymphoma with expansion of mantle zones,
and in situ mantle-cell neoplasia (typical cells
with the characteristic t(11;14) translocation,
scattered in the mantle zone of otherwise nor-
mal-appearing lymph nodes) (Fig. 1). Cytologic
subtypes include classic mantle-cell lymphoma,
the blastoid subtype (with large cells, dispersed
chromatin, and a high mitotic rate), and the
pleomorphic subtype (with cells that vary in
size, although many are large, with pale cyto-
plasm, oval irregular nuclei, and prominent nu-
cleoli) (Fig. 1). The blastoid and pleomorphic
variants usually have a more aggressive natural
history.14

2496 n engl j med 386;26 nejm.org June 30, 2022

The New England Journal of Medicine

Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Mantle-Cell Lymphoma

Pathoph ysiol o gic a l a nd Gene t ic unusual chromosomal translocations. These tu-

Fe at ur e s mors generally also express SOX 11. The natural
history of cyclin D1–negative mantle-cell lym-
The malignant cell is most often a pregerminal- phoma does not appear to differ from that of
center B cell with clonally rearranged immuno- cyclin D1–positive tumors.
globulin genes that are largely unmutated. A
subset of tumors have mutated heavy-chain Pr e sen tat ion a nd Cl inic a l
genes, suggesting a postgerminal-center origin. S y ndrome s
The heavy-chain gene usage is said to be skewed
rather than random, raising the question of Most patients with mantle-cell lymphoma pres-
whether initial events in the lymphomagenesis ent with nonlocalized, palpable lymphadenopa-
are antigen-driven. Lambda light chains are more thy, with or without systemic symptoms. Local-
commonly rearranged than kappa light chains. ized nodal or extranodal disease is present in
The tumor cells express IgM and IgD on the approximately 10% of patients, and more than
surface, as well as CD5, characteristics they 80% have stage III or IV disease at diagnosis,
share with chronic lymphocytic leukemia. The frequently with bone marrow involvement.7,15
cells are negative for CD10 and Bcl-6 and usu- About 30% of patients have fevers, sweats, or
ally do not express CD23. In nearly all cases, the weight loss, but more patients report fatigue.
tumor cells overexpress cyclin D1 (a cell-cycle However, most patients have an Eastern Coop-
regulatory protein that drives cells from the G1 erative Oncology Group performance-status score
phase into the S phase), SOX11 (a transcription of 0 or 1 (on a scale of 0 to 5, with higher num-
factor not normally expressed in B cells that bers reflecting greater disability). Bulky lymph-
influences the expression of several genes in- adenopathy (i.e., masses ≥10 cm in the greatest
volved in cell survival), and Bcl-2 (an antiapopto- diameter) is seen in approximately 25% of pa-
sis protein). These changes tend to promote cell tients, and less than half of patients have an
survival and proliferation, though the precise elevated lactate dehydrogenase level. Central
mechanism of cell transformation and acquisi- nervous system involvement, which is rare at the
tion of proliferative autonomy is not known. The initial presentation, is associated with a very
fraction of tumor cells expressing Ki-67 (a short survival.16
marker for actively proliferating cells that has Mantle-cell lymphoma has a number of other
a number of functions in the cell) is variable in characteristic presentations. One of these in-
different patients and is correlated with aggres- volves circulating lymphoma cells that can be
sive biologic features (see below). confused with chronic lymphocytic leukemia.
The t(11;14)(q13;q32) translocation, which is This possible confusion should be resolved with
common, places cyclin D1 under the transcrip- flow cytometric studies. Both chronic lympho-
tional control of the immunoglobulin heavy- cytic leukemia and mantle-cell lymphoma are
chain gene, which is always active in mature CD5+, but mantle-cell lymphoma is CD20-bright,
peripheral B cells. A large number of other ge- usually CD23−, and CD200−. Chronic lympho-
netic alterations are reported in a variable frac- cytic leukemia is CD20-dim, CD23+, and
tion of cases. Among the most important are CD200+. On immunohistochemical staining,
losses in genes that inhibit proliferation, such as mantle-cell lymphoma is negative for lymphoid
TP53, CDKN2A (encoding p16, which normally enhancer-binding factor 1 (LEF1), whereas
inhibits cyclin D1), and ATM. Gains are also seen chronic lymphoid leukemia is positive for LEF1,
in genes that promote proliferation, such as MYC and fluorescence in situ hybridization shows
and NOTCH. The constellation of aberrations t(11;14) in mantle-cell lymphoma rather than
promoting proliferation influences the natural del(11q), trisomy 12, del(13q), and del(17p),
history of the disease and the response to treat- which are characteristic in chronic lymphocytic
ment (see below). leukemia.
In rare cases of mantle-cell lymphoma, cyclin Patients with an unusually indolent form of
D1 is not expressed. Often these tumors express mantle-cell lymphoma typically present with
cyclin D2, D3, or E instead, as a consequence of splenomegaly, bone marrow involvement, and

n engl j med 386;26  nejm.org  June 30, 2022 2497

The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Prognostic Indexes Used for Mantle-Cell Another unusual presentation of mantle-cell
Lymphoma.* lymphoma is lymphomatous polyposis of the
gastrointestinal tract.19 The polyps can involve
IPI
any part of the gastrointestinal tract, from stom-
Adverse factors ach to colon, but are most frequent in the distal
Age ≥60 yr ileum and colon. Patients can present with a
ECOG PS ≥2 variety of gastrointestinal symptoms, or the
LDH >ULN polyps may be detected incidentally on endos-
Extranodal sites, ≥2 copy. Extensive polyps are found on colonoscopy
Ann Arbor stage III or IV or upper gastrointestinal endoscopy, with the
diagnosis based on examination of an excised
Score: total no. of adverse factors (i.e., 0–5)
polyp. Even in the absence of lymphomatous
MIPI
polyposis, mantle-cell lymphoma frequently in-
Factors volves the gastrointestinal tract, and samples
Age from blind biopsies are sometimes positive.19
ECOG PS
LDH
S taging a nd Pro gnos t ic Inde x e s
WBC
Score: 0.03535 × age [yr] + 0.6978 [if ECOG PS ≥2] + 1.367  Mantle-cell lymphoma is staged with the use
× log10 (LDH level/ULN) + 0.9393 × log10(WBC) of either the Ann Arbor classification20 or the
Simplified MIPI Lugano classification.21 When routine positron-
Factors
emission tomographic (PET) scans are incorpo-
rated, at least 80% of patients have stage III or
Age
IV disease at diagnosis. Routine bone marrow
ECOG PS
biopsies and blind biopsies of the gastrointesti-
LDH nal tract can increase the proportion of patients
WBC with stage IV disease. At the end of planned
Score (points for age, ECOG PS, LDH/ULN, WBC × 106/μl) therapy, restaging should include the positive
0: <50 yr, 0–1, <0.67, <6.7 tests performed at initial staging and a bone
1: 50–59 yr, 0–1, 0.67–0.99, 6.7–9.9 marrow biopsy, if it was not performed initially.
2: 60–69 yr, 2–4, 1.0–1.49, 10.0–14.9
The International Prognostic Index (IPI) is
predictive of the outcome of mantle-cell lym-
3: ≥70 yr, 2–4, ≥1.5, ≥15.0
phoma.22 The Mantle Cell Lymphoma Interna-
* ECOG PS denotes Eastern Cooperative Oncology Group tional Prognostic Index (MIPI) and a simplified
performance status (scores range from 0 to 5, with higher MIPI have been developed specifically for man-
scores indicating greater disability), IPI International Prog­
nostic Index, LDH lactate dehydrogenase, MIPI Mantle Cell
tle-cell lymphoma.23 They predict the outcome
Lymphoma International Prognostic Index, ULN upper and classify the prognosis as better, intermedi-
limit of the normal range, and WBC white-cell count. ate, or worse (Table 1). These indexes are some-
times used in making treatment decisions and
circulating lymphoma cells but without lymph- can also be used to stratify patients in clinical
adenopathy and systemic symptoms (so-called trials. The existing prognostic systems are likely
non-nodal mantle-cell lymphoma). These man- to evolve as therapy for mantle-cell lymphoma
tle-cell lymphomas are rare, typically have an improves.
immunoglobulin heavy-chain variable mutation, Other markers for very high risk mantle-cell
and do not express SOX 11.14,17,18 They are usu- lymphoma include blastoid and pleomorphic
ally characterized by an indolent clinical course cytologic patterns, a Ki-67 index greater than
and frequently do not require immediate ther- 30%,1 and TP53 mutation or deletion.24 These
apy. However, they can progress to symptomatic features are all associated with a poor treatment
disease requiring therapy or transform into an outcome and are often considered an indication
aggressive lymphoma with the acquisition of for intensive therapy. The Ki-67 index has been
TP53 mutations or deletions. combined with the MIPI for a biologic MIPI.25

2498 n engl j med 386;26  nejm.org  June 30, 2022

The New England Journal of Medicine

Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Mantle-Cell Lymphoma

Mantle-cell lymphoma diagnosis

Asymptomatic Symptomatic
Low-volume disease High-volume disease
No high-risk factors High-risk factors
Patient prefers to avoid treatment Patient wants treatment

Younger and healthier patient with
Watch and wait
no serious coexisting conditions
Candidate for autologous trans-
plantation
Older and less healthy patient with
serious coexisting conditions
Not a candidate for autologous trans-
plantation

Treatment goal is complete remission Treatment goal is complete remission

with R-CHOP, bendamustine and with R-CHOP, bendamustine and
rituximab, R-hyper-CVAD, CHP-R rituximab, R-hyper-CVAD, CHP-R
plus bortezomib, or R-CHOP and plus bortezomib, lenalidomide and
high-dose cytarabine rituximab, or ibrutinib and rituximab

Autologous transplantation with

Consider maintenance rituximab
or without maintenance rituximab

Figure 2. Algorithm for Primary Therapy in Patients with Mantle-Cell Lymphoma.

R-CHOP denotes rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; CHP-R cyclophosphamide,
doxorubicin, prednisone, and rituximab; and R-hyper-CVAD rituximab plus hyperfractionated cyclophosphamide,
vincristine, doxorubicin, and dexamethasone.

Quantitative measurement of circulating tumor
DNA and its rate of clearance, as well as studies
of measurable residual disease after treatment,
may allow identification of patients with a par-
ticularly good or poor prognosis.
Pr im a r y Ther a py
A subgroup of patients with mantle-cell lym-
phoma do not require immediate therapy and
can be safely observed (Fig. 2). As noted above,
patients who present with splenomegaly, bone
marrow involvement, and circulating lymphoma
cells but do not have lymphadenopathy are usu-
ally asymptomatic and often do not require im-
mediate therapy.26 In addition, patients with a
nodal presentation but with low-volume disease
and no symptoms can be safely observed. Sev-
eral reports have described patients with man-
tle-cell lymphoma who were observed and did
not receive initial therapy (i.e., “watch and
wait”).17,27-29 As compared with patients who re-
ceived initial therapy, these patients were young-
er and less likely to have an advanced stage of
disease, systemic symptoms, an elevated lactate
dehydrogenase level, nonclassic morphologic
features, an elevated Ki-67 index, or a high IPI
score. Patients who were initially observed had
a better overall survival and were likely to have a
response to therapy when it was administered.
Patients with mantle-cell lymphoma are fre-
quently divided into two groups for initial ther-
apy. One group includes patients who are suffi-
ciently young and healthy to be candidates for
consolidative autologous bone marrow trans-
plantation. The other group of patients are con-
sidered to be poor candidates for high-dose
chemotherapy and autologous transplantation

n engl j med 386;26  nejm.org  June 30, 2022 2499

The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 The n e w e ng l a n d j o u r na l
and are instead treated with standard chemo-
therapy regimens, with or without maintenance
rituximab therapy.
The type and intensity of chemotherapy regi-
mens that are used to induce remission before
autologous bone marrow transplantation is per-
formed have varied widely. A retrospective re-
view from the National Comprehensive Cancer
Network database showed that R-CHOP (CHOP
plus rituximab) alone yielded a lower progres-
sion-free survival than chemotherapy followed
by autologous transplantation.30 However, the out-
come did not differ between R-CHOP followed
by autologous transplantation and more inten-
sive initial regimens, such as rituximab plus
hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone (R-hyper-CVAD),
followed by transplantation. The Southwest
Oncology Group reported that treatment with
rituximab and bendamustine, as compared with
R-hyper-CVAD, caused equally deep initial re-
mission, and more patients receiving rituximab
and bendamustine were able to have cells col-
lected for transplantation.31 The 2-year progres-
sion-free survival in the two groups undergoing
transplantation was equivalent and exceeded 80%.
Young patients who were treated with R-hyper-
CVAD, alternating with high-dose methotrexate
and cytarabine, but who did not undergo trans-
plantation had a 5-year progression-free sur-
vival rate of 57%, with an apparent plateau of
30% at 15 years.32
The Nordic MCL2 trial used alternating
courses of dose-intense CHOP (2-week cycles
rather than 3-week cycles) and high-dose cytara-
bine to prepare patients for autologous trans-
plantation.33 The event-free survival rate at 5 years
was more than 60%, and no relapses were re-
ported after 5 years. However, patients with high
MIPI scores and high Ki-67 expression (indicat-
ing high risk) had a 10-year overall survival rate
of 23%, as compared with 70% for patients with
low or intermediate scores. A report from the
European Mantle Cell Lymphoma Network con-
firmed the better outcome after chemotherapy
followed by autologous bone marrow transplan-
tation when the initial chemotherapy regimen
contained cytarabine, as compared with the
R-CHOP regimen.34,35 The clinical significance of
achieving measurable residual disease is being
studied.36
2500 n engl j med 386;26  nejm.org  June 30, 2022
The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
of m e dic i n e
A good initial chemotherapy regimen for pa-
tients with mantle-cell lymphoma who are not
candidates for high-dose chemotherapy and au-
tologous bone marrow transplantation has been
a focus of clinical trials. R-CHOP was reported
to be superior to a combination of rituximab,
fludarabine, and cyclophosphamide.37 Longer-
term follow-up (median, 7.6 years) confirmed
the superiority of R-CHOP; subsequent random-
ization to rituximab or interferon as mainte-
nance therapy showed the superiority of ritux-
imab.38 The substitution of bortezomib for
vincristine in R-CHOP was superior to R-CHOP
with respect to the complete response rate (53%
vs. 42%), the duration of a complete response (42
months vs. 18 months), and the median overall
survival (90 months vs. 55 months).39,40 Two
studies have shown higher response rates and
longer progression-free survival with bendamus-
tine and rituximab than with R-CHOP.41,42 How-
ever, the addition of bortezomib to bendamus-
tine and rituximab showed no benefit.43 A large,
randomized trial involving patients who were 65
years of age or older evaluated bendamustine
and rituximab, with or without ibrutinib; pa-
tients who had a response received rituximab as
maintenance therapy.44 The ibrutinib-containing
regimen prolonged progression-free survival
(median, 81 months vs. 53 months; hazard ratio
for disease progression, 0.75) and time to the
next treatment but not overall survival.
Patients who do not receive an autologous
transplant as part of initial therapy for mantle-
cell lymphoma frequently receive consolidative
therapy or maintenance therapy with rituximab
or another CD20-directed agent. Two studies
evaluated the use of yttrium-90–labeled ibritu-
momab tiuxetan after R-CHOP or R-hyper-CVAD.
These phase 2 studies showed that the treatment
could be completed, but it is difficult to compare
outcomes with other approaches.45,46 In the Eu-
ropean Mantle Cell Lymphoma Elderly trial,
rituximab was compared with interferon alfa as
maintenance therapy.38 Rituximab maintenance
led to a longer median progression-free survival
(5.4 years, vs. 1.9 years for interferon) and over-
all survival (9.8 years vs. 7.1 years).
Recent trials have studied the use of “chemo-
therapy-free” regimens as the initial treatment
for mantle-cell lymphoma. This neologism is
aimed at public relations, given that the public’s
 Mantle-Cell Lymphoma
idea of chemotherapy is focused on side effects.
In fact, the term is vague and inaccurate. The
agents in “chemotherapy-free” regimens are
chemicals and biologic agents, but they target
parts of the cell that are distinct from the DNA
and mitotic spindle. All these agents have toxic
effects but are often active at doses below the
dose that would induce toxic effects. In one
study, 38 patients received lenalidomide plus
rituximab for their initial treatment. The re-
sponse rate among patients who could be evalu-
ated was 92%, and the complete response rate
was 64%. The 2-year progression-free survival
rate was 85%, and the 2-year overall survival rate
was 97%.47
The combination of ibrutinib and rituximab
was studied in the United States in 50 patients.48
Patients with a very high Ki-67 index or the blas-
toid subtype of mantle-cell lymphoma were ex-
cluded. A total of 71% of the patients had a
complete response, and the 3-year progression-
free survival and overall survival rates were 87%
and 94%, respectively. A Spanish study also
evaluated ibrutinib and rituximab in 50 pa-
tients.49 The complete response rate was 80%,
and 72% of the patients had undetectable mea-
surable residual disease in the peripheral blood
and bone marrow. The overall progression-free
survival rate at 42 months was 81%. A U.S. study
evaluated venetoclax, lenalidomide, and rituxi­
mab in 28 patients.50 The complete remission
rate was 89%, and 71% of the patients had no
measurable residual disease. It must be acknowl-
edged that many of these pilot studies of new
agents have included limited numbers of highly
selected patients.
S a lvage Ther a py
In most patients with mantle-cell lymphoma,
the primary treatment regimen does not result
in a cure, and salvage therapy is required
(Fig. 3). In planning second-line or subsequent
treatments, it is important to take into consider-
ation the fact that risk factors in these patients
vary widely. For example, patients with an asymp­
tomatic relapse might do well for some time
with close observation but no immediate treat-
ment. Other factors to consider in the treatment
decision include the histologic subtype (the
blastoid subtype is likely to require immediate
n engl j med 386;26  nejm.org  June 30, 2022
The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
treatment) and status with respect to Ki-67 ex-
pression and TP53 (high Ki-67 expression and a
TP53 abnormality are both associated with rapid
progression and a poor prognosis). Certainly,
the patient’s age, performance status, and coex-
isting conditions may guide the treatment deci-
sion. The type of previous therapies and the re-
sponse to them, as well as the durability of the
initial response, might also affect treatment
options.
In planning salvage treatment for patients
with mantle-cell lymphoma, it is important to
consider radiotherapy. Mantle-cell lymphoma is
one of the most radiosensitive of all non-Hodg-
kin’s lymphomas, and the response rate at any
treated site, even to low-dose radiotherapy, is
higher than the rate that could be expected with
further chemotherapy treatments. Symptom re-
lief is achieved in more than 90% of patients,
response rates in sites treated by radiotherapy
range from 85 to 100%, and complete remission
rates range from 60 to 70%.51 There are cer-
tainly patients for whom radiotherapy to a symp-
tomatic site is the palliative approach most
likely to resolve symptoms. In the rare case of a
localized relapse, radiotherapy should always be
considered. However, for most patients, mantle-
cell lymphoma is a systemic disease, and long-
term control requires systemic treatment.
In the past, traditional chemotherapy regi-
mens, with or without rituximab, have been the
standard approach. For patients who did not
previously receive bendamustine, both the over-
all and complete response rates have been in the
range of 50% or higher when bendamustine-
containing regimens were administered, and the
outcomes are better than with fludarabine-con-
taining regimens.52 The combination of rituxi­
mab, dexamethasone, cytarabine, and platinum
is a highly active regimen. A study evaluated this
regimen, followed by autologous stem-cell trans-
plantation, in patients who were younger than
66 years of age, with rituximab as maintenance
therapy or observation.53 With a median follow-
up of 50 months, the event-free survival rate at
4 years was 79% in the rituximab group and
61% in the observation group.
A comparison of bendamustine plus rituxi­
mab with bendamustine plus rituximab plus
cytarabine showed superiority for the cytarabine-
containing regimen. The complete response rate
2501
 The n e w e ng l a n d j o u r na l of m e dic i n e

Mantle-cell lymphoma, relapsed

or resistant to initial therapy

Asymptomatic Symptomatic
No life-threatening manifestations High-risk features
Patient prefers to avoid treatment Treatment is indicated

Watch and wait Second-line systemic therapy Symptomatic localized disease

Consider radiotherapy

Not a candidate for allogeneic Otherwise healthy and

transplantation <70 yr of age

Consider bendamustine-based regimen Consider induction of remission

if not previously used with alternative therapy and
New targeted agents: BTK inhibitors, allogeneic transplantation
Bcl-2 inhibitor, IMID

If treatment fails, consider CAR T-cell

therapy or other new agents

Figure 3. Algorithm for Salvage Therapy in Patients with Relapsed Mantle-Cell Lymphoma.
BTK denotes Bruton’s tyrosine kinase, CAR chimeric antigen receptor, and IMID immunomodulatory imide drug.
An example of an IMID is lenalidomide.

was 91%, and the 2-year progression-free sur-
vival rate was 87%.54 However, grade 3 or 4 toxic
effects, especially thrombocytopenia, occurred
in half the patients.
Several new, targeted therapies are active in
patients with relapsed or refractory mantle-cell
lymphoma. These include the Bruton’s tyrosine
kinase inhibitors (irreversible inhibitors: ibruti-
nib, zanubrutinib, and acalabrutinib; reversible
inhibitor: pirtobrutinib), lenalidomide, bortezomib,
the mammalian target of rapamycin (mTOR)
inhibitors temsirolimus and everolimus, the
phosphatidylinositol 3-kinase (PI3K) inhibitors
idelalisib and umbralisib, and the Bcl-2 inhibitor
venetoclax.55-58 These drugs are often given in
combination with rituximab or another anti-
CD20 antibody. The response rates have been
quite high, and when the drugs are used in
combination, the complete response rates are
frequently in the range of 50%. The combination
of ibrutinib and venetoclax was studied in 24
patients, most of whom had relapsed or refrac-
tory disease. Half the patients had a TP53 abnor-
mality, and the majority had a high-risk prog-
nostic score. The complete response rate was
71%, and 67% of the patients had no measurable

2502 n engl j med 386;26  nejm.org  June 30, 2022

The New England Journal of Medicine

Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
 Mantle-Cell Lymphoma
residual disease.59 Another study evaluated ibru-
tinib combined with venetoclax in 21 patients
with relapsed or refractory disease; the complete
response rate was 62%.60 A recent study from
Europe used ibrutinib and bortezomib as induc-
tion therapy, followed by maintenance treatment
with ibrutinib, in 58 patients.61 The response
rate increased to 87% during maintenance treat-
ment, and the median duration of the response
was 22 months. Another recent study used le-
nalidomide plus rituximab, followed by mainte-
nance therapy, in 73 patients.62 The median du-
ration of a response was 31 months. In a 10-year
follow-up of a study of lenalidomide plus ritux-
imab, followed by lenalidomide as maintenance
therapy, the 10-year progression-free survival
rate was 25%, and the 10-year overall survival
rate was 36%.63
Both autologous and allogeneic hematopoi-
etic stem-cell transplants have been used for
patients with relapsed or refractory mantle-cell
lymphoma. Autologous transplants have been
associated with a lower treatment-related death
rate but a very high relapse rate (80 to 90% at
5 years).64 Although allogeneic transplants have
been associated with a high treatment-related
death rate and morbidity, they result in very long
remissions and a probable cure in 30 to 50% of
treated patients.65,66 Unfortunately, given the ad-
vanced age of most patients with mantle-cell
lymphoma, only a subgroup of patients are can-
didates for allogeneic transplantation.
New immunotherapies have had a major ef-
fect on a number of cancers, including some
lymphomas. Unfortunately, inhibition of pro-
grammed cell death 1 (PD-1) or the PD-1 ligand
seems to be minimally active in mantle-cell
lymphoma.67,68 The bispecific T-cell engager
glofitamab (characterized by two Fab arms for
binding CD20 on B cells, along with one Fab
arm for binding CD3 on T cells) was reported to
have an 81% overall response rate and a 67%
rate of complete metabolic response (i.e., PET
scanning became negative).69 The treatment was
associated with both the cytokine release syn-
drome and neurologic toxic effects. The anti-
body–drug conjugate loncastuximab tesirine
(which is CD19-specific with an alkylating agent
payload) has shown activity, with 7 responses,
including 5 complete responses, in 19 patients.70
Chimeric antigen receptor (CAR) T-cell therapy
n engl j med 386;26
The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
1.0
0.8
Probability of Survival
0.6 Late (2006–2011)
Mid (2000–2005)
0.4
0.2
Early (1990–1999)
0.0
0 50 100 150 200
Overall Survival (months)
Figure 4. Overall Survival of Patients with Mantle-Cell Lymphoma
from the Time of Diagnosis.
Data are from the Nebraska Lymphoma Study Group. Rituximab was ap-
proved for low-grade follicular B-cell lymphoma on November 26, 1997.
It became widely used for patients with mantle-cell lymphoma over the
next few years. As noted by the curves showing results after 2000, the in-
troduction of rituximab improved outcomes. Late, mid, and early refer to
the treatment era.
with KTE-X19 (brexucabtagene autoleucel), an
anti-CD19–directed agent, resulted in a 93% re-
sponse rate and a 67% complete response rate in
a study involving 68 patients.71 At 12 months,
the estimated progression-free survival rate was
61%. Both the cytokine release syndrome and
neurologic toxic effects were seen, but none of
these events were fatal. However, 2 patients died
from infections. This approach is likely to re-
place allogeneic transplantation as a salvage
therapy and might become part of up-front
therapy in very high risk patients, as long as
prior therapy does not cause severe lymphocyto-
penia (which would make it difficult to collect
T cells) and long-term follow-up shows that the
responses are durable.
Pro gnosis a nd the P ossibil i t y
of a Cur e
The survival of patients with mantle-cell lym-
phoma has improved with the addition of ritux-
imab and, perhaps, other new treatments. The
overall survival for consecutive patients with
mantle-cell lymphoma treated before and after
the introduction of rituximab by physicians in
the Nebraska Lymphoma Study Group is shown
in Figure 4. With the exception of some patients
nejm.org June 30, 2022 2503
 The n e w e ng l a n d j o u r na l of m e dic i n e

undergoing allogeneic bone marrow transplan- F u t ur e Dir ec t ions

tation, the curability of mantle-cell lymphoma
has been uncertain. In a trial of a high-dose
cytarabine-containing regimen, followed by au-
tologous transplantation, with a median follow-up
of 6.5 years and some patients followed for 10
years, the median event-free survival was 7.4 years,
but relapses occurred as long as 9 years after
treatment.33 Another analysis, involving data
from 1029 patients less than 65 years of age who
were followed for a median of 6.3 years (maxi-
mum follow-up, 17 years) showed significantly
better progression-free and overall survival among
patients who underwent autologous transplanta-
tion than among those who did not, but there
was no clear plateau on either curve.72 Although
some patients with mantle-cell lymphoma never
have a relapse after an initial complete remis-
sion, they are in the minority. Perhaps measure-
ment of measurable residual disease will make it
possible to identify these patients.
The many early studies showing the impressive
antitumor activity of a variety of agents have
created both an opportunity and problems. The
opportunity is the new ability to construct ratio-
nal drug combinations based on mechanisms of
action. The problems concern the combinatorial
possibilities, which are extensive. The capacity
to administer a combination of agents with di-
verse mechanisms of action is largely unexplored
in this disease. In addition, many of the most
promising agents are owned by distinct pharma-
ceutical companies, and encouraging these com-
mercial entities to collaborate, given the risks of
inadequate activity and new toxic effects, is a
disincentive that is sufficient to interfere with
innovation.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Dr. Timothy Greiner, at the University of Nebraska,
for providing the photomicrographs.

References
1. Jaffe ES, Bookman MA, Longo DL.
Lymphocytic lymphoma of intermediate
differentiation — mantle zone lymphoma:
a distinct subtype of B-cell lymphoma.
Hum Pathol 1987;​18:​877-80.
2. Pileri SA, Falini B. Mantle cell lym-
phoma. Haematologica 2009;​94:​1488-92.
3. Weisenburger DD, Kim H, Rappaport
H. Mantle-zone lymphoma: a follicular
variant of intermediate lymphocytic lym-
phoma. Cancer 1982;​49:​1429-38.
4. Williams ME, Westermann CD, Swerd-
low SH. Genotypic characterization of cen-
trocytic lymphoma: frequent rearrange-
ment of the chromosome 11 bcl-1 locus.
Blood 1990;​76:​1387-91.
5. Medeiros LJ, Van Krieken JH, Jaffe ES,
Raffeld M. Association of bcl-1 rearrange-
ments with lymphocytic lymphoma of in-
termediate differentiation. Blood 1990;​
76:​2086-90.
6. Raffeld M, Jaffe ES. bcl-1, t(11;14),
And mantle cell-derived lymphomas. Blood
1991;​78:​259-63.
7. Armitage JO, Weisenburger DD. New
approach to classifying non-Hodgkin’s
lymphomas: clinical features of the major
histologic subtypes: Non-Hodgkin’s Lym-
phoma Classification Project. J Clin Oncol
1998;​16:​2780-95.
8. Herrmann A, Hoster E, Zwingers T,
et al. Improvement of overall survival in
advanced stage mantle cell lymphoma.
J Clin Oncol 2009;​27:​511-8.
9. Dal Maso L, Franceschi S. Hepatitis C
virus and risk of lymphoma and other
lymphoid neoplasms: a meta-analysis of
epidemiologic studies. Cancer Epidemiol
Biomarkers Prev 2006;​15:​2078-85.
10. de Sanjose S, Benavente Y, Vajdic CM,
et al. Hepatitis C and non-Hodgkin lym-
phoma among 4784 cases and 6269 con-
trols from the International Lymphoma
Epidemiology Consortium. Clin Gastro-
enterol Hepatol 2008;​6:​451-8.
11. Grulich AE, Vajdic CM, Cozen W. Al-
tered immunity as a risk factor for non-
Hodgkin lymphoma. Cancer Epidemiol
Biomarkers Prev 2007;​16:​405-8.
12. Wang Y, Ma S. Risk factors for etiol-
ogy and prognosis of mantle cell lym-
phoma. Expert Rev Hematol 2014;​7:​233-
43.
13. The Non-Hodgkin’s Lymphoma Clas-
sification Project. A clinical evaluation of
the International Lymphoma Study Group
classification of non-Hodgkin’s lympho-
ma. Blood 1997;​89:​3909-18.
14. Swerdlow SH, Campo E, Pileri SA, et al.
The 2016 revision of the World Health Or-
ganization classification of lymphoid neo-
plasms. Blood 2016;​127:​2375-90.
15. Zucca E, Stein H, Coiffier B. European
Lymphoma Task Force (ELTF): report of
the workshop on mantle cell lymphoma
(MCL). Ann Oncol 1994;​5:​507-11.
16. Jain P, Dreyling M, Seymour JF, Wang
M. High-risk mantle cell lymphoma: defi-
nition, current challenges, and manage-
ment. J Clin Oncol 2020;​38:​4302-16.
17. Orchard J, Garand R, Davis Z, et al. A
subset of t(11;14) lymphoma with mantle
cell features displays mutated IgVH genes
and includes patients with good progno-
sis, nonnodal disease. Blood 2003;​101:​
4975-81.
18. Fernàndez V, Salamero O, Espinet B,
et al. Genomic and gene expression pro-
filing defines indolent forms of mantle
cell lymphoma. Cancer Res 2010;​70:​1408-
18.
19. Romaguera JE, Medeiros LJ, Hage-
meister FB, et al. Frequency of gastroin-
testinal involvement and its clinical sig-
nificance in mantle cell lymphoma. Cancer
2003;​97:​586-91.
20. Carbone PP, Kaplan HS, Musshoff K,
Smithers DW, Tubiana M. Report of the
Committee on Hodgkin’s Disease Staging
Classification. Cancer Res 1971;​31:​1860-1.
21. Cheson BD, Fisher RI, Barrington SF,
et al. Recommendations for initial evalu-
ation, staging, and response assessment
of Hodgkin and non-Hodgkin lymphoma:
the Lugano classification. J Clin Oncol
2014;​32:​3059-68.
22. International Non-Hodgkin’s Lym-
phoma Prognostic Factors Project. A pre-
dictive model for aggressive non-Hodg-
kin’s lymphoma. N Engl J Med 1993;​329:​
987-94.
23. Hoster E, Dreyling M, Klapper W, et al.
A new prognostic index (MIPI) for pa-
tients with advanced-stage mantle cell
lymphoma. Blood 2008;​111:​558-65.
24. Hernandez L, Fest T, Cazorla M, et al.
p53 Gene mutations and protein overex-
pression are associated with aggressive
variants of mantle cell lymphomas. Blood
1996;​87:​3351-9.
25. Hoster E, Rosenwald A, Berger F, et al.

2504 n engl j med 386;26  nejm.org  June 30, 2022

The New England Journal of Medicine

Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.

Prognostic value of Ki-67 index, cytology,
and growth pattern in mantle-cell lym-
phoma: results from randomized trials
of the European Mantle Cell Lymphoma
Network. J Clin Oncol 2016;​34:​1386-94.
26. Cohen JB, Han X, Jemal A, Ward EM,
Flowers CR. Deferred therapy is associat-
ed with improved overall survival in pa-
tients with newly diagnosed mantle cell
lymphoma. Cancer 2016;​122:​2356-63.
27. Martin P, Chadburn A, Christos P, et al.
Outcome of deferred initial therapy in
mantle-cell lymphoma. J Clin Oncol 2009;​
27:​1209-13.
28. Abrisqueta P, Scott DW, Slack GW, et al.
Observation as the initial management
strategy in patients with mantle cell lym-
phoma. Ann Oncol 2017;​28:​2489-95.
29. Kumar A. Who is a candidate for
watch and wait therapy in mantle cell
lymphoma? Clin Lymphoma Myeloma
Leuk 2019;​19:​Suppl 1:​S109-S111.
30. LaCasce AS, Vandergrift JL, Rodri-
guez MA, et al. Comparative outcome of
initial therapy for younger patients with
mantle cell lymphoma: an analysis from
the NCCN NHL Database. Blood 2012;​
119:​2093-9.
31. Chen RW, Li H, Bernstein SH, et al.
RB but not R-HCVAD is a feasible induc-
tion regimen prior to auto-HCT in front-
line MCL: results of SWOG Study S1106.
Br J Haematol 2017;​176:​759-69.
32. Chihara D, Cheah CY, Westin JR, et al.
Rituximab plus hyper-CVAD alternating
with MTX/Ara-C in patients with newly
diagnosed mantle cell lymphoma: 15-year
follow-up of a phase II study from the MD
Anderson Cancer Center. Br J Haematol
2016;​172:​80-8.
33. Geisler CH, Kolstad A, Laurell A, et al.
Nordic MCL2 trial update: six-year follow-
up after intensive immunochemotherapy
for untreated mantle cell lymphoma fol-
lowed by BEAM or BEAC + autologous
stem-cell support: still very long survival
but late relapses do occur. Br J Haematol
2012;​158:​355-62.
34. Hermine O, Hoster E, Walewski J, et al.
Addition of high-dose cytarabine to im-
munochemotherapy before autologous
stem-cell transplantation in patients aged
65 years or younger with mantle cell lym-
phoma (MCL Younger): a randomised,
open-label, phase 3 trial of the European
Mantle Cell Lymphoma Network. Lancet
2016;​388:​565-75.
35. Hermine O, Jiang L, Walewski J, et al.
Addition of high-dose cytarabine to immu-
nochemotherapy before autologous stem-
cell transplantation in patients aged 65
years or younger with mantle cell lym-
phoma (MCL Younger): a long-term fol-
low-up of the randomized, open-label,
phase 3 trial of the European Mantle Cell
Lymphoma Network. Blood 2021;​ 138:​
Suppl 1:​S380. abstract.
36. EA4151 available through ECOG-
n engl j med 386;26  nejm.org  June 30, 2022
The New England Journal of Medicine
Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.
Mantle-Cell Lymphoma
ACRIN Cancer Research Group. A ran-
domized phase III trial of consolidation
with autologous hematopoietic cell trans-
plantation followed by maintenance ritux-
imab vs. maintenance rituximab alone for
patients with mantle cell lymphoma in
minimal residual disease-negative first
complete remission. New Haven, CT:​Yale
Medicine, 2022 (https://www​.­yalemedicine​
.­org/​­clinical​-­trials/​­rituximab​-­w​-­or​-­w​-­o​-­stem​
-­cell​-­t ransplant​-­in​-­patients​-­with​-­minimal​
-­residual​-­disease​-­neg​-­mantle​-­cell).
37. Kluin-Nelemans HC, Hoster E, Her-
mine O, et al. Treatment of older patients
with mantle-cell lymphoma. N Engl J Med
2012;​367:​520-31.
38. Kluin-Nelemans HC, Hoster E, Her-
mine O, et al. Treatment of older patients
with mantle cell lymphoma: long-term
follow-up of the randomized European
MCL Elderly Trial. J Clin Oncol 2020;​38:​
248-56.
39. Robak T, Huang H, Jin J, et al. Bortezo­
mib-based therapy for newly diagnosed
mantle-cell lymphoma. N Engl J Med 2015;​
372:​944-53.
40. Robak T, Jin J, Pylypenko H, et al.
Frontline bortezomib, rituximab, cyclo-
phosphamide, doxorubicin, and predni-
sone (VR-CAP) versus rituximab, cyclo-
phosphamide, doxorubicin, vincristine,
and prednisone (R-CHOP) in transplanta-
tion-ineligible patients with newly diag-
nosed mantle cell lymphoma: final overall
survival results of a randomised, open-
label, phase 3 study. Lancet Oncol 2018;​
19:​1449-58.
41. Flinn IW, van der Jagt R, Kahl BS,
et al. Randomized trial of bendamustine-
rituximab or R-CHOP/R-CVP in first-line
treatment of indolent NHL or MCL: the
BRIGHT study. Blood 2014;​ 123:​ 2944-
52.
42. Rummel MJ, Niederle N, Maschmeyer
G, et al. Bendamustine plus rituximab
versus CHOP plus rituximab as first-line
treatment for patients with indolent and
mantle-cell lymphomas: an open-label,
multicentre, randomised, phase 3 non-
inferiority trial. Lancet 2013;​381:​1203-10.
43. Smith MR, Jegede O, Martin P, et al.
ECOG-ACRIN E1411 randomized phase 2
trial of bendamustine-rituximab (BR)-
based induction followed by rituximab
(R) ± lenalidomide (L) consolidation for
mantle cell lymphoma: effect of adding
bortezomib to front-line BR induction on
PFS. J Clin Oncol 2021;​39:​Sl7503. abstract.
44. Wang M, Jurczak W, Jurkeman M,
et al. Ibrutinib plus bendamustine and
rituximab in untreated mantle-cell lym-
phoma. N Engl J Med 2022;​386:2482-94.
45. Smith MR, Li H, Gordon L, et al.
Phase II study of rituximab plus cyclo-
phosphamide, doxorubicin, vincristine, and
prednisone immunochemotherapy fol-
lowed by yttrium-90-ibritumomab tiuxetan
in untreated mantle-cell lymphoma: East-
ern Cooperative Oncology Group Study
E1499. J Clin Oncol 2012;​30:​3119-26.
46. Arranz R, García-Noblejas A, Grande
C, et al. First-line treatment with rituximab-
hyperCVAD alternating with rituximab-
methotrexate-cytarabine and followed by
consolidation with 90Y-ibritumomab-tiux-
etan in patients with mantle cell lympho-
ma: results of a multicenter, phase 2 pilot
trial from the GELTAMO group. Haema-
tologica 2013;​98:​1563-70.
47. Ruan J, Martin P, Shah B, et al. Lenalid-
omide plus rituximab as initial treatment
for mantle-cell lymphoma. N Engl J Med
2015;​373:​1835-44.
48. Jain P, Zhao S, Lee HJ, et al. Ibrutinib
with rituximab in first-line treatment of
older patients with mantle cell lympho-
ma. J Clin Oncol 2022;​40:​202-12.
49. Giné E, De la Cruz F, Ubieto AJ, et al.
Efficacy and safety of ibrutinib in combi-
nation with rituximab as frontline treat-
ment for indolent clinical forms of mantle
cell lymphoma: results of the GELTAMO
IMCL-2015 study. Hematol Oncol 2021;​
39:​104-6.
50. Phillips TJ, Danilov AV, Bond DA, et al.
The combination of venetoclax, lenalido-
mide, and rituximab in patients with
newly diagnosed mantle cell lymphoma
induces high response rates and MRD un-
detectability. J Clin Oncol 2021;​39:​Suppl:​
S7505. abstract.
51. Ben Barouch S, Kuruvilla J, Tsang RW,
Yashphe E, Sarid N. Radiotherapy in man-
tle cell lymphoma: a literature review. He-
matol Oncol 2020;​38:​223-8.
52. Rummel M, Kaiser U, Balser C, et al.
Bendamustine plus rituximab versus
f ludarabine plus rituximab for patients
with relapsed indolent and mantle-cell
lymphomas: a multicentre, randomised,
open-label, non-inferiority phase 3 trial.
Lancet Oncol 2016;​17:​57-66.
53. Le Gouill S, Thieblemont C, Oberic L,
et al. Rituximab after autologous stem
cell transplantation in mantle-cell lym-
phoma. N Engl J Med 2017;​377:​1250-60.
54. Bega G, Olivieri J, Riva M, et al. Ritux-
imab and bendamustine (BR) compared
with rituximab, bendamustine, and cyta-
rabine (R-BAC) in previously untreated
elderly patients with mantle cell lympho-
ma. Cancers (Basel) 2021;​13:​6089.
55. Eyre TA, Cheah CY, Wang ML. Thera-
peutic options for relapsed/refractory man-
tle cell lymphoma. Blood 2022;​139:​666-77.
56. Kahl BS, Spurgeon SE, Furman RR,
et al. A phase 1 study of the PI3Kδ inhibi-
tor idelalisib in patients with relapsed/
refractory mantle cell lymphoma (MCL).
Blood 2014;​123:​3398-405.
57. Wang M, Popplewell LL, Collins RH
Jr, et al. Everolimus for patients with
mantle cell lymphoma refractory to or in-
tolerant of bortezomib: multicentre, single-
arm, phase 2 study. Br J Haematol 2014;​
165:​510-8.
2505
 Mantle-Cell Lymphoma

58. Mato AR, Shah NN, Jurczak W, et al.
Pirtobrutinib in relapsed or refractory
B-cell malignancies (BRUIN): a phase 1/2
study. Lancet 2021;​397:​892-901.
59. Tam CS, Anderson MA, Pott C, et al.
Ibrutinib plus venetoclax for the treat-
ment of mantle-cell lymphoma. N Engl J
Med 2018;​378:​1211-23.
60. Wang M, Ramchandren R, Chen R, et
al. Concurrent ibrutinib plus venetoclax
in relapsed/refractory mantle cell lym-
phoma: the safety run-in of the phase 3
SYMPATICO study. J Hematol Oncol 2021;​
14:​179.
61. Novak U, Fehr M, Schär S, et al. Ibru-
tinib plus bortezomib and ibrutinib main-
tenance for relapsed and refractory man-
tle cell lymphoma: final report of a phase
I/II trial of the European MCL Network.
Hematol Oncol 2021;​39:​Suppl:​S107-S108.
abstract.
62. Sharman JP, Melear JM, Yacoub A, et al.
Induction R2 followed by maintenance in
patients with relapsed/refractory mantle
cell lymphoma: interim analysis from the
phase 3b MAGNIFY study. Hematol Oncol
2021;​39:​Suppl:​S108-S109.
63. Gupta A, Schuster SJ, Svoboda J, et al.
Lenalidomide plus rituximab in patients
with rituximab-resistant indolent B-cell
and mantle cell lymphomas: 10-year follow-
up. J Clin Oncol 2021;​39:​S7539. abstract.
64. Freedman AS, Neuberg D, Gribben JG,
et al. High-dose chemoradiotherapy and
anti-B-cell monoclonal antibody-purged
autologous bone marrow transplantation
in mantle-cell lymphoma: no evidence for
long-term remission. J Clin Oncol 1998;​
16:​13-8.
65. Tam CS, Bassett R, Ledesma C, et al.
Mature results of the M. D. Anderson
Cancer Center risk-adapted transplanta-
tion strategy in mantle cell lymphoma.
Blood 2009;​113:​4144-52.
66. Robinson SP, Boumendil A, Finel H,
et al. Long-term outcome analysis of
reduced-intensity allogeneic stem cell
transplantation in patients with mantle
cell lymphoma: a retrospective study from
the EBMT Lymphoma Working Party.
Bone Marrow Transplant 2018;​53:​617-24.
67. Menter T, Bodmer-Haecki A, Dirn-
hofer S, Tzankov A. Evaluation of the di-
agnostic and prognostic value of PDL1
expression in Hodgkin and B-cell lym-
phomas. Hum Pathol 2016;​54:​17-24.
68. Wang L, Qian J, Lu Y, et al. Immune
evasion of mantle cell lymphoma: expres-
sion of B7-H1 leads to inhibited T-cell re-
sponse to and killing of tumor cells. Hae-
matologica 2013;​98:​1458-66.
69. Phillips T, Dickinson M, Morschhaus-
er F, et al. Glofitamab step-up dosing in-
duces high response rates in patients (pts)
with relapsed or refractory (R/R) mantle
cell lymphoma (MCL), most of whom had
failed prior Bruton’s tyrosine kinase in-
hibitor (BTKi) therapy. Blood 2021;​ 138:​
Suppl 1:​130. abstract.
70. Hamadani M, Radford J, Carlo-Stella
C, et al. Final results of a phase 1 study of
loncastuximab tesirine in relapsed/refrac-
tory B-cell non-Hodgkin lymphoma. Blood
2021;​137:​2634-45.
71. Wang M, Munoz J, Goy A, et al. KTE-
X19 CAR T-cell therapy in relapsed or re-
fractory mantle-cell lymphoma. N Engl J
Med 2020;​382:​1331-42.
72. Gerson JN, Handorf E, Villa D, et al.
Survival outcomes of younger patients
with mantle cell lymphoma treated in the
rituximab era. J Clin Oncol 2019;​37:​471-
80.
Copyright © 2022 Massachusetts Medical Society.

images in clinical medicine

The Journal welcomes consideration of new submissions for Images in Clinical
Medicine. Instructions for authors and procedures for submissions can be found
on the Journal’s website at NEJM.org. At the discretion of the editor, images that
are accepted for publication may appear in the print version of the Journal,
the electronic version, or both.

2506 n engl j med 386;26  nejm.org  June 30, 2022

The New England Journal of Medicine

Downloaded from nejm.org by LIZBETH QUINTERO on June 29, 2022. For personal use only. No other uses without permission.
Copyright © 2022 Massachusetts Medical Society. All rights reserved.