HEMATOLOGIC MALIGNANCIES

New Directions for Mantle Cell Lymphoma in

2022
Anita Kumar, MD1; Toby A. Eyre, MD2; Katharine L. Lewis3,4; Meghan C. Thompson, MD1; and Chan Y. Cheah, MD3,4
over view

Mantle cell lymphoma is a rare B-cell non-Hodgkin lymphoma that is clinically and biologically
heterogeneous. Risk stratification at the time of diagnosis is critical. One of the most powerful prognostic
indices is the Mantle Cell Lymphoma International Prognostic Index-Combined, which integrates an estimate
of proliferation (Ki67 index) with the standard Mantle Cell Lymphoma International Prognostic Index clinical
factors. In addition, the presence of TP53 mutation is associated with suboptimal response to intensive
chemoimmunotherapy and particularly dismal survival outcomes. Given their excellent activity in the
relapsed/refractory setting, increasingly, biologically targeted therapeutics—such as covalent Bruton tyrosine
kinase inhibitors, lenalidomide, and venetoclax—are being incorporated into “chemotherapy-free” regimens
and in combination with established chemoimmunotherapy backbones for treatment-na€ıve mantle cell
lymphoma. In addition, risk-adapted treatment programs are increasingly being studied. These programs
tailor treatment according to baseline prognostic factors (e.g., presence of TP53 mutation) and may
incorporate biomarkers of response such as minimal residual disease assessment. Although still
investigational, these studies present an opportunity to move beyond the biology-agnostic, historical fitness-
based treatment selection paradigm and toward a more personalized, tailored treatment approach in mantle
cell lymphoma. After Bruton tyrosine kinase inhibitor failure, many promising standard or investigational
therapies exist, including CAR T-cell therapy (including brexucabtagene autoleucel and lisocabtagene
maraleucel), bispecific antibody therapy targeting CD20-CD3, zilovertamab vedotin (an antibody-drug
conjugate that targets ROR1), and the noncovalent Bruton tyrosine kinase inhibitor pirtobrutinib. These new
therapies show promising efficacy, even among high-risk patients, and will likely translate to improvements in
survival outcomes for patients with progressive mantle cell lymphoma following treatment with a Bruton
tyrosine kinase inhibitor.

PROGNOSTIC MARKERS IN MANTLE CELL LYMPHOMA
Introduction
Mantle cell lymphoma is characterized by the pres-
ence of t(11;14), which juxtaposes the CCDN1 gene
with the immunoglobin heavy chain locus, leading to
overexpression of cyclin D1. Despite this common
genetic hallmark, mantle cell lymphoma is clinically
and biologically heterogeneous, ranging from the
indolent non-nodal leukemic variant to the highly pro-
liferative blastoid variant. Several clinical and biologic
Author affiliations
and support features are predictive of survival outcomes in frontline
information (if and relapsed/refractory mantle cell lymphoma and are
applicable) appear
reviewed below.
at the end of this
article.
Prognostication in the Frontline Setting
Accepted on March
17, 2022, and The Mantle Cell Lymphoma International Prognostic
published at Index and its variations The Mantle Cell Lymphoma
ascopubs.org on
International Prognostic Index (MIPI) was initially
May 13, 2022: DOI
https://doi.org/ devised in 2008 from data from over 400 patients
10.1200/ pooled from the GLGS group and EMCLN trials.1 The
EDBK_349509 MIPI score is calculated as a weighted summation of
pretreatment values of age, ECOG Performance Sta-
tus, lactate dehydrogenase level, and white cell
count. The complex calculation is summarized in
Table 1. The weighted scores defined low-, interme-
diate-, and high-risk groups. A simplified version of
MIPI (s-MIPI) has been devised for routine clinical
practice, as has the biologic MIPI (MIPI-b), in which
tumor cell proliferation measured by the Ki67 index is
added to the MIPI score (Table 1).1 Although the
MIPI-b integrates the Ki67 index, this index effectively
divides patients into only two groups, as very few patients
are in the low-risk group and these patients have similar
outcomes to intermediate-risk MIPI-b cohorts.
More recent external validation of the MIPI was
performed using a large European Mantle Cell
Lymphoma Network cohort of patients from two front-
line clinical trials (958 patients; median age, 65; age
range, 32–87).2 Five-year overall survival (OS) rates
of low-, intermediate-, and high-risk MIPI groups
were 83%, 63%, and 34%, respectively, and the
MIPI was similarly prognostic for time-to-treatment

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 New Directions for Mantle Cell Lymphoma in 2022
PRACTICAL APPLICATIONS

Comprehensive biologic characterization of
mantle cell lymphoma leads to optimal dis-
ease risk stratification and should include an
estimate of proliferation (Ki67 index) and tar-
geted genomic sequencing to assess for
TP53 mutation.

Presence of TP53 mutation is associated
with a poor response to standard chemoim-
munotherapy, and clinical trial participation
is strongly encouraged for this high-risk sub-
set in the frontline and relapsed/refractory
setting.

In patients with high-risk mantle cell lym-
phoma, early referral for consideration of
CAR T-cell therapy is advisable, as similar
efficacy has been observed with CAR T-cell
therapy across subgroups, including patients
with a high-risk Mantle Cell Lymphoma
International Prognostic Index score, blastoid
morphology, high Ki67 index, and TP53
mutation.

The therapeutic landscape is rapidly evolv-
ing in mantle cell lymphoma, including
earlier use of novel biologically targeted
therapies for frontline treatment. In addi-
tion, in relapsed/refractory mantle cell lym-
phoma, there are a number of promising
therapies beyond covalent BTK inhibitors,
including novel immunotherapeutics such
as CAR T-cell therapy and bispecific
antibodies.
failure. Moreover, the four individual factors comprising
the MIPI were independently prognostic for OS and time-
to-treatment failure.
Although the MIPI has been shown to be prognostic and
reproducible, an additional modification has been shown
to have even more discriminatory prognostic power. The
European Mantle Cell Lymphoma Network used the
European Mantle Cell Lymphoma Younger and Mantle
Cell Lymphoma Elderly trial cohorts to integrate Ki67 index
levels and the MIPI score to devise the combination MIPI
(MIPI-c).3 Of the 832 patients (median age, 62), 508
were grouped according to Ki67 index status and MIPI
(Table 1). This modified combination separated patients
into four groups: low, low-intermediate, high-intermediate,
and high risk. Five-year OS rates were 85%, 72%, 43%,
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
and 17% (p < .001), respectively, demonstrating greater
discrimination than the MIPI alone. This score was also
validated using GLSG1996/GLSG2000 trial cohorts.3
TP53 aberrancy The prognostic value of TP53 aberrancy,
represented by a deletion of the p arm of chromosome 17
containing the p53 gene (del17p; assessed by fluores-
cence in situ hybridization or single nucleotide polymor-
phism array analysis) and/or a mutation in the TP53 gene
(assessed by next-generation sequencing or reverse tran-
scription-polymerase chain reaction) or p53 immunohisto-
chemistry expression levels, has been studied in patients
receiving frontline chemoimmunotherapy. The European
Mantle Cell Lymphoma Network analyzed tissue from 365
patients for TP53 expression by immunohistochemistry
and defined cutoffs as low (1%–10%), intermediate
(10%–50%), and high expression (> 50%). By univari-
able and multivariable analysis, high TP53 expression was
strongly prognostic for both inferior time-to-treatment fail-
ure and OS compared with low TP53 expression after
adjusting for MIPI score and Ki67 index (HR, 2.0; p 5
.0054 for time-to-treatment failure, and HR, 2.1; p 5
.0068 for OS).4
Additionally, pooled Nordic MCL2 and MCL3 clinical trial
data assessed the prognostic value of del17p and TP53
mutations in 183 patients with mantle cell lymphoma
receiving intensive frontline therapy.5 TP53 mutations
were observed in 11%, del17p in 16%, NOTCH1 muta-
tions in 4%, and CDKN2A mutations in 20%. All these
genetic subgroups, together with the MIPI, MIPI-c, blas-
toid morphology, and Ki67 index greater than 30%, were
each associated with inferior survival on univariable analy-
sis. However, on multivariable analysis, only the MIPI-c
high-risk group (HR, 2.6; p 5 .003) and TP53 mutation
group (HR, 6.2; p < .0001) retained independent prog-
nostic significance for OS. Patients with disease harboring
a TP53 mutation were enriched for Ki67 index greater than
30%, blastoid morphology, and a high-risk MIPI, and had a
short median OS of 1.8 years. TP53 mutation was a stron-
ger negative prognostic marker than presence of del17p.
Interestingly, when patients without TP53 mutations were
analyzed, the MIPI score was no longer prognostic. More-
over, among these 156 TP53-unmutated cases, no other
biomarker showed any prognostic value (including
CDKN2A deletions, blastoid morphology, Ki67 index >
30%, and MIPI-c).
Overall, these data suggest that the MIPI-c provides a
robust and reproducible prognostic scoring in the immu-
nochemotherapy era and is a useful tool for risk stratifica-
tion. The single strongest negative prognostic marker is
presence of a TP53 mutation. Widespread usage of muta-
tional testing by next-generation sequencing or other tech-
niques such as RT-PCR remains limited but should be
encouraged given its prognostic value.
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook 615
 TABLE 1. Prognostic Risk Scores of Patients With Treated Frontline Mantle Cell Lymphoma1–3,84
616

Scoring System Components Calculation Risk Group Survival

2022 ASCO EDUCATIONAL BOOK | asco.org/edbook

MIPI Age, ECOG PS, LDH, 0.03535 × age (years) 1 0.6978 (if ECOG LR < 5.70 Initial data:
WCC PS > 1) 1 1.367 × log10 (LDH/ULN) 1 IR $ 5.70 LR 5-year OS 60%
0.9393 x log10 (WCC per 106) HR $ 6.20 IR median 51 months
HR median 29 months
Validation:
5-year OS: LR 83%, IR 63%, HR
34% (p < .001)
5-year TTF: LR 59%, IR 37%,
HR 22% (p < .001)
MIPI-c Age, ECOG PS, LDH, - Initial MIPI calculation as above LR: LR MIPI 1 Ki67 < 30% 5-year OS: LR 85%, LI 72%, HI
WCC, Ki67% - Ki67% (< 30% or $ 30%) LI: either LR MIPI 1 Ki67 $ 30% 43%, and HR 17% (p < .001)
or IR MIPI 1 Ki67 < 30%
HI: either IR MIPI 1 Ki67 $ 30%
or HR MIPI 1 Ki67 < 30%
HR: HR MIPI and Ki67 $ 30%
MIPI-b Age, ECOG PS, LDH, CBS: 0.03535 × age (years) 1 0.6978 (if LR: CBS < 5.7 Median OS:
WCC, Ki67% ECOG > 1) 1 1.367 × log10(LDH/ULN) 1 IR: CBS 5.7–6.5 LR not reached
0.9393 x log10(WCC) 1 0.02142 × Ki67%. HR: CBS $ 6.5 IR 58 months
HR 37 months

Kumar et al
s-MIPI Age, ECOG PS, LDH, - Age: 1 point for 50–59, 2 for 60–69, 3 for LR: 0–3 5-year OS: HR 38%
WCC $ 70 years IR: 4–5
- ECOG: 2 points for ECOG 2–4 HR: 6–11
- LDH/ULN ratio: 1 point for 0.67–0.99, 2
points for 1.0–1.49, 3 points for $ 1.50
- WCC 109/L: 1 point 6.7–9.99, 2 points
1.00–14.99, 3 points $ 15.0

Abbreviations: CBS, combined biologic score; ECOG PS, ECOG Performance Status; HI, high intermediate; HR, high risk; IR, intermediate risk; LDH, lactate dehydrogenase; LI, low intermedi-
ate; LR, low risk; MIPI, Mantle Cell Lymphoma International Prognostic Index; MIPI-c, combined MIPI; MIPI-b, biologic MIPI; s-MIPI, simplified MIPI; OS, overall survival; TTF, time-to-treat-
ment failure; ULN, upper limit of normal; WCC, white cell count.

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 New Directions for Mantle Cell Lymphoma in 2022
In summary, at the time of mantle cell lymphoma diagno-
sis, a calculation of the MIPI-c, histopathological subtyp-
ing, and assessment of Ki67 index should be performed
in all cases. If available, TP53 mutational analysis should
also be performed prior to initiation of treatment and with
each subsequent line of therapy, as it provides valuable
prognostic information.
Early Progression of Disease
Multiple data sets have described survival outcomes
according to patient remission duration following frontline
chemoimmunotherapy. Extrapolating survival analyses
from follicular lymphoma,6,7 progression of disease within
24 months has been shown to be a strong negative prog-
nostic factor for OS in both younger patients treated with
high-dose cytarabine-based induction8 and in older
patients who are unable to receive standard immunoche-
motherapy.9 These studies are complemented by a recent
study analyzing patient outcomes (461 patients) according
to time-to-relapse after intensive induction and consoli-
dation autologous stem cell transplantation.10 Dynamic
landmark timepoint modeling showed that time-to-
relapse correlated strongly with OS. The impact of
relapse was greatest for patients whose disease relapsed
within 6 months (5-year OS, 45% for relapsed vs. 71% for
not relapsed disease; HR, 7.68), 12 months (35% for
relapsed vs. 74% for not relapsed disease; HR, 6.68), and
18 months (38% for relapsed vs. 75% for not relapsed dis-
ease; HR, 5.81).
Minimal Residual Disease
Minimal residual disease (MRD) status is an important pre-
dictive marker of survival. There is evidence that undetect-
able MRD following immunochemotherapy in patients with
mantle cell lymphoma predicts superior survival out-
comes.11–13 There are several techniques used to mea-
sure MRD, including real-time quantitative polymerase chain
reaction, nested–polymerase chain reaction, double-droplet
polymerase chain reaction, and next-generation sequencing.
A detailed discussion of the various techniques is outside the
scope of this review.14 Although MRD status is increasingly
integrated into key endpoints of prospective trials,15 MRD-
guided decision-making or routine testing outside of clinical tri-
als is not considered standard practice.
Prognostic Factors in Relapsed/Refractory Mantle Cell
Lymphoma
Covalent BTK (cBTK) inhibitors are a cornerstone of treat-
ment for patients with relapsed/refractory mantle cell lym-
phoma. Although many patients treated with ibrutinib,
acalabrutinib, or zanubrutinib have deep and durable
remissions, there are several prognostic markers associ-
ated with poor outcomes. Identification of these factors
before initiation of a BTK inhibitor is of increasing impor-
tance with the advent of CAR T-cell therapy, which is
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currently most often used in the post-BTK inhibitor space.
The most robust prognostic data are available following
patient outcomes with ibrutinib monotherapy. Pooled data
of 370 patients from prospective trials observed that 117
of 370 (32.6%) patients were considered high-risk on the
s-MIPI, 44 of 370 (11.9%) patients had blastoid morphol-
ogy, and 20 of 144 (13.9%) patients assessed had a
TP53 mutation.16,17 There was a degree of overlap across
these cohorts. The overall response rates (ORR) were
55%, 50%, and 55%, respectively, with complete
responses (CRs) uncommon. The median progression-
free survival (PFS) rates were 6.5 months, 5 months, and
4 months, respectively. Overall, these results demonstrate
that approximately one-third of patients with relapsed/
refractory mantle cell lymphoma receiving ibrutinib mono-
therapy have a poor prognostic feature (high-risk s-MIPI,
blastoid morphology, or TP53 mutation) and have an ORR
of approximately 55% and a median PFS of only 6
months. Ki67 index has also been shown to be a poor
prognostic marker in a cohort of 50 patients with
relapsed/refractory mantle cell lymphoma treated with
ibrutinib/rituximab.18 Patients with a Ki67 index greater
than or equal to 50% (12 patients) had an inferior ORR
(50% vs. 100%), PFS (median, 5.9 months vs. not
reached), and OS (13.6 months vs. not reached) com-
pared with patients with a Ki67 index less than or equal to
50% (37 patients). These findings have been replicated
and further validated in a U.K.-based real-world analysis
of 211 patients with mantle cell lymphoma receiving ibru-
tinib monotherapy at first relapse.19 Biologic factors asso-
ciated with inferior survival were s-MIPI and blastoid
morphology. Adverse clinical factors in this series were
progression of disease within 24 months, increased age,
and poor performance status.
Cellular Therapy
Although factors such as high-risk MIPI, blastoid morphol-
ogy, high Ki67 index, and TP53 mutation are consistently
associated with inferior survival following frontline immu-
nochemotherapy and targeted inhibitors in relapsed/
refractory mantle cell lymphoma, in contrast, outcomes for
high-risk patients treated with brexucabtagene autoleucel
provide some encouragement.20 Subgroup analyses
within ZUMA-2 describe equivalent ORRs for patients with
and without blastoid morphology (14 patients; ORR 93%),
TP53 mutation (6 patients; ORR 100%), Ki67 index
greater than or equal to 50% (32 patients; ORR 94%),
and intermediate- or high-risk s-MIPI (33 patients; ORR
94%). Furthermore, the initial ORRs of patients with (28
patients) and without progression of disease within 24
months (32 patients) were 93% (CR 61%) and 91% (CR
72%).21 The progression of disease within the 24 months
cohort was enriched for higher tumor burden, higher
lactate dehydrogenase, and blastoid morphology.
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook 617
 Kumar et al
Importantly, the PFS (11.3 vs. 29.3 months) and CAR T-
cell expansion were both inferior in the progression of dis-
ease within 24 months cohort. Whether findings will be
similar in patients receiving CAR T-cell therapy in earlier
lines of therapy in future trials and real-world analyses
remains to be fully explored. Finally, a small series (42
patients) has suggested that allogeneic haematopoietic
stem cell transplantation may have similar activity in
patients with relapsed/refractory mantle cell lymphoma
with or without TP53 aberration.22
NEW STRATEGIES ON THE HORIZON FOR TREATMENT-NAÏVE
MANTLE CELL LYMPHOMA
Frontline Treatment of Mantle Cell Lymphoma: The
Clinical and Scientific Rationales for Challenging the
Historical Standard
Chemoimmunotherapy regimens comprise the standard
first-line treatment options for patients with mantle cell
lymphoma.23–31 Although a subset of patients with indo-
lent disease may undergo observation,32,33 most patients
ultimately require therapy. For young, fit, transplant-eligi-
ble patients, an accepted standard of care is induction
chemotherapy incorporating cytarabine and rituximab fol-
lowed by consolidation with an autologous stem cell trans-
plantation and rituximab maintenance.23–25,27,28 For older
patients or those who are transplant ineligible, chemoim-
munotherapy regimens such as bendamustine/rituximab
are recognized as standard approaches in addition to
R-CHOP (rituximab/cyclophosphamide/doxorubicin/vincristine/
prednisone) and VR-CAP (bortezomib/rituximab/cyclophos-
phamide/doxorubicin/prednisone).23,29,30,34
In recent years, advances in our understanding of mantle
cell lymphoma biology and drug development have led
investigators to examine chemotherapy-free treatment
paradigms. Targeted agents, including the cBTK inhibitors
ibrutinib, acalabrutinib, and zanubrutinib, showed unprec-
edented clinical activity in patients with relapsed/refractory
disease and are now second-line options for patients fol-
lowing chemoimmunotherapy.35–40 Furthermore, earlier
incorporation of ibrutinib (e.g., second-line compared with
later lines) is associated with improved response rates,
duration of response, and survival,17,41 suggesting that
even greater clinical activity may be seen in treatment-
na€|ve patients.
Here, we review selected clinical trials incorporating novel-
agents into frontline treatment. We also discuss how, as
reviewed in the prior section, developments in baseline
prognostic testing and novel molecular response tools
(e.g., MRD testing) are being incorporated into study
designs to develop risk-adapted treatment programs in
mantle cell lymphoma.
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Chemotherapy-Free Regimens
Lenalidomide-based combinations One of the earliest trials
to investigate a chemotherapy-free regimen was a multi-
center, phase II study of lenalidomide/rituximab.42 This
trial included patients with mantle cell lymphoma with
either low- or intermediate-risk disease or high-risk dis-
ease (MIPI $ 6.2) with a contraindication to intensive che-
motherapy. Lenalidomide/rituximab induction for 12
months was followed by indefinite lenalidomide/rituximab
maintenance. In the study population, the median age
was 65, 68% had low- or intermediate-risk MIPI, and
68% had a Ki67 index less than 30%. The ORR was 92%
(64% CR; 36 evaluable patients; median follow-up, 30
months).42 With a longer median follow-up of 64 months,
the 3-year PFS was 80% and the estimated 5-year PFS
was 64% with an estimated 5-year OS of 77%. The most
common grade 3 or higher adverse events during induc-
tion included neutropenia (42%) and rash (29%). During
maintenance, aside from neutropenia (42%), grade 3 or
higher toxicities were rare.43
An ongoing phase Ib study attempts to improve upon the
lenalidomide/rituximab regimen by examining the triplet of
venetoclax/lenalidomide/rituximab in patients with treat-
ment-na€|ve mantle cell lymphoma regardless of age or dis-
ease characteristics.44 In the 28 patients treated (median
age, 65; 64% patients with high-risk MIPI), grade 3 or
higher adverse events included neutropenia (68%) and
thrombocytopenia (50%), and there have been no discon-
tinuations because of toxicity. At a median treatment dura-
tion of 278 days, the triplet had an ORR of 96%, and
71% patients had undetectable MRD (clonoSEQ, level
106). Two patients with initial responses, both with TP53
mutations, have progressed.44 Although longer follow-up
will determine the durability of responses, one potential
advantage of this chemotherapy-free regimen is that BTK
inhibitors may be reserved for the relapsed setting.
Bruton tyrosine kinase inhibitor with or without
venetoclax-based combinations Multiple studies are
attempting to incorporate BTK inhibitors into the frontline
setting without the use of chemotherapy. Jain et al45
reported findings from a phase II study of ibrutinib and rit-
uximab for 2 years with continuation of ibrutinib in
patients age 65 or older with treatment-naive mantle cell
lymphoma without a Ki67 index greater than or equal to
50% or blastoid morphology. The ORR was 96%, and
median PFS and OS have not been reached (median fol-
low-up, 45 months). Notably, over half (56%) of the 50
patients discontinued therapy at the median follow-up of
45 months, including 21 patients discontinuing due to tox-
icity.45 Additionally, an ongoing large, randomized, phase
III study is comparing zanubrutinib/rituximab against
bendamustine/rituximab in patients with mantle cell lym-
phoma who are ineligible for autologous stem cell
 New Directions for Mantle Cell Lymphoma in 2022
transplantation (NCT04002297).46 This study has an
expected duration of 7 years and started accrual in
2019.46
A common clinical trial design for frontline chemotherapy-
treatment is a triplet combination of a BTK inhibitor, vene-
toclax, and an anti-CD20 antibody. Synergy of ibrutinib
and venetoclax has been seen in relapsed mantle cell lym-
phoma cells in the preclinical setting and in a phase II trial
of the combination in relapsed mantle cell lymphoma.47,48
These data, along with the safety and clinical activity of
triplet combinations observed in patients with chronic lym-
phocytic leukemia,49–51 provide a rationale to study BTK
inhibitors, venetoclax, and anti-CD20 antibody combinations
for treatment-na€|ve mantle cell lymphoma.52
The OASIS trial was a phase I/II study of the triplet ibruti-
nib/obinutuzumab/venetoclax in patients with relapsed
and treatment-na€|ve mantle cell lymphoma. In Cohort C,
15 treatment-naive patients received the triplet. Neutrope-
nia was the most common grade 3 or higher adverse
events (three patients), and only one treatment-na€|ve
patient discontinued because of adverse events (periph-
eral neuropathy). The ORR after six cycles was 86%, with
73% and 67% of patients attaining undetectable MRD in
the peripheral blood and bone marrow by allele-specific
oligonucleotide polymerase chain reaction, respectively.
With a median follow-up of 14 months, 1-year PFS for the
cohort was 93.3% with a 1-year OS of 100%.52
The combination of acalabrutinib/venetoclax/rituximab has
also shown preliminary safety and efficacy in treatment-
na€|ve patients.53 Preliminary results on 21 patients (71%
intermediate- or high-risk MIPI) have been reported. Com-
mon adverse events included diarrhea (62%) and head-
ache (52%). Neutropenia was the most common grade 3
or higher adverse event (24%). At a median time on study
of 16 months, one patient had discontinued because of
progression of disease. The triplet had an ORR of 100%
at the end of cycle 6, with a median duration of response
of 19 months and a 1-year estimated PFS rate of 89%. At
cycle 6, 75% of patients had undetectable MRD in the
peripheral blood (clonoSEQ assay, 16 patients tested).53
Additional studies that are examining triplet combinations
include the WINDOW-2 study with ibrutinib/rituximab/ven-
etoclax54 and the BOVEN study of zanubrutinib/obinutu-
zumab/venetoclax in mantle cell lymphoma with TP53
mutation.55 These study designs will be highlighted later
in the review.
Combinations of Chemotherapy and Targeted Agents
Several studies have added targeted agents to a chemoimmu-
notherapy backbone.56 Although a review of all ongoing trials is
beyond the scope of this review, Table 2 highlights some key
clinical trials of targeted agents plus chemotherapy.
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How to Move the Needle: Risk-Adapted Study Designs
and Dedicated Studies of Specific Patient Populations
Risk-stratified study designs Given the heterogeneity of
mantle cell lymphoma biology, a single approach is likely
to overtreat or undertreat certain patient subgroups. This
recognition has led to risk-stratified designs. In the
WINDOW-2 study, young patients with mantle cell lym-
phoma are treated with an induction regimen of ibrutinib/
rituximab/venetoclax (12 cycles of ibrutinib/rituximab,
venetoclax added cycles 5–12) and then assigned to fur-
ther consolidation versus observation based on pretreat-
ment disease characteristics.54 Low-risk patients were
defined as those with a Ki67 index less than or equal to
30%, tumors smaller than 3 cm, low MIPI, and lacking
high-risk features, which include TP53, NSD2, NOTCH
mutations, complex karyotype or del17p, MYC positivity,
tumors larger than 5 cm, blastoid/pleomorphic histology,
or partial response after 12 cycles of ibrutinib/rituximab/
venetoclax induction. In part 2, low-risk patients were
assigned to observation, whereas medium- and high-risk
patients received two or four cycles of short-course chemo-
immunotherapy with R-HyperCVAD (rituximab/cyclophos-
phamide/vincristine/doxorubicin/dexamethasone) alternat-
ing with methotrexate/high-dose cytarabine, respectively.54
Among 48 treated patients, ORR to parts 1 and 2 were
96%. Median PFS and OS have not been reached (median
follow-up of 24 months).54
Minimal residual disease-guided study designs The IMCL-
2015 study design incorporates both baseline disease
characteristics and an MRD-guided duration of therapy.57
In this phase II trial, patients with treatment-na€|ve, indo-
lent mantle cell lymphoma (defined by a combination of
prognostic and clinical factors) were treated with ibrutinib
and rituximab. Patients with undetectable MRD (< 1 cell
in 105) for at least 6 months were eligible to stop ibruti-
nib after 2 years of therapy; otherwise, patients remained
on ibrutinib. After 12 months, the ORR was 84% (80%
CR). Sixty-nine percent of patients (24 of 35 evaluable
patients after 24 cycles) discontinued ibrutinib per proto-
col because of undetectable MRD. In the patients who
discontinued ibrutinib, five patients have experienced
MRD-positive relapse (peripheral blood; range to detect-
able MRD, 3–20 months).57 Longer follow-up is needed to
determine the durability of responses.
Using MRD status to guide consolidation therapy is also an
area of ongoing study. An ECOG-ACRIN sponsored phase
III study is examining whether patients with mantle cell lym-
phoma who receive induction frontline chemotherapy and
have undetectable MRD require consolidation with autolo-
gous stem cell transplantation (NCT03267433).58 Patients
with mantle cell lymphoma in PET CR with undetectable
MRD following induction chemotherapy are randomly
assigned to receive either autologous stem cell
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook 619
 TABLE 2. Clinical Trials of Targeted Agents Plus Chemotherapy in Treatment-Naive Mantle Cell Lymphoma
620

Key Eligibility
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook

Regimen/NCT Number Criteria Details of Regimen Primary Endpoint No. of Patients Outcomes Selected Key Adverse Events
Targeted Agents + BR
SHINE study $ 65 years, BR × six cycles followed by 2 PFS Not yet available Not yet available
(NCT01776840)85 ineligible for years of R maintenance and
Phase III randomized intensive either placebo or ibrutinib until
study of ibrutinib 1 BR chemotherapy progression
vs. BR
Phase I/II study of > 65 years, stages Six cycles of lenalidomide 1 BR Phase I: MTD 50 Median PFS: 42 months Grade 3 or higher:
lenalidomide 1 BR86 II–IV followed by lenalidomide cycles Phase II: PFS (median follow-up 31 infection: 42%; neutropenia:
7–13 months) 76%; secondary primary
Median OS: 53 months malignancies: 16%
3-year OS: 73%
Phase II study of $ 65 years or < 65 Rituximab, bortezomib, 18-month PFS of 65% 74 24-month PFS: 70% Grade 3 or higher:
lenalidomide 1 years if transplant bendamustine, dexamethasone or higher (median follow-up 52 neutropenia: 51%;
bortezomib 1 BR87 ineligible/unwilling for a maximum of six cycles months) thrombocytopenia: 35%;
4-year OS: 71.3% anemia: 19%; fatigue: 19%;
neuropathy: 15%
ECOG-ACRIN E1411: Phase> 18 years (1) BR × six cycles followed by R Induction: PFS 373 Median PFS: 64.1 and 64.0 Grade 3 or higher:

Kumar et al
II study of BR 1/ maintenance; (2) BR 1 improvement (for months (median follow-up neutropenia: BVR: 27.5%; BR:
bortezomib followed by bortezomib followed by R bortezomib added to 51 months) 20.9%
R 1/ maintenance; (3) BR followed BR, arms two and (not significantly different; Neuropathy: BVR: 3.8%; BR:
lenalidomide88 by lenalidomide 1 R; (4) BR 1 four), regardless of study did not meet 0%
bortezomib followed by consolidation primary endpoint) Rash: BVR: 4.9%; BR: 6.4%
lenalidomide 1 R
Phase III study of BR 1 $ 65 years (1) BR 1 acalabrutinib vs. (2) BR PFS estimated Not yet available Not yet available
acalabrutinib vs. BR 1 1 placebo 546
placebo
(NCT02972840)89
Targeted Agents + Cytarabine-Containing Regimens
WINDOW-1 study90 # 65 years Part A: Up to 12 cycles of ORR after Part A 131 ORR 98% after Part A Grade 3 or higher:
Phase II study ibrutinib 1 R induction ORR 90% Part B (118 Part A: lymphocytopenia: 14%;
Part B: (1) At the time of CR in patients) rash: 12%; infection: 8%
part A, short course R-HCVAD Median PFS not reached Part B: lymphocytopenia: 73%;
alternating with R 1 high-dose (median follow-up of 42 neutropenia: 19%;
MTX-cytarabine × four cycles months) thrombocytopenia: 30%;
(2) if PR or SD after part A, 3-year PFS: 79% anemia: 17%; myalgia: 9%;
R-HCVAD alternating with R 1 3-year OS: 95% elevated liver enzymes: 9%
high- dose MTX-cytarabine ×
two cycles with reassessment
and R-HCVAD up to eight
cycles or less if CR; (3)
(Continued on following page)

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 TABLE 2. Clinical Trials of Targeted Agents Plus Chemotherapy in Treatment-Naive Mantle Cell Lymphoma (Continued)
Key Eligibility
Regimen/NCT Number Criteria Details of Regimen Primary Endpoint No. of Patients Outcomes Selected Key Adverse Events
discontinue if SD or PD during
R-HCVAD
Phase II study of Stage II–IV mantel Three-phase treatment: (1) 3-year PFS 47 3-year PFS: 64% (median
lenalidomide 1 R-CHOP, cell lymphoma lenalidomide 1 R-CHOP × four follow-up 2.8 years)
R-HiDAC and R 1 cycles; (2) R-HiDAC × two 3-year OS: 85%
lenalidomide91 cycles; (3) monthly R 1
lenalidomide × 6 months
Acalabrutinib 1 BR for 18–70 years, BR 1 acalabrutinib for cycles Stem cell mobilization 12 75% of patients completed Grade 3 or higher:
three cycles ! candidates for 1–3; rituximab 1 cytarabine 1 success rate six cycles thrombocytopenia: 100%;
acalabrutinib, rituximab, ASCT acalabrutinib cycles 4–6. ORR 83% neutropenia: 83%
and cytarabine for three Patients then underwent stem
cycles92 cell collection

New Directions for Mantle Cell Lymphoma in 2022

Phase III ECOG-ACRIN 18–70 years (1) BR 1 high-dose cytarabine; PET CT CR and PB Not yet available Not yet available
study (2) BR 1 high-dose cytarabine MRD negative rate
1 acalabrutinib; (3) BR 1
(NCT04115631)93 acalabrutinib
TRIANGLE study94 # 65 years, fit (1) R-CHOP/R-DHAP induction Superiority of one # Not yet available Not yet available
Phase III study followed by ASCT; (2) ibrutinib study arm:
1 R-CHOP cycles, otherwise comparison of
following (1) and ibrutinib investigator-assessed
maintenance for 2 years; (3) failure-free survival
R-CHOP 1 ibrutinib/R-DHAP
followed by ibrutinib
maintenance for 2 years without
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook 621

ASCT (1–3); R maintenance

Abbreviations: ASCT, autologous stem cell transplant; BR, bendamustine/rituximab; BVR, bendamustine/bortezomib/rituximab; CR, complete response; NCT, U.S. National Clinical Trials;
MTD, maximum tolerated dose; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; R, rituximab; R-CHOP, rituxi-
mab/cyclophosphamide/vincristine/doxorubicin/prednisone; R-DHAP, rituximab/dexamethasone/cytarabine/cisplatin; R-HCVAD, rituximab/cyclophosphamide/vincristine/doxorubicin/dexameth-
asone; R-HiDAC, rituximab/high dose cytarabine; MRD, minimal residual disease; MTX, methotrexate; SD, stable disease; PB, peripheral blood.

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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
 Kumar et al
FIGURE 1. Novel Therapeutic Approaches for Relapsed/Refractory Mantle Cell Lymphoma
transplantation followed by maintenance rituximab versus
maintenance rituximab alone.58 The study has the potential
to establish an MRD-guided treatment strategy.
Dedicated studies for high-risk patient populations Histori-
cal treatment approaches have not considered baseline dis-
ease genetics such as TP53 mutation. Given poor outcomes
for patients with TP53 mutations,5 the BOVEN study is test-
ing the frontline triplet of zanubrutinib/obinutuzumab/vene-
toclax in patients with mantle cell lymphoma with TP53
mutations with an MRD- and response-guided treatment
duration.55 Obinutuzumab is continued through cycle 8,
and the combination of zanubrutinib/venetoclax is contin-
ued for a minimum of 24 months and may be discontinued
or continued based on undetectable MRD status and clini-
cal response. In 17 patients treated, the combination has
been well-tolerated, with no patients discontinuing because
of toxicity. By cycle 3, 100% of patients had undetectable
peripheral blood MRD by flow cytometry (13 patients), and,
in the 14 patients with efficacy-evaluable disease, the ORR
was 86% (CR 64%). At a median follow-up of 4 months, two
patients had progressive disease and one patient died from
an unknown cause.55 The results of this ongoing study will
be important, as it is the first dedicated study of a genetically
selected, very high–risk patient population in the frontline
setting.
In summary, risk-stratification and MRD assessments are
being incorporated into clinical trial designs and fore-
shadow a future in which first-line mantle cell lymphoma
treatment selection moves beyond age and fitness alone
and incorporates mantle cell lymphoma biology. With
these new strategies, a new set of unanswered questions
will emerge. Risk classification systems must be standard-
ized and assessed in routine clinical practice to guide
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
optimal treatment selection. Additionally, if novel agents
are incorporated earlier, the therapeutic landscape and
available options for relapsed disease will also change.
The next section of this review will examine the manage-
ment of relapsed disease.
BEYOND CBTK INHIBITION IN MANTLE CELL LYMPHOMA:
CAR T, BISPECIFIC ANTIBODIES, AND NOVEL SMALL
MOLECULES
Introduction
Over the last decade, BTK inhibitors have become a
mainstay of therapy for patients with relapsed/refractory
mantle cell lymphoma, with several developed for
this indication.35,36,38,39 Although BTK inhibitors have
improved the prognosis of relapsed/refractory mantle cell
lymphoma, therapeutic options for patients who experience
progression during or following BTK inhibitors remain
limited. Novel agents (e.g., venetoclax, lenalidomide),
chemotherapy (e.g., rituximab/bendamustine/cytarabine),
and allogeneic stem cell transplant may all be used in this
setting; however, durable lymphoma responses following
progression during cBTK inhibitor therapy are rare.59–63
New therapies with distinct mechanisms of action, including
novel immunotherapeutics, antibody-drug conjugates, and
non-covalent BTK inhibitors, have demonstrated great
potential for improving outcomes post–BTK inhibitor failure
in relapsed/refractory mantle cell lymphoma (Figure 1).
Anti-CD19 CAR T-Cell Therapy
The development of anti-CD19 CAR T-cell therapy repre-
sents a major advance in the treatment of patients with
chemorefractory B-cell malignancies. The U.S. Food and
Drug Administration approved axicabtagene ciloleucel, an
anti-CD19 CAR T-cell product, for treatment of acute
 New Directions for Mantle Cell Lymphoma in 2022
lymphoblastic leukemia and diffuse large B-cell lymphoma
in 2017 and follicular lymphoma in 2021. Brexucabtagene
autoleucel (KTE-X19) is an anti-CD19 autologous CAR
T-cell product with similar construct to axicabtagene
ciloleucel, including the CD28 costimulatory domain, but
with an additional manufacturing step to promote T-cell
selection and remove circulating malignant B cells. In the
pivotal ZUMA-2 study,20 68 patients with mantle cell lym-
phoma were treated with lymphodepleting chemotherapy
followed by a single infusion of brexucabtagene autoleu-
cel. Eligible patients had received three or more prior lines
of therapy, including a cBTK inhibitor and 88% (60
patients) had prior exposure to at least one cBTK inhibitor.
With a median follow-up of 12 months, the ORR was
93%, with CR of 67%. With longer follow-up of 17.5
months, 70% of patients in CR maintained their response.
Grade 3 or higher cytokine release syndrome, neurotoxic-
ity, and infections occurred in 15%, 31%, and 32% of
patients, respectively, including two deaths secondary to
infection. The ZUMA-2 results led to U.S. Food and Drug
Administration approval of brexucabtagene autoleucel in
July 2020 for all patients with relapsed/refractory mantle
cell lymphoma. Real-world experience with brexucabta-
gene autoleucel was recently reported. In a retrospective
study of patients treated with brexucabtagene autoleucel
across 14 U.S. centers (107 leukapheresed, 93 rein-
fused),64 the ORR in 81 patients with efficacy-evaluable
disease was 86%, with a CR rate of 64%. Grade 3 or
higher cytokine release syndrome and neurotoxicity
occurred in 8% and 33% of patients, respectively. Sev-
enty-four (78%) patients would have met ZUMA-2 trial eli-
gibility, with 22% not meeting eligibility criteria because of
an ECOG Performance Status of 2 or higher (8 patients),
central nervous system involvement (seven patients), prior
therapies (48 patients; no prior BTK inhibitor, 17
patients), six or more prior therapies (12 patients), cytope-
nia (14 patients), renal or hepatic dysfunction (31
patients), other medical conditions (30 patients), and
active infection (two patients). Despite 27% of patients not
meeting ZUMA-2 enrollment criteria, efficacy and toxicity
were similar to that reported in ZUMA-2. In a smaller ret-
rospective study of brexucabtagene autoleucel across
seven European centers (28 leukapheresed; 19 rein-
fused),65 the reported ORR for all patients was 61% (CR
46%) and was 89% for reinfused patients (CR 68%).
Grade 3 or higher cytokine release syndrome and neuro-
toxicity occurred in 5% and 26% patients, respectively.
Because of the differences in regulatory approval between
the European Medicines Agency and the U.S. Food and
Drug Administration, all patients received a prior cBTK
inhibitor. Despite the limitations of retrospective data,
these data suggest that brexucabtagene autoleucel
remains effective and deliverable to patients with mantle
cell lymphoma outside of a clinical trial setting.
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
In the ongoing phase I TRANSCEND NHL001 study
(NCT02631044) patients with relapsed/refractory B-cell
non-Hodgkin lymphoma receive lymphodepleting chemo-
therapy followed by one to two infusions of lisocabtagene
maraleucel (JCAR017), which is an anti-CD19 autologous
CAR T-cell product with a 4-1BB costimulatory domain. In a
cohort of 32 patients with relapsed/refractory mantle cell
lymphoma,66 patients with two or more prior lines of therapy
were treated across two dose levels (dose level 1 5 50 × 106
CAR T cells; dose level 2 5 100 × 106 CAR T cells). The
ORR was 84%, with a CR rate of 59%. Responses, including
CRs, were observed across both dose levels and enrollment
is ongoing at dose level 2. Follow-up remains short at 6
months. Grade 3 or higher cytokine release syndrome, neu-
rotoxicity, and infections occurred in 3%, 12.5%, and 16%
of patients, respectively. In both ZUMA-2 and TRANSCEND
NHL001, efficacy was ob-served in patients with high-risk
biologic features, including TP53 mutation and blastoid
morphology, and in patients with a previous progression of
disease within 24 months event.
In summary, anti-CD19 CAR T-cell therapy is emerging
as an effective therapy for patients with relapsed/refrac-
tory mantle cell lymphoma, including those with high-
risk disease. Longer follow-up will help ascertain
whether CAR T-cell therapy may be curative for a pro-
portion of patients.
Bispecific Antibodies
A number of bispecific antibodies, especially targeting
CD20/CD3, are in development for treatment of B-cell
malignancies.67–71 The reported safety and efficacy
data in the small numbers of patients with mantle cell
lymphoma in early-phase trials for these agents are
encouraging.67–71
Glofitamab Glofitamab is an intravenously administered
anti-CD20/CD3 bispecific T-cell–engaging antibody, engi-
neered with a 2:1 configuration of CD20:CD3 to increase
potency72 and administered in fixed duration of 12 or
fewer cycles. In a phase I clinical trial (NCT03075696),
glofitamab was administered as monotherapy, and in
combination with obinutuzumab to 173 patients with
B-cell non-Hodgkin lymphoma, including six patients with
mantle cell lymphoma.67 Pretreatment administration with
obinutuzumab and a glofitamab “step-up” dosing schedule
were effective cytokine release syndrome mitigation strate-
gies. Updated results have been recently reported for 29
patients with relapsed/refractory mantle cell lymphoma.73
Eligible patients had received one or more prior lines of ther-
apy and were treated in dose escalation with glofitamab (as
either fixed dose or step-up dosing) plus obinutuzumab pre-
treatment (at either 1,000 mg or 2,000 mg). Sixty-nine per-
cent of patients had received prior cBTK inhibitor and 90%
were refractory to one or more prior therapies, with 69%
2022 ASCO EDUCATIONAL BOOK | asco.org/edbook 623
 Kumar et al
with disease refractory to their most recent therapy. The
ORR was 81%, with a CR of 67%, with similar efficacy irre-
spective of prior exposure to a BTK inhibitor. Twelve
patients in CR (85.7%) remained in remission at the time of
reporting; however, median follow-up was short at 2.4
months. Treatment with glofitamab was well-tolerated, with
no patients discontinuing treatment because of adverse
events. Grade 3 or higher cytokine release syndrome, neu-
rotoxicity, and infections occurred in 14.3%, 0%, and
13.8% of patients, respectively. Longer observation is
required to understand the durability of responses; how-
ever, in patients with relapsed/refractory diffuse large B-cell
lymphoma who experienced CR with glofitamab, durability
appears encouraging.74 These data warrant further investi-
gation in patients with relapsed/refractory mantle cell
lymphoma.
Epcoritamab Epcoritamab is a subcutaneously adminis-
tered bispecific CD20/CD3 antibody, administered until
disease progression or unacceptable toxicity. In a phase
I dose escalation study,71 68 patients with relapsed/
refractory B-cell non-Hodgkin lymphoma were treated
with epcoritamab, including four patients with mantle cell
lymphoma. For patients with mantle cell lymphoma, the
ORR was 50% (two patients), with CR in 25% (one
patient). Across all histologic subtypes, no patients dis-
continued treatment because of treatment-related
adverse events, and with a median follow-up of 10
months, treatment with epcoritamab was ongoing in
25% patients. Grade 3 or higher cytokine release syn-
drome and neurotoxicity occurred in 0% and 4% of
patients, respectively, with resolution of neurotoxicity in
less than 24 hours. Injection site reactions occurred in
47% patients, all grade 1–2, and one patient experi-
enced grade 3 tumor lysis syndrome. The expansion
phase of the trial is ongoing, with a larger cohort of
patients with mantle cell lymphoma to be evaluated
(NCT03625037).
Antibody-Drug Conjugates
Zilovertamab vedotin Zilovertamab vedotin is an antibody-
drug conjugate, which binds specifically to receptor tyro-
sine kinase-like orphan receptor-1 (ROR-1), an oncopro-
tein that is pathologically expressed in mantle cell
lymphoma and other malignancies. Results from the
phase I dose escalation75 report promising safety and effi-
cacy in 15 patients with mantle cell lymphoma (ORR,
47%; seven patients; CR in three patients). The most fre-
quently observed adverse events were neutropenia and
peripheral neuropathy, consistent with the use of mono-
methyl auristatin E, the antimicrotubule cytotoxin used in
zilovertamab vedotin. These preliminary data suggest
ROR-1 has promise as a therapeutic target in mantle cell
lymphoma, and further development is ongoing.
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Copyright © 2023 American Society of Clinical Oncology. All rights reserved.
Novel Small Molecule Inhibitors
Pirtobrutinib Although cBTK inhibitor has transformed
the treatment landscape in B-cell malignancies, the
majority of patients will eventually experience disease
progression or treatment intolerance. The most frequent
causes of BTK inhibitor resistance in mantle cell lym-
phoma are mutations in ATM, TP53, and NSD2,76,77
observed in up to 75% of patients who progress on
ibrutinib. Mutations in BTK are less frequent at approxi-
mately 17%,76,77 in contrast to chronic lymphocytic leu-
kemia, where BTK mutations are the dominant cause of
resistance. Pirtobrutinib (LOXO-305) is a highly potent
and selective first-in-class non-cBTK inhibitor, designed
to overcome resistance mutations associated with cBTK
inhibitor use, such as mutations in the C481S BTK
binding site.78 Pirtobrutinib was initially investigated in
dose-escalation and expansion across B-cell non-Hodg-
kin lymphoma subtypes in the phase I/II BRUIN study.
Initial results79 included 61 patients with mantle cell
lymphoma, with a median follow-up of 6 months. The
ORR in 56 patients with efficacy-evaluable disease was
52% (CR 25%). Updated results for 134 patients with
mantle cell lymphoma were recently presented80: 90%
had received prior cBTK inhibitor, 83% of whom had
discontinued for progression. The ORR in 111 patients
with efficacy-evaluable disease was 51%, with a CR of
25%, and ORR was higher among the 11 patients who
were cBTK inhibitor–na€|ve (ORR 83%; CR 18%). Nota-
bly, activity was observed among six patients who had
experienced CAR T-cell failure (ORR 50%). The median
follow-up was 8.2 months for responding patients, with
a median duration of response of 18 months. Across all
patients (non-Hodgkin lymphoma and chronic lympho-
cytic leukemia histologies), all-grade adverse events of
fatigue (23%), diarrhea (19%), neutropenia (18%),
bruising (22%), and contusion (17%) were most fre-
quent; these rates compare favorably with previous
cBTK inhibitor studies.36,38,39 Grade 3 or higher neutro-
penia was observed in 8% of patients, with all other
grade 3 or higher adverse events occurring in less than
1% of patients. Adverse events associated with pirtobruti-
nib were uncommon, with lower rates of atrial fibrillation
(2%), rash (11%), arthralgia (11%), and hypertension
(7%) than those observed with cBTK inhibitors use. Six
patients (1%) have discontinued treatment because of
treatment-related adverse events. BRUIN continues enroll-
ment, and pirtobrutinib is also being developed in phase
III trials as monotherapy and in combination with other
agents across B-cell malignancies. An ongoing phase III
trial in mantle cell lymphoma81 is enrolling patients with
BTK inhibitor–na€|ve relapsed/refractory mantle cell lym-
phoma following one or more prior lines of therapy
(NCT04662255). Patients are randomly assigned to
 New Directions for Mantle Cell Lymphoma in 2022

receive either pirtobrutinib or investigator’s choice of cBTK
inhibitor (ibrutinib, acalabrutinib, or zanubrutinib).
Parsaclisib Parsaclisib is a potent, highly selective, next-
generation inhibitor of PI3Kd. In a phase I dose escala-
tion trial,82 72 patients with relapsed/refractory B-cell
non-Hodgkin lymphoma were treated with parsaclisib
monotherapy. Treatment-related adverse events were
consistent with those previously reported with phosphati-
dylinositol 3-kinase inhibitors, including all-grade
adverse events of diarrhea/colitis (35%), nausea (36%),
fatigue (31%), and rash (31%). Grade 3 or higher colitis
occurred in seven patients (9%). The ORR in patients
with mantle cell lymphoma (nine patients) was 67%.
Parsaclisib has been administered to an additional 108
patients with BTK inhibitor–na€|ve mantle cell lymphoma
in the phase II CITADEL-205 study.83 Given that BTK
inhibitors are widely available for patients with relapsed/
refractory mantle cell lymphoma, and the deep and
durable responses frequently attained with BTK inhibi-
tors, the role of parsaclisib in the mantle cell lymphoma
treatment pathway is unclear, and the efficacy post–BTK
inhibitor therapy is currently unknown.
CONCLUSION
Despite the availability of highly effective frontline thera-
pies for mantle cell lymphoma, an unmet need for treat-
ment options persists for patients experiencing disease
relapse. Although the outlook for patients with lymphoma
progression following cBTK inhibition was initially felt to be
dismal, recent advances, including brexucabtagene auto-
leucel, CD20xCD3 bispecific antibodies, reversible non-
cBTK inhibitors, and antibody-drug conjugates hold hope
for future developments. Optimal sequencing and combi-
nation of these novel agents remains to be established.

AFFILIATIONS CORRESPONDING AUTHOR

1
Memorial Sloan Kettering Cancer Center, New York, NY Anita Kumar, MD, 136 Mountainview Blvd., Basking Ridge, NJ 07920;
2
Cancer and Haematology Centre, Oxford University Hospitals NHS email: kumara2@mskcc.org.
Foundation Trust, Oxford, United Kingdom
3
Department of Haematology, Sir Charles Gairdner Hospital, Perth, AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Australia AND DATA AVAILABILITY STATEMENT
4
Medical School, University of Western Australia, Perth, Australia Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/
10.1200/EDBK_349509.

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