New Directions in Targeted Therapeutic Approaches for Older Adults with Mantle Cell Lymphoma

Michael Wang, MD
Puddin Clarke Endowed Professor
Department of Lymphoma and Myeloma, Division of Cancer Medicine
MD Anderson Cancer Center
New Directions in Targeted Therapeutic Approaches
for Older Adults With Mantle Cell Lymphoma

Disclosures
Consultant: AbbVie, Acerta, ADC Therapeutics, AstraZeneca, Be Biopharma,
BeiGene, BioInvent, Deciphera, DTRM Biopharma (Cayman) Limited, Genentech,
InnoCare, Janssen, Kite, Lilly, Merck, Oncternal, Parexel, PeproMene Bio,
Pharmacyclics, VelosBio
Grants/research support: Acerta, AstraZeneca, BeiGene, BioInvent, Celgene,
Genmab, Genentech, InnoCare, Janssen, Juno, Kite, Lilly, Loxo Oncology,
Molecular Templates, Oncternal, Pharmacyclics, VelosBio, Vincerx
Other financial or material support: AbbVie, Acerta, AstraZeneca, Bantam
Pharmaceutical, Bantam Pharmaceutical, BeiGene, BioInvent, Dava Oncology,
Janssen, Kite, Merck, Pharmacyclics, TS Oncology

Learning Objectives
MCL = mantle cell lymphoma.
Identify clinical and biological prognostic factors that can guide
treatment decision making for older adults with MCL
Evaluate emerging data on targeted therapeutic approaches for
treatment-naive and relapsed/refractory MCL and their applicability to
older adults
Assess mechanisms of resistance to targeted therapies for MCL and
their implications for treatment selection

Mantle Cell Lymphoma: Introduction
SCT = stem cell transplantation; BTK = Bruton tyrosine kinase; ROR1 = receptor tyrosine kinase-like orphan receptor 1; BCL2 = B-cell lymphoma 2;
CAR = chimeric antigen receptor; CD19 = cluster of differentiation 19.
Jain & Wang, 2022
MCL is a rare subtype of B-cell non-Hodgkin’s lymphoma (B-NHL)
The MCL disease course is a repeated process of responses and relapses. During
repeated therapies, there is progressive increase in therapy resistance, which leads
to gradually decreased responses and shorter response durations. In the end, when
resistance is maximum and efficacy is minimum, the patient dies from progressive
MCL
Therapy resistance is the major barrier to cure; MCL remains incurable
With current treatment modalities (chemoimmunotherapy, SCT, covalent and non-
covalent BTK inhibitors, bispecific antibodies, an ROR1 drug conjugate, and BCL2
antagonists), clinical outcomes have improved
The FDA approval of an anti-CD19 CAR T-cell therapy, brexucabtagene autoleucel,
is a landmark advance for patients with refractory MCL

Epidemiology
Jain & Wang, 2022.
MCL accounts for about 3%-10% of NHLs in western countries. The
incidence increases with age. The median age at diagnosis is 68 or 71
years
The incidence is higher in Whites. In Asian countries, the incidence of
MCL is variable (1%-6% of all lymphomas), and the median age is 60
years
Males are predominantly affected by MCL, which is likely related to
recurrent loss of chromosome Y and deletion within the pseudo-
autosomal region 1 (PAR1)

Molecular Pathogenesis of MCL
SOX-11 = sex-determining regions Y (SRY) box transcription factor 11; IgM = immunoglobulin M; IGHV = immunoglobulin heavy chain region variable.
Jain & Wang, 2022.
Factors such as SOX-11 cell cycle dysregulation, genomic instability, distinct gene
expression, microenvironmental milieu, and epigenetic aberrations are critical in the
growth and development of MCL
CD5-positive “B1a” cells producing IgM were reported as the possible cell of origin
Conventional MCLs are hypothesized to derive from naive pre-germinal center B cells
of the mantle zone that do not undergo germinal center reaction and exhibit unmutated
IGHV genes, overexpression of SOX-11, high genomic complexity, and nodal disease
with an aggressive disease course
Another subset of MCL originates from antigen-experienced post-germinal
center/memory B cells and exhibits mutated IGHV, lack of SOX-11, a stable genome,
and a leukemic non-nodal, indolent clinical course. Non-nodal MCL has fewer copy
number alterations and fewer structural variants

Molecular Pathogenesis of MCL (cont.)
Jain & Wang, 2022.

Major Pathogenetic
Aberrations in MCL

Major Aberrations in Pathogenesis of MCL
UTR = untranslated region; BAX = BCL2-associated X; GC = germinal center; EpiCMIT = epiCMIT = epigenetic determined cumulative mitoses;
TP53 = tumor protein 53; BCR = B-cell receptor; PI3K = phosphoinositide-3-kinase; mRNA = messenger RNA.
Jain & Wang, 2022.
Cyclin D dysregulation
• Truncation 3’ UTR
• Inhibits BAX
• Dysregulation G1-S phase
transition
• Higher expression of cyclin D
signature
• Transcriptome downregulation
SOX-11 oncogene
• Prevent GC reaction
• Suppresses Bcl6
• Block PAX5 and terminal
differentiation
• + Angiogenesis PDGFA
• + Cell adhesion FAK kinase
• High CD70 immunosuppression
• Enhancer with SOX-11 promoter
Epigenetic aberrations
• DNA methylation
• Histone modification
• Chromatin organization
• Higher epiCMIT score
• Gain of function NSD2 mutations
• Loss of function KMT2D mutations
• SMARA4/SWI mutations
Unstable genome
• Recurrent breakage fusion
bridge cycles
• Chromothripsis
• TP53 alterations
• High aneuploidy in high
risk MCL
Metabolic reprogramming
• OXPHOS pathway
overactivation in ibrutinib-
resistant MCL
• MYC overexpression
BCR and microenvironment
• BTK/NFkB
• PI3K/AKT/mTOR pathway
• NFKBIE mutations
• High CD 163-positive
macrophages and high T
regulatory cells
• NFkB pathway mutations: BIRC3,
TRAF2
• CSF-1R axis and tumor
associated macrophages
Miscellaneous
• Gain of function mutations
• NOTCH1, NOTCH2
• HNRNPH non-coding
mutations
• Aberrant mRNA processing
• Transcription regulation:
UBR5, EF2B mutations

Molecular Pathogenesis of MCL (cont.)
Jain & Wang, 2022.
Constitutive overexpression of cyclin D1 with translocation t(11;14) (q13;q32)
is the hallmark oncogenic step in almost all MCLs
The juxtaposition of the DNA coding sequence for cyclin D1 at 11q13 with the
enhancer immunoglobulin heavy chain joining region at 14q32 promotes cell
cycle transition from G1 to S phase and promotes cell proliferation
In situ mantle cell neoplasia refers to the presence of cyclin D1–positive cells
in the inner mantle zone of lymphoid follicles
This entity exhibits an indolent course, with low risk of progression to overt MCL
These cases must be distinguished from MCL to avoid unnecessary systemic therapy
Cyclin D Dysregulation

Cyclin D1 Overexpression
Chromosomal translocation t(11;14) (q13;q32) is detected in the majority of
MCL cases. Healthy individuals can demonstrate t(11;14) in their peripheral
blood
Major breakpoints occur near the 5’ end in the major translocation cluster of
the CCND1 gene. Overexpressed cyclin D1 activates cyclin-dependent
kinases (CDKs) 4 and 6, which in turn phosphorylate and inactivate Rb (a
tumor suppressor gene) and promote transition from the G1 to S phase
Cyclin D1 also interacts with chromatin-remodeling, histone-modifying
enzymes and transcription factors and impairs the transcriptome, likely due
to the accumulation of RNA polymerase II with cyclin D1
CCND1 = cyclin D1 coding gene; RNA = ribonucleic acid.
Jain & Wang, 2022.

Cyclin D1 Overexpression (cont.)
Jain & Wang, 2022.
A cyclin D1–dependent transcription signature is associated with poor
outcomes. Perinucleolar localization of the CCND1 allele is important
since these areas are rich in RNA polymerase II, leading to activation
of cyclin D1 transcription
A short, truncated form of cyclin D1 (deletion affecting the 3'
untranslated region of cyclin D1 containing AU-rich elements)
stabilizes the cyclin D1 transcript, resulting in elevated cyclin D1
mRNA. Elevated levels of the truncated form of cyclin D1 are
associated with poor clinical outcome

CCND1 Gene Mutations
Jain & Wang, 2022.
Y44D mutation increases stability of the encoded protein
This gene is stable and can contribute to ibrutinib resistance in MCL
CCND1 mutations were observed in non-nodal MCL and were
associated with ibrutinib resistance

Atypical Cryptic Cyclin D1–Positive MCL
FISH = fluorescent in situ hybridization; IHC = immunohistochemistry.
Jain & Wang, 2022.
In unusual cases, variant cyclin D1 translocations such as t(2;11) (p11;q13)
and t(11;22) (q13;q11.2) can exist, in which the MCL cases show cyclin D1
rearrangement with light chain partners (IgK or IgL) instead of IgH, but
immunohistochemistry (IHC) for cyclin D1 is positive
Conventional karyotype or fusion or break-apart FISH probes fail to detect
variant translocations
Occasionally, cyclin D1 may not be detectable by IHC but is detectable by
FISH, and this can be seen in the presence of cyclin D1b isoform or a
mutation in the C-terminal domain of cyclin D1

Atypical Cyclin D1–Negative MCL
Jain & Wang, 2022.
In less than 1%-2% of MCL patients, cyclin D1 is undetectable by both
IHC and by FISH [t(11;14)]
In such cases, cyclin D2 or cyclin D3 gene rearrangements or
upregulated cyclin E can be observed. Generally, the clinical
presentation and gene expression profile of these cases are like those
of conventional MCL
In very rare situations, all cyclins D1, D2, and D3 can be negative
(triple-negative MCL). Cyclin E can be overexpressed and is
associated with aggressive blastoid MCL

Epigenetic Aberrations
Jain & Wang, 2022.
DNA methylation, histone modification, and chromatic organization are intricately
involved in MCL pathogenesis. Integrated genomics approaches reveal that
complex genomic variants and higher degree of DNA methylation are associated
with higher proliferation and aggressive behavior of MCL cells
Somatic mutations in epigenetic regulator genes include loss-of-function mutation
in the KMT2D (MLL2) gene and diminished H3K4 methylation levels. Mutated SWI-
SNF chromatic remodeling complex (SMARCA4, SMARCA2, and ARID2) genes
are associated with resistance to ibrutinib/venetoclax in MCL
DNA methylation profiling demonstrated 2 distinct clusters of MCL patients; the
majority of patients belong to Cluster 1, which is associated with unmutated IGHV
and an aggressive disease course, while Cluster 2 is associated with mutated
IGHV and indolent MCL

SOX-11 Oncogene Overexpression
The majority of MCL cells overexpress SOX-11
The exception is leukemic, nonmodal variant MCL, in which SOX-11 is generally negative
Cyclin D1 and STAT2 both regulate SOX-11 expression. SOX-11 super-
enhancer region is demethylated and promotes SOX-11 expression
SOX-11 overexpression can influence MCL in various ways
Constitutive activation of PAX-5, blocking differentiation of B-cells to plasma cells
Augmented BCR signaling
Suppression of Bcl-6 to avoid germinal center transit of MCL cells with unmutated IGHV
Promotion of angiogenesis via platelet-derived growth factor alpha (PDGF)
Promotion of invasiveness by cell-adhesion-mediated drug resistance via CXCR4, focal
adhesion kinases (FAKs), leading to enhanced PI3K/AKT signaling
Induces immunosuppressive microenvironment: increased Treg infiltration, downmodulation of
antigen processing, reduced T-cell activation
STAT2 = signal transducer and activator of transcription 2; CXCR4 = chemokine receptor type 4 aka fusin; Treg = regulatory T-cells.
Jain & Wang, 2022.

Genomic Instability
Higher degree of aneuploidy is a feature of aggressive-histology MCL
The approximate number of somatic mutations is 3,700 per case in
MCL
Pronounced chromosomal complexity (chromothripsis, breakage-
fusion-bridge cycles), copy number changes, and higher epiCMIT
score further contribute to genomic complexity
Somatic mutations can contribute to genomic instability
Jain & Wang, 2022.

TP53 Mutations
The TP53 gene is a tumor suppresser gene located at 17p13.1
Alterations in the TP53 gene by deletion or mutations can promote
genomic instability, cell cycle upregulation, inhibition of apoptosis, and
higher proliferation
TP53 mutations predict an aggressive disease course and inferior
outcomes in MCL
Jain & Wang, 2022.

ATM Mutations
ATM = ataxia telangiectasia–mutated.
The ATM tumor suppressor gene is located on 11q22-q23
ATM mutations are observed in approximately 30%-50% of MCL
cases at initial diagnosis
ATM is critically associated with DNA damage repair and plays
an important role in the regulation of cell cycle progression

Oxidative Phosphorylation
OXPHOS = oxidative phosphorylation.
Overexpression of the OXPHOS pathway was associated with
ibrutinib resistance in MCL
Inhibition of the OXPHOS pathway suppressed MCL growth in
mouse models of MCL

Microenvironmental Impact and BCR Signaling Kinases
CSF-1 = colony stimulating factor 1; mTOR = mammalian target of rapamycin.
Jain & Wang, 2022.
Cellular interactions in the MCL tissue microenvironment and the interplay of
cytokines are vital to support cell growth. Higher levels of CD163-positive (M2)
macrophages were associated with inferior outcomes
The lymph node microenvironment in MCL exhibits differential overexpression of
genes involved in BCR signaling and canonical NFkB pathways
M2 tumor–associated macrophages (CD163-positive) play an important role in
promoting MCL cell survival via CSF-1; therefore, CSF-1R inhibition is being
investigated
Targeting various BCR signaling kinases (PI3K, mTOR, BTK) and interactions with
stromal cells can overcome treatment resistance. Additional studies on the
cytokine-chemokine milieu and its impact on cellular interactions are ongoing

Miscellaneous Aberrations
UBR5 = ubiquitin protein ligase mutation; CLL = chronic lymphocytic leukemia.
Jain & Wang, 2022.
Gain-of-function truncating mutations in the NOTCH1 and NOTCH2 genes mediate apoptosis
resistance and induce MYC expression
Other mutations (ie, UBR5) are infrequent in MCL and influence transcription and post-
transcription processes. UBR5 is associated with blastoid transformation and B-cell
maturation. Other aberrant somatic mutations include MAP2K14, NOTCH2, BIRC3, SP140,
KMT2D, CARD11, SMARCA4, and BTK
Activation of PI3K/AKT and the integrin-β1 signaling pathway can be associated with acquired
ibrutinib resistance. In contrast to CLL, BTK C481S mutations and BCL2 mutations are
infrequent in MCL
Altered splicing of the HNRNPH1 gene associated with RNA processing is also observed
Most recently, data obtained from integrated analyses of DNA and RNA sequencing in MCL
identified 4 distinct genomic clusters of MCL patients with differing clinical outcomes

Clinical and Initial Diagnostic Workup
GI = gastrointestinal; CNS = central nervous system.
Jain & Wang, 2022.
Conventional MCL (the majority of MCLs) commonly presents with disease-
associated symptoms and lymphadenopathy, cytopenias, or lymphocytosis and
varying degrees of bone marrow involvement
Enlargement of spleen and tonsils/Waldeyer’s ring and segmental involvement of
the GI tract (lymphomatous polyposis) are frequent. Extranodal involvement of
kidneys, soft tissues, skin, the CNS, and other body sites are observed
In asymptomatic indolent or “smoldering” MCL, patients commonly present with
non-nodal leukemic MCL (absolute monoclonal lymphocyte count >5,000 cells/µL)
with splenomegaly. This form of MCL can masquerade as CLL. These patients can
also present with nodal/extranodal disease, with/without lymphocytosis

Clinical and Initial Diagnostic Workup (cont.)
MIPI = MCL International Prognostic Score.
Jain & Wang, 2022.
Broad Clinical Categories of MCL Based on Initial Assessment
Clinical presentation Clinicopathologic features
Indolent MCL (slow-
growing and
asymptomatic;
uncommon)
• Symptoms: asymptomatic and/or without any B symptoms (drenching
(drenching night sweats, unintentional weight loss of >10% normal body
body weight over 6 months or less, fever >38º C
Asymptomatic leukemic,
leukemic, non-nodal MCL
MCL (uncommon)
• Lymphocytosis in peripheral blood with/without splenomegaly
• Generally negative for SOX-11 expression in biopsies, exhibits mutated
mutated IGHV gene
Conventional MCL (most
(most common)
• Triple-positive MCL: nodal/non-nodal involvement, bone marrow and
tract involvement by MCL (symptomatic disease)
• Symptomatic bulky nodal/extranodal disease (CNS, GI, tonsil, skin)
• Further categorizes by MIPI risk score, Ki-67%
Clinically conventional
MCL but atypical
pathology (very rare)
• IHC cyclin D1–negative but FISH-positive for t(11;14) (q13;q32) due
CCND1 mutations or mutation in 3’ C-terminal end of cyclin D impairing
impairing antibody binding (clone SP4), mutations in cyclin D isoforms
isoforms (1a, 1b)
• IHC cyclin D1–positive but FISH-negative for t(11;14) (q13;q32) due
cryptic translocation in non-IgH partner light chains (IGK (2;11) and/or
and/or IGL
• IHC cyclin D1–negative and FISH-negative for t(11;14)(q13;q32) due
cyclin D1–negative but cyclin D2– or D3–positive MCL; in rare cases,
cases, patients can have triple–cyclin D–negative MCL (negative for D1,
D1, D2, and D3, that is cyclin E–positive MCL)
MCL patients commonly present
with B symptoms or disease site–
associated symptoms. Patients can
be asymptomatic with/without
lymphocytosis
It is critical to perform diagnostic
and prognostic assessment at the
initial diagnosis. Initial workup
includes history and physical exam;
assessment of performance status,
comorbidities, and B symptoms;
laboratory investigations; bone
marrow aspiration/biopsy; and
involved tissue biopsy

Jain & Wang, 2022.
Typical MCL immunophenotype is CD5, CD20, CD19, sIgM/sIgD, FMC-7–positive B cells with
monoclonal kappa/lambda light chains, dim/negative CD23, and strong cyclin D1 expression by
IHC. IHC analysis of involved nodal/extranodal tissues shows a strong nuclear staining for cyclin
D1 (BCL-1 or PRAD-1). Most MCLs are SOX-11–positive. The percentage of MCL cells positive
for Ki-67 from the involved non-marrow tissue biopsies is prognostic
Cytogenetic assessment for karyotype or FISH showing translocation t(11;14) (q13; q32) is a
diagnostic hallmark (90%-95% of MCLs). FISH for TP53 or deletion of 17p is recommended.
Whenever feasible, molecular studies may include somatic mutation of IGHV genes and/or
targeted DNA sequencing for somatic mutations
TP53, NOTCH1/2, SMARCA4, NSD2, and CCND1 gene mutations are useful for prognosis
Detailed histopathologic assessment of involved tissue biopsy is mandatory to distinguish
aggressive-histology MCL (blastoid/pleomorphic) from classic histology

Imaging includes an assessment with contrast-enhanced PET-CT or CT
Endoscopic evaluation of the upper and lower gastrointestinal tract with segmental
biopsies to confirm stage I-II disease can be done but is not mandatory. About
40%-80% of patients exhibit GI tract involvement by MCL at baseline
Cardiac assessment prior to starting BTK inhibitor therapy is recommended
Lumbar puncture and MRI of brain/spine are performed in cases with suspected
CNS involvement
Other exploratory studies that are not required for diagnosis but could be
performed (if feasible) include minimal residual disease (MRD) assessment
PET = positron emission tomography; CT = computed tomography; MRI = magnetic resonance imaging.
Jain & Wang, 2022.

Differential Diagnosis
Jain & Wang, 2022.
Lymphoid malignancies:
Small lymphocytic lymphoma (SLL)/CLL
Follicular lymphoma
Splenic marginal zone lymphoma
B-cell prolymphocytic leukemia (B-PLL)
Translocation t(11;14) (q13;q32) can be observed in a fraction of patients with
multiple myeloma (20%-25%), SLL/CLL (2%-5%), and plasma cell leukemia
In addition, variations in immunophenotype of MCL include CD10-positive MCL,
CD5-negative MCL, cyclin D1–negative MCL, CD200–positive MCL, SOX-11–
negative MCL, and CD23-positive MCL
In situ mantle cell neoplasia should be distinguished from MCL

Initial Staging and Restaging
The Lugano staging system is conventionally used to stage patients
with MCL; however, the current Lugano classification is limited and
does not account for MCL localized in the GI tract or for primary
leukemic non-nodal MCL
Furthermore, using serial imaging (PET-CT or CT scan), the 2014
Lugano lymphoma response criteria are used to demonstrate the
response to treatment
Jain & Wang, 2022.

Prognostic Factors
Advanced age, poor performance status, and significant comorbidities portend a poor
prognosis. In addition, MIPI risk scoring is commonly used
The simplified MIPI score is based on a weighted sum of performance status, age, LDH
levels above upper limit of normal, and white blood cell count. It divides patients into low-,
intermediate-, and high-risk categories
The 5-year OS rates for the low-, intermediate-, and high-risk MIPI categories were 81%,
63%, and 35%, respectively, and were validated in the context of European randomized
clinical trials with chemoimmunotherapy
The prognostic value of the simplified MIPI risk score is further improved by adding the
value of Ki-67% (MIPIb). A cutoff Ki-67% of >30% is commonly accepted as high-risk.
Additional modifications, such as MIPIb with expression of miR-18b and “MIPI genetic” with
TP53 and KMT2D gene mutations, are being explored to refine this score
LDH = lactate hydrogenase; OS = overall survival; MIPIb = biologic MIPI.
Jain & Wang, 2022.

Prognostic Factors (cont.)
Other established prognostic factors include aggressive-histology MCL (blastoid or
pleomorphic) and TP53 aberrations. Aggressive-histology MCL has an inferior prognosis
compared with classic-histology MCL. TP53 gene aberrations (mutations or deletions) are a
well-established high-risk factor in MCL
TP53 mutations fell under Cluster C4 in the comprehensive genomic study of MCL and
were associated with an activated MYC pathway, hyperproliferation, deletion of 9p, and
worse clinical prognosis. At diagnosis, frequency of TP53 mutations is about 11%-25%; the
frequency increases to 45% at relapse
Presence of both TP53 deletion (detected by FISH) and TP53 mutations (detected by DNA
sequencing) was associated with the worst survival. TP53 gene mutations may coexist with
other aberrations such as NOTCH1 mutation (71%), deletion of CDKN2A (del9p21) (31%),
and deletion of TP53 (del17p13) (31%). TP53 mutations may coexist with NSD2 mutations
in patients with ibrutinib resistance
Jain & Wang, 2022.

Lack of SOX-11 with mutated IGHV identified a subset of MCL patients with a favorable
prognosis
Patients with IGHV mutation (>3% deviation from the germline sequence) may exhibit a
better outcome compared with those with unmutated IGHV; however, this is not well
established in MCL
A complex karyotype, defined as having 3 or more chromosomal abnormalities in addition to
t(11;14), is generally considered a high-risk factor
The MCL35 assay is an RNA expression–based molecular assay from which a 17-gene
proliferation signature was derived to predict prognosis after first-line chemoimmunotherapy
In another study, a 6-gene signature (AKT3, BCL2, BTK, CD79B, PIK3CD, and SYK) was
predictive of poor outcome but exhibited higher sensitivity to ibrutinib in cell lines
Elevated levels of sIL-2Rα and the pro-inflammatory cytokines IL-8 and CCL4 (MIP-1β) in
sera are associated with poor prognosis in MCL patients
Jain & Wang, 2022.

Clinical factors: patients developing early disease progression (progression within 12-24 months
after receiving first-line therapy such as intensive chemoimmunotherapy with/without SCT)
exhibit poor outcomes
MRD-positive disease: MRD assessment in MCL is still investigational (flow cytometry from
bone marrow if involved at baseline), peripheral blood PCR for IgH
BTK inhibitor refractoriness: MCL patients who have disease progression on ibrutinib have a
median survival of 2.9 months (n=114)
Among 80 relapsed MCL patients who discontinued ibrutinib, outcomes of patients with
progression on ibrutinib (n=41) were poor, with median survival of 9 months (range 6-10)
Response to subsequent treatments was about 30%. Some potential mechanisms of BTKi
resistance in MCL include metabolic reprogramming with the prominent oxidative
phosphorylation pathway, 17q gain, BIRC5/survivin upregulation. Unlike CLL/SLL, BTK C481S
mutation is infrequent in ibrutinib-resistant MCL (10%-15%)
MRD = minimal residual disease; PCR = polymerase chain reaction; BTKi = BTK inhibitor.
Jain & Wang, 2022

Initial Approach to Newly Diagnosed Patient with MCL
CBC = complete
blood count.
Jain & Wang, 2022.
Initial
assessment
of patient
with MCL
Clinical assessment
• Performance status
• Age (< or ≥65 years)
• Disease related symptoms
• B symptoms
Comorbidities, especially cardiovascular risk assessment
• Nodal and extranodal involvement
• Spleen
• Gastrointestinal tract involvement
• Bone marrow infiltration
Basic investigations
• CBC with differential
• LDH
• Renal and liver function tests
• Serum calcium, uric acid, prothrombin time
with INR, HIV 1 and 2, hepatitis B and C
(HBcAb HBsAg, HCV Ab), beta-2
microglobulin (B2M)
Imaging/procedures
• Tissue biopsy, bone marrow biopsy with aspirate
• CT neck, chest, abdomen, and pelvis with contrast or
PET/CT
• Electrocardiogram, echocardiogram
• Upper GI endoscopy and colonoscopy with
segmental biopsies (for staging and full clinical
assessment)
Other investigations as indicated
• Protein electrophoresis
• Urine analysis
• Lipid profile, Hba1C, antinuclear
antibodies, cytokine panel, ferritin,
C-reactive protein, CMV, HHV-6,
pregnancy level
• Lumbar puncture, CSF flow, MRI of
brain and spine
Tissue biopsy
• Lymph node or non-nodal tissue core
needle/excisional biopsy and fine needle
aspirate (only for flow cytometry and
genomic testing)
• Hematopathology review of biopsy for
confirming the diagnosis of MCL
Bone marrow aspirate
• For flow cytometry, immunophenotype assessment
• FISH testing (11:14)(q13:q32), TP53 aberration and
MYC rearrangement, karyotype testing
• Genomic assessment for TP53, CCND1, SMARCA4,
KMT2D, NSD2
Tissue biopsy
• For cyclin D1, SOX-11, and Ki-67%
in lymphoma cells (except from
bone marrow), CD20, CD19, Pax-5,
CD5, CD10, and others
Histopathology review of biopsies to determine and
confirm the diagnosis of MCL
• Classic vs aggressive MCL (blastoid or pleomorphic)
• Ki-67%: low (<30%) vs high (≥30%)
• SOX-11 positive vs negative
• TP53 aberrant vs normal TP53
Atypical MCL
• Cyclin-D1 negative MCL
• CD5-negative MCL
• CD23-positive MCL
Molecular tests
• Somatic hypermutation status of IGHV
genes (mutated vs unmutated)
• Somatic mutations in TP53, KMT2D,
NSD2, SMARCA4, CCND1, ATM,
CDKN2A, NOTCH1, NOTCH2 genes

Treatment of Patients with MCL
Jain & Wang, 2022.
Treatment options for an individual MCL patient can be determined by initial
assessment
Rituximab-based chemoimmunotherapies with/without auto-SCT are standard first-line
treatment for young, physically fit patients
Therapeutic relevance of BTK inhibition in lymphoma was initially demonstrated in
canine lymphoma models by Honigberg et al. This seminal paper drove human trials
with BTK inhibitors (ibrutinib, acalabrutinib, zanubrutinib) in lymphoma. Venetoclax (a
BLC2 antagonist) is being investigated in refractory MCL
FDA approval of brexucabtagene autoleucel (anti-CD19 CAR T) is the most recent
advance in relapsed MCL. But patients with triple-resistant (refractory to BTK inhibitors,
venetoclax, and anti-CD19 CAR-T), and high-risk MCL are a significant challenge

Treatment of Patients with MCL (cont.)
Jain & Wang, 2022.
Generally, treatment approach can be decided based on patients
falling into the following clinical categories:
Indolent or smoldering asymptomatic
Untreated (age <65 or age ≥65 years), all risk categories
Relapsed: BTK inhibitor–naïve
Relapsed: BTK inhibitor–refractory
Triple–relapsed/refractory: ultra–high risk

Indolent or Smoldering Asymptomatic
Jain & Wang, 2022.
About 10%-20% of MCL patients can present with an asymptomatic presentation. This
includes non-nodal leukemic phase with splenomegaly or nodal MCL with no symptoms. A
wait-and-watch approach is recommended
Generally, these patients may exhibit good performance status; no B symptoms or
asymptomatic, non-bulky disease with normal LDH levels; low Ki-67% (<30%); and non-
aggressive cytomorphology
Generally, patients with indolent MCL with high-risk features can be observed without using
systemic therapy for about 18-24 months
Although not a standard practice, patients are sometimes referred for leukapheresis to
control lymphocytosis when the absolute lymphocyte count is >50,000 cells/µL, and are
then administered consolidation treatment
Limited-stage disease (stages I/II), can either be observed alone or can receive either local
radiation or systemic therapy if they are symptomatic or exhibit high-risk disease

Age and Therapy Selection
Jain & Wang, 2022.
Age is a very important factor for determining frontline therapy
<65 and >65 years old
My range: 60-70, depending on performance status and comorbidities

Elderly Patients
R-CHOP = rituximab/cyclophosphamide/doxorubicin hydrochloride/vincristine/prednisolone;
R-CHVP = rituximab/cyclophosphamide/doxorubicin hydrochloride/bortezomib/prednisolone; JCO = Journal of Clinical Oncology
Jain & Wang, 2022.
R-CHOP, maintenance rituximab
R-CHVP (bortezomib replacing vincristine)
Bendamustine/rituximab (BR), maintenance rituximab
R-lenalidomide
R-ibrutinib (recently published in JCO)

Previously Untreated Elderly Patients >65 Years
PFS = progression-free survival; ara-C = cytarabine arabinoside; ORR = overall response rate; CR = complete response.
Jain & Wang, 2022.
Median age of MCL diagnosis is around 70 years. Most elderly patients exhibit
comorbidities and are generally ineligible for SCT or intensive chemoimmunotherapy
Based on the data from 2 different phase 3 randomized trials, the BR combination has
become the standard first-line treatment for elderly MCL patients
In 2013, Rummel and colleagues reported that compared with R-CHOP, BR was non-
inferior in PFS and was less toxic. A 9-year follow-up confirmed these initial results.
Similarly, 5-year follow-up of the BRIGHT study (which included indolent NHL)
demonstrated the superiority of BR over R-CHOP for improved PFS
A phase 2 study investigated the R-BAC500 regimen (BR + 500 mg/m2 low-dose ara-C on
Days 2-4 every 4 weeks). The ORR and CR were 91% each, and 50% of the 57 patients
developed grade 3-4 neutropenia. After 7 years of follow-up, 7-year PFS and OS rates were
56% and 63%, respectively; 14% of patients had developed second cancers. Maintenance
rituximab after BR did not demonstrate an improvement in outcomes

Previously Untreated Elderly Patients >65 (cont.)
IR = ibrutinib/rituximab.
Jain & Wang, 2022.
Non-chemotherapy options
Lenalidomide with rituximab was investigated in 38 patients. A 7-year follow-up of this
study showed that 33% were in remission beyond 7 years, but 42% of patients had
grade 3 or higher neutropenia, and 16% developed second primary cancers
A phase 2 study on the combination of ibrutinib with rituximab in elderly patients with
non-blastoid/pleomorphic and Ki-67% <50% was reported by Jain et al. With a median
follow-up of 45 months, PFS and OS were not reached, and ORR and CR were 96%
and 71%, respectively. Overall, 28 patients (56%) discontinued therapy. Grade 3 or
higher atrial fibrillation was 22%. The combination of IR was highly effective; however,
the authors recommend that elderly patients undergo cardiovascular risk assessment
prior to ibrutinib

Relapsed BTK Inhibitor–Naive Setting
ITK = IL-2 receptor inducible kinase; Th-2 = T helper-2.
Jain & Wang, 2022.
Ibrutinib is an irreversible, covalent inhibitor of BTK (a TEC kinase). Ibrutinib
has off-target effects on other TEC kinases, partially explaining the adverse
effects such as bleeding and cardiac arrythmias (mainly atrial fibrillation)
Lymphocytosis after ibrutinib is not considered a sign of disease
progression. Ibrutinib can also improve T-cell function by increasing the
persistence of activated T cells, inhibiting ITK and blocking Th-2
differentiation
Ibrutinib

Relapsed BTK Inhibitor–Naive Setting (cont.)
A pooled analysis of ibrutinib-treated relapsed MCL patients with a median
follow-up of 41.5 months was also reported. Among the 370 patients, 17%
continued to receive treatment for more than 4 years. The median PFS and
OS were 12.5 and 26.7 months, respectively. Blastoid MCL and TP53-
mutated MCL exhibited inferior response rates
Cardiovascular effects, arrythmias (mainly atrial fibrillation), and
hypertension are critical to watch for in patients taking ibrutinib. Ibrutinib can
also induce platelet dysfunction, contributing to bleeding tendency.
Therefore, in patients taking ibrutinib, concomitant anticoagulant and
antiplatelet therapy should be carefully evaluated
Jain & Wang, 2022.
Ibrutinib

Ibrutinib for Relapsed/Refractory MCL
Dreyling et al, 2022.

Baseline Characteristics of Pooled Dataset
LOT = line of therapy;
sMIPI = simplified MIPI.
Rule et al, 2017; Rule et al, 2019.
Among the 370
patients, 99
(26.8%) had 1
prior LOT, 271
(73.2%) had >1
prior LOT, and
162 (43.8%) had
≥3 prior LOT
PCYC-1104
(N=111)
SPARK
(N=120)
RAY
(N=139)
Pooled
(N=370)
Median age, years 68 67.5 67 67·5
ECOG performance status
0-1 89% 91% 99% 94%
2 10% 9% 1% 6%
> 2 1% 0% 0% 1%
sMIPI
Low risk (1-3) 14% 24% 32% 24%
Intermediate risk (4-5) 38% 48% 47% 45%
High risk (6-11) 49% 28% 22% 32%
Median prior lines of treatment (range) 3 (1-5) 2 (1-8) 2 (1-9) 2 (1-9)
Blastoid histology 15% 9% 12% 12%
Bulky disease (≥5 cm) 39% 53% 54% 49%
Extranodal disease 54% 60% 60% 58%
Prior lenalidomide 24% 19% 6% 16%
Prior bortezomib 43% 100% 22% 54%
Prior stem cell transplant 11% 33% 24% 23%
Bone marrow involvement 49% 42% 47% 46%
Lactate dehydrogenase 80% 43% 42% 54%
Beta 2-microglobulin 0% 38% 34% 25%
Prior high-intensity therapy 35% 43% 24% 34%

Baseline Characteristics of Patients With 1 Prior LOT
POD = progression of disease; POD24 = POD within 24 months.
Ibrutinib for Relapsed/Refractory MCL: Overall and by POD
Patients with POD24 on the
frontline regimen
(n=43)
Patients with POD≥24 on
frontline regimen
(n=56)
Total patients with
1 prior LOT
(N=99)
Age <70 years, n (%) 20 (46.5%) 35 (62.5%) 55 (55.6%)
Age ≥70 years, n (%) 23 (53.5%) 21 (37.5%) 44 (44.4%)
Simplified MIPI, n (%)
High risk 14 (32.6%) 12 (21.4%) 26 (26.3%)
Intermediate risk 22 (51.2%) 23 (41.1%) 45 (45.5%)
Low risk 7 (16.3%) 21 (37.5%) 28 (28.3%)
Blastoid variant, n (%)
Yes 5 (11.6%) 1 (1.8%) 6 (6.1%)
No 38 (88.4%) 55 (98.2%) 93 (93.9%)
Bulky disease ≥5 cm, n (%)
Yes 21 (48.8%) 18 (32.1%) 39 (39.4%)
No 22 (51.2%) 38 (67.9%) 60 (60.6%)
Refractory disease, n (%)
Yes 8 (18.6%) 1 (1.8%) 9/79 (11.4%)
No 33 (76.7%) 37 (66.1%) 70/79 (88.6%)
TP53 status, n (%)
Mutated 6 (14.0%) 2 (3.6%) 8/40 (20.0%)
Wild type 9 (20.9%) 23 (41.1%) 32/40 (80.0%)
NA 28 (65.1%) 31 (55.4%) –

Patient Disposition
AE = adverse event; d/c = discontinuation.
At data cutoff (March 2021), 24 (6.5%)
patients were still receiving ibrutinib in the
CAN3001 study
Median ibrutinib exposure for these
patients was 7.8 years (range: 7.1-9.7)
The most common reasons for
discontinuation of ibrutinib were
progressive disease (61.9%), followed by
AEs (12.2%)

Duration of Ibrutinib Treatment
Dreyling et al, 2022
Of the total 370 patients:
115/370 (31.1%) were treated with
ibrutinib for ≥2 years
45/370 (12.2%) were treated for
≥5 years

Ibrutinib Outcomes Were Best in Patients With 1 Prior
LOT
CI = confidence interval; PR = partial response; SD = stable disease; PD = progressive disease; NE = not estimable; NR = not reached; DOR = duration of response.
End point
Overall
(N=370)
Prior lines of treatment
1 (n=99) >1 (n=271)
PFS, median (95% CI), months 12.5 (9.8-16.6) 25.4 (17.5-51.8) 10.3 (8.1-12.5)
Patients with CR (n=102) 68.5 (51.7-NE) NR (38.0-NE) 67.7 (41.7-NE)
Patients with PR (n=156) 12.6 (10.3-16.6) 24.2 (13.9-36.5) 10.5 (8.3-12.9)
Overall response rate, n (%) 258 (69.7%) 77 (77.8%) 181 (66.8%)
CR 102 (27.6%) 37 (37.4%) 65 (24.0%)
PR 156 (42.2%) 40 (40.4%) 116 (42.8%)
SD 43 (11.6%) 11 (11.1%) 32 (11.8%)
PD 56 (15.1%) 8 (8.1%) 48 (17.7%)
NE/unknown 8 (2.2%) 1 (1.0%) 7 (2.6%)
Missing 5 (1.4%) 2 (2.0%) 3 (1.1%)
DOR, median (95% CI), months 21.8 (17.2-26.4) 35.6 (23.2-66.5) 16.6 (12.9-21.3)
Patients with CR (n=102) 66.4 (49.5-NE) NR (35.6-NE) 65.6 (40.0-NE)
OS, median (95% CI), months 26.7 (22.5-38.4) 61.6 (36.0-NE) 22.5 (16.2-26.7)
Patients with CR (n=102) NR (NE-NE) NR (74.3-NE) NR (NE-NE)

PFS by Best Response (CR vs PR)
In patients who achieved a CR
(n=102):
Median PFS and DOR were 68.5
and 66.4 months, respectively
Median OS was NR, with a 5-
year OS rate of 83%
The durability of response in
patients who achieved a CR was
similar regardless of number of
prior LOT

PFS and OS by Prior LOT
PFS and OS were better in ibrutinib-treated patients with 1 prior LOT (n=99)
than in patients with >1 prior LOT (n=271)
Median PFS was 25.4 months and median OS was 61.6 months
ORR was 77.8%, with a CR rate of 37.4% and a median DOR of 35.6 months

PFS With Ibrutinib in Patients With 1 Prior LOT
2L = second-line; CIT = chemoimmunotherapy.
Median PFS with 2L ibrutinib
was longest (57.5 months) in
patients with extended
response to frontline CIT
(POD≥24; n=56)
Median DOR in these
patients was NR
Ibrutinib for Relapsed/Refractory MCL: By Frontline POD24 vs POD≥24

Patients Achieving Longer PFS With Ibrutinib vs Prior
Regimen
Patients with longer PFS on ibrutinib
prior regimen (n=184)
Patients with shorter PFS on ibrutinib
prior regimen (n=185)
Age <70 years, n(%) 120 (65.2%) 89 (48.1%)
Age ≥70 years, n(%) 64 (34.8%) 96 (51.9%)
Simplified MIPI, n/N(%)
High-risk 45/182 (24.7%) 71/185 (38.4%)
Intermediate-risk 84 (46.2%) 80 (43.2%)
Low-risk 53/182 (29.1%) 34/185 (18.4%)
Bulky disease (≥5 cm), n/N(%)
Yes 80/183 (43.7%) 100/184 (54.3%)
No 103/183 (56.3%) 84/184 (45.7%)
Blastoid variant, n(%)
Yes 16 (8.7%) 27 (14.6%)
No 168 (91.3%) 158 (85.4%)
TP53 status, n/N(%)
Mutated 4/63 (6.3%) 16/81 (19.8%)
Wild type 59/63 (93.7%) 65/81 (80.2%)
Ibrutinib for Relapsed/Refractory MCL: Baseline Characteristics

Incidence of BTKi-Specific AEs of Clinical Interest
SAE = serious AE.
Years on Ibrutinib
AE, n (%)
<1
(n=370)
1 to <2
(n=180)
2 to <3
(n=115)
3 to 4
(n=83)
4 to <5
(n=62)
5 to <6
(n=45)
6 to <7
(n=32)
≥7
(n= 27)
Overall
(N=370)
Grade ≥3 AEs 251 (67.8%) 86 (47.8%) 39 (33.9%) 31 (37.3%) 22 (35.5%) 17 (37.8%) 9 (28.1%) 7 (25.9%) 302 (81.6%)
SAEs 175 (47.3%) 61 (33.9%) 34 (29.6%) 23 (27.7%) 19 (30.6%) 15 (33.3%) 8 (25.0%) 6 (22.2%) 241 (65.1%)
Major hemorrhage 18 (4.9%) 4 (2.2%) 3 (2.6%) 2 (2.4%) 0 1 (2.2%) 0 0 27 (7.3%)
Atrial fibrillation
Grade ≥3 16 (4.3%) 5 (2.8%) 4 (3.5%) 0 1 (1.6%) 1 (2.2%) 1 (3.1%) 0 25 (6.8%)
SAE 15 (4.1%) 2 (1.1%) 2 (1.7%) 0 1 (1.6%) 1 (2.2%) 1 (3.1%) 0 22 (5.9%)
Diarrhea
Grade ≥3 11 (3.0%) 3 (1.7%) 1 (0.9%) 0 1 (1.6%) 0 0 0 15 (4.1%)
SAE 4 (1.1%) 0 1 (0.9%) 0 1 (1.6%) 0 0 0 6 (1.6%)
Hypertension
Grade ≥3 10 (2.7%) 6 (3.3%) 3 (2.6%) 2 (2.4%) 0 0 0 1 (3.7%) 19 (5.1%)
SAE 0 0 0 0 0 0 0 0 0
Rash
Grade ≥3 4 (1.1%) 0 0 0 0 0 0 0 4 (1.1%)
SAE 1 (0.3%) 0 0 0 0 0 0 0 1 (0.3%)
Arthralgia
Grade ≥3 2 (0.5%) 1 (0.6%) 1 (0.9%) 1 (1.2%) 0 0 0 0 4 (1.1%)
SAE 1 (0.3%) 0 0 1 (1.2%) 0 0 0 0 2 (0.5%)

Incidence of BTKi–Specific AEs of Clinical Interest
(cont.)
TEAE = treatment-related AE.
With up to 9.7 years of follow-up, the most frequent grade ≥3
TEAEs (in ≥5% of patients) included neutropenia (17.0%),
pneumonia (13.5%), thrombocytopenia (12.4%), anemia (10.5%),
atrial fibrillation (6.8%), and hypertension (5.1%)
During the 2 additional years of follow-up since the last reported
2019 data cutoff, the overall AE profile remained largely
unchanged, indicating that long-term use of ibrutinib may not
lead to cumulative toxicities

Ibrutinib: Conclusions
R/R = relapsed/refractory.
Dreyling et al, 2022; Kumar et al, 2019.
This pooled analysis of ibrutinib treatment in R/R MCL with extended follow-up of
nearly 10 years indicates that a notable number of patients had durable disease
control for >5 years
Patients with only 1 prior LOT and those achieving a CR continued to have the best
outcomes with ibrutinib
Treatment with single-agent ibrutinib in R/R MCL appears to have mitigated the
historical trend of successive declines in median PFS with each line of CIT,
regardless of age and prior LOT
There was no emerging toxicity with ibrutinib during extended follow-up
Taken together, these findings support the long-term efficacy and safety of single-agent ibrutinib in
R/R MCL. Ibrutinib represents a significant advancement in treating MCL and should be considered a
standard-of-care 2L treatment option, regardless of a patient’s initial response to frontline therapy

Single-Agent Ibrutinib
PFS declines with each successive line of CIT
POD status is an adverse prognostic factor
With ibrutinib:
Despite shorter PFS in POD24 than POD≥24, ibrutinib outshined in
patients with POD24 than second-line CIT
Median PFS with ibrutinib was >4 years in POD≥24 patients, equivalent
to 15-month improvement versus frontline PFS
Ibrutinib reversed the trend of declining PFS reported in CIT
retreatment
May Mitigate the Trend of Successive PFS Declines in R/R MCL Patients

Ibrutinib: Rapid Nodal Response
Chang et al, 2011.
Accompanied by Egress of CD19/CD5–Positive B-cells
50%
100%
150%
200%
ALC
%
Change
from
Baseline
Day 2
Lymphocyte Count
CD5
CD5
CD19 CD19
Day 1 Day 8

KTE-X19 = brexucabtagene autoleucel.
Wang, Munoz, et al, 2022.
Phase 2 ZUMA-2 study:
Patients pre-treated with BTKi received KTE-X19
Median PFS = 11.3 months (POD24) vs 29.3 months (POD≥24)
CAR T-cell expansion peak was higher in patients who received prior
ibrutinib versus acalabrutinib
Data suggest unique potential of ibrutinib to enhance CAR T-cell
expansion and improve overall outcome in R/R MCL, regardless of
POD status
CAR-T for Progressions After Second-Line Ibrutinib Treatment

Acalabrutinib
Acalabrutinib is a second-generation covalent, irreversible inhibitor of BTK. Better
selectivity and minimal off-target kinase (EGFR, TEC, ITK) inhibitory activity of
acalabrutinib provide distinct advantages over ibrutinib
A low incidence of atrial fibrillation and cardiovascular side effects and lesser risk of
bleeding compared with ibrutinib were noted with acalabrutinib in a randomized
clinical trial in CLL. In the pivotal ACE-LY-004 multicenter phase 2 trial in relapsed
MCL (n=124), patients had a median of 2 lines of prior therapy
After a median follow-up of 38.1 months, the ORR was 81% with 48% CR, the
median PFS was 22.5 months, and the median OS was 59 months. Any grade
atrial fibrillation was seen in 2.4% of patients. Headache, diarrhea, fatigue, and
myalgia were the most common side effects
EGFR = epidermal growth factor receptor.
Jain & Wang, 2022.
Patients with Relapsed BTK Inhibitor–Naive MCL

Acalabrutinib for Relapsed/Refractory MCL
IHP = International Harmonization Project; IRC = independent review committee.
Wang et al, 2018; Cheson et al, 2014; Cheson et al, 2007.
The primary end point was
investigator-assessed ORR
according to the 2014 Lugano
Classification
High concordance was observed
between investigator- and IRC-
assessed ORR and CR (91% and
94%, respectively)
IRC-assessed ORR by 2007 IHP
criteria (exploratory end point) was
75%, with a CR rate of 30%
ACE-LY-004 Initial Analysis: Response to Acalabrutinib
ORR using the 2014 Lugano Classification
Type of response
N=124
Investigator-
assessed
n (%)
IRC-assessed
N (%)
ORR (CR + PR) 100 (81%) 99 (80%)
Best response
CR 49 (40%) 49 (40%)
PR 51 (41%) 50 (40%)
SD 11 (9%) 9 (7%)
PD 10 (8%) 11 (9%)
Not evaluable 3 (2%) 5 (4%)

Change in Tumor Burden and Best Response Status
aMaximum change from baseline in SPD for all treated patients with baseline and ≥1 postbaseline lesion measurement; 6 subjects were excluded due
to early PD by evidence other than CT (n=4), started subsequent anticancer therapy (n=1) or death (n=1).
SPD = sum of product diameters.
Cheson et al, 2014; Wang et al, 2018.
Most patients (94%) experienced a reduction in lymphadenopathya
ACE-LY-004: Acalabrutinib for Relapsed/Refractory MCL

1
11
10
17
15
19
17
24
1
2
4
7
2
5
6
10
12
5
5
8
1
1
1
3
2
6
1
0 10 20 30 40 50 60
Pneumonia
Neutropenia
Anemia
Pyrexia
Nausea
Cough
Myalgia
Fatigue
Diarrhea
Headache
Grade 1 Grade 2
Grade 3 Grade 4
100
Grade ≥3 AEs Occurring in ≥5% of All Patients
AEs Occurring in ≥15% of Patients
Most Common Adverse Events
Wang et al, 2018.
ACE-LY-004: Acalabrutinib for Relapsed/Refractory MCL
.

SHINE: Ibrutinib + Bendamustine/Rituximab
First-Line Treatment for Older Patients with MCL
Published on 3rd June 2022

Bendamustine/Rituximab
VR-CAP = bortezomib/rituximab/cyclophosphamide/doxorubicin/prednisone.
Jain & Wang, 2022; Wang, Jurczak et al, 2022.
Older patients with newly diagnosed MCL are usually treated
with chemoimmunotherapy regimens such as BR, R-CHOP, or
VR-CAP
BR has become the most commonly used first-line regimen
BR alone
Improved PFS compared with R-CHOP (35 vs 22 months) and has a
better safety profile
BR with rituximab maintenance:
Significantly improved PFS compared with BR alone in 2
independent real-world studies
First-Line MCL Treatment in Older Patients

Ibrutinib: First-in-Class Once-Daily BTK Inhibitor
Dreyling et al, 2022; Wang, Jurczak et al, 2022.
Ibrutinib has transformed the care of patients with relapsed/refractory
MCL; it is particularly effective and durable at first relapse
78%
37%
67%
24%
0
20
40
60
80
100
ORR CR
%
of
patients
1 prior LOT (n = 99) > 1 prior LOT (n = 271)
Ibrutinib + BR demonstrated activity in first-line MCL in a phase 1b study

SHINE: Ibrutinib + BR
Wang, Jurczak, et al, 2022.
Randomized, Double-Blind, Phase 3 Study
Primary end point: PFS (investigator-assessed) in the ITT population
Key secondary end points: response rate, time to next treatment, overall survival,
safety
Enrolled between May
2013 and November
2014 at 183 sites
N=523
R
1:1
BR induction for 6 cycles
Rituximab maintenance
every 8 weeks for 12 cycles
Ibrutinib 560 mg (4 capsules daily) until PD or unacceptable
toxicity
Patients
• Previously untreated MCL
• ≥65 years of age
• Stage II-IV disease
• No planned stem cell
transplant
Stratification factor
• Simplified MIPI score
(low vs intermediate vs
high)
if CR or PR
if CR or PR Rituximab maintenance
every 8 weeks for 12 cycles
Placebo (4 capsules daily) until PD or unacceptable toxicity
BR induction for 6 cycles

Patient Disposition and Treatment Exposure
SHINE: Ibrutinib + BR for Untreated MCL
Screened
(N=589)
Randomized
(N=523)
Ibrutinib + BR (N=261)
• Received therapy (N=259)
Excluded (n=66)
• Not eligible (n=52)
• Other (n=14)
Placebo + BR (N=262)
• Received therapy (N=260)
• Received 6 cycles of BR (n=209)
• Received ≥1 dose of R maintenance (n=206)
• Ibrutinib duration: 24.1 months (range: 0.2-95.2)
• Received 6 cycles of BR (n=215)
• Received ≥ 1 dose of R maintenance (n=210)
• Placebo duration: 34.1 months (range: 0.0-97.5)
Discontinued therapy (n=220)
• AE (n=103)
• PD (n=28)
• Withdrawal of consent (n=34)
• Death (n=26)
• Other (n=29)
Discontinued therapy (n=201)
• PD (n=91)
• AE (n=63)
• Withdrawal of consent (n=21)
• Death (n=15)
• Other (n=11)
Median follow-up: 84.7 months (7.1
years)
Data cutoff: June 30, 2021

Baseline Characteristics
Wang, Jurczak et al, 2022.
Ibrutinib + BR
(n=261)
Placebo + BR
(n=262)
Median age (range), years 71 (65.0%-86.0%) 71 (65-87%)
≥75 years, n (%) 74 (28.4%) 82 (31.3%)
Male, n (%) 178 (68.2%) 186 (71.0%)
ECOG PS 1, n (%) 127 (48.7%) 118 (45.0%)
Simplified MIPI, n (%)
Low-risk 44 (16.9%) 46 (17.6%)
Intermediate-risk 124 (47.5%) 129 (49.2%)
High-risk 93 (35.6%) 87 (33.2%)
Bone marrow involvement, n (%) 198 (75.9%) 200 (76.3%)
Blastoid/pleomorphic histology, n (%) 19 (7.3%) 26 (9.9%)
Extranodal, n (%) 234 (89.7%) 226 (86.3%)
Bulky (≥5 cm), n (%) 95 (36.4%) 98 (37.4%)
TP53 mutated, n (%) 26 (10.0%) 24 (9.2%)
TP53 mutation status unknown, n (%) 121 (46.4%) 133 (50.8%)

Primary End Point of Improved PFS Was Met
Ibrutinib + BR and R maintenance achieved…
Significant improvement in median PFS
by 2.3 years (6.7 vs 4.4 years)
25% reduction in risk of PD or death
Ibrutinib + BR
Patients at Risk
Placebo + BR
261 228 207 191 182 167 152 139 130 120 115 106 95 78 39 11 0
262 226 199 177 166 158 148 135 119 109 103 98 90 78 41 11 0
0
0
10
20
30
40
50
60
70
80
90
100
PFS
(%)
6 12 18 24 30 36 42 48
Months
54 60 66 72 78 84 90 96
Ibrutinib + BR
Placebo + BR
Ibrutinib +
BR
(n=261)
Placebo +
BR
(n=262)
Median PFS,
months (95% CI)
80.6
(61.9-NE)
52.9
(43.7-71.0)
Stratified HR
(95% CI)
0.75 (0.59-0.96)
P value 0.011

PFS Hazard Ratio in Subgroups
ECOG = Eastern Cooperative Oncology Group; PS = performance status.
Hazard ratio (HR) 95% CI
0.75 0.59-0.96
0.77 0.58-1.02
0.65 0.40-1.06
0.78 0.60-1.03
0.59 0.35-1.00
0.67 0.45-0.99
0.78 0.58-1.06
0.69 0.49-0.99
0.77 0.56-1.08
0.85 0.44-1.65
0.50 0.34-0.73
0.57 0.41-0.78
1.02 0.71-1.48
0.71 0.51-0.97
0.78 0.54-1.13
Characteristic, n/N Ibrutinib + BR Placebo + BR
All patients 116/261 152/262
Sex
Male 88/178 111/186
Female 28/83 41/76
Race
White 92/199 118/206
Non-White 24/62 34/56
Age
<70 years 39/99 62/108
≥70 years 77/162 90/154
ECOG PS
0 53/134 72/141
1-2 63/127 80/121
Simplified MIPI at baseline
Low risk (0-3) 15/44 21/46
Intermediate risk (4-5) 42/124 76/129
Low/intermediate risk (0-5) 57/168 97/175
High risk (6-11) 59/93 55/87
Tumor bulk
<5 cm 64/165 90/163
≥5 cm 51/95 62/98
Favors Ibrutinib + BR Favors Placebo + BR
0.4 0.6 0.8 1.0 1.4 1.8

PFS in High-Risk Subgroups
Months
0
0
10
20
30
40
50
60
70
80
90
100
PFS
(%)
6 12 18 24 30 36 42 48 54 60 66 72 78 84 90
Ibrutinib + BR
Patientsat Risk
Placebo + BR
26 21 15 14 13 11 9 7 6 5 4 4 4 3 1 1
24 16 11 9 8 7 7 7 5 4 4 4 4 4 4 1
Ibrutinib + BR
Placebo + BR
Ibrutinib + BR
Placebo + BR
0
0
10
20
30
40
50
60
70
80
90
100
PFS
(%)
6 12 18 24 30 36 42 48
Months
54 60 66 72 78 84 90
Ibrutinib + BR
Patientsat Risk
Placebo + BR
19 14 12 10 8 7 7 7 7 6 6 5 5 5 1 0
26 19 11 10 10 10 9 8 6 4 4 4 4 4 3 1
Ibrutinib + BR
(N = 19)
Placebo + BR
(N = 26)
Median PFS, months 25.6 10.3
HR (95% CI) 0.66 (0.32-1.35)
Ibrutinib + BR
(N = 26)
Placebo + BR
(N = 24)
Median PFS, months 28.8 11.0
HR (95% CI) 0.95 (0.50-1.80)
Blastoid or pleomorphic TP53-mutated

Response Rate
CR rate was
numerically higher in
the ibrutinib arm
(65.5% vs 57.6%;
P<0.057)
0
10
20
30
40
50
60
70
80
90
100
Ibrutinib + BR Placebo + BR
PR: 24.1%
PR: 30.9%
CR: 65.5% CR: 57.6%
ORR: 89.7% ORR: 88.5%
Response
Rate
(%)
(N=261) (N=262)

Time To Next Treatment
TTNT = time to next treatment.
Subsequent therapy at
second-line:
Ibrutinib arm:
52/261(19.9%)
BTKi: 6/52 (11.5%)
Placebo arm:
106/262 (40.5%)
BTKi: 41/106
(38.7%)
0
0
10
20
30
40
50
60
70
80
90
100
TTNT
(%)
6 12 18 24 30 36 42 48
Months
54 60 66 72 78 84 90 96
Ibrutinib + BR
Patients at Risk
Placebo + BR
261 231 209 192 184 174 155 147 140 131 126 119 111 102 60 21 0
262 231 203 189 171 167 157 146 137 125 117 113 109 101 67 23 2
Ibrutinib + BR
Placebo + BR
Ibrutinib + BR
(n=261)
Placebo + BR
(n=262)
Median
TTNT,
months
NR 92.0
HR (95% CI) 0.48 (0.34-0.66)

Pruritus
Constipation
Decreased appetite
Vomiting
URTI
Cough
Fatigue
Pneumonia
Anemia
Thrombocytopenia
Pyrexia
Rash
Nausea
Diarrhea
Neutropenia
Frequency (%)
Ibrutinib + BR (N=259) Placebo + BR (N=260)
*
*
Common Treatment-Emergent Adverse Events
(≥20%)
URTI = upper respiratory tract infection.
75 50 25 0 25 50 75
Grade 1-2
Grade 3-4

TEAEs of Clinical Interest With BTKis
aDifference of ≥5% in any-grade TEAE. Any bleeding is based on Haemorrhage Standardized MedDRA Query (SMQ) (excluding laboratory terms).
Major bleeding includes any grade 3 or higher bleeding and serious or central nervous system bleeding of any grade.
MDS/AML = myelodysplastic syndromes/acute myeloid leukemia.
These adverse events were generally not treatment-limiting
During the entire study period, second primary malignancies (including skin
cancers) occurred in 21% in the ibrutinib arm and 19% in the placebo arm;
MDS/AML occurred in 2 and 3 patients, respectively
Ibrutinib + BR
(n=259)
Placebo + BR
(n=260)
Any grade Grade 3 or 4 Any grade Grade 3 or 4
Any bleedinga 42.9% 3.5% 21.5% 1.5%
Major bleeding 5.8% – 4.2% –
Atrial fibrillationa 13.9% 3.9% 6.5% 0.8%
Hypertension 13.5% 8.5% 11.2% 5.8%
Arthralgia 17.4% 1.2% 16.9% 0

Overall Survival
aThe most common grade 5 TEAE was infections in the ibrutinib and placebo arms: 9 versus 5 patients. Grade 5 TEAE of cardiac disorders occurred
TEAE = treatment-emergent adverse event.
Ibrutinib + BR
Patientsat Risk
Placebo + BR
261 239 221 208 197 187 171 163 158 152 145 138 128 118 70 25 0
262 244 223 212 203 197 188 177 171 165 159 154 147 137 90 31 2
0
0
10
20
30
40
50
60
70
80
90
100
Patients
Alive
(%)
6 12 18 24 30 36 42 48
Months
54 60 66 72 78 84 90 96
Ibrutinib + BR
Placebo + BR
55%
57%
Ibrutinib + BR
(n=261)
Placebo + BR
(n=262)
Median OS,
months
NR NR
HR (95% CI) 1.07 (0.81-1.40)
Cause of death
Ibrutinib + BR
(n=261)
Placebo + BR
(n=262)
Death due to PD and TEAE 58 (22.2%) 70 (26.7%)
Death due to PD 30 (11.5%) 54 (20.6%)
Death due to TEAEsa 28 (10.7%) 16 (6.1%)
Death during post-treatment
follow-up excluding PD and
TEAEs
46 (17.6%) 37 (14.1%)
Total deaths 104 (39.8%) 107 (40.8%)
Death due to COVID-19: 3 patients in
the ibrutinib arm during the TEAE period
and 2 patients in the placebo arm after
the TEAE period
Exploratory analysis of cause-specific
survival including only deaths due to PD
or TEAEs showed an HR of 0.88

Conclusions
ASCT = autologous SCT.
Consistent and expected
AEs with the known
profiles of ibrutinib and BR
A new benchmark for
first-line treatment of
older patients with MCL
or those unsuitable for
ASCT
Median PFS of 6.7
years:
a statistically significant
and clinically meaningful
2.3-year PFS advantage
SHINE is the first phase 3 study to show that ibrutinib in combination with
chemoimmunotherapy is highly effective in patients with untreated MCL

Ibrutinib Combinations
Ibrutinib with rituximab (IR) in relapsed MCL demonstrated that after a 4-year
follow-up, the CR improved from 44% to 58%. Median PFS was 43 months, and
median OS was not reached
Addition of lenalidomide to IR was investigated in the PHILEMON study. The
ORR was 76% (56% CR) after a median follow-up of 40 months
The AIM study from Australia reported results from a combination of ibrutinib
and venetoclax (I+V) in 23 patients with relapsed MCL (2 prior lines of therapy).
The combination resulted in an ORR of 71% with 62% CR (with PET-based
assessment) at Week 16. Median PFS was 29 months, and OS was 32 months.
Because of CNS penetration, ibrutinib has a potential for further investigations
in CNS MCL
Ibrutinib with venetoclax and obinutuzumab in 24 patients with relapsed MCL
demonstrated a CR of 67%
Jain & Wang, 2022.

Ki-67: 60%, blastoid
Ki-67: 100%, blastoid
Ki-67: 60%, nodular
-100
-80
-60
-40
-20
0
20
40
60
80
100
120
140
160
%
Ibrutinib/Rituximab Regimen in Relapsed MCL
Wang et al, 2013; Wang et al, 2016.

Ibrutinib/Rituximab: Relapsed/Refractory MCL
Wang et al, 2016.

Zanubrutinib
Zanubrutinib is a selective, covalent, irreversible BTK inhibitor
that is FDA approved for relapsed MCL
In a phase 2 study of 86 patients from China, zanubrutinib
demonstrated an 84% ORR and a 68% CR in relapsed MCL
(median of 2 prior lines)
In a pooled analysis of 112 relapsed MCL patients with a 2-year
median follow-up, the ORR was 85%, with a CR of 62%. Grade 3
or higher atrial fibrillation occurred in 0.89% of patients
Jain & Wang, 2022.

Venetoclax
Jain & Wang, 2022; Davids et al, 2021.
Venetoclax is an orally administered, selective inhibitor of the anti-apoptotic BCL2
protein. In a phase 1 trial, relapsed MCL patients achieved an ORR of 75%, CR of
21%, and median PFS of 14 months. None of the 28 patients were BTKi-refractory.
Median PFS was 11.3 months after longer follow-up of 38 months
Venetoclax was well tolerated with adverse events including nausea (49%), diarrhea (46%), fatigue
(44%), and hematologic AEs all grades <20%.
A multicenter European study described efficacy of venetoclax monotherapy in 20
patients with relapsed MCL (median 3 prior lines of therapy). Another study with 24
relapsed MCL patients (median 5 prior lines of therapy; 67% BTKi-refractory),
demonstrated an ORR of 50% and a CR of 21%
Venetoclax is being actively investigated in combination with various agents, with
BTKis in the front line and in the relapsed/refractory setting
Relapsed, Covalent BTK Inhibitor–Refractory MCL

Pirtobrutinib
Jain & Wang, 2022.
Pirtobrutinib (LOXO-305) is a novel, reversible, non-covalent, and
orally administered BTKi that inhibited both wild-type and C481-
mutated BTK in preclinical studies. As a reversible BTKi, pirtobrutinib
forms a non-covalent bond and can inhibit Y223 autophosphorylation
of all active BTK mutants
In the pivotal phase 1/2 BRUIN trial, in 134 relapsed-refractory MCL
patients, the median number of prior lines of therapy was 3 (range 1-
9), and 90% of patients had been exposed to a prior BTKi

Pirtobrutinib (cont.)
Jain & Wang, 2022.
The ORR was 51% and CR was 25% in BTKi-pretreated MCL, while in
BTKi-naive MCL patients, the ORR was 82% and CR was 18%
With a median follow-up of 8.2 months, the median duration of
response was 18 months
Grade 3-4 bruising and atrial fibrillation were noted in <2% of patients
Pirtobrutinib holds great promise in patients with relapsed/refractory
MCL

R-BAC and Stem Cell Transplantation (SCT)
Jain & Wang, 2022; McCulloch et al, 2020.
R-BAC regimen (rituximab/bendamustine/ara-C)
In a multi-institutional retrospective report on 36 patients in whom prior BTKi therapy had
failed (median 2 prior lines of therapy), the R-BAC regimen (rituximab/bendamustine/ara-
C) demonstrated an 83% ORR and a 60% CR. Median PFS was 10 months, and median OS
was 12.5 months
No treatment-related deaths. 56% needed dose reductions and 6% stopped treatment
due to toxicity. 47% were hospitalized with febrile neutropenia, 68% required blood
transfusion
Autologous SCT is conventionally used as a consolidation strategy after completing
first-line intensive chemoimmunotherapy. In a multicenter retrospective analysis, 70
patients with relapsed MCL who received allogeneic (allo)-SCT were described. Allo-
SCT can provide long-term disease control in about 30% of MCL patients. Ibrutinib
before allo-SCT can be efficacious as a bridging therapy

ZUMA-2: Brexucabtagene Autoleucel
Jain & Wang, 2022.
A major landmark in the treatment of relapsed MCL patients is the FDA
approval of the anti-CD19 CAR-T brexucabtagene autoleucel (BA) based on
the pivotal ZUMA-2 study
ZUMA-2 was a single-arm, international, multicenter, open-label, phase 2
trial in which 68 relapsed MCL patients received BA therapy. All patients had
disease progression on BTKis (68% BTKi-refractory and 32% relapsed after
BTKi). Patients had a median of 3 prior lines of therapy (range 1-5)
Patients underwent leukapheresis and lymphocyte-depleting chemotherapy
(fludarabine/cyclophosphamide for 3 days) followed by CAR T infusion at a
target dose of 2×106 CAR T cells/kg
Patients with high-risk MCL included 17 (25%) with blastoid histology, 6
(17%) with TP53 mutations, and 34 (69%) with Ki-67% ≥50%

ZUMA-2: Brexucabtagene Autoleucel (cont.)
Jain & Wang, 2022.
After a median follow-up of 28.8 months, the ORR was 91% (68% CR).
Median DOR, PFS, and OS were 25 months, 25 months, and not reached,
respectively. At 6 months, 40% of patients remained in CR, and 79% were
MRD-negative
Furthermore, the ORRs were >90% in patients with TP53 mutations,
POD24, and high Ki-67%, and 80% in patients with blastoid histology
The most common grade ≥3 adverse events (31% of patients) were
cytopenias (69%), infections (32%), and grade ≥3 CRS (15%), with
neurotoxicity in 31% of patients

ZUMA-2: Brexucabtagene Autoleucel (cont.)
Jain & Wang, 2022.
In this real-world experience, 78% of patients would not have met the
criteria for the ZUMA-2 study, but these patients had a best overall
response of 89% and a CR of 81%
Grade 3-4 CRS and neurotoxicity were observed in 8% and 35% of
patients, respectively
BA therapy is currently approved by the FDA for patients with relapsed
and refractory MCL (irrespective of the number of lines of therapy
and/or prior exposure to BTKi). Major limitations of this therapy are
the cost, feasibility (administration at specialized centers), and
complications

Triple-Refractory MCL
Jain & Wang, 2022.
We are noticing patients who belong to a very high-risk subset
of patients with MCL, “triple-refractory” MCL: patients whose
disease progressed on BTKis, venetoclax, and BA therapy
Patients with progression after BA therapy have a median OS of
4.1 months. These patients have very limited treatment options
due to their highly refractory disease. Advances in molecular
pathogenesis of CAR T-cell exhaustion are required to
understand and circumvent the mechanisms of CAR T resistance
in MCL
Resistant to BTKi, Venetoclax, and CAR T-Cell Therapy With BA

Treatment of Patients with Newly Diagnosed
MCL
ALC = absolute lymphocyte count.
Jain & Wang, 2022.
Asymptomatic, physically fit
with no organ system
dysfunction, and low-risk
MCL
Wait and watch
If PD, then treat as C or D
Asymptomatic, physically fit
with no organ system
dysfunction, and high-risk
MCL
Wait and watch or clinical trial
for smoldering or indolent
high-risk MCL
If asymptomatic
hyperleukocytosis (ALC
<30,000/μL with/without
splenomegaly >20 cm)
• Systemic therapy
(with/without apheresis)
If asymptomatic
hyperleukocytosis (ALC
>50,000/μL with platelets
<50,000/μL)
• Systemic therapy
(with/without apheresis)
Symptomatic, fit patient, age <65
Clinical trial
Radiation alone if localized stage I-II
disease
Radiation with systemic therapy if localized
stage I-II disease with high-risk features
If transplant-eligible and with high-risk
features:
• R-maxi-CHOP/R-HIDAC (with auto-SCT)
Nordic regimen then rituximab
maintenance
• R-CHOP/R-DHAP plus auto-SCT then
rituximab maintenance
WINDOW-1 regimen
• Ibrutinib/rituximab then 4 cycles of R-
HCVAD chemotherapy followed by
ibrutinib rituximab maintenance for
high-risk MCL
Miscellaneous
• BR
• VR-CAP
• R-BAC
• Lenalidomide/rituximab
Symptomatic, age ≥65, or
physically unfit patients with
frailty
Clinical trial
Radiation alone if localized stage I,
II disease
Ibrutinib/rituximab (if no
significant cardiovascular disease)
• BR
• R-BAC
• Lenalidomide-rituximab
• VR-CAP
• R-CHOP
Factors to consider for
selecting therapy
• Age
• Performance status
• Comorbidities
• Disease-related
symptoms
• Degree of organ
system involvement
• Access to clinical
trials
High-risk features
• Blastoid/pleomorphic
MCL
• Ki-67% ≥50%
• TP53 aberrations and
complex genomics and
karyotype
• CNS involvement
A B C D

Promising Novel Therapies
Jain & Wang, 2022.
Zilovertamab vedotin (ZV) is an anti-ROR1 antibody-drug conjugate.
ROR1 is an oncofetal protein that is widely expressed on MCL cells. ZV
comprises a humanized monoclonal antibody, zilovertamab vedotin,
with a proteolytically cleavable linker and the anti-microtubule
cytotoxin monomethyl auristatin E. Binding of ZV to tumor cell ROR1
results in rapid internalization and monomethyl auristatin E release
The phase 1 study enrolled 51 patients with relapsed aggressive
lymphoma, including 17 with relapsed MCL. Grade 3-4 adverse events
were peripheral neuropathy in 8% of patients and low ANC in 31% of
patients. An ORR of 53% and a CR of 12% were observed in MCL
patients
Zilovertamab Vedotin

Promising Novel Therapies (cont.)
PROTAC = proteolysis-targeting chimera.
Jain & Wang, 2022.
BTK degrader: Apart from the newer non-covalent and reversible BTKis such
as pirtobrutinib, degrading BTK is considered a promising strategy for MCL.
PROTACs are bivalent small molecules with a ligase-binding element, a
linker, and a targeted protein. Phase 1 trials of BTK degraders are ongoing
BCL2 antagonists: Highly selective BCL2 and/or BCL-XL antagonists with
potential to minimize toxicities such as thrombocytopenia and potential to
act against BCL2-mutant B-cell lymphomas are being developed
Bispecific T-cell engagers can engage CD3 and redirect T cells against the
clonal B cells expressing various antigens such as CD20. The main agents
being investigated in MCL include anti–CD20-CD3s such as glofitamab,
epcoritamab (subcutaneous route of administration), odronextamab, and a
combination of mosunetuzumab with anti-CD79b polatuzumab

Promising Novel Therapies (cont.)
Jain & Wang, 2022.
Newer cellular therapies
Lisocabtagene maraleucel (liso-cel), a CD19-directed 4-1BB CAR T-
cell product, is being studied in the clinical trial MCL-Transcend
NHL-001. In the phase 1 study, defined and equal CD4- and CD8-
positive cell doses were administered separately
Patients had received a median of 3 prior lines of therapy, and 88%
had prior exposure to ibrutinib
Median follow-up was 6 months (n=32), and the ORR was 84% (CR
66%)
Grade ≥3 toxicities were CRS (3%) and neurotoxicity (12%)
More data after longer follow-up will be reported

BRUIN: Pirtobrutinib for Previously Treated MCL
Wang, Shah et al, 2021.

Patient Characteristics
aCalculated as percent of patients who
received a prior BTK inhibitor.
b3 patients had both auto and allo stem cell
transplants.
IMiD = immunomodulatory drug.
Wang, Shah et al, 2021
Characteristics MCL (n=134)
Median age (range), years 70 (46%, 88%)
Female / male, n (%) 30 (22%) / 104 (78%)
Histology
Classic
Pleomorphic/blastoid
108 (81%)
26 (19%)
ECOG PS, n (%)
0
1
2
82 (61%)
50 (37%)
2 (2%)
Median number prior lines of systemic therapy
(range)
3 (1, 9%)
Prior therapy, n (%)
BTK inhibitor
Anti-CD20 antibody
Chemotherapy
Stem cell transplantb
IMiD
BCL2 inhibitor
Proteasome inhibitor
CAR T
PI3K inhibitor
120 (90%)
130 (97%)
122 (91%)
30 (22%)
23 (17%)
20 (15%)
17 (13%)
7 (5%)
5 (4%)
Reason discontinued prior BTKia
Progressive disease
Toxicity/other
100 (83%)
20 (17%)

-100
-75
-50
-25
0
25
50
75
100
100
-100
-75
-50
-25
0
25
50
75
*
Maximum
%
change
in
SPD
from
baseline
Pirtobrutinib: Efficacy in MCL
Efficacy was also seen in patients with
prior:
Stem cell transplant (n=28): ORR 64%
(95% CI: 44-81)
CAR T-cell therapy (n=6): ORR 50%
(95% CI: 12-88)
BTK-pretreated MCL patients n=100
Overall response rate, % (95% CI) 51% (41-61)
Best response
CR, n (%) 25 (25%)
PR, n (%) 26 (26%)
SD, n (%) 16 (16%)
BTK-naive MCL patients n=11
Overall response rate, % (95% CI) 82% (48-98)
Best response
CR, n(%) 2 (18%)
PR, n(%) 7 (64%)
SD, n(%) 1 (9%)

Pirtobrutinib: Duration of Response in MCL
Median follow-up of 8.2
months (range: 1.0-27.9
months) for responding
patients
60% (36 of 60) of
responses are ongoing
Median duration of
response: 18 months
(95% CI: 4.6-NE)

Pirtobrutinib: Safety Profile
DLT = dose-limiting toxicity; MTD = maximum tolerated dose; RP2D = recommended phase 2 dose.
No DLTs reported and MTD not reached
96% of patients received ≥1 pirtobrutinib dose at or above
RP2D of 200 mg daily; 1% of patients (n=6) permanently
discontinued due to treatment-related AEs
All doses and patients (n=618)
Treatment-emergent AEs (≥15%), %
Treatment-related AEs,
%
AEs Grade 1 Grade 2 Grade 3 Grade 4 Any grade Grades 3/4 Any grade
Fatigue 13% 8% 1% - 23% 1% 9%
Diarrhea 15% 4% <1% <1% 19% <1% 8%
Neutropenia 1% 2% 8% 6% 18% 8% 10%
Contusion 15% 2% - - 17% - 12%
AEs of special
interest
Grade 1 Grade 2 Grade 3 Grade 4 Any grade Grades 3/4 Any grade
Bruising 20% 2% - - 22% - 15%
Rash 9% 2% <1% - 11% <1% 5%
Arthralgia 8% 3% <1% - 11% - 3%
Hemorrhage 5% 2% 1%g - 8% <1% 2%
Hypertension 1% 4% 2% - 7% <1% 2%
Atrial
fibrillation/flutter
- 1% <1% <1% 2%h - <1%

Pirtobrutinib: Conclusions
Wang, Shah et al, 2021; Eyre et al, 2021.
Pirtobrutinib demonstrates promising efficacy in MCL patients
previously treated with BTK inhibitors, a population with
extremely poor outcomes
Favorable safety and tolerability are consistent with the design of
pirtobrutinib as a highly selective and non-covalent (reversible)
BTK inhibitor
A randomized, global, phase 3 trial comparing pirtobrutinib with
investigator’s choice of covalent BTK inhibitors in BTK-naive
relapsed MCL is ongoing (BRUIN MCL-321; NCT04662255)

Zilovertamab Vedotin for Non-Hodgkin
Lymphoma
Wang, Mei et al, 2021.

ROR1 and Zilovertamab Vedotin
Borcherding et al, 2014; Danesmanesh et al, 2013; Vaisitti et al, 2021.
ROR1 is an oncofetal protein important for
embryonic development
Physiologic expression disappears before birth
Pathologic expression of ROR1 often reappears in
aggressive hematologic and solid tumor cancers
ROR1 is present on the tumor cell surface and
amenable to targeting with antibody-based
therapeutics
Zilovertamab vedotin (MK-2140) is an ADC of:
The humanized monoclonal antibody, UC-961, with no
normal tissue cross-reactivity
A cleavable linker and the anti-microtubule toxin,
MMAE
Binding to tumor cell ROR1 causes rapid
internalization and lysosomal trafficking to deliver
MMAE
Zilovertamab Vedotin
Antibody
(UAC-961)
Linker Toxin
(MMAE)

Zilovertamab Vedotin Grade 3 or 4 Adverse
Events
aNo deaths were attributed to study therapy; 1 patient died due to acute respiratory failure not related to treatment.
bIncludes the preferred terms peripheral sensory neuropathy, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensorimotor neuropathy.
Non-Hodgkin Lymphoma
All Patients
N=51
Grade 3 or 4 AEs in ≥3 Patients, n (%) All-causea Treatment-related
Decreased neutrophil count 16 (31.4%) 16 (31.4%)
Decreased hemoglobin 8 (15.7%) 3 (5.9%)
Febrile neutropenia 4 (7.8%) 2 (3.9%)
Peripheral neuropathyb 4 (7.8%) 4 (7.8%)
Decreased platelet count 4 (7.8%) 4 (7.8%)
Diarrhea 3 (5.9%) 2 (3.9%)
Increased lipase 3 (5.9%) 2 (3.9%)
Pneumonia 3 (5.9%) 1 (2.0%)

Zilovertamab Vedotin Overall Response Rate
aPatients with CLL/SLL and AML did not achieve a response.
bAt the time of data cutoff, 3 patients with RT experienced a partial response but only had 1 post-baseline assessment.
BOR = best overall response.
All patientsa
N=51
DLBCL
n=13
MCL
n=17
Prior CAR-T or CAR-
NK
n=15
ORR, %
(95% CI)
33.3
(20.8-47.9)
38.5
(13.9-68.4)
52.9
(27.8-77.0)
40.0
(16.3-67.7)
BOR, n (%)
CR 5 (9.8%) 3 (23.1%) 2 (11.8%) 2 (13.3%)
PR 12 (23.5%)b 2 (15.4%) 7 (41.2%) 4 (26.7%)

Zilovertamab Vedotin Summary and Conclusions
Wang, Mei et al, 2021
The novel anti-ROR1 ADC zilovertamab vedotin was associated
with a tolerable safety profile in Schedule 1 of this study
Few DLTs were observed up to the MTD of 2.5 mg/kg
The most common AEs were fatigue and neutropenia
GI AEs included nausea and diarrhea
The primary cumulative toxicity was peripheral neuropathy
No ROR-mediated toxicities (infusion reactions or tumor lysis
syndrome) were observed

Zilovertamab Vedotin Summary and Conclusions
(cont.)
Zilovertamab vedotin demonstrated clinical activity in patients
with relapsed NHL
The ORR was 38.5% for patients with DLBCL and 52.9% for patients
with MCL
For patients who previously received CAR-T/CAR-NK, the ORR was
40.0%
Targeting the ROR1 pathway with zilovertamab vedotin is a
promising therapeutic option for heavily pretreated patients with
relapsed NHL

Special Considerations in MCL Treatment
Jain & Wang, 2022.
CNS involvement by MCL
CNS involvement is noted mostly at the time of relapse (<5% of
MCL cases)
Patients can present with any neurological symptoms and may have
leptomeningeal or parenchymal disease, as seen by cerebrospinal
fluid evaluation and/or MRI of the brain and spine
Previous retrospective studies demonstrated that some baseline
characteristics (blastoid MCL, very high LDH levels, high Ki-67%)
are associated with CNS involvement. The outcomes of CNS-MCL
are very poor (median survival <6 months)

Special Considerations in MCL Treatment (cont.)
Jain & Wang, 2022.
Ibrutinib and zanubrutinib have been shown to penetrate the
blood-brain barrier. A higher dose of ibrutinib (840 mg vs 560
mg) improves the cerebrospinal fluid concentration in patients
with CNS lymphoma
In a retrospective study with 84 patients who developed CNS
relapses, 26 patients were treated with ibrutinib (560 mg daily),
and 58 patients received standard chemoimmunotherapy. The
ibrutinib cohort demonstrated an improved response rate (72%
vs 39%) and 1-year OS (61% vs 16%) compared with
chemoimmunotherapy

Special Considerations in MCL Treatment (cont.)
Jain & Wang, 2022.
COVID infection and MCL
Infection with COVID has impacted the care of MCL patients in multiple
ways. Several studies have reported that patients with B-cell lymphoid
malignancies who develop COVID infection exhibit inferior serologic
response and COVID-specific T-cell response compared to healthy
controls
In addition, when these B-NHL patients receive anti-CD20 monoclonal
antibodies, their serologic response after vaccination is impaired,
making them more prone to persistent COVID infection. The same is
true for BTKi agents. The response to a booster vaccine is also
impaired (50% lower) in B-NHL patients compared with healthy
controls
Vaccination for all B-NHL patients is recommended irrespective of the
type of treatment, including patients who received CAR-T therapy

Tips on Treating MCL From My Experience
XRT = radiation therapy; asa = aspirin.
Importance of the frontline therapy
Risk stratification
Role of XRT
Trial choices (all trials are not created equal)
Management of side effects from ibrutinib
Atrial fibrillation: use caution, change drugs, rhythm control, nodal ablation
Bleeding: avoid major bleeding, be aware of potential peptic ulcers, recent
GI bleeding, etc; do not use BTKi + warfarin nor BTKi + Asa + oral
anticoagulation
Diarrhea, usually soft stool: rule out infection, use drug breaks, colestipol
Infections: detect and treat early; pay attention to sinusitis and rid of it
early
Muscle cramps: tonic water, reequip, etc.

FAQ
For a transplant-eligible relapsed MCL patient, who achieved CR2
by BTKi, would you just continue BTKi, or ASCT, or allo-SCT as
soon as possible?
For TP53-mutated, blastoid/pleomophic MCL, what is your
treatment strategy? How early would you consider allo SCT vs
CAR T-cell therapy?
Do you expect non-covalent BTKi (pirtobrutinib) to replace
covalent BTKi?

Tips on Treating MCL From My Experience (cont.)
WBC = white blood cell; LA = lymphadenopathy.
XRT should be considered, especially for bulky tumors; could XRT
multiple sites at the same time or in sequence
Trials are not created equal
Intervene early
Be cautious on watch and wait: WBC 30,000/μL, spleen 20 cm, LA 3 cm
Try to visit an academic center early
Have a strategy versus one step at a time

BTK Inhibitor Side Effects
Jain & Wang, 2022.
Rash
Bleeding
Infections
Atrial fibrillations
Muscle cramps
Diarrhea
Fatigue

Key Takeaways
Jain & Wang, 2022.
MCL has become a highly treatable lymphoma, but patients frequently
relapse. Initial workup is very important to these patients. Precise molecular
features of each MCL patient are helping in the risk stratification of any
patient
The focus in the treatment of MCL may gradually shift towards “chemo-free”
therapies such as BTK inhibitors, venetoclax, and brexucabtagene autoleucel,
minimizing the need for SCT
Enroll MCL patients in clinical trials. Despite these advances, disease
resistance is still noted (“triple-resistant MCL”), and these patients are
challenging to treat
Non-covalent BTKis, BiTE antibodies, anti-ROR1 antibodies, and next-
generation CAR T cells are promising. With persistent collaborative efforts,
we aim to finally reach our goal of curing patients with MCL

Case 1: Ms. MB
Ms. MB is a 45-year-old woman with relapsed MCL who is taking
ibrutinib. Two days into the treatment course, she developed
extreme lymphocytosis with WBC 200,000/μL. She has mild
fatigue
What are the symptoms you need to ask her about, and what
exams should you do?
A. Headache, nausea
B. Fundi examination
C. Shortness of breath and/or dyspnea on exertion
D. Serum viscosity
E. A, B, and C
F. All of the above

Case 1: Ms. MB (cont.)
Ms. MB is a 45-year-old woman with relapsed MCL who is taking
ibrutinib. Two days into the treatment course, she developed
extreme lymphocytosis with WBC 200,000/μL. She has mild
fatigue
What are the symptoms you need to ask her about, and what
exams should you do?
A. Headache, nausea
B. Fundi examination
C. Shortness of breath and/or dyspnea on exertion
D. Serum viscosity
E. A, B, and C
F. All of the above

Case 1: Ms. MB (cont.)
After the above evaluation is negative, what should you do?
A. If there any symptoms and signs, go to the ER immediately
B. Do nothing but continue ibrutinib
C. If there are no symptoms or signs, hold ibrutinib, wait for WBC to
be less than 30,000/μL, and then restart, monitoring WBC closely
D. Screen for PE if she has shortness of breath
E. Give intravenous rituximab at the regular rate
F. If she has any of the above symptoms, do leukapheresis to lower
WBC to less than 60,000-80,000/μL, then admit her to hospital and
give rituximab at 25 mL/hour flat rate

Case 2: Mr. JF
A 68-year-old gentleman who originally came from Santiago, Chile, now
residing in Houston, came to the clinic with suspected CLL or lymphoma. The
patient’s CT scan showed a spleen of 25 cm. However, there were no
enlarged lymph nodes on the scan. Bone marrow biopsy showed MCL. He
was positive for CD20 and cyclin D1; SOX-11 was negative. The WBC count is
300,000/μL with 95% being lymphocytes
What therapeutic choice would you use?
A. Leukapheresis then ibrutinib
B. Leukapheresis followed by rituximab followed by bendamustine
C. Leukapheresis followed by R-CHOP
D. Chest CT with angiogram to rule out PE, followed by rituximab
E. Leukapheresis, CT angiogram to rule out PE, and admit to the hospital for
rituximab with a flat rate of 25 mL/hr,; when WBC is less than 50,000/μL, then
ibrutinib daily

Case 2: Mr. JF (cont.)
A 68-year-old gentleman who originally came from Santiago, Chile, now
residing in Houston, came to the clinic with suspected CLL or lymphoma. The
patient’s CT scan showed a spleen of 25 cm. However, there were no
enlarged lymph nodes on the scan. Bone marrow biopsy showed MCL. He
was positive for CD20 and cyclin D1; SOX-11 was negative. The WBC count is
300,000/μL with 95% being lymphocytes
What therapeutic choice would you use?
A. Leukapheresis then ibrutinib
B. Leukapheresis followed by rituximab followed by bendamustine
C. Leukapheresis followed by R-CHOP
D. Chest CT with angiogram to rule out PE, followed by rituximab
E. Leukapheresis, CT angiogram to rule out PE, and admit to the hospital for
rituximab with a flat rate of 25 mL/hr,; when WBC is less than 50,000/μL, then
ibrutinib daily

Case 3: Mr. EL
A 71-year-old gentleman with a history of MCL presented himself to
your clinic for continuation of therapies for relapsed MCL. He was
previously treated with R2, bendamustine, rituximab, and ibrutinib. He
further relapsed with P53 mutation, a tumor of 5 cm near the
mediastinum, and other enlarged lymphadenopathies throughout the
body. His Ki-67 is 80% with methodology blastoid
What is your next therapy?
A. Acalabrutinib
B. Induction chemotherapy followed by autologous stem cell transplant
C. Chemotherapy with hyperCVAD
D. R-Bac
E. Arrange for CAR T-cell therapy
CVAD = cyclophosphamide/vincristine sulfate/doxorubicin hydrochloride/dexamethasone.

Case 3: Mr. EL (cont.)
A 71-year-old gentleman with a history of MCL presented himself to
your clinic for continuation of therapies for relapsed MCL. He was
previously treated with R2, bendamustine, rituximab, and ibrutinib. He
further relapsed with P53 mutation, a tumor of 5 cm near the
mediastinum, and other enlarged lymphadenopathies throughout the
body. His Ki-67 is 80% with methodology blastoid
What is your next therapy?
A. Acalabrutinib
B. Induction chemotherapy followed by autologous stem cell transplant
C. Chemotherapy with hyperCVAD
D. R-Bac
E. Arrange for CAR T-cell therapy

Case 4: Mr. KD
An 80-year-old man with a history of MCL for the past 15 years relapsed
after many therapies. These therapies included R- bendamustine, R-
CHOP, R2, ibrutinib, VTX, and CAR T-cell therapy. He now presents with a
large longitudinal tumor in the left leg of 7 cm with severe pain and local
edema. The biopsy showed Ki-67 95%, pleomorphic variant
What is your choice of therapy?
A. High-dose CTX and rituximab with immediate admission to hospital
B. Dexamethasone, R2, and bortezomib (DR2IVE)
C. Radiation therapy
D. A + definitive radiation therapy
E. A + low-dose radiation therapy
F. High-dose definitive radiation therapy
VTX = venetoclax.

Case 4: Mr. KD (cont.)
An 80-year-old man with a history of MCL for the past 15 years relapsed
after many therapies. These therapies included R- bendamustine, R-
CHOP, R2, ibrutinib, VTX, and CAR T-cell therapy. He now presents with a
large longitudinal tumor in the left leg of 7 cm with severe pain and local
edema. The biopsy showed Ki-67 95%, pleomorphic variant
What is your choice of therapy?
A. High-dose CTX and rituximab with immediate admission to hospital
B. Dexamethasone, R2, and bortezomib (DR2IVE)
C. Radiation therapy
D. A + definitive radiation therapy
E. A + low-dose radiation therapy
F. High-dose definitive radiation therapy
VTX = venetoclax.

References
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