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

Kami Maddocks, MD
Professor-Clinical, Division of Hematology
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center
New Directions in Targeted Therapeutic Approaches
for Older Adults With Mantle Cell Lymphoma

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Disclosures
Dr. Maddocks discloses the following relevant financial relationships:
Consultant: AbbVie, ADC Therapeutics, AstraZeneca, Beigene, Bristol Myers Squibb,
Epizyme, Genentech, Genmab, Incyte, Janssen, Kite, Lilly, MorphoSys, Seagen
USF Health has mitigated all relevant financial relationships

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
aNot yet FDA approved
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)
MCL disease course is a repeated process of responses and relapses. With
repeated therapies, resistance increases leading to gradually decreased
responses and shorter response durations.
Therapy resistance is the major barrier to cure; MCL remains largely
incurable
With current treatment modalities (chemoimmunotherapy, SCT, covalent and
non-covalent BTK inhibitors, CAR-T cell therapy, bispecific antibodies, and
BCL2 antagonists), clinical outcomes have improved.

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 roughly 70 years
The incidence is higher in White individuals. In Asian countries, the
incidence of MCL is variable (1%-6% of all lymphomas), and the
median age is 60 years
Male predominance

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

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

Cyclin D1 Overexpression
Chromosomal translocation t(11;14) (q13;q32) is detected in the
majority of MCL cases.
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
CCND1 = cyclin D1 coding gene; RNA = ribonucleic acid.
Jain & Wang, 2022.

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

TP53 Mutations
The TP53 gene is a tumor suppressor 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
Presence of both TP53 deletion (detected by FISH) and TP53 mutations
(detected by DNA sequencing) was associated with the worst survival
At diagnosis, frequency of TP53 mutations is about 11%-25%; the
frequency increases to 45% at relapse
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

Clinical Presentation
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

Initial Diagnostic Workup (cont.)
Diagnostic biopsy, consideration LN biopsy, BM biopsy
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
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

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
LDH = lactate hydrogenase; OS = overall survival; MIPIb = biologic MIPI.
Jain & Wang, 2022.

Prognostic Factors (cont.)
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
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
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.
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
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
<65-70 and >65-70 years old
Comorbidities considered

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-BTKi
R-BAC

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.
Lenalidomide with rituximab was investigated in 38 patients
7-year follow-up of this study showed that 33% were in remission beyond 7 years
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
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
Non-chemotherapy options

Previously Untreated Elderly Patients >65 (cont.)
IR = ibrutinib/rituximab.
Jain et al, 2023.
A phase 2 study on the combination of acalabrutinib with rituximab in
elderly patients with MCL was reported by Jain et al:
2-year PFS and OS were 92% and 96%, respectively
ORR and CR were 94% and 90%, respectively
22% of patients had atrial fibrillation at baseline
1 patient had recurrence of grade 2 atrial fibrillation; 1 patient had recurrence of grade 3
unstable angina
Non-chemotherapy options (cont.)

Relapsed MCL: BTKi-Naive Setting
Covalent BTK Inhibitors
Ibrutinib, first-in-class BTKi
Acalabrutinib
Zanubrutinib
Zanubrutinib
Nemtabrutinib Pirtobrutinib
Irreversible
Reversible
Ibrutinib
TK
TKL
CK1
STE
AGC
CMGC CAMK
Other
Acalabrutinib
TK
TKL
CK1
STE
AGC
CMGC
CAMK
Other

PFS and OS by Prior Lines of Therapy (LOT)
Dreyling et al, 2022.
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
Ibrutinib for Relapsed/Refractory MCL

Pooled Analysis of 3 Clinical Trials: PFS by Best Response
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 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

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%)

Ibrutinib: Conclusions Inform Future BTKi
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

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
.

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.

Zanubrutinib for Relapsed MCL: Pooled Analysis
Song et al, 2023.
112 patients, 36.6% second-line, 63.4%
later-line
After weighting, PFS was similar for
second-line and later-line zanubrutinib, but
OS was significantly improved in second-
line vs later-line groups
Safety
Any grade ≥3 AE: 53.6%
Discontinuation due to AE: 12.5%
Any grade:
Atrial fibrillation: 3%
Diarrhea: 25%
Hemorrhage: 5%
Hypertension: 12%
Efficacy and Safety

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.

SYMPATICO: Ibrutinib/Venetoclax for Relapsed MCL
INV = Investigator.
Wang et al, 2023.
Phase 3, randomized,
double-blind trial of
ibrutinib/venetoclax vs
ibrutinib/placebo
267 patients
ECOG PS 0-1
Any risk level
Design and PFS

Sympatico: Ibrutinib/Venetoclax for Relapsed MCL
Ibrutinib +
Venetoclax (n=134)
Ibrutinib +
Placebo (n=133)
HR (or Rate Ratio)
(95% CI)
P value
Median PFS, global,
investigator-assessed
31.9 months 22.1 months 0.65 (0.47-0.88) 0.0052
Median PFS, global,
independent review
31.8 months 20.9 months 0.67 (0.49-0.91) 0.0108
Median TTNT NR 35.4 months 0.60 (0.40-0.89) 0.0096
ORR 82% 74% 1.10 (0.97-1.25) 0.1279
CR 54% 32% 1.66 (1.24-2.22) 0.0004
Median DOR 42.1 months 27.6 months
Median duration of CR NR 40.8 months
Median OS 44.9 months 38.6 months 0.85 (0.62-1.19) 0.3465
Wang et al, 2023.
Efficacy End Points

Sympatico: Ibrutinib/Venetoclax for Relapsed MCL
Wang et al, 2023.
Safety
Adverse events (ibrutinib/venetoclax vs ibrutinib/placebo)
Any grade ≥3 84% vs 76%
Neutropenia 31% vs 11%
Pneumonia 13% vs 11%
Thrombocytopenia 13% vs 8%
Anemia 10% vs 3%
Diarrhea 8% vs 2%
Leukopenia 7% vs 0%
MCL 7% vs 12%

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

Primary End Point of Improved PFS Was Met
Wang, Jurczak et al, 2022.
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 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

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

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
Relapsed, Covalent BTK Inhibitor–Refractory MCL

-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: A Highly Selective Non-Covalent BTKi
Wang, Shah et al, 2021.
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)
BRUIN: Pirtobrutinib for Previously Treated MCL
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
FDA-approved in January 2023

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

Treatment for Relapsed, Covalent BTKi-Refractory MCL
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
In a multicenter retrospective analysis of 70 patients with relapsed
MCL, allogeneic (allo)-SCT provided long-term disease control in
about 30%. 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 (brexu-cel)
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 brexu-cel 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
Brexu-cel 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

CAR-T for Progressions after Second-Line Ibrutinib
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

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 brexu-cel therapy
Patients with progression after brexu-cel 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 Brexu-Cel

Promising Novel Therapies
Jain & Wang, 2022.
Zilovertamab vedotin (ZV) is an anti-ROR1 antibody-drug conjugate.
ROR1 is an oncofetal protein widely expressed on MCL cells
Important for embryonic development
Physiologic expression disappears before birth
Pathologic expression of ROR1 often reappears in aggressive hematologic and solid tumor
cancers
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

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

Case 1: Ms. MB
Ms. MB is a 72-year-old woman with relapsed MCL who is taking
acalabrutinib. Within a few days of starting treatment, she developed
a headache. She has no neurologic signs or symptoms.
What do you recommend?
A. Stop the acalabrutinib until resolution and then dose reduce
B. Change to Zanubrutinib
C. Medically manage with OTC medications and counsel her that it should resolve
D. Order MRI brain

Case 1: Ms. MB
Ms. MB is a 72-year-old woman with relapsed MCL who is taking
acalabrutinib. Within a few days of starting treatment, she developed
a headache. She has no neurologic signs or symptoms.
What do you recommend?
A. Stop the acalabrutinib until resolution and then dose reduce
B. Change to Zanubrutinib
C. Medically manage with OTC medications and counsel her that it should
resolve
D. Order MRI brain

Case 2: Mr. JF
A 68-year-old man came to the clinic with new lymphadenopathy. He
recently moved to the area but has a history of MCL treated 13 years
ago with Nordic Regimen followed by ASCT. He has work up with
repeat biopsy that confirms MCL. What do you recommend for
treatment?
What therapeutic choice would you use?
A. Ibrutinib
B. Acalabrutinib
C. Zanubrutinib
D. Pirtobrutinib
E. R-BAC
F. B or C

Case 3: Mr. EL
A 71-year-old man 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 man 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

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

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