ASH Hematology Review Series

Indolent Lymphomas and Mantle Cell Lymphoma

Sonali M. Smith, MD
Disclosures for Sonali M. Smith, MD FASCO
In compliance with ACCME policy, ASH requires disclosures to the session audience:

• Employment: spouse is employed by Caris

• Consultancy: Adaptive, ADC Therapeutics, Gilead, Gamida Cell, BMS,
Morphosys, Janssen, Karyopharm
• Research Funding: Genentech/Abbvie, Epizyme, BMS/Celgene

Discussion of off-label drug use:

What is lymphoma?
Lymphoma is a family of blood cancers
derived from mature lymphocytes

B-cells T-cells NK-cells

• Lymphocytes normally fight viruses, bacteria, fungi, and foreign organisms

• Lymphocytes travel in lymphatic system
• These cells can grow in nodal and extranodal locations
US Burden of disease 2022

~80K new cases/year

~20K deaths/year
> 500K people living
with lymphoma

https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-
and-figures/2022/cancer-facts-and-figures-2022.pdf
Distribution of mature lymphoid
malignancies

Teras CA Cancer J Clin 2016 Nov 12;66(6):443-459

Older conceptual approach to lymphomas based on
clinical behavior
1. Slow growing
Low grade = indolent
2. Incurable
lymphoma
3. More common in elderly
MCL?
Intermediate grade = 1. Fast growing
aggressive lymphoma
2. Potentially curable
3. Occurs in all age groups
T-NHL?
1. Very fast growing
High grade = highly
aggressive lymphoma 2. Highly curable
3. Bimodal peak (i.e. Burkitt
lymphoma)
Conceptual approach to B-cell lymphomas: start
with normal B-cell journey

Kuppers Nat Rev Cancer. 2005 Apr;5(4):251-62

Conceptual approach to B-cell lymphomas: where
in ontogeny does a specific subtype arise?
DLBCL (ABC type) Memory B cell Prolymphocytic leukemia

Splenic marginal- B-CLL

zone lymphoma
Marginal zone
MALT lymphoma

Germinal center
Mantle
Plasmablast Plasma Multiple
GC zone cell
Naïve B cell myeloma
B cell

Lymphoplasmacytic lymphoma/Waldenström’s
macroglobulinemia

B-CLL
(unmutated V gene)
Mantle cell lymphoma
B-CLL (unmutated V-region genes)

Follicular lymphoma
Burkitt’s lymphoma Classical Hodgkin’s lymphoma
DLBCL (GC type)

Kuppers Nat Rev Cancer. 2005 Apr;5(4):251-62

INDOLENT LYMPHOMAS
Key features and types of Indolent Lymphomas
KEY FEATURES: MAJOR SUBTYPES:
• Slow-growing • Follicular lymphoma
• Waxing and waning course • Marginal zone lymphoma
• Increased incidence in industrialized • Lymphoplasmacytic lymphoma
countries • Hairy cell leukemia
• Lifelong risk of transformation to an • Chronic lymphocytic
aggressive histology leukemia/small lymphocytic
• Incurable lymphoma
Follicular Lymphoma
• 2nd most common non-Hodgkin lymphoma in The United States
– ~14,000 new cases/year
• Etiology unknown (?environmental)
• Prototype of low grade lymphomas
– Indolent course with median survival > 15 years
– Waxing and waning course
– Incurable
– Advanced stage in ~2/3 of patients (due to marrow involvement)
• Increases with age
– Median age 6th decade of life
– 25% are under age 40 years
• Risk of transformation over time is 2-3% per year
FL survival is improving for most patients

SEER data Stanford data

Swenson, et al., J Clin Oncol 23:5019-5026, 2005

Tan Blood 2013 Aug 8;122(6):981-7
DIAGNOSIS
Importance of sufficient tissue: concept of
”architecture”
“

nodular
Bottom Line:
• Need sufficient
” tissue to determine
architecture
“

diffuse
”
Working formulation (simplified)
1. Overall pattern
2. Cell size
3. Nuclear shape
FL Diagnosis: CD10+CD20+BCL2+ by IHC
and t(14;18) by FISH

Image ID: 63988

Authors: Kavita Umrau,
MBBS
Category: Lymphoma: Mature B-cell and
Plasma cell Neoplasms > Low-grade B-cell
lymphoma > Follicular Lymphoma

CD10 BCL6 BCL2 Ki67

Copyright © 2022 American Society of Hematology. Copyright restrictions may apply.
Histologic grade: FL1-2 vs. FL3A vs. FL3B
FL1-2 FL3A FL3B

Low
power
FL1 < 5 cb/hpf
FL1-2
FL2 5-15 cb/hpf
High
power
FL3A
FL3 >15 cb/hpf
FL3B
Ki-67

cb = centroblast
hpf = high powered field
slides courtesy of G. Venkataraman, The University of Chicago
FL3A vs. FL3B: Two very different
diseases
No diff with
anthracycline for FL3a

Bottom Line:
• treat FL3B the same as
DLBCL
• Treat FL3A the same as
FL1-2

Wahlin Br J Haem 156:225-233, 2011

Staging: Cotswold revision of Ann Arbor staging
→Lugano criteria

A: absence of B symptoms (fever, night sweats, weight loss > 10%)

B: presence of B symptoms
E: extranodal involvement
S: splenic involvement
X: bulky disease > 10 cm

www.lls.org; Cheson J Clin Oncol. 2014 Sep 20;32(27):3059-68

Other/Less common types of FL (WHO 2016)
• In situ follicular neoplasia: renamed from in situ FL because of the low
risk of progression to lymphoma

• Duodenal-type FL: localized to small bowel with low risk for dissemination

• Pediatric-type FL: occurs in children/young adults (rarely in older

patients); a nodal disease with large, expansile, highly proliferative
folliculars with prominent blastoid follicular center cells, BCL2 neg;
excellent prognosis and responds to conservative approaches

• FL with 1p36 deletion: often presents as a “diffuse” FL, BCL2 neg, often a
localized mass in inguinal region

Swerdlow Blood. 2016 May 19;127(20):2375-90

PROGNOSIS AT DIAGNOSIS
FLIPI: Follicular lymphoma international
prognostic index
• Retrospective analysis of
4167 pts 1985-1992
• 10 objective: OS Ø > 4 nodal sites
Ø LDH > ULN
• No rituximab in treatment
Ø Age > 60 y
Ø Stage III-IV disease
Ø Hemoglobin < 12g/dL

**despite being from pre-rituximab

era, FLIPI retains significance**

BUT: FLIPI score does NOT tell you

when to treat…

Solal-Celigny Blood 2004 104:1258-1265

”GELF” (and NCCN) criteria: High tumor burden (HTB) vs.
Low tumor burden (LTB)
• Lymph node/radiographic findings:
– Lymph nodes or tumor mass > 7cm
– Nodes > 3 cm in 3 distinct areas
– Symptoms related to organ compression, pleural effusion/ascites,
splenic enlargement, renal/liver/bone involvement
• Biologic criteria: Bottom Line:
– Elevated LDH or B2M • Treatment depends on
– Cytopenias due to marrow involvement tumor burden and
– Lymphocytosis symptoms, not on stage or
• Symptoms
– B symptoms
grade (unless grade 3B)
– pruritus
– Depressed performance status
• Time-dependent criteria
– Lymphoma progression over past 3 months

See Table 2 Smith ASH Ed Book 2013

PROGNOSIS AT RELAPSE
Follicular lymphoma snapshot:
outcome after relapse
Median survival for follicular lymphoma approaches 20
years, but…

Link et al. BJH, 2018; 184: 660-63

Rivas-Delgado et al. BJH 2018; 184: 753-59 Casulo J Clin Oncol. 2015 Aug 10;33(23):2516-22

PFS declines with each OS declines with each Early relapse (POD24)
subsequent relapse subsequent relapse predicts 5y OS of 50%

25
Early Relapse of FL After R-CHOP Defines Patients at
High Risk for Death
Early progression
of disease (POD)
Stage 2-4 FL
R-CHOP
N = 588 No POD within
2 years of
diagnosis

Casulo C, et al. J Clin Oncol. 2015;33(23):2516-2522.

Cause of death by EFS24 status

Bottom Line:
Relapse within 2
years of initial
chemoimmunotherapy
is associated with
poor prognosis

Tun Blood Adv 2022 Sep 13;6(17):5210-5221

TREATMENT APPROACH: FL
Localized FL: role and dose of radiotherapy

Bottom Line:
Low dose (and very
low dose?) RT is a
historical standard
FORT trial: 24 Gy > 4 Gy and provides excellent
for local control local control
BUT: no diff in OS
(and PFS not reported)
24 Gy = 40-45 Gy

Hoskin Lancet Oncol 2021 Mar;22(3):332-340; Lowry Radiother Oncol 2011 Jul;100(1):86-92
Localized FL: alternative options

Lymphocare
analysis Bottom Line:
(registry; non- Localized FL has an
randomized)
excellent prognosis with a
variety of management
approaches

No difference in OS for any approach

which is ~ 90% @ 5y

Friedberg J Clin Oncol. 2012 Sep 20; 30(27): 3368–3375

Basic Approach to
Advanced Stage Treatment-Naïve FL
Follicular
lymphoma

No indication for Indication for Rx

Rx

Watch R Low High

/wait mono tumor tumor
burden burden
Why consider “watch and wait” for
asymptomatic patients?
RP3 trial
• rituximab x 4 doses vs.

• rituximab x 4 doses
plus maintenance
rituximab vs.

• ”watch and wait”

Bottom Line:
Treatment of asymptomatic patients with rituximab
monotherapy improves PFS but not OS: Equipoise!

Ardeshna Lancet Oncol. 2014 Apr;15(4):424-35

 Is there a role for maintenance rituximab in
low tumor burden patients? (RESORT trial)

R Rituximab
A maintenance*
N = 299 N 375 mg/m2 BUT: no difference
Rituximab D q 3 months
375 mg/m2
q week ´ 4
CR or PD O
M
in treatment failure-
Rituximab
I
Z retreatment at free survival or
E progression*
375 mg/m2 q week ´ 4 overall survival

Kahl J Clin Oncol. 2014 Oct 1;32(28):3096-102

Treatment of symptomatic advanced stage
(usually high tumor burden) patients
Chemoimmunotherapy +/-
maintenance rituximab

OR

Lenalidomide + rituximab

OR

Clinical Trial
Treatment of symptomatic advanced stage
(usually high tumor burden) FL patients
Chemoimmunotherapy +/-
maintenance rituximab

OR

Lenalidomide + rituximab

PFS
OR

Clinical Trial
No diff in OS, but big diff in side effects
Rummel Lancet 2013 Apr 6;381(9873):1203-10
Treatment of symptomatic advanced stage
(usually high tumor burden) patients
RELEVANCE Trial: R2 vs.
chemoimmunotherapy
Chemoimmunotherapy +/-
maintenance rituximab

OR

Lenalidomide + rituximab

OR

Clinical Trial
No diff in OS, but some diff in side effects
Morchhauser N Engl J Med. 2018 Sep 6;379(10):934-947
Should we give maintenance rituximab after chemoimmunotherapy
for high tumor burden patients? PRIMA trial
• Primary endpoint: PFS

CHOP x 6 +
Rituximab x 8 Maintenance Rituximab
Patients
375 mg/m2 q2m x 2 yrs
with
CR, PR (n = 505)
treatment CVP x 8 +
naïve Grade Rituximab x 8
I-IIIa FL
Observation
(n = 513)
(n = 1,193) FCM x 6 +
Rituximab x 8

No BR

Salles G et al. Lancet 2011;377:42-51.

PRIMA Results

PFS Time to
next
lymphoma
treatment

Time to OS
next chemo

Salles Lancet 2011

I rarely gave maintenance until… 10-year f/u for
PRIMA

Bottom Line:
Maintenance improves
progression-free but not
overall survival in almost
all FL settings—shared
decision-making with
patients is essential

(Rethinking this in COVID era)

BachyJ Clin Oncol. 2019 Nov 1;37(31):2815-2824

TRANSFORMATION
Biopsy is critical at time of progression
RF’s for
transformation:
Poor PS
High LDH
B symptoms
FL grade 3a
High FLIPI
del1q, del6q, +2,
PRIMA: poor prognosis of +3q, +5)
BCA: 75% of early loss of B2M
progressing patients transformed disease increased T-reg
after BR had compared to FL progression cells
after chemoimmunotherapy TP53, PIM1,
transformed disease
B2M mut
Bottom Line:
Transformation occurs
early, and always biopsy!
Sarkozy J Clin Oncol 2016 Aug 1;34(22):2575-82; Freeman Blood 2019 Aug 29;134(9):761-764. doi:
10.1182/blood.2019000258.
Treatment Approach to transformed FL
• Two major guiding principles:
– Prior treatment for follicular lymphoma
– Histology at time of transformation
Prior treatment for Histology at time of
FL transformation

No prior Prior Prior HGBL +/-

DLBCL
chemotherapy anthracycline bendamustine? DHL/THL
TREATMENT OF RELAPSED
FOLLICULAR LYMPHOMA
FL: Clinical categories and treatment options
clinical trial Double-
• BR POD24
autoHCT? refractory FL
• R-CHOP +/- MR
• R-CVP • PI3Ki
• Ritux monoRx • CAR-T
• Len-ritux* • AlloHCT

Newly diagnosed
FL1-3a RISK FOR TRANSFORMATION

HTB vs. LTB,

Relapse 2
Relapse 1

Relapse
symptomatic vs. asymptomatic

3+
Biopsy critical at
relapse to r/o
• ASCT • Radiation therapy
transformation
• Benda + Obinu or Radioimmunotherapy *not approved
Ritux • Ritux monoRx HTB = high tumor burden
LTB = low tumor burden
• Len-rituximab • Tazemetostat POD24 = early progression of disease w/i
• PI3Ki 24m of initial treatment

44
Options in the relapsed/refractory setting:
NO DATA ON SEQUENCING
▪ Chemo/autoHCT
▪ AlloHCT
▪ Radioimmunotherapy (ibritutumomab tiuxetan)
▪ Immunomodulatory agents (lenalidomide)
▪ PI3K inhibitors (idelalisib, duvelisib, copanlisib, umbralisib)
▪ EZH2 inhibitors (tazemetostat)
▪ CAR-T
▪ Bispecific antibodies**, clinical trials

**not approved
45
Cellular Therapy: chimeric antigen receptor
engineered T-cells (CAR-T)

ZUMA-5 ELARA

Axi-cel Tisa-cel Liso-cel

Adapted from van der Steegan et al. Nat Rev Drug Discov, 2015
ZUMA-5: Response rate, duration of response, PFS

DoR
NR
94%
ORR
79%
CR
PFS
NR

Median f/u 17.5m

Jacobson Lancet Oncol. 2022 Jan;23(1):91-103

Efficacy Outcomes in Patients With FL by POD24
Status
Follicular Lymphoma (n=78)a

Parameter (95% CI) With POD24 Without POD24

(n=49) (n=29)
Median DOR, months 38.6 (14.5–NE) NR (24.7–NE)
24-month rate, % 61.1 (44.3–74.3) 72.4 (50.2–85.9)
Median PFS, months 39.6 (13.1–NE) NR (25.7–NE)
24-month rate, % 57.3 (41.2–70.4) 73.0 (51.1–86.2)
Median OS, months NR (39.6–NE) NR (NE–NE)
24-month rate, % 77.6 (63.1–86.9) 85.9 (66.7–94.5)
• Patients with FL who had POD24 benefitted from axi-cel, with estimated medians and 24-month rates
of DOR and PFS consistent with all efficacy-eligible patients
- Medians of DOR and PFS among patients without POD24 were not yet reached at data cutoff

Slide courtesy of Dr. Sattva Neelapu, ASH 2021 #93 48

ELARA: Tisagenlecleucel for R/R Follicular Lymphoma

Screening, apheresis, Optional

and cryopreservation bridging chemotherapya
First efficacy assessment
Tisagenlecleucel Month 3
manufacturing
Restaging,
Enrollment Lymphodepletion

Tisagenlecleucel
infusionb
Safety and efficacy
follow-up
every 3 months until Month 12,
every 6 months until end of study

Key eligibility criteria Study treatment Endpoints

• ≥18 years of age • Lymphodepleting chemotherapy options Primary: CR by IRC
were (Lugano classification
• FL grade 1, 2, or 3A
• Fludarabine (25 mg/m2 IV daily for 3 days) + 2014)
• Relapsed/refractory disease cyclophosphamide (250 mg/m2 IV daily for 3
days)
• No evidence of histological transformation/FL
• Bendamustine 90 mg/m2 IV daily for 2 days Secondary: ORR,
3B
DOR, PFS, OS, safety
• No prior anti-CD19 therapy or allogeneic HSCT • Tisagenlecleucel dose range (single IV
infusion) was: 0.6-6×108 CAR-positive viable
T cells

Slide courtesy of Fred Locke

ELARA: phase 2 international trial of tisa-cel in
FL (n=97)
Patient Characteristics Efficacy Results of extended
• Age: Follow-up Analysis (n=97 pts,
• Med age 57y median F/U 17 months)
• 25% > 65y
• Prior Treatment: Endpoint % (95% CI)
• Med 4 prior Tx (range, ORRa 86.2 (77.5-92.4)
2-13)
• 76% > 3 prior Tx CRRa 69.1 (58.8-78.3)
• Disease features:
• 60% FLIPI > 3 12-mo PFS 67.0 (56.0-75.8)
• 63% with POD24
• 78% refractory 9-mo DOR 86.5 (74.7-93.1)
disease
• 68% double refractory
5
0
Fowler Nat Med. 2022 Feb;28(2):325-332
ELARA: Duration of response and PFS (med follow up 9.9m)

DoR

PFS

Fowler Nat Med. 2022 Feb;28(2):325-332

How to move forward from the toolbox to individualized
sequence of treatment in follicular lymphoma?

Right tool for the

right job
MARGINAL ZONE LYMPHOMA
Marginal zoneMarginal
lymphomazone lymphoma

Extranodal MZL of Splenic

Nodal MZL
MALT tissue MZL 20-
5-10%
70% 30%

• Third most common subtype of NHL

Gastric Non-gastric • Median age 6th decade
• Females > males
• Often stage IE presentation
Marginal Zone Lymphoma:
Pathology and Immunophenotype

Lymphoepithelial Nodal MZL Splenic MZL

lesion in EN MALT
Shared features:
clonal expansion of centrocyte-like and monocytoid-like B-cells from marginal
zone with interfollicular expansion, scattered immunoblasts*
Negative for
Immunophenotype: MYD88
mutation
CD20+CD79a+CD19+CD5- CD10- CD23- BCL6- cyclinD1-

Slides courtesy of Girish Venkataraman, MD

There are some shared and some distinct
pathogenetic lesions

Bertoni F1000Res. 2018 Mar 28;7:406.

ENMZL pathogenesis: role of inflammation and/or
chronic antigenic stimulation

Schrueder J Hematop. 2017 Sep 25;10(3-4):91-107

MZL (esp EN MZL) is an antigen-driven disease and characterized
by recurrent balanced translocations
SITE ANTIGENIC GENETIC ALTERATION
ASSOCIATION
Stomach H. Pylori MALT1, FOXP1, BCL10, MALT1, t(11;18) predicts for
TNFAIP3 inact
resistance to H. pylori
Intestinal Campylobacter jejuni MALT1, BCL10
eradication
Cutaneous Borrelia Burgdorferi FOXP1, MALT1,

Ocular adnexal Chlamydia psittaci FOXP1, MALT1, TNFAIP3 inact

Pulmonary Achromonas MALT1, BCL10, TNFAIP3 inact

xylosoxidans
Salivary gland Sjogren’s disease MALT1, BCL10, TNFAIP3 inact

Thyroid Hashimoto’s FOXP1, MALT1, TNFAIP3 inact

thyroiditis

Schrueder J Hematop. 2017 Sep 25;10(3-4):91-107

TREATING THE TRIGGER
HPE eradication in HP positive stage IE or
IIE gastric ENMZL
• Treatment
– Triple therapy (PPI plus 2 antimicrobials) or Quadruple therapy (PPI,
bismuth, tetracycline, metronidazole) for 14 days acceptable
– Increasing resistance to clarithromycin

• Results
– Meta-analysis of 32 studies with over 1400 patients
– 77.5% HPE
– Response 78% vs. 56% for stage IE versus other
– Response 82% vs. 54% for disease limited to the mucosa versus versus
deeper invasion

Ruskone-Fourmestraux EGILS Consensus Report Gut 2011

Post-treatment follow up in stage IE or IIE
gastric ENMZL
• Responses can be slow
• NCCN guidelines: Repeat endoscopy/biopsy at 3 months if asymptomatic
• t(11;18) predicts for resistance to HPE

HP neg, MZL neg observe Bottom Line:

Need to wait at least 3
If no sx, observe months after treatment to
HP neg, MZL pos
If sx, RT assess response!!
HP pos, MZL neg 2nd line abx
HP pos, MZL pos 2nd line abx +/- RT

www.nccn.org; Ruskone-Fourmestraux EGILS Consensus Report Gut 2011

Splenic marginal zone lymphoma
Management considerations:
• Follow indolent lymphoma/FL approach
• W/W appropriate for many patients
• If treatment is needed:
• Rituximab +/- maintenance
• Bendamustine-rituximab
• splenectomy
• Pneumococcal, meningococcal,
haemophilus influenza, and hepatitis B
vaccinations should be given at least 2
Splenic Marginal Zone Lymphoma With Villous Lymphocytes – Peripheral Blood - 6. weeks before splenectomy
Image ID: 3302
Authors: Peter Maslak

Category: Lymphoma: Mature B-cell and Plasma cell Neoplasms > Splenic lymphomas > Splenic Marginal Zone Lymphoma

Copyright © 2022 American Society of Hematology. Copyright restrictions may apply.

Relapsed/refractory MZL: BTKi are active
Ibrutinib monotherapy in r/r MZL

Zanubrutinib monotherapy in r/r MZL

Phillps Blood Adv 2022 Jun 14;6(11):3472-3479 Noy Blood Adv. 2020 Nov 24;4(22):5773-5784
MANTLE CELL LYMPHOMA
Mantle Cell Lymphoma: introduction

• Genetic hallmark: t(11;14)

• 3-6% of all NHL cases
• Median age: 58 years; M:F ratio: 3:1
• Typically advanced stage
– B symptoms: < 50% cases
– 90% extranodal involvement: BM,
blood, liver, GI
– Generalized adenopathy: 70% to 90%
– CNS involvement at relapse: 4% to
22% (↑ with blastoid) DIAGNOSIS:
• Survival is improving Flow: CD20+, CD19+, CD5+, FMC7+, CD23-
, Cyclin D1+
FISH: t(11;14)(q13;q32)

Ghielmini Blood. 2009 Aug 20;114(8):1469-76

MCL is a heterogeneous disease
• Morphologic variants (usually SOX11 pos)
– Classical
– Blastoid
• Clinical variants
– “indolent” MCL→can be safely observed at initial diagnosis (usually
SOX11 neg)
• Treatment is often based on
– Age
– Comorbidities (i.e. “fit” vs. “not fit”)

Induction Consolidation Maintenance?

MCL Prognosis: 3 key variables are MIPI,
proliferation, and p53/17p del status
Simplified MIPI OS by Ki67 status PFS/OS by p53 mut
status

< 10%

> 30%

Aukema Blood. 2018 Jan 25;131(4):417-420; Determann Blood. 2008 Feb

15;111(4):2385-7; Hoster Blood 2008 Jan 15;111(2):558-65
Classic mantle cell lymphoma: overview of
treatment approach
YOUNG/FIT Induction Consolidation Maintenance?

Nordic
RCHOP/RDHAP autoHCT Maint R x 3y
R-HCVAD
OLDER/UNFIT

BR
(RCHOP) XX Maint R x 2-3y
(Len-R)
Intensive Induction and Upfront ASCT leads to
very long-term remissions
Nordic MCL Regimen LyMa Regimen
R-maxiCHOP / R-AraC R-CHOP / R-DHAP

• Median EFS 7.4 yrs • Median EFS: 6.9 yrs

• Median OS > 10 yrs • 5yr OS: 75%

Geisler CH, et al. Br J Haematol. 2012;158:355

Delarue R, et al. Blood. 2013;121:48
69
Maintenance rituximab after autologous
stem cell transplant improves survival

Randomized trial testing

no maintenance versus
3y of maintenance

Le Gouill N Engl J Med. 2017 Sep 28;377(13):1250-1260

Initial treatment for “unfit” patients

StIL: BR vs. RCHOP

Other initial regimens:
Len-rituximab
R-CVP
SHINE: BR +/- ibrutinib* (not FDA-approved)
Wang N Engl J Med 2022 Jun 30;386(26):2482-2494; Rummel Lancet 2013 Apr 6;381(9873):1203-10
Treatment approach in rel/ref MCL
• No data on sequencing
• List of options:
– BTK inhibitors
– Lenalidomide-rituximab
– Venetoclax
– Chemoimmunotherapy (if long duration of response to prior treatment)
– Bortezomib-based treatment
• Potential role of delayed autoHCT
• Allogeneic HCT
• CAR-T * (not yet FDA-approved) APPROVED!

Modified from NCCN.org

ZUMA-2: CAR-T in rel/ref MCL
Key patient features:
• N=74 enrolled PFS
patients
• Med age 65 y
• ORR
Ki-67 > 50% 69%
by IRRC Assessment Was 93% (95% CI, 84 – 98) and CR Rate Was
• 67%
TP53 mut
(95% CI, 17%
53 – 78)
• Blastoid 25%
100 93% ORR
Efficacy-
90 PR
Evaluable
CR
Best Objective Response, %

80 N = 60
Median follow-up (range), mo 12.3 (7.0 – 32.3)
70
60
67% CR Patients with ≥ 24 mo follow-up, n (%) 28 (47)
OS
(n = 40)
Median time to response (range), mo
50
Initial response 1.0 (0.8 – 3.1)
40
CR 3.0 (0.9 – 9.3)
30
Patients converted from PR/SD to CR, n (%) 24 (40)
20
27% PR 3% 3% PR to CR 21 (35)
10 (n = 16) (n = 2) (n = 2)
SD to CR 3 (5)
0
ORR SD PD
Investigator-assessed ORR in N = 60 was 88% (CR rate 70%), with 95% and 90% concordance between IRRC- and investigator-assessed ORR and CR rate, respectively. IRRC-assessed ORR in ITT (N = 74) was 85% (CR Rate 59%).
CR, complete response; IRRC, Independent Radiology Review Committee; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease.

Wang et al

Wang N Engl J Med 2020; 382:1331-1342

ASH 2019 Abstract 754 Wang N Engl J Med 2020; 382:1331-1342 73

Summary: Indolent lymphomas and
mantle cell lymphoma
• Follicular lymphoma • Marginal zone lymphoma
– Prototype of indolent lymphomas with • Three major subtypes
excellent outcomes for majority of pts • Prototype of antigen-driven disease
– Early progression of disease is • Often localized presentation
associated with inferior survival
• BTKi are active
– Observation is appropriate until
• Mantle cell lymphoma
symptomatic disease
• Rare and aggressive subtype of
– Many options for management, but
lymphoma
incurable by standard approaches
• Treatment depends on age and fitness
– Lifelong risk of transformation (but it
usually occurs early) • BTKi are active, being tested in initial
treatment
THANK YOU!
EXTRA SLIDES
“Cheat sheet” of IHC/flow associated with lineage in
heme malignancies

T-cell markers B-cell markers Myeloid markers

CD2 CD19 CD33
CD3 CD20 CD34
CD4 CD22 MPO
CD5 CD23
CD7
CD8

Other key markers Hodgkin lymphoma

CD10 “CALLA” (GC CD15*
marker) CD30*
*not lineage specific CD45 “LCA” Weak PAX5