i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource. This live or zoom broadcasted hematology/oncology fellowship program will bring an expert faculty member to your institution to discuss the latest developments and expert perspectives in the treatment of follicular lymphoma.

1. Tailoring Therapy for Follicular Lymphoma
Based on the Latest Evidence
Christopher Flowers, MD, MS, FASCO
Chair, Professor, Department of Lymphoma/Myeloma
MD Anderson Cancer Center

2. Disclosures
Consultant: AbbVie, AstraZeneca, Bayer, BeiGene, Bio Ascend, Bristol
Myers Squibb, Celgene, Denovo Biopharma, Foresight Diagnostics,
Genentech/Roche, Genmab, Gilead, Karyopharm, Pharmacyclics/
Janssen, Seagen, Spectrum
Grants/research support: 4D, AbbVie, Acerta, Adaptimmune, Allogene,
Amgen, Bayer, Celgene, Cellectis, EMD Serono, Genentech/Roche,
Gilead, Guardant, Iovance, Janssen, Kite, Morphosys, Nektar, Novartis,
Pfizer, Pharmacyclics, Sanofi, Takeda, TG Therapeutics, Xencor,
Ziopharm
i3 Health has mitigated all relevant financial relationships

3. Learning Objectives
FL = follicular lymphoma.
Evaluate molecular profiling recommendations that can inform
personalized care plans for patients with FL
Differentiate the mechanisms of action, efficacy, and safety of
emerging agents for FL
Assess the clinical application of novel therapeutic strategies for
patients with newly diagnosed and relapsed/refractory FL

4. Case 1: Ms. SM
PET = positron emission tomography; CT = computed tomography; LN = lymph node;
R-CHOP = rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone.
61-year-old woman diagnosed with FL grade 1/2
Asymptomatic
Noted on exam and PET/CT to have the following:
2-cm LN left cervical chain; multiple mesenteric LN 1.7-2.3 cm; palpable right
inguinal LN ~2.5 cm
Bone marrow biopsy: negative
Which option is most suitable for this patient?
A. R-CHOP
B. Rituximab + lenalidomide (R2)
C. Watch and wait
D. Obinutuzumab + bendamustine

5. Case 1: Ms. SM (cont.)
62-year-old woman diagnosed with FL grade 1/2
Stage III low tumor burden
Now with fatigue/weight loss, all prior LN larger but all <5 cm
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. R2
C. Watch and wait
D. Obinutuzumab + bendamustine

6. Case 1: Ms. SM (cont.)
SUV = standardized uptake value.
65-year-old woman originally diagnosed with FL grade 1/2
Stage III low tumor burden
Had a partial response to R x4 doses; no maintenance
Now with return of increased in prior areas (largest 4 cm) and new para-
aortic LN 6 cm
SUVmax = 5

7. Case 1: Ms. SM (cont.)
B-R = bendamustine/rituximab; axi-cel = axicabtagene ciloleucel.
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. R2
C. Watch and wait
D. Tazemetostat
E. R-CHOP
F. B-R
G. Axi-cel

8. Case 1: Ms. SM (cont.)
LDH = lactate dehydrogenase.
66-year-old woman with relapsed FL grade 1/2 following rituximab x4 doses
No maintenance with 3-year disease control
Now with progression on B-R
LDH 520 units/L
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. R2
C. Watch and wait
D. Tazemetostat
E. R-CHOP
F. B-R
G. Axi-cel

9. Case 2: Mr. TD
CR = complete response.
72-year-old man diagnosed with stage III FL high tumor burden
Treated with B-R x6 cycles and achieved a CR
2.5 years later, he had progression of disease
Biopsy confirmed relapsed FL grade 1-2
Which option is most suitable for this patient?
A. R-CHOP
B. R2
C. Tazemetostat
D. Obinutuzumab + bendamustine

10. Case 2: Mr. TD (cont.)
79-year-old man diagnosed with stage III FL high tumor burden
Treated with B-R x6 cycles and achieved a CR
2.5 years later, he had progression of disease
Then treated (at age 76) with R-CHOP x6 cycles with maintenance
and achieved a CR
Now has relapsed with bulky disease in the abdomen (largest LN 7 cm
in mesentery)
Which option is most suitable for this patient?
A. Axi-cel
B. R2
C. Tazemetostat
D. Obinutuzumab + bendamustine

11. Annual Incidence of Lymphoid Cancers in the US
Teras et al, 2016.
US Cancer Statistics for Lymphoid Malignancies by WHO Subtypes
Overall Survival
FL
WHO = World Health Organization; HL = Hodgkin lymphoma; MZL = marginal zone lymphoma; PTCL = peripheral T-cell lymphoma;
MCL = mantle cell lymphoma; BL = Burkitt lymphoma; MF = mycosis fungoides; HCL = hairy cell leukemia; LPL = lymphoplasmacytic lymphoma;
WM = Waldenstrom macroglobulinemia;DLBCL = diffuse large B-cell lymphoma; PCN = plasma cell neoplasms; CLL = chronic lymphocytic leukemia;
SLL = small lymphocytic lymphoma.

12. Follicular Lymphoma Pathogenesis
Huet, Sujobert & Salles, 2018.
VDJ = variable diversity joining; Ag = antigen; GC = germinal center; CSR = class-switch recombination; sIgM = switched but immunoglobulin M–expressing; SHM = somatic hypermutation;
ISFN = in situ follicular neoplasia; PFL = FL with partial involvement follicular lymphoma; BCL-2 = B cell lymphoma 2 protein; AID = activation-induced cytidine deaminase.

13. Pathway Gene Function Frequency Oncogenic Alteration
Epigenetic and
transcriptional
regulation
KMT2D Histone H3K4 methyltransferase 70%-90% Loss of function
CREBBP
Histone H3K27 and H3K17
acetyltransferase
50%-70% Loss of function
Histone-encoding genes Histone linkers and core histones 20%-30% Unknown
EZH2 Histone H3K27 methyltransferase 10%-30% Gain of function
EP300
Histone H3K27 and H3K18
acetyltransferase
10%-20% Loss of function
MEF2B Transcription factor 10%-20% Gain of function
BCR signaling
IGH and IGL variable domains Promotes N-glycosylation ~80% Gain of function
CARD11 BCR-NF-κB signaling pathway 10%-15% Gain of function
Survival
BCL-2 Anti-apoptosis
Translocations ~85%
~85%
Gain of function
Mutations ~50% Unknown
SOCS1, STAT6, and STAT3 JAK-STAT signaling 20% Gain of function
NOTCH1, NOTCH2, NOTCH3,
NOTCH4, DTX1, and SPEN
NOTCH pathway 18% Unknown
Immune escape
HVEM Receptor ~50% Loss of function
EPHA7 Ephrin receptor 70% Loss of function
Common Genetic Alterations in Follicular Lymphoma
KMT2D = histone-lysine N-methyltransferase 2D; CREBBP = cyclic AMP response element binding protein; EZH2 = enhancer of zeste homolog 2; MEF2B = myocyte enhancer binding factor 2B;
BCR = B-cell receptor; IGH = immunoglobulin heavy locus; IGL = immunoglobulin lamda locus; CARD11 = caspase recruitment domain family member 11; NF- κB = nuclear factor-κB;
SOCS1 = suppressor of cytokine signaling 1; STAT = signal transducer and activator of transcription; HVEM = herpesvirus entry mediator; EPHA7 = ephrin type-A receptor 7.
Huet, Sujobert & Salles, 2018.

14. Follicular Lymphoma International Prognostic Index (FLIPI)
OS = overall survival; Hgb = hemoglobin.
Solal-Céligny et al, 2004.
Survival of 1,795 Patients According to Risk Group
Number
factors
FLIPI risk
group
10-year
0-1 Low 70%
2
Intermediate
50%
≥3 High 35%
FLIPI risk factors
>4 lymph nodes
Age >60 years
Stage III/IV
High LDH
Hgb <12 g/dL

15. Clinicogenetic Risk Models Predict Early Progression of
FL
Pastore et al, 2015; Jurinovic et al, 2016.

16. Clinicogenetic Risk Models Predict Early Progression of FL (cont.)
Pastore et al, 2015; Jurinovic et al, 2016.

17. Gene Expression Score for Outcome Prediction in FL
Huet, Tesson et al, 2018.
FLIPI intermediate
FLIPI high
FLIPI low

18. Treatment Dependence of Prognostic Gene Expression in
FL
Bolen et al, 2021.

19. Newly Diagnosed FL:
Current Standards of Care
and Unmet Needs

20. How Can FL Patients Present?
BM = bone marrow.
LLS, 2020.
Lymphadenopathy
Palpable mass, edema
Splenomegaly
Abnormal blood counts
Skin lesions, endoscopy findings
Staging: exam, labs, imaging (CT, PET), ? BM

21. Unmet Needs in Personalizing Therapy for FL
Nastoupil et al, 2018.
Unmet Needs
 Model to predict early relapse
 Tools to inform treatment
selection
 Predictive biomarkers
 Novel therapies
Goals
 Identify high-risk patients for
access to clinical trials and
novel therapies
 Identify low-risk patients for
shorter duration and less toxic
therapy
 Improve outcomes in later lines

22. Considerations in the Choice of Therapy for an FL Patient
Indications for therapy
Bulk of disease
Comorbidities
Toxicity concerns
Interest in and availability of clinical trials
Risk of transformation
Grade (typically, I treat FL grade 1, 2, and 3A similarly)
Nastoupil et al, 2012.
At Diagnosis or Relapse

23. Which Patients With FL Need Treatment?
GELF = Groupe d'Etude des Lymphomes Folliculaires; BNLI = British National Lymphoma Investigation.
Brice et al, 1997; Nastoupil et al, 2012; Ardeshna et al, 2003.
GELF Criteria
High tumor bulk defined by either
• Tumor >7 cm
• 3 nodes in 3 distinct areas, each >3 cm
• Symptomatic splenic enlargement
• Organ compression
• Ascites or pleural effusion
Presence of systemic symptoms
Serum LDH or ß2-macroglobulin above normal values
values
Leukemia or blood cytopenia
BNLI Criteria
Rapid disease progression in the preceding 3 months
months
Life-threatening organ involvement
Renal or liver infiltration
Bone lesions
Systemic symptoms or pruritus
Hb <10g/dL or WBC <3.0x109/L or platelet count
<100x109/L; related to marrow involvement

24. Criteria for Therapy Requirement
NCCN, 2022.
Follicular lymphoma
Requiring therapy Not requiring therapy
B symptoms
Cytopenia due to BM infiltration
Leukemic phase
Elevated LDH
Pleural effusion or ascites
Bulk: node >7 cm
≥3 nodes >3 cm
Discomfort due to tumor masses
Watch and wait

25. A General Framework for Initial Therapy for FL
Kahl & Yang, 2016; Nastoupil et al, 2012; NCCN, 2022.
Staging
evaluation
Localized
Advanced indolent
Advanced with
symptoms
Rituximab-chemo
(R-chemo)
Watch and wait
Rituximab (R)
Obinutuzumab-chemo
(G-chemo)
Watch and wait
Radiotherapy
No chemo?

26. Case 1: Ms. SM (cont.)
62-year-old woman diagnosed with FL grade 1/2
Stage III low tumor burden
Now with fatigue weight loss, all prior LN larger but all <5 cm
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. R2
C. Watch and wait
D. Obinutuzumab + bendamustine

27. Newly Diagnosed FL:
Practice-Changing Trials

28. Initial Treatment for Advanced Disease
CIT = chemoimmunotherapy; PFS = progression free survival; CVP = cyclophosphamide/vincristine sulfate/prednisone; AE = adverse events; TTNT = time to next treatment.
Rummel et al, 2013; Flinn, van der Jagt, et al, 2019; Marcus et al, 2017; FDA, 2017; Morschhauser et al, 2018; Salles et all, 2011; Bachy et al, 2019; Drugs.com, 2011.
CIT is generally recommended for active therapy
StiL trial
phase 3
B-R vs R-CHOP
BRIGHT trial
phase 3
B-R vs
R-CHOP/R-CVP
GALLIUM trial
phase 3
G- vs R-chemo
• B-R superior to R-
R-CHOP
• Trend toward PFS
benefit with B-R vs
R-CHOP/R-CVP
• Superior PFS with G-
G- vs R-chemo, but
no difference in OS
• More grade 3-5 AEs
AEs with G
(75% vs 68%)
• Approval in 2017 for
for initial
chemotherapy and
maintenance G
R2 considered in certain
patients (eg, desiring
chemotherapy-free
regimens)
RELEVANCE trial
phase 3
R2 (lenalidomide + R) vs
R-chemo
• Similar efficacy with R2
compared with R-
R-chemotherapy
• Less hematologic toxicity
toxicity with R2, but more
more grade 3/4 cutaneous
cutaneous toxicity (7% vs
vs 1%)
R maintenance for
who respond to
therapy
PRIMA trial
phase 3
rituximab maintenance
• Superior PFS (and TTNT),
but not OS, with R
maintenance
• FDA approved in 2011 as
as maintenance therapy in
in patients with FL who
respond to induction
therapy

29. GALLIUM: G-Chemo vs R-Chemo
iNHL = indolent non-Hodgkin lymphoma; ECOG = Eastern Cooperative Oncology Group; PS = performance status; D = day; C = cycle;
Q3W = every 3 weeks; Q4W = every 4 weeks; CR = complete response; EOI = end of induction; IV = intravenous; Q2Mo = every 2 months;
PD = progressive disease; INV = investigator; IRC = independent review committee; EFS = event-free survival; DFS = disease-free survival;
DOR = duration of response; ORR = objective response rate; FDG-PET = fluorodeoxyglucose PET.
Marcus et al, 2017.
International, Open-Label, Randomized Phase 3 Study
Primary end point
• PFS (INV-assessed in FL)
Secondary and other end points
• PFS (IRC-assessed)
• CR/ORR at EOI (± FDG-PET)
• OS, EFS, DFS, DOR, TTNT
• Safety
Previously untreated CD20-positive iNHL
• Age ≥18 years
• FL grade 1-3a or
splenic/nodal/extranodal MZL
• Stage III/IV or stage II bulky disease (≥7
cm) requiring treatment
• ECOG PS 0-2
• Target FL enrollment: 1,200
1:1
R
A
N
D
O
M
I
Z
A
T
I
O
N
G-chemo
G 1,000 mg IV on D1, D8,
D15 of C1 and D1 of C2-8
(Q3W) or C2-6 (Q4W)
plus CHOP, CVP, or
bendamustine
R-chemo
R 375 mg/m2 IV on D1 of
C1-8 (Q3W) or C1-6
(Q4W) plus CHOP, CVP,
or bendamustine
CR or PR
at EOI visit
G
G 1,000 mg IV Q2Mo for 2
years or until PD
R
R 375 mg/m2 IV Q2Mo for
2 years or until PD

30. GALLIUM: G-Chemo vs R-Chemo (cont.)
aStratified analysis. Stratification factors: chemotherapy regimen, FLIPI risk group, geographic region.
Marcus et al, 2017.
Investigator-Assessed PFS
0.8
0.6
0.4
0.2
0
1.0
Probability
R-chemo (n=601)
G-chemo (n=601)
Time (months)
12 18 24 30 36 42 48 54
6
0
No. of patients at risk
R-chemo
G-chemo
505
536
463
502
378
405
266
278
160
168
68
75
10
13
562
570
601
601
0
0
R-chemo
n=601
G-chemo
n=601
Patients with event
event
n (%)
144
(24.0%)
101
(16.8%)
3-yr PFS, %
(95% CI)
73.3
(68.8, 77.2)
80.0
(75.9, 83.6)
HR (95% CI)
P valuea
0.66 (0.51, 0.85)
P=0.001
Median follow-up: 34.5 months

31. GALLIUM: G-Chemo vs R-Chemo (cont.)
Marcus et al, 2017.
AEs in >20% Overall Induction phase Maintenance phase
G-chemo R-chemo G-chemo
R-chemo
n=597
G-chemo
n=548
R-chemo
Neutropenia 289 (48.6%) 260 (43.6%) 247 (41.5%) 235 (39.4%) 105 (19.2%) 70 (13.1%)
Nausea 279 (46.9%) 278 (46.6%) 272 (45.7%) 266 (44.6%) 23 (4.2%) 35 (6.5%)
Constipation 210 (35.3%) 188 (31.5%) 197 (33.1%) 176 (29.5%) 21 (3.8%) 16 (3.0%)
Diarrhea 160 (26.9%) 131 (21.9%) 117 (19.7%) 98 (16.4%) 54 (9.9%) 46 (8.6%)
Vomiting 139 (23.4%) 122 (20.4%) 120 (20.2%) 103 (17.3%) 25 (4.6%) 22 (4.1%)
Fatigue 214 (36.0%) 218 (36.5%) 195 (32.8%) 186 (31.2%) 40 (7.3%) 59 (11.0%)
Pyrexia 164 (27.6%) 127 (21.3%) 143 (24.0%) 111 (18.6%) 29 (5.3%) 25 (4.7%)
Infusion reaction
reaction
351 (59.0%) 292 (48.9%) 345 (58.0%) 279 (46.7%) 39 (7.1%) 36 (6.7%)
Headache 122 (20.5%) 101 (16.9%) 106 (17.8%) 87 (14.6%) 27 (4.9%) 27 (5.0%)
Cough 152 (25.5%) 144 (24.1%) 83 (13.9%) 71 (11.9%) 86 (15.7%) 88 (16.4%)
Adverse Events:

32. RELEVANCE: R2 vs R-chemo in Frontline FL
Morschhauser et al, 2018; Morschhauser et al, 2021.
Figure 2. Progression-Free Survival by IRC (A) and Overall Survival (B)
in the Intention-to-Treat Population
Figure 1. Consort Diagram

33. Rates of Anti–SARS-CoV-2 Spike Protein IgG Antibody Seroconversion
HM = hematological malignancies.
Ribas et al, 2021.
Patients With Different Histologies of HM Compared With Healthy
Subjects

34. Serologic Response SARS-CoV-2 Vaccinations: Patient Characteristics
Greenberger et al, 2021; LLS, 2021.
While many patients with HM fail to mount a full antibody response, the safety profiles of SARS-CoV-2 mRNA vaccines are similar compared
with age-matched healthy individuals
Therefore, patients with blood cancer are encouraged to get the SARS-CoV-2 vaccines as recommended by NCCN guidelines
Prospective national
registry (LLS National
Patient Registry):
https://www.ciitizen.com/lls/
NCT04794387
was used to assess the
serologic response to
vaccinations against
SARS-CoV-2
Cancer diagnosis Neg (n=357) Pos (n=1,088) All patients (n=1,445)
Acute lymphoblastic leukemia 2 (11.8%) 15 (88.2%) 17 (100.0%)
Acute myeloid leukemia 3 (8.8%) 31 (91.2%) 34 (100.0%)
Burkitt lymphoma 0 (0.0%) 1 (100.0%) 1 (100.0%)
Chronic lymphocytic leukemia 233 (35.8%) 417 (64.2%) 650 (100.0%)
Chronic myeloid leukemia 1 (2.9%) 33 (97.1%) 34 (100.0%)
Diffuse large B cell lymphoma 11 (21.2%) 41 (78.8%) 52 (100.0%)
Follicular lymphoma 22 (22.4%) 76 (77.6%) 98 (100.0%)
Hairy cell leukemia 0 (0.0%) 7 (100.0%) 7 (100.0%)
Hodgkin lymphoma 1 (1.5%) 64 (98.5%) 65 (100.0%)
Mantle cell lymphoma 15 (55.56%) 12 (44.4%) 27 (100.0%)
Marginal zone lymphoma 13 (38.2%) 21 (61.8%) 34 (100.0%)
Multiple myeloma 9 (4.9%) 175 (95.1%) 184 (100.0%)
Non-Hodgkin lymphoma not specified 10 (20.8%) 38 (79.2%) 48 (100.0%)
Primary mediastinal (thymic) large B cell lymphoma
lymphoma
0 (0.0%) 4 (100.0%) 4 (100.0%)
Smoldering multiple myeloma 0 (0.0%) 29 (100.0%) 29 (100.0%)
T-cell lymphoma 2 (15.4%) 11 (84.6%) 13 (100.0%)
Waldenstrom macroglobulinemia 25 (25.8%) 72 (74.2%) 97 (100.0%)

35. Patients %
Stay during COVID-19
Hospital 75 66.4%
COVID-19 ward 59/75 83.8%
ICU 16/75 14.2%
Of which, invasive mechanical ventilation 10/16 8.8%
Home 38 33.6%
Overall mortality at 30 days 14 12.4%
Attributable to COVID-19 9/14 64.3%
+ Hematological malignancy 3/14 21.4%
Mortality according to type of hematological malignancy
Acute lymphoid leukemia 0/3 0.0%
Chronic lymphoid leukemia 2/28 7.1%
Acute myeloid leukemia 0/5 0.0%
Chronic myeloid leukemia 0/1 0.0%
Myelodysplastic syndrome 2/7 28.6%
Hodgkin lymphoma 1/4 25.0%
Non-Hodgkin lymphoma 6/36 16.7%
Myelofibrosis 1/3 33.3%
Polycythemia vera 0/2 0.0%
Systemic mastocytosis 1/2 50.0%
Multiple myeloma 1/20 5.0%
Aplastic anemia 0/2 0.0%
Mortality for patients with active hematological malignancy
Yes 7/14 50.0%
No 7/14 50.0%
Mortality for patients with chemoimmunotherapy or radiotherapy
In the last 3 mos 10/14 71.4%
>3 mo/watch and wait 4/14 28.6%
Outcome of Vaccinated Patients That Developed COVID-19 Infection
Low serologic
response rate to anti–
SARS-CoV-2 vaccines
in patients with HM
may translate to
higher rates of
infections
This has previously
been described
following monoclonal
antibody treatment
Pagano et al, 2022.

36. Novel Therapeutic Approaches
for Relapsed/Refractory FL
36

37. Case 1: Ms. SM (cont.)
65-year-old woman originally diagnosed with FL grade 1/2
Stage III low tumor burden
Had a partial response to R x4 doses; no maintenance
Now with return of increased size in prior areas (largest 4 cm) and new para-
aortic LN 6 cm
SUVmax = 5
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. Rituximab + lenalidomide
C. Watch and wait
D. Tazemetostat
E. R-CHOP
F. B-R
G. Axi-cel

38. Poorer Outcomes in the R/R Setting
R/R = relapsed/refractory.
Link et al, 2019; Casulo et al, 2015.
National LymphoCare Study
PFS by Treatment Line
First line: 79.4 months
Second line: 18.0 months
Third line: 10.0 months
Fourth line: 8.3 months
Fifth line: 8.2 months
Line of treatment, median PFS

39. Progression of Disease in 24 Months Predicts Poor Survival
POD24 = progression of disease within 24 months.
Casulo, Dixon et al, 2022; Casulo et al, 2017.
Analysis of >5000 patients on 13 clinical trials
POD24 independently associated with increased risk of death or progression
POD24 predicted by:
Male sex
Poor PS
High-risk FLIPI
Elevated ß2-macroglobulin
For patients with POD24,
death more likely in the
following:
Age >60
Male sex
PS ≥2
High-risk FLIPI
Hgb <12
Elevated ß2-macroglobulin

40. Relapsed/Refractory FL (LEO CReWE)
Casulo, Larson et al, 2022.
441 patients with R/R FL
Non-transformed grade 1-3a
≥2 prior lines of systemic therapy, including an alkylating agent and an anti-CD20
For lines of therapy 3 and later (any therapy):
5-year OS: 75% (95% CI: 70-79)
PFS: 17 months
ORR: 70% (95% CI: 65-74)
Patients refractory to an alkylating agent have lower ORR (68% vs 77%) and lower 5-
year OS (72% vs 81%; HR 1.60) than patients not refractory to an alkylating agent
Mortality at 5 years: 17% from lymphoma, 3% other causes, 9%
unknown
Treatment Patterns and Outcomes After 3+ Lines of Therapy

41. Current Practice Strategies for
Relapsed/Refractory FL
42

42. B-Cell Receptor Pathway
Hallek, 2013.
Acalabrutinib
Venetoclax, ABT-737,
obatoclax, oblimersen
Idelalisib
Copanlisib
Umbralisib
Duvelisib
Venetoclax

43. Novel Therapies in Relapsed/Refractory FL
Lymphoma Research Foundation, 2021; Gilead, 2022; Secura Bio, 2021; US Food and Drug Administration, 2022.
2017 2019 2020 2021
R2: Rituximab +
lenalidomide
Tazemetostat
Umbralisib
(withdrawn)
Lisocabtagene
maraleucel
Axicabtagene
ciloleucel
Obinutuzumab
Duvelisib
(withdrawn)
Copanlisib
2018
2014
Idelalisib
(withdrawn)
2022
Tisagenlecleucel

44. NHL Treatment: Relapsed/Refractory FL
HDT = high-dose therapy; SCT = stem cell transplantation.
NCCN, 2022.
Second-line and later therapy
Bendamustine + obinutuzumab or rituximab (except if
prior bendamustine)
CHOP + obinutuzumab or rituximab
CVP + obinutuzumab or rituximab
Lenalidomide ± rituximab
PI3K inhibitors
Copanlisib
Tazemetostat
EZH2 mutation positive
EZH2 wild type or unknown relapsed/refractory disease
with no satisfactory alternative options
CAR T-cell therapy
Axi-cel
Consolidation or extended dosing
(optional)
Rituximab maintenance
Obinutuzumab maintenance
(rituximab refractory)
HDT plus autologous SCT
Allogeneic SCT for selected
patients

45. Practice-Changing Trials for
Relapsed/Refractory FL
46

46. Lenalidomide Mechanism of Action: B-Cell Non-Hodgkin
Lymphoma
Gribben et al, 2015.

47. Lenalidomide in Follicular Lymphoma
Flowers et al, 2020.
First-line treatment options Relapsed treatment options
Rituximab (R) Rituximab (R)
R-chemotherapy R-chemotherapy
R2 R2
Study Lenalidomide dosing Study Lenalidomide dosing
Zucca et al, 2019
15 mg/day with rituximab
for 18 weeks
Witzig et al, 2009
25 mg/day Days 1-21 (28-
day cycle) for up to 52
weeks
Fowler et al, 2014
20 mg/day Days 1-21 (28-
day cycle) with rituximab
for up to 12 cycles
Leonard et al, 2015
15-25 mg/day Days 1-21
(28-day cycle) ± rituximab
Martin et al, 2017
20-25 mg/day Days 1-21
(28-day cycle) with
rituximab for up to 12
cycles
Chong et al, 2015 10 mg daily with rituximab
Morschhauser et al, 2018
20 mg/day Days 1-21 (28-
day cycle) with rituximab
x6 cycles followed by 10
mg/day Days 1-21 (28-day
cycle) for 12 cycles in
patients with CR
Andorsky et al, 2019
20 mg/day Days 1-21 (28-
day cycle) with rituximab
for 12 cycles followed by
1:1 randomization for
patients with ≥SD to
maintenance lenalidomide
10 mg/day Days 1-21 with
rituximab versus rituximab
alone

48. AUGMENT (NHL-007): R/R FL or MZL
Leonard et al, 2019.
R2 vs Rituximab Monotherapy
12 months
R/R
FL or MZL
(n=358)
Placebo
Rituximab weekly x4 then every month x4
Lenalidomide 20 mg
Rituximab weekly x4 then every month x4
Primary end point: PFS

49. Case 1: Ms. SM (cont.)
66-year-old woman with relapsed FL grade 1/2 following R x4 doses
No maintenance with 3-year disease control
Now with progression on B-R
LDH 520 units/L
Which treatment option is most suitable for this patient?
A. Rituximab alone
B. R2
C. Watch and wait
D. Tazemetostat
E. R-CHOP
F. B-R
G. Axi-cel

50. Case 2: Mr. TD (cont.)
72-year-old man diagnosed with stage III FL with high tumor burden
Treated with B-R x6 cycles and achieved a CR
2.5 years later, he had progression of disease
Biopsy confirmed relapsed FL grade 1-2
Which option is most suitable for this patient?
A. R-CHOP
B. R2
C. Tazemetostat
D. Obinutuzumab + bendamustine

51. Case 2: Mr. TD (cont.)
79-year-old man diagnosed with stage III FL high tumor burden
Treated with B-R x6 cycles and achieved a CR
2.5 years later, he had progression of disease
Then treated (at age 76) with R-CHOP x6 cycles with maintenance and achieved a CR
Now has relapsed with bulky disease in the abdomen; largest LN 7 cm in mesentery
Which option is most suitable for this patient?
A. Axi-cel
B. R2
C. Tazemetostat
D. Obinutuzumab + bendamustine

52. AUGMENT: R2 vs Rituximab Monotherapy
a2 patients in each group had an ECOG PS of 2.
bBulky disease = at least 1 lesion that is ≥7 cm or at least 3 lesions with ≥3 cm in the longest diameter, by investigator review.
c2 patients in the R2 group and 1 patient in the R-placebo group did not have FLIPI scores recorded.
ULN = upper limit of normal.
Leonard et al, 2019.
Characteristic, n (%)
R2
(n=178)
Rituximab-placebo
(n=180)
Median age, years (range) 64 (26-86) 62 (35-88)
Age ≥60 years 108 (61%) 106 (59%)
Age ≥65 years 82 (46%) 73 (41%)
ECOG PS 1-2a 62 (35%) 52 (29%)
Positive BM involvement, n involved/performed (%) 33/106 (31%) 31/111 (28%)
Ann Arbor stage III or IV at study entry 137 (77%) 124 (69%)
Bulky diseaseb (≥7 cm or ≥3 cm x3) 45 (25%) 49 (27%)
High tumor burden per GELF criteria 97 (54%) 86 (48%)
Histology
FL 147 (83%) 148 (82%)
MZL 31 (17%) 32 (18%)
LDH > ULN 43 (24%) 39 (22%)
B-symptoms 16 (9%) 12 (7%)
FLIPI scorec
0 or 1 52 (29%) 67 (37%)
2 55 (31%) 58 (32%)
3 to 5 69 (39%) 54 (30%)
Baseline Characteristics (ITT)

53. AUGMENT: R2 vs Rituximab Monotherapy (cont.)
ITT = intent to treat; CI = confidence interval; NE = not estimable; NR = not reached.
Leonard et al, 2019.
Primary End Point: Progression-Free Survival (ITT, IRC)
Median PFS
R2
(n=178)
Rituximab-
placebo
(n=180)
HR
(95% CI)
P value
By IRC, mo
(95% CI)
39.4
(22.9-NE)
14.1
(11.4-16.7)
0.46
(0.34-0.62)
<0.001
By investigator,
mo (95% CI)
25.3
(21.2-NR)
14.3
(12.4-17.7)
0.51
(0.38-0.69)
<0.0001

54. AUGMENT: R2 vs Rituximab Monotherapy (cont.)
*Refractory = no response or progressive disease <6 months after the last dose.
Leonard et al, 2019.
Prespecified Subgroup PFS Analysis (IRC, ITT)

55. AUGMENT: R2 vs Rituximab Monotherapy (cont.)
Leonard et al, 2019.
Grade 3/4 neutropenia (50% vs 13%) and leukopenia (7% vs 2%) higher with R2
Efficacy and Safety
Progression-Free
Survival
Overall Survival
PFS
Probability
Months Since Randomization
R2
R-placebo
Months Since Randomization
OS
Probability
R2
R-placebo
Median PFS by IRC
• R2 = 39.4 months
• R-placebo = 14.1 months
HR=0.46
2-year OS
• R2 = 93%
• R-placebo = 87%
Median follow-up: 28.3 months

56. mPFS = median PFS; mOS = median OS; ALT = alanine transaminase; AST = aspartate aminotransferase.
Gopal et al, 2014; Dreyling et al, 2017; Flinn, Miller, et al, 2019; Dreyling et al, 2020; Fowler et al, 2021; Zydelig® prescribing information, 2020; Copiktra® prescribing information, 2019.
Idelalisib Copanlisib Duvelisib Umbralisib
Isoform
targeted
δ α, δ δ,γ δ,CK1ε
ORR in FL
patients
54% 59% 42% 45%
mPFS 11 months 12.5 months 9.5 months 10.6 months
mOS 20.3 months 42.6 months 28.9 months N/A
Serious AEs
of interest
Black box warnings:
Hepatotoxicity
Diarrhea/colitis
Pneumonitis
Infection
Intestinal perforation
perforation
Most common
grade 3/4 AEs:
Hyperglycemia
Hypertension
Neutropenia
Pneumonia
Black box warnings:
Diarrhea/colitis
Infection
Pneumonitis
Skin reaction
Most common grade 3/4
3/4 Aes:
Neutropenia
Diarrhea
ALT/AST elevation
PI3K Inhibitors Approved for R/R FL

57. EZH2, a Histone Methyltransferase, in FL
Morschhauser et al, 2017; Morschhauser et al, 2020; Makita & Tobinai, 2018.
In normal B-cell biology, EZH2 regulates
germinal center formation
EZH2 mutations can lead to oncogenic
transformation by locking B cells in
germinal state and preventing terminal
differentiation
EZH2-activating mutations found in
~20% of patients with FL
Tazemetostat: selective, oral, first-in-
class EZH2 inhibitor
Whether WT or mutant, EZH2 biology is
relevant to FL

58. Tazemetostat: EZH2 Inhibitor
COO = cell of origin; GCB = germinal center B-cell; Mt = mutant; WT = wild type; BID = twice a day; PK = pharmacokinetic.
Morschhauser et al, 2018.
PRESCREENING
COHORT
ALLOCATION
ELIGIBILTY,
ENROLLMENT
EOT
FOLLOW-UP
DLBCL, GCB
EZH2 Mt (n=60)
FL, EZH2 WT
(n=45)
FL, EZH2 Mt (n=45)
DLBCL, non-GCB
(n=60)
DLBCL, GCB
EZH2 WT (n=60)
Archival tissue
Central lab COO, EZH2
Tazemetostat 800 mg BID until
PD or withdrawal
ORR, PFS, DOR, safety, PK OS
Clinical Activity and Favorable Safety in a Phase 2 Multicenter Study
Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

59. Tazemetostat: Relapsed FL Activity by EZH Mutation Status
Morschhauser et al, 2020.
Best response, IRC assessed
FL EZH2 Mt
(n=45)
FL EZH2 WT
(n=54)
Objective response rate (CR + PR), n (%) 95% CI
31 (69%)
53-82
19 (35%)
23-49
Complete response 6 (13%) 2 (4%)
Partial response 25 (56%) 17 (31%)
Stable disease 13 (29%) 18 (33%)
Progressive disease 1 (2%) 12 (22%)
No data/unknown 0 5 (9%)
Final responses, IRC assessed n=31 n=19
Median duration of response, months 10.9 13.0
Median progression-free survival, months 13.8 11.1
Median overall survival, months NR NR

60. Tazemetostat Efficacy
Morschhauser et al, 2020.
EZH2 Mt EZH2 WT
Response ≥6 months 61% 53%
Response ≥12 months 23% 37%
Response ≥18 months 19% 21%
EZH2 Mt EZH2 WT
%
Patients
With
Response
Duration of Response (months) Duration of Response (months)
Durability of Response in Both Cohorts

61. Tazemetostat: Safety Profile
Morschhauser et al, 2020.
• 5% of all patients
discontinued
treatment
• 9% had dose
reductions due to
treatment-related
AEs
Treatment-emergent adverse Treatment-related adverse
Grade 1-2 Grade 3 Grade 4 Grade 1-2 Grade 3 Grade 4
Nausea 23 (23%) 0 0 19 (19%) 0 0
Diarrhea 18 (18%) 0 0 12 (12%) 0 0
Alopecia 17 (17%) 0 0 14 (14%) 0 0
Cough 16 (16%) 0 0 2 (2%) 0 0
Asthenia 15 (15%) 3 (3%) 0 13 (13%) 1 (1%) 0
Fatigue 15 (15%) 2 (2%) 0 11 (11%) 1 (1%) 0
Upper respiratory
tract infection
15 (15%) 0 0 1 (1%) 0 0
Bronchitis 15 (15%) 0 0 3 (3%) 0 0
Abdominal pain 12 (12%) 1 (1%) 0 2 (2%) 0 0
Headache 12 (12%) 0 0 5 (5%) 0 0
Vomiting 11 (11%) 1 (1%) 0 6 (6%) 0 0
Back pain 11 (11%) 0 0 0 0 0
Pyrexia 10 (10%) 0 0 2 (2%) 0 0

62. CAR T-Cell Therapy: Axi-Cel
CAR = chimeric antigen receptor.
Yescarta® Prescribing Information, 2022; Neelapu et al, 2018; van der Stegen et al, 2015.
Axi-cel is an autologous anti-CD19 CAR T-cell therapy
Axi-cel is approved in the US and EU, for the treatment of adult patients with
relapsed or refractory large B-cell lymphoma after 2 or more lines of
systemic therapy

63. ZUMA-5 Study Design: Axi-Cel in R/R FL
mAb = monoclonal antibody.
Neelapu, 2021; Jacobson et al, 2022.
Key ZUMA-5 Eligibility Criteria
• R/R FL (grades 1-3a) or MZL (nodal
or extranodal)
• ≥2 prior lines of therapy that must have
included an anti-CD20 mAb combined
with alkylating agent
R/R NHL
(N=157) Leukapheresis
Conditioning
Chemotherapy
Fludarabine 30 mg/m2
IV and
cyclophosphamide 500
mg/m2 on Days -5, -4,
-3
Axi-Cel Infusion
2x106 CAR-positive cells/kg on
Day 0
Post-treatment assessment and
long-term follow-up periods
Primary End Point
• ORR (IRRC-assessed per the
Lugano classification)
Key Secondary End Points
• CR rate (IRRC-assessed)
• Investigator-assessed ORR
• DOR, PFS, OS
• AEs
• CAR T cell and cytokine levels

64. .
ZUMA-5: Axi-Cel in R/R FL
Among efficacy-eligible patients with iNHL (n=109), the ORR was 92% (95% CI: 85-96), with a
76% CR rate
Among all treated patients with iNHL (n=149), the ORR was 92% (95% CI: 86-96), with a 77%
CR rate
Neelapu, 2021; Jacobson et al, 2022.
ORR by Central Review
All Patients (n=109) Patients with FL (n=86)

65. ZUMA-5: Axi-Cel in R/R FL (cont.)
Neelapu, 2021; Jacobson et al, 2022.
Median OS was not yet reached in efficacy-eligible patients with FL or MZL
Among patients with FL, 3 deaths occurred after Month 24
No disease progression events occurred after Month 24
PFS and OS

66. ZUMA-5: Axi-Cel in R/R FL (cont.)
CRS = cytokine release syndrome; NEs = neurologic events.
Neelapu, 2021; Jacobson et al, 2022.
Consistent with prior reports, the most common grade ≥3 AEs in all treated
patients were neutropenia (33%), decreased neutrophil count (28%), and
anemia (24%)
Grade ≥3 CRS and NEs occurred in 7% of patients (6% FL; 8% MZL) and
19% of patients (15% FL; 36% MZL), respectively
Most CRS cases (120 of 121) and NEs (82 of 87) of any grade resolved by data cutoff
Nearly half of NEs (49%) resolved ≤2 weeks after onset; most NEs (76%) resolved ≤8
weeks after onset
Grade ≥3 cytopenias present ≥30 days post-infusion were reported in 34%
of patients (33% FL; 36% MZL), most commonly neutropenia in 29% of
patients (27% FL; 36% MZL)
Safety Results

67. TRANSCEND: Liso-Cel for R/R Follicular Lymphoma Grade 3b
Liso-cel = lisocabtagene maraleucel.
Abramson et al, 2020; FDA, 2021.
Median 3 (1-8) lines of prior therapy
ORR: 73% (95% CI: 66.8%-78.0%)
CR: 53% (95% CI: 46.8%-59.4%)
OS: 21.1 months
PFS: 6.8 months
Approved in February 2021 for R/R large B-cell
lymphoma after ≥2 lines of systemic therapy
Baseline characteristics Patients (n=269)
Diffuse large B-cell lymphoma, not
not otherwise specified
137 (51%)
Diffuse large B-cell lymphoma
transformed from indolent
lymphomas
• From follicular lymphoma
• From other indolent subtypes
78 (29%)
60 (22%)
18 (7%)
High-grade B-cell lymphoma with
with gene rearrangements in MYC
MYC and BCL-2 or BCL-6 or both
both
36 (13%)
Primary mediastinal B-cell
lymphoma
15 (6%)
Follicular lymphoma grade 3B 3 (1%)
CD-19–Directed CAR T-Cell Therapy

68. TRANSCEND : Liso-Cel (cont.)
Abramson et al, 2020.
Consistent with other CAR T
Most common grade ≥3:
Neutropenia 60%
Anemia 37%
Thrombocytopenia 27%
CRS in 42% of patients, grade ≥3: 2%
Neurologic toxicity in 30%, grade ≥3: 10%
Dose-limiting toxicity: 6% (9 patients)
Prolonged cytopenias, hypogammaglobulinemia, infections
Safety Results: Treatment-Emergent Adverse Events

69. ELARA: Tisagenlecleucel for R/R FL Grade 1, 2, and 3a
Fowler et al, 2022.
PFS at 12 months: 67%
Median PFS not reached
Safety Analysis Set (n=97)
Selected AEs Any grade Grade ≥3
Any TRAE 78.4% 46%
CRS 48.5% 0
Neutropenia 33.0% 32.0%
Anemia 24.7% 13.4%
Any neurological 37.1% 3.1%
Headache 23.7% 1%
Any gastrointestinal 41.2% 4.1%
Approved May 2022 for R/R
follicular lymphoma after ≥2 prior
lines of systemic therapy
Efficacy Analysis Set (n=94)
Complete response
(95% CI)
69.1%
(59%-78%)
Partial response 17.0%
Stable disease 3.2%
Progressive disease 9.6%
Grade 1, 2, and 3a Without Histologic Transformation

70. Structure of Selected BiTE and Bispecific Antibodies
BiTE = bispecific T-cell engager.
Schuster, 2021.

71. Bispecific Antibodies Under Investigation for R/R FL
SAEs = serious AEs.
Budde et al, 2021; Hutchings, Morschhauser et al, 2021; Patel et al, 2021; Hutchings, Mous et al, 2021; Bannerji et al, 2022.
Bispecific Phase and details N ORR SAEs Grade ≥3 AEs >10%
Mosunetuzumab Phase 1/2 90 80% CRS 44%
Neutropenia 27%
Hypophosphatemia 17%
Glofitamab
Phase 1/2, with
obinutuzumab
171 65.7%
CRS 50.3%
Fever 46%
Neutropenia 25%
Infections 18%
Plamotamab Phase 1
53
(all level)
43.4% CRS 62.5%
Epcoritamab Phase 1/2 68 68%
CRS 59%
Fever 69%
Hypophosphatemia 16%
Neutropenia 15%
Anemia 13%
Pneumonia 12%
Odronextamab Phase 1 145 51%
CRS 61%
Fever 73%
Anemia 25%
Lymphopenia 19%
Hypophosphatemia 19%
Neutropenia 19%
Thrombocytopenia 14%
Targets: CD20 x CD3

72. Mosunetuzumab: Anti-CD20xCD3 Bispecific Antibody for R/R FL
Budde et al, 2022.
Single-arm, phase 2 study
90 patients with R/R FL
Grade 1-3a
2 or more prior lines of therapy
Efficacy by Independent review committee assessment
Objective response rate 72 (80%)
Complete response rate 54 (60%)
Median duration of response 22.8 months
Safety and Efficacy
Accelerated approval
December 2022
Safety Analysis (n=90)
Selected AEs Any grade Grade ≥3
Any TRAE 83 (92%) 46 (51%)
CRS 40 (44%) 2 (2%)
Fatigue 33 (37%) 0
Headache 28 (31%) 1 (1%)
Neutropenia 26 (28%) 24 (27%)
Pyrexia 26 (28%) 1(1%)
Hypophosphatemia 24 (27%) 15 (17%)

73. Key Takeaways
In the modern era, the median OS of FL is approaching 20
years
Treatment options for newly diagnosed advanced-stage FL
include multiple immunochemotherapy regimens ± anti-
CD20 maintenance
Several approved options for relapsed/refractory FL

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80. Christopher Flowers, MD, MS, FASCO
Contact: crflowers@mdanderson.org
Questions?