management of indolent lymphoma in the elderly patient · follicular lymphoma international...
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MD Anderson
Disclosures
Follicular Lymphoma 2
1 HONORARIUM
Bayer, Celgene, Genentech, Gilead/KITE, Janssen, Juno, Merck, Novartis,
Spectrum, TG Therapeutics
2 RESEARCH SUPPORT
Celgene, Genentech, Janssen, Karus, Merck, TG Therapeutics
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Clinical Presentation of Follicular Lymphoma
3Pathogenesis of Follicular Lymphoma
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Initial Presentation
4Pathogenesis of Follicular Lymphoma
50 year old M with no significant
PMH presents with 2 month history
of L neck adenopathy (11/2014).
After a brief decrease in size
following a course of oral antibiotics,
with recurrence of adenopathy he
was referred to ENT for further eval.
Otherwise asymptomatic, no B
symptoms.
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Initial Presentation Continued
5Pathogenesis of Follicular Lymphoma
Biopsy of the L neck adenopathy
revealed:
Follicular lymphoma, grade 1
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Initial Staging/Work Up
6Pathogenesis of Follicular Lymphoma
Bone marrow biopsy results:
Follicular Lymphoma present 5-10%
Stage IV
LDH is > ULN
CBC is normal
PET/CT results:
Hypermetabolic adenopathy above
and below the diaphragm
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Early Steps of Follicular Lymphomagenesis
7Pathogenesis of Follicular Lymphoma
Huet. Nature. April 2018
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Common Genetic Alterations in FL
8Pathogenesis of Follicular Lymphoma
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Clinical Presentation
9Pathogenesis of Follicular Lymphoma
▪Lymphadenopathy
▪Palpable mass, edema
▪Splenomegaly
▪Abnormal blood counts
▪Skin lesions
▪Endoscopy findings
▪Abnormal imaging findings
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Prognostic Tools for Newly Diagnosed Follicular
Lymphoma
10Pathogenesis of Follicular Lymphoma
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Cause of Death in FL in the Rituximab Era
Follicular Lymphoma 11
Sarkozy. JCO 2018
MD Anderson 12Pathogenesis of Follicular Lymphoma
Follicular Lymphoma International Prognostic Index (FLIPI)
Solal-Celigny P, et al. Blood 2004;104:1258-65.
Risk factors:
Nodal sites > 4
Stage III/IV
LDH > ULN
Hgb < 12 g/dL
Age > 60 y
Low risk – 0-1
Intermediate – 2
High – 3-5
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Follicular Lymphoma International Prognostic Index 2 (FLIPI-2)
13Pathogenesis of Follicular Lymphoma
Risk factors:
B2M > ULN
Mass > 6 cm
BM involved
Hgb < 12 g/dL
Age > 60 y
Low risk – 0
Intermediate – 1-2
High – 3-5
Federico M. et al, JCO 2008; 27:4555-4562.
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M7-FLIPI: Incorporation of Molecular Features
14Pathogenesis of Follicular Lymphoma
Pastore A, et al. Lancet Oncol. 2015;16:1111-22.
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Indications for Treatment
15Pathogenesis of Follicular Lymphoma
1. Brice P, et al. J Clin Oncol. 1997:15:1110-7.
2. Ardeshna KM, et al. Lancet. 2003;362:516-22.
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Initial Therapy for Newly Diagnosed Follicular
Lymphoma
16Pathogenesis of Follicular Lymphoma
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General Approach to Initial Therapy for FL
17Pathogenesis of Follicular Lymphoma
R+Lenalidomide
W&W: watch and wait; R: rituximab; G:obinutuzumab
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Rituximab vs. Watch and Wait for Low Tumor Burden FL
18Pathogenesis of Follicular Lymphoma
Ardeshna KM, et al. Lancet Oncol. 2014;15:424-35 .
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RESORT Trial: Rituximab x 4 Followed by Maintenance vs.
Retreatment
19Pathogenesis of Follicular Lymphoma
Kahl BS, et al. J Clin Oncol. 2014;32:3096-102. .
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Approach to Indolent/Low Tumor Burden, Advanced Stage FL
20Pathogenesis of Follicular Lymphoma
Watch and wait acceptable (encouraged)
• Allows the opportunity to assess the pace of the disease
• Spare patients side effects of therapy
Rituximab x 4 if observation is undesirable/minimal symptoms
• No maintenance, re-treatment when appropriate
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Initial Treatment Course – Clinical Vignette
21Pathogenesis of Follicular Lymphoma
50 y/o patient opts for W&W given he
is asymptomatic
• Within 6 months, he experiences
progression in size of lymph
nodes
• Biopsy confirms no evidence of
transformation, still grade 1/2 FL
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BR vs. RCHOP for Untreated, Advanced Stage FL
22Pathogenesis of Follicular Lymphoma
Rummel MJ, et al. Lancet. 2013:381:1203-10. and
updated ASCO 2017
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Maintenance after Frontline Chemoimmunotherapy
23Pathogenesis of Follicular Lymphoma
Salles G, et al, ASH 2017
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GALLIUM: Obinutuzumab vs. Rituximab with Chemotherapy
followed by Maintenance
24Pathogenesis of Follicular Lymphoma
Marcus R, et al. N Engl J Med. 2017; 377:1331-44.
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GALLIUM: Obinutuzumab vs. Rituximab with chemotherapy
and maintenance: High grade adverse events
25Pathogenesis of Follicular Lymphoma
Marcus R, et al. N Engl J Med. 2017; 377:1331-44.
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Influences of the Microenvironment on FL cells
26Pathogenesis of Follicular Lymphoma
Huet. Nature. April 2018
Interactive loop between FL cells and
macrophages in FL tissue provides a persistent
low-level signal essential for survival.
Kuppers & Stevenson. Blood. May 2018
Recurrent genetic alterations allow immune
escape, shifting immune and stromal cells towards
a supportive phenotype.
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RELEVANCE: Lenalidomide + Rituximab (R2) vs. Chemo-R
27Pathogenesis of Follicular Lymphoma
Morschhauser F, et al, NEJM 2018
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RELEVANCE: Lenalidomide-Rituximab (R2) vs Chemo-R
Similar Response and PFS
28Pathogenesis of Follicular Lymphoma
Morschhauser F, et al, NEJM 2018
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RELEVANCE: Lenalidomide-Rituximab (R2) vs Chemo-R
Safety comparisons
29Pathogenesis of Follicular Lymphoma
Morschhauser F, et al, NEJM 2018
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Tools to Inform Maintenance Therapy: PET/CT
30Pathogenesis of Follicular Lymphoma
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Maintenance R after Frontline BR is more impactful among
those achieving a PR
31Pathogenesis of Follicular Lymphoma
Patients who achieved a CR
following ≥ 4 cycles of BR
Patients who achieved a PR
following ≥ 4 cycles of BR
Hill. BJH. 2018
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Approach to High Tumor Burden, Advanced Stage FL
32Pathogenesis of Follicular Lymphoma
▪ Bendamustine + Rituximab induction
- potential for less toxicity, greater/similar efficacy to R-CHOP
(PFS but no OS advantage)
- If concern for occult transformation, consider R-CHOP
▪ Obinutuzumab + chemo (PFS but no OS advantage)
- No subcutaneous option
- Perhaps “commits” to maintenance based on GALLIUM
- Potentially more infection with maintenance after bendamustine
▪ Lenalidomide + Rituximab (No PFS or OS advantage)
- Potential for less toxicity
▪ Maintenance Rituximab (PFS but no OS advantage)
- Not routine, offered/acceptable
s/p 6 cycles of BR
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Beyond frontline therapy, how do we approach
relapsed FL?
33Follicular Lymphoma
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Early Relapse of FL (<24 months) Defines Poor Risk Group
34
Casulo et. al. JCO 2015
Emerging Role of PI3K inhibitors for R/R FL
35
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Link et al, 2018.
Probability of Progression-Free Survival After
Multiple Treatments
Treatment LineMedian PFS
Years (95% CI)
First 6.62 (6.10-7.20)
Second 1.50 (1.35-1.70)
R-mono 1.50 (1.26-2.11)
R-chemo 1.48 (1.08-1.77)
Third 0.83 (0.68-1.09)
Fourth 0.69 (0.50-0.97)
Fifth 0.68 (0.43-0.88)
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Lenalidomide + Rituximab in R/R FL
37
AUGMENT
Leonard. ASH 2018 Abstract
CD20 Monoclonal Antibody Combinations in R/R FL
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Lenalidomide + Rituximab Improves PFS compared with
Rituximab Alone in R/R FL
38CD20 Monoclonal Antibody Combinations in R/R FL
Leonard. ASH abstract #445, 2018
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Targeting Signaling Pathways in R/R FL
39Emerging Role of PI3K inhibitors for R/R FL
Idelalisib
Copanlisib
Duvelisib
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PI3K Isoforms in B cell Malignancies
40Emerging Role of PI3K inhibitors for R/R FL
Class I
PI3K Isoform
Cellular
ExpressionPrimary Physiological Role
Delta (δ) Leukocytes• B-cell signaling, development,
and survival
Alpha (α) Broad
• Insulin signaling and angiogenesis
• Resistance mechanism in at least
some lymphomas
Beta (β) Broad • Platelet function
Gamma (γ) Leukocytes • Neutrophil and T-cell function
1. Okkenhaug K, Vanhaesebroeck B. Nat Rev Immunol 2003;3:317–330. 2. Seiler T et al. Drugs 2016; 76: 639–646. 3. Tzenaki N, Papakonstanti EA. Front Oncol
2013;3:40. 4. Brana I, Siu LL. BMC Med 2012;10:161. 5. Iyengar S et al. Blood 2013;121:2274–2284. 6. Psyrri A et al. Clin Cancer Res 2009;15:5724–5732.
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Idelalisib (PI3Kδi) in R/R FL
41Emerging Role of PI3K inhibitors for R/R FL
• 90% had improvement in
lymphadenopathy
• 57% had ≥50% decrease from
baseline
Gopal. NEJM, 2014
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Idelalisib is Active in Early Relapse
FL
42Emerging Role of PI3K inhibitors for R/R FL
POD24 Ad Hoc Subgroup Efficacy Results
Gopal et al. Blood Adv. 2017
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Copanlisib (pan-PI3Ki) in R/R FL
43Emerging Role of PI3K inhibitors for R/R FL
ORR 59%, 14% CR in R/R FL
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Hyperglycemia Associated with Copanlisib
44Emerging Role of PI3K inhibitors for R/R FL
Measurement of blood glucose for patients (n=27) from the 0.8 mg/kg
dose cohort during the first treatment cycle1
• Hyperglycemia was transient
• Maximum change from baseline observed
5 hours post-infusion
• Plasma glucose approached baseline levels
24 hours post-infusion, and prior to subsequent
infusions (eg, Day 8)
Morschhauser F et al. ASH Annual Meeting 2017; Atlanta, GA. Abstract 125; Zinzani ASH 2018 abstract 1618
Efficacy2Diabetic
(n=20)
Non-diabetic
(n=122)
Best Response, n (%)
CR 2 (10) 22 (18)
PR 6 (30) 56 (46)
ORR 8 (40) 78 (64)
SD 8 (40) 32 (26)
PD 1 (5) 2 (2)
NA/NE 2 (10) 10 (8)
Median PFS, months 7.2 13.8
Median DOR, months 7.1 14.9
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Anderson 45Emerging Role of PI3K inhibitors for R/R FL
Measurement of systolic blood pressure for patients (n=27) from
the 0.8 mg/kg dose cohort during the first treatment cycle
• Hypertension was transient
• No patients experienced Grade 4 hypertension
• The percent of patients with new or worsening G3
hypertension per cycle was relatively constant over
the course of treatment
1. Morschhauser F et al. Presented at: American Society of Hematology
Annual Meeting 2017; December 9–12, 2017; Atlanta, GA. Abstract 1256.
2. Dreyling M et al. Ann Oncol 2017;28:2169-2178. 3. Dreyling M et al. J Clin
Oncol 2017;35:3898–3905.
Hypertensives
(n=41)
Non-
Hypertensives
(n=101)
Best Response, n (%)
CR 11 (27) 13 (13)
PR 14 (34) 48 (48)
ORR 25 (61) 61 (60)
SD 10 (24) 30 (30)
PD 2 (5) 1 (1)
NA/NE 4 (10) 8 (8)
Median PFS,
months19.0 11.3
Median DoR,
months22.6 10.9
Hypertension Associated with Copanlisib
Copanlisib has Activity in R/R FL
46
CHOP, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone/prednisolone; CVP, cyclophosphamide, vincristine, prednisone/prednisolone; FL, follicular lymphoma; MZL, marginal zone lymphoma; R, rituximab.
Santoro A et al. Presented at: American Society of Hematology Annual Meeting 2018; December 1-4, 2018; San Diego, CA. Abstract 395.
Progressed
in <24 mo.Progressed
in ≥24 mo.
CHRONOS-1
N=140
34%
23%
21%
2%Other
2%
R-containing
therapies
80%
Chemotherapy
18%
R-CHOP
R-other
(chemotherapy)
R-CVP
R only
POD <24 mo.
n=93 (66.4%)
POD >24 mo.
n=47 (33.6%)
Median time, months
From 1st line of treatment 11.0 35.3
To progression for most
recent prior therapy
7.0
(65.6% refractory)
15.7
(48.9% refractory)
• There were 140 patients that were evaluable based on their progression of disease (POD)
from first-line treatment
• Principal histologies in the POD24 subset analysis were FL (102 patients) and MZL (23
patients)
First-line treatments in the POD24 subgroup
analysis
• 85% of FL patients received some form of R-
chemotherapy as first-line treatment
Emerging Role of PI3K inhibitors for R/R FL
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Duvelisib (PI3K γδ i) in R/R FL
47Emerging Role of PI3K inhibitors for R/R FL
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Toxicity Profile of Duvelisib
48Emerging Role of PI3K inhibitors for R/R FL
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Novel Therapies Under Development
50Refractory Follicular Lymphoma
Mosunetuzumab: a Bispecific Antibody Targeting
CD3 and CD20
ADCC, antibody-dependent cell-mediated cytotoxicity Mosunetuzumab investigator brochure
Malignant B cell
• Mechanism of action
– Redirects T-cells to engage and eliminate
malignant B-cells
– Conditional agonist: T-cell activation dependent
on B-cell engagement
– Amino-acid substitution (N297G) to inactivate
ADCC and avoid destruction of engaged T cells
• Full-length humanized IgG1 antibody
– Longer half-life than fragment-based drug
formats
– PK properties enable QW to Q3W dosing
– Does not require ex-vivo T-cell manipulation
– Off the shelf, readily available treatment
Efficacy of Mosunetuzumab in R/R FLEarly evidence of durable CR; no relapses observed to date
Data cut-off date: 17 August 2018†Complete response, assessed by the investigator with or without positron emission tomography, marked for efficacy-evaluable patients (when SPD data available).
• Median duration of CR: not reached
• Median duration of follow-up for CR: 330 days
(range 54–788 days)
B1 0.4/1.0/2.8 mg
B2 0.8/2.0/4.2 mg
B4 1.0/2.0/6.0 mg
B5 0.8/2.0/6.0 mg
B6 1.0/2.0/9.0 mg
B7 1.0/2.0/13.5 mg
100
Ch
an
ge
in
SP
D (
%)
–50
–100
0
50
*Complete responder†
* * * * * * * * * *
0 200 400 600 800
CRPDPRSD
Best overall response
ORR 21/35 (60.0%)
CR 12/35 (34.3%)
Group B R/R FL Group A and B R/R FL
Ch
an
ge
in
SP
D f
rom
ba
se
lin
e (
%)
Study day
–100
–50
0
50
100
Budde. ASH abstract 2018
Advani. ASCO abstract 2018
Advani. ASCO abstract 2018
CD19 CAR T-cell Products in Pivotal Trials in R/R FL
NCI U Penn FHCRC / SCH
Retrovirus Lentivirus Lentivirus
Kite Pharma Novartis Juno Therapeutics
KTE-C19 CTL-019 JCAR017 (CD4:CD8 = 1:1)
Axicabtagene ciloleucel Tisagenlecleucel Lisocabtagene maraleucel
Axi-cel Liso-cel
CD19 Ab
Hinge
Transmembrane
Signal 2
Signal 1
Gene transfer
4-1BBCD28
CD3z CD3z
4-1BB
CD3z
Adapted from van der Steegen et al. Nat Rev Drug Discov, 2015
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Conclusions
With technological advances, our evolving understanding of FL biology
will likely inform new therapies.
- Still aiming for cure
Given there are numerous treatment options, risk stratification is key.
As the majority of patients with FL can anticipate a normal life span,
consideration of the impact of treatment options on QOL is imperative.
56Follicular Lymphoma
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Acknowledgements
57Follicular Lymphoma
LRF
Patients and their caregivers
MDACC faculty:
Christopher Flowers
Sattva Neelapu
Michael Green
R. Eric Davis
Nathan Fowler