Professeur Gilles SALLES

From genetics to the clinic: Follicular lymphoma

대한혈액학회 Korean Society of Hematology

COI disclosureName of author ： Gilles SALLES

I currently have, or I have had in the past two years, receivedfinancial compensations for participating to advisory boards,consulting, or educationnal events from the followingcompanies: Abbvie, Amgen, BMS, Celgene, Gilead, Epizyme, Janssen,

Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda

Farmers exposed to pesticides present a dramatic increase of t(14;18) frequency

detected in peripheral blood

Roulland et al. J Exp Med, 203, 2425–2431(2006)

Population t(14;18) frequencyand FL development

Roulland et al. J Clin Oncol 2014;32:1347

~ 15 year follow-up of 520,000 health population ~

Higher frequency of circulating t(14;18)+ Cells in individuals that will develop FL

23 fold higher risk to develop FLif t(14;18)+ frequency > 10-4

Mutational burden in Follicular Lymphomagenesis

Mamessier et al. Haematologica 99(3): 484, 2014

Early steps of Follicular Lymphoma

Huet et al., Nat Rev Cancer 2018

Okusun J et al. Nat Genet 46:176, 2014 Green M et al, Blood 121:1604; 2013

Clonal heterogeneity in FL over time

Araf S et al. Leukemia, 2018Sarkozy C, Huet S et al, Oncotarget 2017

Intraclonal and spatial heterogeneity in FL:

TumorSerum

1-10%

10-20%

60-70%

Clone frequency

< 1%

Genomic alterationssubverting the microenvironment

Huet et al., Nat Rev Cancer 2018

Treatment paradigms in FL

1. All patients don’t have the same outcome

2. First line therapy: standards and options ?

3. What are our treatments goals ?

Treatment paradigms in FL

1. All patients don’t have the same outcome

2. First line therapy: standards and options ?

3. What are our treatments goals ?

The Follicular Lymphoma International Prognostic Index (FLIPI): Overall survival

Prob

abili

ty o

f sur

viva

l

Months

P < 0.0001

Good (0−1)

Intermediate (2)

Poor (3−5)

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84

N = 1,795

Solal-Céligny P, et al. Blood 2004; 104:1258−1265.

– Age < 60 vs. ≥ 60

– Hemoglobin level ≥ 12g/dL vs. < 12g/dL

– Serum LDH level ≤ ULN vs. > ULN

– Ann Arbor stage I – II vs. III – IV

– Number of nodal sites involved ≤ 4 vs. > 4

13Gilles Salles

PRIMA-prognostic index (PRIMA-PI)2 parameters: bone marrow and beta2-microglobulin

Bachy E et al, Blood 2018

Improving clinical indexes with mutations or GEP ?

m7-FLIPI 23-gene score

Pastore et al. Lancet Oncol2015 16:1111-1121

Huet et al. Lancet Onoclogy2018 19:549-561

Median 10.8 y

Median 3.1 y

Treatment paradigms in FL

1. All patients don’t have the same outcome

2. First line therapy: standards and options ?

3. What are our treatments goals ?

Study name and author Follow-upOverall survival (%)

PControl Rituximab

M3902; Marcus et al.1 4 years 77 83

GLSG; Hiddemann et al.2 5 years 84 90

M39023; Herold et al.3 4 years 75 89

FL2000; Salles et al.4 5 years 79 84

(high risk pts)

Cochrane analysis:HR = 0.63 [0.51–0.79]

Schulz H et al. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003805.

Rituximab + chemotherapy hasimproved overall survival

1. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586. 2. Buske C, et al. Blood 2008; 112:abstract 2599.

3. Herold M, J Clin Oncol 2007; 25:1986–1992.4. Salles G, et al. Blood 2008; 112:4824–4831.

PRIMA: study design

PD/SDoff study

Rituximab maintenance375 mg/m2

every 8 weeks for 2 years‡

Observation‡

CR/CRuPR Random 1:1*

Immunochemotherapy8 x Rituximab

+8 x CVP or

6 x CHOP or6 x FCM

High tumor burden

untreated follicular lymphoma

INDUCTION MAINTENANCE

Registration

* Stratified by response after induction, regimen of chemo, and geographic region‡ Frequency of clinical, biological and CT-scan assessments identical in both armsFive additional years of follow-up

PRIMA : Progression Free Survival at 10 years(from randomization)

18Oral Session - Abstract #48659th ASH Annual Meeting, Atlanta, GA, December 9-12, 2017PRIMA 10 YEARS

P

FLIPI groups in PRIMA patients (1)

FLIPI groups in PRIMA patients (2)

21

Study designInternational, open-label, randomized Phase III study

*FL and MZL pts were randomized separately; stratification factors: chemotherapy, FLIPI (FL) or IPI (MZL) risk group, geographic region; †CHOP q3w × 6 cycles, CVP q3w × 8 cycles, bendamustine q4w × 6 cycles; choice by site (FL) or by pt (MZL); ‡Pts with SD at EOI were followed for PD for up to 2 years; §Confirmatory endpoint

Primary endpoint Secondary and other endpoints• PFS (INV-assessed in FL) • PFS (IRC-assessed)§

• OS, EFS, DFS, DoR, TTNT• CR/ORR at EOI (+/− FDG-PET)• 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 (≥7cm) requiring treatment

• ECOG PS 0–2• Target FL enrolment: 1200

G-chemoG 1000mg IV on D1, D8, D15 of C1 and D1 of C2–8 (q3w) or C2–6 (q4w) plus

CHOP, CVP, or bendamustine†

R-chemoR 375mg/m2 IV on D1 of C1–8 (q3w) or

C1–6 (q4w) plus CHOP, CVP, or bendamustine†

GG 1000mg IV

q2mo for 2 years or until PD

RR 375mg/m2 IV

q2mo for 2 years or until PD

Induction Maintenance

Randomized 1:1*

CR or PR‡

at EOI visit

GALLIUM : Obinutuzumab in 1st line tttR-chemo versus G-chemo

Marcus R et al. N Engl J Med 2017;377:1331-1344.

Marcus R et al. N Engl J Med 2017;377:1331-1344.

Kaplan–Meier Estimates of Investigator-Assessed Progression-free Survival and Overall Survival among

Patients with Follicular Lymphoma.

23

Safety summary (FL)

% (n)R-chemo(n=597)

G-chemo(n=595)

Any AE 98.3% (587) 99.5% (592)Grade ≥3 AEs (≥5% in either arm) 67.8% (405) 74.6% (444)

Neutropenia 37.9% (226) 43.9% (261)Leucopenia 8.4% (50) 8.6% (51)Febrile neutropenia 4.9% (29) 6.9% (41)IRRs* 3.7% (22) 6.7% (40)Thrombocytopenia 2.7% (16) 6.1% (36)

Grade ≥3 AEs of special interest by category (selected)

Infections† 15.6% (93) 20.0% (119)IRRs‡ 6.7% (40) 12.4% (74)Second neoplasms§ 2.7% (16) 4.7% (28)

SAEs 39.9% (238) 46.1% (274)AEs causing treatment discontinuation 14.2% (85) 16.3% (97)Grade 5 (fatal) AEs 3.4% (20) 4.0% (24)**Median (range) change from baseline in IgG levels at end of induction, g/l¶ -1.46 (-16.4–9.1)

†† -1.50 (-22.3–6.5) ‡‡

*As MedDRA preferred term; †All events in MedDRA System Organ Class ‘Infections and Infestations’; ‡Any AE occurring during or within 24h of infusion of G or R and considered drug-related; §Standardized MedDRA query for malignant or unspecified tumors starting 6 mo after treatment start; ¶Ig levels were measured during screening, at EOI and end of maintenance and during follow-up; **Includes patient who died after clinical cut-off date from AE starting before cut-off date; ††n=472; ‡‡n=462 Marcus R, et al. ASH presentation 2016 (Abstract 6)

24

Phase III GALLIUM study

AEs by chemo*

*Safety population, i.e. all randomised FL pts who received at least one dose of study drug; †includes 6 pts with fatal AEs that occurred after start of new anti-cancer therapy (G-benda, 4; R-benda, 2)

n (%) of pts reporting ≥1 event

R-benda,n=338

G-benda,n=338

R-CHOP,n=203

G-CHOP,n=193

R-CVP,n=56

G-CVP,n=61

Any AE 331 (97.9) 338 (100) 201 (99.0) 191 (99.0) 56 (100) 61 (100)

Grade 3–5 AE 228 (67.5) 233 (68.9) 151 (74.4) 171 (88.6) 30 (53.6) 42 (68.9)

SAE 160 (47.3) 176 (52.1) 67 (33.0) 76 (39.4) 19 (33.9) 26 (42.6)

Grade 5 (fatal) AE† 16 (4.7) 20 (5.9) 4 (2.0) 3 (1.6) 1 (1.8) 1 (1.6)

AE leading to treatment discontinuation 48 (14.2) 52 (15.4) 31 (15.3) 32 (16.6) 9 (16.1) 11 (18.0)

• Grade 3–5 AEs most frequent with CHOP (neutropenia, leukopenia, febrile neutropenia, IRRs); SAEs and fatal AEs most frequent with benda

• Frequency of grade 5 AEs similar to R-CHOP arms in SABRINA (5.7%, i.v.; 3.6%, s.c.)

Hiddemann W, et al. ICML 2017 (Abstract 107)

Lessons from GALLIUM(my own perspective)

Obinutuzumab is more active in front line FL combined with chemotherapy (Benda, CHOP, CVP)

- response rate, MRD, PET-CT, PFS, TNTT- not OS, but usual in FL

The pattern of toxicities raises some questions:more infectious toxicities with G in R-CHOP/CVPmore toxicities in both Benda arms- only monitored randomized trials provide an accurate evaluation of new agents toxicities

R

RELEVANCE : phase 3 study design(Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001)

1st lineFL

n = 1000

R2 maintenance

Rituximab maintenance

R2

R-Chemo

CR, CRu, PR

CR, CRu, PR• R-Chemo investigator choice of R-CHOP, R-CVP,

R-B

• Lenalidomide

20 mg x 6 cycles, if CR then 10 mg

International, multi-centre, randomised study(Frank Morchhauser, Nathan Fowler)

• Co-primary endpoints CR/CRu rate at 2.5 years PFS

RELEVANCE: INTERIM PFS BY IRC

Data cut-off 31May2017.

• At a median follow-up of 37.9 months, interim PFS was similar in both arms

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

PFS

Prob

abili

ty (I

RC

)

R2

R-chemo

Months from Randomization

0 6 12 18 24 30 36 42 48 54 60 66

513 435 409 393 364 282 174 107 49 0R2Number of Patients at Risk

517 474 446 417 387 287 175 109 51 1 0R-chemo

13

14

28

R2(n = 513)

R-chemo (n = 517)

Events, n (%) 119 (23) 111 (21)3-year PFS (95% CI)

77% (72%-80%)

78% (74%-82%)

HR (95% CI) 1.10 (0.85-1.43)P value 0.48

Co-Primary Endpoint: Interim PFS (~50% events)

Morschhauser et al., NEJM 2018

Treatment paradigms in FL

1. All patients don’t have the same outcome

2. First line therapy: standards and options ?

3. What are our treatments goals ?

Sarkozy C, Maurer M et al., JCO 2018

Lymphoma still represents the leading cause of death in patients with FL

ALL

> 70 y< 60 y

Sarkozy C, Maurer M et al., JCO 2018, on line

Not achieving EFS 24 (IC treated) or EFS12 (non-IC) is associated

with a poor outcome

(A) Overall survival (OS) from a risk-defining event after diagnosis in patients who received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in the National LymphoCare Study group.

Carla Casulo et al. JCO 2015;33:2516-2522

©2015 by American Society of Clinical Oncology

Is EFS24 a good surrogate enpoint ?

33

OS of PRIMA pts accrding to EFS24Event 24m (18m post randomisation)

Observation 137 / 513 (26%)R-maintenance 75 / 505 (15%)

G Salles, in preparation

Is EFS24 a good surrogate enpoint ?

34

OS of PRIMA pts accrding to EFS24Event 24m (18m post randomisation)

Observation 137 / 513 (26%)R-maintenance 75 / 505 (15%)

G Salles, in preparation

OS after early progression for pts with R-maintenance is poorer than OS after early progresssion

for pts in the observation arm

Histological transformation at first progression in PRIMA patients

Progression with HT appears to occur early (10 vs. 23 months) More than 1/3rd (37%) of the biopsies performed during the first

year of follow-up showed transformed disease (58% of all HT)Sarkozy et al, JCO , 2016

Patients randomizedN=1018

No progressionN=554

ProgressionN=463

No BiopsyN=269, 58%

BiopsyN=194, 42%

FLHistology

N=154, 79.4%

Histological Transformation

N=40, 20.6%

Sarkozy C, Maurer M et al., JCO 2018, on line

Histological transformation is a predominant factor associated

with the risk of lymphoma related death

Withouttransformation

Withtransformation

Clonal dynamic at progression

Huet et al., Nat Rev Cancer 2018

Future strategies for the treatment of patients with FL

1. Monoclonal antibodies- New anti-CD20 (ofatumomab, obinutuzumab, ublituximab, ..)- Antibody drug conjugates ? Bi-specific Abs ?

2. Kinase inhibitors : - idelalisib, copanlisib (and Co) ; ibrutinib (and Co)

3. Improving rituximab efficacy with other agents:- Imids ® (lenalidomide), anti-PD1, …

4. New targeted agents: - venetoclax- tamezetostat

The increase in patients survival implies new challenges

Important endpoints for future/ongoing studies evaluating therapeutic strategies in FL :

Quality of response Surrogate for PFS as well as OS ?

Quality of life Ability to deliver second line treatments Long term toxicities

… and Overall Survival

�From genetics to the clinic: �Follicular lymphoma 대한혈액학회 Korean Society of Hematology��COI disclosure�　�Name of author ：　Gilles SALLESSlide Number 3Population t(14;18) frequency� and FL developmentMutational burden in Follicular LymphomagenesisEarly steps of Follicular LymphomaClonal heterogeneity in FL over timeIntraclonal and spatial �heterogeneity in FL: Genomic alterations �subverting the microenvironmentTreatment paradigms in FLTreatment paradigms in FLThe Follicular Lymphoma International Prognostic Index (FLIPI): Overall survivalSlide Number 13Improving clinical indexes �with mutations or GEP ?Treatment paradigms in FLRituximab + chemotherapy has�improved overall survivalPRIMA: study designPRIMA : Progression Free Survival at 10 years�(from randomization) FLIPI groups in PRIMA patients (1)FLIPI groups in PRIMA patients (2)Study designMarcus R et al. N Engl J Med 2017;377:1331-1344.Safety summary (FL)�Phase III GALLIUM studyAEs by chemo*Lessons from GALLIUM�(my own perspective)RELEVANCE : phase 3 study design�(Rituximab and LEnalidomide Versus ANy ChEmotherapy, FL-001)relevance: Interim PFS By IRCTreatment paradigms in FLSlide Number 30Slide Number 31Slide Number 32Is EFS24 a good surrogate enpoint ?Is EFS24 a good surrogate enpoint ?Histological transformation at first progression in PRIMA patientsSlide Number 36Clonal dynamic at progressionFuture strategies for the treatment of patients with FLThe increase in patients survival �implies new challengesSlide Number 40