low grade lymphomas modern treatment strategies …€¦ · 22/6/2018 · event, n (%) 46 (7.7) 35...

LOW GRADE LYMPHOMAS

MODERN TREATMENT STRATEGIES IN

FOLLICULAR LYMPHOMA

Anton Hagenbeek, M.D., Ph.D.

Department of Hematology

Academic Medical Center

University of Amsterdam

Amsterdam, The Netherlands

E-mail: [email protected]

DISCLOSURES ANTON HAGENBEEK

None

Bcl-6 CD 20

CD 10Bcl-2Piris, Valencia, 2006

Grade 1 Grade 2 Grade 3

Follicular Lymphoma : Grading

Histological subtype Number of centroblasts/HPF

Grade I 0–5

Grade II 6–15

Grade III > 15

Grade IIIa centrocytes still present

Grade IIIb centroblasts form solid sheets with

no residual centrocytes

Piris, Valencia, 2006

Follicular lymphoma is characterized by

t(14;18)

WHO CLASSIFICATION

Natural History of Follicular Lymphoma

and Improved Overall Survival

• Median age 65

– 5-10% of patients are younger than 40 years

• Advanced disease at diagnosis

– 20% have early stage disease

• Median overall survival ~20 years :

chronic disease !

1997-2003

1987-1996

1976-1986

1965-1975

Stanford University Experience

Tan et al. Blood 122:981-987, 2013; Casulo et al. Ann Onc 11: 2311-2317, 2015

TREATMENT OF ADVANCED

STAGE FOLLICULAR NHL

• Wait-and-see strategy

• Remission - induction treatment

• Maintenance treatment

TREATMENT OF ADVANCED STAGE

FOLLICULAR NHL - FIRST LINE




Is the “Wait-and-See” strategy

in advanced stage follicular

lymphoma still valid?

• Several prospective , randomized

phase III clinical trials showed no

difference in Overall Survival between

“Wait and See” and immediate

treatment with Chemo or Rituximab

ABANDON WAIT-AND-SEE POLICY ?

Anno 2019 : NO !

Not until:

• Immediate treatment = curative

• Better overall survival (clinical trials!)

• Better quality of life

• Better prognostic indices

– Clinical (FLIPI ; FLIPI-2 = still valid in R-

chemo era)

– Biological (gene expression profiling, tissue

microarrays, etc.)

R-CVP MORE THAN DOUBLES TIME TO

PROGRESSION , RELAPSE OR DEATH

159CVP

R-CVP 162

129

144

87

132

64

112

51

105

39

84

29

73

14

40

5

16

0

5

0

0

R-CVP: median 34 months

CVP: median 15 months

Even

t-fr

ee p

rob

ab

ilit

y

Patients at risk:

p<0.0001

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 6 12 18 24 30 36 42 48 54 60

Study month

Solal-Celigny P, et al. Blood 2005;106:106a (Abstract 350)

* Median follow-up 42 months

Rituximab combined with chemotherapy (R-chemo) has improved Overall Survival (OS) in patients with advanced FL

OS, %

Study name and author Follow-up, years Control R-chemo p-value

M3902: Marcus et al. (2008)1 4 77 83 ✓

GLSG: Buske et al. (2008)2 5 84 90 ✓

M39023: Herold et al. (2007)3 4 74 87 ✓

FL2000: Salles et al. (2008)4 5 79 84✓

(high-risk pts)

Cochrane analysis:HR 0.63 (95% CI: 0.51, 0.79)5

1. Marcus R, et al. J Clin Oncol 2008;26:4579–862. Buske C, et al. ASH 2008 presentation (Abstract 2599)

3. Herold M, J Clin Oncol 2007;25:1986–924. Salles G, et al. Blood 2008;112:4824–31

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

SPECIFIC QUESTIONS IN FIRST LINE

• Which chemo is preferred ?

• Choice of anti-CD20 antibody ?

• Chemo-free regimens ?

R-CVP VS R-CHOP VS R-FM IN NEWLY DIAGNOSED

ADVANCED STAGE FOLLICULAR NHL(Federico et al., Lugano 2011)

534 patients were randomized

3 yrs TTF 3 yrs OS

(%) (%)

8x R-CVP1 47 97

6x R-CHOP + 2x R 57 96

6x R-FM + 2x R3 60 92

TTF : 1-2: p=0.026; 1-3: p=0.023; 2-3: p=0.979

NB: Neutropenia after R-FM > R-CHOP : OR 1.96; p=0.004

Conclusion : R-CHOP standard of care ….. (FLIPI 3-5 ?)

StiL NHL 1-2003 study design : R-Bendamustine versus R-CHOP in previously untreated indolent NHL or MCL

R-BendaUp to 6 cycles of rituximab

375 mg/m2 on D1+ bendamustine 90 mg/m2

on D1 and D2 q4w

R-CHOPUp to 6 cycles of rituximab

375 mg/m2 on D1+ CHOP q3w

Randomized 1:1*

Pts with previously untreated, stage

III–IV MCL, FL, Waldenström’s

macroglobulinemia,

SLL, or MZL (N=420)

Rummel M, et al. ASCO presentation 2017 (Abstract 7501)Rummel M, et al. Lancet 2013;381:1203–10

• 10-year update

Non-inferiority trial : Primary endpoint PFS

B-R VS CHOP-R : TOXICITIES (ALL CTC-GRADES)

B-R (n=260) CHOP-R (n=253)

no. of pts no. of pts P value

Alopecia - +++ < 0.0001

Paresthesias 18 73 < 0.0001

Stomatitis 16 47 < 0.0001

Skin (erythema) 42 23 = 0.0122

Allergic reaction (skin) 40 15 = 0.0003

Infectious complications 96 127 = 0.0025

- Sepsis 1 8 = 0.0190

StiL NHL 1-2003 : 10-year update confirmed superiority of R-Bendamustine over R-CHOP in previously untreated iNHL or MCL (median follow-up : 117 months)

TTNT (as surrogate for PFS)

Pro

bab

ility

0 12 24 36 48 60 72 84 96 108 132 156 1680

0.25

0.50

0.75

1.00

144120

R-BendaR-CHOP

MedianTTNT, mo

NR56.0

Salvage,events

77109

Time (months)

No difference in OSRummel M, et al. ASCO presentation 2017 (Abstract 7501))

p<0.0001HR 0.55 (95% CI: 0.41, 0.73)

DOES IT REALLY MATTER IN WHICH SEQUENCE

THE DIFFERENT EFFECTIVE CHEMO-

IMMUNOTHERAPY REGIMENS ARE GIVEN?

➢ Patients may receive between 1 and 10 (?) regimens during the

course of their disease ….

R-Chlorambucil

R-CVP

R-CHOP

R-FM

R-FCM

R-FND

R-Bendamustine

R-etcetera +/- Rituximab maintenance

NB: Not a single regimen yields cures !

Worldwide choice of 1st line treatment in follicular lymphoma

121

10

121

28

140

52

12

29

1

145

18

5461

2

26

62

6

45

102

12 194 4 21

186 4 4 9

70

5

0

50

100

150

200

Pa

tie

nts

(n)

Bendamustine, n=686 CHOP, n=399 CVP, n=117

Hiddemann et al., ICML 2017

R-CHOP or R-Bendamustineor R-CVP (shorter PFS) ? : no clearcut advice…

https://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwifqrbftuvYAhWHJewKHb5_DHIQjRwIBw&url=https://www.eacr.org/our-partnerships/esmo&psig=AOvVaw3sx0QmxMz9DPrn5CYt5TIX&ust=1516705581608311

http://www.google.nl/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwis9qLssO7YAhXB-aQKHfFwBCoQjRwIBw&url=http://www.b-s-h.org.uk/&psig=AOvVaw0nr9lpuYuKk4AKDYqDzrK7&ust=1516807079299977

Marcus R, et al. N Engl J Med 2017;377:1331–44

GALLIUM study design: Obinutuzumab (G)-chemo versus Rituximab (R)-chemo plus G/R maintenance in patients with previously untreated, CD20+ iNHL

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

International, open-label, randomized phase III study in 1202 patients

Previously untreatedCD20+ 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 enrolment: 1200

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

CVP, or bendamustine†

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

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

G

G 1000 mg IVq2m for 2 years or until PD

R

R 375 mg/m2 IVq2m for 2 years or until PD

Induction Maintenance

Randomized 1:1*

CR or PR‡

at EOI visit

authorities in your country according to your national requirements

GALLIUM : PFS was significantly improved with G-chemo versus R-chemo

1. Hiddemann W, et al. J Clin Oncol 2018 [Epub ahead of print)

2. Marcus R, et al. N Engl J Med 2017;377:1331–44

PFS after 41.1 months median follow up

No. of patients at riskG-chemo 601 561 505 464 438 396 267 149 77 18 0 0R-chemo 601 569 535 505 478 420 291 176 85 25 1 0

R-chemo (n=601) G-chemo (n=601)

3-year PFS, %(95% CI)

75 (71, 78)

82(78, 85)

HR (95% CI), p-value† 0.68 (0.54, 0.87), p=0.0016

No. of patients at riskG-chemo 601 563 502 463 438 394 271 151 73 16 0 0R-chemo 601 571 532 497 476 414 287 179 79 22 0 0

R-chemo (n=601) G-chemo (n=601)

3-year PFS, %(95% CI)

79 (75, 82)

83(80, 86)

HR (95% CI), p-value† 0.72 (0.56, 0.93), p=0.012

G-chemo (n=601)R-chemo (n=601)Censored+

0.1

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

12 18 24 30 36 424860 54 60 66

IRC-assessed PFS

Time (months)Time (months)

G-chemo (n=601)R-chemo (n=601)Censored+

0.1

0.2

0.4

0.6

0.8

1.0

Pro

bab

ility

12 18 24 30 36 424860 54 60 66

INV-assessed PFS

Infections and infestations General disorders and administration site conditions

Cardiac disorders Gastrointestinal disorders

Neoplasms benign, malignant, and unspecified

Nervous system disorders Respiratory, thoracic, and mediastinal disorders

Metabolism and nutrition disorders

GALLIUM : Incidence, nature, and timing of grade 5 (fatal) AE’s by treatment received


*

0 100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400

Induction Maintenance Follow-up

1500

†

Time of death (no. of days from Cycle 1, Day 1)

Total Infections

G-benda(n=337)

20 (5.9%) 9 (2.7%)

R-benda(n=338)

15 (4.4%) 2 (0.6%)

G-CHOP(n=191)

3 (1.6%) 1 (0.5%)

R-CHOP(n=201)

4 (2.0%)

G-CVP(n=61)

1 (1.6%)

R-CVP(n=56)

1 (1.8%)


GALLIUM : OS was similar with G-chemo and R-chemo

R-chemo(n=601)

G-chemo(n=601)

Patients with event, n (%)

46(7.7)

35(5.8)

3-year OS,% (95% CI)

92.1(89.5, 94.1)

94.0(91.6, 95.7)

HR (95% CI),p-value*

0.75 (0.49, 1.17),p=0.21

Median follow-up: 34.5 months

No. of patients at riskR-chemo 601 588 566 549 527 399 265 160 58 2 0

G-chemo 601 584 573 563 549 416 271 161 55 0 0

0.8

0.6

0.4

0.2

0

1.0

Pro

bab

ility

+

Time (months)12 18 24 30 36 42 48 6060 54

Censored

G-chemo (n=601)

R-chemo (n=601)

0

20

40

60

80

100

R-chemo G-chemo

Pa

tie

nts

(%

)

MRD status by treatment arm at EOI (in PB/BM)Christiane Pott et al. , ASH 2018

N= 296 28 325

15.9%

84.1%92.1%

7.9%

56

).

MRD-positive

MRD-negative

• In pooled PB/BM, more patients treated with G-chemo

versus R-chemo achieved an MRD response at EOI

p=0.0011

PFS by MRD status at EOI*

*Combined results for all patients treated with G and R

No. of patients at risk

564 540 512 494 469 452 426 367 230 127 27 12

70 60 54 48 47 44 37 33 14 5

Pro

ba

bilit

y o

f P

FS

Time (months since EOI)

1.0

0.8

0.6

0.2

072

0.4

540 6 12 18 24 30 36 42 48 60 66

• PFS was improved in patients who were MRD-negative versus those who were MRD-positive

HR 0.38 (95% CI: 0.26–0.56); p<0.0001MRD-negative

MRD-positive

HR 0.95 (95% CI: 0.98–1.33); p=0.6976

PFS by MRD status at EOI and treatment arm


264 248 235 225 217 210 196 173 112 65 16 7

46 38 33 29 28 25 18 16 8 2

300 292 277 269 252 242 230 194 118 62 11 5

24 22 21 19 19 19 19 7 6 3

Pro

ba

bil

ity o

f P

FS

Time (months since EOI)

1.0

0.8

0.6

0.2

072

0.4

540 6 12 18 24 30 36 42 48 60 66

• PFS was similar in patients achieving MRD negativity independent of treatment arm

• MRD positive patients treated with R-chemo appear to have worse outcomes

G-chemo MRD-negative

R-chemo MRD-negative

G-chemo MRD-positive

R-chemo MRD-positiveHR 0.25 (95% CI: 0.16–0.39); p<0.0001

Landmark PFS analysis by MRD status*

*Patients were included if no PFS event had occurred by the specific time points.

• MRD status during maintenance is closely associated with clinical relapse

and achievement of MRD negativity is of high prognostic relevance


580 561 538 515 499 478 445 324 212 103 23 8

24 18 17 14 11 10 10 10 7 1

Pro

ba

bil

ity o

f P

FS

Time (months since maintenance month 4)

1.0

0.8

0.6

0.2

0

0.4

540 6 12 18 24 30 36 42 48

MRD response: 0–4 months

MRD-negative

MRD-positive

60 66 72


541 521 500 479 465 436 367 233 131 25 11

21 17 13 12 11 10 9 7 2

Pro

ba

bil

ity o

f P

FS


1.0

0.8

0.6

0.2

0

0.4

540 6 12 18 24 30 36 42 48


MRD-negative

MRD-positive

60 66 72


530 519 504 481 452 407 279 171 47 19 1

18 11 10 6 6 6 3 3

Pro

ba

bil

ity o

f P

FS


1.0

0.8

0.6

0.2

0

0.4

540 6 12 18 24 30 36 42 48


MRD-negative

MRD-positive

60 66 72

COMMENTS TO THE RESULTS OF THE GALLIUM

STUDY

• Significantly more antibody given in the

G-chemo arm (1.5 times more)

• More cytopenias,infections and infusion-

related reactions in the G-chemo arm

• With only 7% increase in PFS and no

difference in OS : G-chemo new standard of

care ?

• NB. Toxicity with G-Bendamustine

(T cell depletion in Bendamustine arm)

• Co-primary endpoints (superiority* trial)– CR/CRu rate at 120 weeks

– PFS

• R-chemo– Investigator choice of R-CHOP, R-CVP, or R-Benda

• R2

– Lenalidomide 20 mg D2–22 x 6 ; 28-day cycles(if CR : then 10 mg) + Rituximab

RELEVANCE study design : R + Lenalidomide (R2) versus R-chemo, followed by R maintenance

Previously untreated patients with advanced FL

requiring treatment per GELF1,2 (N = 1,030)

R2

R-chemo(R-CHOP, R-B, R-CVP)

Rituximab

Rituximab1:1

n = 513

n = 517

R2

Stratification• FLIPI score (0-1 vs 2 vs 3-5)• Age (> 60 vs ≤ 60 years)• Lesion size (> 6 vs ≤ 6 cm)

Treatment period 1(~6 months)

Treatment period 2(~1 year)

Treatment period 3(~1 year)

Total treatment duration: 120 weeks

International, multicenter, randomized study

RELEVANCE: R2 did not demonstrate superiority over R-chemo for either of the co-primary endpoints (CR/CRuand PFS)

R2

(n=513)R-chemo (n=517) p-value

CR/CRu at 120 weeks, %

By IRC 48 53 0.13

By INV 55 58 0.38

Interim PFS (~50% events)

R2 vs R-chemo: HR (95% CI) by IRC 1.10 (0.85, 1.43)0.48

R2 vs R-chemo: HR (95% CI) by INV 0.94 (0.73, 1.22)0.63

3-year PFS (IRC / INV) 77 / 77 78 / 78 —

3-year OS, % 94 94 —

*Median follow-up : 37.9 months Fowler NH, et al. ASCO , 2018 (Abstract 7500)

RELEVANCE: Neutropenia and Neutropenic Complications (Entire Treatment Period)

Patients, n (%) R2 (n = 507) R-chemo (n = 503)

Grade 3/4 neutropenia* 160 (32) 252 (50)

Grade 4 neutropenia 41 (8) 154 (31)

Nadir ANC < 100/μL 5 (1) 32 (6)

Median time to onset of first grade 3/4 lab neutropenia 3.7 months 0.6 months

Grade 3/4 infections associated with grade 3/4 neutropenia 10 (2) 20 (4)

Febrile neutropenia* 11 (2) 34 (7)

Febrile neutropenia requiring hospitalization 8 (2) 26 (5)

Infections requiring hospitalization 46 (9) 60 (12)

Received growth factors 117 (23) 340 (68)

Per protocol, patients in the R2 arm had more frequent laboratory assessments than the R-chemo arm

RELEVANCE : Conclusions

R2 was not superior to R-chemo based on CR/CRu at 120 weeks and interim PFS

- R2 and R-chemo showed similar efficacy results

- Continued follow-up for more mature PFS and OS results is ongoing

Important differences in safety profiles were observed between arms :

– R-chemo: More frequent neutropenia (grade 3/4), febrile neutropenia, growth factor usage, nausea, vomiting, neuropathy, and alopecia

– R2: More frequent cutaneous reactions, tumor flare, and diarrhea

These results show that R2, a novel immunomodulatory approach, is a potential first-line option for patients with FL requiring treatment

QOL, MRD, and PET data to be presented in future meetings

PRIMA study design : Rituximab maintenance versus observation after induction immuno-chemotherapy

PD/SDoff study

Rituximab maintenance375 mg/m2 IVevery 8 weeks

for 2 years†

Observation‡

Randomized 1:1*

Immunochemotherapy8 x Rituximab

+8 x CVP,

6 x CHOP, or6 x FCM

Pts with high tumor burden,

previously untreated

FL (N=1018)

Induction Maintenance

CR/CRuor PR

Salles G, et al. ASH presentation 2017 (Abstract 486)Salles G, et al. Lancet 2011;377:42–51

• Five additional years of follow-up (10-year update)

PRIMA : PFS at 10 years from randomization confirmed benefit of Rituximab maintenance over observation (no difference in OS)

0 1 2 3 4 5 6 7 8 9 10 11 12

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

No. of patients at riskObservationRituximab

415445

513505

336406

290372

251333

217309

200284

155231

147208

122170

4167

14

00

Time from randomization (years)

p<0.0001HR 0.61 (95% CI: 0.52, 0.73)

Estimated10-year PFS

51%

35%Rituximab maintenanceObservation

Pro

bab

ility

Salles G, et al. ASH presentation 2017 (Abstract 486)

BRIGHT study design : R-Bendamustine versus R-CVP/R-CHOP in previously untreated iNHL or MCL

*Median follow-up: 65.0 months (R-Benda) ; 64.1 months (R-CVP/R-CHOP)†

Within 30 days of first dose

Screening

R-CHOP or R-CVP

Standard treatment assignment Randomization

Randomization

R-Benda 28-day cycle x 6–8

R-CHOP 21-day cycle x 6–8

R-Benda 28-day cycle x 6–8

R-CVP 21-day cycle x 6–8

Treatment 5-year follow-up

6-8 cycles

Pts with previously untreated iNHL or

MCL (N=447)

End-of-treatment assessment

Flinn I, et al. ASCO presentation 2017 (Abstract 7500)Flinn IW, et al. Blood 2014;123:2944–52

NB. No difference in Overall Survival Kahl BS, et al. ASH presentation 2017 (Abstract 484)

BRIGHT post-hoc analysis: Rituximab maintenance markedly prolonged duration of response in FL patients after first-line R-Bendamustine

0 2 4 6 8 10 12 18 24 30 42 54 720

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ility

604836 66

Maintenance vs no maintenance:

HR 0.50 (95% CI: 0.26, 0.95) , p=0.0298

R maintenance after R-Benda

No maintenance after R-Benda

No. of patients at riskMaintenanceNo maintenance

80 79 77 77 77 77 69 68 63 59 0 0305762 56 54 53 53 53 48 46 44 43 38 23 003641

5779 7455

Duration of response (months)

TREATMENT OF RELAPSED

FOLLICULAR NHL

• Re-induce a remission with R + non-cross

resistant chemo ; antibody maintenance ?

• Consolidate with autologous / allogeneic

stem cell transplantation in high risk

patients ?

• Introduce new agents (clinical trials)

R

A

N

D

O

M

I

Z

E

D

CHOP every

21 days

maximum 6

cycles

Rituximab +

CHOP every

21 days

maximum 6

cycles

EORTC 20981 Intergroup Phase III Trial

in Relapsed / Refractory Follicular Lymphoma :

Study Design

R

A

N

D

O

M

I

Z

E

D

Observation

Rituximab

maintenance*

*375mg/m2

every 3 months

for 2 years or until relapse

CR

PR

RITUXIMAB MAINTENANCE PROLONGS

PFS IN RELAPSED FOLLICULAR NHL(UPDATED EORTC 20981 STUDY)

R-maintenance

median: 44 mo

Observation

median: 16 mo

0 1 2 3 4 5 6 7 8

p < 0.0001

Time (years) after randomisation

0

20

40

60

80

100

PF

S (

%)

van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858.

GADOLIN study: Bendamustine vs Bendamustine +

Obinutuzumab in Rituximab-refractory iNHL

Sehn LH, et al. Lancet Oncol. 2016;17:1081-93.

Response monitored by CT scan

post-induction, then every 3 months

for 2 years, then every 6 months

Rituximab-refractory

CD20 + iNHL

(including FL, MZL, and

SLL), n = 413

Stratification factors

• NHL subtype (FL vs other)

• Prior therapies (≤ 2 vs > 2)

• Refractory type (R-mono vs

R-chemo)

• Geographic region

CR/PR/SD

R1:1

Obinutuzumab

1,000 mg i.v. Days 1, 8, and 15 Cycle 1;

Day 1 Cycles 2–6 (28-day cycles)

Bendamustine

90 mg/m2/day i.v. Days 1 and 2

Cycles 1–6 (28-day cycles)

Obinutuzumab

maintenance

1,000 mg i.v. q2mo

for 2 years

or until progression

Bendamustine

120 mg/m2/day

Days 1 and 2

Cycles 1–6 (28-day cycles)

GADOLIN study: Obinutuzumab improves OS in

recurrent iNHL when added to Bendamustine

• The addition of

Obinutuzumab also

improved PFS in patients

who were refractory to both

alkylators and rituximab

– HR 0.56 (0.40–0.78)

Sehn LH, et al. Lancet Oncol. 2016;17:1081-93.

Time (months)

PF

S (

%)

0 546 12 18 24 30 36 42 48

Median PFS = not reached

Median PFS = 14.9 months

HR 0.55 (95% CI 0.40–0.74)

p = 0.0001

Censored

Obinutuzumab + Bendamustine

Bendamustine monotherapy

0

20

40

60

80

100

CHEMO-FREE TREATMENT OF

RELAPSED FOLLICULAR NHL

1. R2 versus Lenalidomide alone

(randomized phase II ALLIANCE trial)

2. R2 versus Rituximab + Placebo

(randomized phase III AUGMENT trial)

• R2 : Rituximab + Revlimid / Lenalidomide

CALGB 50401 (ALLIANCE) : R2 is more active than

Lenalidomide alone in recurrent FL (with similar toxicity)

Phase 2 study in patients with grade 1–3a relapsed FL after ≥ 1 rituximab-based regimen

• Myelosuppression was the most common grade 3–4 AE in both arms

• No significant difference in thrombosis between arms (p = 0.157)

Leonard JP, et al. J Clin Oncol. 2015;33:3635-40.

Grade 3–4 AEs

in > 1 patient, %

Lenalidomide

(n = 45)

R2

(n = 44)

Gr. 3 Gr. 4 Gr. 3 Gr. 4

Hae

ma

tolo

gic Neutropenia 16 0 16 4

Thrombocytopenia 0 0 4 0

Lymphopenia 1 0 3 0

Fatigue 9 0 11 2

Thrombosis 9 7 2 2

Rash 2 2 4 0

Infection (with neutropenia) 4 0 2 0

AST 4 0 0 0

20%

39%

33%

37%

0%

20%

40%

60%

80%

100%

L (n = 45) LR (n = 46)

Res

po

nse

(%

)

PR

CR

p = 0.029

ORR 53%

ORR 76%

0 1 2 3 4 5

CALGB 50401 (ALLIANCE) : Lenalidomide and

Rituximab (R2) in patients with recurrent FL

Leonard JP, et al. J Clin Oncol. 2015;33:3635-40.

TTP

Time since study entry (years)P

rob

ab

ilit

y o

f p

rog

res

sio

n

0

1.0

0.8

0.6

0.4

0.2

X2 = 9.3

p = 0.002

Lenalidomide

R2

n = 45

n = 46

CharacteristicLenalidomide arm

(n = 45)R2 arm (n = 46)

Patients,

n%

Patients,

n%

Age, years

median 63 64

range 34–85 36–89

FLIPI 36 35

Low 33.3 51.4

Intermediate 41.7 28.6

High 25.0 20.0

TTP since last lenalidomide

dose, years1.6 1.4

Stage 4.5 45

I–II 22.3 33.4

III–IV 77.8 66.7

LDH 44 44

> NL 15.9 2.3

ASH 2018 , ABSTRACT 445

AUGMENT: A Phase III Randomized Study of Lenalidomide Plus Rituximab (R2) vs Rituximab/Placebo

in Patients With Relapsed/Refractory Indolent Non-Hodgkin Lymphoma

John P. Leonard,1 Marek Trneny,2 Koji Izutsu,3 Nathan H. Fowler,4 Xiaonan Hong,5 Jun Zhu,6 Huilai Zhang7 Fritz Offner,8 Adriana Scheliga,9

Grzegorz Nowakowski,10 Antonio Pinto,11 Francesca Re,12 Laura Maria Fogliatto,13 Phillip Scheinberg,14 Ian Flinn,15 Claudia Moreira,16

David Liu,17 Stacey Kalambakas,17 Chengqing Wu,17 Pierre Fustier,18 and John G Gribben,19

on behalf of the AUGMENT study investigators

1Meyer Cancer Center, Weill Cornell Medicine and New York Presbyterian Hospital, New York, NY; 2Charles University Hospital, Prague, Czech Republic ; 3National Cancer Center Hospital, Tokyo, Japan; 4The University of

Texas MD Anderson Cancer Center, Houston, TX; 5Fudan University Shanghai Cancer Center, Shanghai, China; 6Beijing Cancer Hospital, Beijing, China; 7Tianjin Medical University Cancer Institute and Hospital, Tianjin,

China; 8UZ Gent, Gent, Belgium; 9INCA Instituto Nacional De Câncer, Rio de Janeiro, Brazil; 10Mayo Clinic, Rochester, MN; 11Istituto Nazionale Per Lo Studio E La Cura Dei Tumori Fondazione Giovanni Pascale, Napoli, Italy;

12Azienda Ospedaliero-Universitaria di Parma, Parma, Italy; 13Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil;

14 Division of Hematology, Hospital A Beneficência Portuguesa, São Paulo, Brazil; 15SCRI Tennessee Oncology Nashville, Nashville, TN; 16Instituto Português de Oncologia Do Porto Francisco Gentil Epe, Porto, Portugal;

17Celgene Corporation, Summit, NJ; 18Celgene Corporation, Boudry, Switzerland; 19Centre for Haemato-Oncology, Barts Cancer Institute, London, United Kingdom

STUDY DESIGN AUGMENT TRIAL: RANDOMIZED DOUBLE BLIND PHASE III TRIAL

• Primary endpoint: PFS by IRC (2007 IWG criteria w/o PET)

R-lenalidomide (R2)Rituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5

Lenalidomide: 20 mg/d*, d1-21/28 (12 cycles)

R-placeboRituximab: 375 mg/m2 d1, 8, 15, 22 of cycle 1; d1 of cycles 2-5

Placebo: matched capsules (12 cycles)Stratification

• Prior rituximab (yes vs no)

• Time since last therapy (≤ 2 vs > 2 y)

• Histology (FL vs MZL)

Key eligibility criteria

• MZL or FL (grades 1-3a) in need of

treatment

• ≥ 1 prior chemotherapy, immunotherapy

or chemoimmunotherapy

• Not rituximab refractory

≤ 12 cycles or until PD, relapse, or intolerability

1:1

Relapsed/refractory

FL and MZL

(N = 358)*10 mg if CrCl between 30 to 59 mL/min.

5-year follow-up

for OS, SPMs,

subsequent

treatment, and

histological

transformations

• Prophylactic anticoagulation / antiplatelet Rx recommended for at risk patients

• Growth factor use was allowed per ASCO/ESMO guidelines1,2

RESPONSE (ITT) – AUGMENT TRIAL

• Median DOR was 36.6 mo (95% CI, 22.9-NR) for R2 vs 21.7 mo (95% CI, 12.8-27.6) for R-placebo, HR 0.53 (95% CI, 0.36-0.79), p = 0.0015

PRIMARY ENDPOINT AUGMENT : PROGRESSION-FREE SURVIVAL (ITT, IRC)

Median PFS

R2

(n = 178)

R-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) < 0.0001

By investigator, mo (95% CI) 25.3 (21.2-NE) 14.3 (12.4-17.7) 0.51 (0.38-0.69) < 0.0001

PFS by IRC*

Median follow up: 28.3 months

OVERALL SURVIVAL IN PATIENTS WITH FOLLICULAR LYMPHOMA (PRESPECIFIED SUBGROUP ANALYSIS) – AUGMENT TRIAL

Data cutoff June 22, 2018.

• 35 total deaths (11 R2, 24 R-placebo)

• 2-year OS was 95% (95% CI, 90%-98%) for R2 and 86% (95% CI, 79%-91%) for R-placebo

Median follow up: 28.3 months

CONCLUSIONS – AUGMENT TRIAL

• AUGMENT met its primary endpoint as R2 demonstrated statistically

significant and clinically relevant superiority over R-placebo for the primary

endpoint of PFS

– PFS advantage in prespecified subgroups, except MZL, was consistent with overall

population

–Overall survival advantage for R2 in the follicular lymphoma subgroup

R2 represents an important new treatment option in patients

with previously treated indolent NHL.

Stem cell transplantation in high-risk FL

• N= 121, median FU 13 yrs

• Pre-rituximab era

• 60 patients have relapsed

• 15 deaths from MDS/AML

• Apparent PFS plateau at 48%

1. Rohatiner AZ, et al. J Clin Oncol. 2007 ;25:2554-9.

2. Evens AM, et al. Cancer. 2013;119:3662-71.

Autologous SCT in second remission for FL1

3 yr FFS similar:

57% auto vs. 52% allo

OS: ASCT better

3 yr OS: 87% auto vs. 61% allo

NCCN FL database: auto-SCT vs. allo-SCT2

Autologous SCT in early progressor FL

• Retrospective analysis NLCS/CIBMTR

• 349 early progressors on rituximab-based ICT (2 years)

• Matched, half received auto-SCT, half did not

• 5-year OS 60 and 67% (p = 0.16)

CIBMTR, Center for International Blood and

Marrow Transplant Research;

NLCS, National LymphoCare Study.

Casulo C, et al. Biol Blood Marrow Transplant.

2018;24:1163-71.

Improved OS when receiving auto-SCT

within 1 year of treatment failure

5 yr OS with auto-HCT 73%

5 yr OS without auto-HCT 60%

p-value 0.05

(n = 123)

The role of allogeneic transplantation in R/R FL

Autologous transplantation

• Early use of auto-HCT

consolidation should be

considered a standard therapy

option for high-risk patients who

experience early failure of

chemo-immunotherapy (< 2

years)

• For patients with FL who

experience failure of frontline

therapies late (> 2 years),

deferring auto-HCT until later in

the disease course is

reasonable

Allogeneic transplantation

• Best reserved for medically fit

patients with heavily pretreated

disease, persistent marrow

involvement, refractory, but low-bulk,

disease

• For patients who experience a

failure to mobilize stem cells for

auto-HCT

• A reasonable option for patients who

experience failure with a prior

autograft

Hamadani M, Horowitz MM. J Oncol Pract. 2017;13:798-806.

HDACi

The World of “Biologics” in NHL

BCL2i

Co-Stimulatory

Molecules

IMiDs

PI3K/Syki

Monoclonal

AntibodiesBTKi

Adoptive/Active

Immunotherapy

Conjugated

Antibodies

CAR-T

Vaccines

Rituximab

Obinutuzumab

BiTE

antibodies :

Blinatumumab

Ofatumumab

Anti-CD19

Lenalidomide

Thalidomide

Pomalidomide

C-122

Proteosome

Inhibitors

Bortezomib

Carfilzomib

Oprozomib

Obatoclax

Venetoclax

PNT-2258

Ibrutinib

ACP-196

ONO-4059

Idelalisib ,

Copanlisib

Duvelisib

Vorinostat

Panobinostat

Evirolimus

GS-9973

Fostamatinib

Urelumab

Nivolumab

Pidilizumab

Brentuximab Vedotin

SAR3419

Otlertuzumab

Zevalin

Polatuzumab

Inotuzumab Ozogamicine

B-cell receptor signaling activates

different oncogenic pathways

Lenz G, Staudt LM. N Engl J Med. 2010;362:1417-29.

Isoform Idelalisib

(IC50-nM)1

Duvelisib

(IC50-nM)2

Copanlisib

(IC50-nM)3

TGR-1202

(IC50-nM)4

P110a 20,000 1410 0.4–1 10,000

P110b 1,900 26.2 10–18 800

P110g 3,000 19.6 93 400

P110d 8 0.36 3–10 24

PI3K inhibitors inhibit different PI3K isoforms

1. Lannutti, Blood, 2011

2. Winkler DG, Faia KL, et al.Chem Biol. 2013 20:1364-74.

3. Haike K et al. Presented at: American Society of Hematology Meeting on Lymphoma

Biology; August 10–13, 2014; Colorado Springs, Colorado. Abstract 48.

4. Vakkalanka et al Poster from RP5264 Rhizon

Idelalisib : Selective PI3K inhibitor in

double refractory iNHL

Gopal AJ, et al. N Engl J Med. 2014;370:1008-18.

Tumor response

Idelalisib 150 mg b.i.d. continuously Therapy maintained

until progression

Single-arm phase 2 study (n = 125)

Rituximab + alkylator-

refractory iNHL

Long-term

follow-up

ORR 57%

CR 6%

50

0

−50

−100

75

25

−25

−75

SP

D o

f m

easu

red

lym

ph

no

de

s (

best

% c

ha

ng

e f

rom

baseli

ne)

Individual patients (n = 125)

FL (n = 72)

SLL (n = 28)

MZL (n = 15)

LPL/WM (n = 10)

64

Copanlisib in r/r indolent B-cell lymphoma

2-year follow-up of CHRONOS-1

FL

(n=104)

MZL

(n=23)

SLL

(n=8)

WM / LPL

(n=6)

Total

(N=142)

Best response,

n (%)

Complete

response

21

(20.2)3 (13.0) 0 0 24 (16.9)

Partial

response40 (38.5) 15 (65.2) 6 (75.0) 1 (16.7) 62 (43.7)

Stable disease 34 (32.7) 2 (8.7) 1 (12.5) 3 (50.0) 40 (28.2)

Unconfirmed

stable disease1 (1.0) 0 0 0 1 (0.7)

Progressive

disease2 (1.9) 0 1 (12.5) 0 3 (2.1)

NE / NA 0 3 (13.0) 0 2 (33.3) 12 (8.5)

ORR, n (%) 61 (58.7) 18 (78.3) 6 (75.0) 1 (16.7) 86 (60.6)

DCR, n (%) 91 (87.5) 20 (87.0) 7 (87.5) 4 (66.7) 122 (85.9)

Dreyling M et al. , ASH 2018 , poster # 1595 Idelalisib : ORR 57% ; CR 6%

FL

MZL

SLL

WM / LPL

0

25

50

75

100

125

150

–25

–50

–75

–100

Individual patients (n=126)aB

es

t c

ha

ng

e in

ta

rge

t le

sio

n s

ize

fro

m b

as

eli

ne

(%

)

Venetoclax in NHL: phase I/II studyFowler, ASH 2016

• ORR FL (n=29) 38% (44% at 1200 mg); CR

14%

• No clinical TLS

Venetoclax in NHL: Phase I/II studyFowler, ASH 2016

• Median PFS FL 11 months

• High bcl2 expression not a perfect

biomarker for venetoclax activity

• combination with Rituximab?

Care in combination of more than two agents in FL?

Study Patient population Key points

Rituximab + Lenalidomide +

Ibrutinib (Alliance A051103)1

Previously untreated

FL

• High incidence of rash (all grades: 82%)

• Efficacy of the triplet similar to

Rituximab-Lenalidomide in the same

patient population

Idelalisib + Lenalidomide +

Rituximab (phase I Alliance

A051201 and A051202)2

R/R lymphoma • Excessively toxic combination

• Grade 3–4 neutropenia in 63%

• Grade 3–4 rash in 50%

Idelalisib + Lenalidomide +

Rituximab (NCT01088048)3

R/R indolent

lymphoma

• Significant hepatotoxicity

• ALT elevation (all grades) was noted in

85%

• Two patients died due to toxicity

1. Ujjani CS, et al. Blood. 2016;128:2510-6.

2. Smith SM, Lancet Haematol. 2017;4:e176-82.

3. Cheah CY, et al. Blood. 2015;125:3357-9.

Caveats about chemo-free combinations (no preclinical models to predict…)

1. Monoclonal antibodies

– Antibody-drug conjugates

– Bispecific antibodies

2. New kinase inhibitors

3. Improving Rituximab efficacy with other agents (chemo-free regimens)

– IMiDs® (lenalidomide), anti-PD-(L)1 / Immune Checkpoint Inhibitors …

1. New targeted agents

– Venetoclax

– Tamezetostat

– Many others

2. CAR T-cells

3. Intelligent combinations

Future strategies for the management of patients

with Follicular Lymphoma

PROGNOSTIC FACTORS IN FOLLICULAR

LYMPHOMA :

1. PRIOR TO STARTING 1st LINE TREATMENT

2. DURING TREATMENT

RISK PROGNOSTIFICATION IN FOLLICULAR

LYMPHOMA :

PRIOR TO STARTING TREATMENT

FLIPI

FLIPI-2

PRIMA-PI

Total Metabolic Tumor Volume

Circulating Tumor DNA (liquid biopsies)

m7-FLIPI

23 gene score by GEP

• Derived from prospective data (mostly - 68% - in R-treated patients ! )may be more relevant than FLIPI

• Simplified score calculation

• Includes baseline characteristics from FLIPI (age, haemoglobin level) plus:

– Bone marrow infiltration

– Longest diameter of largest lymph node >6cm

– 2 microglobulin level >ULN

1. Federico M, et al. J Clin Oncol 2009;27:4555–622. Casulo C. Best Pract Res Clin Haematol 2018;31:15–22

3. Bachy E, et al. Blood 2018 [Epub ahead of print]

FLIPI-2, an externally validated prognostic tool, predicts PFS

Number at risk

LowIntHigh

1.0

0.8

0.6

0.4

0.2

0.0

0 20 40 60 80 100

Progression free survival (month)

Surv

ival

pro

bab

ility

FLIPI-2

No of events

LowIntHigh

20276270

74619442

65504311

63414225

51346171

2615666

000

CensoredLogrank p<.0001

• 2 parameters, both easilymeasured clinically

– Bone marrow involvement

– β2 microglobulin

• Easy to score

• Primary objective: to provide basis for building more sophisticated and integrated biomolecular scores

Bachy E, et al. Blood 2018 [Epubahead of print]

PRIMA-PI is a new prognostic index for FL patients treated with first line immuno-chemotherapy

2M

Bone marrowinvolvement

YesIntermediate

risk

No Low risk

>3 mg/L High risk

3 mg/L

Bachy E, et al. Blood 2018 [Epub ahead of print]

PRIMA‐PI identifies high-risk patients at least as successfully as FLIPI and is at least as discriminatory for EFS

FLIPI PRIMA-PI

n (%) 5-year EFS, % (95% CI) n (%) 5-year EFS, % (95% CI)

Low 126 (28) 76 (66, 83) 168 (36) 77 (69, 83)

Intermediate 159 (35) 64 (55, 72) 136 (29) 57 (48, 66)

High 165 (37) 45 (37, 53) 158 (34) 44 (35, 52)

EFS by FLIPI risk category EFS by PRIMA-PI risk category1.0

0.8

0.6

0.4

0.2

0.00.0 2.5 5.0 7.5 10.0 12.5 15.0

Number at riskLowIntHigh

No. of eventsLow 29Int 57High 90

126159165

546050

864

000

Surv

ival

pro

bab

ility

EFS (years)

+ CensoredLog-rank p<0.0001

1.0

0.8

0.6

0.4

0.2

0.00.0 2.5 5.0 7.5 10.0 12.5 15.0

Number at riskLowIntHigh

No. of eventsLow 41Int 62High 82

168136158

795641

962

000

Surv

ival

pro

bab

ility

EFS (years)

+ CensoredLog-rank p<0.0001

Prognostic parameters in FL at diagnosis : Total Metabolic Tumor Volume (TMTV), circulating tumor cells and cell-free DNA

Delfau-Larue MH, et al. Blood Advances 2018;2:807–16

• Significant correlation between TMTV and both CTCs and cfDNA

• 4-year PFS is lower in FL patients with:

– TMTV >510 cm3

– CTCs >0.0018 PB cells

– cfDNA >2550 equivalent-genome/mL

• Compared with TMTV alone:

– cfDNA is predictive of outcome

• PFS is shorter in patients with high levels of both TMTV and cfDNA

– CTCs do not provide additional prognostic information

PFS by TMTV and cfDNA level*

p=0.009

L/L n=20L/H or H/L n=21H/H n=20

100

60

40

20

0

PFS

(%

)

0 20 60 120

Time (months)

80

1008040

INTEGRATION OF GENE MUTATIONS

IN RISK PROGNOSTIFICATION IN

FOLLICULAR LYMPHOMA

The m7-FLIPI

Pastore et al. , Lancet Oncology , September 2015

German Cancer Consortium (DKTK)

M7FLIPI : FAILURE-FREE SURVIVAL (FFS)PASTORES ET AL. 2015


M7FLIPI : OVERALL SURVIVAL (OS)


RECLASSIFYING RISK GROUPS

RISK PROGNOSTIFICATION IN

FOLLICULAR LYMPHOMA :

DURING TREATMENT

POD 24

EFS12 / EFS24

CR30

PET-CT status at the end of induction

MRD status at the end of induction

Carla Casulo, Michelle Byrtek, Keith L. Dawson, Xiaolei

Zhou, Charles Farber, Christopher R. Flowers, John D.

Hainsworth, Brian K. Link, Andrew D. Zelenetz,

Jonathan W. Friedberg

Early Relapse of Follicular Lymphoma After R-CHOP Uniquely Defines Patients at High Risk for Death: an Analysis From

the National LymphoCare Study

Overall Survival of Patients With Follicular Lymphoma Who Relapsed (POD)Within 2 Years of R-CHOP

▪ 122 (21%) patients were classified as early progressors

▪ Two-year OS (95% CI) was 71% (61.5–78.0)

▪ Five-year OS (95% CI) was 50% (40.3–58.8)

1.0

0 1 2 3 4 5 6 7 8 9 10

0.0

0.2

0.4

0.6

0.8

Patients at risk:

101 78 69 58 49 45 33 14 6 0

Time (years)

Surv

ival pro

babili

ty

122

Early Progressor

420 420 407 387 363 344 252 144 33 0420Reference=

Early =

Reference Group

Evaluation of Complete Response Rate at 30 Months

as a Surrogate Endpoint for Progression-Free

Survival in First-Line Follicular Lymphoma Studies:

Analyses of Individual Patient Data of 3837 Patients

From the FLASH Database

Daniel J. Sargent, Qian Shi, Sabine De Bedout, Christopher Flowers,

Nathan Hale Fowler, Tommy Fu, Anton Hagenbeek, Michael Herold,

Eva Hoster, Jane Huang, Eva Kimby, Marco Ladetto, Franck

Morschhauser, Tina Nielsen, Kenichi Takeshita, Nancy Valente,

Umberto Vitolo, Emanuele Zucca, Gilles A. Salles, on behalf of the

FLASH (Follicular Lymphoma Analysis of Surrogacy Hypothesis) group

Results : Primary Surrogacy Evaluation

R2WLS

(95% CI)

R2Copula

(95% CI)

0.88

(0.77, 0.96)

0.86

(0.72, 1.00)

30 months complete

response rate met the

pre-specified

surrogacy qualification

criteria for PFS-0.5 0.0 0.5 1.0 1.5 2.0

Log(OR) on 30mCR

-1.5

-0.5

0.0

0.5

Lo

g(H

R)

on

PF

S

)log(636.0093.0)log( 30mCRPFS ORHR

-1.0

Rituximab trials

Non-rituximab trials

Induction trials

Maintenance trials

Object size is proportional to sample size

• Optimal implementation of prognostic tools in FL has yet to be achieved

– Standard indices , such as FLIPI , are still used but may overestimate an individual patient’s level of risk

– m7-FLIPI remains a research tool, but is being validated prospectively in several trials

– Gene-Expression Profiling shows promise and may allow for individualised therapy

– Early disease progression (POD24) is a robust predictor of reduced OS and provides an opportunity to evaluate novel agents

• Until prognostic tools are available in the clinic to determine which patients are at high risk, this population remains unidentifiable

Summary - Prognostic Factors in Follicular Lymphoma

FOLLICULAR LYMPHOMA : CONCLUSIONS AND CHALLENGES FOR

THE FUTURE

• Many promising new agents available

• Improve results by….

– Better understanding of lymphomagenesis

– Better understanding of succes and failure of treatment

– Develop tailored treatment based on prognostic factors

– Rational development of novel combinations / chemo-free regimens

– Perform correlative studies of response with molecular and cellular characteristics of the lymphoma

If possible, treat patients in clinical trials !

Steered by world leaders in hem-oncology, the Lymphoma Hub is an online resource of key information on lymphoma and CLL. The Lymphoma Hub supports community hematologists and oncologists in making informed treatment decisions and ensuring patients have access to the latest therapies available.

19/03/2019

www.lymphomahub.com

Twitter Handle: @lymphomahub

Facebook URL: www.facebook.com/lymphomahub/

User Name: @lymphomahub

LinkedIn URL: www.linkedin.com/company/3352172/

Channel Name: Lymphoma Hub

Channel URL: https://www.youtube.com/user/lymphomahub

Hashtags: #lymsm #lymphoma

http://www.lymphomahub.com/

https://www.linkedin.com/company/3352172/

https://www.youtube.com/user/lymphomahub

EURASIAN FEDERATION OF ONCOLOGYVIth Hematology ForumMoscow , May 17-19 , 2019

Meet-the-Expert breakfast sessionsPoster session

Acute-and chronic leukemias / MDSNHL / Hodgkin lymphomaMultiple myelomaChronic myeloproliferative disorders (PV,ET,MF)Stem cell transplantationMRDT-cell therapies , incl. CAR-T cells

Register at : www.hem.eafo.info

19/03/2019

http://www.hem.eafo.info/

low grade lymphomas modern treatment strategies …€¦ · 22/6/2018 · event, n (%) 46 (7.7) 35...

Documents