FOLLICULAR

LYMPHOMA

Ann Janssens

MD, PhD

Hematology

UZ Leuven

BHS course: indolent lymphoma

7th february 2015

Non Hodgkin Lymphoma Epidemiology US 1998-2011

Follicular

22 %

20%

Mantle Cell

6 %

4.8%

DLBCL

35 %

39.2%

MALT

8 %

Marginal Zone

3 %

10% Others

6 %

anaplastic T/null

2 %

1.1%

Péripheral T cell

7 %

2% lymphoblastic

2 %

Burkitt

1 %

2%

SLL/ CLL type

8 %

5.3%

Non Hodgkin’s Lymphoma Classification Project, Blood 1997

Go et al. EHA 2014, abstract

M age 67y

M 52.5%

B 83%

T/ NK 5%

NOS 12%

Lyplasmocytic ly

1.4%

T-AILD

0.8%

Incidence FL Europe

5-7/100000

WHO: B-cell neoplasms

• Precursor B-cell neoplasm

– B-ALL, lymfoblastenlymfoom

• Mature B-cell neoplasms – B-cell chronic lymphocytic leukemia/small lymphocytic

lymphoma

– B-cell prolymphocytic leukemia

– Lymphoplasmacytic lymphoma

– Splenic marginal zone B-cell lymphoma Hairy cell leukemia

– Plasma cell myeloma/plasmacytoma/MGUS

– Extranodal marginal zone B-cell lymphoma (MALT)

– Nodal marginal zone B-cell lymphoma

– Follicular lymphoma

– Mantle cell lymphoma

– Diffuse large B-cell lymphoma

– Burkitt lymphoma/Burkitt cell leukemia

stage 3-4 at diagnosis 80%

bone marrow invasion 50%

FL-cells are the malignant

counterpart of normal germinal

center B-cells

How to diagnose and stage a FL?

• Clinical data

– Personal history

– Clinical examination

• Blood examination – Full blood count

– LDH

2 microglobulin

– HIV, hep B-C

• Histopathology

• Bone marrow/threphine

• Imaging

Diagnosis of FL on histopathology

• Lymph node biopsy

– Inguinal nodes not first choice due to reactive changes

– Cervical nodes are prefered

– A growing node is also prefered

• Fine needle aspiration DD reactive vs suspected H&N regio: DD epithelioma

• Core biopsy: no impression of Ln-strukture

FL immunohistochemistry

CD20

CD10 Bcl-2

FL immunohistochemistry

CD3

CD4 CD8

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 Treat as a DLBCL

Treat as a FL

BONE MARROW EXAMINATION

Bone marrow aspirate

+ biopsy

+ immunophenotyping

+ genetics

• For diagnosis or staging FL? Yes

• Unexplained cytopenia (disease related, auto-immune, drug related) Yes

• Confirming complete remission

after treatment : Yes

CD20

Bone marrow infiltration in FL

+ additional genetic abnormalities

T(14;18) genetic hallmark of FL

How to diagnose and stage CLL?

• Clinical data – Personal history: most asympthomatic, only 5% reveal B-symptoms

– Clinical examination: 25% lymphadenopathies, 15% organomegaly

• Blood examination: leukocytosis due to a lymphocytosis

• Histopathology

• Bone marrow/threphine

• Imaging:

- CT-scan neck, thorax, abdomen & pelvis

- PET-CT

International prognostic index for

follicular lymphoma ( FLIPI-index)

• Age :< of > 60 jaar

• Stage :I, II vs III, IV

• LDH :nl vs elevated

• Hb :> 12 vs <12 g/dl

• N° of nodal sites :> 4

• Number of Nodal sites > 4

LDH > normal

Age > 60

Ann Arbor Stage III-IV

• Hemoglobin < 12

‘N O L A S H’

Follicular Lymphoma

Survival according FLIPI-index

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

10 y OS

71%

51%

36%

N= 1795

Factors,

n Risk Patients, % 5-Yr OS, % 10-Yr OS

0-1 Good 36 91 71

2 Intermediate 37 78 51

3 Poor 27 53 36

M, 51y, new diagnosis FL

Male

<60j

Stage 4

Bone marrow +

LDH nl

Hb >12

B2 elevated

T(14;18)+

FLIPI: 2

FLIPI2: 2

M, °60y, relapsing FL

Male

60y

Stage 4

Bone marrow +

LDH nl

Hb >12

B2 nl

New Ln biopsy: FL

grade 1-2

T(14;18)pos

FLIPI: 2

FLIPI2: 1

Follicular lymphoma:

Disease transformation

Transformation to aggressive

lymphoma in ±37% of patients in the

15y following diagnosis

Lister, JCO, 2007

Survival Patterns are Different for

Indolent and Aggressive NHL

0

25

50

75

100

0 1 2 3 4 5 6 7 8

Pro

bab

ilit

y o

f su

rviv

al

(%)

Years

Indolent NHL (e.g. Follicular lymphoma)

Aggressive NHL (e.g. Diffuse large B-cell lymphoma)

The Non-Hodgkin’s Lymphoma Classification Project. Blood 1997;89:3909–3918

Treatment options for FL

Treatment

modalities

CVP

CHOP

Flu-combinations

Bendamustine

High-dose therapy

Watchful

waiting

Monoclonal Ab

CIT=

chemo +

Mo Ab

Chlorambucil ,

Cyclophosphamide

Radiotherapy

Kinase inhibitors

Lenalidomide

….

Follicular Lymphoma: Treatment

• stage I en II ( <3 nodi): involved field irradiation

• Stad III-IV: >60j en asymptomatisch

– Watch and wait

– 50% nood aan behandeling binnen de 24m

– 80 à 90% behandeld eerste 5 j

– ± 20% spontane remissies!

• Stad III-IV: <60j en >60j met symptomen

– Chlorambucil, CVP, CHOP, a-interferon

– Fludarabine en combinaties

– Rituximab, R-CVP of R-CHOP of R-FCM, Rituximab onderhoud

– Zevalin consolidatie

– Autologe transplantatie als consolidatie

– Allogene transplantatiediagnose

Radiotherapy for localised FL

• Involved field radiotherapy – 37% relapse free at 20y (Macmanus et al)

– 50% stage I cured, 25% stage II (MDACC)

– PFS influenced by tumor size < or > 3 cm and stage I vs II

– Relapses possible even after 30y, however rare > 10y

– 2% “in-field” failure-rate at 20 years

– 85% of failures in “out-of-field” nodal sites

• Extended field radiotherapy-TLI (stage III-IV) (excessive toxicity, > secondary cancers)

• IFRT with chemotherapy (eradication occult disease)

– + Chl, CVP, CHOP,…

– TROG/ALLLG trial ongoing: Involved field RT 30-36 Gy with or

without R-CVP x 6 ( ongoing till 2022)

Treatment guidelines: stage 1-2

• RT preferred treatment of localized FL

• 24-30 (36) Gy (no difference between 24-45Gy),

involved field

• No data that show that RT is better than other treatment

modalities, also not observation (no prospective trials, only

retrospective data, data acquired before the R-era)

• If RT toxicity outweights the potential benefits then

observation is a reasonable alternative

Hiddemann et al, Leukemia, 2014

Dreyling et al, ESMO guidelines, Ann Oncol 2014

Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

LymphoCare database

• FL stage 1:

– 27% IFRT

– 28% CIT

– 12% R

– 23% Other R+ IFRT

N= 471

Friedberg JW et al., JCO, 2009 and

Only 206

staged with a

bone marrow

Follicular Lymfoma

Treatment • stage I en II ( <3 nodi): involved field bestraling

• Stage III-IV: asymptomatic or/and low tumor burden

– Watch and wait

– 50% in need for treatment <24mo

– 80 à 90% treated in the coming 5y

– ± 20% spontaneous remissions!

• Stage III-IV: <60j en >60j met symptomen

– Chlorambucil, CVP, CHOP, a-interferon

– Fludarabine en combinaties

– Rituximab, R-CVP of R-CHOP of R-FCM, Rituximab onderhoud

– Zevalin consolidatie

– Autologe transplantatie als consolidatie

– Allogene transplantatiediagnose

Wait and see if…

• No systemic symptoms

• < 3 nodal sites

• no bulky nodes

• No splenomegaly >16cm

• No effusions

• No compressive symptoms

• No circulating lymphoma cells

• No cytopenia

• No rapid disease progression

• No renal infiltration

• No bone lesions

• No life treatening organ involvement

• Impairment of qol

• Induction of – myelosuppression,

– fatigue,

– secondary leukemia

• Impairment of collection of

stem cells

• Induction of tumor resistance ?

Increasing risk of transformation ????

Ardeshna et al, Lancet 2003

Before R era: W&W vs Chl

mTTT: 2.6y

At 10y: 19% not treated

( 40% of >70y)

Higher risk of transformation if W&W???

3 trials

W &W vs Promace-MOPP

W & W vs predimustin

W&W vs IFN-a

No gain in OS

R-era: W&W vs R stage II-IV, non-bulky (2004-2009)

Ardeshna et al, Lancet Oncol, 2014

Ardeshna et al, Lancet Oncol, 2014

R-era: W&W vs R stage II-IV, non-bulky (2004-2009)

OS 3y

W&W 94%

R + MR 97%

Improved psychological well-being in the R arms

Time to chemo- or radiotherapy longer in the R-arm

Will early

treatment

impair

further

treatment

wit R or

R-

chemo?

R-era: R with maintenance or

retreatment

Kahl, JCO, 2014

Time to treatment failure identical

Till progression

Median follow-up: 4.5 y

Low tumor burden GELF

• No systemic symptoms

• < 3 nodal sites of > 3cm

• no bulky nodes (< 7)

• No splenomegaly >16cm

• No vital organ compression

• No compressive symptoms

• > 5000 clonal lymphocytes

• No cytopenia

• Hb <10,

• plt <100000,

• PMN <1500

FLIPI

low 17%,

intermediate 47%,

high 36%

Kahl, JCO, 2014

GELF: Groupe pour l’etude de lymphome folliculaire

Kahl B S et al. JCO 2014;32:3096-3102

©2014 by American Society of Clinical Oncology

Treatment guidelines

low tumor burden FL

• Observation if not fulfilling criteria for starting

treatment according GELF-BLNI criteria

• If results of Ardeshna should be confirmed, R

immediately as risk of relapse is reduced???

Hiddemann et al, Leukemia, 2014

Dreyling et al, ESMO guidelines, Ann Oncol 2014

Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

Follicular Lymphoma

Treatment • stad I en II ( <3 nodi): involved field bestraling

( relapsen mogelijk zelfs na 30j)

• Stad III-IV: >60j en asymptomatisch

– Watch and wait

– 50% nood aan behandeling binnen de 24m

– 80 à 90% behandeld eerste 5 j

– ± 20% spontane remissies!

• Stage III-IV: symptomatic and/or high tumor burden

– Chlorambucil, CVP, CHOP, a-interferon

– Fludarabine en combinaties, bendamustine

– Rituximab-chemo

– Rituximab maintenance

– Radio-immunotherapy (Zevalin)

– Autologeous transplantation

– Allogeneic transplantation

Marcus-trial: R-CVP vs CVP - PFS

R-chemo is the standard of care for high tumor burden FL

Is one chemotherapeutic

regimen better than another?

R-CVP

R-CHOP

R-FM R-

Benda

Primary Rituximab and MAintenance

Study

PDs/SDs

off study

Rituximab maintenance

1 dose every 8 weeks

for 24 months

Observation

CR/PR

R-CVP 8

or R-CHOP 6 + 2R

or R-FCM 6 + 2R

or R-MCP 6 + 2R

Untreated

follicular NHL

An intergroup international study co-ordinated by

R

A

N

D

O

M

I

Z

E

R-CHOP 74%

R-CVP 23%

R-FCM 3,5%

Salles G et al., JCO, 2011

Friedberg JW et al., JCO, 2009 and

WW

18%

XRT

5%

R-mono

14%

R-Chemo

53%

Chemo

3%

Clincal trial

6%

Other

1%

National LymphoCare Study Initial Treatment

R-CHOP 55%

R-CVP 23.1%

R-F 15.5%

Other 6.4%

• 2004-2007

• 2728 pat enrolled

• 80% at non academic

sites

• Median age 61y

• F 52%, whites 91%

• Grade 1: 43%,

grade 2: 29%,

grade 3: 19%

• Stage I 17%,

II 15%,

III 29%,

IV 37%

500 pat grade 3:

PFS & OS not

significantly

different between

R-CHOP

and R-CVP (median follow-up: 4.5 yrs)

PFS in FL after 1st line treatment

Responses in FL according to 1st line

treatment

Federico, JCO, 2013

TTF 3y OS

R-CVP 46% 98%

R-CHOP 64% 95%

R-FM 61% 93%

N= 534

M age 56 y

R-FM: more myelotoxicity and

secondary malignancies

The Bright trial:

BR vs RCVP/RCHOP in iNHL and MCL

• Excluded: transformed disease, CLL-SLL, grade 3 FL

• Median age 58-60 y

• iNHL: BR 213, RCVP/CHOP 206

• MCL BR 37, RCHOP 37%

• CR for BR or R-CVP/CHOP non inferior

• More nausea and emesis for BR, antiemetics equal

• Less neuropathy for BR

• Neutropenia > CHOP although more G-CSF use

• Lymphopenia > BR: 66 vs 33%

Efficacy equal

Toxicity different

Flinn, ICML 2013, abstract 084

BR RCHOP RCVP

ORR 97% 90% 83%

CR 31% 23% 23%

Treatment guidelines

for FL with high tumor burden

• CIT except when chemotherapy is contraindicated

• F-based regimen no 1st line treatment due to

toxicities

• No preference between R-CHOP, R-benda vs R-

CVP

Hiddemann et al, Leukemia, 2014

Dreyling et al, ESMO guidelines, Ann Oncol 2014

Kuruvilla et al, Canadian guidelines FL 1st line, Clin Lymph Myeloma Leuk 2015

… after induction treatment

consolidation maintenance

Radioimmunotherapy

autoSCT

? R- maintenance

Median follow-up: 73 mo

PFS 6y favors R-arm: 59.2 vs 42.7% (p<0.0001)

Benefits seen in all 3 FLIPI groups,

CR increased after 2y of maintenance

No difference in OS

Salles et al, Lancet, 2011

Maintenance after 1st line

• R new standard of maintenace after

induction when >PR

• Expensive

• Toxic.

– More infections

– More neutropenia

maintenance Re-treatment

Vidal et al, JNCI 2009

Rituximab maintenance in FL Infection-related adverse events in patients with follicular

lymphoma treated with rituximab maintenance compared

with observation

Hazard ratio 1.99 ( CI 1.21-3.27)

Van Oers: gr 3-4 infections:

9.7% vs 2.4%

Duration of remission in patients

with indolent NHL

Years

First course Second Third Fourth course

Treatment No. Treated RR, % Duration, Yrs Survival, Yrs

First 204 88 2.6 9.2

Second 110 78 1.1 4.6

Third 63 76 1.1 3.5

Fourth 37 68 0.5 1.2

Johnson et al. J Clin Oncol. 1995;13:140-147.

No Curative treatment available for advanced stages

Goal of treatment:

effective and durable

disease control (OS-PFS)

with minimal toxiciy and

maintaining qol

Maintenance “R” in folliculair lymfoom

na tweede respons op CHOP of R-CHOP

Van Oers et al., Blood, 2006

Considerations for subsequent therapy

• Age

• Comorbidities

• Candidate for transplant ?

• Previous treatment(s)

• Period of previous remission

• Refractory to R-monotherapy or R-chemo

• Tolerance of previous treatments

• Patient’s preference

Fit or unfit?

But… not all patients respond to R or R-chemo

1st line R-chemo SD and/or progression

R-CVP 20%

R-CHOP < 10%

R-MCP 10%

R-Benda < 10%

>2nd line R-chemo SD and/or progression

R-CHOP 30%

R-FCM 30%

1 st line R SD and/or progression

R (Gela phase 2) 27%

R (Ardeshna) 27%

≈ 25%

≈ 15%

≈ 30%

And… some relapse or progress during

maintenance

SD and/or progression

R + R maintenance 1st line 20%

R-CHOP + IFNa 20%

EORTC 20981: R/3m/24m 30% at <2.5y

GLSG: R/6m 20% at <15m

≈ 25%

… during upfront and 1th relapse

treatment approximately

70% of patients with iNHL

become refractory to rituximab

Treatment options for

rituximab refractory iNHL

• Radioimmunotherapy

• Monoclonal antibodies

• Hematopoietic transplantation

• Chemotherapy: bendamustine

• New drugs ??? – Immunomodulatory agents

– B-cell receptor signalling inhibitors

– mTor pathway inhibitors

– Proteasoom inhitors

– Histose deacetylase inhibitors

– Apoptosis inducing agents BH3mimetics

– …

RIT in R-refractory

iNHL

• 9o Y-ibrutumomab (Zevalin)

• N= 57 (54 FL)

• M age: 54y

• Median number of previous R/: 4 (1-9)

• 76% resistant to last chemo

• All no reponse or relapse <6m to R monotherapy

Witzig et al, JCO 2002, 20:3262-3269

ORR (FL) 74%

CR 15%

TTP 6.8m

TTP for responders 8.7m

90Y

90Y

90Y

Bendamustine (Levact): active in R-refractory patients

• Relapsed/refractory indolent lymphoma 120 mg/m² d1-2

(n= 52)

– ORR 73%, CR 11%, remission duration 16m

• Relapsed/refractory indolent lymphoma: (n= 76),

Refractory to R (61% FL )

– ORR 77% CR 34%, response duration 9m (indolent)

– Alkylator refractory OR 66%

• R refractory indolent NHL (n=100) ( FL 62%)

– ORR 84% CR 32%, Respons duration 9.3m

Cheson et al., JCO 2009

Autologeous stem cell transplantation

• Improve disease control with no impact on OS – In RCT’s longer PFS compared to control arm ( chemo,

postremission IFN) but OS not changed

– Outcomes comparable if R before autotransplant

• Low transplant related mortality

• Transplant contamination by lymphoma (in vivo or ex vivo purging give better outcomes)

• 10-20% secondary malignancies ( 10% t-MN)

• Indications for autoTx: ??? – “go go” patients (<70y without comorbidity) at first (???) relapse

– relapse within 24m after an anthracycline containing regimen

• No data on autoTx in R-refractory patients – If relapse <1y after treatment: dismal prognosis, candidate for alloTx

Allogeneic stem cell transplantation

• The only curative treatment option for iNHL !

• Advantages: – Stem cells free of lymphoma and prior chemotherapy induced DNA damage

• Lower relapse rate

• Lower rate of secondary malignancies

– Graft vs lymphoma effect • Plateau in relapses (20% at 3à 5y postTx)

• Disadvantages: – Requirement of a HLA- matched donor

– TRM >20% (higher if chemo-R disease)

– cGvHD ≈50%

• RIC: better outcome >50y and more comorbidities

• Indications for allo Tx: – No CR to upfront treatment

– Duration of response <2y

– Relapse after autologeous Tx , if bone marrow burden is high and disease is refractory

but… Better outcome if chemosensitive

• No data on allo Tx in R-refractory patients

Chemo-free treatment

for FL • Monoclonals

– Optimize dose and shedule of rituximab

– Other anti-CD20 monoclonals

– Combine antiCD20 with antiCD22, 80, 74, 37

– Combine with G- or GM-CSF, IL2, IL-12, IFN-a

• Lenalidomide – Combine with rituximab ( more CR, more neutropenia)

– Combine with GA-101 (GALEN phase 1b)

• Target PD1-PDL1: pidilizumab ORR 19/35 with CR 14

• Target CD137 (T), Kir (NK), CD47 (phagocytosis)

• Bcl2-inhibitors

• Kinase inhibitors: – Idelalisib in double Refr FL: ORR 57%, mDOR 12.5 mo

– Ibrutinib R/R FL: ORR 56%, PFS 1y 50%, with R, with BR

Educational session FL EH 2014, G. Salles,

Kinase inhibitors

lenalidomide

Bcl-2 antagonists

Monoclonal antibodies

0

60

0 2 4 6 8

4-Year

N Death Estimate

CHOP + Mab 179 18 91%

ProMace 425 189 79%

CHOP 356 226 69%

Years After Registration

OS by Treatment

Reprinted with permission. © 2008 American Society of Clinical Oncology.

All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23:8447-8452.

1980s

1990s

Overa

ll S

urv

ival

(%)

1990s-2000s

40

20

100

80

10

Improving Survival of Follicular NHL:

Impact of Antibody-Based Therapy

FOLLICULAR

LYMPHOMA

Easy to treat…

….

difficult to cure