First-line management of follicular lymphoma: Will induction and maintenance treatment prolong survival?

Robert Marcus Department of Haematology,

Addenbrooke’s Hospital, Cambridge, UK

Trial 1: R-CVP versus CVP study design

• Follicular NHL (IWF B, C, D)

• Stage III−IV 18 years• No prior Rx• Measurable

disease• Central

histology review

RANDOMISE

CVP x 4 cycles(q3wk)

R-CVP x 4 cycles (q3wk)

CVP x 4 cycles(q3wk)

R-CVP x 4 cycles (q3wk)

SD PD

off study

CR, PR

Rituximab 375 mg/m2 iv day 1Cyclophosphamide 750 mg/m2 iv day 1Vincristine 1.4 mg/m2 iv day 1Prednisolone 40 mg/m2 po days 1–5

RESTAGE

Marcus R, et al. Blood 2005; 105:1417–1423.

Participating sites

Australia K Bradstock, J Catalano, R Herrmann, J McKendrick, J Norman, D Rosenfeld, K Taylor

Belgium M Bron, R De Bock, F Offner

Brazil C Chiattone

Canada A Belch, I Bence-Bruckler, M Crump, D Forrest, K Imrie, KS Robinson, C Shustik

France S Castaigne, P Solal-Céligny

Israel M Shaklai

Poland A Dmoszynska, K Kuliczkowski, J Walewski

Portugal F Placido, J Raposo, J Veiga

Spain JN Batista, M Constenla, E Flores, J Gomez Codina, J Guma, A Rueda

Switzerland T Cerny, R Zenhausern

UKD Cunningham, DJ Dunlop, E Fitzsimons, BW Hancock, C Hatton, P Johnson, R Marcus, G Morgan, A Pagliuca, R Pettengell, M Potter, C Poynton, S Proctor

Patient characteristics

CharacteristicR-CVP

(n = 162)CVP

(n = 159)

Median age, years 52 53

Histology

Grade 3 FL, % 9 8

Bulky disease, % 39 46

FLIPI 3−5 (poor prognosis), % 40 47

FLIPI 2 (intermediate prognosis), % 41 37

FLIPI 0−1 (good prognosis), % 19 15

Central review of pathology performed on 90% of patientsFL diagnosis confirmed in 95% of patients

Marcus R, et al. Blood 2005; 105:1417–1423.

Response rates*

* Response up to 42 days after completion of treatment

ResponseR-CVP

(n = 162)CVP

(n = 159)p-value

CR/CRu (%) 41 10 p < 0.0001

PR (%) 40 47

ORR (%)(CR+CRu+PR)

81 57 p < 0.0001

Marcus R, et al. Blood 2005; 105:1417–1423.

Conclusions

Rituximab plus CVP improved:─ Overall and complete response rates─ TTP, TTNLT, DFS─ Overall survival

Addition of rituximab did not substantially increase regimen toxicity

8 cycles of R-CVP should be considered as standard treatment for previously untreated FL

Trial 2: R-CHOP versus CHOP study design

RANDOMISATION

6–8 cycles x CHOP

6–8 cycles x CHOP plus

rituximab

RANDOMISATION

PBSCT

Standard IFN-maintenance

Intensive IFN-maintenance

Standard IFN-maintenance

Hiddemann W, et al. Blood 2005; 106:3725–3732.

Patients > 60 years (> 65 years)

Patients < 60 years (< 65 years)

CR, PR

CR, PR

TTF is significantly improved with rituximab-based induction therapy

Buske C, et al. Blood 2006; 108:Abstract 482.

CHOP (37/109)Median 2.1 years

R-CHOP (78/112) Median 5 years

p < 0.0001

Patients aged > 60 years

Years0 1 2 3 4 5 6

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0

Overall survival is significantly improved with rituximab-based induction therapy

CHOP (89/109)

R-CHOP (102/112)

4-year OS R-CHOP: 90%CHOP: 81%

Years0 1 2 3 4 5 6

Pro

bab

ilit

y

0.0

0.2

0.4

0.6

0.8

1.0

p = 0.039

Buske C, et al. Blood 2006; 108:Abstract 482.

Patients aged > 60 years

Survival is significantly improved with R-CHOP in all FLIPI subgroups

FLIPI 0–1: Low risk p = 0.0091FLIPI 2: Intermediate prognosis p < 0.0001 FLIPI 3–5: Poor prognosis p = 0.0001

Median NR

Time (years)

Su

rviv

al p

rob

abil

ity

01 2 3 40 5

0.2

0.4

0.6

0.8

1.0

6

R-CHOP

Median NR

CHOP

Time (years)

Su

rviv

al p

rob

abil

ity

01 2 3 40 5

0.2

0.4

0.6

0.8

1.0

6

Median 4.1 years

Median 3.0 yearsMedian 4.0 years

Median 2.0 years

Buske C, et al. Blood 2006; 108:Abstract 482 and unpublished data.

Rituximab 375mg/m2 iv d 1Mitoxantrone 8 mg/m² iv d 3 and 4Chlorambucil 3 x 3mg/m² po d 3–7Prednisolone 25 mg/m² po d 3–7

Advanced FL, IC and MCL

18–75 yearsNo prior

rituximabCentral histology

reviewWritten informed

consent

RANDOMISED

R-MCP6 cycles(q4wk)

MCP6 cycles(q4wk)

RESTAGING

SDPD

off study

CR, PR

IFN-maintenance for FL

Trial 3: R-MCP versus MCP study design

R-MCP2 cycles(q4wk)

MCP2 cycles(q4wk)

Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

Rituximab-based induction therapy significantly improves survival in patients with FL

p = 0.0096

R-MCP: Median NR

MCP: Median NR

0

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Time (months)

ITT population: Median follow-up 47 months

4-year OS R-MCP: 87%MCP: 74%

Herold M, et al. J Clin Oncol 2007; April 9 (Epub).

PFS is significantly improved with R-MCP in all FLIPI subgroups

FLIPI 2: Intermediate prognosis p = 0.0016 FLIPI 3–5: Poor prognosis p = 0.0011

Time (months)

Su

rviv

al p

rob

abili

ty

010 20 30 400 50

0.2

0.4

0.6

0.8

1.0

60

Median NR4-year PFS: 82%

Median NR 4-year PFS: 61%

Time (months)

Su

rviv

al p

rob

abili

ty

010 20 30 400 50

0.2

0.4

0.6

0.8

1.0

60

Median 36 months4-year PFS: 43%

Median 26.5 months4-year PFS: 36%

R-MCP MCP

Herold M, et al. J Clin Oncol 2007; April 9 (Epub) and unpublished data.

Trial 4: R-CHVP-IFN vs CHVP-IFN study design

αIFN 2b, 4.5 MU tiw for 18 months (3 MU if aged 70 yr)

d1 Cyclophosphamide 600 mg/m2

d1 Doxorubicin 25 mg/m2 d1 Etoposide 100 mg/m2 d1–5 Prednisolone 40 mg/m2

every month for 6 months (arm A & B) then every 2 months in arm A

Rituximab: 375 mg/m2

R

Arm A

Arm B

Staging including CT-scan and bone marrow biopsy

12 months6 months

Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

Eve

nt-

free

su

rviv

al

0

25

50

75

100

0 10 20 30 40 50 60

p < 0.0001

70Months

EFS and OS are significantly increased with rituximab-based therapy

67%

46%

R-CHVP + IFN- (Arm B)

91%

84%CHVP + IFN- (Arm A)

Ova

rall

su

rviv

al

0

25

50

75

100

0 10 20 30 40 50 60

p = 0.029

70Months

CHVP + IFN- (Arm A)

R-CHVP + IFN- (Arm B)

Foussard C, et al. J Clin Oncol 2006; 24(18S):Abstract 7508.

First-line rituximab-based induction therapy improves overall survival

1. Foussard C, et al. J Clin Oncol 2006; 24:Abstract 7508.2. Herold M, et al. J Clin Oncol 2007; April 9 (Epub).3. Hiddemann W, et al. Blood 2005; 106:3725–3732.

4. Marcus R, et al. Blood 2006; 108:Abstract 481.

Induction regimen Outcome (median) Overall survival

CHVP R + IFN-1 EFS NR vs 3 yrs p < 0.0001

3.5 yr 91% vs 84%p = 0.029

MCP R2 PFS NR vs 29 mo p < 0.0001

4 yr 87% vs 74%p = 0.0096

CHOP R3 TTF NR vs 31 mop = 0.0006

2 yr 95% vs 90%p = 0.016

CVP R4 TTP 34 mo vs 15 mop < 0.0001

4 yr 83% vs 77%p = 0.0290

Rituximab-based induction therapy: Conclusions

R-Chemo yields superior results to chemotherapy in four prospective randomised trials

The FLIPI predicts outcome in all studies─ Prognosis was worse with a high FLIPI score─ Majority of patients with poor prognosis will relapse

within 4–5 years─ There does not seem to be a TTP/PFS ‘plateau’

of any subgroup in any trial yet

24

Hiddemann W, et al. Blood 2006; 108:Abstract 483.

Su

rviv

al p

rob

abil

ity

Time (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 36 48 60 72

p < 0.0001

Number of patients at risk:NHL 1996NHL 2000

538 485 457 419 386 332794 621 440 250 108 8

2420

125 46 0

84 96 108 120

GLSG study NHL 2000

GLSG study NHL 1996

Overall survival improvement with rituximab in FL

Rituximab maintenance after CVP in untreated indolent NHL: ECOG 1496 study design

Phase III trial of CVP ± rituximab maintenance401 patients with previously untreated

indolent NHL, 322 randomised

Observation

Rituximab maintenance • 375 mg/m2 q1wk 4• q6mo 4

RANDOMISED

PR, CR or SD

CVP 6–8 cycles

p = 0.0000003

Median PFS from randomisation: 15 mo vs 61 mo

Years from maintenance randomisation

Rituximab maintenance (n = 120)

Observation (n = 117)

Rituximab maintenance therapy significantly prolongs PFS in FL

0 1 2 3 4 5 60.0

0.2

0.4

0.6

0.8

1.0

Pro

bab

ilit

y

Hochster H, et al. Blood 2005; 106:Abstract 349.

Rituximab monotherapy induction and maintenance in first-line treatment of FL

Patients(n)

Median FU

(months)

Induction regimen

Maintenance schedule

Median PFS/EFS(months)

Minnie PearlPhase II1

38† 55 R-Mono* q6mo x 4* PFS: 52

SAKK 35/982

64 36 R-Mono* q2mo x 4EFS: 19 vs 36

p = 0.009

1. Hainsworth JD, et al. Blood 2003; 102:Abstract 1496.2. Ghielmini M, et al. Blood 2004; 103:4416–4423.

* 375 mg/m2 rituximab once weekly x 4† Follicular lymphoma patients onlyFU = follow-up

Rituximab maintenance q2mo x 4

PD, SD off study

Long maintenance

Rituximab375 mg/m²weekly x 4

Short maintenance

RPR, CR

Rituximab maintenance q2mo until relapse (maximum 5 years)

SAKK 35/03 study: Efficacy of extended rituximab maintenance therapy in FL

SDPD

off study

Indolent NHLstages III–IV,

untreated

Rituximab maintenance

therapy 1 x q8wk

for 24 months

Observation

8 x rituximab+

8 x CVPor 6 x CHOP or 6 x FCM

CR, PR

PRIMA study: Efficacy of rituximab-based induction and

maintenance in first-line indolent NHL

RANDOMISE

RiCHOP trial: Efficacy of ASCT followed by rituximab

maintenance in indolent NHL

Rituximab maintenance

1 x q8wk for 24 months

CR, PRR-CHOP x 6 + R x 2

HDTASCT

RANDOMISE

SDPD

off study

N > 600 patients with indolent FL (< 65 years old). Study start 2007

A note of caution! Incidence of hepatitis B reactivation with rituximab

Out of 456 patients, 32 were Hep B positive ─ 14 received rituximab monotherapy ─ 18 received rituximab plus chemotherapy

Group Patients (n) HBsAg HBsAb HBcAbLiver event

(%)

A 12 – + + 3 (25)

B 6 – – + 2 (33)

C 8 – Not available + 2 (25)

D 6 + Variable Variable 4 (66)

A total of 5 patients developed liver failure (15%)

Hanbali A, et al. Blood 2006; 108:Abstract 2766.

But…prophylactic lamivudine can reduce the incidence of hepatitis during chemotherapy

Non-randomised comparison of lymphoma patients treated with prophylactic lamivudine during chemotherapy with historical controls─ 100 mg was administered daily for up to 64 weeks

% Control(n = 116)

% Lamivudine

(n = 40) p-value

Hepatitis incidence during chemo 52 18 0.000

Disruption in chemo administration 37 10 0.001

Li Y, et al. Cancer 2006; 106:1320–1325.

Lamivudine prophylaxis reduced the incidence of hepatitis

Outstanding questions in first-line therapy for FL

Do more intensive therapies yield superior results than R-CVP?─ If so do ALL patients require such therapy, or only

poor prognosis patients? ─ Which component provides superior results?

Anthracycline, interferon or both?Does maintenance have a role in first-line FL?─ PRIMA trial to provide evidence

Do PBSCT or other approaches have a role in first-line therapy?