www.ebmt.org #EBMT2015

STANDARD THERAPY OF FL AND THE ROLE OF AUTOLOGOUS STEM CELL TRANSPLANTATION

Silvia Montoto

Haemato-oncology, St Bartholomew’s Hospital, London, UK

11th Educational Course LWP. Treatment of malignant lymphoma: state of the art

and role of stem cell transplantation. Heidelberg 24-26 September 2015

2

• To review the standard management of patients with follicular lymphoma (FL)

• To understand the indications for autologous stem cell transplantation (ASCT) in FL

Objectives

3

• Long survival

• Multiple relapses

• Risk of histological transformation

• Incurable (with conventional treatment)

Natural history and clinical course of FL

Barts 1997-2007

4

Improvement in the outcome of patients with FL

SBH, 1977-2007

Years 0 10 20 30

0.00

0.25

0.50

0.75

1.00

1977-1984

1985-1996

1997-2007

p=0.0025

1987–1993

1976–1986

1960–1975

100

60

40

20

0

80

0 5 10 15 20 25 30

Adapted from Horning S, Semin Oncol 1993

5

Follicular lymphoma: objectives of first-line treatment

• Cure?

• Reduction in the risk of histological

transformation?

• Symptomatic improvement

6

Expectant management

Ardeshna et al, Lancet, 2003

7

Expectant management

• 60-75% of patients require treatment at a median time of 2-3 yrs

• In 20% of patients in the observation arm treatment was started by ‘physician’s decision’ (Brice et al, JCO, 1997)

8

Expectant management and risk of histological transformation: randomised studies

• Chlorambucil vs W&W Ardeshna et al, Lancet, 2003

• Prednimustine vs IFN-2 vs W&W Brice et al, JCO, 1997

• ProMACE-MOPP vs W&W Young et al, Semin Hematol, 1988

No data

No diffs risk HT

Chemo risk HT

9

Expectant management: Watch and wait study

Ardeshna et al, Lancet Oncol , 2014

(A) Expectant management

(B) Rituximab (C) Rituximab +

maintenance

Randomisation

10

Expectant management: Watch and wait study

Ardeshna et al, Lancet Oncol , 2014

11

• Does not impair OS in the pre-rituximab era

• No evidence in randomised trials that W&W increases the risk of

histological transformation

• Rituximab prolongs PFS in comparison with W&W

• The majority of the patients need treatment

• Still STANDARD in asymptomatic patients

W&W: summary of data

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Rituximab + chemotherapy

Series Follow-up RR/CR PFS/EFS OS

Hiddemann/Buske et al,

2005/2008

58 mo R-CHOP> CHOP (RR, not CR)

R-CHOP> CHOP R-CHOP> CHOP

(p=0.049)

Herold et al,

2007

47 mo R-MCP> MCP R-MCP> MCP R-MCP> MCP

Marcus et al,

2008

53 mo R-CVP> CVP R-CVP> CVP R-CVP> CVP

Salles et al,

2008

5 yrs R-CHVP-I> CHVP-I R-CHVP-I> CHVP-I =

Forstpointner et al,

2004

18 mo R-FCM> FCM

R-FCM> FCM =

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Symptomatic patients: more is not better (pre-rituximab)

179 patients/Barcelona (1977-1997)

0 2 0 4 0 6 0 8 0 1 0 0

C H O P

C V P

Chlorambucil

10-yr overall survival Complete response

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Single agent vs combination chemotherapy

Series Regimens CR PFS/EFS OS

Lister, 1978 CB vs CVP CVP> CB - -

Hoppe, 1981 CF vs CVP vs RT CF = CVP = RT CF = CVP = RT CF = CVP = RT

Kimby, 1994 CB-P vs CHOP CHOP> CB-P CHOP = CB-P

CHOP = CB-P

Peterson, 2003 CF vs CHOP-B CF = CHOP-B CF = CHOP-B CF = CHOP-B

Hagenbeek, 2006

Flu vs CVP Flu> CVP

Flu = CVP

Flu = CVP

….before rituximab

15

Single agent vs combination chemotherapy in the R-era

Rummel et al, Lancet, 2013

16

So, why or when combination chemotherapy?

• Better response rate?

• Longer response duration?

• High-risk FLIPI?

• Anthracyclines to reduce the risk of HT?

• Faster response

17

Do we need doxorubicin to reduce the risk of transformation?

Al-Tourah et al, JCO, 2008

Randomised study: PCOP vs PACOP The addition of doxo does NOT influence the risk the HT Lepage et al, Hematological Oncology, 1990

18

Even better

Salles et al, Lancet, 2011

* * * *

19

Conclusions: initial management of FL in the rituximab era

• Asymptomatic patients: expectant management

• Symptomatic patients: R-bendamustine/ R-CHOP depending

on:

• Clinical behaviour

• Urgency to obtain a response (bulky, compression)

• But always: + rituximab!!

• + maintenance

• Plan ahead (patients might still need a transplant!)

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Relative survival of patients with FL

Swenson et al, JCO, 2005

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HDT-ASCR in first-line in FL

PFS/EFS OS

GLSG

(Lenz et al, 2004)

Chemo<HDT -

GOELAMS

(Deconinck et al, 2006;

Gyan et al, 2009)

Chemo<HDT Chemo=HDT

GELA

(Sebban et al, 2006)

Chemo=HDT Chemo=HDT

GITMO/IIL (Ladetto et al, 2008)

R-Chemo<R-HDT R-Chemo=R-HDT

22

HDT-ASCR vs chemotherapy in relapsed FL

Schouten et al, JCO, 2003

23

HDT-ASCR in FL: long follow-up

Montoto et al, Rohatiner et al, Kornacker et al,

Leukemia, 2007 JCO, 2007 Annals of Oncol, 2009

24

Treatment of FL in 2015

• Does prior treatment with rituximab impair the results of HDT-ASCR?

• Does HDT-ASCR offer any advantage in patients treated with rituximab?

25

Impact of prior rituximab on EFS and OS

El-Najjar et al, Annals Oncol, 2014

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Impact of prior rituximab on EFS and OS

El-Najjar et al, Annals Oncol, 2014

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Impact of rituximab and HDT-ASCR at relapse

p=0.002 p=0.052

p=0.005 p=0.052

No prior rituximab Prior rituximab

Le Gouill et al, Haematologica, 2011 -- - - transplanted patients non-transplanted patients

EFS EFS

OS OS

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Is HDT-ASCR + rituximab better than HDT-ASCR?

Rituximab maintenance

(375mg/m2 every 2 months x 4)

Rituximab in-vivo purging

Rituximab in-vivo purging

Rituximab maintenance

(375mg/m2 every 2 months x 4)

Group A Group B Group C Group D

AUTOLOGOUS STEM CELL TRANSPLANT

Observation Observation

No purging No purging

RANDOMISATION

Pettengell et al, JCO, 2013

Maintenance vs observation: 5-yr PFS 59% vs 43% (p= 0.02)

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Is HDT-ASCR + rituximab better than rituximab?

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EBMT FL transplant consensus: objective and method

• To define indications for HSCT in patients with FL in the rituximab era using a consensus method

Consensus methods:

• Used when no evidence-based data is available

• To obtain expert opinion in a systematic manner

• Transparent and explicit methods of reaching consensus

• To allow participants to express their views impersonally

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Final results: consensus IN FAVOUR (1st line)

Disagree Neither agree nor disagree

Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly (7) (8) (9)

HDT-ASCR is NOT an appropriate treatment option to consolidate 1st remission in patients responding to immuno-chemotherapy, outside the setting of clinical trials 0 0 0 0 0 0

1 (8%)

3 (25%)

8 (67%)

32

Final results: consensus AGAINST (1st line)

Disagree Neither agree nor disagree

Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly (7) (8) (9)

HDT-ASCR is an appropriate treatment option to consolidate 1st remission in patients with high-risk FLIPI at diagnosis

HDT-ASCR is an appropriate treatment option to consolidate 1st remission in patients with grade 3a FL

6 (50%) 5

(42%)

1 (8%)

0 0 0 0 0 0

8 (67%)

3 (25%)

1 (8%)

0 0 0 0 0 0

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Final results: consensus IN FAVOUR (relapse)

Disagree Neither agree nor disagree

Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly (7) (8) (9)

In patients in 1st relapse with chemo-sensitive disease, HDT-ASCR is an appropriate treatment option to consolidate remission

Remission consolidation with HDT-ASCR is an appropriate treatment option in 1st relapse in patients with a short response duration (<3 years) after immuno-chemotherapy

Remission consolidation with HDT-ASCR is an appropriate treatment option in 1st relapse in patients with high-risk FLIPI at relapse

34

Final results: consensus IN FAVOUR (relapse)

Disagree Neither agree nor

disagree Agree

Strongly Disagree Moderately (1) (2) (3)

4 5 6 Moderately Agree Strongly (7) (8) (9)

Remission consolidation with HDT-ASCR is an appropriate treatment option in patients in second or subsequent relapses with chemo-sensitive disease

0 0 0

1 (8%)

0 0

3 (25%)

6 (50%)

2 (17%)

35

Final results: NO consensus

Disagree Neither agree nor

disagree Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly (7) (8) (9)

Remission consolidation with HDT-ASCR is NOT an appropriate treatment option in 1st relapse in patients with a long response duration (longer than 3-5 years) after immuno-chemotherapy

Remission consolidation with HDT-ASCR is NOT an appropriate treatment option in 1st relapse in patients with low-risk FLIPI at relapse

Remission consolidation with HDT-ASCR is NOT an appropriate treatment option in 1st relapse in rituximab-naïve patients

0

2 (17%)

2 (17%)

0 0 0

4 (33%) 2

(17%) 2

(17%)

0

3 (25%) 1

(8%)

2 (17%)

2 (17%)

0

3 (25%)

0

1 (8%)

0

3 (25%) 1

(8%) 0

2 (17%)

0

2 (17%)

2 (17%)

2 (17%)

36

Conclusions

• HDT-ASCR remains a strong treatment option at first

relapse in the rituximab and new drugs era:

• Response duration <3 years

• High-risk FLIPI at relapse

• No consensus on avoiding HDT-ASCR in low-risk patients

• HDT-ASCR is still an appropriate treatment option at

second/subsequent relapses in the rituximab and new

drugs era

37

Thank you!!

38

Expectant management in the rituximab era: ‘LymphoCare’ study

Friedberg et al, JCO, 2009

39

What chemotherapy with rituximab

Federico et al, JCO, 2013

40

Effect of maintenance in OS

Vidal et al, JNCI, 2011

41

Do all patients benefit from maintenance?

Kahl et al, JCO, 2014

Asymptomatic, low tumour burden, indolent NHL

42

Do all patients benefit from maintenance?

Kahl et al, J Clin Oncol, 2014

Median RD: 34mo

56 pts: re-treatment 1→ 61% resp, RD: 18mo

12 pts: re-treatment 2→ 67% resp, RD: 12mo

4 pts: re-treatment 3→ 0 resp

43

Final results: consensus IN FAVOUR

44

Final results: partial consensus IN FAVOUR

Disagree Neither agree

nor disagree Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly

(7) (8) (9)

Remission consolidation with HDT-

ASCR is an appropriate treatment

option in 1st relapse in patients

previously treated with rituximab 0 0 0 0

2 (17%)

0

2 (17%)

8 (67%)

0

Partial consensus IN FAVOUR

45

Final results: consensus AGAINST

46

Final results: partial consensus AGAINST (1st line)

Disagree Neither agree

nor disagree Agree

Strongly Disagree Moderately

(1) (2) (3) 4 5 6

Moderately Agree Strongly

(7) (8) (9)

HDT-ASCR is an appropriate

treatment option to consolidate 1st

remission in patients with PR after

immuno-chemotherapy

2 (17%)

3 (25%)

3 (25%)

1 (8%)

1 (8%)

1 (8%)

1 (8%)

0 0

Partial consensus AGAINST

47

Final results: NO consensus