transformed lymphoma: biology and treatment - … lymphoma: biology and treatment silvia montoto...

Transformed lymphoma:biology and treatment

Silvia MontotoCentre for Haemato-Oncology

Barts Cancer Institute

www.cancer.qmul.ac.uk

Years

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

0.00

0.25

0.50

0.75

1.00

N =330

Years

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

0.00

0.25

0.50

0.75

1.00

N =330

40

50

60

70

80

90

100

%V

iability


Observation Experiments Treatment

0

10

20

30

0.01 0.1 1 10 100 1000

Concentration (uM)

Information

Problem

Solution


Histological transformation (HT)

• Frequent event

• Change in histology

The problem

• Change in clinical course

• Poor prognosis


Impact of HT on outcome

Survival from HT

0.50

0.75

1.00

Not transformed =237

Overall survival according to HT

0.75

1.00

p= 0.3

Survival from HT vs survival from 1st

relapse in de novo DLBCL

The problem

Years0 2 4 6 8 10121416182022242628303234

0.00

0.25

0.50 Not transformed =237

Transformed = 88

0 10 20 30

0.00

0.25

0.50

Transformed follicular

de novo DLBCL

p= 0.3


How to improve the outcome of tFL

• Reduce the risk of HT

– What patients are at high risk of HT?

– Does the initial management impact on the risk ofHT?

The problem

• Improve the response at the time of HT

– Does initial management impact on the outcomeafter HT?

– What is the best treatment at the time of HT?


Treatment of tFL• Heterogeneous population:

– Number of previous treatment lines

– Type of previous treatment

• Investigational trials:

The problem

• Investigational trials:

– Excluded from FL studies

– Excluded from DLBCL studies

• Data extrapolated from DLBCL studies


tFL and DLBCLThe information

Davies A et al, Br J Haematol, 2006


Impact of initial management on the risk of HT

Series Risk of HT

Hubbard (1982) RT ↑ risk of HT

Acker (1983) No impact

The information

Horning (1984) No impact of expectant management

Giné (2006) No impact of CB-CVP vs CHOP

Montoto (2007) Expectant management ↑ risk of HT


Impact of initial therapy on the risk of HTThe information

Prospective randomised study:PCOP vs PACOP

The addition of doxorubicin doesNOT influence the risk of HT


Lepage et al, HematologicalOncology, 1990

Al-Tourah et al, JCO, 2008

Impact of W&W on the risk of HTThe information

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

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

No data

No diffs riskHT


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

Chemo riskHT

Treatment for HT

= treatment for DLBCL (in most cases) CHOP-R

BUT…CHOP-R already given at the time of HT

The information

AND…outcome of tFL DLBCL at relapse

2nd line chemotherapy for DLBCL?


Treatment for HTSeries Treatment at HT SFT (median)

Hubbard (1982)63% combinationchemotherapy

11 mo

Yuen (1995) 60% doxo-containing chemo 22 mo

The information

Bastion (1997) 58% CHOP-like 7 mo

Giné (2006)23% CHOP

57% VIA, MINE/ESHAP1.2 yrs

Montoto (2007) 73% doxo-containing chemo 1.2 yrs


Treatment for HT: CHOP-RThe information

1.0

.8

.6

CHOP-R (N= 23) 5yr OS: 61%

CHOP-like (N= 85) 5yr OS: 33%

Courtesy of Joseph M Connors and Abdul Al-Tourah, unpublished data


14121086420

.4

.2

0.0

CHOP-like (N= 85) 5yr OS: 33%

p= 0.01

Improvement over timeThe information


Tam et al, ICML-10 Lugano 2008

• Chemoterapy-naïve patients• Rituximab at HT

Non-CHOP-R treatments for HT

Treatment Series N

(tFL/total)

Previous

rituximab

RR HDT EFS/TTF

MINE/ESHAP Rodriguez

1995

14/92 - 64%

(HT)

No Median TTF: 8mo (HT)

Mini-BEAM Girouard 18/104 - 50% 37% -

The information

Mini-BEAM Girouard

1997

18/104 - 50%

(HT)

37% -

R-EPOCH Jermann

2004

18/50 8/50 68% 61% Median EFS: 12mo (HT)

No detailed data on results with ICE/R-ICE in patients with HT


Non-CHOP-R treatments for HT: RIT

Series N (tFL/total) RR CR PFS

(median)

OS

Kaminsky

2000

14/59 79% 50% 14 mo 4yrs: 62%

Vose 10/47 60% 50% RD: 12 mo Median: 36 mo

The information

Vose

2000

10/47 60% 50% RD: 12 mo Median: 36 mo

Davies

2004

7/41 71% 28% RD: 41 mo NS


Non-CHOP-R treatments for HT: RITThe information

Kaminsky et al, Blood, 2000


Non-CHOP-R treatments for HT:lenalidomide

The information

Patients N RR CR/CRu PFS

(median)

All patients 33 45% 21% 5 mo

Czuczman et al, BJH, 2011


tFL 23 56% 26% 8 mo

tCLL/SLL 7 0 0 2 mo

Treatment for HT: autologous SCT

The information

Williams et al, JCO, 2001


Treatment for HT: autologous SCTThe information

0.50

0.75

1.00

Pro

babil

ity

FL (N: 50)

Montoto et al, ICML-2011


Time (years)0 5 10 15

0.00

0.25

p: NS

Pro

babil

ity

tFL (N: 30)

Treatment for HT: autologous SCTThe information

Series N RD/PFS for tNHL(median)

5-yr PFS

Williams (JCO 2001) 50 13 mo 30%

Sabloff (BBMT 2007) 23/138 11 mo 25%


Montoto (ICML-11) 30/80 7 mo* 45%

Eide (BJH 2011) 30 26 mo** 32%

* 16 relapse: 15 Bx (5 FL, 8 DLBCL, 2 NK); ** 13 relapse: 7 Bx (4 FL, 3 DLBCL)

Treatment for HT: allotransplantThe information

Rezvani et al, JCO, 2008


Thomson et al, JCO, 2009

Open questions in the treatment of HT

• Do doxo-containing regimens decrease the

risk of HT?

• Do patients NEED doxo-containing regimens

The information

at the time of HT?

• Is HDT necessary for all patients with HT?

• Can something different be done?


Answers

• Risk of HT as an end-point in randomised

trials

• Include HT in trials for ‘aggressive’

lymphomas

: how to get themThe solution

lymphomas

• Search for specific molecular therapeutic

targets


Years

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

0.00

0.25

0.50

0.75

1.00

N =330

Years

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

0.00

0.25

0.50

0.75

1.00

N =330

40

50

60

70

80

90

100

%V

iability


Observation Experiments Treatment

0

10

20

30

0.01 0.1 1 10 100 1000

Concentration (uM)

What we do at Barts:

Treat as DLBCL:• R-CHOP (if no prior doxo)• 2nd line chemo for DLBCL• HDT unless:

little prior treatmentlocalised disease (?)

Maintenance rituximab for HT?

HT is an exclusion criteria in:

• Studies of maintenance after first-line:

Ghielmini, Blood 2004

Hochster, JCO 2009

The information

Salles, Lancet 2011

• Studies of maintenance at relapse:

Ghielmini, Blood 2004

Van Oers, Blood 2006


Maintenance rituximab for HT:maintenance rituximab in DLBCL?

The information

After CHOP-R After HDT in first-line


Haberman et al, JCO, 2006 Haioun et al, Annals of Oncology, 2009

transformed lymphoma: biology and treatment - … lymphoma: biology and treatment silvia montoto...

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