Lymphomes diffus à grandes cellules B en rechute -...

Lymphomes diffus à grandes cellules B

en rechute

C. Thieblemont

DES Hématologie, 15 janvier 2016

Mr C. , 46 ans

• 02/2013: DLBCL – stade II, aaIPI 1(LDH)

– 1ère ligne: R-CHOP21 x6: RC, TEP neg

• 01/2014: Orchidectomie: DLBCL – stade IV (péritoine, rate, adp coelio-mésentériques, mediastin, sus clav

et axillaire, BOM neg) LDH>N, PS:0. aaIPI: 2

• Questions: – Demandez-vous des compléments d’analyses histologiques à votre

ana-path? Si oui, lesquels?

– Quelle stratégie thérapeutique proposez-vous? • Quel est le meilleur traitement de rechute?

• Associez-vous du Rituximab ou non

– Inclut-elle une autogreffe ou allogreffe ou les 2?

– Votre collègue de Lille vous dit : on a une nouvelle drogue qui cible la cellule au niveau épigénétique. Les résultats sont vraiment incroyables. Discute avec ton patient ! De toute façon il est réfractaire à la chimio…!

DLBCL WHO classification - 2008

Diffuse large B-cell lymphoma (DLBCL), not otherwise specified (NOS) Common morphologic variants

Centroblastic

Immunoblastic

Anaplastic

Molecular subgroups Germinal-centre B-cell-like (GCB) Activated B-cell-like (ABC)

Immunohistochemical subgroups CD5-positive DLBCL

Germinal-centre B-cell-like (GCB) Non-germinal-centre B-cell-like (Non-GCB)

DLBCL subtypes

T-cell/histiocyte-rich large B-cell lymphoma

Primary DLBCL of the CNS

Primary cutaneous DLBCL, leg type

Epstein-Barr virus–positive DLBCL of the elderly

Other lymphomas of large B cells

Primary mediastinal (thymic) large B-cell lymphoma

Intravascular large B-cell lymphoma

DLBCL associated with chronic inflammation

Lymphomatoid granulomatosis ALK-positive DLBCL

Plasmablastic lymphoma

Large B-cell lymphoma arising in HHV8-associated multicentric Castleman disease

Primary effusion lymphoma

Borderline cases

between DLBCL and Burkitt lymphoma

between DLBCL and classical Hodgkin lymphoma

DLBCL = One Shot Cancer

• Only patients who reached a CR with the first line chemotherapy have a chance to be cured

– Most true (with positive PET scan) PR progress

• A minority of patients who progressed responded to salvage chemotherapy and will be transplanted

– Only 40% of transplanted patients did not relapse

Objective of 1rst line treatment

Reach a CR and prevent a relapse

Hétérogénéité clinique

R-CHOP

B Coiffier ICML 2008 – 7400 patients

60%

20%

20%

Suvie globale

Refractory (resistant) DLBCL

= by a less than 50% decrease in lesion size with treatment in the absence of new

lesion development

Progressive disease

= - appearance of any new lesion

- or a 50 percent increase in the longest diameter of a previously identified lesion

- or new/recurrent involvement of the bone marrow

Relapsed disease

= Appearance of any new lesion after attainment of an initial complete remission

refractory /relapse DLBCL definition

J. Friedberg – uptodate dec 2015

Définition : « Refractory DLBCL »

R-CHOP

Thieblemont C & Gisselbrecht, 2009

Refractory :

- Relapsed < 1 year

- No response to R-CHOP

Mr C. , 46 ans





• Questions: – Demandez-vous des compléments d’analyses histologiques à

votre ana-path? Si oui, lesquels?





Histology - DLBCL - relapse

ABC DLBCL GCB DLBCL

Bio CORAL - Cell of origin - GEP

From ABC and GCB

signatures Alizadeh et al.

Nature 2000

45% 55%

Thieblemont C et al, J Clin Oncol 2012

Histology - DLBCL - relapse

Bio CORAL - FISH analysis

Patients analysed (n=249) GC

Hans

nonGC

Hans

n

analysed

%

Present

(%)

Present

(%)

bcl2/18q21 breakpoint 161

Present

39 67 33

bcl6/3q27 breakpoint 161

Present

19 41 59

cmyc/8q24 breakpoint 161

Present

Complex (double hit, triple hit)

17

(75)

63 37 GC ABC

100 0

Cuccuini W, et al, Blood 2013

Relapsed DLBCL : biopsy

Friedberg J et al. Hematology 2011

Mr C. , 46 ans











Thieblemont C. et al. Current Oncology Reports 2009, 11:386–393


R ICE

R DHAP

R ESHAP

R ASHAP

R GEMOX

R ADOX

R-CHEMO – Phase II

ORR = 45 -90%

CR = 10-75%

Rituximab in salvage

R CHEMO vs CHEMO FOR SALVAGE

Vellenga E et al (Blood. 2008;111: 537-543)

RITUXIMAB improves DHAP-VIM-DHAP

Response rate 75% vs 54%

Overall survival

Failure free survival Failure free survival Patients with CR/PR and BEAM/SCT

CORAL trial: RICE v DHAP

Relapsed/

refractory

DLBCL

n = 396

R

A

N

D

O

M

I

S

E

R-ICE

x 3

R-DHAP

x 3

ASCT BEAM

SD, PD

off study

PR, CR

R

A

N

D

O

M

I

S

E

Rituximab 375 mg/m2

q2mo x 6

Observation only

Gisselbrecht C, et al. J Clin Oncol 2010; 28:4184–4190.

R-DHAP = rituximab, dexamethasone, high-dose cytarabine, cisplatin

R-ICE = rituximab, ifosfamide, carboplatin, etoposide

Which salvage regimen is the best?

Place of immunotherapy

Post-transplantation?

R-ICE Day 1 2 3 21

Rituximab

375 mg/m²

VP16

100 mg/m²

Carboplatin AUC (5)

max 800

Ifosfamide 5 g/m²

Continous infusion 24 h

+ Mesna

+ GCSF 5 µg/kg

R

I

C

E

C. Gisselbrecht et al JCO 2010

R-DHAP Day 1 2 3 4 21

Rituximab

375 mg/m²

Cisplatin

100 mg/m²

Cytosine Arabinoside

2000 mg/m²/12H

Dexamethasone

40 mg (total dose)

C. Gisselbrecht et al JCO 2010

R-ICE R-DHAP

N 239 % N 230 %

Response including deaths COMPLETE RESPONSE

57

24

60

26

UNCONFIRMED COMPLETE RESPONSE 30 13 25 11

PARTIAL RESPONSE 65 27 63 27

STABLE DISEASE 26 11 26 11

PROGRESSIVE DISEASE 46 19 39 17

DEATH 7 3 11 5

PREMATURE WITHDRAWAL / NOT EVALUATED/missing

8 2 6 2

Total 239 100 230 100

Response after induction treatment including

deaths for all patients (induction ITT)

Gisselbrecht C et al. ASCO 2011

63 .6 % 64.3 %

Arm of treatment

Nb patients

Nb responders with successful

mobilization MARR

(%)

R-ICE 239 123 51.5

R-DHAP 230 130 56.5

52.3% 54.5 %

CORAL

C. Gisselbrecht et al. JCO 2010

R-ICE and R-DHAP : similar activity

47%

51% 42%

31%

PFS OS

At 3 years

Multivariate analysis for survival

p value

Prior rituximab exposure and early relapses characterized a poor prognosis subgroup.

Poor results: Response Rate < 50%, PFS 30%

Gisselbrecht C et al. ASCO 2011

PFS EFS OS

Prior rituximab 0.004 0.001 0.07

Relapse < 12 months < 0.0001 <0.0001 <0.0001

sIPI > 1 < 0.0001 <0.0001 <0.0001

Treatment arm 0.3 0.3 0.2

Gisselbrecht C et al. JCO 2010;28:4184-4190

Prior R and

Relapse<12 months

The Coral Study

The Influence Of Prior R And Time To Relapse

R-DHAP R-ICE

p = NS p = 0.01

Progression Free Survival

p = 0.06 p = NS

Overall Survival

GC

GC

ABC

ABC

GC

ABC

ABC

GC

5 phase III (most in young pts)

1st author Drug N pts ORR Median OS

Median PFS

Median DoR

Aribi ESHAP GDP

48 48

55% 63%

3y: 11% 3y: 20%

Cuccuini MYC+ R-ICE/R-DHAP MYC_ R-ICE/R-DHAP

28 133

50% 69%

4y: 29% 4y: 62%

4y: 18% 4y: 42%

Gisselbrecht R-ICE/R-DHAP + auto 396 63% 3y: 49% 3y 37%

Pettengell Pixantrone Comparator

68 69

37% 14%

10.2 m 7.6 m

5.3 m 2.6 m

Vellenga DHAP + auto R-DHAP + auto

112 113

54% 75%

2y: 52% 2y: 59%

2y: 31% 2y: 52%

Conclusions: - Salvage with rituximab is superior - MYC+ at time of relapse are worse - At time of first progression, curative option is recommended - Pixantrone might be a good option in multiple PD

Mr C. , 46 ans

• 02/2013: DLBCL – stade II, aaIPI 1(LDH) – 1ère ligne: R-CHOP21 x6: RC, TEP neg

• 01/2014: Orchidectomie: DLBCL

– stade IV (péritoine, rate, adp coelio-mésentériques, mediastin, sus clav et axillaire, BOM neg) LDH>N, PS:0. aaIPI: 2

• Questions: – Demandez-vous des compléments d’analyses histologiques à votre ana-path?

Si oui, lesquels?

– Quelle stratégie thérapeutique proposez-vous? • Quel est le meilleur traitement de rechute? • Associez-vous du Rituximab ou non



HDT + ASCT in eligible patients

Philip T, et al. NEJM 1995

Gisselbrecht C, et al. JCO

2011

PARMA STUDY EFS and OS according to treatment

Philip T, et al. N Engl J Med 1995;333:1540–5

Eligible <60 years old

Second line : DHAP x 2 (no R)

EFS OS

MEDIAN FOLLOW-UP : 8.3 yrs

PARMA STUDY

tell us other informations

C Guglielmi et al J.C.O. 1998

• ASCT works only in chemosensitive disease

• ASCT will not benefit patients who relapse

within 12 m of their diagnosis

ORR ( 2 DHAP) 40% 69%

5y PFS 30% 50%

Time to relapse < 12m >12m

Allograft?

Van Kampen JCO 2011

Relapse after autologous EBMT retrospective analysis

101 patients

37 Myeloablative 64 Reduced Intensity

Indication to discuss :

- Late relapse

- Chemosensitive patients

Mr C. , 46 ans











Novel therapies for lymphoma

Modified from: Younes, Nat. Rev. Clin. Oncol. 8, 85–96 (2011)

Novel therapies for lymphoma

Modified from: Younes, Nat. Rev. Clin. Oncol. 8, 85–96 (2011)

Novel Monoclonal Antibodies

Small drugs targetting

signaling pathways

Salvage regimens

• Lot of phases II, retrospective analyses and a few phases III

• PubMed: 84 studies

– 2 phase I

– 51 phase II

– 5 phase III

– 24 retrospective analyses

• Number of patients: 10 to 533

Salvage regimens

• Endpoints

– ORR in 92%

– OS in 68%

– PFS in 87%

– DFS in 11%

– DoR in 31%

• Limited median follow-up

18 single agent phase II 1st author Drug N pts ORR Median

OS Median

PFS Median

DoR

Borchmann Pixantrone 24 27% 106 d

Buckstein Sunitinib 15 0 2.2 m 3.4 m

Coiffier Ofatumumab 81 13% 2.6 m 9.5 m

Coiffier Rituximab 54 31% >105 d

Crump Vorinostat 18 6% 3: 17%

De Vos Dacetuzumab 46 9% 36 d

Friedberg Fostamatinib 23 23% 2.7 m

Macpherson Lip. doxorubicin 18 23% 34 w 16 w

Morschhauser 90Y-ibritumomab 94 52% 21.4 m 5.9 m

Morschhauser Obinituzumab 40 32% 2.7 m 9.8 m

Rizzieri Paclitaxel 34 37%

Robertson Enzastaurin 55 22% 4: 15%

Rothe Rituximab 21 8.6 m 3.8 m

18 single agent phase II (2) 1st author Drug N pts ORR Median

OS Median

PFS Median

DoR

Smith Temsirolimus 32 28% 7.3 m 2.6 m 2.4 m

Tobinai Rituximab 68 35% 52 d 245 d

Vose Lenalidomide 134 27% 3.7 m 12 m

Wiernick Lenalidomide 29 35% 4 m 6.2 m

Witzig Lenalidomide 217 28% 2.7 m 4.6 m

Conclusions - Maximum response rate: 30-40% - Rituximab same ORR and PFS in different studies - Median PFS: less than 6 months - Median DoR: 6-12 months

9 two drugs phase II

1st author Drug N pts ORR Median OS

Median PFS

Median DoR

Evens Gemcitabine – bortezomi

16 10% 6.3 m 1.6 m

Fayad R – inotuzumab Ozo. 77 74% 2y: 69% 17.1 m 17.7 m

Ohmachi R – bendamustine 59 63% 6.7 M

Papageorgiou Gemcitabine – vinorelbine

22 50% 12.9 m 8.1 m

Strauss R – epratuzumab 15 47% 5.7 m 6.4 M

Vacirca R – bendamustine 48 46% 3.6 m 17.3 m

Wang R – lenalidomide 45 33% 10.7 m 3.7 m 10.2 M

Younes Paclitaxel – topotecan 66 48% 6 m

Zinzani R – lenalidomide 23 35% 1.5 y

Conclusions on this analysis

• Single agent:

– Response rate between 20% to 30%

– Median PFS less than 6 months

• Two drugs: slightly better results

New drugs for patients non eligible for HDT / ASCT

Germinal center

B cell-like (GCB)

Activated

B cell-like (ABC)

Cell of Origin

Oncogenic

Mechanisms

Clinical

Outcome

Germinal center

B cell

Post-Germinal

Center B cell

•t(14;18)

translocation of BCL-

2

•Chr. 2p amplification

of c-rel locus

Constitutive

activation

of NF-kB

pathway

Favorable

60% 5-yr survival

Poor

35% 5-yr survival

Jeelall YS et al. Immunol Cell Biol. 2011

NF-KB pathway

BCR signalling cascade is

generally antigen- dependent

Jeelall YS et al. Immunol Cell Biol. 2011

Hallmark of ABC-like DLBCL : constitutional NF-KB activation

Oncogenic gene mutation

•CARD11 10%

•CD79A/B 20%

•A20 30%

•MYD88 39%

Ngo VN, Nature 2006 - Lenz G, Science 2008 Davis RE, Nature 2010- Compagno M, Nature 2009

Inhibitors of Tyrosine kinase in DLBCL

Modified from Wiestner, JCO 2013. nucleus

Oral drug

Fostamatinib disodium R406 Rafetinib

dasatinib

IPI-145

iBTK

Inhibitors of Tyrosine kinase in DLBCL

Modified from Wiestner, JCO 2013.

iBTK

nucleus

BTK inhibitor PCI-32765 induces tumor

regression in relapsed/ refractory ABC DLBCL

Wilson W et al. ASH 2012, Abstract 623, ASH Annual Meeting, Atlanta, 10-13 December 2012

PCI-32765 at a fixed dose of 560 mg po once daily x 35 days (1 cycle).

Evaluation after 2 cycles

- Tumoral cells

- Environment

Cancer =

Immune Environment

New immunomodulartory AB

Immunomodulators

Lenalidomide, …

• Monoclonal Abs activate stimulatory receptors or block

inhibitory receptors expressed on the surface of immune cells

and thereby enhance their function

Cell Receptors Mechanisms of action

T cells CD137

OX40

CTLA-4

PD-1

adaptive immune response

Dendritic cells CD40 antigen presentation

NK cells KIR innate immune

MoAbs targeting immune cells

Immunomodularoty ABs lymphoma

Clinical trials

R. Houot et al., 2011

Take home messages – relapse / refractory DLBCL

1. Situation péjorative

2. Confirmer la rechute avec une biopsie

3. Le patient est – il éligible pour un traitement intensif avec autogreffe?

4. Si ce n’est pas le cas , traitement de rattrapage – dose conventionnelle ou

5. Evaluation du patient pour un traitement de phase précoce

60% 40%


ICE

DHAP..

What Else?

± ASCT

R-ICE

R-DHAP

R- Other

± ASCT/

Past Present Future

increasing cure

Dense- R

New molecules

(e.g. new anti CD 20, GA 101, antiBTK, CD40…. anti-angiogenics

lenalidomide)

± ASCT/ RIC allo

Better tolerability

PET-evaluation

OS benefit Prolonging OS?

TREATMENT OPTIONS for RELAPSED / REFRACTORY DLBCL

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