Relapse in Diffuse Large B-cell Lymphoma Treatments

Relapse in Diffuse Large B-cell Lymphoma

Treatments

Corinne HAIOUN

Unité Hémopathies Lymphoïdes- CHU Henri MondorUniversité Paris Est Créteil

Sousse, May 2012

On February 10th, the merging of the GELA and the Goelams lymphoma groups resulted in the birth of the new group Lysa. Lysa, The Lymphoma Study Association

Rituximab effect

• Major breakthrough with the combination of rituximab with chemotherapy

• R-CHOP became the standard for the majority of patients

• But some patients continue to not respond to or relapse after R-CHOP

CD20+ DLBCL18–60 years

IPI 0,1Stages II–IV,I with bulk(n = 823)

MInT triallow risk

Pfreundschuh M, et al. Lancet Oncol 2006;7:379–91

Relapse rate10-20%

How many patients will relapse?

GELA trials In DLBCL with ASCT

< 60 yrs, 2–3 aaIPI factors

ACVBP

0 2 4 6

HD-MTX

CBVM

PBSCT

13

Wk

R-ACVBP

0 2 4 6

HD-MTX

BEAM

PBSCT

13

Wk

LNH98-3B

LNH03-3B

R

Rituximab

Observation

First introduction of rituximab

POOR RISK PATIENTS

Relapse rate20-30%

How many patients will relapse?

Low-risk patients High-risk patients

Low-risk patients High-risk patients

Relapse rate40-60%

R-CHOP studies > 60y :

Coiffier B, et al. ASCO 2007.

How many patients will relapse?

Median follow-up 7 yPFSEFS

DFS OS

Registry data also show these improvements

BCCA registry1 Czech Republic registry2

Time (years)

N = 292p < 0.0001

1.0

0.8

0.6

0.4

0.2

0

0 2 4 51 3

Time (months)

p = 0.0007

0 24 84 9612 36

Post-rituximab

Pre-rituximabProb

abili

ty

R-Chemo (n = 120)3-year OS: 88.7%

Chemo (n = 256)3-year OS: 73.2%

48 60 72

1. Updated from: J Clin Oncol 2005; 23:5027–5033.2. Blood 2005; 106:Abstract 2444.

1.0

0.8

0.6

0.4

0.2

0

6 7

GELA randomized studies

• LNH-87• LNH-93• LNH-98• LNH-03

1. Young, aaIPI=0 (F Reyes)• CHOP+RT vs. ACVBP

2. Young aaIPI=1 (P Morel)• Stratification on bcl-2 protein expression • ACVBP + seq. consol. or HDT

3. Young, aaIPI>1 (C Gisselbrecht)• ACVBP vs. early HDT

4. Elderly, IPI=0 (G Fillet)1. CHOP vs. CHOP + RT

• Elderly, IPI>0 (H Tilly)1. CHOP vs. ACVBP

8

Four generations of GELA studies

Total ACVBP Other arms

LNH-87 3114 1381 1733LNH-93 3830 1268 2562LNH-98 1377 585 792LNH-03 592 297 295

All 8913 3531 5382

Overall Survival: All patients7400 patients, 18-80 years old

10Coiffier B et al. EHA 2009

Studies with/without rituximab

Without rituximab With rituximab

Coiffier B et al. EHA 2009

Studies with/without rituximab

Without rituximab With rituximab

Percentage of patients in each groups

Without / With rituximab

No relapse 50 61Late relapse 13 13PR 8 10Early relapse 11 8No response 18 8

Coiffier B et al. EHA 2009

PFS and OS of 87/93/98 studies

7 years: PFS = 47.5% [46-49%]; OS = 56% [54-57%]

8-9%

7400 patients18-80 years old

Coiffier B et al. EHA 2009

months from inclusion

Eve

nt-f

ree

surv

ival

(%

)

ABMT (n=55)

DHAP (n=54)

Parma study: event-free survival

100

80

60

40

20

00 15 30 45 60 75 90

Chemo-sensitive responders:ORR 58%, CR 25%

p=0.002

(Updated from JY Blay et al., Blood 1998)

Relapsed aggressive lymphoma (DLBCL)

Patients candidates to HDT/ASCT (<60-65y)

Accepted strategy

Short salvage chemotherapy

Evaluation of response

HDT/ASCT

Questions

1.- Which optimal salvage chemotherapy regimen?

2.- Will rituximab combined with salvage chemotherapy be effective if previously

used first-line?

3.- Is rituximab useful as maintenance therapy after HDT/ASCT?

CORAL Trial of RICE v DHAP

CD20+ DLBCLRelapsed/Refractory

R-ICE x 3

R-DHAP x 3

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

SD/POD → Off

PR/CR →

→A BS EC AT M

R x 6

Obs

N=400

Which salvage regimen is the best?

Place of immunotherapy post transplantation?

Gisselbrecht C. J Clin Oncol 2010

Patient distribution

Australasia

60

Germany

113

Cesz Republic

36

France

128

Belgium

31

Israel

13

US

9

Sweden

13

Switzerland

24

481 patients30/6/2008

Ireland

4

UK

50Thank you to all investigators and pathologists

CORAL Study

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

Arm of treatment

AllARM A / R-

ICEARM B / R-

DHAP

N % N % N %

Response after first line

129 53 122 52 251 53COMPLETE RESPONSE

UNCONFIRMED COMPLETE RESPONSE 31 13 24 10 55 12

PARTIAL RESPONSE 44 18 49 21 93 20

STABLE DISEASE 11 5 13 6 24 5

PROGRESSIVE DISEASE 27 11 25 11 52 11

NOT EVALUATED 0 0 1 1 1 0

PATIENTS ENROLLED IN CORAL STUDY ACCORDING TO RESPONSE TO FIRST LINE TREATMENT

Gisselbrecht C et al. asco 2011

PATIENTS CHARACTERISTICS R-ICE (243) R-DHAP (234)

Median age 54 y 55 y Sex M 156 147 F 87 87

Stage I-II 93 89 Stage III-IV 149 143

ENS > 1 67 78

LDH > Nl 126 117

S-AaIPI 0-1 142 139S-AaIPI 2-3 93 88

<12 months 107 106

12 months 133 122Gisselbrecht C et al. asco 2011

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 TO INDUCTIVE SALVAGE TREATMENTS

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

Gisselbrecht C et al. asco 2011

Arm of treatmentARM A / R-ICE ARM B / R-DHAP

N % N %

Consolidation treatment (BEAM)

123 51 132 57Yes

No 116 49 98 43

Total 197 100 191 100

CONSOLIDATION with BEAM

Main Reasons for premature withdrawals:•Progressive lymphoma: 53%•Toxicity: 7%•Collection failure: 7-11% (CD 34/kg < 2.106)•Deaths: 4%

Gisselbrecht C et al. asco 2011

EFS (induction ITT) OS (induction ITT)

EFS and OS by induction treatment

Su

rviv

al p

rob

abil

ity

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72OS (months)

Su

rviv

al p

rob

abil

ity

EFS (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72

p = 0.2672 p = 0.3380

R-ICER-DHAP

R-ICER-DHAP

No. of subjects Event Censored Median

R-ICE 239 71% )170(

29% )69( 6.51

R-DHAP 230 67% )153(

33% )77( 7.49

No. of subjects Event Censored Median

R-ICE 239 52% (125) 48% (114) 34.53

R-DHAP 230 49% (112) 51% (118) 58.97

481 patients first randomised from 24 July 2003 to 30 June 2008245 patients randomised in the second part from 21 October 2003 to 21 October 2008

PROGRESSION-FREE SURVIVAL ACCORDING TO

PRIOR RITUXIMAB (INDUCTION ITT)

PROGRESSION-FREE SURVIVAL

ACCORDING TO FAILURE FROM DIAGNOSIS (INDUCTION ITT)

N=160

N=228

N=147

N=241

31%

64%

30%

62%

Failure from diagnosis =>= 12 months

EVENT-FREE SURVIVAL BY PRIOR RITUXIMAB - INDUCTION ITT

Failure from diagnosis > 12 months

Standard salvage regimen does not overcome poor prognosis of early relapse

Failure from diagnosis =< 12 months

N= 106

N= 54

N= 41

N= 187

Response p

Patients CR/Cru/PR

All patients 245 63 %

CR/CRu 147 38%

Prior Rituximab No 122 83% <0.0001

Yes 124 51%

Relapse > 12 months 140 88% <0.0001Refractory < 12 months 106 46%

s IPI < 2 160 71% <0.0002> 1 76 52%

CORAL STUDY RESPONSE RATE ACCORDING TO PROGNOSTIC FACTORS

TAKE HOME MESSAGESbased on CORAL study

A new profile of relapses and refractory patients after rituximab is seen

Prognostic factors affecting response and survival are:

• relapse < 12 months• secondary IPI>1• prior rituximab exposure

When rituximab has been used during first-line therapy: optimal salvage combination remains to be determined? New drugs mandatory–

CORAL Trial of RICE v DHAP

CD20+ DLBCLRelapsed/Refractory

R-ICE x 3

R-DHAP x 3

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

SD/POD → Off

PR/CR →

→A BS EC AT M

R x 6

Obs

N=400

Which salvage regimen is the best?

Place of immunotherapy post transplantation?

Gisselbrecht C. J Clin Oncol 2010

PFS OS

CORAL maintenance: PFS/OS by treatment arm

Su

rviv

al p

rob

abil

ity

Overall survival (months)

Su

rviv

al p

rob

abil

ity

PFS (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72

p = 0.8314 p = 0.7547

Observation

Rituximab

Observation

Rituximab

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72

n EventCensore

d Median

Observation 120 43% (52) 57% (68) 58.22

Rituximab 122 45% (55) 55% (67) 57.59

n Event Censored Median

Observation 120 33% (40) 67% (80) 62.92

Rituximab 122 36% (44) 64% (78) NA

CORAL: Prognostic factors for maintenance post-ASCT – multivariate Cox Model

EFS PFS OS

Parameter p-value

Hazardratio

(95% CI) p-value

Hazardratio

(95% CI) p-value

Hazardratio

(95% CI)

Prior treatment with rituximab: no

0.1979 0.748 0.3509 0.808 0.2874 0.760

Failure from diagnosis < 12 months

0.4658 1.179 0.4536 1.188 0.5665 1.159

Age-adjusted IPI 2–3 0.0030 1.846 0.0007 2.028 0.0004 2.252

Response after complete induction: PR

0.2050 1.295 0.4286 1.180 0.4638 1.186

Arm of treatment: R-ICE 0.0853 1.417 0.0676 1.457 0.0716 1.511

Arm of second randomisation: Rituximab

0.9208 1.020 0.6104 1.111 0.4822 1.175

CORAL maintenance: OS by gender

Su

rviv

al p

rob

abili

ty

OS (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60 72

p = 0.0066

Female

Male

Analysis of maximum likelihood estimates

Parameter DFParameterestimate

Standarderror

Chi-Square Pr > ChiSqHazardeatio

95% Hazard ratio confidence limits

brasrand2 RITUXIMAB 1 0.19196 0.22723 0.7137 0.3982 1.212 0.776 1.891

aaipi 2-3 1 0.89373 0.22754 15.4281 <.0001 2.444 1.565 3.818

SEX MALE 1 0.63522 0.25860 6.0341 0.0140 1.887 1.137 3.133

Gisselbrecht C, et al..

MATERIAL : Paraffin blocks

Primary BiopsyN = 189 (47%)

Relapse BiopsyN = 147 (37%)

Matched pairsN = 87 (22%)

Diagnosis Relapse = CORAL

Patients randomized N = 400

Patients analyzedN = 249 (63%)

FR

Subclassification of de novo DLBCL

(Hans CP et al. Blood. 2004)

34%76%

non-GCBGCB

5-Year OS

CD10

GCB

bcl6

MUM1

non-GCB

GCB

non-GCB

+

_+

_

+

_

Progression Free Survival

R-DHAPR-ICE

p = 0.04p = NS

Non GCGC

31%

27%

52%

32%

3 years3 years

Hans algorithm

R-ICE (n=61) R-DHAP (n=54).

R-ICE (n=56) R-DHAP (n=61)

Thieblemont C et al JCO 2011

C-MYC C-MYC probe, split-signalprobe, split-signal

Pattern YY YGR

Patients analysed ( n=161) n

MYC + 28 17 % Simple 7

Complex BCL2 BCL6 BCL2 and BCL6

21 13 4 4

MYC - No breakpoint

133 83 %

MYC+ DLBCL treated in CORAL study

Cuccuini W. et al., Blood 2012

p = 0.0113p = 0.0322

MYC+ n=28

MYC- n=133

42%

18%

62%

29%

MYC+ DLBCL is associated with a poor prognosis

PROGRESSION FREE SURVIVAL OVERALL SURVIVAL

4 years 4 years

Cuccuini W. et al Blood 2012

R-DHAPR-ICE

p = .1832

p = .0324

MYC+

MYC-

OVERALL SURVIVAL

26% 31%

MYC+ DLBCL : No impact of treatment arm

3 years 3 years

Cuccuini W. et al Blood 2012

TAKE HOME MESSAGES

Molecular characteristics are “similar” at diagnosis and relapse.

• Differential efficacy of non-based anthracycline chemotherapy within molecular subtypes of DLBCL

• MYC rearrangement is associated with a bad prognosis, independently from the type or treatment or other biological prognostic classification

Importance of realizing molecular characterization in DLBCL for a rational development of treatment.

Clinical prognostic factors remain very important

Elderly patients (>65y), not eligible for HDT

No standard of care

R- GemOx, R GDP, ESHAP, VIM, Ifosfamide-etoposide…

R - GemOx Protocol

8 CYCLES DELIVERED EVERY 2 WEEKSNo dose adjustment for hematological toxicity.

Next cycle delayed until recovery ( A N C > 1 x 109 / L and platelets > 100 x 109 / L ).

In case of neurotoxicity, dose reduction was planned for oxaliplatin only.

Rituximab 375 mg / m2 d1

Gemcitabine 1000 mg / m2 (10 mg / m2 / min) d2

Oxaliplatin 100 mg / m2

( over 2 hours, after Gemcitabine

administration )d2

Haioun C et al. ASCO 2010

R-

GEMOX

R-

GEMOX

R-

GEMOX

R-

GEMOX

R-

GEMOX

R-

GEMOX

R-

GEMOX

R-

GEMOX

R - GemOx Study : Study design

C2 C3 C4 C5 C6 C7 C8C1

E

Consolidation Induction

W2 W4 W6 W8 W10 W12 W14W0 W16

Evaluation of response: if CR, CRu or PR, start

consolidation

Response to

treatmentE = EnrollmentW = WeekC = Cycle

Follow-up 0

Median time between last TX and start of R-GEMOX (months)

14 [ 1 - 130 ]

Primary refractory, (%) 6 (12%)

1st relapse, (%) 36 (74%)

2 nd relapse, (%) 7 (14%)

Delay from last TX < 1 year, (%) 22 (46%)

Patient Characteristics ( n = 49 )

PREVIOUS THERAPIES 

ACVBP / CHOP / Others (%) 67 / 31 / 2

Rituximab, (%) 37 (63%)

Autologous stem cell Transplantation, (%) 13 (27%)

Response after induction TX (4 cycles)

60.4 %

CI : [ 45.3% - 74.2% ]

n %

Complete Response 11 23

Unconfirmed Complete Response 10 21

Partial Response 8 17

Stable Disease 2 4

Progressive Disease 5 10

Death 4 8

Premature withdrawal 8 17

Total 48 100

Response at the end of TX

n %

Complete Response 11 23

Unconfirmed Complete Response 7 15

Partial Response 4 8

Stable Disease 4 8

Progressive Disease 13 27

Death 8 17

Not evaluated 1 2

Total 48 100

45.8 %

CI : [ 31.4% - 60.8% ]

Months60 12 18 24 30 36 42 48 54 60

0.8

0.6

0.4

0.2

0

1

Su

rviv

al p

rob

abili

ty

Progression - Free Survival

3 - year PFS rate 20.1% [ 9.8 - 32.4 % ]

Median PFS (months) 5.3 [ 2.6 - 9.6 % ]

Median follow-up: 41 months

PFS according to delay from last

Treatment (< or > 1 year )

Months60 12 18 24 30 36 42 48 54 60

0.8

0.6

0.4

0.2

0

1

Su

rviv

al p

rob

abili

ty

n MEDIAN MONTHS)

Time of last treatment / C1 < 1 year 22 3Time of last treatment / C1 > 1 year 26 10

Time last treatment / C1 < 1 yearTime last treatment / C1 > 1 year

p = 0.0166

PREVIOUS RITUXIMAB

TIME LAST TX AND C1

N MEDIAN95% CI LOWER

95% CI UPPER

MIN MAX

PFS (months)

No < 1 Year 7 12 5 - 1 49

No > 1 Year 10 11 7 - 1 46

Yes < 1 Year 15 2 1 3 0 6

Yes > 1 Year 16 9 5 30 1 55

PFS according to delay from last TX ( < or > 1 year ) and previous rituximab TX

Months60 12 18 24 30 36 42 48 54 60

0.8

0.6

0.4

0.2

0

1

Su

rviv

al p

rob

abili

ty Previous rituximab : No & Time last treatment / C1 < 1 yearPrevious rituximab : No & Time last treatment / C1 > 1 yearPrevious rituximab : Yes & Time last treatment / C1 > 1 yearPrevious rituximab : Yes & Time last treatment / C1 < 1 year

p < 0.0001

TAKE HOME MESSAGES

This prospective multicenter trial suggest that

R - GemOx regimen is a safe outpatient salvage

regimen.

The response rate of 60%, after 4 cycles, observed

across a wide age range of patients appears similar to

the response rate obtained with other salvage regimens

(RICE, R-DHAP…) and appears less toxic.

The familiarity of practicing oncologists with the

GemOx combination for other malignancies will allow it

to be largely applied to lymphoma.

A new profile of patients relapsing less than one year after the end of last treatment and previously treated xith rituximab come out from this trial (median PFS: 2 months), and will help the design of future studies with new drugs

This regimen could be considered as a platform for new combinations

Targeted Therapy for Cancer

Younes A. (2010) Beyond chemotherapy: new agents for targeted treatment of lymphoma.Nat Rev Clin Oncol. doi:10.1038/nrclinonc.2010.189.

Mounier N, Gisselbrecht C. Best Practice and Research Clinical Hematology, 2012

Monoclonal antibodies

Naked MAb Rituximab anti-CD20 Alemtuzumab anti-CD52 Epratuzumab anti-CD22 Galiximab anti-CD80 Humanized anti-CD20s (ocraluzumab, ofatumomab, veltuzumab) Modified anti-CD20s (GA 101, R603) Bevacizumab anti-VEGF Zanolimumab anti-CD4 siplizumab anti-CD2

MAb + radionucleide 90Y ibritumomab tiuxetan anti-CD20 131I tositumomab anti-CD20

MAb + toxin CMC-544 (calicheamicin) anti-CD22 SAR3419 (DM4, maytansinoid) anti-CD19

| August 2010

Depositato presso AIFA in data 20/09/2010

| 03 Feb 2011

Humanized IgG4 anti-CD22 mAb G5/44

Calicheamicin

Me

O

O

NH

NHN

O

S

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HOO

OCH3

NH O

O

OCH3

N

CH3CH2O

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HOCH3

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OH

CH3

S

CH3

OCH3

OCH3

I

O

O

O

O

S

Me Me

O

CH3

AcBut linker

Adapted from:1. DiJoseph JF et al. Blood. 2004;103:1807-1814.

Inotuzumab ozogamicin(CMC-544)

Structure of CMC-544, a CD22-targeted immunoconjugate of CalichDMH

Inotuzumab ozogamicin Structure

Response Rate With Inotuzumab Ozogamicin at the MTD (1.8 mg/m2)

Main toxicity thrombocytopenia

How to combine CMC with chemotherapy ?

Phase II R-GEMOX/R-CMC 544 in Recurrent DL B-cell Lymphomas

Enro

llmen

t

1 28 42 56 70 84 98 112 126 140 168 182

Re-stage

Recurrent CD22+ B-cell NHL

rituximab rituximab rituximab rituximab

Dose levels-2 = 0.8 mg/m2

-1 = 1.3 mg/m2

0 = 1.8 mg/m2

NHL, non-Hodgkin’s lymphoma. F Offner, C HaiounG

EM

OX

GE

MO

X

GE

MO

X

GE

MO

X

GE

MO

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Re-stageinotuzumab

GE

MO

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MERCI !!!