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
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I
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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
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MO
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GE
MO
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Re-stageinotuzumab
GE
MO
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MERCI !!!