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BHS SUBCOMMITTEE ON LYMPHOPROLIFERATIVE DISORDERS. Fritz Offner
BHS SUBCOMMITTEE ON LYMPHOPROLIFERATIVE DISORDERS.
Fritz Offner
BHS subcommittee LPD
Marc Andre
Christophe Bonnet
Andre Bosly
Dominique Bron
Bernard Deprijck
Hilde Demuynck
Virginie Dewilde
Daan Dierickx
Ann Janssens
Fritz Offner
Wilfried Schroyens
Anne Sonnet
Fabienne Trullemans
Achiel Vanhoof
Eric Vandenneste
Gregor Verhoef
Pierre Zachee
Purpose
Provide guidelines for practice
Provide a scientific reference advice for off-label prescription in Belgium
Publish guidelines on BHS website and on paper for Belgian audience (Acta Clinica, BJ Hematol, BJ Oncol, …)
In Malignant lymphoproliferative disorders 7 areas need recommendations
CLL
Follicular Lymphoma
Aggressive Lymphoma
Mantle cell Lymphoma
Indolent Lymphoma
Hodgkin Disease
T cell NHL
In Malignant lymphoproliferative disorders 7 areas need recommendations
CLL
Follicular Lymphoma
Aggressive Lymphoma
Mantle cell Lymphoma
Indolent Lymphoma
Hodgkin Disease
T cell NHL
BHS GUIDELINES FOR FOLLICULAR LYMPHOMA AND FUTURE DEVELOPMENTS.
Debussche S, A Van Hoof , A Sonnet, C Bonnet, , A Janssens, G Verhoef, D Dierickx, V De Wilde, D Bron, W Schroyens, E Van Den Neste, Offner F On behalf of the BHS Lymphoproliferative Working Party
Questions to adress for BHS guidelines 1. Diagnostic and followup position of PET-CT
2. Which criteria define need for treatment ?
3. Choice between CVP or CHOP ?
4. Position of Bendamustine 1st line ?
5. Maintenance pro/con ?
6. RIT ?
7. Position of transplant ?
BHS guidelines 1st line
1. Diagnostic and followup position of PET-CT There is no consensus; level 3 evidence for use in
postRx prediction
2. Which criteria define need for treatment ? Either GELF or GLSG since they have been at basis of
large randomized trials
3. Choice between CVP or CHOP ? R-CHOP is to be preferred if cardiac status allows it, but this is under challenge of bendamustine
4. Position of Bendamustine 1st line ? Not final at time of publication 2012, meanwhile accepted but not yet published
Criteria for initiating therapy
GELF GSGLGNHL
N° nodal sites >3 each 3 cm Stage III-IV
Bulky disease > 7 cm 7.5 mediastinum 5 elsewhere
Symptoms B or compressive B
Hb Not included >10 g/dl
ANC <1000/µl <1500/µl
Platelets <100000/µl <100000/µl
Leukemic cells > 5000/µl Not included
Disease progression Steady progression Rapid progression
BHS guidelines 1st line
5. Maintenance pro/con ? There is level 1 evidence in PFS but not for OS in favor of rituximab maintenance following R-CHOP, R-CVP or R-FCM. In case of infectious complications, Ig levels should be monitored and eventually substituted.
6. RIT ? The use of radio-immunotherapy in consolidation in first line has not been compared to maintenance anti-CD20 and data do not yet support superiority. This strategy is off label and not reimbursed in Belgium.
7. Position of transplant ? Autologous stem cell transplantation in first remission is not recommended outside of clinical trials.
BHS guidelines relapse
1. Diagnostic and followup position of PET-CT
Unknown, guidance for rebiopsy in case of suspected transformation
2. Which criteria define need for retreatment ?
Very unclear
BHS guidelines relapse
3. Choice of chemotherapy ? The BHS recommends R-chemo followed by maintenance for relapse FL. (superior for PFS, OS when including patients not previously treated with rituximab).
There is no superiority for any given chemotherapy regimen and rituximab monotherapy can be proposed in unfit patients or patients with a low tumor burden at relapse.
Autologous transplantation is an appropriate consolidation in the fit patient in 2nd or further remission
BHS guidelines relapse
4. RIT ? Radioimmunotherapy is useful in second or third relapse in patients who are not transplant candidates
5. Position of transplant ? Autologous stem cell transplantation in 2nd remission is recommended in the fit patient in early relapse outside of clinical trials.
Guidelines and individualised treatment
Validated therapies
Patient comorbidities
tolerance
Previous responses, toxicities
Anticipated perspective
future treatment
needs
Conclusion : Which parts can be individualized ? 1st line in need of cytotoxic treatment
CHOP or CVP or Benda
Anti-CD20 antiCD-20, RIT ?
Add Imids ? Other Abs ? Reassess vaccines with imids, antibodies ?
CHOP or CVP or Benda or Fara based
Anti-CD20 Anti-CD20
Transplant candidate
Conclusion : 1 st or further sensitive relapse in need of treatment
Non-transplant candidate
CHOP or Benda or HDT
Anti-CD20 Autotransplant, RIT ?
Add Imids, Velcade, Other Ab, signal transduction inhibitors
Anti-CD22,19, experimental
Transplant candidate
Conclusion : non-sensitive relapse in need of treatment
Non-transplant candidate
HDCT
Anti-CD20 ? Autotransplant
Add Imids, Velcade, Other Ab, signal transduction inhibitors
Allotransplant, RIT ?
Bendamustine, RIT ?
Lymphoma: the challenge … 10 years ago
1. Fisher RI, et al. N Engl J Med. 1993;328:1002-6. 2. Horning SJ. Semin Oncol. 1993;20(Suppl. 5):75-88.
Diffuse large B-cell lymphoma1 Overall survival
Follicular lymphoma2 Overall survival
Pa
tie
nts
(%
)
Years after randomization
0
20
40
60
80
100
0 1 2 3 5 4 6
Pro
ba
bil
ity
(%
)
Years
0
20
40
60
80
100
0 5 10 15 25 20 30
1960–1976 (195)
1976–1987 (513)
1987–1992 (314)
CHOP
m-BACOD
ProMACE-cytaBOM
MACOP-B
Lymphoma: substantial progress… in the last 10 years
FL2000 study2
Overall survival
1. Feugier P, et al. J Clin Oncol. 2005;23:4117-26. 2. Salles G, et al. Blood. 2008;4824-31.
Su
rviv
al p
rob
ab
ilit
y
Years
0
0.2
0.4
0.6
0.8
1.0
p = 0.0245
0 1 2 3 5 4 6
CHVP+1
R-CHVP+1
LNH 98.5 study1
Overall survival
Su
rviv
al p
rob
ab
ilit
y
Years
0
0.2
0.4
0.6
0.8
1.0
p = 0.0004
0 1 2 3 5 7 4 6 8
CHOP
R-CHOP
Targeted agents approved by the Food and Drug administration for the treatment of B-cell
non-Hodgkin lymphoma and Hodgkin lymphoma and year of first approval.
Stathis A , Ghielmini M Ann Oncol 2012;23:x92-x98
© The author 2012. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. all rights reserved. For permissions, please email:
Antibody developments in NHL
Anti-CD20 further generations Sc Rituximab : may revolutionize ambulatory treatment
2nd generation Ofatumumab fully human
Veltuzumab humanized
Ocrelizumab
3rd generation : engineered Fc part to increase ADDC Obinutuzumab : GA101 glycoengineered type 2
PRO 131921
aME-133v
TRU015
Rituximab biosimilars ;Redditux, Mabion, Merck, Sandoz, Boehringer,…
rHuPH20 ARM PLACEBO ARM
Mabthera sc Fixed dose= 1400 mg (11.7 ml)
ORR
33%
44%
GA101-CHOP: GAUDI (first-line FL)
Dyer MJS, et al. ASH 2012; Abstract 3686 (poster).
35%
60% 53.7%
39%
* Unconfirmed CRs were classified as PRs
PR
CR
Response rate at end of induction: G-CHOP: 95 % G-Benda 92,7 %
G-CHOP G-Benda
Only immunomodulation: lenalidomide and rituximab
Phase III study starting: RELEVANCE ClinicalTrials.gov Identifier: NCT01476787 Estimated Enrollment:1000 Start Date:November 2011 Estimated Study Completion Date:June 2024
PRIMA
Antibody developments in NHL
“Promising” targets CD 23 lumiliximab CD 40 SGN-40, HCD-122 CD 74 hLL1 CD80 galiximab
Ongoing development : Anti-CD19 Anti-CD22 Anti-CD30
Early development : Anti-CD37 Anti-CD70
New monoclonal antibodies and small molecules with relative target that have entered clinical
evaluation for lymphomas (see also Table 2).
Stathis A , Ghielmini M Ann Oncol 2012;23:x92-x98
© The author 2012. Published by Oxford University Press on behalf of the European Society for
Medical Oncology. all rights reserved. For permissions, please email:
The current challenges in Ab-ADC development
Ab-ADC Which target ? What linker ? What is the best conjugate ? Should there be more than 1 target/ conjugate ?
Selective signal transduction inhibitors Tumor cells rarely depend on one signal transduction pathway Tumoristatic and not tumoricidal Expect short PFS : giant problem for approval
Will Imids expand and revive the scope of immunotherapy ? Vaccines CARD
Targets for ADC in NHL
Anti-CD19 Unconjugated SAR 3419 : antiCD19-DM4 Blinatumomab Preclinical anti-CD19-MMAE
Anti-CD22 Unconjugated CMC-544 Inotuzumab ozogamycin (IgG4) Genentech RG7593 humanized IgG1 anti-CD22 monoclonal
antibody, conjugated to monomethyl auristatin E (MMAE)
Anti-CD79b –MMAE
Anti-CD30-MMAE : brentuximab vedotin
Anti-CD70-MMAE
The toxins IC50 in nM range
DNA- damaging : doxorubicin analog
Calicheamycins
Duocarmycins
Toxicities : cardiac, liver, thrombocytopenia
Microtubule targeting : vinblastin analog
Auristatins (MMAE, MMAEF)
Maytansinoids (DM-1,DM-4)
Toxicities : neurological, thrombocytopenia
CD22-targeted Chemotherapy: Inotuzumab Ozogamicin (CMC-544)
Humanized IgG4 anti-CD22
NAc-gamma calicheamicin
DMH
O C
H O 3
Me
O
O
NH O
NHN
Me Me
S
H
H O O
O C H 3
N H O
O
O C H 3
N
E t O
O H H 3
C H
O C H 3
H N H O
O O
O H
C H 3
S
C H 3
O C H 3
O C H 3
I
O
O
O O
S
O
CH3
AcBut linker
Phase I/II Inotuzumab + Rituximab in Recurrent B-cell Lymphomas
Enro
llmen
t
1 28 56 84
Re-stage Re-stage
28-day cycle Day 1: rituximab 375 mg/m² Day 2: inotuzumab 0.8, 1.3, 1.8 mg/m² Treatment: 4 cycles; additional 4 cycles (8 max) if clinical benefit
Recurrent CD22+ B-cell NHL
rituximab rituximab rituximab rituximab
Dose levels 1 = 0.8 mg/m2 2 = 1.3 mg/m2
3 = 1.8 mg/m2
inotuzumab inotuzumab inotuzumab inotuzumab
NHL, non-Hodgkin’s lymphoma. Fayad et al JCO in press
Response Rate With Inotuzumab Ozogamicin at the MTD (1.8 mg/m2)
Patients received 1 dose of drug and had both baseline and post-treatment disease assessments
ORR = complete + partial responses
MTD, maximum tolerated dose; ORR, overall response rate; CR(u), complete response (including unconfirmed); FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma.
Waterfall plot in follicular NHL vs DLBCL
Progression-free Survival
PFS, mo
n Median 95% CI
FL 38 NR 23.6-NR
DLBCL 43 15.6 6.8-NR
Refractory 30 1.8 1.0-3.9
PFS, progression-free survival; FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; CI, confidence interval; NR, not reached.
100
75
50
25
0
Pro
bab
ility
of
PFS
(%
)
0 5 10 15 20 25 30 35 40 45
Time since first dose (months)
DBLCL
FL
Refractory
Overall Survival
Survival at 1 year n 1-year OS rate 95% CI
FL 38 95% 80%-99%
DLBCL 41 80% 64%-90%
Refractory 28 NR NR
OS, overall survival; FL, follicular lymphoma; DLBCL, diffuse large B-cell lymphoma; CI, confidence interval; NR, not reached.
100
75
50
25
0
Pro
bab
ility
of
OS
(%)
0 5 10 15 20 25 30 35 40 45
Time since first dose (months)
DBLCL
FL
Refractory
Incidence of Drug-related Adverse Events Reported for 15% of Patients for R-CMC544
Adverse event, n (%)
All grades
(n = 118)
Grade 3/4
(n = 118)
Thrombocytopenia 59 (50) 36 (31)
Neutropenia 35 (30) 21 (18)
Increased AST 41 (35) 3 (2)
Increased AP 33 (28) 1 (1)
Hyperbilirubinemia 29 (25) 3 (2)
Increased ALT 23 (19) 2 (2)
Increased LDH 21 (18) 3 (2)
Nausea 52 (44) 1 (1)
Vomiting 23 (19) 1 (1)
Fatigue 47 (40) 3 (2)
Pyrexia 20 (17) 1 (1)
Chills 18 (15) 1 (1)
AST, aspartate aminotransferase; AP, alkaline phosphatase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase.
Drug-related serious events were reported for 12 (14%) patients
Ongoing research in CD22-ADC
Target Disease Phase
CD22 inotuzumab ozogamycin
ALL 3 Phase 1,including elderly 1 Phase 3 vs invest choice
DLBCL 5 R-CMC Phase 2 trials 1 prior to autoTx Phase 1 3 in pts not candidate for Tx -phase 3 vs invest choice (Benda, Gemzar) -phase 1 combined R-CVP, GDP -phase 1 sandwich R-GEMOX/R-CMC Phase 1 combo alloTx (Fara, Benda) Phase1 in pt not candidate for anthracyclins
FL 2 R-CMC Phase 2 1 combined R-CVP Phase 1 1 Phase 3 R-CMC vs invest choice (R-CVP or R-FND)
All NHL Phase 1 R-CMC plus temsirolimus Phase 2 R-refractory
Genentech R7593 NHL Phase 1 R-R7593
Pattern of expression of CD19 and CD20 antigens during B-cell development and associated
malignancies.
Blanc V et al. Clin Cancer Res 2011;17:6448-6458
©2011 by American Association for Cancer Research
Structure of SAR3419.
Blanc V et al. Clin Cancer Res 2011;17:6448-6458
©2011 by American Association for Cancer Research
Clinical activity of SAR3419 in 35 evaluable patients with relapsed CD19+ B-cell lymphoma ,
(B) by histologic subtype, and (C) by rituximab sensitivity.
Younes A et al. JCO 2012;30:2776-2782
©2012 by American Society of Clinical Oncology
Ongoing research in CD19-ADC
Target Disease Phase
CD19 Maytansinoid SAR3419
Any NHL Single agent Phase 1
DLBCL Transformed
Single agent phase 1 R-SAR3419 in non Tx candidate Phase 2
ALL Induction plus maintenance Phase 1
Medimmune MEDI-551 naked Ab
Any NHL Phase 2
DLBCL +ICE or DHAP Phase 2
B-CLL R-benda vs M-Benda Phase 2
Blinatumomab C-ALL MRD phase 2 Relapse setting
B-NHL Relapse phase 1
Lymphoma 10 years from now ?
Chemotherapy will likely disappear
Target approach ?
Signature apporach ?
Immune control strategies will improve : Vaccines
CART
Maybe GVH will be dissociated from GVL in alloTx
Lymphoma 10 years from now ? The target approach
Chemotherapy will be replaced :
Chemo-immunotherapy by Ab-Imid followed or preceded by Ab-ADC
Steroids may be replaced by more selective signal transduction inhibitors
Imids may enhance immune control strategies :
Vaccines CD40 conjugates
CART CD19
Lymphoma 10 years from now The signature approach ?
High throughput screens will show pathway activation signature
Combination therapy of signal transduction inhibitors will be given
Chemo-immunotherapy by Ab-Imid followed or preceded by Ab-ADC may serve for debulking or consolidation
Maintenance combination ?
The future of lymphoma ?
Chemotherapy
Id vaccine Moabs
Allotransplant
Chemo-immunotherapy
ADC
Imids
RIT
Tx
CT
Combination immunotherapy
Immuno-ADC
ADC
