Response criteria for NHL

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ESMO Conference Lugano (ECLU) Lugano,
Switzerland, July 5-8th, 2007 Advances in the
treatment of hematological malignancies
The clinical use of antibodies in hematological
malignancies Armando López-Guillermo Department
of Hematology Hospital Clínic Barcelona, Spain
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Treatment of malignant hematology disorders

• Surgery
• Radiotherapy
• Chemotherapy
• Transplantation (auto, allo)
• Biological response modifiers
• Immunotherapy
• Monoclonal antibodies
• Vaccines
• Gene therapy

Targeted therapy ? Anti-tumor efficacy ? Toxicity
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Questions for a monoclonal antibody

• Which target?
• Mechanisms of action
• Characteristics of the monoclonal antibody
• Toxicity immediate, long term effects
• How to use it?
• Alone
• In combination with chemotherapy
• When to use it?
• Induction
• Maintenance
• High dose ASCT

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Optimal target for MoAb therapy

• Specific antigen
• Present at high density in tumor cells
• Absent (or low concentration) in normal cells (or
  present in non-critical cells)
• Stable expression
• No modulation
• No internalization

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Correlation between in vitro sensitivity to
Rituximab and CD20 expression
Bellosillo et al., Blood 982771-2777, 2001
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Mechanisms of antibody-mediated cell killing
Apoptosis viainduction of intracellularsignaling
pathways
Antibody-dependentcellular cytotoxicity (ADCC)
Complement-dependentcytotoxicity (CDC)
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The anti-tumor effect also depends of some MoAb
features

• Humanized (at least chimeric) MoAbs reduce the
  risk of rapid immune neutralization
• MoAb / Fc receptor interaction is critical in
  mediating ADCC
• Conjugated MoAbs increase cytotoxicity
• Radiation emitters
• Drugs
• Toxins

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Potential targets for MoAb treatment in
hematological malignancies
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MoAbs in hematological malignancies (Registered
in EU)
NHL non-Hodgkins lymphoma CLL chronic
lymphocytic leukemia AML acute myeloid leukemia
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Rituximab structure
Chimeric anti-human CD20 monoclonal antibody
VH
Murine variable regions
C?1
VL
Human constant ? region
C?
Human constant Fc region
Variable region murine IgG1 kappa
anti-CD20 Constant region human IgG1 heavy chain
and kappa light chain
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(No Transcript)
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Rituximab

• Phase I trial
• demonstrated binding to CD20 antigen
• infusional toxicity in patients with circulating
  B cells
• clinical activity - even with single dose of
  50100mg/m2
• Phase II trial
• significant activity of 375mg/m2 x 4 in
  follicular NHL
• confirmed in pivotal trial in relapsed low grade
  NHL patients
• approved by US FDA in 11/97

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Rituximab for follicular lymphoma

• Single agent response rates
• 50 in relapsed patients (6 CR)
• 7580 in newly-diagnosed patients
• Extended schedule or maintenance
• improves TTP to 35 years for newly-diagnosed
  patients

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Rituximab plus chemotherapy for follicular
lymphoma
Kaplan-Meier analysis of time to progression
R-CHOP
Czuczman, JCO 1999 17268-76 Czuczman, JCO 2004
224711-6
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Rituximab plus chemotherapy for follicular
lymphoma (frontline)
CR complete response PFS progression-free
survival OS overall survival Plt.05 at 4
years at 2 years
Marcus, Blood 2005 1051417-23 (1) Marcus, ASH
2006 (481) (2) Hiddemann, Blood 2005
1063725-32 (3) Herold, JCO 2007 251986-92 (4)
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Maintenance in follicular lymphoma (FL)

• Maintenance after response is a classical concept
  in FL (chlorambucil, interferon)
• Rituximab as maintenance is safe and feasible
• Different schedules of administration
• Relapsed patients improvement in 3-yr PFS
• Observation Rituximab P value
• CHOP1 32 48 .004
• FCM2 45 70 .03
• After 1st-line treatment PRIMA trial

Van Oers, Blood 2006 1083295-301(1) Forstpointne
r, Blood 2006 1084003-8 (2)
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SWOG 8516 randomised trial in advanced stage
aggressive NHL
100
80
60
Survival ()
40
20
0
5
10
15
Years after registration
Updated from Fisher RI et al. N Engl J Med
19933281002
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GELA Trial in Large B-cell Lymphomas
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GELA 98.5 Improving CHOP-21 byadding rituximab
Overall survival
1.0
0.8
R-CHOP
0.6
Probability
0.4
CHOP
0.2
P 0.0073
0.0
0
1
2
3
4
5
6
7
Years
Coiffier B, N Engl J Med 2002 346235-42 Feugier
P, J Clin Oncol 2005 23411726
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R-chemotherapy vs. chemotherapy alone in DLBCL
? CR, ? PFS and ? OS in different settings -
GELA/LNH 98.5 (60-80 years)1,2 - ECOG 4494
(60-80 years maintenance arm)3 - MINT (young
low-risk patients)4 - RICOVER (CHOP-14)5 -
HOVON (CHOP-14)6
Coiffier, NEJM 2002 (1) Feugier, JCO 2005
(2) Habermann, JCO 2006 (3) Pfreundschuh, Lancet
Oncol 2006 (4) Pfreundschuh, ASH 2006 (205)
(5) Sonneveld, ASH 2006 (210) (6)
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Rituximab ? CHOP for DLBCL in British Columbia
overall survival by treatment era
1.0 0.8 0.6 0.4 0.2 0
Post-rituximab
Probability of survival
Pre-rituximab
p0.0001
0 1 2 3 4
Years
Sehn LH, et al. J Clin Oncol 200523502733
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Addition of Rituximab to chemotherapy in
lymphoproliferative disorders
CR rate PFS OS FL ? ? ? DLB
CL ? ? ? MCL ? ? ? CLL ? ? ?
FL follicular lymphoma DLBCL diffuse large
B-cell lymphoma MCL mantle-cell lymphoma CLL
chronic lymphocytic leukemia Rituximab as
maintenance therapy
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Radiolabeled antibodies
If platelet count 100-150x109/L 0.3 mCi/Kg
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Monoclonal antibodies
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Other monoclonal antibodies in lymphomas

• Anti-CD20 (IMMU-106, hA20)
• Anti-CD22 (epratuzumab, CMC-544)
• Anti-CD30 (SNG-30, iramumab)
• Anti-CD40 (SNG-40)
• Anti-CD80 (galiximab)
• Anti-CD2 (siplizumab)
• Anti-CD4 (L3T4)

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Gemtuzumab-Ozogamycin (GO) in acute myeloid
leukemias

• Conjugated MoAb AntiCD33 calicheamicin
• Limited role in advanced disease (single-agent,
  CT)
• Preliminary promising results in front-line
  combined regimens
• MRC experience reduced relapse incidence (?10)
  in low intermediate-risk
  pts
• On-going randomized trials (SWOG S016)
• Role as in-vivo purging strategy before autoSCT?
  (ECOG 1900)
• Role in pts with persistent MRD (APL, CBF-AML)?
• Hepatic toxicity issue the VOD/SOS syndrome
• Dose-limiting (3 mg/m2)
• Interference with stem-cell transplantation

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Conclusions

• Monoclonal antibodies (MoAb) represent a major
  advance towards a targeted treatment aimed to
  increase the anti-tumor effect with substantial
  reduction of therapy-related toxicity
• In general, MoAb are safe, well-tolerated and
  have anti-tumor activity in a variety of clinical
  settings
• The combination of chemo and immunotherapy is a
  solid reality that nowadays constitute the
  standard treatment for many patients with
  lymphoma or leukemia