AntiCD20 antibodies in the treatment of malignant lymphoma

1
Anti-CD20 antibodies in the treatment of
malignant lymphoma

• M.H.J.van Oers
• Dept Hematology
• Academic Medical Center Amsterdam

Snapperdag 25-10-2006
2
Anti-CD20 antibodies in malignant lymphoma

• introduction
• anti-CD20
• clinical results
• radioimmunotherapy

3
Malignant Lymphomas

• tumours of the immune system
• malignant counterparts of normal (mature)
  lymphocytes
• 85-90 B cell origin

4
WHO CLASSIFICATION OF B CELL NEOPLASMS

• Precursor B cell lymphoblastic leukemia /
  lymphoma
• B CLL / small lymphocytic lymphoma
• B cell prolymphocytic leukemia (PLL)
• Lymphoplasmacytic lymphoma
• Splenic marginal zone B cell lymphoma
• Hairy cell leukemia (HCL)
• Plasma cell myeloma
• Nodal marginal zone lymphoma
• Follicular lymphoma (indolent lymphoma)
• Mantle cell lymphoma
• Diffuse large B cell lymphoma (aggressive
  lymphoma)
• Extranodal marginal zone (MALT) lymphoma
• Mediastinal large B cell lymphoma
• Primary effusion lymphoma
• Burkitts lymphoma

5
WHO CLASSIFICATION OF B CELL NEOPLASMS

• Precursor B cell lymphoblastic leukemia /
  lymphoma
• B CLL / small lymphocytic lymphoma
• B cell prolymphocytic leukemia (PLL)
• Lymphoplasmacytic lymphoma
• Splenic marginal zone B cell lymphoma
• Hairy cell leukemia (HCL)
• Plasma cell myeloma
• Nodal marginal zone lymphoma
• Follicular lymphoma (indolent lymphoma)
• Mantle cell lymphoma
• Diffuse large B cell lymphoma (aggressive
  lymphoma)
• Extranodal marginal zone (MALT) lymphoma
• Mediastinal large B cell lymphoma
• Primary effusion lymphoma
• Burkitts lymphoma

6
Rationale for immunotherapy of lymphoma

• Despite achieving remissions, patients with
  indolent NHL are not cured by current therapy
• In aggressive NHL cure rates are still very
  unsatisfactory due to relapses and primary
  resistance to chemotherapy
• Treatment of minimal residual disease may alter
  course of the disease

• IT has a different mechanism of action (Ab CTL)
• IT may provide greater tumour specificity
• IT may be less toxic

7
Immunotherapy of lymphoma

• active vaccination strategies
• passive monoclonal antibodies
• allogeneic transplantation (non-myeloablative)

8
Immunotherapy of lymphoma

• active vaccination strategies
• passive monoclonal antibodies
• allogeneic transplantation (non-myeloablative)

9
History of antibody therapy

• Ehrlich, 1890 To find chemical substances that
  have special affinities for pathogenic organisms,
  and would be magic bullets which would go
  straight to the organisms at which they were
  aimed
• Hericourt, 1895 antibodies alone may not be
  sufficient to cure malignancy but might increase
  survival when used in combination with other
  therapies

10
Tumor-specific passive immunotherapymonoclonal
antibodies

• Unconjugated antibodies
• conjugated antibodies
• radio-isotopes
• toxins
• cytostatic drugs
• cytokines/ chemokines
• enzymes
• ..

11
Anti-CD20 antibodies in malignant lymphoma

• introduction
• anti-CD20
• clinical results
• radioimmunotherapy

12
Tumor-specific passive immunotherapyregistered
monoclonal antibodies

• Lymphoid malignancies (lymphoma/CLL)
• anti-CD20 Rituximab Mabthera
• anti-CD52 Alemtuzumab MabCampath
• 131I anti-CD20 Tositumomab Bexxar (USA)
• 90 Y anti-CD20 Ibritumomab tiuxetan Zevalin

13
CD20 as a therapeutic target

• Although not tumor specific, B-cell
  restricted
• Not on stem cells, early B cell precursors or
  plasma cells
• Present on most B-cell NHL
• Present on all tumor cells
• High copy number in (follicular) lymphoma
• Stable in membrane, no modulation
• No polymorphisms

14
CD20 Expression in B-Cell Development
Plasma cell
15
CD20

• Ligand not known
• CD20 knockout mice normal B cells
• Ca influx B cell activation regulation of
  cell cycle?

16
Rituximab (Mabthera) a mouse/ human chimeric
anti- CD20 monoclonal antibody
Murine variable regions bind specifically to
CD20 on normal/ malignant B-cells
Human K constant regions

• Human IgG1 Fc domain
• interacts with human effector mechanisms
  (ADCC, CDC)
• low immunogenicity

17
Anti- CD20 (Rituximab Mabthera) mechanism of
action
Malignant B-cell
CD20
Killer Leukocyte
CD20
Direct induction of apoptosis
Adapted from Male D, et al., Advanced Immunology
1996 1.11.16
18
Anti-CD20 antibodies in malignant lymphoma

• introduction
• anti-CD20
• clinical results
• radioimmunotherapy

19
Rituximab pivotal trialMcLaughlin, JCO
1998162825-33

• Multicenter open label phase II trial
• 166 patients with relapsed low grade NHL
• Rituximab 375 mg/m2 weekly x 4

• ORR 48, 6 CR
• Median duration of response 11.6 months

• favourable safety profile (fever, chills)
• host antibody responses (HACA) rare
• B cell depletion no increase in infections

20
November 1997 FDA approval of rituximab
(MabThera / Rituxan) as the first antibody for
cancer therapy
21
Rituximab monotherapy response ratein relation
to tumor type
Combination with chemotherapy better ?
22
Rituximab combination with chemotherapy

• Rationale
• Mechanisms of action are not cross resistant
• Each therapy efficacious
• Toxicities do not overlap
• Rituximab increases sensitivity to chemotherapy
• Potential to clear minimal residual disease?

Demidem A et al . Cancer Biotherapy
Radiopharm 199712(3)177-86.
23
Chemotherapy Rituximab phase III randomised
trials

• Diffuse Large B cell Lymphoma
• Induction treatment (n3)
• Follicular Lymphoma
• Induction treatment (n4)
• Maintenance treatment (n4)

24
Chemotherapy Rituximab phase III randomised
trials

• Diffuse Large B cell Lymphoma (DLBCL)
• GELA study Coiffier et al. NEJM 2002 346
  235

25
CHOP vs R-CHOP in DLBCL 60-80 yearsEvent-free
survival 4-year update
1.0
0.8
0.6
51 MabThera CHOP
Probability of event-free survival
0.4
29 CHOP
0.2
p0.00001
0 1 2 3 4 5
Years
Coiffier et al 2004.
26
CHOP vs R-CHOP in DLBCL 60-80 yearsOverall
survival 4-year update
1.0 0.8 0.6 0.4 0.2 0
59 MabThera CHOP
P0.01
Probability of overall survival
47 CHOP
p0.01
0 1 2
3 4 5
Years
Coiffier et al.2004
27
CHOP vs R-CHOP Overall Survival and bcl-2
expression
1.0
1.0
0.9
0.9
0.8
0.8
R-CHOP
0.7
0.7
R-CHOP
0.6
0.6
0.5
0.5
CHOP
0.4
0.4
CHOP
0.3
0.3
0.2
0.2
0.1
0.1
Bcl-2 protein not expressed
Bcl-2 protein expressed
0.0
0.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
5.0
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Chemo vs R-Chemo in DLBCL lt 60 yrs
Time to Treatment Failure
1.0
R-CHEMO
81
N161
0.9
0.8
0.7
p lt 0.000005 ?crit 0.00192
0.6
Probability FTF
0.5
CHEMO
58
0.4
N165
0.3
0.2
0.1
0.0
5
10
15
25
35
45
50
0
20
40
30
M o n t h s
Median time of observation 24 months
?-crit for updated interim analysis
Pfreundschuh ASCO 2004 abstr 6500
29
CVP Rituximab in untreated stage III/ IV
follicular NHL
Marcus et al Blood 1051417, 2005
30
EORTC 20981 phase III trialR-maintenance
treatment relapsed follicular NHL
R A N D O M I S E D
R A N D O M I S E D
CHOP every21 daysmaximum six cycles
Observation
Rituximab CHOP every21 daysmaximum six cycles
Rituximab maintenance
375mg/m2 every 3 months for 2 years or until
relapse
van Oers MH, et al. Blood 2006 July 27 (Epub).
31
EORTC 20981 Intergroup phase III trialendpoints
and follow-up

• Induction step (n465)
• Endpoint response to treatment
• Median follow-up 39 months
• Maintenance step (n334)
• Endpoint progression free survival from the date
  of randomization for maintenance
• Median follow-up 33 months

van Oers MH, et al. Blood 2006 July 27 (Epub).
32
EORTC 20981 Intergroup phase III trial
Progression free survival from 2nd randomization
Rituximab maintenance median 51.6months
Observation median 15 months
Hazard ratio 0.40
van Oers MH, et al. Blood 2006 July 27 (Epub).
33
EORTC 20981 Intergroup phase III trial
Progression free survival from 2nd randomization
Subgroups according to induction treatment
median 51.9 months
median 42.2 months
med. 23.1 months
med. 11.6 months
Hazard ratio 0.30
Hazard ratio 0.54
van Oers MH, et al. Blood 2006 July 27 (Epub).
34
EORTC 20981 Intergroup phase III trial Overall
survival from 2nd randomization
R-maintenance 3 yrs 85.1
observation 3 yrs 77.1
Hazard ratio 0.52
35
Rituximab in diffuse large B-cell lymphoma

• Rituximab plus CHOP is now internationally
  accepted as the standard first line treatment for
  both young and elderly patients with diffuse
  large B-cell lymphoma
• In relapsed diffuse large B-cell lymphoma
  trials ongoing

36
2006 state of the art treatment of FL

• Induction treatment should be R-Chemo
• Rituximab maintenance is the new standard
• First line after chemo induction (ECOG)
• after R-chemo induction ?? (PRIMA)
• Relapse after chemo or R-chemo induction
• (EORTC 20981)
• (GLSG)

37
Open questions

• Optimal dose and schedule/duration
• Patient selection
• Bcl-2 protein expression
• FcyRIII polymorphisms
• Gene expression profiling
• Is it cost-effective ? If so can we afford it ??
  ( 8000 Euro)

38
Anti-CD20 antibodies in malignant lymphoma

• introduction
• anti-CD20
• clinical results
• radioimmunotherapy

39
Tumor-specific passive immunotherapymonoclonal
antibodies

• Unconjugated antibodies
• bispecific antibodies
• conjugated antibodies
• radio-isotopes
• toxins
• cytostatic drugs
• cytokines/ chemokines
• enzymes

40
Advantages of radioimmunotherapy

• Lymphomas are highly radiosensitive
• Does not depend on host immune effector
  mechanisms
• Cross fire --gt cell kill of cells that are
  antigen-negative or that are not reached by the
  antibody

41
Crossfire
Unconjugated MoAb
42
Choice of Isotope
Zevalin Bexxar
43
Radio-immunotherapy in indolent lymphoma

• Low dose,non-myeloablative
• In relapse
• In first line
• High dose, myeloablative
• In relapse

(To) many phase II trials. Only 1 published phase
III
44
Rituximab versus 90 Y anti-CD20 ( Zevalin)
in relapsed indolent lymphoma (n143)
Witzig et al. JCO 200220 2453-2463
45
Radioimmunotherapy with anti-CD20 in indolent
lymphoma

• ORR (65-80) and CR rate (20-50) superior to
  unconjugated antibody
• Active in rituximab-refractory patients (ORR 74)
• Long remission duration in CR patients
• Registered indication relapsed or refractory
  indolent or transformed lymphoma

46
Radioimmunotherapy disadvantages

• Myelosuppression
• Cost
• Logistics more complex than with unmodified
  MoAb
• Long term side effects (MDS HAMA)
• For 131I
• Radiation exposure to personnel, family
• Need to block thyroid

47
Radio-immunotherapy in lymphomaQuestions

• Activity in different subtypes
• Activity in combination with chemotherapy (phase
  III) and in maintenance (HOVON 48)
• Comparison with rituximab and chemotherapy in
  first/ second line of therapy
• Randomised comparison 131I anti-CD20 and 90 Y
  anti-CD20
• Other mcAb other isotopes

48
Conclusions

• Anti-CD20 antibodies have become an essential
  component of treatment of NHL
• The commercial success of rituximab has boosted
  the development of other monoclonal antibodies

49
MoAb in NHL
50
(No Transcript)
51
FcyRIII polymorphism and the response to
Rituximab (Cartron, Blood 2002)

• Homozygous V158 90 ORR
• Heterozygous or homozygous F158 51 ORR
• Not relevant with R-CHOP?

52
Prediction of response to rituximab

• Gene expression profiling
• different patterns in responders vs
  nonresponders

53
Subtypes of CD20 antibodies