Low grade B cell Low grade B cell

Lymphoid Malignancies (LGBLM)Lymphoid Malignancies (LGBLM)

This term is used to describe mainly 2 major disease This term is used to describe mainly 2 major disease

entities of adults and elderly (median age >50) that entities of adults and elderly (median age >50) that

originate from mature (predominantly small) originate from mature (predominantly small)

B lymphocyteB lymphocyte

Indolent B cell NHL

B cellCLL

REAL/WHO ClassificationREAL/WHO Classification Precursor B-CellPrecursor B-Cell

B lymphoblasticB lymphoblastic

Mature (Peripheral) B-CellMature (Peripheral) B-Cell

B-cell CLL/small lymphocytic lymphomaB-cell CLL/small lymphocytic lymphoma

Follicular lymphoma [Grades I, II , III]Follicular lymphoma [Grades I, II , III]

Marginal zone B-cell lymphomaMarginal zone B-cell lymphoma

MALT typeMALT type

Nodal marginal zone B-cell lymphomaNodal marginal zone B-cell lymphoma

Splenic marginal zone B-cell lymphomaSplenic marginal zone B-cell lymphoma

Lymphoplasmocytic lymphoma (immunocytoma)Lymphoplasmocytic lymphoma (immunocytoma)

Mantle-cell lymphomaMantle-cell lymphoma

Diffuse large B-cell lymphomaDiffuse large B-cell lymphoma

Burkitt lymphomaBurkitt lymphoma

Precursor T-CellPrecursor T-Cell

T lymphoblasticT lymphoblastic

Mature (Peripheral) T-CellMature (Peripheral) T-Cell

Mycosis fungoides/Sezary syndromeMycosis fungoides/Sezary syndrome

Adult T-cell lymphoma/leukemiaAdult T-cell lymphoma/leukemia

Peripheral T-cell lymphoma, notPeripheral T-cell lymphoma, not

otherwise specifiedotherwise specified

Angioimmunoblastic T-cell lymphomaAngioimmunoblastic T-cell lymphoma

Anaplastic large T/null-cell lymphomaAnaplastic large T/null-cell lymphoma

Entranodal nasal NK/T-cell lymphomaEntranodal nasal NK/T-cell lymphoma

Enteropathy type T-cell lymphomaEnteropathy type T-cell lymphoma

Hepatosplenic gd T-cell lymphomaHepatosplenic gd T-cell lymphoma

Subcutaneous panniculitic-like T-cellSubcutaneous panniculitic-like T-cell

lymphomalymphomaAdapted from Harris et al. Blood, 84: 1361, 1994 & Harris et al. JCO 17: 3835, 1999

Low Grade B Cell LymphomaFrequency and Diagnostic Accuracy

Type Frequency Accuracy

Follicular center cell 22% 94%

Marginal zone B-cell, MALT 8% 86%

Marginal zone B-cell, nodal 2% 63%

Small lymphocytic/CLL 7% 87%

Lymphoplasmocytoid 1% 56%

40%Adapted from Harris et al. Blood; 84: 1361, 1994

• Chronic lymphocytic leukemia/small lymphocytic lymphoma

• B-cell prolymphocytic leukemia• Splenic marginal zone lymphoma• Hairy cell leukemia

• .Hairy cell leukaemia-variant• Splenic lymphoma/leukemia,

unclassifiable• Splenic diffuse red pulp small B-cell

lymphoma• Lymphoplasmacytic lymphoma• Waldenstrom’s macroglobinemia•Heavy chain diseases

• Alpha heavy chain disease• Gamma heavy chain disease• Mu heavy chain disease

• Plasma cell myeloma

• Solitary plasmacytoma of bone

• Extraosseous plasmacytoma

• Extranodal marginal zone

lymphoma of mucosa-associated

• ymphoid tissue (MALT type)

• Nodal marginal zone lymphoma

• Pediatric nodal marginal zone

lymphoma

• Follicular lymphoma

• Pediatric follicular lymphoma

• Primary cutaneous follicle center

lymphoma

Low Grade B cell Lymphoma according to the last WHO classification 2008.

Adapted from Harris et al 2008

Low Grade B cell Lymphoma

Is it equally common throughout the world

An EGYPTIAN large study (1009 cases)Frequency of Low Grade B cell Lymphoma : 8%

Follicular subtypes : 5%

Azim et al. Proc ASCO; abs#72, 1998

Low grade B cell Lymphoid Low grade B cell Lymphoid MalignanciesMalignancies

(LGBLM)(LGBLM)

o Natural History / Biological behaviorNatural History / Biological behavior

o TreatmentTreatment response and outcomeresponse and outcome

Similarities

LGBLMLGBLMNatural History & Biology Natural History & Biology

1.1. Histological transformation to high gradeHistological transformation to high grade

lymphoma observed in 30-40% of follicularlymphoma observed in 30-40% of follicular

lymphoma and 5-10% of SLL/CLLlymphoma and 5-10% of SLL/CLL

2.2. Spontaneous remission Spontaneous remission (20%)(20%) especially especially

in low grade follicular lymphomain low grade follicular lymphoma

Acker et al. JCO ;1:11, 1983

Horning and Rosenberg N Engl J Med ;311: 1471, 1984

Tendencyfor

LGBLMNatural History and Biology

3. BM and peripheral blood involvement is common because the mature B lymphocytes retain their normal ability to traffic throughout the lymphatic system and hence the majority of patients have an advanced stage at the time of diagnosis

Grogan Ann Oncol7; (suppl 6): 3, 1996

LGBLMLGBLMNatural History & BiologyNatural History & Biology

4.4. The vast majority of neoplastic B cells are non The vast majority of neoplastic B cells are non

proliferating i.e In the Go phase (Quiescent proliferating i.e In the Go phase (Quiescent

phase) of the cell cyclephase) of the cell cycle

e.g.e.g. 99% of B CLL cells are in the Go phase at the time 99% of B CLL cells are in the Go phase at the time

of diagnosis of diagnosis

Caligaris Cappio et al. JCO 17: 399, 1999

LGBLMLGBLMNatural History & BiologyNatural History & Biology

5.5. Disease progression is mediate (at least initially) via Disease progression is mediate (at least initially) via

gradual accumulation of malignant mature B gradual accumulation of malignant mature B

lymphocytes rather than rapid proliferation. These lymphocytes rather than rapid proliferation. These

cells enjoy a cells enjoy a selective survival advantageselective survival advantage relative to relative to

their normal counterpartstheir normal counterparts

e.g.e.g. CD5 +ve B cells has an average ½ life ofCD5 +ve B cells has an average ½ life of

5-7 days versus several weeks-months in case of 5-7 days versus several weeks-months in case of

CLL/SLLCLL/SLL

Maclenna & Gray Immunol; Rev91: 61, 1986

LGBLMNatural History and Biology

6.

Majority of follicular NHL have genetic abnormality involving translocation between chromosomes 14 and 18 [t (14 ; 18) ( q 32 ; q 21)]

Overexpression of BCL-2 gene (originally on chromosome 18)

BCL-2 is an anti-apoptotic protein

Korsmyer Blood; 80: 879, 1992

Cells Refusing to Die

Translocation between chromosomes 14 and 18 [t (14 ; 18) ( q 32 ; q 21)] which results in

BcL2 overexpression

This brings the BCL2 gene under the control of immunoglobulin heavy chain gene (IgH) enhancers and leads to overexpression of BCL2 protein

LGBLMLGBLMCells refusing to dieCells refusing to die

The tThe t(14 ; 18) translocation (seen in the majority of translocation (seen in the majority of

follicular lymphoma) is exceedingly rare in follicular lymphoma) is exceedingly rare in

SLL/CLL. However BCL-2 protein is consistently SLL/CLL. However BCL-2 protein is consistently

over expressed in these cells. Furthermore over expressed in these cells. Furthermore

SLL/CLL SLL/CLL do not respond to extra cellular do not respond to extra cellular

apoptotic signalsapoptotic signals

Caligamis Cappio et al. JCO 17: 399, 1999

Cells Refusing to Die

Treatment of LGBLMLGBLMGeneral Rules

LGBLMLGBLM

1. The majority of LGBLM are quite sensitive to

radiotherapy and wide range of chemotherapeutic drugs

including: Alkylating agent, Corticosteroids,

Anthracyclines & Purine analogs

2. Induction of remission is high especially in chemo-naive

patients. However CRs are not as highly seen in

aggressive lymphoma. More frequent CRs are

encountered in follicular lymphoma compared to other

subtypes of LGBLM

Treatment Response/Outcome

LGBLMLGBLM

3.3. The major therapeutic challenges in these disease is the The major therapeutic challenges in these disease is the

maintenance of remission (not the induction of remission) maintenance of remission (not the induction of remission)

as almost all the patients in remission would subsequently as almost all the patients in remission would subsequently

relapse ( relapse ( ++ histologic transformation ) histologic transformation )

4.4. Because of eventual relapse no curative treatment has Because of eventual relapse no curative treatment has

been established before the era of Rituximab. been established before the era of Rituximab.

Treatment Response/Outcome

No prospective study has shown that treatment of No prospective study has shown that treatment of

asymptomatic patientsasymptomatic patients (low tumor burden) at the time (low tumor burden) at the time

of diagnosis would prolong survival.of diagnosis would prolong survival.

Low grade B cell lymphomaManagement of advanced stage

Treatment strategy

Treatment of indolent lymphomaTreatment of indolent lymphoma

NCI studyNCI study

Young et al Semin. Hematol 25: 11, 1988 .Young et al Semin. Hematol 25: 11, 1988 .

Conclusion Conclusion

45 patients initial aggressive therapy initial aggressive therapy (ProMace/Mopp) followed by total lymphoid irradiation(ProMace/Mopp) followed by total lymphoid irradiation

44 patients were observed, No initial therapy (Watch &Wait)

VS

No survival advantage over Watch & Wait

Indications to initiate treatment in LGBLM

GELF criteria (High tumor Burden)

Leukemia or blood cytopenia

Mass > 7cm

Nodal sites > 3 (3cm)

Constitutional symptoms

Substantial spleenomegaly

Ureteric/mediastinal/epidural compression

Serous effusion

Solal Celigny P et al. N Engl Med;329: 1608, 1993

Follicular Lymphoma International Prognostic Index

(FLIPI)The best predictive five parameters

Age > 60

Stage III/IV

Increased LDH

HB < 12 gm

Number of nodal sites 5 or more

The records of 1795 patients with full clinical and 10 years survival data from Europe , North America and some far east countries were used to construct this prognostic model.

The Follicular Lymphoma International Prognostic Index (FLIPI): Overall survival

Pro

bab

ility

of

surv

ival

Months P < 0.0001

Good (01)

Intermediate (2)

Poor (35)

1.0

0.8

0.6

0.4

0.2

00 12 24 36 48 60 72 84

N = 1,795

Risk groupNo. of factors

Patients (%)

5-year (%)

10-year (%)

Relative risk

Good 01 36 91 71 1.0

Intermediate 2 37 78 51 2.3

Poor 3 27 53 36 4.3

Solal-Céligny P, et al. Blood 2004; 104:12581265.

Treatment of LGBLM Symptomatic patients/high tumor burden

For many decades, the standard therapy for symptomatic low grade B cell lymphoid malignancies (low grade lymphoma and CLL) was based on alkylating agents (usually chlorambucil) with or without prednisone

The triple combination of cyclophosphamide, vincristine and prednisone (CVP) and /or external beam radiotherapy have been recommended if rapid response is required for relief of sever symptoms

Portlock CS Semin Oncol; 17(1):51, 1990

AnthracyclineAnthracycline based regimens can based regimens can

produce higher response rates (and CRs) produce higher response rates (and CRs)

compared to compared to CVPCVP oror ChlorambucilChlorambucil. .

However no improvement in long-term However no improvement in long-term

disease free or overall survival has been disease free or overall survival has been

demonstrateddemonstrated. . Vose Ann Oncol 7; (suppl 6):13, 1996

Treatment of LGBLM

Conventional ChemotherapiesOverall survival of patients treated with

cyclophosphamide vs. CHOP-Bléo (from Peterson et al.,JCO 2003)

The positive impact of adding alfa-Interferon to ADR based regimen in

follicular lymphoma with high tumor burden

(GELF-86 Trial)

Solal-Celignc et al. JCO 16(7): 2332, 1998

N=123

N=119

2005 cases at a median follow up period of 7 years2005 cases at a median follow up period of 7 years

Conclusions Conclusions

Addition of Interferon alpha did significantly improve Addition of Interferon alpha did significantly improve survival incase of: survival incase of:

1.1. Use of relatively intensified chemotherapy (ADR or Use of relatively intensified chemotherapy (ADR or

Mitoxantrone based regimens)Mitoxantrone based regimens)

2.2. Adequate dose of interferon alpha ( Adequate dose of interferon alpha ( ≥ 5 million unit per 5 million unit per

injection and injection and ≥ 36 million unit / month) 36 million unit / month)

Rohatiner et al. Proc. ASCO; abs#1053, 2002

Meta analysis of 10 randomized studies Meta analysis of 10 randomized studies evaluating the role of evaluating the role of interferon in interferon in

follicular lymphoma follicular lymphoma

Purine AnalogsPurine Analogs Rational for use in LGBLMRational for use in LGBLM

They have unique Cytotoxicity against both dividing and non They have unique Cytotoxicity against both dividing and non

dividing lymphocytes (Go phase)dividing lymphocytes (Go phase)Seto et al J Clin Inves. 75; 377, 1985

They can initiate programmed cell deathThey can initiate programmed cell death

Potential synergy with other useful drugs: Potential synergy with other useful drugs:

cyclophosphamide & mitoxantronecyclophosphamide & mitoxantrone

Carson& Ribeiro Lancet 341; 1251, 1993

Koel et al. Proc AACR38 : 2; abs#10,1997

Fludarabine monotherapy in low grade lymphoma

PreviouslyTreated

Previouslyuntreated

Response rate 40-50%

CR 12-15%

Redman et al. JCO 10:790, 1992 Hiddman e al. Semin Oncol 20; (suppl7): 28, 1993

Response rate 65-70%

CR 35%

Solal-Celigny et al. JCO14: 514, 1996Pigaditou et al. Semin Oncol 20;(suppl 7): 24, 1993

Fludarabine is particularly effective in LGLwhile it has

a much lower activity inhigh grade NHL (RR 10-15%)

Redman et al. JCO 10:790, 1992

Fludarabine combination in LGBC lymphomasFMD regimen

Previously Treated Recurrent/refractory (N=51)

oResponse rate 94%oCR 47%oResponse duration 21 mons

of CR

Mclaughlin et al. JCO 14: 1262, 2996

FMD protocolFludarabine 25mg/m2 D1,2,3Mitoxantrone 10mg/m2 D1Dexamethasone 20mg D1-5Recycle every 4 weeks x 8

Phase III study

Fludarabine x 8 CVP x 8

68% ORR 51%

38% CR 15%

21mon TTP 15mon

68% 5 years 60% (NS)survival

Number : 381 casesImmediately treated : 248Treatment after W/W : 133

P = 0.001

Marcus et al. Ann Oncol 13; (suppl2): abs#181, 2002

Adverse EventsNumber : 381

Immediately treated : 248Treatment after W/W : 133

28% Neutropenia (Gr III/IV) 12% (p<0.005)

8% Thrombo (Gr III/IV) 1% (p<0.01)

2% Infection 3%

Alopecia more significant

Fludarabine CVP

Marcus et al. Ann Oncol 13; (suppl2): abs#181, 2002

FM compared to CHOP in follicular lymphoma (BCL2 +ve

BM/PB)

FM X 6 CHOP x 6

72 Number 68

68% CR 42%

39% Molec CR 19%

P=0.003

P=0.001

Zinzani et al. JCO 2004 (july)

Toxicity of chemotherapyToxicity of chemotherapy Zinzani et al, JCO 2004Zinzani et al, JCO 2004

FM

(n=72)

CHOP

(n=68)

Grade 3-4 toxicity No. Pts % No. Pts % p

Neutropenia

Nausea/vomiting

Alopecia

Peripheral Neurologic Toxicity

Constipation

22

2

10

0

0

30

3

14

/

/

27

15

58

18

22

39

22

85

26

32

n.s.

0.000

0.000

0.000

0.000

What is the optimal first-line chemotherapy?

Up-front Anthracycline: why and why not?

• PROS

– More quickly active

– Active on a minor

large cell population ?

• CONS– Cardiac toxicity– Alopecia– Hampers salvage

treatments– No beneficial effect of

CHOP vs regimens without adriamycin in Terms of OS

CHOP is not a standard first-line regimen for low grade lymphoma.Adriamycin is an important drug for :

- relapses- histological transformations

Should we use Fludarabine as

first line inLGB Lymphoma

…??

Wijermans et al. Eur J hematology; 50: 292, 1993

Fludarabine may induce unique Fludarabine may induce unique

toxicitiestoxicities

Fludarabine is both Fludarabine is both myelotoxicmyelotoxic and and lymphotoxiclymphotoxic

leading to marked immuno suppression leading to marked immuno suppression

susceptibility to opportunistic infections susceptibility to opportunistic infections

(reduction of CD4 T helper cells is seen up to 1 (reduction of CD4 T helper cells is seen up to 1

year of discontinuation of the drug)year of discontinuation of the drug)

Fludarabine may induceFludarabine may induce

unique toxicities including:unique toxicities including:

1.1. Stem cell depletionStem cell depletion

2.2. Hemolytic anemiaHemolytic anemia

3.3. NeurotoxicityNeurotoxicity

4.4. Pulmonary toxicityPulmonary toxicity

5.5. Hearing lossHearing loss

6.6. Renal impairmentRenal impairment

Effect of up-front Anthracycline and Purine analogue on risk of transformation

Anthracycline-based

Alkylator plus purine analogue

Transformation 18% 27%

5-year risk of transformation

9% 24% (p < 0.0095)

Annual risk of transformation(10 year follow-up)

1.5% 3.0%

J Clin Oncol 2006; 24:Abstract 7510.

• Retrospective review of 260 patients

Low Grade B Cell Lymphoma

Fludarabine

Currently available data do not recommend the use

of this agent as first line outside controlled clinical studies except in CLL and

SLL

Low Grade B Cell Lymphoma Fludarabine

• In cases with small lymphocytic lymphoma (as in CLL) there is a good reason to use first line Fludarabine in combination with Cyclophosphamide with or without Mitoxantrone.

• Also in patients with Lymphoplasmacytic Lymphoma and macroglobuliaemia ,Fludarabine usually in combination with Cyclophosphamide may be considered in front line management.

• In Hairy cell leukemia treatment with another purine analog (2CDA) is considered as the standard of care in this disease. Of notice , 85% of the treated patients achieve very durable remissions with only 2 courses of 2CDA

FLUDARABINE IN W M

FLUDARABINE CAP

N=46 N=46

OR 30% 11% p=0.019

MRD 19Ms 3Ms p<0.01

Leblond el al Blood,2001

Bendamustine

Bendamustine

• Bendamustine is a novel nitrogen mustard and antimetabolite hybrid which is noncross-resistant with other alkylating agents.

• This drug has been extensively used in East Germany for over 40 years with activity in NHL, chronic lymphocytic leukemia, and multiple myeloma, with an acceptable safety profile. During the last few years, the drug was made available in other countries

• Bendamustine was found to be one of the most promising agents in the treatment of B cell NHL.

• Around 70% of patients with relapsed/refractory low grade B cell NHL and mantle cell lymphoma respond to Bendamustine as single agent,

( including 15-30% CRs), thus setting the new standard for drug activity in such patients

Bendamustine

Friedberg JW, Cohen P, Chen L et al. Bendamustine in patients with rituximab-refractory indolent and transformed non-Hodgkin's lymphoma: Results from a phase II multicenter, single-agent study. J Clin Oncol 2008;26:204–210

TargetTarget therapy in NHL

Target Target Antigens in in Lymphoid MalignanciesLymphoid Malignancies

B cell T cell

CD19

CD20

CD22

HLA-DR

CD52

CD3

CD52

CD25

CD4/8

TCRIdiotype

CD23

• Many cell-surface antigens are expressed on lymphoma cells which are virtually always expressed on their nonmalignant counterparts as well.

• Therefore, the malignant B cells can be targeted and eradicated by specific antibodies directed against their surface antigens.

• However surface antigens suitable for targeting should have certain features to allow effective and safe therapeutic use in the clinic.

CD 20 as an Ideal Target for Immunotherapy of B cell Lymphomas

1. CD20 is a transmembrane surface antigen involved in B cell growth and maturation

2. It is expressed only on B cells (precursor and mature) BUT NOT on stem cells, normal mature plasma cells or other normal tissues

3. It is expressed on more than 85% of B cell LymphomaAnderson et al. Blood;63 : 1424, 1984

Tedder & Engel. Immunol Today;15 : 450, 1994

CD20 expression in B-cell malignanciesH

isto

log

y

0 100 200 300 400 500 600

Adapted from Maloney GD. Semin Hematol 2000;37(4 Suppl. 7):17–26

Mean channel fluorescenceLP = lymphocyte predominantPLL = prolymphocytic leukaemia

Burkitt’s lymphoma

CLL

CLL/PLL

Follicular small cell

Hairy cell

Large cell

LP/Waldenström’s

Mantle cell

Marginal zone

Small cleaved

CD20 as an Ideal TargetCD20 as an Ideal Target

4. It can be safely eradicated from the body

without causing excessive toxicity, since normal

B-cells will re-emerge following differentiation

from stem cells, while serum immunoglobulin

levels can be maintained by persisting plasma

cells.

CD20 as an Ideal Target Antigen

5.5. It is not normally shed from the cell surface and serum It is not normally shed from the cell surface and serum levels of the antigen are undetectable. levels of the antigen are undetectable.

o If a cellular target was also found in soluble form in If a cellular target was also found in soluble form in significant levels in the blood, this could attenuate significant levels in the blood, this could attenuate the function of the therapeutic antibody.the function of the therapeutic antibody.

Press et al. Blood ;69:584, 1987

•Although not tumor specific, it is B-cell restricted

Rituximab binding Rituximab binding to to CD 20

Rituximab

Rituximab versus Ofatumumab binging to CD20

Extra-cellular domain

Intra-cellular

Transmembrane

CD20CD20

Ofatumumab

Rituximab : A mouse/human chimaeric monoclonal antibody

Rituximab is a chimeric human IgG1 kappa antibody, with a variable region isolated from a Murine anti-CD20 antibody

The rest of the antibody is of human origin allowing invivo ADCC, CDC

Adapted from Reff et al. Blood; 83: 435, 1994

Complement fixation

CD20on malignantcell surface

Active signaling (apoptosis induction)

ADCC

FcR

CR3

Rituximab : Proposed Mechanisms of Action Fcg receptors

affinity with IgG1

Antibody-dependent cellular cytotoxicity

major mechanism of action of rituximab

• in vitro have shown that depletion of malignant B cells by rituximab requires the presence of functional mononuclear cells.

• binding of the antibody’s Fc portion to Fcγ receptors expressed in immune cells with cytotoxic capabilities such as

– monocytes,

– natural killer cells

– granulocytes, – which would then lead to destruction of rituximab-bound B cells

either by phagocytosis or by the release of cytotoxic granules contained in immune effector cells.

Rituximab: Induction of apoptosisInduction of apoptosis

• In vitro studies have shown that engagement of CD20 by rituximab triggers a cascade of intracellular signaling events and selectively down-regulates the antiapoptotic molecule bcl-2 and subsequently enhance drug-induced apoptosis. – This is mediated via inhibition of the MAPK

signaling pathway, as well as NF-κB pathways, two major survival pathways in B cells .

Alas S, Bonavida B. Rituximab inactivates signal transducer and activator of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of bcl-2 and sensitization to cytotoxic drugs.Cancer Res 2001;61:5137-44

Rituximab Rituximab

• As monotherapy Rituximab produces high response rate As monotherapy Rituximab produces high response rate

with extremely favorable toxicity profilewith extremely favorable toxicity profile

• Classic dosing 375mg/m2/week x 4 Classic dosing 375mg/m2/week x 4

Unique therapeutic featuresUnique therapeutic features

McLaughlin et al. JCO; 16:2825, 1998

Previously untreatedPreviously untreated 70% 70%Colombat et al Blood;97:101, 2001

Previously treated 50% Previously treated 50% (166 patients)(166 patients)

Median TTP = 12.5 m

Rituximab as an ideal partner to use with convential chemotherapy

Alas et al Clin. Cancer Res; 7: 709, 2001Alas et al Clin. Cancer Res; 7: 709, 2001

•Rituximab may act synergistically on induction of

apoptosis with the following chemotherapeutic drugs:

FludarabineFludarabine

DoxorubicinDoxorubicin

CisplatinumCisplatinum

Ara-cAra-cRational for use in Rational for use in

combinationcombination

(concomitantly)(concomitantly)

14

2

69

0

20

40

60

80

100

Rituximab +Fludarabine +Complement

FludarabineRituximab +Complement

Cel

l Lys

is (

%)

Cell Lysis

Golay et al. Blood; 96(suppl 1)339a, abs#1463, 2000

Expression of CD55 (complement inhibitor)

CD

55+ C

ells

(%

)

No Fludarabine Fludarabine

55

96

0

20

40

60

80

100

Rituximab and Fludarabine reciprocal Rituximab and Fludarabine reciprocal synergy in LGBLMsynergy in LGBLM

Fludarabine Downregulates Fludarabine Downregulates Complement InhibitorsComplement Inhibitors

FludarabineFludarabine downregulates membrane expression of CD55, a complement inhibitor

R-chemotherapy

Study name and author Follow-upOverall survival (%)

PControl Rituximab

M3902; Marcus et al.1 4 years 77 83 GLSG; Hiddemann et al.2 5 years 84 90

M39023; Herold et al.3 4 years 75 89

FL2000; Salles et al.4 5 years 79 84 (high risk pts)

Cochrane analysis:HR = 0.63 [0.51–0.79]

Schulz H et al. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003805.

Rituximab + chemotherapy in first-line FL: Effect on overall survival

1. Marcus R, et al. J Clin Oncol 2008; 26:4579–4586. 2. Buske C, et al. Blood 2008; 112:abstract 2599.

3. Herold M, J Clin Oncol 2007; 25:1986–1992.4. Salles G, et al. Blood 2008; 112:4824–4831.

Conclusions

• Several large prospectively randomised phase III studies

– demonstrating superiority of R plus standard chemotherapy compared to chemotherapy alone

Immunochemotherapy new standard in the first-lineand salvage treatment of advanced stage follicular lymphoma

B-R vs CHOP-R as Initial Therapy for FL and MCL

first interim analysis Median observation period 18 months

315 patients

Rummel et al, Proc ASH, 2007

Toxicity

IF YOU TREAT BY CLASSIC CVP AND THERE IS NO

PROGRESSION

CVP ± rituximab maintenance in untreated FL (ECOG 1496): trial design

Hochster HS, et al. Proc Am Soc Clin Oncol 2004; 22:Abstract 6502.Hochster HS, et al. Blood 2005; 106:Abstract 349.

• Phase III trial of CVP ± rituximab maintenance

• 401 patients with previously untreated follicular NHL, 322 randomised

Observation

Rituximab maintenance • 375 mg/m2 q1wk 4• q6mo 4

RANDOMISE

PR, CR or stable

CVP 6–8

cycles

ECOG 1496 observation vs rituximab maintenance after CVP: PFS

HR = hazard ratio

100-

80-

60-

40-

20-

0- 0 2 4 6 8

HR = 0.4One-sided log rank p < 0.0000001

Rituximab maintenance

Observation

PF

S (

%)

Time (years)

Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.

HR = hazard ratio

Time (years)

ECOG 1496 observation vs rituximab maintenance after CVP: OS

Hochster H, et al. J Clin Oncol 2009; 27:1540–1542.

0 2 4 6 8

100-

80-

60-

40-

20-

0-

Rituximab maintenance

Observation

Ove

rall

su

riva

l(%

)

HR = 0.6One-sided log rank p < 0.08

E1496: follicular lymphoma survival1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5 6

Years from maintenance randomisation

MR (120)

OBS (117)

Log-rank one-sided p=0.03HR 0.5 (0.3–1.1)

Pro

bab

ilit

y

HR = hazard ratio; MR = maintenance rituximab; OBS = observation

Hochster HS, et al. Blood 2005; 106:Abstract 349.

E1496: OS at 3 years from randomisation

Characteristic (n) MR Obs p valueHR

(95% CI)

All patients 92% 83% 0.03 0.5 (0.3–1.1)

FLIPI score

0–2 (118) 91% 88% 0.08 0.5 (0.1–1.4)

3–5 (68) 91% 70% 0.16 0.6 (0.2–1.7)

Tumour burden

Low (85) 93% 99% 0.38 1.3 (0.2–7.9)

High (152) 92% 74% 0.01 0.4 (0.2–0.6)

Residual disease

Minimal (170) 95% 90% 0.11 0.5 (0.2–1.5)

Gross (134) 89% 75% 0.08 0.5 (0.3–1.5)

Total events 12 21 – –Hochster HS, et al. Blood 2005; 106:Abstract 349.

IF YOU TREATED BY CLASSIC SINGLE AGENT OR CVP AND THEN

YOUR PATIENT PROGRESSED

EORTC 20981

• Phase III trial of CHOP ± R, with or without rituximab maintenance

• 474 patients with relapsed/refractory follicular NHL, 316 randomised for maintenance/observation

RANDOMISE

CHOP x 6

R-CHOP x 6

Observation

Rituximab maintenance • 375 mg/m2

• q3mo to relapse or 2 yrs maintenance

RANDOMISE

Van Oers MHJ, et al. Blood 2005; 106:Abstract 353

EORTC 20981:

response to induction therapy

*p<0.0001 (Mantzel Haenszel test for trend)

Van Oers MHJ, et al. Blood 2005; 106:Abstract 353

CHOP (%) R-CHOP (%)

ORR 167 (73) 199 (85)*

CR 36 (16) 69 (29)*

PR 131 (57) 130 (56)

NC 24 (10) 13 (6)

PD 22 (10) 6 (3)

Death 2 (1) 1 (<1)

Not ass. 16 (7) 15 (6)

Total 231 234

EORTC 20981 phase III trial

PFS after CHOP (n=145)

Overall log-rank test: p<0.0001; HR: 0.30

Years0 1 2 3 4 5

Overall log-rank test: p=0.004; HR: 0.54

PFS after R-CHOP (n=189)

Years0 1 2 3 4 5

MabThera maintenance therapyMedian 42.2 months

ObservationMedian 11.6 months

ObservationMedian 23.1 months

MabThera maintenance therapyMedian 51.9 months

PF

S (

%)

PF

S (

%)

100

90

80

70

60

50

40

30

20

10

0

van Oers MHJ, et al. Blood 2006;108:3295–301

100

90

80

70

60

50

40

30

20

10

0

Progression free-survival from second randomisation

Subgroups according to induction treatment

O N Number of patients at risk55 69 31 11 4 132 76 61 38 20 4

O N Number of patients at risk55 98 59 31 13 434 91 65 48 27 8

Overall survival from 2nd randomisation: subgroup analysis

OS after CHOP

100908070605040302010

0

Years0 1 2 3 4 5 6

Overall log-rank test: p=0.073HR: 0.52

OS

(%

)

OS after R-CHOP

Years0 1 2 3 4 5 6

Overall log-rank test: p=0.059HR: 0.49

OS

(%

)

100908070605040302010

0

van Oers MHJ, et al. Blood 2005;106:107a (Abstract 353) Updated in oral presentation

MabThera maintenance therapy

Observation

MabThera maintenancetherapy

Observation

O N Number of patients at risk19 69 42 23 7 212 76 49 30 8 2

O N Number of patients at risk20 98 87 57 27 7 011 91 80 63 39 11 2

Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.

van Oers 2006

Forstpointner 2006Ghielmini 2004

Hainsworth 2005 Hochster 2005 Hochster 2007

Subtotal (95% CI)

HR (95% CI) HR (95% CI)Weight (%)

0.51 (0.31–0.86)

0.49 (0.18–1.30)0.50 (0.27–0.92)

0.86 (0.49–1.49)0.51 (0.25–1.04)4.51 (0.47–43.4)

0.60 (0.45–0.79)

Meta-analysis: Rituximab maintenance

improves overall survival

0.001 0.1 10 1000

15.2

29.1

8.120.7

25.3

1.5

100

p < 0.0003

1

Favours rituximab Favours observation

Study

Meta-analysis: Rituximab maintenanceInfectious adverse events

• As expected, there were more infections with prolonged rituximab

• However, the absolute numbers were low and discontinuation rates were low

• No deaths were associated with infections

Vidal L, et al. J Natl Cancer Inst 2009; 101:248–255.

Favours

observation

Favours

rituximab

p = 0.007

0.1 0.5 1 20.2 5 10

Rituximab maintenance

• the GELA (the PRIMA study) is currently evaluating the benefit of a 2-year rituximab maintenance after rituximab plus chemotherapy.

• More than 1200 patients have been currently registered, and the first interim analysis may be presented in ASH 2009.

Rituximab Resistance

• Approximately 50% of patients with relapsed/refractory

CD20+ follicular lymphomas do not respond to initial

therapy with rituximab (innate resistance)

• close to 60% of prior rituximab responding patients will not longer benefit with retreatment with this monoclonal antibody (acquired resistance).

• Whether these forms of rituximab-resistance are due to an adaptive property of the malignant B cell or to an impaired host’s immune effector mechanisms remains unclear.

• The properties of the host’s FcγR to which the antibody

binds on leukocyte effector cells influences the efficacy of

rituximab therapy.

• Three classes of FcγR (FcγRI, FcγRII and FcγRIII) have

been described in immune effector cells.

• the FCGR3A gene encodes FcγRIIIa(CD16) with either the

amino acid phenylalanine (F) or valine (V) at amino acid

position 158.

Cartron G, Dacheux L, Salles G, et al. Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene.

Blood.2002;99:754-758.

Antibody-dependent cellular cytotoxicity

major mechanism of action of rituximab

• Change in a single amino acid significantly affects the affinity of the FcγRIIIa for human immunoglobulin G1 and the subsequent efficacy of ADCC.

• it is now well established that human IgG1 binds more strongly to homozygous FcγRIIIa-158 valine/valine (V/V) expressed in natural killer (NK) cells than homozygous FcγRIIIa-158 phenylalanine/phenylalanine (F/F) or heterozygous FcγRIIIa-158F carriers.

Host-related mechanisms

SAKK 35/98

Ghielmini M, et al. Blood 2004; 103:4416–4423.

• Phase III trial of rituximab maintenance therapy

• 202 patients with previously untreated (n=64) or relapsed/refractory FL; 151 (51 previously untreated) patients randomised

Observation

Rituximab maintenance • 375 mg/m2

• q2mo (3, 5, 7, 9)

RANDOMISE

PR, CR or stable

Rituximab

• 375 mg/m2

• q1wk 4

SAKK 35/98 results: Event-free survival

polymorphism 0f FcγRIIIa(CD16)

M. Ghielmini1*, et alAnnals of Oncology 16: 1675–1682, 2005

Rituximab maint : median 23.2 Ms

Observation: median 11.8 months

maintenance

Observation

Second generation anti CD20 Anti-Bodies

• several groups engineer the Fc portion of MAbs

as a strategy to increase their binding to the low-

affinity receptors FcγRIIIa-158F/F or V/F (which

accounts for the large majority of the population)

that augments ADCC and ultimately try to

improve the response to antibody therapy.

Second generation antibody therapies may offer improved efficacy

• New anti-CD20 antibodies are under development and show promising early clinical efficacy, including:

• GA101 (humanised antibody with increased ADCC

and cell death)• Ofatumumab (fully human)• Ocrelizumab (humanised)• Veltuzumab (humanised)

Radio Immunotherapy

+MAb RadioIsotope

Cytotoxicity attributed to MAB for (Antigen +ve) in addition to

target irradiation for antigen +ve and adjacent antigen –ve tumor cells

(cross firing)Leading to potential advantage

of increasing tumor cell killing (& increased toxicity)

Radio Immunotherapy (RIT) VS

Conventional External Beam Radiotherapy

• RIT delivers radiation at a continuous but variable dose rate (starting low then building up as the

MAB accumulates in the tumor and finally decreasing according to the biological half life of

the isotope)• Unlike the external beam radiation (daily fractions) RIT provides continuous delivery of radiation and hence offering less opportunity of

repair of DNA sublethal damage

Press Semin Hematology 37 (7): 2 , 2000

Radio Immunotherapy in LGBLM

• B cell Lymphoma are particular candidates for RIT because of their inherent radiation sensitivity

• The relative immune paresis specially seen in previously treated patients would reduce the likely

hood of developing HAMA

• Systemic nature of the disease would render systemic RIT a more logic approach compared to

localized / extended field irradiation

Radio Immunotherapy for Low Grade Lymphoma

Ibrituxomab (parent of Rituximab) Tusimomab+ linker chelator (Tiuxetan) + radioisotope I-131+ radioisotope Yttrium-90

Murine MAb

FDA approved (Feb 2002) FDA approved

Zevalin Bexxar

Are we improving survival in LGBCL

• The MD Anderson Cancer Center reported 580 patients with stage IV disease treated from 1972 until 2002 with different immunochemotherapy regimens.

• These investigators reported a marked improvement in 5-year failure-free survival (from 29% to 60%) and overall survival (OS; from 64% to 95%) in this period.

Liu Q, Fayad L, Cabanillas F, et al. J Clin Oncol. 2006;

Are we close to a cure in first-line treatment of patients with follicular

lymphoma?

Treatment of LGBLMFew Steps Forwards

Better histo-pathological classification (clinically distinct entities)

Better understanding of the

disease biology on molecular basisBetter target therapyMore effective salvage therapy

YES

Improvement of OAS