Treatment of non-Hodgkin Lymphomas

Over 40 different types of NHL: reflection of the complex growth and differentatition of normal (B) lymphocytes

Treatment of non-Hodgkin lymphomageneral principles

It is (still ) not possible to select a specific treatment for each type of NHL

Therefore NHL are divided into major subgroups:

– Indolent types (follicular lymphoma)– Aggressive types (diffuse large B cell lymphoma)– Very aggressive types (Burkitt)

Treatment of non-Hodgkin lymphomaconsiderations as to choice of therapy

• Type of lymphoma (WHO classification)

• Ann Arbor stage (I to IV)

• localizations

• Risk profile/prognostic score of the patient

• Which treatment is possible?

non-Hodgkin LymphomasClinical Staging

• History/ Physical examination• CT scan thorax• CT scan abdomen• 18FDG-PET scan: aggressive lymphomas• Bone marrow biopsy

CT scans in lymphoma

18 FDG-PET scan in lymphoma

non-Hodgkin Lymphoma Ann Arbor Staging

A = no symptoms

B = fever (unexplained)

night sweats

weight loss >10%

Treatment of non-Hodgkin lymphoma approach till 2004

Indolent (stage II-IV)*

• “Wait and see”

• (mild) chemotherapy

• (low dose) radiotherapy

Aggressive (stage II-IV) **

• CHOP chemotherapy 1x / 3 weeks,8x

* Stage I(II): high dose radiotherpy ** Stage I: 3x CHOP + radiotherapy

Survival of NHL patients (till 2004)

Years since diagnosis

indolent

aggressive

very aggressive

100%

50%

10 20

The results of the treatment of patients with NHL have been improved impressively by the use of antibodies directed against the lymphoma cells

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

CD20 Expression in B-Cell Development

Plasma cellPluripotent

stem cellLymphoid stem cell

Pre-B cell B cell Activated B cell

Bone marrow Blood, lymph

CD 20

Press. Semin Oncol 1999;26(5 suppl 14):58

Anti-CD20 (Rituximab= Mabthera®)mechanism of action

Adapted from Male D, et al., Advanced Immunology 1996: 1.1–1.16

Malignant B-cell

Complement

CD20

CD20

Direct induction of apoptosis

Killer Leukocyte

Anti-CD20 (Rituximab= Mabthera®)side effects

• Mild and transient, mainly during first infusion

• Fever, chills ( prevention)

• Temporary drop in blood pressure, dyspnea

• Rare: antibodies against rituximab

CHOP ± Rituximab in DLCL in the elderly (60-80 yr)Pr

obab

ility

of e

vent

-free

sur

viva

l

Years0 1 2 3 4 5

p=0.00001

51% CHOP + rituximab

29% CHOP

1.0

0.8

0.4

0.6

0.2

Coiffier et al.

DLCL in the elderly :Rituximab improves overall survival

Years

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4 5

p=0.01

59% Rituximab + CHOP

47% CHOP

Prob

abili

ty o

f ove

rall

surv

ival

Coiffier et al.

Rituximab maintenance prolongs progression-free survival in relapsed Follicular lymphoma

R-maintenancemedian: 44 mo

Observationmedian: 16 mo

0 1 2 3 4 5 6 7 8

p < 0.0001

Time (years)

0

20

40

60

80

100

PFS

(%)

van Oers MHJ, et al. J Clin Oncol 2010; 28:2853-2858.

S

NH C

NH90

Zevalin™(Ibritumomab tiuxetan)

Mouse anti-CD20

Radiolabeled anti-CD20 antibodies in the treatment of relapsed folicular lymphoma

• Response % higher than with “naked” anti-CD20

• Response duration ~ similar to “naked” anti-CD20

• High dose : response (5-10 years) cure ?

• Also effective in patients resistant to “naked” anti-

CD20

Zevalin as consolidation in FL:PFS in All Patients*

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66

PFS time from randomization (months)

Prop

ortio

n re

mai

ning

pr

ogre

ssio

n fr

ee (%

) Log rankP < 0.0001HR 0.463

Zevalin: median 37 mon = 208

Control: median 13.5 mon = 206

*Median observation 3.5 years. Hagenbeek et al. ASH 2007, abstr 643

New targets lymphoma treatment

non-Hodgkin’s LymphomasTreatment

• Surgery: NEVER !!• Wait and see (indolente lymfomen)• Radiotherapy: stage I indolent

stage I aggressive (+CT!)• (poly) chemotherapy• Immunotherapy: monoclonal antibodies• Immuno-chemotherapy

non-Hodgkin LymphomasTreatment Results

Malignancy Grade

Stage Cure Rate (%)

Indolent I / II * III / IV

50-60 0 !!

Aggressive I/ II III / IV

70-80 40-45

* 15 / 10%

non-Hodgkin’s LymphomasSummary

Indolent Aggressive

Stage I < 15% ~ 30%

Survival untreated

years months

Response to mono-CT

++ ---

Response to poly-CT

++ ++

Response to anti-CD20

++ ++

Cure rare frequent

New developments in the treatment of lymphoma

• New monoclonal antibodies (HumaxCD20, CD22)

• Radio-immunotherapy

• New agents (bortezomib, lenalidomide, bendamustine, apoptosis-inducers, small molecules)

• New combinations

• Allogeneic SCT (RIST)

Unconjugated anti-CD20-mAbs in lymphoma (Rituximab )

• Monotherapy in relapsed indolent lymphoma

– ORR ~ 50 % (6% CR)– Response duration ~1 year

• Combination with chemotherapy (induction)

– Indolent lymphoma– Aggressive lymphoma

• Maintenance treatment : Indolent lymphoma

CVP ± Rituximab in first line stage III/ IV follicular NHLMarcus et al Blood 2004

RANDOMISED

CHOP every21 days

maximum six cycles

Rituximab + CHOP every

21 daysmaximum six cycles

EORTC 20981 phase III trial:R-CHOP versus CHOP in relapsed follicular NHL

RANDOMISED

Observation

Rituximab maintenance*

*375mg/m2 every 3 months for 2 years or until relapse

Van Oers et al ASH 2005

Rituximab maintenance significantly improves overall survival from 2nd rand.

Years0 1 2 3 4 6

0102030405060708090

100

Patie

nts

(%)

p = 0.011HR: 0.52

5

Rituximab maintenance: 3 years 85.1%

Observation: 3 years 77.1%

van Oers M, et al. Blood 2006; 108:3296–3301.

Therapy of aggressive NHLTherapy of aggressive NHL• polychemotherapy• golden standard till 2004 : CHOP

Drug Dose Route Day

Cyclophosphamide 750 mg/m2 i.v. 1

Doxorubicin (hydroxydaunorubicine)

50 mg/ m2 i.v. 1

Vincristine (oncovin) 1.4 mg/ m2 * i.v. 1

Predniso(lo)ne 100 mg p.o. 1-5

* max. dose per cycle: 2 mg

non-Hodgkin’s lymphoma Why treatment with antibodies?

• With present chemotherapy no or insufficient cure

• Treatment of minimal residual disease after chemotherapy might improve prognosis

• Antibodies are more specific than cytostatic drugs

• Antibodies are less toxic

• Antibodies have a different mechanism of action

Conclusions

• Monoclonal antibodies have become an important component of treatment of malignant lymphomas

• Combination of Rituximab and chemotherapy : new standard for untreated and relapsed indolent and aggressive lymphoma

• After induction (in relapsed FL): Rituximab maintenance

• Radio-immunotherapy has yielded promising results