Non-Hodgkins Lymphoma

Non-Hodgkin´s lymphoma
Univ. Prof. Dr. Werner Linkesch
Leiter der Klinischen Abteilung für Hämatologie
LKH-Univ. Klinikum Graz
Univ. Klinik für Innere Medizin
NON-HODGKIN’S LYMPHOMA
(NHL)
• Approximately 1.5 million people worldwide are living with
non-Hodgkin’s
lymphoma (NHL), and it is estimated that
300,000 people die each year from the disease
• 1 new case diagnosed every 9 minutes*
• 81% increase in incidence of NHL between
1973 -1990
• NHL is the third fastest growing cancer (excluding
the US) in terms of population in the world
• NHL is leading cause of death due to cancer in
men aged 20-40 years
*US
*US statistics
statistics
1
Proposed WHO Classification of Lymphoid Neoplasms
B-Cell neoplasms
Precursor B-cell neoplasm:
Precursor B-lymphoblastic leukemia/lymphoma (precursor B-ALL)
Mature (peripheral) B-cell neoplasms:
B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes)
Hairy cell leukemia
Plasma cell myeloma/plasmacytoma
Extranodal marginal zone B-cell lymphoma of MALT type
Nodal marginal zone B-cell lymphoma (+/- monocytoid B cells)
Follicular lymphoma
Mantle-cell lymphoma
Diffuse large B-cell lymphoma
Mediastinal large B-cell lymphoma
Primary effusion lymphoma
Burkitt's lymphoma/Burkitt cell leukemia
Proposed WHO Classification of Lymphoid Neoplasms
T-cell and NK-cell neoplasms
Precursor T-cell neoplasm:
Precursor T-lymphoblastic lymphoma/leukemia (precursor T-ALL)
Mature (peripheral) T-cell neoplasms:
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemia
Aggressive NK-cell leukemia
Adult T-cell lymphoma/leukemia (HTLV1+)
Extranodal NK/T-cell lymphoma, nasal type
Enteropathy-type T-cell lymphoma
Hepatosplenic gamma-delta T-cell lymphoma
Subcutaneous panniculitis-like T-cell lymphoma
Mycosis fungoides/Sezary syndrome
Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type
Peripheral T-cell lymphoma, not otherwise characterized
Angioimmunoblastic T-cell lymphoma
Anaplastic large-cell lymphoma, T/null cell, primary systemic type
2
Major NHL Types
Category
Percentage Incidence
31%
22%
8%
7%
7%
6%
2%
2%
2%
2%
2%
Diffuse Large B Cell
Follicular
Marginal Zone B-Cell, MALT
Peripheral T-cell
Small B-lymphocytic (CLL)
Mantle cell lymphoma
Primary mediastinal large B-cell
Anaplastic large T/null cell
High grade B-cell, Burkitt-like
Marginal Zone B-cell, nodal
Precursor T-lymphoblastic
Indolent
Aggressive
Highly aggressive
Frequency of NHL Subtypes in
Adults
Composite lymphomas (12%)
Small lymphocytic (6%)
Follicular (22%)
Mantle cell (6%)
Peripheral T-cell (6%)
Marginal zone B-cell,
MALT (5%)
Diffuse large B-cell (31%)
Other subtypes with a
frequency <2% (9%)
Marginal zone B-cell, nodal (1%)
Lymphoplasmacytic (1%)
Armitage et al. J Clin Oncol 1998;16:2780–2795
3
NHL-Etiology
• Etiology typically unknown
• Strong association with long-term immunosuppressive
therapy
• Pathogen:
–
–
–
–
–
–
–
EBV (Burkitt’s lymphoma, PTLD)
HHV-8 (body cavity, multiple myeloma)
Hepatitis C
HTLV-1 (Adult T-cell leukemia, lymphoma)
Helicobacter pylori (MALT lymphoma)
C. jejuni Immunoproliferative small intestinal disease (IPSID)
Chlamydie psitacci (ocular adnexal lymphoma)
The indolent lymphomas
•
•
•
•
•
Follicular lymphoma
Lymphoplasmacytic lymphoma (Waldenström’s
macroglobulinemia)
Extranodal marginal zone B-cell lymphoma
(MALT lymphoma)
CLL
Hairy cell leukemia
4
The aggressive lymphomas
•
•
•
•
•
DLCL
Peripheral T cell lymphoma
Anaplastic large cell lymphomas
FL, grade III
Mantle cell lymphoma
Staginguntersuchungen
5
Follikuläres Keimzentrumslymphom
Follicular Lymphoma International
Prognostic Index
Age
Ann Arbor stage
> 60 y
III-IV
Hemoglobin level
< 120 g/L
Serum LDH level
> ULN
Number of nodal sites > 4
Solal-Céligny, Blood 2004
6
Outcome to risk group as defined by the
Follicular Lymphoma International Prognostic
Index
•
Number of factors*
10-year OS, % (SE)
Low
0-1
Intermediate
2
High
>3
70.7 (2.7)
50.9 (2.7)
35.5 (2.8)
• * Factors adversely affecting survival in the FLIPI include age
greater than 60 years; Ann Arbor stage III-IV; number of nodal
sites greater than 4; serum LDH level greater than the upper limit
of normal; and hemoglobin level less than 120 g/L.
•
OS indicates overall survival; SE, standard error;
Follikuläres Keimzentrumslymphom
Grad I u. II
Inzidenz
steigend, z.Z. 10-17 / 100 000 / Jahr
Altersgipfel
50 - 60. Lebensjahr
Immunologisches Profil
SIg+, CD10+/-, CD 20+/-CD 23-/+, CD 5Genetik
t 14;18 , bcl2
Prognose
CSIII u. IV 8-10 a, konstante Rezidivrate (15%/a), Transformation 5-10%/a
7
Therapieindikationen
bei indolenten NHL
CS I und II immer da kurativer Ansatz !
CS III und IV wenn:
•B Symptome
•Sonstige Lymphomsymptome
•Erkrankungsprogression
•„bulky disease“
•Hämatopoetische Insuffizienz
•(drohende) Komplikationen durch Lymphomkompression
•Therapiewunsch
•Experimentelle Therapie bei jungen Patienten
Follikuläres Keimzentrumslymphom
Grad I u. II
Therapie
•
CS I, II, (IIIA)
(15 -20%)
•
CS III, IV
(80 -85%)
Rx (30-40Gy EF), Intention: kurativ
wait and watch (40%!, Therapieindikation nach duchschn. 18 M)
CHOP-R, R-CHOP
COP (CVP) (Cyclophosphamid, Vincristin, Prednisolon)
MCP (Mitoxantron, Chlorambucil, Prednisolon)
Leustatin, Fludarabin, FC, FND +/- R
Rituximab Monotherapie
Radiokonj. Anti CD 20 (Y90, J131)
Rx (20-30Gy IF)
Autologe Stammzelltransplantation (=SCT)
Allogene SCT (myeloablative, non myeloablativ, RIST)
8
9
10
11
12
13
Diffuse large B cell
Lymphoma (DLBCL)
• Most frequent NHL type (31%)
• Clinics: Usually aggressive
• Phenotype: Histologic subset and Immunophenotype:
CD19+; CD22+; CD10-/+; SIg+
• Putative cell of origin: Large transformed B-cells
harbouring somatic hypermutation of the Ig genes
(ongoing mutations in some cases)
Diffuse large B cell
Lymphoma
14
15
GELA LNH-98.5: study design
2
Cyclophosphamide 750mg/m
Doxorubicine 50mg/m
Vincristine 1.4mg/m
Prednisone 40mg/m /d x 5 days
2
2
• Patients 60–80 years old
with untreated DLCL
2
3 weeks
8 cycles
• Primary endpoint: eventfree survival
– events: progression,
relapse, new alternative
treatment, death from
any cause
• Intent-to-treat analysis
CHOP
MabThera 375mg/m
2
• 399 patients with a median
follow-up of 4 years
16
17
18
Before treatment
At 2 cycles
At 4 cycles
FDG-PET (–)
19
Rationale der
Radioimmuntherapie bei NHL
• NHL sind von Natur aus sehr strahlensensibel
• Die Radiotherapie kann bei NHL in frühen
Stadien kurativ sein
• Radioaktiv markierte Antikörper bringen die
Strahlung zielgerichtet zum Tumor
• Die Radioimmuntherapie kann sowohl Ziel- als
auch Nachbarzellen vernichten (“KreuzfeuerEffekt”) und so auch grosse oder gering
vaskularisierter Tumoren erreichen
CD20 is an Ideal Target for
Radioimmunotherapy
• CD20 antigen:
– Proven target for
lymphoma therapy
Malignant B-cell
– Expressed only
on B-lineage cells
– Does not shed into
circulation
CD20
antigen
– Does not modulate
upon antibody
Ibritumomab
Zevalin®
Tiuxetan
binding
90Y
Zelenetz. Curr Opin Oncol 1999;11:375–380
Press et al. Blood 1987;69:584–591
Wood. Am J Health Sys Pharm 2001;58:215–229
20
Die Radioimmuntherapie ermöglicht einen
“Kreuzfeuer-Effekt”
Nackter Antikörper
Radioaktiv markierter Antikörper
131I-Tositumomab (BEXXAR) Therapy as Initial
Treatment for Follicular Lymphoma
21
FIT Trial - Primary End Point: Median PFS in All
Patients*
*Median observation period was 3.5 years.
Hagenbeek A et al., Blood 2007; 110:#643
FIT Trial: PFS in Patients With CR/CRu After First-Line
Therapy
Hagenbeek A et al., Blood 2007; 110:#643
22
23