2. B cell malignancies
Pre-B acute lympho-
blastic leukemia
B cell lymphoma Chronic lympho-
cytic leukemia
Multiple myeloma
Progressive B lymphocyte maturation
Bone marrow
Lymph node,
lymph, blood,
bone marrow
Lymph node,
lymph, blood,
bone marrow
Bone marrow
Lymphoid stem cell Maturing B cell
many stages
Mature B cell Plasma cell
3. Histologic Classification of
Non-Hodgkin’s Lymphomas
1. Rappaport - 1966
2. Lukes and Collins - 1974
3. Kiel - 1974
3. Dorfman -
1974
4. Bennet et al., - 1974
5. Lennert - 1974
6. WHO - 1976
7. Working Formulation - 1982
8. REAL - 1994
9. WHO - 1999
4. Non-Hodgkin’s Lymphoma
Lukes-Collins & Kiel Classifications
Lukes-Collins System – US
Kiel System – Europe
Differentiation of B-cell and T-cell lymphomas
5. Non-Hodgkin’s Lymphoma
Working Classification
Developed in 1980’s
NCI Investigators reviewed Rappaport, Lukes-
Collins, and Kiel systems
n=1175
Goal was to clarify… now a new system!
No consideration to B-cell or T-cell typing
Goal was to group lymphomas according to
aggressiveness (low, intermediate, high)
6. Non-Hodgkin’s Lymphoma
Working Classification
Low Grade
– Small Lymphocytic
– Follicular small-cleaved cell
– Follicular mixed small-cleaved and large cell
Intermediate Grade
– Follicular large cell
– Diffuse small cleaved cell
– Diffuse mixed small and large cell
– Diffuse large cell
High Grade
– Large cell immunoblastic
– Lymphoblastic
– Small non-cleaved cell (Burkitt's and non-Burkitt's type)
7. Non-Hodgkin’s Lymphoma
REAL Classification
Revised European-American Lymphoma
Mid 1990’s – International Lymphoma Study Group
(informal group of hematopathologists)
Using immunophenotype, cytogenetics, molecular
diagnostics
Reclassified lymphomas by diagnostic criteria and
not by risk categories
10. Hodgkin
Lymphoma
Non Hodgkin Lymphoma
Highly
Aggressive
Aggressive
Indolent
B cell
Follicular
SLL/CLL
Marginal zone
LP (WM)
T/NK cell
Mycosis fungoides
Sezary syndrome
Primary cut ALCL
B cell
Pre-B
lymphoblastic
Burkitt
T/NK cell
Pre-T
lymphoblastic
B cell
DLBCL
FLg3 and tFL
Mantle cell
Primary effusion
T/NK cell
ALCL
Angioimmunoblastic
Subq panniculitis-like
Blastic NK
Extnanodal NK/T
nasal
Enteropathy-type
Hepatosplenic
PTCL nos
Classical HL
(NS, MC, LR,
LD)
Nodular
lymphocyte
Predominant
(NLPHL)
Multiple
Myeloma
11. Non-Hodgkin’s Lymphoma
WHO Classification
Bruce Cheson, MD and the NCI International Working
Group reported in January 1999
Adopted in 2001, Revised in 2008
Discredited the Working (non-REAL)
Classification
Based on REAL (Non-working) Classification
Cheson et al. J Clin Oncol. 1999 Apr;17(4):1244
12. WHO/REAL Classification of Lymphoid Neoplasms
B-Cell Neoplasms
Precursor B-cell neoplasm
Precursor B-lymphoblastic leukemia/lymphoma
(precursor B-acute lymphoblastic leukemia)
Mature (peripheral) B-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§
T and NK-Cell Neoplasms
Precursor T-cell neoplasm
Precursor T-lymphoblastic leukemia/lymphoma
(precursor T-acute lymphoblastic leukemia
‡ Formerly known as lymphoplasmacytoid lymphoma or
immunocytoma
II Entities formally grouped under the heading large granular
lymphocyte
leukemia of T- and NK-cell types
* Provisional entities in the REAL classification
Mature (peripheral) T neoplasms
T-cell chronic lymphocytic leukemia / small
lymphocytic lymphoma
T-cell prolymphocytic leukemia
T-cell granular lymphocytic leukemiaII
Aggressive NK leukemia
Adult T-cell lymphoma/leukemia (HTLV-1+)
Extranodal NK/T-cell lymphoma, nasal type#
Enteropathy-like T-cell lymphoma**
Hepatosplenic γδ T-cell lymphoma*
Subcutaneous panniculitis-like T-cell lymphoma*
Mycosis fungoides/Sézary 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
Hodgkin’s Lymphoma (Hodgkin’s Disease)
Nodular lymphocyte predominance Hodgkin’s lymphoma
Classic Hodgkin’s lymphoma
Nodular sclerosis Hodgkin’s lymphoma (grades 1 and 2)
Lymphocyte-rich classic Hodgkin’s lymphoma
Mixed cellularity Hodgkin’s lymphoma
Lymphocyte depletion Hodgkin’s lymphoma
† Not described in REAL classification
§ Includes the so-called Burkitt-like lymphomas
** Formerly known as intestinal T-cell lymphoma
# Formerly know as angiocentric lymphoma
13.
14. Indolent (35%)
Diffuse large
B-cell (31%)
Armitage et al. J Clin Oncol. 1998;16:2780–2795
Mantle cell (6%)
Peripheral T-cell (6%)
Other subtypes with a
frequency 2% (9%)
Frequency of NHL Subtypes in Adults
Composite
lymphomas (13%)
15. Non-Hodgkin’s Lymphoma
Diffuse Large Cell
Very Aggressive
Curable if chemo-sensitive upfront, not so if chemo-
refractory or relapses within 6 months
Most common of all lymphomas
Accounts for ~ 31% of all lymphomas
21. BMT for Non-Hodgkin’s Lymphoma
Indications
1. Refractory disease
2. Relapse
3. High risk in CR
4. Lymphoblastic, Burkitt’s, and gamma delta-t-cell
lymphomas
23. Treatment of non-Hodgkin lymphoma
general 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)
24. Treatment of non-Hodgkin lymphoma
considerations 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?
29. 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
30. Survival of NHL patients (till 2004)
Years since diagnosis
indolent
aggressive
very aggressive
100%
50%
10 20
31. The results of the treatment of
patients with NHL have been improved
impressively by the use of antibodies
directed against the lymphoma cells
32. Rituximab : 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
33. CD20 Expression in B-Cell Development
Plasma cell
Pluripotent
stem cell
Lymphoid
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
34. Anti-CD20 (Rituximab)
side effects
Mild and transient, mainly during first infusion
Fever, chills ( prevention)
Temporary drop in blood pressure, dyspnea
Rare: antibodies against rituximab
35. The CD20 molecule
Transmembrane
phosphoprotein
Single extracellular loop
Natural ligand not identified
Physiologic function uncertain
Knockout phenotype normal
Expressed on most B-cell
malignancies
Resistant to internalisation or
shedding after ligation by
antibody
Associates with CD40, CD53,
MHC class II, CD81
Extracellular
1 2 3 4
37. GELA-LNH 98.5: CHOP vs Rituximab +
CHOP in Previously Untreated DLBCL
Cyclophosphamide 750 mg/m²
Doxorubicin 50 mg/m²
Vincristine 1.4 mg/m²
Prednisolone 40 mg/m²/day x 5 days
3 weeks 8 cycles
Rituximab + CHOP 375 mg/m²
Coiffier B, et al. N Engl J Med 2002; 346:235–243
GELA phase III trial
38. EVENT FREE SURVIVAL OVERALL SURVIVAL
Coiffier B et al. N Engl J Med 2002;346:235-242.
39. Ten-year follow-up of the GELA LNH98.5
study
Comparing R-CHOP to CHOP in diffuse large B-cell
lymphoma .
-Coiffier B, et al. ASH 2009: Abstract 3741.
40. 10-year follow-up of the GELA LNH-98.5
study (R-CHOP vs CHOP in DLBCL): EFS
Time (years)
0 2 4 6 8 10
0.0
0.2
0.4
0.6
0.8
1.0
CHOP 19%
R-CHOP 34%
p < 0.0001
Event-free
rate
Coiffier et al. Blood 2009 114: Abstract 3741.
41. Eligibility criteria:
• Diffuse large B-cell
lymphoma
• Previously untreated
• Aged 60-80 years
• Age-adjusted IPI 1-3
R-CHOP14
CHOP14 x 8 cycles
Rituximab x 8 cycles
(n = 98)
(n = 202)
R
A
N
D
O
M
I
Z
E
Interim Results of R-CHOP14 vs. R-CHOP21 in
Elderly Patients With DLBCL: LNH03-6B GELA
Primary endpoint : event-free survival
Secondary endpoints: OS, PFS, DFS, ORR
Median follow-up: 24 months
Delarue et al. ASH 2009; abstract 406.
Darbepoetin
alfa
Standard
intervention
for anemia
Darbepoetin
alfa
R-CHOP21
CHOP21 x 8 cycles
Rituximab x 8 cycles
(n = 103)
Standard
intervention
for anemia
42. Event-free survival
Median EFS :
- 22 months (R-CHOP14) vs NR (R-CHOP21)
2-year EFS :
- 48% (R-CHOP14) vs 61% (R-CHOP21)
43. Revised IPI in the Rituximab era
Risk group
No of IPI
factors
Patients
%
4-year PFS % 4-year OS %
Standard IPI
Low 0–1 28 85 82
Low–intermed 2 27 80 81
High–
intermed
3 21 57 49
High 4–5 24 51 59
Revised IPI
Very good 0 10 94 94
Good 1–2 45 80 79
Poor 3–5 45 53 55
Sehn LH, et al. Blood 2007; 109:1857–1861.
44. R
Rituximab (375mg/m²)
1 15 29 43 57 71 85 99
PBSC PBSC
PBSC
mCHOEP II
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
43 64
22
1 77 98
14 36 56
mCHOEP III
CYC 4500
ADR 70
VCR 2
ETO 960
PRD 500
mCHOEP IV
CYC 6000
ADR 70
VCR 2
ETO 1480
PRD 500
DSHNHL : R-MegaCHOEP vs R-CHOEP-
Young, high-risk patients with aggressive B-cell
lymphoma
mCHOEP I
CYC 1500
ADR 70
VCR 2
ETO 600
PRD 500
CHOEP-14
CYC 750
ADR 50
VCR 2
ETO 300
PRD 500
PRD and VCR doses are
absolute, all others are per m²
days
45. DSHNHL 2002-1 – MegaCHOEP-Event-free survival
Months
0 10 20 30 40 50 60 70
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
R-CHOEP-14
R-MegaCHOEP
p=0.050
• In young patients with high-risk aggressive B-cell lymphoma, R-MegaCHOEP was
NOT superior to conventional R-CHOEP therapy and was associated with
significantly more toxic effects.
• R-CHOEP-14 encouraging Efficacy
48. “Double hit” lymphoma
subgroup of particularly aggressive B cell lymphoma
3-5% of DLBCL and high grade B cell lymphoma
c-MYC and BCL2 translocation
complex cytogenetics
poor prognosis
A variety of therapies have been used, none proven to be
superior than others
Sunderl M, et al. Am J Surg Pathol. 2010;34:327-340.
49. Overall survival DLBCL by clonal karyotype
Macpherson Macpherson et al. JCO 1999
double hit (13)
c-myc (11)
Other (15)
British Columbia
Cacncer Agency
1986-1996
51. The impact of Rituximab in DLBCL
Improved survival in GCB and non-GCB DLBCL
Fu K, Weisenberger DD, Choi WW, et al. Addition of rituximab to
standard chemotherapy improves the survival of both germinal
center B-cell-like and non-germinal center B-cell-like subtypes of
DLBCL. J Clin Oncol 2008;26:4587-4594.
Lenz G, Staudt LM. Aggressive lymphomas. New Engl J Med
2010;362;1417-1429.
53. 3188672-53
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Overall
survival
(%) Rituximab group (n=68)
Control group (n=53)
P<0.001
Time (years)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Event-free
survival
(%)
Rituximab group (n=68)
Control group (n=53)
P=0.0053
Time (years)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Overall
survival
(%)
Rituximab group (n=68)
Control group (n=53)
P<0.001
Time (years)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10
Event-free
survival
(%)
Rituximab group (n=68)
Control group (n=53)
P=0.0022
Time (years)
Germinal Center and Non-Germinal Center DLBCL
Fu K, Weisenberger DD, Choi WWL, et al. J Clin Oncol 2008;26:4587-4594.
54. What are the treatment options for
relapsed patients with DLBCL?
55. Relapsed DLBCL patients: Three distinct
subgroups with different prognoses
Rituximab plus chemotherapy has dramatically improved outcomes in
DLBCL compared with the pre-Rituximab era
─ Increases the chance of cure vs chemotherapy alone1
─ Increases overall survival in a clinical setting2
However, up to 40% of patients relapse after standard chemo
immunotherapy
Relapse after CR3 PR with persistent disease3 Refractory3
Best relative
prognosis
Occasionally benefit from
salvage regimens but
generally have a poor
outlook
May benefit from non-
cross resistant
salvage regimens and
ASCT
1. Coiffier B, et al. Blood 2009; 114:Abstract 3741. 2. Sehn LH, et al. J Clin Oncol 2005;23:5027–5033. 3. Sud R, et al. Haematologica 2008; 93:1776–1780.
57. CORAL Trial of RICE v DHAP
CD20+ DLBCL
Relapsed/Refractory
R-ICE x 3
R-DHAP x 3
R
A
N
D
O
M
I
Z
E
R
A
N
D
O
M
I
Z
E
SD/POD → Off
PR/CR →
→
A B
S E
C A
T M
R x 6
Obs
N=400
Which salvage regimen is the best?
Orlando ASCO May 2009 / Coral study C. Gisselbrecht
59. Optimising salvage therapy in relapsed
aggressive lymphoma
Rituximab plus chemotherapy is routinely used for
patients with relapsed DLBCL
─ May improve response rates compared with
chemotherapy alone
What is the optimum salvage chemotherapy
regimen?
─ Similar efficacy for Rituximab-ICE vs Rituximab-DHAP
─ Other studies are ongoing
60. Management of DLBCL
Not in CR
Relapse
Second-line
therapy
Second-line
therapy
Investigational
or BSC
HDT/ASCT
Investigational
or BSC
CR/PR
CR/PR NR
NR
R-CHOP or R-CHOP-like
CR
Cure
61. non-Hodgkin’s Lymphomas
Treatment
Surgery: NEVER !!
Wait and see (indolente lymfomen)
Radiotherapy: stage I indolent
stage I aggressive (+CT!)
(poly) chemotherapy
Immunotherapy: monoclonal antibodies
Immuno-chemotherapy
64. Therapy 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
65. 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
66. Precautions with Rituximab
Hepatitis B reactivation : check and offer Lamivudine
to patients at risk
PML – very rare complication , usually in heavily
pretreated patients – only 57 cases world wide high
fatality rate
Other viruses ( CMV , adeno ) : isolated case reports
only
67. 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
68. Signposts for the future
Most patients are > 60 years of age – how to tailor
therapy for this age group
Early levels of “R” determine response – new trials to
exploit this
Can we utilise the signalling pathways in ABC
subtype to design new rational therapy
Newer MoAbs ( GA-101 , Ofatumomab ) to be explored
on DLBCL
