1. 1
Dalla terapia “empirica”alle linee guida
nei Linfomi Indolenti ed Aggressivi
Alessio P. Perrotti
DH Ematologia
Ospedale S.Eugenio - Roma
29 Marzo 2014

2. 2
Linfocitici
7%
Burkitt
1%
Linfoblastici
2%
T periferici
7%
Anaplastici
2%
Altri 8%
Linfoplasmacitoidi
2%
Marginali
8%
Diffusi a grandi
cellule B
35%
Mantellari
6%
Follicolari
22%
Non-follicolari
Distribuzione dei Linfomi Non-Hodgkin

3. 3
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)

4. 4
A practical way to think of lymphoma
Category Survival of
untreated
patients
Curability To treat or
not to treat
Non-Hodgkin
lymphoma
Indolent Years Generally not
curable
Generally defer
Rx if
asymptomatic
Aggressive Months Curable in
some
Treat
Very
aggressive
Weeks Curable in
some
Treat
Hodgkin
lymphoma
All types Variable –
months to
years
Curable in
most
Treat

5. 5
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?

6. 6
non-Hodgkin’s Lymphomas
treatment till 1997
• Surgery
• Wait and see (indolent lymphoma)

7. Watch & wait versus immediate treatment for
asymptomatic advanced stage indolent NHL:
Overall Survival
Observation (n = 151)
Chlorambucil (n = 153)
100
80
60
40
20
0
0
Years
4 8 12 16 20 24
Cumulativesurvival(%)
Median 5-year 10 -year 15 -year
Chlorambucil 5.9 years 57% 35% 21%
Observation 6.7 years 58% 34% 22%
Ardeshna et al, Lancet, 2003; 362: 516

8. non-Hodgkin’s Lymphomas
treatment till 1997
• Surgery
• Wait and see (indolent lymphoma)
• Radiotherapy: stage I indolent
stage I aggressive (+CT!)
• (poly) chemotherapy

9. 9
CHOP
Advances in the treatment of
aggressive NHL
SINGLE DRUG SINGLE DRUG SINGLE DRUG
SINGLE DRUG SINGLE DRUG SINGLE DRUG
CHOP CHOP
CHOP CHOP CHOP
0
100
MACOP-B ProMACE-CytaBOM
m-BACOD F-MACHOPACVB

10. 10
Period 1970-1985
CR rate ~50%
Long term survival ~30-35%
THE CHOP ERA (1°)
Aggressive NHL:
Treatment of advanced disease

11. 11
Period 1985-1993
CR rate 60-85%
Long term survival 50-60%
The 2nd and 3rd generation era
Aggressive NHL:
Treatment of advanced disease

12. 12
SWOG Trial
Regimen N°pts RC % EFS % OS
%
CHOP 225 44 41 54
m-BACOD 223 48 46 52
ProMACECytaBOM 233 56 46 50
MACOP-B 218 51 41 50

13. 13
CHOP is the gold standard in DLCL
Fisher RI et al. N Engl J Med 1993;328:1002–6
100
80
60
40
20
0
0 5 10 15
Overallsurvival(%)
CHOP
MACOP-B
ProMACE-CytaBOM
m-BACOD
CHOP 6-yrs OS= 42%

14. 14
The results of the treatment of
patients with NHL have been improved
impressively by the use of antibodies
directed against the lymphoma cells

15. 15
Immunotherapy has changed the
clinical course of NHL
* Age-adjusted to 2000 US standard population Adapted from Molina A. Annu Rev Med 2008; 59:237–250.
15
10
5
0
Rateper100,000*
NHL mortality
Rituximab
(1997)Fludarabine
(1991)
Etoposide
(1983)
Cisplatin
(1978)
20102005200019951990198519801975
90Y ibritumomab
tiuxetan
(2002) 131I tositumomab
(2003)

16. • Kohler G, Milstein C: “Continuous cultures
fused cells secreting antibody of
predefined specificity.”
Nature 1975; 256:495

17. 17
Hybridoma Technology
B-cell:
Produces antibodies
cannot be cultured
in vitro for a long time
Immunisation or Infection
Hybridoma cell:
Produces monoclonal antibodies
Can be cultured indefinitely
Myeloma cell:
No antibody
production.
Can be cultured
indefinitely
Humanisation
of antibody

18. 18
murine 1975
…momab
chimeric 1984
…ximab
humanised 1988-1991
…zumab
Humanisation
human 1994–1999
…mumab
Immunogenic Less immunogenic
Monoclonal antibodies

19. 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

20. 20
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

21. 21
The pivotal study
• 166 patients with relapsed or refractory
low-grade or follicular lymphoma (FL)
• MabThera monotherapy (375 mg/m2,
once-weekly for 4 weeks)
• Non-bulky disease (<10 cm)
• At least 1 prior chemotherapy
McLaughlin P, J Clin Oncol 1998

22. 22
Grade 3-4 toxicities
• Infusion-related reactions
• Cytopenia (1 or more lineages)
• Cardiac events
• Pulmonary events (BOOP)
• Infections
• Stevens-Johnson syndrome
• Abdominal pain
Grade 3-4 toxicities are rare with MabThera
monotherapy

23. 23
CHOP ± Rituximab in DLCL in the elderly (60-80 yr)Probabilityofevent-freesurvival
Years
0 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.

24. 24
DLCL in the elderly :
Rituximab improves overall survival
Years
1.0
0.8
0.6
0.4
0.2
0
0 1 2 3 4 5
p=0.01
59% Rituximab + CHOP
47% CHOP
Probabilityofoverallsurvival
Coiffier et al.

25. 25
INDICAZIONI LNH RCP RITUXIMAB
• Follicolare III-IV stadio non trattato in associazione a
chemioterapia
• Mantenimento nel Follicolare rispondente alla induzione
• Monoterapia nel Follicolare III-IV stadio
chemioresistente o in recidiva dopo chemioterapia
• Linfoma non Hodgkin CD20+ diffuso a grandi cellule B in
associazione a CHOP

26. 26
INDICAZIONI LEGGE 648/96 PER
RITUXIMAB
• LNH a cellule B (CD20+) di qualunque
istologia in associazione con regimi vari di
polichemioterapia impiegati per il
trattamento di 1° linea o di salvataggio,
inclusi i regimi di condizionamento
pretrapianto di cellule staminali
emopoietiche
determinazione AIFA 18.05.2011

27. 27
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60 72 84 96 108 120
Follow-up, months
FLIPI 0-1 FLIPI 2 FLIPI 3-5
Overall Survival
Follicular lymphoma without Rituximab (1988-2003)
FLIPI OS% 5-yr HR (CI95) P
0-1 89 (82-93) 1.00
2 72 (61-81) 2.96 (1.69-5.17) <0.001
3-5 52 (39-64) 5.13 (2.95-8.90) <0.001
3-5 vs 2 1.73 (1.07-2.80) 0.025

28. 28
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60 72
Follow-up, months
FLIPI 0-1 FLIPI 2 FLIPI 3-5
Overall Survival
Follicular lymphoma with Rituximab (2003-2010)
FLIPI OS% 5-yr
0-1 91 (78-96)
2 93 (85-96)
3-5 86 (77-91)
Log-rank test: P=0.027

29. 29
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60
Follow-up, months
IPI 0-1 IPI 2 IPI 3 IPI 4-5
Overall Survival
DLBCL without Ritux (1988-2003)
01

30. 30
0.00
0.25
0.50
0.75
1.00
0 12 24 36 48 60
Follow-up, months
IPI 0-1 IPI 2 IPI 3 IPI 4-5
Overall Survival
DLBCL with Ritux (2003-2007)
1

31. 31
non-Hodgkin’s Lymphomas
Treatment (after 1997)
• Surgery
• Wait and see (indolent lymphoma)
• Radiotherapy: stage I indolent
stage I aggressive (+CT!)
• (poly) chemotherapy
• Immuno-chemotherapy
• Transplantation
• New drugs

32. 32
Nathan Fowler, Sattva Neelapu, Fredrick Hagemeister,
Peter McLaughlin, Larry W. Kwak, Jorge Romaguera,
Michelle Fanale, Luis Fayad, Robert Orlowski, Michael Wang, Francesco Turturro,
Yasuhiro Oki, Linda Lacerte,
Felipe Samaniego
Department of Lymphoma/Myeloma,
MD Anderson Cancer Center, Houston, TX, USA
Fowler N, Neelapu S, Hagemeister F, et al. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. Oral presentation at: Annual Meeting and
Exposition of the American Society of Hematology 2012; December 8-11; Atlanta, GA.
Abstract 901
Lenalidomide and Rituximab for
Untreated Indolent Lymphoma:
Final Results of a Phase II Study

33. 33
Fowler et al: Results
Efficacy All evaluable
patients
(n = 103)
SLL
(n = 30)
MZL
(n = 27)
FL
(n = 46)
ORR, n (%) 93 (90) 24 (80) 24 (89) 45 (98)
CR/CRu, n (%) 66 (64) 8 (27) 18 (67) 40 (87)
PR, n (%) 27 (26) 16 (53) 6 (22) 5 (11)
SD, n (%) 8 (8) 4 (13) 3 (11) 1 (2)
PD, n (%) 2 (2) 2 (7) 0 0
Projected 36-months PFS, % 78 66 89 81
33
CRu, unconfirmed CR; PD, progressive disease; SD, stable disease.
Fowler N, Neelapu S, Hagemeister F, et al. Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study. Oral presentation at: Annual Meeting and
Exposition of the American Society of Hematology 2012; December 8-11; Atlanta, GA.

34. 34
GRAZIE PER LA
ATTENZIONE