Transcript MMD 6223- Haematology

LYMPHOMES NON
HODGKINIENS
François Sestier, MD, PhD
Abdelouahed Naslafkih, MD, PhD
AQTV, Montréal, 14 Mai 2009
Programme de médecine d’assurance et
expertise en sciences de la santé,
Université de Montréal
www.mae.umontreal.ca
er
1
manuel
• Low grade
-diffuse lymphocytic
Stage
-nodular lymphocytic
I
class 3 = pp2yrs,std 7th yr
-nodular histiocytic
II
class 2= pp3yrs,std 8th yr
III
IV
• Intermediate-High grade
-diffuse lymphocytic, poorly diff
-diffuse lymphocytic-histiocytic
-Burkitt’s lymphoma
-Unclassified
Rating
class 1= pp5yrs,std 11th yr
DEC to +100, +cl1
Stage
I
II
III
IV
Rating
class 2
class 1
+100, + class 1
DEC to +200 + class 1
ième
2
manuel
• Low grade lymphomas:
-Stage 1 : PP 3yrs , then
+50 and 10$ x 7 yrs
11th yr : +50
-Stage II: PP 3 yrs , then
+50 and $15 x 7 yrs
11th yr : + 50
-Other stages : PP 10 yrs, then
15$ x 5yrs
16th yr : std
Les LNH sont-ils des risques
standards s’ils survivent
7 à 16 ans ??
OBJECTIFS
• Identifier la littérature médicale la
plus récente concernant la mortalité
des LNH
• Calculer la mortalité observée en
utilisant une méthodologie
actuarielle
LNH: définition
et épidémiologie
1.
Definition: malignant disease of the lymphoid
system, highly heterogeneous, both histologically
and clinically, with several classifications
2. Epidemiology:
- annual incidence: 5-10 new cases per 100 000
persons,
- age distribution: middle-age patients and the
elderly,
- males are affected more often than females
(1.5:1.0).
Incidence selon l’âge au diagnostic
Source : SEER-Cancer statistics Review 1995-2004
Increasing incidence with age.
Differences between SEER registries 2002-2004 and 1975-1977.
Non-Hodgkin lymphoma classification
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
1. Low grade
2. Intermediate grade
3. High grade
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
Low grade
A - Small lymphocytic cell.
B - Follicular, predominantly small cleaved cell
C - Follicular mixed, small cleaved and large cell.
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
Intermediate grade
DEFG-
Follicular, predominantly large cell.
Diffuse small cleaved cell.
Diffuse mixed, small and large cell.
Diffuse large cell.
Histologic classification of nonHodgkin’s lymphomas - Working
Formulation (WF)
High grade
H -Large cell immunoblastic.
I -Lymphoblastic.
J -Small noncleaved cell: Burkitt’s
Staging: Ann Arbor
I. 1 lymph node region or structure
II. >1 lymph node region or structure, same
side of diaphragm
III. Both sides of diaphragm
IV. Extranodal sites beyond “E” designation
subscripts: A, B, E, S
ANN ARBOR and SEER classifications
Stages
ANN ARBOR
I
II
III
One group of lymph nodes affected.
Two or more teritories affected, located
at one side of the diaphragm.
Localized
Regional
On both sides of the diaphragm.
Spread beyond the lymph nodes,
IV
Stages SEER
Distant
(to other organs: bone marrow, liver or
lungs).
Fever (at least 38°C during 15 days without infection), night sweats or weight lost at least 10 %
during the previous 6 months are indicated by the suffix letter A or B.
Source : http://www.rapidesregional.com/CPM/CancerAnnualReport2002.htm
Source:
NCDB, Commission on Cancer, AcoS. Benchmark Reports v1.1 - November 1, 2002.
Rapid City Regional Hospital Cancer Registry.
Source:
NCDB, Commission on Cancer, AcoS. Benchmark Reports v1.1 - November 1, 2002.
Rapid City Regional Hospital Cancer Registry.
Source:
NCDB, Commission on Cancer, AcoS. Benchmark Reports v1.1 - November 1, 2002.
Rapid City Regional Hospital Cancer Registry.
Follicular lymphoma and long term
survival
Gandhi, Blood Rewiews,2005,19:165-178
Prognostic Index
IPI
FLIPI
International prognostic Index
Follicular Lymphoma International prognostic index
Risk factors
Risk factors
Age > 60 years
Age > 60 ans
Spread beyond lymph nodes ≥ 2 sites
Lymph nodes ≥4 sites affected
High serum LDH
High serum LDH
Stages III and IV
Stages III et IV
Performance status (ECOG PS) ≥ 2
Hemoglobine < 12 g/dl
Risk class
Risk class
Low : 0 or 1
Low : 0 or 1
Intermediate : 2
Intermediate : 2
High : 3 - 5
High : ≥ 3
Adapted from: Perea et al. Prognostic indexes in follicular lymphoma: a comparison of different
prognostic systems. Ann Oncol 2005; 16:1508-1513
The International
Non-Hodgkin's
Lymphoma Prognostic
Factors Project
NEJM 1993;329:987-994
A Predictive Model for Aggressive Non-Hodgkin's Lymphoma
USA, Europe, Canada, 1982-1987
3273 patients (1274  60 years)
NEJM 1993;329:987-994
Factors Independently Prognostic
of Overall Survival
NEJM 1993;329:987-994
Development of a Molecular Predictor of Survival in Follicular Lymphoma
Dave, S. S. et al. N Engl J Med 2004;351:2159-2169
LYMPHOMA SURVIVAL: a
textbook approach
Southwest Oncology Group
lymphoma survival
LNH
• Surviennent chez le jeune adulte et
la personne agée
• Il faut dond tenir compte de l’âge
dans le calcul de la mortalité
NHL: Mortality ratio by age groups,
SEER 9 Registries for 1988-2003
Age at
Mortality ratio (MR%)
2 years
5 years
10 years
<45 years
5600
5500
2000
45-54 years
1800
1200
750
55-64 years
800
600
400
65-74 years
475
350
225
≥75 years
400
275
200
diagnosis
LNH: MR at 5 years by stages
SEER data (1988-2001)
Stage
Survival %
MR (%)
Relative
Expected
Localized
68.8
85.4
325
Regional
61.7
-
386
Distant
44.9
-
560
All stages
56.3
-
438
NHL: Mortality ratio by follow-up period
SEER 9 Registries , 1988-2003
Years
0-1
0-2
0-3
0-4
0-5
0-6
0-7
0-8
0-9
0 -10
MR (%)
Men
680
Women
660
Both
670
680
600
630
555
515
545
485
448
475
430
400
420
385
360
376
350
229
343
318
300
310
290
275
285
265
255
260
CCCW-NHL Registry
Kroll et al. Ann Oncol 2003;14:131-139
Netherlands, 1981-89
1164 patients, age : 64 yrs, 50% women
Overall survival
(%)
5 yrs
10 yrs
Nodal (n = 635)
Extra nodal (n = 389)
Extensive (n = 140)
41
41
29
23
24
12
MR
5 yrs
713%
713%
956%
10 yrs
397%
386%
555%
NHL: Mortality ratio (MR) at 2, 5, 10, and 15 years
Mortality ratio (MR %)
2 years
5 years
10 years
15 years
All
761
475
375
400
Follicular
445
445
425
578
DLCB
995
520
365
430
DLCB: diffuse large B-cell lymphomas
Adapted from: Krol et al. Leukemia&Lymphoma 2003
CCCW (The Comprehensive Cancer Center West)
1168 patients diagnosed with NHL between1981 and 1989.
Median age at diagnosis: 66 years, 49% males , Follow-up 15 years
Survival of patients with NHL vs. Dutch population
Source: Krol et al. Leukemia&Lymphoma 2003
NHL-Diffuse
The Comprehensive Cancer Center West, 1981-89
470 patients with
diffuse large B cells
lymphomas ,
49% males,
median age: 66 years
NHL-DLCB
Mortality ratio (MR %)
2 yrs
5 yrs
10 yrs
15 yrs
995
520
365
430
After 15 years  all patients died
From: Krol et al. Leukemia & Lymphoma 2003; 44(3):451-458.
CCCW-NHL Registry
Indolent and agressive NHL
Netherlands, 1981-89
1167 Patients, age : 64 yrs, 50% women
Follow-up: 8 years
Maartense et al. Cancer 2000; 89(12):2667-2676
CCCW-NHL Registry.
Maartense et al. Cancer 2000; 89(12):2667-2676
Effect of age
NHL: MR at 5 and 8 years by type and age
Type
Age at diagnosis (years)
<60
60-64
65 -69
70 -74
≥75
MR : 5 yrs
1290
395
338
525
170
MR : 8 yrs
1360
434
400
360
300
MR : 5 yrs
2360
900
745
540
317
MR : 8 yrs
1360
690
550
360
395
Indolent
Agressive
Adapted from : Maartense et al. Cancer 2000; 89 :2667-2676
CCCW-NHL Registry.
Maartense et al. Cancer 2000; 89(12):2667-2676
Effect of age on MR
Age group
<60 yrs
60 – 64 yrs
65 – 69 yrs
70 – 74 yrs
75 yrs
Mortality Ratios
Indolent
DLBL
1150%
1360%
450%
695%
410%
560%
330%
350%
200%
265%
Mortality Ratios
Age group
Indolent
DLBL
<60 yrs
1150%
1360%
60 – 64 yrs
450%
695%
65 – 69 yrs
410%
560%
70 – 74 yrs
330%
350%
75 yrs
200%
265%
Maartense et al. Cancer 2000; 89(12):2667-2676
Localized aggressive lymphoma
Rey et al. NEJM 2005;352:1197
France, 1993-2000
647 patients (318 ACVBP, 329 CHOP+RX)
Age : 46 years, 60% men
Stage I : 66%
Stage II : 32%
Stage IV : 2%
95% IPI score= 0
Follow-up : 8 years
Deaths = 115
Mortality Ratio* = 560%
Côte d'Or registry,France,
451 patients diagnosed with NHL between 1980-92
NHL: Mortality ratio (MR) at 5 years by different variables
Variables
Gender
Age
Grade
MR%
Men
Women
20 – 64 years
300
200
980
≥65 years
Low
Intermediate
High
Unknown
1980-1983
250
185
280
515
475
263
Period of diagnosis 1984-1987
1988-1991
Source : Rolland-Portal et al. Int J Epidemiol 1997; 26 :945-952
400
275
NHL: MR at 5 and 10 years by grade
(Register Côte d’Or)
Relative survival
Mortality ratio
5 yrs
10 yrs
5 yrs
10 yrs
Low grade
80
74
280
193
Interm. and high grade
52
41
605
368
All grades
60
49
500
316
Follicular lymphoma
Montoto et al. Ann Oncol 2002;13:523-530
Spain, 1977-1997
201 patients, 53% men
Age : 54 years
Stage I: 10%, II: 9%, III: 15%, IV: 66%
Overall survival : 71% at 5 years, 48% at 10 years
MR* = 973% at 5 years
= 785% at 10 years
*Life table Spain, Total population 1980-89
Time to treatment failure (TTF) and overall survival (OS)
in 201 patients with follicular lymphoma
MR = 785%
(10yrs)
Montoto, S. et al. Ann Oncol 2002 13:523-530
Survival of 389 follicular
lymphomas : std at 10 yrs????
Diffuse large B-cell lymphoma
( aggressive lymphomas)
US,1987-1998
128 Patients, (46% men)
Age : 65 years
5-year overall survival: 43%
Mortality Ratio* = 722%
Colomo et al. Blood 2003:101:78-84
Indolent lymphoma
Follicular vs. Non Follicular lymphoma
Corradini et al. J Clin Oncol 2004;22:1460-1468
Italy,1990-99
70 patients,60% men
Age: 47 years
87% stage IV
Overall survival at 12 yrs
Follicular subtype: 76%,
Non-Follicular : 49%,
MR = 514%
MR = 1311%
Relapsed Follicular Lymphoma
Autologous Bone Marrow Transplantation
Freedman et al. Blood 1999;94:3325-3333
USA, 1985-1995
153 Patients, 53% men
Age: 43 years
(66%: stage IV, 24% stage III, 7% stage II, 3% stage I)
Survival : 69% at 12 years
MR* = 1330%
*Life table US 1989-92
20 yrs survival after ABMT from diagnosis for
153 patients with indolent follicular lymphoma.
MR* = 1330%
Freedman, A. S. et al. Blood 1999;94:3325-3333
20 yrs survival after ABMT from diagnosis for
153 patients with indolent follicular lymphoma.
MR* = 1330%,
Not std!!
Freedman, A. S. et al. Blood 1999;94:3325-3333
Low grade NHL: Follicular Lymphoma
by age, stage and histologic type
MR at 5, 10, and 15 years
FSC: small cleaved-cell follicular lymphoma; FM: mixed follicular lymphoma; FLC: large-cell follicular lymphoma
Age
Age <60 years
Follow-up
Age ≥60 years
5 yrs 10yrs 15yrs 5yrs 10yrs 15yrs
Localized/regional
FSC, FM
FLC
1983-89
325
275
1990-99
307
277
1983-89
415
232
1990-99
475
300
1983-89
560
465
1990-99
550
385
1983-89
1020
560
1990-99
717
370
200
200
420
310
480
355
578
361
570
385
700
455
725
460
865
545
965
500
245
220
Distant stage
FSC, FM
FLC
287
287
300
345
Adapted from: Swenson et al. J Clin Oncol 2005; 23:5019-5026, ref. 12
Localized Intermediate and high-grade
Non-hodgkin's lymphoma
Soutwest Oncology Group, 1988-1995
442 patients (CHOP: 201; CHOP+RX :200)
Age : 59 years
5-year overall survival :
CHOP : 72%
CHOP+RX : 82%
Miller et al. NEJM 1998;339:21-26
5-year overall survival
CHOP+RX : 82%
CHOP : 72%
MR* = 396% CHOP+RX
MR* = 648% CHOP
*Life table US,1989-91
Miller et al. NEJM 1998;339:21-26
MR = 396%
MR = 675%
MR = 1390%
*Life table US,1989-91
Miller et al. NEJM 1998;339:21-26
Intermediate or high-grade NonHodgkin lymphoma
Italy, 1984-1998
186 patients, 52% men
Age: 56 years
Overall survival : 60.4% at 10 years
Mortality ratio = 495%
Rossini et al. Cancer 2004;100:350-355
Intermediate or high-grade NonHodgkin lymphoma
MR by stage
Stage I-II = 431%
Stage III-IV = 995%
MR by IPI
IPI 1 = 260%
IPI 2 = 495%
IPI 3 = 800%
IPI 4 = 1170%
Rossini et al. Cancer 2004;100:350-355
NHL mortality: Relative risk by IFLP
(Follicular Lymphoma International Prognostic Index)
Adapted from: Solal-Céligny et al. Blood 2004; 104 :1258-1265
Group
Prognostic factors
RR
Low risk
0-1
1.0
2
2.3
≥3
4.3
Intermediate risk
High risk
High grade NHL
International Non-Hodgkin's Lymphoma Prognostic Factors Project 1982-98
Mortality Ratio according to Life Table US, 1985-1989)
3273 patients
aggressive NHL (High/interm grades),
Age at diagnosis: 65 years, Follow-up: 5 years
All
Male
Female
Age ≤60 years
Age >60 years
I
II
III
Stages
IV
I/II
III/IV
Adapted from: NEJM 1993
MR%
420
420
410
655
355
158
275
425
577
245
525
NHL: Mortality ratio at 2 and 5years by IPI
IPI
All patients
Age ≤60 yrs
Age >60 yrs
MR (%)
2 years
5 years
0 ou 1
275
210
Low-Intermediaite
2
613
435
High-Intermediaite
3
866
535
High
4 ou 5
1360
815
Low
0
325
245
Low-Intermediaite
1
708
480
High-Intermediaite
2
1475
965
High
3
2500
1365
Low
0
225
240
Low-Intermediaite
1
375
330
High-Intermediaite
2
655
395
High
3
945
585
Low
Adapted from: The International NHL Prognostic Factors Project. NEJM 1993
NHL stages III-IV:
Mortality by therapeutic modalities
GELA study 18 France, 1993-1998
708 patients aggressive lymphoma (stages III / IV); 80% diffuse
large B-cell
Median age at diagnosis : 65 years ; 56% males
2 treatment groups (ACVBP and CHOP).
Median follow-up period was 68 months.
Survival at 5 years was 46% and 38% respectively
Expected survival from Life table France, 1995-99.
FU: 5 yrs
MR%
ACVBP
CHOP
Total
645
785
715
The International Lymphoma Study Group
Classification of Non-Hodgkin’s Lymphoma
1403 cases (untreated) from 8 countries, 1988-90
Omaha, NE: 200
Vancouver, Canada: 202
Cape Town, South Africa: 196
London, UK: 120
Locarno, Switzerland: 80
Lyon, France: 195
Wurzburg, Germany: 210
Hong Kong: 200
Blood 1997;89:3909-3918
NHL Classification Project
Survival by histologic type and the International Prognostic Index
Consensus diagnosis
Age
(Years)
Male
(%)
Follicular, all grades
59
Mantle cell
5-year survival
%
Index
0/1
Index
4/5
42
84
17
63
74
57
0
Marginal zone B-cell, MALT
61
45
89
40
Marginal zone B-cell, nodal
58
41
76
50
Small lymphocytic (CLL)
65
53
76
38
Diffuse large B-cell
64
55
73
22
Primary mediastinal large B-cell
37
34
77
0
High-grade B-cell, Burkitt-like
55
59
71
0
Precurssor T-lymphoblastic
25
74
29
40
Peripheral T-cell, all types
61
56
36
15
Anaplastic large T/null cell
33
69
81
83
Blood 1997;89:3909-3918
NHL Classification Project
Blood 1997;89:3909-3918
Mortality Ratio ( life table Canada 1990-92)
Consensus diagnosis
MR
Index 0/1
Index 4/5
Follicular, all grades
330%
2900%
Mantle cell
587%
----
Marginal zone B-cell, MALT
185%
1330%
Marginal zone B-cell, nodal
545%
1320%
Small lymphocytic (CLL)
280%
925%
Diffuse large B-cell
306%
1312%
Primary mediastinal large B-cell
3393%
----
High-grade B-cell, Burkitt-like
2850%
----
24366%
18600%
Peripheral T-cell, all types
1368%
2338%
Anaplastic large T/null cell
3170%
2665%
Precurssor T-lymphoblastic
Common types of lymphoma and 5-year survival
Age
(Yrs)
Survival
5 yrs
Exp. survival
MR
B cell Lymphocytic
65
51%
88%
500%
Mantel cell
63
27%
90%
1100%
Extranodal marginal Zone B
(MALT)
60
74%
92%
350%
Follicular
59
72%
93%
450%
Diffuse large B Cell
lymphoma
64
46%
89%
625%
Burkit’s lymphoma
31
45%
99%
7350%
Precursor T Cell
lymphoblastic
28
26%
99%
11805%
Anaplastic Large T / Null cell
34
77%
99%
2500%
Peripheral T cell NHL
61
25%
93%
1600%
Type of lymphomas
Life table US, 1998
Adapted From: Harrison’s Principles of Internal Medicine, 16th ed. 2005
The indolent lymphomas
Adapted from Up To Date (source: J Clin Oncol 1997;17:3835)
B-cell Neoplasms
Age
P
P’
MR
65
51%
88%
500%
Follicular (grade I and II)
59
72%
93%
450%
Marginal zone B- cell lymphoma
60
74%
92%
350%
Mantle cell lymphoma
63
27%
90%
1100%
Small lymphocytic/B cell L ymphocytic
leukemia
Lymphoblastic lymphoma
P = Observed survival at 5 yrs
P’= Expected survival (life table US 1989)
Lymphomes indolents
•
•
•
•
Sont incurables
Invasion moelle osseuse
Rémission spontanée dans 25 % des cas
Rechutes 2-3 après et ensuite de plus en plus
rapidement
• Sur-mortalité persist e après 10 ans
• Certains LNH chez les personnes agées peuvent
être assurés avec surprime (?)
• Les LNH indolents doivent être refusés
Tel: 1-877-343-7606
Fax : 1-514-343-7074
E-mail:
franç[email protected]