LYMPHOMES NON HODGKINIENS

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LYMPHOMES NON HODGKINIENS

• François Sestier, MD, PhD
• Abdelouahed Naslafkih, MD, PhD
• AQTV, Montréal, 14 Mai 2009
• Programme de médecine dassurance et expertise en
  sciences de la santé,
• Université de Montréal
• www.mae.umontreal.ca

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1er manuel

• Low grade
• -diffuse lymphocytic Stage
  Rating
• -nodular lymphocytic I
  class 3 pp2yrs,std 7th yr
• -nodular histiocytic II
  class 2 pp3yrs,std 8th yr
• III
  class 1 pp5yrs,std 11th yr
• IV
  DEC to 100, cl1
• Intermediate-High grade Stage
  Rating
• -diffuse lymphocytic, poorly diff
  I class 2
• -diffuse lymphocytic-histiocytic
  II class 1
• -Burkitts lymphoma
  III 100, class 1
• -Unclassified
  IV DEC to 200 class 1

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2ième 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

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• Les LNH sont-ils des risques standards sils
  survivent
• 7 à 16 ans ??

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OBJECTIFS

• Identifier la littérature médicale la plus
  récente concernant la mortalité des LNH
• Calculer la mortalité observée en utilisant une
  méthodologie actuarielle

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LNH définition et épidémiologie

• 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
  (1.51.0).

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Incidence selon lâge au diagnostic Source 
SEER-Cancer statistics Review 1995-2004
Increasing incidence with age. Differences
between SEER registries 2002-2004 and 1975-1977.
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Non-Hodgkin lymphoma classification
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Histologic classification of non-Hodgkins
lymphomas - Working Formulation (WF)

• 1. Low grade
• 2. Intermediate grade
• 3. High grade

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Histologic classification of non-Hodgkins
lymphomas - Working Formulation (WF)

• Low grade
• A - Small lymphocytic cell.
• B - Follicular, predominantly small cleaved cell
• C - Follicular mixed, small cleaved and large
  cell.

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Histologic classification of non-Hodgkins
lymphomas - Working Formulation (WF)

• Intermediate grade
• D - Follicular, predominantly large cell.
• E - Diffuse small cleaved cell.
• F - Diffuse mixed, small and large cell.
• G - Diffuse large cell.

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Histologic classification of non-Hodgkins
lymphomas - Working Formulation (WF)

• High grade
• H -Large cell immunoblastic.
• I -Lymphoblastic.
• J -Small noncleaved cell Burkitts

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Staging Ann Arbor

• I. 1 lymph node region or structure
• II. gt1 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

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ANN ARBOR and SEER classifications
Stages ANN ARBOR Stages ANN ARBOR Stages SEER
I One group of lymph nodes affected. Localized
II Two or more teritories affected, located at one side of the diaphragm. Regional
III On both sides of the diaphragm. Distant
IV Spread beyond the lymph nodes, (to other organs bone marrow, liver or lungs). Distant
Fever (at least 38C 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/CancerAnnualRep
ort2002.htm
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Source NCDB, Commission on Cancer, AcoS.
Benchmark Reports v1.1 - November 1, 2002.Rapid
City Regional Hospital Cancer Registry.
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Source NCDB, Commission on Cancer, AcoS.
Benchmark Reports v1.1 - November 1, 2002.Rapid
City Regional Hospital Cancer Registry.
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Source NCDB, Commission on Cancer, AcoS.
Benchmark Reports v1.1 - November 1, 2002.Rapid
City Regional Hospital Cancer Registry.
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Follicular lymphoma and long term survival
Gandhi, Blood Rewiews,2005,19165-178
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Prognostic Index
IPI International prognostic Index FLIPI Follicular Lymphoma International prognostic index
Risk factors Age gt 60 years Spread beyond lymph nodes 2 sites High serum LDH Stages III and IV Performance status (ECOG PS) 2 Risk factors Age gt 60 ans Lymph nodes 4 sites affected High serum LDH Stages III et IV Hemoglobine lt 12 g/dl
Risk class Low  0 or 1 Intermediate  2 High  3 - 5 Risk class Low  0 or 1 Intermediate  2 High  3
Adapted from Perea et al. Prognostic indexes in
follicular lymphoma a comparison of different
prognostic systems. Ann Oncol 2005 161508-1513
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The International Non-Hodgkin's Lymphoma
Prognostic Factors Project NEJM 1993329987-994

A Predictive Model for Aggressive Non-Hodgkin's
Lymphoma
USA, Europe, Canada, 1982-1987 3273 patients
(1274 ? 60 years)
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NEJM 1993329987-994
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Factors Independently Prognostic of Overall
Survival
NEJM 1993329987-994
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Development of a Molecular Predictor of Survival
in Follicular Lymphoma
Dave, S. S. et al. N Engl J Med 20043512159-2169
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LYMPHOMA SURVIVAL a textbook approach
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Southwest Oncology Group lymphoma survival
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LNH

• Surviennent chez le jeune adulte et la personne
  agée
• Il faut dond tenir compte de lâge dans le calcul
  de la mortalité

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NHL Mortality ratio by age groups, SEER 9
Registries for 1988-2003
Age at diagnosis Mortality ratio (MR) Mortality ratio (MR) Mortality ratio (MR)
Age at diagnosis 2 years 5 years 10 years
lt45 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
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LNH MR at 5 years by stages SEER data
(1988-2001)
Stage Survival Survival MR ()
Stage Relative Expected MR ()
Localized 68.8 85.4 325
Regional 61.7 - 386
Distant 44.9 - 560
All stages 56.3 - 438
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NHL Mortality ratio by follow-up period SEER 9
Registries , 1988-2003
Years MR () MR () MR ()
Years Men Women Both
0 - 1 680 660 670
0 - 2 680 600 630
0 - 3 555 515 545
0 - 4 485 448 475
0 - 5 430 400 420
0 - 6 385 360 376
0 - 7 350 229 343
0 - 8 318 300 310
0 - 9 290 275 285
0 -10 265 255 260
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CCCW-NHL Registry
Kroll et al. Ann Oncol 200314131-139

• Netherlands, 1981-89
• 1164 patients, age 64 yrs, 50 women

Overall survival () Overall survival () MR MR
5 yrs 10 yrs 5 yrs 10 yrs
Nodal (n 635) 41 23 713 397
Extra nodal (n 389) 41 24 713 386
Extensive (n 140) 29 12 956 555
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NHL Mortality ratio (MR) at 2, 5, 10, and 15
years
Mortality ratio (MR ) Mortality ratio (MR ) Mortality ratio (MR ) 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. LeukemiaLymphoma 2003
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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. LeukemiaLymphoma 2003
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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 ) NHL-DLCB Mortality ratio (MR ) NHL-DLCB Mortality ratio (MR ) 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.
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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
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CCCW-NHL Registry. Maartense et al. Cancer 2000
89(12)2667-2676 Effect of age
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NHL MR at 5 and 8 years by type and age
Type Age at diagnosis (years) Age at diagnosis (years) Age at diagnosis (years) Age at diagnosis (years) Age at diagnosis (years)
Type lt60 60-64 65 -69 70 -74 75
Indolent
MR 5 yrs 1290 395 338 525 170
MR 8 yrs 1360 434 400 360 300
Agressive
MR 5 yrs 2360 900 745 540 317
MR 8 yrs 1360 690 550 360 395
Adapted from  Maartense et al. Cancer 2000
89 2667-2676
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CCCW-NHL Registry. Maartense et al. Cancer 2000
89(12)2667-2676 Effect of age on MR
Age group Mortality Ratios Mortality Ratios
Age group Indolent DLBL
lt60 yrs 1150 1360
60 64 yrs 450 695
65 69 yrs 410 560
70 74 yrs 330 350
?75 yrs 200 265
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Age group Mortality Ratios Mortality Ratios
Age group Indolent DLBL
lt60 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
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Localized aggressive lymphomaRey et al. NEJM
20053521197

• France, 1993-2000
• 647 patients (318 ACVBP, 329 CHOPRX)
• 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

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Côte d'Or registry,France, 451 patients
diagnosed with NHL between 1980-92
NHL Mortality ratio (MR) at 5 years by different
variables
Variables Variables MR
Gender Men 300
Gender Women 200
Age 20 64 years 980
Age 65 years 250
Grade Low 185
Grade Intermediate 280
Grade High 515
Grade Unknown 475
Period of diagnosis 1980-1983 263
Period of diagnosis 1984-1987 400
Period of diagnosis 1988-1991 275
Source  Rolland-Portal et al. Int J Epidemiol
1997 26 945-952
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NHL MR at 5 and 10 years by grade (Register Côte
dOr)
Relative survival Relative survival Mortality ratio 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
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Follicular lymphomaMontoto et al. Ann Oncol
200213523-530

• 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
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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 13523-530
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Survival of 389 follicular lymphomas std at 10
yrs????
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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 200310178-84
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Indolent lymphomaFollicular vs. Non Follicular
lymphomaCorradini et al. J Clin Oncol
2004221460-1468

• Italy,1990-99
• 70 patients,60 men
• Age 47 years
• 87 stage IV
• Overall survival at 12 yrs
• Follicular subtype 76, MR 514
• Non-Follicular 49, MR 1311

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Relapsed Follicular LymphomaAutologous Bone
Marrow TransplantationFreedman et al. Blood
1999943325-3333

• 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
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20 yrs survival after ABMT from diagnosis for
153 patients with indolent follicular lymphoma.
MR 1330
Freedman, A. S. et al. Blood 1999943325-3333
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20 yrs survival after ABMT from diagnosis for
153 patients with indolent follicular lymphoma.
MR 1330, Not std!!
Freedman, A. S. et al. Blood 1999943325-3333
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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 lt60 years Age lt60 years Age lt60 years Age 60 years Age 60 years Age 60 years
Follow-up 5 yrs 10yrs 15yrs 5yrs 10yrs 15yrs
Localized/regional Localized/regional
FSC, FM 1983-89 325 275 200 420 310 245
FSC, FM 1990-99 307 277 480 355
FLC 1983-89 415 232 200 578 361 220
FLC 1990-99 475 300 570 385
Distant stage
FSC, FM 1983-89 560 465 287 700 455 300
FSC, FM 1990-99 550 385 725 460
FLC 1983-89 1020 560 287 865 545 345
FLC 1990-99 717 370 965 500
Adapted from Swenson et al. J Clin Oncol 2005
235019-5026, ref. 12
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Localized Intermediate and high-grade
Non-hodgkin's lymphoma

• Soutwest Oncology Group, 1988-1995
• 442 patients (CHOP 201 CHOPRX 200)
• Age 59 years
• 5-year overall survival
• CHOP 72
• CHOPRX 82

Miller et al. NEJM 199833921-26
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5-year overall survival CHOPRX 82 CHOP
72 MR 396 CHOPRX MR 648 CHOP
Life table US,1989-91
Miller et al. NEJM 199833921-26
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MR 396 MR 675 MR 1390
Life table US,1989-91
Miller et al. NEJM 199833921-26
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Intermediate or high-grade Non-Hodgkin 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 2004100350-355
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Intermediate or high-grade Non-Hodgkin 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 2004100350-355
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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
Intermediate risk 2 2.3
High risk 3 4.3
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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 3273 patients aggressive NHL (High/interm grades), Age at diagnosis 65 years, Follow-up 5 years MR
All All 420
Male Male 420
Female Female 410
Age 60 years Age 60 years 655
Age gt60 years Age gt60 years 355
Stages I 158
Stages II 275
Stages III 425
Stages IV 577
Stages I/II 245
Stages III/IV 525
Adapted from NEJM 1993
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NHL Mortality ratio at 2 and 5years by IPI
IPI MR () MR ()
IPI 2 years 5 years
All patients Low 0 ou 1 275 210
Low-Intermediaite 2 613 435
High-Intermediaite 3 866 535
High 4 ou 5 1360 815
Age 60 yrs Low 0 325 245
Low-Intermediaite 1 708 480
High-Intermediaite 2 1475 965
High 3 2500 1365
Age gt60 yrs Low 0 225 240
Low-Intermediaite 1 375 330
High-Intermediaite 2 655 395
High 3 945 585
Adapted from The International NHL Prognostic
Factors Project. NEJM 1993
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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 ACVBP CHOP Total
MR 645 785 715
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The International Lymphoma Study Group
Classification of Non-Hodgkins 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 1997893909-3918
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NHL Classification Project Survival by histologic
type and the International Prognostic Index
Consensus diagnosis Age (Years) Male () 5-year survival 5-year survival
Consensus diagnosis Age (Years) Male () Index 0/1 Index 4/5
Follicular, all grades 59 42 84 17
Mantle cell 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 1997893909-3918
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NHL Classification Project Blood
1997893909-3918 Mortality Ratio ( life table
Canada 1990-92)
Consensus diagnosis MR MR
Consensus diagnosis 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 ----
Precurssor T-lymphoblastic 24366 18600
Peripheral T-cell, all types 1368 2338
Anaplastic large T/null cell 3170 2665
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Common types of lymphoma and 5-year survival
Type of lymphomas Age (Yrs) Survival 5 yrs Exp. survival Life table US, 1998 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
Burkits 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
Adapted From Harrisons Principles of Internal
Medicine, 16th ed. 2005
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The indolent lymphomas Adapted from Up To Date
(source J Clin Oncol 1997173835)
B-cell Neoplasms B-cell Neoplasms Age P P MR
Small lymphocytic/B cell L ymphocytic leukemia 65 51 88 500
Lymphoblastic lymphoma
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
P Observed survival at 5 yrs P Expected
survival (life table US 1989)
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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

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Tel [phone]Fax [phone] E-mail
françois.sestier_at_umontreal.ca