LYMPHOMES NON HODGKINIENS

François Sestier, MD, PhDAbdelouahed 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.cawww.mae.umontreal.ca

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 -Burkitt’s lymphoma III +100, + class 1 -Unclassified IV DEC to +200 + class 1

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

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 non-Hodgkin’s lymphomas - Working

Formulation (WF)

1. Low grade2. Intermediate grade

3. High grade

Histologic classification of non-Hodgkin’s lymphomas - Working

Formulation (WF)

Low grade

A - Small lymphocytic cell.B - Follicular, predominantly small cleaved

cellC - Follicular mixed, small cleaved and large

cell.

Histologic classification of non-Hodgkin’s 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.

Histologic classification of non-Hodgkin’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 structureII. >1 lymph node region or structure,

same side of diaphragmIII. Both sides of diaphragmIV. Extranodal sites beyond “E”

designation

subscripts: A, B, E, S

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.

DistantIV

Spread beyond the lymph nodes,

(to other organs: bone marrow, liver

or lungs).

ANN ARBOR and SEER classifications

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

IPIInternational prognostic Index

FLIPIFollicular Lymphoma International prognostic index

Risk factors

Age > 60 years

Spread beyond lymph nodes ≥ 2 sites

High serum LDH

Stages III and IV

Performance status (ECOG PS) ≥ 2

Risk factors

Age > 60 ans

Lymph nodes ≥4 sites affected

High serum LDH

Stages III et IV

Hemoglobine < 12 g/dl

Risk class

Low : 0 or 1

Intermediate : 2

High : 3 - 5

Risk class

Low : 0 or 1

Intermediate : 2

High : ≥ 3

Prognostic Index

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, 1982-19873273 patients (1274 60 years)

NEJM 1993;329:987-994

NEJM 1993;329:987-994

Factors Independently Prognostic of Overall Survival

Dave, S. S. et al. N Engl J Med 2004;351:2159-2169

Development of a Molecular Predictor of Survival in Follicular Lymphoma

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

Age at

diagnosis

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

NHL: Mortality ratio by age groups, SEER 9 Registries for 1988-2003

Stage Survival % MR (%)

Relative Expected

Localized 68.8 85.4 325

Regional 61.7 - 386

Distant 44.9 - 560

All stages 56.3 - 438

LNH: MR at 5 years by stages SEER data (1988-2001)

YearsMR (%)

Men Women Both

0 - 1680 660 670

0 - 2680 600 630

0 - 3555 515 545

0 - 4485 448 475

0 - 5430 400 420

0 - 6385 360 376

0 - 7350 229 343

0 - 8318 300 310

0 - 9290 275 285

0 -10265 255 260

NHL: Mortality ratio by follow-up period SEER 9 Registries , 1988-2003

Netherlands, 1981-891164 patients, age : 64 yrs, 50% women

Overall survival (%)

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%

Kroll et al. Ann Oncol 2003;14:131-139CCCW-NHL Registry

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

NHL: Mortality ratio (MR) at 2, 5, 10, and 15 years

Adapted from: Krol et al. Leukemia&Lymphoma 2003

DLCB: diffuse large B-cell lymphomas

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-DLCB

Mortality ratio (MR %)

2

yrs5 yrs 10 yrs

15

yrs

995 520 365 430

470 patients with diffuse large B cells lymphomas , 49% males, median age: 66 years

From: Krol et al. Leukemia & Lymphoma 2003; 44(3):451-458.

After 15 years all patients died

NHL-DiffuseThe Comprehensive Cancer Center West, 1981-89

CCCW-NHL Registry

Netherlands, 1981-89

1167 Patients, age : 64 yrs, 50% women

Follow-up: 8 years

Indolent and agressive NHL

Maartense et al. Cancer 2000; 89(12):2667-2676

CCCW-NHL Registry. Maartense et al. Cancer 2000; 89(12):2667-2676

Effect of age

Type Age at diagnosis (years)

<60 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

NHL: MR at 5 and 8 years by type and age

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 groupMortality Ratios

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

Age groupMortality Ratios

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%

Localized aggressive lymphoma

Rey et al. NEJM 2005;352:1197

France, 1993-2000647 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 yearsDeaths = 115

Mortality Ratio* = 560%

Côte d'Or registry,France,

451 patients diagnosed with NHL between

1980-92

Variables MR%

GenderMen 300

Women 200

Age20 – 64 years 980

≥65 years 250

Grade

Low 185Intermediate 280High 515Unknown 475

Period of

diagnosis

1980-1983 263

1984-1987 400

1988-1991 275

NHL: Mortality ratio (MR) at 5 years by different variables

Source : Rolland-Portal et al. Int J Epidemiol 1997; 26 :945-952

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

NHL: MR at 5 and 10 years by grade(Register Côte d’Or)

Follicular lymphomaMontoto et al. Ann Oncol 2002;13:523-530

Spain, 1977-1997201 patients, 53% menAge : 54 yearsStage 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

Montoto, S. et al. Ann Oncol 2002 13:523-530

Time to treatment failure (TTF) and overall survival (OS) in 201 patients with follicular

lymphoma

MR = 785% (10yrs)

Survival of 389 follicular lymphomas : std at 10

yrs????

Diffuse large B-cell lymphoma

( aggressive lymphomas)US,1987-1998128 Patients, (46% men)Age : 65 years5-year overall survival: 43%

Mortality Ratio* = 722%

Colomo et al. Blood 2003:101:78-84

Indolent lymphomaFollicular vs. Non Follicular lymphoma

Corradini et al. J Clin Oncol 2004;22:1460-1468

Italy,1990-9970 patients,60% menAge: 47 years87% stage IVOverall survival at 12 yrs

Follicular subtype: 76%, MR = 514%Non-Follicular : 49%, MR = 1311%

Relapsed Follicular LymphomaAutologous Bone Marrow Transplantation

Freedman et al. Blood 1999;94:3325-3333

USA, 1985-1995153 Patients, 53% menAge: 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

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%

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!!

Low grade NHL: Follicular Lymphomaby age, stage and histologic type

MR at 5, 10, and 15 years

Age Age <60 years Age ≥60 years

Follow-up 5 yrs10yr

s

15yr

s

5yr

s

10yr

s

15yr

s

Localized/regional

FSC, FM1983-89 325 275 200 420 310 245

1990-99 307 277 480 355

FLC1983-89 415 232 200 578 361 220

1990-99 475 300 570 385

Distant stage

FSC, FM1983-89 560 465 287 700 455 300

1990-99 550 385 725 460

FLC1983-89 1020 560 287 865 545 345

1990-99 717 370 965 500

FSC: small cleaved-cell follicular lymphoma; FM: mixed follicular lymphoma; FLC: large-cell follicular lymphoma

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, 1988-1995442 patients (CHOP: 201; CHOP+RX :200)Age : 59 years5-year overall survival : CHOP : 72%CHOP+RX : 82%

Miller et al. NEJM 1998;339:21-26

Miller et al. NEJM 1998;339:21-26

5-year overall survivalCHOP+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

Intermediate or high-grade Non-Hodgkin lymphoma

Italy, 1984-1998186 patients, 52% menAge: 56 years

Overall survival : 60.4% at 10 yearsMortality ratio = 495%

Rossini et al. Cancer 2004;100:350-355

Intermediate or high-grade Non-Hodgkin lymphoma

MR by stage Stage I-II = 431%Stage III-IV = 995%

MR by IPIIPI 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

factorsRR

Low risk 0 - 1 1.0

Intermediate

risk 2 2.3

High risk ≥ 3 4.3

High grade NHL

3273 patients aggressive NHL (High/interm grades), Age at diagnosis: 65 years, Follow-up: 5 years

MR%

All 420Male 420Female 410 Age ≤60 years 655 Age >60 years 355

Stages

I 158II 275III 425IV 577I/II 245III/IV 525

International Non-Hodgkin's Lymphoma Prognostic Factors Project 1982-98Mortality Ratio according to Life Table US, 1985-1989)

Adapted from: NEJM 1993

IPI MR (%)

2 years 5 yearsAll 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 >60 yrs

Low 0 225 240

Low-

Intermediaite

1 375 330

High-

Intermediaite

2 655 395

High 3 945 585

NHL: Mortality ratio at 2 and 5years by IPI

Adapted from: The International NHL Prognostic Factors Project. NEJM 1993

FU: 5 yrs ACVBP CHOP Total

MR% 645 785 715

GELA study 18 France, 1993-1998708 patients aggressive lymphoma (stages III / IV); 80% diffuse large B-cellMedian age at diagnosis : 65 years ; 56% males2 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.

NHL stages III-IV: Mortality by therapeutic modalities

The International Lymphoma Study Group Classification of Non-Hodgkin’s

Lymphoma1403 cases (untreated) from 8 countries,

1988-90Omaha, NE: 200

Vancouver, Canada: 202Cape Town, South Africa: 196London, UK: 120Locarno, Switzerland: 80Lyon, France: 195Wurzburg, Germany: 210Hong Kong: 200

Blood 1997;89:3909-3918

Consensus diagnosisAge

(Years)Male(%)

5-year survival %

Index0/1

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

NHL Classification ProjectSurvival by histologic type and the International Prognostic Index

Blood 1997;89:3909-3918

Consensus diagnosisMR

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%

NHL Classification ProjectBlood 1997;89:3909-3918

Mortality Ratio ( life table Canada 1990-92)

Type of lymphomas

Age (Yrs)

Survival5 yrs

Exp. survivalLife 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%

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%

Common types of lymphoma and 5-year survival

Adapted From: Harrison’s Principles of Internal Medicine, 16th ed. 2005

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%

The indolent lymphomasAdapted from Up To Date (source: J Clin Oncol 1997;17:3835)

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: 1-877-343-7606Tel: 1-877-343-7606Fax : 1-514-343-7074Fax : 1-514-343-7074

E-mail: E-mail: françois.sestier@umontreal.cafrançois.sestier@umontreal.ca