7/100,000 30% of all lymphomas male predominance heterogeneous group of tumors consisting of...

DLBCL

7/100,00030% of all lymphomas male predominanceheterogeneous group of tumors

consisting of large, transformed B-cells with prominent nucleoli and basophilic cytoplasm, a diffuse growth pattern and a high (>40 percent) proliferation fraction

60% advanced at presentationBM in 30%; EN 40%

DLBCL

tumor cells in DLBCL generally express pan B-cell antigens (CD19, CD20, CD22, CD79a), as well as CD45, along with monoclonal surface membrane IgM; occasionally other heavy chain isotypes are present.

Ki 67: > 40%70% BCL-625-80% BCL-2T(14;18) 30%; cmyc translocation 5-

15%

Large cell lymphoma: distinct clinical pathologic subtypes

T cell rich large B cell lymphomaPrimary diffuse large B-cell

lymphoma of the mediastinum, also called primary mediastinal large B-cell lymphoma

Intravascular lymphomaLymphomatoid granulomatosis, an

Epstein-Barr virus (EBV) positive large B-cell lymphoma

Primary Mediastinal DLBCL

7% of large B cellThymic B cell originCo-express weakly CD30Female predominance 4th decadePresents with massive mediastinal

disease, sometimes with SVC syndrome

Good prognosisGEP similar to HD

Case

59 y.o lawyer referred for 20 lb weight loss over 3 months, night sweats and new axillary adenopathy. Previously healthy. Grew up on a farm. Non smoker. No family history. Married with 2 kids in university

On exam: looks unwell. Palpable 2-3 cm nodes in axillae, supraclavicular and inguinal regions

Labs: Hgb 120 g/L, LDH 400 CT scans and excisional biopsy ensue

Diffuse Large B cell Lymphoma (Aggressive)

John

John gets staged…..

CT scans of abdomen and pelvis: retroperitoneal nodes and mesenteric nodes

Bone marrow aspirate and biopsy: negative

Gallium scan: gallium avid disease above and below the diaphragm in sites of nodal enlargement

HIV negativeStage IIIA

He has many questions….

How common is this cancer?What does his sub-type mean?What causes it? Are his kids at risk?What is his prognosis?What treatments are available?Can we predict if he will relapse?What if he does relapse?

Current Incidence and Mortality

Table 1Estimated New Cases and Deaths for Cancer Sites by Sex,Canada - 2005


What causes it? Are his kids at risk?

What is his prognosis?What treatments are available?Can we predict if he will relapse?What if he does relapse?

Etiology Familial/Genetic (RR=2-3)

Cancer susceptibility genes Immunosuppression

acquired▪ AIDS (100x), post transplant (30-50x)

congenital▪ SCID, CVI, Wiskott Aldrich, AT

Viral: HIV, HTLV-1(5%), EBV, HHV8, Hepatitis C

Bacterial: H Pylori (6X)

Etiology Continued

Occupational Phenoxyacetic acid herbicides Farmers: organophosphate insecticides Fertilizers solvents

Social Increased diet of animal protein, fat and

meat Hair dyes


What causes it? Are his kids at risk?


International Prognostic Factor Index (IPI)

Factors Included Patients of all ages

Age >=60 LDH > normal Performance status

2-4 Ann Arbor stage III-

IV Extra-nodal

involvement (>1 site)

Age adjusted Stage LDH Performance status

DLBCL: Survival by IPI

Armitage and Weisenburger, 1998

The International Non-Hodgkin's Lymphoma Prognostic Factors Project, N Engl J Med 1993;329:987-994

Outcome According to Risk Group Defined by the International Index and the Age-Adjusted International Index

Biologic Factors

BadKi-67P53CD5+LDHB-2-

microglobulinC-reactive

proteinBCL-2C-mycSurvivinCyclin D2

GoodCD10BCL-6CD40

5 yr OS

CD10 negative positive

44%74%

Bcl-6negativepositive

30%69%

Cyclin D2Negativepositive

58%11%

MUM 1negativepostive

66%36%

TMAGCB

Non-GCB76%34%

Hans, C. P. et al. Blood

2004;103:275-282

Rosenwald, A. et al. N Engl J Med 2002;346:1937-1947

Subgroups of Diffuse Large-B-Cell Lymphoma According to cDNA Gene-Expression Profiles

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Hans, C. P. et al. Blood 2004;103:275-282

Figure 2. Results of immunoperoxidase staining

They found that the GCB and non-GCB subtypes of DLBCL could be accurately predicted using a panel of only 3 immunostains

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Hans, C. P. et al. Blood 2004;103:275-282

Figure 1. Decision tree for immunoperoxidase TMA classification of DLBCL

Lymph node IHC

CD20+ BCL2+ BCL6+ CD10+ Ki67+ 50% CD5- CD23- Cyclin D1-

John Has GCB-type DLBCL

CHOP or CHOP-like chemotherapy is the mainstay chemotherapy treatment for large cell lymphomas

Q 3 week cycles6-8 cyclesCyclophosphamide 750 mg/m2 Adriamycin: 50 mg/m2 day 1Vincristine 1.4 mg/m2 IV day 1Prednisone 100 mg po daily x 5

days

Fisher, R. I. et al. N Engl J Med 1993;328:1002-1006

Overall Survival in the Treatment Groups

Copyright © American Society of Clinical Oncology

Coiffier, B. J Clin Oncol; 23:6387-6393 2005

Fig 1. (A) Event-free survival, (B) progression-free survival, and (C) overall survival with a median follow-up of 5 years in CHOP (cyclophosphamide,

doxorubicin, vincristine, prednisone) and R-CHOP (rituximab-CHOP) -treated patients in the LNH-98.5 study

28%

50%


Coiffier, B. J Clin Oncol; 23:6387-6393 2005

Low Risk

0-1

High risk

2-3


Thieblemont, C. et al. J Clin Oncol; 25:1916-1923 2007

Fig 2. Five-year follow-up results of the Groupe d'Etude des Lymphomes de l'Adulte study in patients 60 to 80 years old comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with the rituximab plus CHOP (R-CHOP) regimen


Fu, K. et al. J Clin Oncol; 26:4587-4594 2008

Fig 3. Subclassification on the basis of the cell of origin was predictive of (A) overall and (B) event-free survival in patients with diffuse large B-cell lymphoma who were treated with rituximab plus standard

chemotherapy


Fu, K. et al. J Clin Oncol; 26:4587-4594 2008

Fig 2. Addition of rituximab to standard chemotherapy improved the overall and event-free survival of patients in both the (A, B, respectively) germinal center B-cell-like and the (C, D, respectively) non-

germinal center B-cell-like subgroups of diffuse large B-cell lymphoma

CD20+ DLBCL18-60 years

IPI 0,1Stages II-IV,I with bulk

6 x CHOP-like+ 30-40 Gy (Bulk, E)

6 x CHOP-like+ Rituximab

+ 30-40 Gy (Bulk, E)

Random.

Trial

Design

Chemo(n=411)

R-Chemo(n=413)

Complete remission (CR/CRu) 68%* 86%*

Partial remission (PR) 12% 7%

No change (NC) 4% 1%

Progressive disease (PD) 11%** 4%**

** p=0.0018 (Fisher’s exact test)* p<0.0005 (Fisher’s exact test)

Remission

Rates

JOHN KERR

Myriam --- % response rates (p56) don't match values divided by n eg CR for Chemo, n=113 and 113/165 is 68%, but on p56 is given as 70%

R-CHEMO

CHEMO

p < 0.000005crit = 0.00192*

81%

58%

Median time of observation: 24 months

0.0

5 10 15 25 30 35 45 50

0.10.2

0.3

0.40.50.60.7

0.80.9

0

M o n t h s

Pro

bab

ility

FT

F

1.0

20 40

*: -crit for updated interim analysis

Time to Treatment Failure

p=0.0026


0.05 10 15 25 30 35 45 50

0.10.20.3

0.40.50.6

0.7

0.8

0.9

0

M o n t h s

Pro

bab

ility

Su

rviv

al

1.0R-CHEMO

CHEMO

20 40

95%

85%

Overall Survival

The standard of care for newly diagnosed large B cell lymphomas is CHOP-R

Improved overall survival of 10-14%

Improved progression-free survival of 20-23%

Well tolerated, safe with no excess increased toxicity

Adds roughly $16,000 extra to cost of CHOP

Should he have 6 or eight cycles of CHOP-R?

Six, not eight cycles of bi-weekly CHOP with rituximab (R-CHOP-14) is the preferred treatment for elderly patients with DLBCL: results of the

RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma

Study Group (DSHNHL)

RICOVER 60

M. Pfreundschuh, M. Kloess, R. Schmits, S. Zeynalova, E. Lengenfelder, A. Franke, H. Steinhauer, M. Reiser, M. Clemens, C. Nickenig, M. de Wit, A. Ho, H. Eimermacher, L. Truemper, M. Hoffmann, R. Mertelsmann, B.

Metzner, H. Mergenthaler, R. Liersch, U. Duehrsen, L. Balleisen, F. Hartmann, V. Poeschel, N. Schmitz, M. Loeffler for the DSHNHL

Questions addressed

• Can CHOP-14 be improved by

rituximab?

• Are 8 cycles better than 6?

RICOVER 60:

objectives

CD20+ DLBCL

stages I–IV

61–80 years

Random2x2

Factorialdesign

RICOVER 60: trial design

6 x CHOP-14+ 36 Gy (Bulk, E)



+ 8 x rituximab


+ 8 x rituximab

8 doses of rituximab regardless ofnumber of cycles of chemotherapy

CHOP-14 vs R-CHOP-14

Fai

lure

-fre

e su

rviv

al (

%)

8 x (R)-CHOP-14(n=415)

6 x (R)-CHOP-14(n=413)

p=0.000025 -crit* = 0.031

57%

70%64%

62%

p=0.23

Fai

lure

-fre

e su

rviv

al (

%)

100

80

60

40

20

0

100

80

60

40

20

0

6/8 x R-CHOP-14(n=414)

6/8 x CHOP-14(n=414)

0 5 10 15 20 25 30 35 40 45 0 5 10 15 20 25 30 35 40 45

Months Months

6 cycles vs 8 cycles

RICOVER 60: time to treatment failure

53%

58%

p=0.125p=0.724

70%

70%

8 x R + 6 x CHOP-14 vs 8 x R-CHOP-14

100

80

60

40

20

0

0 5 10 15 20 25 30 35 40 45

Months

Fai

lure

-fre

e (%

)

8 x CHOP-14(n=210)

6 x CHOP-14(n=204)

Fai

lure

-fre

e (%

)

100

80

60

40

20

0

8 x R-CHOP-14(n=203)

8 x R + 6 x CHOP-14(n=211)

0 5 10 15 20 25 30 35 40 45

Months

6 x CHOP-14 vs 8 x CHOP-14

RICOVER 60: time to treatment failure


Su

rviv

ing

(%

)

100

80

60

40

20

0

0 5 10 15 20 25 30 35 4045 Months

6 x CHOP-14 (n=204)8 x R + 6 x CHOP-14 (n=211)8 x CHOP-14 (n=210)8 x R-CHOP-14 (n=203)

RICOVER 60: survival

Case

Should He Have Maintenance Therapy?

ECOG 4494 Phase III Trial:

R-CHOP v CHOP +/- MR

RANDOMIZED

Stratified by IPI(0-1 vs 2-4)

CHOP

1 2 3cycle 4 5 6 7 8

Rituximab

RANDOMIZED

Stratified by IPICR/PR; Induction

Maintenance Rituximab

(MR) q 6 m x 2 yr

Observation

(N=632) (N=415)1 2 3cycl

e 4 5 6 7 8

Outcome According toInduction and Maintenance Therapy

Treatment 2 year FFS* 2 year OS

R-CHOP + MR 79% 87%

R-CHOP + OBS 77% 85%

CHOP + MR 74% 83%

CHOP + OBS 45% 72%

* Significant FFS interaction (HR=2.10, p=0.05) This is the data on responding patients.

You recommend 6 cycles of CHOP-R……

You repeat his CT scans and he is in complete remission after his chemotherapy


How common is this cancer?What does his sub-type mean?What causes it? Are his kids at risk?What is his prognosis?What treatments are available?Can we predict if he will relapse?What if he does relapse?


Spaepen, K. et al. J Clin Oncol; 19:414-419 2001

Fig 4. Kaplan-Meier estimate of PFS in 26 patients with a positive [18F]FDG-PET after therapy compared with 67

patients with a negative [18F]FDG-PET after therapy

N=26

N=67


Spaepen, K. et al. J Clin Oncol; 19:414-419 2001

Fig 2. Prognostic value of [18F]FDG-PET scan in a patient with presumed CR on CDM. Residual FDG-uptake cervical (left) and mesenteric (right). Patient relapsed after 838 days; a cervical biopsy was positive for NHL

Case continued……

John returns to workHe is followed every 3 months for

the first 2 yearsAt his 18 month visit, he complains

of a new 2 cm neck nodeAn excisional biopsy confirms

DLBCL identical to initial biopsyOn re-staging, he is found to be

stage IIA, IPI LI

What do we do now?

Options: Salvage chemotherapy

Cisplatin or gemcitabine based Salvage chemotherapy followed by

ASCT 25% chance of 2 year disease free survival

Palliative radiation or low dose chemotherapy Survival 6 months

Rituxan alone Overall response 35%; time to progression 2

months Radioimmunoconjugates

His best bet is high dose chemotherapy

Autologous

Allogeneic

Availability 90% 25%

Exploits dose-response

yes yes

Graft vs. lymphoma

no yes

Graft vs. Host no yes

Graft contamination

likely no

Treatment Related Mortality

2-5% 20-30%

Curative 30% 50%

Philip, T. et al. N Engl J Med 1995;333:1540-1545

Kaplan-Meier Curves for Event-free Survival of Patients in the Transplantation and Conventional-Treatment Groups

Philip, T. et al. N Engl J Med 1995;333:1540-1545

Kaplan-Meier Curves for Overall Survival of Patients in the Transplantation and Conventional-Treatment Groups

Rituximab Plus AuHCT in Patients With DLBCL

Fenske TS, et al. ASH 2007. Abstract 19.

Patients with DLBCL in GBMTR database,

1996-2003

(N = 1006)

Rituximab within 3 months of AuHCT

(n = 188)AuHCT

No Rituximabwithin 3 months of AuHCT

(n = 818)Characteristic Rituximab

(n = 188)No Rituximab

(n = 818)P Value

Median age, yrs (range) 58 (20-76) 52 (18-75) < .001

Karnofsky performance score < 90%, % 39 37 .52

Largest mass size ≥ 5 cm before AuHCT, % 28 35 .28

> 2 chemotherapy regimens given, % 56 40 < .001

Year of AuHCT Between 1996 and 1998 Between 1999 and 2001 Between 2002 and 2003

44749

59347

< .001

Retrospective analysis

Rituximab Plus AuHCT in Patients With DLBCL

Fenske TS, et al. ASH 2007. Abstract 19.

Progression-Free Survival

Per

cen

tag

e o

f P

atie

nts

Rituximab (n = 188) No Rituximab (n = 818)

Overall Survival

6249

3949

38 32

0

20

40

60

80

100

Year 1

P = .002P = .01

P = .16

Year 3 Year 5

6857

4860

45 40

P = .032P = .003

P = .13

Year 1 Year 3 Year 50

20

40

60

80

100

What if he had presented with localized disease at diagnosis (stage 1-2)?

Limited stage DLBCL

Study N Design PFS (p value) OS (p value)

Miller NEJM 1998

401 CHOP x 3 + IF RTCHOP x 8

77%64% (.03)

82%72% (.02)

BonnetJCO 2007

576 (age > 60)

CHOP x 4CHOP x 4 + IF RT

61%64% (NS)

72%68% (NS)

ReyesNEJM 2005

648(age < 61)

CHOP x 3 + IF RTACVBP + Seq consolidation

74%82%(<.001)

81%90%(.001)


Persky, D. O. et al. J Clin Oncol; 26:2258-2263 2008

Fig 1. (A) Progression-free and (B) overall survival of 60 eligible patients enrolled in a Southwest Oncology Group (SWOG) trial of three cycles of R-CHOP followed by involved-field radiation therapy


Persky, D. O. et al. J Clin Oncol; 26:2258-2263 2008

Fig 3. Overall survival of 60 eligible patients receiving R-CHOP(3) plus IFRT (from S0014) is compared with that of 68 eligible patients receiving CHOP(3) plus IFRT (from S8736), matched for limited disease,

aggressive B-cell histologies, and presence of at least one stage-modified International Prognostic Index (IPI) risk factor

Stage Modified IPI: age, stage 2, LDH and ECOG

Conclusions: limited stage IPI

CHOP-R x 3 + IF RTPatients with more than 1 RF on

stage modified IPI might do as well with chemo alone x 6-8 cycles

This excludes bulky diseaseNo benefit to IF rads if 6-8 cycles

chemo

New agents and approaches

RadioimmunotherapyProtein Kinase-C inhibitorsVelcadeAngiogenesis InhibitorsAnti-BCL-2RevlimidGaliximab and epratuzumabNewer humanized RituxanEPOCH-R

Current or Pending Aggressive NHL Trials at Sunnybrook

LY-11: RCT of CHOP-r x 8 vs. CHOP-R x 6 then ASCT in newly diagnosed age < 65 with DLBCL with 2-3 aaIPI factors

Ly-12: RCT of R-DHAP vs. R-GDP in relapsed DLBCL or transformed NHL f/B ASCT then 2nd randomization to R maintenance or observation

Sunitinib in relapsed DLBCL or primary mediastinal large cell NHL (pending)

Risk stratification by PET scans with modified therapy?

Summary

NHL is the fifth most common cancer Large cell lymphoma comprises 30% of all

lymphomas Untreated, survival in months 60% are curable today

Rituxan + anthracycline containing chemotherapy standard upfront

New techniques for prognosis and prediction of relapse

High dose chemotherapy and stem cell transplant is recommended for young relapsed patients

The roles of RIT and PET and new agents are emerging

The role of maintenance immunotherapy unknown at this time

7/100,000 30% of all lymphomas male predominance heterogeneous group of tumors consisting of...

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