Audience Response Question?

(1)

3:30 PM - 4:15 PM Session 4:

Non-Hodgkin’s Lymphomas:

Optimizing Therapeutic Choices for Initial Management Speaker:

Arnold S. Freedman, MD

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Presenter Disclosure Information

The following relationships exist related to this presentation:

• Dr Arnold S. Freedman has no relationships to disclose.

Off Label/Investigational Discussion

In accordance with Pri-Med Institute policy, faculty have been asked to disclose discussion of unlabeled or unapproved use(s) of drugs or devices during the course of their presentations.

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Initial management issues in lymphoma

• Follicular lymphoma

• Diffuse large B cell lymphoma • Mantle cell lymphoma

• T cell lymphomas

4

What is the optimal initial chemotherapy for a patient with symptomatic follicular lymphoma?

1. CVP (or CHOP) + rituximab

2. CVP followed by maintenance rituximab 3. Chemotherapy + radioimmunoconjugate 4. Fludarabine + rituximab

Audience Response Question ?

5

International study 8 cycles of therapy TTF primary endpoint

Approx. 45% patients FLIPI 3-5

R-CVP vs CVP

Marcus R, et al.

Marcus R, et al. Blood.Blood.2005;105(4):14172005;105(4):1417--1423.1423.

6

• 4167 patients

• Age > 60, Stage III/IV, > 4 nodal sites, LDH,

Hgb < 12

– Low risk 0-1 – Intermediate risk 2 – High risk 3-5

Prognosis in follicular NHL follicular lymphoma IPI (FLIPI)

(2)

7

Follicular Lymphoma International Prognostic Index (FLIPI)

Solal-Céligny P, et al. Blood. 2004;104(5):1258-1265.

Low risk 0-1 Intermediate risk 2 High risk 3-5 8 Event-free survival median follow-up 53 months FLIPI 0, 1 FLIPI 2 FLIPI >3

Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.

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Overall Survival

median f/u 53 months

Marcus R, et al. J Clin Oncol. 2008;26:4579-4586. 10

Phase III trials of chemo vs R chemo in previously untreated follicular NHL

Marcus CVP vs CVP-R improved OS

Hiddemann CHOP vs CHOP-R improved OS

Herold MCP vs MCP-R improved OS

Foussard CHVP vs CHVP-R improved OS in

+ interferon high FLIPI only

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E1496 (ECOG, CALGB) 6 - 8 cycles of CVP Maintenance rituximab (4 doses q 6 m x 2 y)

Approx. 37% patients FLIPI 3-5

Maintenance rituximab or observation after CVP

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Progression-free Survival

(3)

13

Overall Survival

Hochster H, et al. J Clin Oncol. 2009;27:1607-1614. 14

Radioimmunotherapy

Radioimmunotherapyas Consolidation of First as Consolidation of First

Remission Therapy in Follicular NHL

Morschhauser

MorschhauserF, et al. F, et al. J J ClinClinOncolOncol. 2008;26:5156. 2008;26:5156- -5164. 5164.

Progression-free Survival

All patients

All patients PR to inductionPR to induction CR to inductionCR to induction

Morschhauser

MorschhauserF, et al. F, et al. J J ClinClinOncolOncol. 2008;26:5156. 2008;26:5156--5164.5164.

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Fludarabine and Rituximab for Previously

Untreated Patients

27 patients, 50% IPI 0,1 27 patients, 50% IPI 0,1 Phase II study Phase II study ORR 90% ORR 90% CR 80% CR 80% Grade 3, 4

Grade 3, 4 neutropenianeutropenia(27%)(27%)

Herpes infections 15%

Czuczman MS, et al. J Clin Oncol. 2005;23:694-704

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Is “maintenance” rituximab justified?

Following induction chemotherapy (ECOG 1496)

Improves PFS

Borderline improvement in OS MRD associated with longest PFS Following induction R +chemotherapy Currently no data

Yes

No

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Will “maintenance” rituximab improve outcome following induction R + chemotherapy?

• PRIMA trial (2 years R at 1 dose q 3 months) following R + chemotherapy induction therapy (non-randomized). • Perhaps if one treats ….

– A high risk population at risk of early relapse,

– and/or with therapy with median time to progression < 30 months (CVP-R).

(4)

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Will “maintenance” rituximab improve outcomes following induction R + chemotherapy?

• Perhaps not with more aggressive initial treatment

(R-CHOP)

– Median time to progression > 4 year

– Few events during the 2 years of maintenance therapy

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Is “maintenance” rituximab justified?

• Yes, in relapsed, rituximab-naïve patients following chemotherapy or R-chemotherapy

– Improved PFS – Improved OS

• But this group no longer exists …

21

Which Regimen? CHOP vs CVP

Jones SE, et al. Cancer. 1983;51(6):1083-1090. 22

What is the optimal initial chemotherapy for a patient with symptomatic follicular lymphoma?

1. CVP (or CHOP) + rituximab

2. CVP followed by maintenance rituximab 3. Chemotherapy + radioimmunoconjugate 4. Fludarabine + rituximab

Audience Response Question

?

23

Many diseases Relevance of the IPI Cell of origin (GC vs ABC) Impact of current therapy New entities

Update on Diffuse Large B Cell Lymphoma

Diffuse Large B Cell Lymphoma

_(DLBCL)

DLBCL NOS

DLBCL NOS (not otherwise specified)(not otherwise specified)

T cell/

T cell/histiocytehistiocyte--rich rich large B cell rich rich large B cell

lymphoma

Primary

Primary mediastinalmediastinallarge Blarge B--cell lymphomacell lymphoma Intravascular large B cell lymphoma

Intravascular large B cell lymphoma

Lymphomatoid

Lymphomatoidgranulomatosisgranulomatosis (EBV+ large (EBV+ large B

B--cell lymphomacell lymphoma

Primary

Primary cutaneouscutaneousDLBCL, leg typeDLBCL, leg type

EBV positive DLBCL of the elderly

(5)

Diffuse Large B Cell Lymphoma

DLBCL associated with chronic inflammation

Large B cell lymphoma arising in HHV8

Large B cell lymphoma arising in HHV8--associated associated

multicentric

multicentricCastlemanCastleman’’ssdiseasedisease Primary effusion lymphoma

Primary effusion lymphoma

B cell lymphoma, unclassifiable, with features

intermediate between DLBCL and

intermediate between DLBCL and BurkittBurkitt’’ss

lymphoma

B cell lymphoma, unclassifiable, with features

intermediate between DLBCL and Hodgkin

intermediate between DLBCL and Hodgkin’’s s

lymphoma lymphoma 26

IPI

• Age > 60 • LDH > nl * • PS > 1 * • Stage III/IV * • EN sites > 1 * for aa IPI

IPI

CHOP-based Therapy

N Engl J Med. 1993;329(14):987-994.

Modification of the IPI following

CHOP+R

Low 0,1; Low

Low 0,1; Low--IntInt2;2;

High

High--IntInt3; High 4,53; High 4,5

Very good 0; Good

1,2; Poor

1,2; Poor >>33

Cell of Origin and Prognosis

CHOP

CHOP--RR

Treatment of Early Stage Disease

Chemotherapy +/

-

radiation

Bulky early stage disease

Treatment of Early Stage Disease

Update of SWOG 8736

CHOP x 3 + RT v CHOP x 8

(6)

Treatment of Stage I/II DLBCL:

Impact of

Rituximab

CHOP

CHOP--R x 3 + RTR x 3 + RT

>

>1 risk factor1 risk factor CHOP x 3 + RT or CHOP x 3 + RT or CHOP x 8 CHOP x 8 Age > 60, LDH > Age > 60, LDH > nmlnml, , PS PS >>2, Stage II2, Stage II

R

-

CHOP Alone for Early Stage DLBCL

MiNT

Study

Patients

Patients <<60, bulky 60, bulky stage I, II stage I, II--IVIV IPI 0, 1 IPI 0, 1 q 21 d cycles x 6 q 21 d cycles x 6 PFS PFS OSOS

For low volume, early stage disease

CHOP

CHOP--R x 6 has excellent outcomeR x 6 has excellent outcome

CHOP

-

R + Radiotherapy for Bulky

Early Stage DLBCL (

MiNT

)

No randomized No randomized study +/ study +/--RTRT CHOP CHOP--R x 6 + R x 6 + 30 30--40 40 GyGyto bulky to bulky sites sites EFS EFS Bulky disease

Bulky disease unfavorableunfavorableeven with RT.even with RT. Still unclear whether RT is beneficial.

Still unclear whether RT is beneficial.

Treatment of Advanced Stage DLBCL

•

•Patients Patients <<60 or > 60, CHOP60 or > 60, CHOP--R higher DFS and R higher DFS and OS than CHOP

OS than CHOP

•

•No advantage of adding No advantage of adding etoposideetoposide

•

•No role for maintenance R following CHOPNo role for maintenance R following CHOP--RR

•

•CHOPCHOP--R 14 x 6 cycles equivalent to 8 cyclesR 14 x 6 cycles equivalent to 8 cycles

•

•Is CHOPIs CHOP--R 14 better than CHOPR 14 better than CHOP--R 21?R 21?

R

-

CHOP 21

vs

R

-

CHOP 14

R

R--CHOP 21 x 8 CHOP 21 x 8 vsvsRR--CHOP 14 x 6 CHOP 14 x 6 2 more doses

2 more doses rituximabrituximab+ G+ G--CSF)CSF) Primary endpoint overall survival

Primary endpoint overall survival

1080 patients randomized, median age 61

More grade III/IV

More grade III/IVneutropenianeutropeniain Rin R--CHOPCHOP--2121 More thrombocytopenia in R

More thrombocytopenia in R--CHOPCHOP--1414 No difference in CR/Cru, limited follow

No difference in CR/Cru, limited follow--upup

More info at ASH 2009

CNS Prophylaxis

High risk associated with: testicular, breast,

epidural, or sinus involvement, high IPI,

multiple EN sites, B symptoms, and BM

involvement.

Only 2.8

Only 2.8--5% of patients develop CNS 5% of patients develop CNS

disease.

R

R--CHOP may decrease risk (RICOVER trial), CHOP may decrease risk (RICOVER trial),

but not seen in R

(7)

CNS Prophylaxis

SWOG study (no

SWOG study (no rituximabrituximab) ) ––80% of CNS relapses on 80% of CNS relapses on therapy or < 6 months following therapy

therapy or < 6 months following therapy

Intraparenchymal/intraspinal

Intraparenchymal/intraspinal> > leptomenigealleptomenigeal

I.T.

I.T. methotrexatemethotrexateprobably insufficientprobably insufficient

I.T. and high dose MTX probably better (GELA ACVBP

vs

vsCHOP, no CHOP, no rituximabrituximab))

Benefit and method remains uncertain

EBV+ DLBCL of the Elderly

Age > 50

No prior immunodeficiency

9% of cases of DLBCL in Asia, seen more now in

Western countries

70%

70% extranodalextranodaldiseasedisease 50% high or high intermediate IPI

50% high or high intermediate IPI

Median survival 2 years

B Cell Lymphoma, Unclassifiable, with Features

Intermediate between DLBCL

and

and BurkittBurkitt’’ssLymphomaLymphoma

Atypical

Atypical immunophenotypeimmunophenotype

c

c--mycmyc: typical and atypical rearrangements.: typical and atypical rearrangements.

Some previously called

Some previously called BurkittBurkitt--like lymphoma, like lymphoma,

BLL not in new WHO classification.

Frequently has

Frequently has cc--mycmycand and

bcl

bcl--2 rearrangements2 rearrangements (

(““doubledouble--hit lymphomahit lymphoma””).).

B Cell Lymphoma, Unclassifiable, with Features

Intermediate between DLBCL

and

and BurkittBurkitt’’ssLymphomaLymphoma

bcl

bcl--2 protein expressed, Ki2 protein expressed, Ki--67 high.67 high.

Nodal, EN disease, BM and CNS.

Uncertain how best to treat (CHOP

Uncertain how best to treat (CHOP--R R

or

or BurkittBurkitt’’ssregimens ?).regimens ?).

41

Clinical factors and biologic markers are of prognostic relevance.

The IPI is still useful.

The challenge is adjusting therapy based on new prognostic factors.

Update of DLBCL

42

2. What is the treatment approach for a 60 yo man with stage IV mantle cell lymphoma?

Audience Response Question ?

1. CHOP-R

2. CHOP-R and consider ASCT 3. Induction therapy and ASCT ?

(8)

43

Prognostic factors Chemotherapy Autologous SCT

What should be the initial therapy for mantle cell lymphoma?

44Herrmann A, et al. J Clin Oncol. 2009;27:511-518.

Survival of MCL

1975-86 vs 1996-2004

Deferred Initial Therapy in MCL

OS observed v early Rx

OS observed v early Rx OS observed v early Rx OS observed v early Rx

following first Rx

Martin P, et al. J

Martin P, et al. J ClinClinOncolOncol. 2009;27:1209. 2009;27:1209--1213.1213.

46

Prognostic factors: age, PS, LDH, WBC

Hoster E, et al. Blood. 2008;111(2):558-565.

Mantle Cell Lymphoma: MIPI

Prognosis of MCL: Ki

-

67

CHOP

CHOP--RR _araRRara--HyperCVADHyperCVAD--cc , , mtxmtx, ,

48 CHOP-R: Improved RR, CR rate, TTF No difference in OS Meta-analysis (3 studies) improved DFS, trend of improved OS with rituximab Lenz G, et al. J Clin Oncol. 2005;23(9):1984-1992.

(9)

49 MD Anderson SWOG CR 87% 58% PFS 64% (3 y) 89% (1 yr) OS 82% (3y) 91% (1 yr) Off study 29% 42%

Romaguera JE, et al. J Clin Oncol. 2005;23(28):7013-7023.

Hyper CVAD/cytarabine-methotrexate + rituximab

50

FFS OS

Romaguera JE, et al. J Clin Oncol. 2005;23(28):7013-7023.

Hyper CVAD/cytarabine-methotrexate + rituximab MD Anderson

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PFS OS

Auto SCT vs INF-α in 1st CR/PR

following CHOP (European MCL Network)

Dreyling M, et al. Blood. 2005;105(7):2677-2684.

Auto SCT in 1

stst

_remission

(HOVON Group)

R

R--CHOP x 3, CR or PR >> CHOP x 3, CR or PR >> HiDACHiDAC+ BEAM + ASCT+ BEAM + ASCT “

“This leads to longThis leads to long--term, but probably not durable, term, but probably not durable, remissions

remissions”” vanvan’’ttVeer MB et al. Veer MB et al. Br J Br J HaematolHaematol. . 2009;44:5242009;44:524--530.530.

53

Bortezomib Bendamustine Lenalidomide

Cyclin D1 kinase inhibitors Allogeneic SCT

Future options in upfront treatment?

54

2. What is the treatment approach for a 67 y.o. man with stage IV mantle cell lymphoma?

Audience Response Question ?

1. CHOP-R

2. CHOP-R and consider ASCT 3. Induction therapy and ASCT

(10)

55

• Subtypes

• Prognosis

• Therapy

What is the optimal

initial therapy for T cell lymphoma?

56Rizvi MA, et al. Blood. 2006;107(4):1255-1264.

T cell lymphomas subtypes

57 T cell lymphomas: prognosis by subtype 58 T cell lymphomas: do anthracyclines matter? PTCL-NOS Angioimmunoblastic TCL

Treatment of PTCL:

Alternatives to CHOP

CHOP +

CHOP + alemtuzumabalemtuzumab

71% CR

Opportunistic infection, EBV

lymphoma

In phase III trial

Upfront

Autologous

SCT for PTCL

83 patients

51% high

51% high--intint, high IPI, high IPI Rx with CHOP Rx with CHOP 65 (79%) had CR or PR 65 (79%) had CR or PR 55 (66%) underwent ASCT 55 (66%) underwent ASCT No randomized trials. No randomized trials. ASCT in CR1 reasonable ASCT in CR1 reasonable option. option.

(11)

61

Many different diseases, different prognosis

Current treatment limited benefit for majority

One size (Rx) does not fit all

Autologous transplant reasonable in CR1

T cell lymphomas

Thank you for attending Master Class for Oncologists

63

Questions & Answers

?

64Haioun C, et al. Blood. 2005;106(4):1376-1381.