rena buckstein february 2009. using case based methods, review the current epidemiology,...

Case Based NHL teaching for Medical Oncologists

Rena BucksteinFebruary 2009

Objectives

Using case based methods, review the current epidemiology, classification and diagnosis of DLBCL and FL

Discuss approach to treatments with supporting evidence Immunochemotherapy Radioimmunoconjugates High dose therapy and SCT Newer approaches and agents

NHL: Incidence and Mortality

Canada6,220 new cases2650 deaths Fifth most

commontype of cancer

in females and males in

Canada 1/46 chance

lifetime risk Increasing since

early 1970s but now levelling

Year

1975 1978 1983 1988 1993 1998 20040

2.5

20.0

17.5

15.0

12.5

10.0

7.5

5.0

11.1

5.6

11.9

5.9

14.0

6.7

17.2

7.5

18.8

8.28.7

7.0

19.420.4

Rate per 100,000

Incidence

Mortality

Age-Specific Incidence of

Non-Hodgkin Lymphoma

2000-2004

Incidenceper100,000

0

110

100

90

80

70

60

50

40

30

20

10

0-4

5-9

10

-14

15

-19

20

-24

25

-29

30

-34

35

-39

40

-44

45

-49

50

-54

55

-59

60

-64

65

-69

70

-74

75

-79

80

-84

85

+

0.6 0.9 1.2 1.8 2.4 3.4 4.9 7.410.5

15.522.6

32.0

45.1

63.4

80.0

100.8

Age

NHL: DemographicsNHL: Demographics• Increases with age

102.0

112.1

<1* <16 cases per time interval

<1

*

0.0

115

Copyright ©2007 American Society of Hematology. Copyright restrictions may apply.

Hematology 2007;2007:509-520

Figure 1. Schematic representation of normal B-cell ontogeny in the germinal center


Hematology 2007;2007:509-520

Figure 4. Schematic representation of t(14;18)+ B-cell clones and the genesis of follicular lymphoma

Case

A 60-year-old woman is diagnosed with stage IV FL Hemoglobin is 11 g/dL, platelets 120,

LDH upper normal limit No bulky disease She has some fatigue but no other

symptoms or other significant past medical history

What is her prognosis?

CD20 MIB 1

H & E

FL: grading and reportingGrade Grade 1: 0-5 centroblasts/hpf Grade 2: 6-15 centroblasts/hpf Grade 3: > 15 centroblasts/hpf

3a: centrocyes present 3b: solid sheets of centroblasts

Pattern reporting Follicular: > 75% follicular Follicular and diffuse: 25-75% follicular Focally follicular: < 25% follicular

FL: variants and immunophenotype

Diffuse Follicle center lymphoma Grade 1: 0-5 centroblasts/hpf Grade 2: 6-15 centroblasts/hpf Grade 3b: call DLBCL

Cutaneous follicle center lymphoma Immunophenotype

SIg+ (IgM +/- IgD, IgG or rarely IgA) Bcl2+ (except cutaneous), CD20+, CD10+,

CD5-, CD22+, CD79a+)

Follicular lymphoma: genetic abnormalities

t(14;18) 80%+7 20%+18 20%3q27-28 15%6q23-26 15%17p 15%BCL2 rearranged 80%

Agricultural pesticide use and the risk of t(14;18)-defined subtypes of NHL in Nebraska

175 tumour blocks with NHL cases T(14;18) by FISH Compared exposures to herbicides, fungicides and

fumigants in 65 + cases versus 107 negative cases with those among 1432 control subjects

Compared with farmers who never used pesticides, the risk of t(14;18) + NHL was increased in farmers who used Animal insecticides (OR 2.6; 95% CI 1.0-6.9) Crop insecticides (OR 3.0; 95% CI 1.1-8.2) Herbicides (OR 2.9; 95% CI 1.1-7.9) Fumigants (OR 5.0; 95% CI 1.7-14.5) Risk increased with longer duration of use No association with t(14;18) negative NHL

FLIPI

International initiative (27 centers US, Europe, UK)

FL patients Jan 1985-Dec 1992> 5 yrs F/up5120 registered cases, with 4167

(81%) eligibleminimum criteria for stagingperformance status, albumin, b2

microglobulin not included in Cox Model

Updated from Solal-Céligny P, et al. Ann Oncol 2002;13(Suppl. 2):18 (Abstract 54)

Risk Status: FLIPI

Factors:1. Age > 602. Ann Arbor Stage III-IV3. Number of nodal sites > 44. Serum LDH level > upper limit of

normal5. Hemoglobin < 12g/dL

FOLLICULAR Philippe Solal-Céligny et al. Blood . 2004. 104:1258-1265.

FLIPI

Risk Group

# factors % of patients

5 yr OS 10 yr OS

Low 0-1 36 91 71

Int 2 37 77 51

High >3 27 52 36

Blood 2004; 104:1258-1265.Philippe Solal-Céligny et al. Blood . 2004104:1258-

1265

Pro

bab

ilit

y o

f su

rviv

alOverall survival according to FLIPI

1.0

0.8

0.6

0.4

0.2

0

0 12 24 36 48 60 72 84

Months

Good

Intermediate

Poorp <0.0001

Follicular lymphoma and the immune system

Spontaneous remissions in up to 20%

Role of alpha interferon Idiotype vaccinesTumor microenvironment immune

signature

Survival Predicted by Molecular features of Tumor Infiltrating Immune Cells

International collaborative studyGene expression profiling of 191

biopsy specimens for untreated FLConstructed molecular predictor of

survival from GEP’s in training set and validated in independent set

Two signatures called IR-1 and IR-2 were found to be significantly discriminating

Immune response signatures: can be averaged into survival predictor score

IR1: favorablegenes encoding T cell markers

(CD7, CD8B1, ITK, LEF1 and STAT4)IR2: unfavorable genes preferentially expressed in

macrophages, dendritic cells or both (TLR5, FCGR1A, SEP10, LGMN, C3AR1)

Development of a Molecular Predictor of Survival in Follicular Lymphoma.

FL: Natural history

IncurableWaxing and waning courseMultiple treatment courses over

patient lifetimeOS 10-12 yearsW&W appropriateAnthracyclines upfront provide no

survival advantage

Gallagher CJ, et al. J Clin Oncol 1986; 4:1470-80.

Follicular Lymphoma:Duration of Chemotherapy-Induced Remissions

Duration of Remission (Years)

100

0

20

40

60

80

•0 1 2 3 8

1st (N=74)

2nd (N=20)

3rd (N=18)

4th (N=8)

FL response to treatment: historical

75-85% response rates to standard chemotherapy

CR rates are short(12-36) months duration of response to chemo:

prognostic survival if CR or PR < 1 yr.: 2.4 yrs survival if CR or PR > 1 yr.: 6 yrs

response rates decline with further chemo

▪ regimen 1: 16 months▪ regimen 2: 11 months▪ regimen 3: 9 months▪ regimen 4: 3.2 months

Case

60 y.o man presents with painless single inguinal LN measuring 2x3 cm

PE and staging confirms localizedLDH and labs are normalBiopsy: follicular grade 2How to treat this patient?

Treatment options

1. watch and wait2. Radiation3. Chemotherapy alone + R

maintenance4. R-chemotherapy +/- maintenance5. Rituximab alone +/- maintenance6. Radioimmunotherapy7. HDT stem cell transplant

Is radiotherapy curative for stage I and II low grade follicular lymphoma?

Stage I and II follicular non-Hodgkin’s lymphoma: long-term follow-up of no initial therapy

Advani R. et al JCO 2004

Estimated survivals at 5, 10 and 20 years were 97%, 85% and 22%

Case history details

VPL, 35 years old, hairdresser, female, black. December 2003: cervical lymph nodes (left 3 cm, right 2

cm) with progressive increase. March 22, 2004 (first appointment): cervical lymph nodes

of 2 cm, no organ enlargements.

Lab tests Hb 13.4 g/dL; Ht 40%, WBC: 6,300/mm3 Biochemistry: normal (including LDH and ß2

microglobuline). Serology: HIV, hepatitis, CMV, HTLV I,II negative.

Bone marrow aspiration: Hypercellular - 56% lymphoid cells

Bone marrow biopsy: multifocal paratrabecular infiltration by lymphoid cells

Cytogenetics: normal Chest CT: 1-2 lymph nodes (para tracheal, para aortic and

pulmonary) Abdomen CT– small bulk extensive lymphadenopathy

Lymph node cervical biopsy: B cell follicular lymphoma grade 2 (WHO)

How to treat?

Newly Diagnosed Advanced Stage Patient: Asymptomatic

How would you treat her?

1. Watch and wait2. CVP + R3. CHOP + R4. Rituximab monotherapy +/-

maintenance5. Bexxar or Zevalin6. Autologous Stem Cell Transplant7. Allogeneic Stem Cell Transplant

Initial Therapy

Watch and Wait 3 randomized trials to support this in low

tumour burden NHL▪ GELF 1997: no rx vs prednimustine vs

interferon alfa▪ NCI 1988: no rx vs. ProMACE-MOPP▪ BNLI 2003: no rx vs. chlorambucil

Ardeshna et al. Lancet 2003; 362: 516-22

Overall

Cause- specific

Time to Treatment

Ardeshna et al. Lancet 2003; 362: 516-22Median time to first treatment 2.6 yrs

Patient history continues

2 years later, patient complains of B symptoms

CT re-imaging: extensive bulky retroperitoneal and peri-renal LN’s

HB 110, plt 100


1. Watch and wait2. CVP + R3. CHOP + R4. Rituximab monotherapy +/-


Newly Diagnosed Patient with Advanced Disease: Symptomatic

Criteria for starting cytotoxic therapy

GELF CRITERIA

High tumor bulk any of: Tumor > 7 cm 3 nodes in 3 distinct areas

> 3 cm each Symptomatic

splenomegaly Organ compression Ascites or pleural effusion Systemic symptoms ECOG > 1 Increased LDH or

B2microglobulin

BNLI CRITERIA

Any of: Rapid generalized disease

progression in preceding 3 mos

Life threatening organ involvement

Renal or macroscopic liver infiltration

Bone lesions Symptoms Hgb < 10 or WBC < 3 or

plt < 100 if do to BMI

target cell

plus antibody

antigen

naturalkillercell

targetcell

macrophageFc receptor

FcFab

Fc receptor

Rituximab

Infusional side effects tolerableDepletes B cells for about 6 monthsNot myelosuppressiveDoes not increase infectious riskCan be re-used with equal efficacy in

respondersAdditive or synergistic effects with

chemotherapy

Study Design: CVP +/- R

Follicular NHL (IWF B, C, D)

Stage III–IV ³18 years No prior treatment Measurable disease Central histology

review

RANDOMIZED

CVP x 4 cycles(every 3 weeks)

Rituximab + CVP x 4 cycles

(every 3 weeks)

RESTAGING

CVP x 4 cycles(every 3 weeks)

Rituximab + CVP x 4 cycles

(every 3 weeks)

SD, PD off treatment

CR, PR

Rituximab 375mg/m2 i.v. day 1Cyclophosphamide 750mg/m2 i.v. day 1Vincristine 1.4mg/m2 i.v. day 1Prednisone 40mg/m2 p.o. days 1–5

Marcus R. et al. Blood. 2005; 105: 1417-1423

Patient Characteristics

Variable

CVP (n=159)

R-CVP (n=162)

Age (Median)

53

52

IPI Low Int High

44% 49% 2%

45% 47% 1%

FLIPI 0-2 3-5

47% 47%

49% 44%

Imrie K. et al. Proc. ASCO 2005; abstract 6525

Summary of outcomesmedian follow-up: 30 months

Endpoint CVP(n-159)

R-CVP(n=162) p

Response rate

Median time to treatment failure(months)

57%

7

81%

27

<0.0001

<0.0001

Median duration of response(months) 14 35 <0.0001

Median disease-free survival(months) 21 not

reached 0.0009

Median time to new anti-lymphoma treatment or death (months)

12 not reached <0.0001

KM estimates for overall survivalat 30 months 85 89 NS

KM = Kaplan-Meier; NS = not statistically significantImrie K. et al. Proc. ASCO 2005; abstract 6525

CVP ± Rituximab in Previously Untreated Follicular NHL: Time to Treatment Failure

CVP

Rituximab + CVP

Patients at risk: 30 months follow-up

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0

0 3 6 9 12 15 18 21 24 27 30 33

Months

Pro

bab

ility

of

even

t-fr

ee

surv

ival

Rituximab + CVP: median 27 months

CVP: median 7 months

p<0.0001

Risk reduction: 67%

159 100 87 67 43 29 14 13 9 1 0 0

162 140 123 114 95 73 50 37 20 8 3 0

Marcus et al. Blood. 2005;105:1417-1423

CVP ± Rituximab in Previously Untreated Follicular NHL: Time to Progression, Relapse or Death

Rituximab + CVP: median 32 months

CVP: median 15 months

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00 3 6 9 12 15 18 21 24 27 30 33

Months

Pro

bab

ility

of

even

t-fr

ee

surv

ival

p<0.0001

CVP

Rituximab + CVP

Patients at risk

159 140 130 106 75 49 31 24 16 2 0 0

162 156 143 134 110 83 60 44 25 9 3 0

Marcus et al. Blood. 2005;105:1417-1423

30 months follow-up

Conclusions

The addition of rituximab to first-line treatment with CVP improves response rate, response duration and time to progression without increasing toxicity

The benefit in terms of TTP of adding rituximab is observed in all prognostic groups.

In the presence of treatment with R-CVP, only the FLIPI score has additional predictive value Imrie K. et al. Proc. ASCO 2005; abstract 6525

GLSG: CHOP vs R-CHOPFor First Line Therapy of Follicular Lymphoma

Randomization

6 - 8 x CHOP

6 - 8 x CHOP +

Ritux

CR, PR

CR, PR

Randomization

PBSCT

standard IFN-maintenance

intensive IFN-maintenance

standard IFN-maintenance

Hiddemann W et al. Blood. 2005;106; 3725-32

pts. < 60 yrs.

pts. > 60 yrs.

N=187

N=201


Hiddemann, W. et al. Blood 2005;106:3725-3732

Figure 2. Time to treatment failure and duration of response after CHOP and R-CHOP


Hiddemann, W. et al. Blood 2005;106:3725-3732

Figure 3. OS after start of therapy for CHOP and R-CHOP

(P = .016).

Response Rate

2-Year Event Free Survival

Case continued…

Patient achieves a 4 year remission after CVP-R but relapses with similar clinical presentation

How to treat?


1. Watch and wait2. CVP + R3. CHOP + R +/- maintenance4. Rituximab monotherapy +/-


Rituximab in remission induction and maintenance treatment of relapsed follicular NHL ASH 2005 - EORTC/Intergroup

(Final analysis)

M.H.J. van OersM. Van Glabbeke

I. TeodorovicC. Rozewicz

R.KlasaR.E.Marcus

M.WolfE Kimby

A.Hagenbeek

RANDOMIZED

CHOP every21 days

maximum 6 cycles

Rituximab + CHOP every

21 daysmaximum 6

cycles

Intergroup phase III trial – Final analysis

RANDOMIZED

Observation

Rituximab maintenance*

CRPR

MR - Rituximab 375 mg/m2 q 3 mos for 2 years

n = 319 evaluable (median F/U 33 mos)

Intergroup Study - PFS (2nd Randomization)

Overall log-rank test: p<0.0001Hazard ratio: 0.40

O N Number of patients at risk

110 167 90 42 17 5 Observation66 167 126 86 47 12 MabThera

Treatment

100

90

80

70

60

50

40

30

20

10

0

0 1 2 3 4 5Years

MR 52 mos

Observation: 15 mos

Pro

gre

ssio

n-f

ree

surv

ival

(%

)

(years)

0 1 2 3 4 5

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment55 69 31 11 4 1

32 76 61 38 20 4

Observation

Mabthera

Progression free survivalafter CHOP

Overall Logrank test: p<0.0001

(years)

0 1 2 3 4 5

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment55 98 59 31 13 4

34 91 65 48 27 8

Observation

Mabthera

Progression free survivalafter R-CHOP

Overall Logrank test: p=0.004

Intergroup phase III trial Progression free survival (2nd randomization)

median: 42.2 months

med. 11.6 monthsmed. 23.1 months

median: 51.9 months

Subgroups according to induction treatment

Hazard ratio: 0.30 Hazard ratio: 0.54

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment39 167 148 99 50 14 2

23 167 155 112 69 19 4

Observation

Mabthera

Overall survivalfrom 2nd randomization


Intergroup phase III trial Overall survival (2nd randomization)

MR at 3 years - 85%

Observation at 3 years - 77%

(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100


12 76 75 49 30 8 2

Observation

Mabthera

Overall survivalafter CHOP


(years)

0 1 2 3 4 5 6

0

10

20

30

40

50

60

70

80

90

100


11 91 80 63 39 11 2

Observation

Mabthera

Overall survivalafter R-CHOP


OS from 2nd randomization: subgroup analysis

Hazard ratio: 0.52 Hazard ratio: 0.49

Intergroup phase III trial Overall survival (2nd randomization)

Copyright restrictions may apply.

Schulz, H. et al. J. Natl. Cancer Inst. 2007 99:706-714; doi:10.1093/jnci/djk152

Summary: Rituximab + chemotherapy in follicular NHL

Recommended for first or second line combination (> 6 randomized trials support)

No one regimen clearly superior to another

Role of re-treatment combination unknown

Maintenance Rituximab is associated with improved PFS and OS after CVP alone first line and after CHOP or CHOP-R second line

Case continued alternate scenario

Patient gets CVP-R and enters complete remission.

4 years later, presents with night sweats and rapidly progressive axillary and inguinal nodes

LDH is elevated and patient has widespread bulky adenopathy

What would you do?

Transformed FL

Population based series from BC lymphoma database (n=600) median follow up 109 months

28% developed transformation at median of 40 months (63% by biopsy)

Annual rate 3% per year continuously

Advanced stage at diagnosis only RFMedian post transformation survival

1.7 years (better if limited with 5 yr OS 66% vs. 19%)

Copyright © American Society of Clinical Oncology

Al-Tourah, A. J. et al. J Clin Oncol; 26:5165-5169 2008

Fig 1. The actuarial risk of transformation in patients with follicular lymphoma


Al-Tourah, A. J. et al. J Clin Oncol; 26:5165-5169 2008

Fig 2. The impact of transformation on the overall survival

What about high dose therapy?

Autologous Stem Cell Transplants in relapsed FL

In 2nd or 3rd remission: 1 small RCT (CUP trial n=140) Schouten JCO 2003)

4 yr Survival advantage (46 vs 77%): Role of purging unknown

Multiple Phase 2 studies: PFS benefit Curative?

Pooled St Barts and MSK experience (n=121) Median f/up 13.5 years Plateau in PFS @ 12 years of 48% Best in second remission RD and OS better compared with age matched controls not

transplanted CY/TBI: secondary leukemia and MDS (n=15)

Molecular remissions predict for better RFS Rituximab or RIT may change durability of

remissions (cure?)

Fig 1. Remission duration of all patients.

Rohatiner et al. JCO 2007

http://jco.ascopubs.org.myaccess.library.utoronto.ca/content/vol25/issue18/images/large/zlj0180760920001.jpeg

Auto versus Allo?

Registry data: No proven survival benefit of allo

over auto RFS 80% but TRM 30% in some series

Allo has early plateau in PFS curve In 1 study, no difference between

syngeneic or allo….??? DLI has been shown to work

Allo may play a role in chemoinsensitive young patients with short remissions

Allo can rescue a relapsed auto failure

Radioimmunoconjugates

Efficacy of Unlabeled Tositumomab Enhanced Through the Crossfire Effect of

Iodine-131

Unlabeled “cold” Antibody Radiolabeled Antibody

Courtesy of Andrew Zelenetz, MD.

Radio-immunoconjugates

Zevalin BexxarSource 90Y 131IType ß mixed ß, Energy (MeV) 2.3 0.6Path (mm) 5 1T1/2 (d) 2.6 8Setting out-pt out-

ptImaging no yesThyrotoxic no yes

Radioimmunoconjugates

Advantages

Effective in heavily pre treated patients May surpass preceding

responses Effective in Rituximab

refractory patients Patients who achieve CR

have long RD Toxicity mild Treatment short Can be re-used Radiosensitive disease

Disadvantages

Limited # centers Some require dosimetry Not recommended for Plts

< 100 or BM > 30% % prior marrow radiation

may limit AML/MDS? Delayed hematologic

toxicity Expense Some require isolation for

5-8 days Used early: long term

effects? Effects on re-treatment?

Efficacy of single-regimen RIT for relapsed/refractory FL.

Reference Agent Phase n Patient selection Response rates

Duration of response

Kaminski et al (2000)

Bexxar®

I/II 42 Relapsed or refractory CD20+ B-cell low- and intermediate-grade NHL

ORR 71%CR32%

Median PFS 12 months (for CR 20 months)

Vose et al (2000)

Bexxar®

II 47 Relapsed or refractory CD20+ B-cell low-grade and transformed NHL

ORR 57%CR 32%

Median DR 9·9 months (for CR 19·9 months)

Kaminski et al (2001)

Bexxar®

II 60 Relapsed or refractory CD20+ B-cell low-grade and transformed NHL

ORR 65%CR 20%

Median DR 6·5 months

Witzig et al (1999)

Zevalin®

I/II 51 Relapsed or refractory CD20+ B-cell low- and intermediate-grade NHL or MCL

ORR 67%CR 26%

Estimated DR 11·7 + months

Witzig et al (2002a)

Zevalin®

III 143 Relapsed or refractory low-grade FL or transformed NHL

ORR 80%CR 30%CRu 4%

Estimated DR 14·2 months

Wiseman et al (2002)

Zevalin®

II 30 Relapsed or refractory low-grade FL or transformed NHL and mild thrombocytopenia

ORR 83%CR 37%CRu 6%

Estimated TTP 9·4 months (for responders 12·6 months)

Witzig et al (2002b)

Zevalin®

II 54 Rituximab-refractory FL ORR 74%CR 15%

Estimated TTP 6·8 months (for responders 8·7 months)

New agents and approaches

Anti-idiotype vaccines……????BendamustineLenalidomideVelcadeZevalin for consolidationRituxan re-treatmentGaliximab (anti-CD80), epratuzumab

(anti CD22), anti CD40


Liu, Q. et al. J Clin Oncol; 24:1582-1589 2006

Fig 2. Overall survival according to treatment regimen

AlgorithmNew

diagnosis

Limited stage: XRT

Advanced stage:

•W + W

•CVP-R+M

•CHOP-R+M

•Clinical trial

First Relapse

•CVP-R +M

•CHOP-R+M

•FCM-R + M

•ASCT

•Allo BMT

•RIT

•Clinical Trial

Second Relapse

•CVP +/-R

•CHOP +/- R

•FCM +/- R

•ASCT

•Allo BMT

•RIT

•Clinical Trial

rena buckstein february 2009. using case based methods, review the current epidemiology,...

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