Overview of current treatment options in Low Grade Lymphoma

Christos Emmanouilides MD, PhDAssoc. Professor UCLA /

Interbalkan Hospital, Thessaloniki, Greece

Classification: REAL/WHO Categories

“Indolent” B-cell Lymphomas

B-cell T-cell B-cell

♦

*Small lymphocytic/ chronic lymphocytic

♦

Plasma cell myeloma

♦

*Marginal zone/MALT

♦

*Follicular

♦

Mantle cell

♦

Diffuse large B-cell

♦

Burkitt’s

T-cell

♦

Mycosis fungoides♦

Angioimmunoblastic

♦

Peripheral (NOS)♦

Anaplastic large cell

Precursor cell Mature (peripheral) cell

♦

Lymphoblastic leukemia/lymphoma

* Indolent BCL

Armitage et al. Armitage et al. J Clin OncolJ Clin Oncol. 1998;16:2780. 1998;16:2780––2795.2795.

About Half of all Lymphomas are Low Grade

Follicular (22%)Follicular (22%)

Diffuse large BDiffuse large B--cell (31%)cell (31%)

Small lymphocytic (6%)Small lymphocytic (6%)

Mantle cell (6%)Mantle cell (6%)

Peripheral TPeripheral T--cell (6%)cell (6%)

Marginal zone BMarginal zone B--cell, cell, MALT (5%)MALT (5%)

Other subtypes with a Other subtypes with a frequency <2% (9%)frequency <2% (9%)

Marginal zone BMarginal zone B--cell, nodal (1%)cell, nodal (1%)Lymphoplasmacytic (1%)Lymphoplasmacytic (1%)

Composite lymphomas (12%)Composite lymphomas (12%)

Follicular Lymphoma: Issues:

•Is there a preferred class of chemotherapy drugs?

•Is there a prefered combination

•How should rituximab be used?

•Does rituximab have a prefered chemo-companion?

•Value of Radioimmunotherapy / New drugs

•Value of transplants

Grading Follicular NHL

1

2

3

0-5 cblsts

6-15

>15

Follicular grade 3 is better treated as aggressive NHL

Chemotherapy

Alkylator – based

Nucleoside analogue – based

• Do anthracyclins matter?• Are combintions better?• Disease-free survival or overall survival?

Studies of alkylators RR (CR) TTP OS N

Peterson(1)

CHOP- BCyclophosphamide

93% (60%)*89% (66%)

33%*25%

44%46%

All 10yr data

228

Kimby(2)

Chlorambucil/ PrednisoneCHOP

36%

60%

41%44%

5 yr survival

259

1. Peterson BA et al. Prolonged single-agent versus combination chemotherapy in indolent follicular lymphomas: a study of the cancer and leukemia group B. J Clin Oncol. 2003;21:5-15.

2. Kimby E, et al. Chlorambucil/prednisone vs. CHOP in symptomatic low-grade non-Hodgkin's lymphomas: a randomized trial from the Lymphoma Group of Central Sweden. Ann Oncol. 1994;5 Suppl 2:67-71.

All alkylator regimens are considered “equivalent” for overall survival

i.e. CHOP is not mandatory

Fludarabine in Indolent NHL

Activity in:– Follicular– Small Lymphocytic

– Small Lymphocytic /CLL– Lymphoplasmacytic

– Marginal zone

Disease Stage– First Line– Second line and beyond

– (Reduced intensity Allograft conditioning)

R.E Marcus A. Hagenbeek, H. Eghbali, S. Monfardini, E. Resegotti, PJ Hoskin,C. de Wolf-Peeters, K. McLennan, E. Staab-Renner, A. Schott, I. Teodorovic,

A. Negrouk, M. van Glabbeke and DC Linch

FLUDARABINE compared to CVP in newly diagnosed patients with stage III/IV low Grade NHL

Final analysis of a prospective, randomized phase III intergroup study in 381 patients

ResponseFludarabine CVP

n=194 n=187

ORR 75 % 58 %CR 39 % 17 %PR 36 % 41 %

Stable disease 2 % 15 %

Progressive disease 23 % 27 %

p-value ORR < 0.001 CR < 0.001

100100

8080

2020

00

4040

6060

00 11 22 33 44 55 66 77 88

Progression – free Survival ITT analysis

O N Number of patients at risk:151 194 127 79 53 34 18 12 1153 187 107 68 48 36 17 9 4

FludaFludaCVPCVP

Overall Logrank test: p=0.2353Overall Logrank test: p=0.2353

YearsYears

progression free survival of 13.6 months in previously untreated patients

Fludarabine Versus CVP in Recurrent Low-Grade NHL

Regimen RR / CR PFS OS n

Klasa et al: CVP

Fludara

52%(9%)

64%(7)

9.1 mos

11 mos

44 mos

57 mos

relapsed dz.

91

Klasa RJ et al. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol. 2002 Dec 15;20(24):4649-54.

PFS favors FLU vs CVP in Relapsed f NHL.

P = 0.03

Overall Survival

No difference

Conclusion from Single agent Studies

Fludarabine is more active in terms of response rate and duration compared to CVP.

No clear survival advantage , likely due to cross-over

REFERENCE

DRUGS USED

No. ofPTS

CR%

PR%

CR+PR

%

Keating et al, 1997 Fludarabine, Mitoxantrone,

Dexamethasone 31 81 16 97

Zinzani et al, 2000 Fludarabine, Mitoxantrone 27 67 22 89

Emmanouilides et al 1998

Fludarabine, Mitoxantrone 31 69 25 94

*Fludarabine 25 mg/m2 x 3

Mitoxantrone 10 mg/m2 x 1

Fludarabine combinations: FND / FM* in indolent NHL

Velasquez WS, et al. J Clin Oncol. 2003;21:1996-2003. Figure reprinted with permission from the American Society of Clinical Oncology.

0%0%

20%20%

40%40%

60%60%

80%80%

100%100%

00 2424 4848 7272 9696Months After RegistrationMonths After Registration

Fludarabine + MitoxantroneFludarabine + MitoxantroneAt RiskAt Risk

7878FailuresFailures

5252

4-Year Estimate 4-Year

Estimate38%38%

Progression-Free SurvivalProgression-Free Survival

FLUDARABINE AND MITOXANTRONE (FN) IN LOW-GRADE LYMPHOMA (S9501)

Fludarabine and Mitoxantrone in relapsed patients Highly active

29 patientsORR 90%Remission duration 12 monthsAble to mobilise ~50% of patients attempted

Seymour et al Ann Oncol 2001

F: 25mg/m2 x3,C: 200 mg/m2 x3,M: 8 mg/m2

Montoto S, et al. Blood. 2003;102. Abstract 1456.

80%80%CRCR

6 Cycles of FCM n = 756 Cycles of FCM n = 75

17%17%PRPR

76% 76% 24-Mos FFS24-Mos FFS75%75%Molecular ResponseMolecular Response

FLUDARABINE, CYCLOPHOSPHAMIDE, AND MITOXANTRONE (FCM) IN UNTREATED FOLLICULAR

LYMPHOMA

With Cyclophosphamide

With both:FCM

With Mitoxantrone 71-94 % ORR with 20-80 % CR

80-97 % ORR with 66 - 80% CR

72-88% ORR with 27-66% CR

Patients with Fludarabine-containing regimens: High activity

Conclusion: Fludarabine combinations are highly active

Conclusion from chemotherapy studies

Alkylator-based therapies are considered equivalent in general

Fludarabine-based therapies seem to provide increased response rates and DFS advantage

Studies of fludarabine combinations seem to be particularly attractive when a remission is desired

Unclear benefit on OS

The Rituximab era: Is there a preferred companion?

Augmentation of Cytotoxicity in vitro with Chemotherapy- Rituximab Coexposure

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0

10.8 11.2

38.6

2.5

32.8

11.8

41.6

8.59

26.4

50

40

30

20

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Con

trol

Ritu

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Ritu

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Alas S, Bonavida B, Emmanouilides C: Anticancer Research 2000

R plus fludarabine in indolent NHL: efficacy

ORR = 88%,

CR/CRu = 75%,PR = 13%

Median duration of response = 35+ months

bcl-2 molecular conversions: 13/15 (87%) in peripheral blood; 14/16 (88%) in bone marrow

Czuczman MS, et al. Blood 2001;98:601a (Abstract 2518)/ JCO 2005

Early results of first-line randomized studies adding R: alkylators (ASCO 05)

CHOP 91 48 % (3 years)

R-CHOP 97 77%

ChEP -IFN 29% 86 63 (30 mos)

R-ChEP-IFN 63 94 78

MCP 21 65 Med:19.7 mos

R-MCP 42 85 NR (85% in remission)

Author Tx CR ORR EFS

Hiddemann

Solal- Seligny

Herold

Data with Fludarabine-based at least equal

Forstpointner1 van Oers2

R-FCM FCM R-CHOP CHOP

Overall response rate (%) 94* 70 83* 72

Complete response rate (%) 40* 23 29* 15

1. Forstpointner R, et al. Blood 2004; 104:3064–3071. 2. van Oers MHJ, et al. Blood 2006; 108:3295–3301.

* p < 0.001

• A randomized trial in patients with stage IV follicular lymphoma compared concurrent FND + Rituximab vs sequentially

Jiang et al, ASH 2003 (# 1444)

FND + concurrent R: Synergy

FND + R FND >> R

CRPR

85%15%

77%23%

MolResp(AT 6 MOS)

91% 66% P=0.019

FFS at 5 y 70% 44% P=0,009

Randomization

4 x FCM

4 x FCM +

Rituximab

Randomization

CR,PR

CR,PR

4 xRituximab

4 xRituximab

Observation only

FCM vs. R-FCM followed by R- Maintenance vs. Observation

For Salvage Therapy

Hiddemann et al: Sem Oncol 03/ Blood 2004

X

CR for FCL: 48% 55%

CR for 1st line 23 34

ORR for 1st line 71 87

FCM R-FCM

FCM vs. R-FCM:

The addition of Rituximab maintenance increased OS from 55 to 82%

Rituximab maintenance (45/67)

Observation (25/71)

Observation (49/71)%

Rituximab maintenance (56/67)

Response duration Overall survival

Years0 1 2 3 4 7

Years0 1 2 3 4 7

00.10.20.30.40.50.60.70.80.91.0

p = 0.0010

Forstpointner R, et al. Blood 2006; 108:4003–4008.

5

Prob

abili

ty

After R-FCM induction therapy

Rituximab maintenance improves clinical outcome vs observation (GLSG)

5 60

0.10.20.30.40.50.60.70.80.91.0

6

p = 0.0562

CLL: 1st line R-FC

Tam CS, et al. J Clin Onc 2007;25:18S (7008)

Response n (%)CR 217 (72)nPR 31 (10)PR 37 (12)

NR 12 (4)Early death / LFU 3 (1)

Results: long times to progression in patients with CR

Median follow-up was 62 m– TTP was

• 80 months for CR patients• 80 months for nPR• 27 months for PR

– 5-year survival• 90% CR• 81% nPR• 37% PR

Tam CS, et al. J Clin Onc 2007;25:18S (7008)

Long-term safety of R-FCInfection risk per year ~10% in first year, ~4% in second year, then ~1% up to sixth year

– T-lymphopaenia-related opportunistic infections during first year only– Varicella zoster infections predominantly in first and second years– bacterial infections up to fifth year

Tam CS, et al. J Clin Onc 2007;25:18S (7008)

Late complications

1-year risk

%

5-year risk

%Late cytopaenia* 18 23

Richter transformation <1 3

Myelodysplasia <1 3

*8% infection risk

Fludarabine M vs CHOP (+/- R) in FL

Zinzani et al JCO July 2004. Italian Multicentre group.

CR rate:– FM: 68%– CHOP: 42%

Molecular remission:– FM : 71%– CHOP: 51%

FM

CHOP

PFS curves of patients treated with FM + rituximab and patients submitted to CHOP + rituximab

Zinzani et al, JCO 2004Zinzani et al, JCO 2004

Impact of Rituximab: New Standard of care

Randomized studies of adding Rituximab to chemotherapy

– Improves RR, TTP

– Improves Overall Survival with F/ FND (McLaughlin, Jiang), CHOP (90 vs 81% 4 y.OS: Buske-Hiddemann: ASCO 2006)

– Maintenance increases survival for relapsed indolent lymphoma and likely after 1st line tx.

– Rituximab monotherapy +/- maintenance acceptable tx option

Conclusions: Fludarabine in Indolent Lymphoma

Single Agent fludarabine– Superiority to standard alkylators in terms of responses– Well tolerated

Fludarabine combinations:– Very potent

Fludarabine Combinations plus Rituximab:– Evidence suggests this could be the best strategy.

Radioimmunotherapy

Naked antibody

Radiolabeled antibody

Representative Patient: 111In-Labeled Zevalin™ Monoclonal Antibody Imaging

Abdominal CT

Abdominal SPECT

4 hours 66 hours 139 hours

106-00-158RS

Zevalin Administration is Simplified in Europe

Rituxan® 250 mg/m2

Followed by111In Zevalin™

5 mCi

Rituxan 250 mg/m2

Followed by90Y Zevalin™

(0.4 or 0.3 mCi/kg*; max dose 32 mCi)

Imaging dose Therapeutic dose

1 2 3 4 5 6 7Day 8Scans

2–24 hours 48–72 hours

90–120 hours (optional)

*0.4 mCi/kg (14.8 MBq/kg) in patients with a platelet count ≥150,000/μL or 0.3 mCi/kg (11.1 MBQ/kg) with a platelet count 100,000–149,000/μL. Maximum 1184 MBQ

9

or or

X

X X X

Zevalin vs Mabthera: Results in relapsed Low Grade or transformed NHL

90Y ibritumomab tiuxetanRituximab

International Workshop NHL Response Criteria

16

30

0102030405060708090

100

PatientPatient s (%)s (%)

P = .002

P = .04

90Y ibritumomab tiuxetan

Rituximab

80

56

OR CROR CR

Facts about ZevalinWell tolerated

Brief Treatment

Cytopenia is reversiblle; no increase in AML/MDS

Subsequent treatments are possible

Safe in geriatric patients

Needs coordination with Nucl Medicine

Increased efficacy of Zevalin with earlier use in FL

3Emmanouilides et al. Blood 20034Sweetenham et al. Blood 2004

100%100%

4 prior therapies (median)

2 prior therapies (median)

1 prior

therapy

No prior therapies

74%

86%90%

15%

40%

54%62%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Ritux.-refr. pat.1 Phase III2 Analysis3 1st line4

1Witzig et al. J Clin Oncol 20022Gordon et al. Clin Lymph 2004

PR

CR

* Induction eft to the discretion of the treating physician, e.g. CLB, CHOP, CVP, Fludara®, rituximab etc. n = 414

CLB, chlorambucil; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CVP, cyclophosphamide, vincristine, prednisone

Remission induction

chemotherapy*CR/PR**

Zevalin®

No furthertreatment

Start of studyNewly

diagnosedfollicular

NHLStage III–IV

Randomization

NRPD Off study

• Inclusion phase accrual: 414 patients, last inclusion 20.1.2005)

EU/Canada first-line treatment of FL: A positive consolidation study:

Treatment algorithm for follicular NHL

†Consider collection of peripheral blood progenitor cells for future transplant

Modified fromWinter JN, et al. Hematology (Am Soc Hematol Educ Program) 2004:203–20

Stage I-II disease Stage III-IV disease

Involved field radiotherapy

Indications to treat*

Yes No

Watch and wait

Rituximab+Fludarabine- based Indications to treat

Radioimmunotherapy

Subsequent chemotherapy / Transplantation (Age limitation)

†

СΠАCИБO

Bendamustine

Bortezomib

Lenalidomide

Other Abs

epratuzumab

galiximab

anti-CD40

Other antiCD20

Histone Deacetylase Inh

Angiogenesis Inh

Immunotherapy - vaccines

Transplants