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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
% C
ytot
oxic
ity
0
10.8 11.2
38.6
2.5
32.8
11.8
41.6
8.59
26.4
50
40
30
20
10
0
Con
trol
Ritu
xim
a b
CD
DP
Ritu
xim
a b +
CD
DP
Flu d
ara b
ine
Ritu
xim
a b +
fl ud a
r abi
ne
Vin
blas
tine
Ritu
xim
a b +
vinb
last
ine
Adr
iam
y cin
Ritu
xim
a b +
Adr
iam
y cin
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