1. 11th European Congress on HEMATOLOGIC MALIGNANCIES - from clinical science to clinical practice
Barcelona (Spain), March 13-15, 2015
Session V: Follicular lymphoma Frontline therapy for advanced follicular lymphoma
Armando López-Guillermo
Servicio de Hematología
Hospital Clínic
Barcelona, Spain

2. Follicular lymphoma CD10+ CD5- D43- CD20+ bcl6+ bcl2+
Bcl2/JH
NHL Classification Project 1997

3. Follicular lymphoma Median age: 60 years Advanced stage: 80%
Nodal disease; BM+
CR rate: 10-80%
OS: 10 years (↑)
No plateau in PFS or OS curves
Clínic Barcelona 2014

4. Dogma in treatment of follicular lymphoma (FL)
FL is an incurable disease; trying to cure is not worthy
For asymptomatic patients better W&W
Any treatment is acceptable: none modifies survival
Quality of response does not matter
Response duration (and survival!) shortens at each relapse

5. Follicular lymphoma RISK
Transplant (auto/allo)
TREATMENT
Purine analogues
R-chemotherapy
High
Chemotherapy
Rituximab
Alkylators
Risk (FLIPI, …)
Age and ECOG
Treatment at relapse
Philosophy of each center
Watchful waiting
RISK
Low

6. Follicular Lymphoma Response and survival according to treatment
179 patients/Barcelona

7. Rituximab plus chemo in first-line FL: overall survival benefit across all studies
Study
Regimen
Follow-up
Overall survival (%)
p-value
Control
Rituximab
M390211
CVP ± Rituximab
4 years 77 83
0.029
GLSG2,3
CHOP ± Rituximab
5 years 84 90
0.0493
M390234,5
MCP ± Rituximab 74 87
0.0205
FL20006
CHVP + IFN ± Rituximab 79
0.025
(high-risk pts)
1. Marcus R, et al. J Clin Oncol 2008; 26:4579– Hiddemann W, et al. Blood 2005; 106:3725– Buske C, et al. Blood 2008; 112:Abstract Herold M, et al. J Clin Oncol 2007; 25:1986– Herold M, et al. Ann Oncol 2008; 19(Suppl 4):Abstract Salles G, et al. Blood 2008; 112:4824–4831 7

8. Rituximab combinations in FL
CR rate Toxicity
R-CVP ↓ ↓
R-CHOP ↑ ↓
R-FC/FCM/FMD ↑↑ ↑↑
R-CT+ASCT ↑↑↑ ↑↑↑
R-Other MoAb limited information
R-BENDA > R-CHOP?1
R-CHOP>R-COP>R-FM?2
1- Rummel, Lancet 2013; 2- Federico, J Clin Oncol 2013

9. Kaplan-Meier analysis of probability of (A) time to treatment failure and (B) progression-free survival according to intention-to-treat principle.
Federico M et al. JCO 2013;31:

10. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial
All patients
Benda-R:
Higher CR rate
Longer PFS / EFS
≈OS (at present)
Less toxicity
Follicular lymphoma
Rummel MJ, Lancet 2013;381:1184

11. CR-rate ratios with 95% CIs
CR-rate ratios with 95% CIs. CR-rate ratio and P value for a Sup test are calculated using the Cochran–Mantel–Haenszel test stratified by predetermined standard treatment and lymphoma type (mantle cell vs other types).
Ian W. Flinn et al. Blood 2014;123:

12. How can we improve positive response in patients after induction?
Observation
Induction
(R, R-CVP, R-CHOP, R-FCM, etc)
CR/PR
Maintenance
Other: ASCT, RIT, vaccines, etc. 12

13. Benefits of rituximab maintenance in patients with FL
Relapsed disease
Induction treatment
PFS
Overall survival
Rituximab alone1 ↑ =
Chemo alone2,3
R-chemo2–4
↑ =
Initial treatment
Induction treatment
PFS
Overall survival
Rituximab alone1 ↑ =
Chemo alone5
↑ *
R-chemo
PRIMA
*p = 0.08
1. Ghielmini M, et al. Blood 2004; 103:4416–4423.
2. van Oers MHJ, et al. Blood 2006; 108:3295– van Oers MHJ, et al. J Clin Oncol 2010; 28:2853–2858.
4. Forstpointner R, et al. Blood 2006; 108:4003– Hochster H, et al. J Clin Oncol 2009; 27:1607–1614. 13

14. Rituximab maintenance
PRIMA: study design
INDUCTION
MAINTENANCE
Rituximab maintenance
375 mg/m2 every 8 weeks
for 2 years‡
Registration
High
tumor burden
untreated
follicular
lymphoma
Immunochemotherapy
8 x Rituximab
+ 8 x CVP or
6 x CHOP or
6 x FCM
CR/CRu PR
Random 1:1*
Observation‡
PD/SD
off study
* Stratified by response after induction, regimen of chemo, and geographic region
‡ Frequency of clinical, biological and CT-scan assessments identical in both arms
Five additional years of follow-up

15. PRIMA : Primary endpoint (PFS): 3 years
1.0
0.8
75%
Rituximab maintenance
0.6
Event-free rate
58%
0.4
Observation
Stratified HR = 0.55
95% CI: 0.44–0.68
p <
0.2
0.0 6 12 18 24 30 36 42 48 54 60
Time (months)
Patients at risk
505
472
445
423
404
307
207 84 17 –
513
469
415
367
334
247
161 70 16 –
Salles et al., Lancet 2011

16. PRIMA 6 years follow-up Progression free survival from randomization
HR= 0.57
P<0001
Median follow-up since randomization : 73 months

17. Progression-free survival in major subgroups
Salles G, Lancet 2011;377:42-51

18. PRIMA 6 years follow-up Overall survival
HR= 1.027
P=.885
Median follow-up since randomization : 73 months

19. PRIMA: grade 3/4 adverse events
Observation Maintenance
Total (17%) 121 (24%)
Febrile neutropenia 7 (1%) 19 (4%) *
Infections 5 (1%) 22 (4%) *
Neoplasias 17 (3%) 20 (4%)
CNS alterations 13 (3%) 10 (2%)
Cardiopaties 5 (1%) 11 (2%)
* Only in 1/19 and in 4/22 patients maintenance treatment with rituximab was discontinued after neutropenia or infection, respectively
Salles G, Lancet 2011;377:42-51

20. How can we improve positive response in patients after induction?
Observation
Induction
(R, R-CVP, R-CHOP, R-FCM, R-Benda, etc)
CR/PR
Maintenance
Other: ASCT, RIT, vaccines, etc. 20

21. Morschhauser, J Clin Oncol 2008; 26:5156-64
90Y-ibritumomab
ibritumomab
Morschhauser, J Clin Oncol 2008; 26:

22. Outcome of the patients according to treatment arm (90Y-ibritumomab vs
Outcome of the patients according to treatment arm (90Y-ibritumomab vs. Control)
A: Progression-free survival (PFS) – all
B: PFS – patients in CR or CRu
C: PFS – patients in PR
D: Time to next treatment
Morschhauser F et al. JCO 2013;31:

23. Outcome of the patients according to treatment arm (90Y-ibritumomab vs
Outcome of the patients according to treatment arm (90Y-ibritumomab vs. Control)
Morschhauser F et al. JCO 2013;31:

24. Rituximab Maintenance
ZAR study: Design
Registration
Induction
Consolidation / Maintenance
90Y-Ibritumomab
tiuxetan
1 dose
Follow-up
5 years
Untreated FL
stages II–IV
R-CHOP
x 6 R*
CR/PR
Rituximab Maintenance
1 dose every 8 weeks
for 24 months
PDs/SDs
off study
*Stratification by response (CR / PR)
ClinicalTrials.gov: NCT

25. 90Y Ibritumomab Tiuxetan
Primary endpoint: Progression-free survival (PFS)
79%
Rituximab
(N=62; failed 14)
59%
90Y Ibritumomab Tiuxetan
(N=64; failed 25)
HR=0.501
(95%CI: )
P=0.03
ZAR trial - updated October 2014

26. Progression-free survival (PFS) by arm
Patients in CR after R-CHOP
Patients in PR after R-CHOP
90Y Ibritumomab Tiuxetan
Rituximab
ZAR trial - updated October 2014

27. Overall survival (OS) ZAR trial - updated October 2014
Causes of death: progression (8), GVHD (1)
ZAR trial - updated October 2014

28. How can we improve positive response in patients after induction?
Observation
Induction
(R, R-CVP, R-CHOP, R-FCM, R-Benda, etc)
CR/PR
Maintenance
Other: ASCT, RIT, vaccines, etc. 28

29. Consensus project on hemopoietic transplant in FL
EBMT Lymphoma Working Party
Consensus project on hemopoietic transplant in FL
HDT-ASCR is not an appropriate treatment option to consolidate first remission in patients with FL responding to immunochemotherapy, outside the setting of clinical trials
In patients in first relapse with chemo-sensitive disease HDT-ASCR is an appropriate treatment option to consolidate remission
Allogeneic transplantation should be considered in patients with relapse after HDT-ASCR
Reduced-intensity/ non-myeloablative conditioning regimens are generally more appropriate in patients receiving an allogeneic transplant.
Montoto S, Haematologica 2013;98:

30. Still many questions to answer …
Best partner for rituximab? (benda?)
Best schedule of maintenance?
Maintenance plus other approaches? (i.e., ASCT?)
New drugs, new targets, including chemo-free regimens, vaccines?, etc.

31. Rituximab Veltuzumab
Tositumumab Ofatumumab
PRO Obinutuzumab (GA-101)
Ocrelizumab
CD20
Milatuzumab
Apolizumab
IMMU-114
LYM-1
CD74+
HLA-DR20
CD22
Ecrulizumab
Inotuzumab ozagamicin
B-cell
XmAb5574
Blinatumumab
CD19
CD80
Galiximab
Alemtuzumab
CD52
TRAIL
MepatumumabLexatumumabConatumumab
CD40
DacetumumabHCD122
Candidate cell surface molecule targets for B-cell lymphoproliferative disorders

32. Phase 3 trials in follicular lymphoma
R-CT (x6-8)
(CHOP, COP, benda)
GA-CT (x6-8)
Maintenance
R/8 weeks x 2 years
GA/8 weeks x 2 years CR PR R
Untreated FL
GALLIUM

33. Some therapeutic opportunities in B-cell lymphomas
B-cell receptor signaling
SRC-family kinases (BTK, SYK, PKCβ)
Phosphatidilinositol 3-kinase (PI3K) - mTOR pathway
NFκB pathway
IKKβ inhibitors
Heat shock protein 90 (HSP90) inhibitors
Proteasome inhibitors
BCL2 family (antiapoptosis)
Tumor microenvironment
Anti-vascular endothelial growth factor
Immunomodulators
Other PKCβ
Tumor suppresor activity (histone-deacetylase)
BCL-6, MYC, farnesyl transferase …
Geldanamycin
Bevacizumab
Lenalidomide
Pomalidomide
Ibrutinib
Fostamatinib
CAL101
Everolimus
Temsirolimus
Ridaforolimus
Bortezomib
Carfilzomib
Navitoclax
Enzastaurin
Vorinostat
Romidepsin
Panabinostat
Belinostat

34. Some therapeutic opportunities in B-cell lymphomas
B-cell receptor signaling
SRC-family kinases (BTK, SYK, PKCβ)
Phosphatidilinositol 3-kinase (PI3K) - mTOR pathway
NFκB pathway
IKKβ inhibitors
Heat shock protein 90 (HSP90) inhibitors
Proteasome inhibitors
BCL2 family (antiapoptosis)
Tumor microenvironment
Anti-vascular endothelial growth factor
Immunomodulators
Other PKCβ
Tumor suppresor activity (histone-deacetylase)
BCL-6, MYC, farnesyl transferase …
Ibrutinib
Fostamatinib
CAL101
Everolimus
Temsirolimus
Ridaforolimus
Geldanamycin
Bortezomib
Carfilzomib
Navitoclax
Bevacizumab
Lenalidomide
Pomalidomide
Enzastaurin
Vorinostat
Romidepsin
Panabinostat
Belinostat

35. Rituximab plus lenalidomide in untreated indolent NHL: Study design
Rituximab 375 mg/m2 Day 1 of each 28-day cycle
Previously untreated FL, SLL and MZL
Lenalidomide 20 mg* Days 1–21 of each 28-day cycle
Can proceed to 12 cycles (both drugs) if clinical benefit after 6 cycles
FL, SLL and MZL cohorts analysed separately
* Lenalidomide dose escalation (10–15–20 mg) for SLL patients
SLL = small lymphocytic lymphoma
MZL = marginal zone lymphoma
Fowler et al (#137)
11-ICML

36. Rituximab plus lenalidomide in untreated indolent NHL: Response
CR rate (all patients) improved from 35% at cycle 3 to 65% at cycle 6+
40% of patients were PCR positive at baseline. This was reduced to 12% after cycle 3 and 5% after cycle 6
2-year PFS 83% (FL), 95% (MZL) and 88% (SLL)
SLL n = 24
MZL n = 24
FL n = 45 n %
ORR 20 83 21 88 44 98
CR/CRu 6 25 16 67 38 85 PR 14 59 5 13
Stable disease 2 8 3 1
Progression –
Fowler et al (#137)
11-ICML

37. Safety and activity of lenalidomide and rituximab in untreated indolent lymphoma: an open-label, phase 2 trial
Fowler NH, Lancet Oncol 2014;15:1311-8

38. EFFICCACY RITUXIMAB R-LENA (N=77) (N=77) CR/CRu 25% 36% PR 36% 45%
Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10
EFFICCACY
RITUXIMAB R-LENA
(N=77) (N=77)
CR/CRu % %
PR % %
Not evaluable % %
Kimby E, ASH 2014 #799

39. Phase 3 trials in follicular lymphoma
R-CT (x6-8)
(CHOP, COP, benda)
GA-CT (x6-8)
Maintenance
R/8 weeks x 2 years
GA/8 weeks x 2 years CR PR R
Untreated FL
GALLIUM
R-CT (x6-8)
(CHOP, COP, benda) R2
(R + lena)
Maintenance
R/8 weeks x 2 years
(lena 1 year; R 2 years) CR PR R
Untreated FL
RELEVANCE

40. Follicular lymphoma: survival according to the decade of diagnosis
Clínic Barcelona 2015