1. Session V: Follicular Lymphoma
New possibilities for relapsing follicular lymphoma Massimo Federico, MD

2. Improving Survival of Follicular NHL:
OS by Treatment
100
1990s-2000s 80 60
1990s
Overall Survival (%) 40
1980s
4-Year
N Death Estimate
CHOP + Mab %
ProMace %
CHOP % 20 2 4 6 8 10
Years After Registration
Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Fisher RI, et al. J Clin Oncol. 2005; 23:

3. TTF by arm (N=504) Events = 213 P R-CHOP vs R-CVP 0.003
R-FM vs R-CVP
R-CHOP vs R-FM 0.763
Federico M, et al. J Clin Oncol Apr 20;31(12):

4. Response Duration Progressively Shortens with Each Relapse
Johnson WM, et al. J Clin Oncol. 1995;13(1):

5. So, a significant proportion of patients need a second chance

6. First relapse Observation for asyntomatic FL
High dose CHT followed by ASCT or alloSCT
CHT with monoclonal antibody-based therapy depending on initial therapy (R-CVP, R-CHOP, BR)
RIT
Monoclonal antibody-based therapy (R)
Clinical trial, if available

7. Recommended treatment strategies in follicular lymphoma

8. Recommended treatment strategies in follicular lymphoma

9. Warm (and not Hot) Topics:
Relapsed FL
To transplant or not to transplant?

10. Modena Cancer Registry Diagnosis of FL from 1997 to 2012
124 relapsed
13/342 (4%)
PBSC first line
9/124 (7%) PBSC second line
22 patient received transplant
Median Follow up 134 months
one pt who received second line PBSC died 54 mo after diagnosis

11. Progression-free survival
High-dose therapy improves PFS and survival in relapsed follicular non-Hodgkin's lymphoma: results from the randomized European CUP trial.
Progression-free survival
Schouten H C et al. JCO 2003;21:
©2003 by American Society of Clinical Oncology

12. Consensus was reached that:
Indications for HSCT in patients with FL: a consensus project of the EBMT-Lymphoma Working Party
Consensus was reached that:
high-dose therapy with ASCT is also appropriate in second/subsequent chemo-sensitive relapses;
allotransplant (preferably a reduced intensity conditioning-allotransplant) should be considered at relapse after HDT with ASCT.
Montoto S. et al Haematologica 2013; vol. 98, n.7,

13. 2015 Jan;90(1):56-61

14. Aim of the study Primary Endpoint Secondary endpoints
To analyse any effect of the type of first-line treatment (alkylating agents vs anthracyclines vs nucleoside analogues +/- rituximab) on the outcome of second-line treatments received by patients with relapsed follicular lymphoma
To potentially identify an optimal sequence of first-line and salvage treatments in follicular lymphoma
Primary Endpoint
Time to next treatment after first relapse (Time to next treatment – TTNT)
Secondary endpoints
Progression free survival after relapse
Overall survival

15. Inclusion criteria
First-line treatment with one of the following regimens:
AA: alkylating agents both as monotherapy or in combination (e.g. CVP) +/- rituximab
AC: anthracyclin containing CHOP or CHOP-like regimens +/- rituximab
NA: nucleoside analogues containing regimens (e.g. fludarabine)+/- rituximab
Second-line treatment after relapse occurred during the period from 2000 and 2008

16. Rossi G. et al AJH 2015 Jan;90(1):56-61

17. TTNT after relapse by sequence of first- and second-line treatments
HR = (95CI ), P<0.001
AC → HSCT
Other sequences
CI95%
Rossi G. et al adapted

18. Conclusions
First-line AC-containing chemotherapy obtained a better TTNT after relapse compared to AA- or NA-containing therapies.
Second-line treatment programs including HSCT obtained the best TTNT compared to any other regimen.
the efficacy of salvage auto-HSCT was highest when patients had received AC-containing CHT at first-line
First-line AC-CHT followed by autologous HSCT at relapse was the most effective treatment sequence in patients with follicular lymphoma
Rossi G. et al AJH 2015 Jan;90(1):56-61

19. FOLL05 Salvage treatment%
Chemotherapy 98 55
PBSCT 33 19 RT 9 5
W&W 12 7
Palliative 3 2
Death before therapy 1
Loss to FU NA 11

20. FOLL05 PFS after relapse (# events 35/131)
N (%) SAR % 3-yrs
CHT 98 (75) 86 (77-92)
PBSCT 33 (25) 87 (69-95)
Log-rank, p =0.966
Renyi, p=0.833

21. FOLL05 Survival after relapse (SAR, n=131)
N (%) SAR % 3-yrs
CHT 98 (75) 86 (77-92)
PBSCT 33 (25) 87 (69-95)
Log-rank, p =0.327
Renyi, p=0.647

22. The Follicular Lymphoma Chronicle Journal
Transplant or RIT??

23. Kaplan-Meier plots for progression-free survival (PFS)
Morschhauser, F. et al. J Clin Oncol; 26:

24. ARA-C with R in vivo purging ARA-C with R in vivo purging
A PHASE III MULTICENTER, RANDOMIZED STUDY COMPARING CONSOLIDATION WITH 90YTTRIUM-LABELED IBRITUMOMAB TIUXETAN (ZEVALIN®) RADIOIMMUNOTHERAPY VS AUTOLOGOUS STEM CELL TRANSPLANTATION (ASCT) IN PATIENTS WITH RELAPSED FOLLICULAR LYMPHOMA (FL) AGED YEARS
3x R-chemo regimens
CR,PR
Randomization
ARA-C with R in vivo purging
ARA-C with R in vivo purging
consolidation with RIT
consolidation with ASCT (BEAM)
R maintenance
R maintenance

25. FLAZ12 Ibrutimab tiuxetan vs ASCT for refractory and relapsed FL
MRD
3 R-CHEMO REGIMENS
(R-CHOP, R-DHAP, R-FM, R-ICE, R-IEV, R-B)
BLIND RANDOMIZATION
Pts stratified based on Center characteristics and response
CR-PR
MRD
SD-PD
Any salvage treatment
ARA-C 2g/sqm b.i.d. 2 days
with Rituximab in vivo purging
PBSC
harvest
MRD
Randomization unblinding
Arm A
consolidation with
RIT
Arm B:
consolidation with
ASCT
MRD
Rituximab maintenance
every three months for 8 courses
(starting three months after consolidation)
At relapse
ASCT With
Previously collected PBSC
MRD
At relapse

26. Active Drugs in R/R follicular lymphoma
Bendamustine
Lenalidomide
……….
………..

27. Bendamustine
Phase N
ORR CR
PFS BR II 63
90% NR 24
Rummel et al. JCO 2005 66
92%
55% 32
Robinson et al. JCO 2008
BR vs FR
III
219
82% vs 49%
39% vs 16%
30 vs 12
Rummel et al., ASH 2010
B mono
100
75%
17% 9
Kahl et al. 74
77%
34%
8.3
Friedberg et al., JCO 2008
Overall response rate (ORR) between 82% and 92% with a median PFS of 23 to 30 months in combination with rituximab
Most important side effects of single-agent bendamustine or the BR combination were grade 3 or 4 neutropenia, neutropenic fever, and infections , largely manageable

28. Bendamustine: Italian experience
Relapsed/refractory
First line elderly FL
Retrospective analysis 1/07-12/09
175 NHL in 24 Italian centers
48 FL, 60 indolent, 34 DLBCL
79 relapse, 35 refractory, 61 PD
Median age 69 years
ORR 71% CR 29%
ORR 23% Benda, 77% BR
FL 17% Benda, 72% BR
FLE09 study
Elderly patients with FL at diagnosis
Rituximab-BM 4 months+ 4 Rituximab
ORR 83% after R-BM
93% end of treatment
Rigacci et al Ann Hematol 91;1013, 2012
Boccomini et al 12 ICML Lugano 2013

29. Lenalidomide Lenalidomide single agent in FL
Relapsed refractory grade 1-2 FL
Lenalidomide 25 mg days 1-21 q 28
N° pts
ORR %
CR %
PFS OS FU
Witzig
NHL 001 22 27 9
4.0
N/A
4.4
Grade 3 FL
N° pts
ORR %
CR %
PFS OS FU
Wiernick
NHL 002 6 60 20
4.0
N/A
3.7
Witzig
NHL 003 19 42 11
8.9
9.2

30. Lenalidomide and rituximab
Phase II study of Rituximab-Lena
Frontline treatment.
Phase II study of Rituximab-Lena
R/R indolent NHL
Pts
ORR%
CR (%) FL 17
94%
16 (34%)
SLL 3
100%
1 (33%)
MZL 8
63%
4 (50%)
Pts
ORR%
CR (%) FL 22
77%
9 (41%)
SLL 2
50%
1 (50%)
MZL 3
67%
2 (67%)
Fowler, ASH 2009.
Tuscano , BJH, 2014, 165, 375–381
CALGB phase II randomized study in recurrent FL
Rituximab and Lenalidomide vs Lenalidomide alone
Pts
ORR%
EFS
neutropenia
Lena only 45
49%
1.2 yrs
16% R2 44
75%
2.0 yrs
19%
Leonard, ASCO 2012

31. RENOIR
A randomized phase iii multicenter trial assessing Efficacy and Toxicity of a combination of Rituximab and Lenalidomide (R2) vs Rituximab alone as maintenance after chemoimmunotherapy with Rituximab-Bendamustine for relapsed/refractory fl patients not eligible for autologous transplantation
Primary Objective
To evaluate in patients responsive to induction whether
the R2-MANT program may improve PFS
compared to patients treated with R-MANT

32. Renoir: treatment design
REALPSED/REFRACTORY
FOLLICULAR LYMPHOMA
NEED TO THERAPY
PCR analysis for Bcl-2 rearrangement on PB/BM
Rituximab 375 mg/m2 day 0 or 1 (day 8 on cycle 1)
Bendamustine 90 mg/m2 iv days 1-2
R-Bendamustine x 4 once a month
Restaging and PCR analysis for Bcl-2 rearrangement on PB/BM
CR/PR NR
OFF
Random R2
R alone
Rituximab 375 mg/m2 day 1 q 90 days (8 cycles)
Lenalidomide (10 mg dd 1-21 q 28) (24 cycles)
Rituximab 375 mg/m2 day 1 q 90 days (8 cycles)
Clinical and
molecular follow-up
months 12, 18, 24 and 30 (end of study)

33. Renoir Study
Participants: 50
Enrollement period: 36 months

34. Single agent or combination CHT
Second or greater relapse
Single agent or combination CHT
Monoclonal antibody-based therapy
Immunomodulatory Agents
High dose CHT followed by ASCT or alloSCT

35. Promising novel agents in the clinic
Monoclonal antibodies
Unlabeled
Radiolabeled
Immunoconjugates
Novel constructs and bispecifics
Proteosome inhibitors
BTK, PI3K inhibitors

36. Potential Antibody Targets for B-Cell Lymphomas
Evolving Standards of Care in Non-Hodgkins Lymphoma
VA Indolent Lymphoma v4
12/7/ :59 PM
12/7/ :59 PM
Potential Antibody Targets for B-Cell Lymphomas
CD40
CD52
CD37
CD74
CD80
CD23
Death receptors
CD22
HLA-DR
CD20
CD19
Surface immunoglobulin
CD5
B cell
Cheson BD, et al. N Engl J Med. 2008;359; Copyright © [year of publication] Massachusetts Medical Society. All rights reserved.
Philip J. Bierman, M.D. 36

37. Antibodies in Follicular Lymphoma
GA101: Anti-CD20 antibody
Obinutuzumab (GA101) in Patients With R/R Indolent NHL:
Results From the Phase II GAUGUIN Study
Salles GA, et al. J Clin Oncol. 2013, 31 (23) pp

38. The 1,600/800-mg dose schedule of obinutuzumab (GA101) has encouraging activity with an acceptable safety profile in relapsed/refractory iNHL.
Salles GA, et al. J Clin Oncol. 2013, 31 (23) pp

39. Obinutuzumab (GA101) plus CHOP or FC in relapsed/refractory follicular lymphoma: results of the GAUDI study (BO21000)
At induction end, 96% (27/28) of patients receiving G-CHOP (CR, 39% [11/28]) and 93% (26/28) receiving G-FC (CR, 50% [14 of 28]) achieved responses. G-CHOP and G-FC had an acceptable safety profile with no new or unexpected AEs, but G-FC was associated with more AEs than G-CHOP.
Radford J, et al. Blood 2013 Aug 15;122(7):

40. MEDI-551, a Humanized Monoclonal Antibody directed against CD19, in subjects with Relapsed or Refractory Advanced B-cell Malignancies
Hamadani M et al. Blood 2013;122:1810
©2013 by American Society of Hematology

41. Complete remissions (CRs) of chemotherapy-refractory large-cell lymphomas in patients receiving anti-CD19 chimeric antigen receptor T cells.
James N. Kochenderfer et al. JCO 2015;33:
©2015 by American Society of Clinical Oncology

42. Betalutin— Mechanism of action

43. Treatment schedule

44. Best tumour response by dose level

45. Small-Molecule Inhibitors in Follicular Lymphoma
Ibrutinib (PCI-32765): BTK inhibitor
Idelalisib (GS-1101): PI3K delta inhibitor
IPI-145: PI3K delta and gamma inhibitor
Ibrutinib (PCI-32765)
Idelalisib (CAL-101, GS-1101)
IPI-145

46. Antitumor response in all evaluable patients.
(A) Best responses in the 48 patients evaluated by computed tomography scan for change from baseline in the sum of the largest diameter of each target lesion; negative values indicate
tumor shrinkage.
(B) Time on study for all 56 patients grouped by histology; bars describe the reason for patient discontinuation.

47. Idelalisib EMA Indication:
in combination with R for the treatment of adult patients with CLL:
- who have received at least one prior therapy, or
- as first line treatment in the presence of 17p deletion or TP53 mutation in patients unsuitable for chemo-immunotherapy.  
as monotherapy for the treatment of adult patients with FL that is refractory to two prior lines of treatment.

48. Idelalisib PI3Kδ inhibition by idelalisib in patients
with relapsed indolent lymphoma.
Figure 1. Best Overall Response
Gopal AK et al. N Engl J Med 2014 Mar 13;370(11):

50. First or second relapse
In conclusion……
Follicular Lymphoma
Salvage Treatment
Relapsed/ Refractory
First or second relapse
High dose,
FLAZ 12 (≤ 65 yrs)
RENOIR
> Second relapse
or elderly
New drugs

51. THANK YOU!
THANK YOU!