Management of Relapsed/Refractory
Follicular Lymphoma David Macdonald, MD, FRCPC
QEII Health Sciences, Halifax NS
Disclosures
Research Support/P.I. Lundbeck
Employee N/A
Consultant Amgen, Gilead, Janssen, Lundbeck, Roche
Major Stockholder N/A
Speakers Bureau N/A
Honoraria N/A
Scientific Advisory Board Lymphoma Canada
Management of Relapsed/Refractory Follicular Lymphoma
A 72 year old man was diagnosed with FL 8 years ago. He was treated with RCVP followed by maintenance Rituximab, then two years later he received BR which he completed 2.5 yrs ago. He now has symptomatic relapse, biopsy confirms FL grade 1. ECOG is 1, creat is normal, Hgb is 106, WBC 3.9
How would you treat him now? • retreatment with RCVP
• retreatment with BR
• RCHOP
• Fludarabine-based treatment +/- R
• idelalisib
Front-line management of Indolent Lymphoma has changed
• The old paradigm • no clinical trial had shown a survival benefit of one first-line therapy
over another
• incurable disease with relapsing/remitting pattern but progressive resistance
• treatment goal – maximize QOL , minimize toxicity
• chlorambucil fludarabine CVP CHOP platinum
The old paradigm
Tan, Blood. 2013 Aug 8; 122(6): 981–987.
Era 1 1960-75
Era 2 1976-86
Era 3 1987-96
Era 4 1997-03
Follicular Lymphoma, EFS after first-line treatment, Stanford Experience 1960-2003
Front-line management of Indolent Lymphoma has changed
• The new paradigm • clinical trials of front-line treatment show remarkable
improvements in duration of first remission
• incurable disease with relapsing/remitting pattern and progressive resistance, but new therapies emerging during the lifetime of current patients
• overall survival has probably doubled in past 20 years
• treatment goal – maximize remission quality, minimize toxicity
• BR + maintenance R ??? ???
iNHL: Recent Advances that have Impacted Current Practice
1. Hiddemann M, et al, Blood 2005;106(12):3725-3732. 2. Marcus R et al. J Clin Oncol. 2008;26(28):4579-4586. 3. Salles G, et al: Lancet 2011; 377(9759):42-51 4. Rummel MJ, et al. Lancet. 2013;381(9873):1203-1210. 5. Flinn IW, et al. Blood. 2014;123(19):2944-2952.
Addition of immunotherapy (rituximab) to standard chemotherapy
regimen (CVP and CHOP) improved outcomes for patients with iNHL1,2
Rituximab maintenance (2 years) prolongs progression free
survival (43% vs 26% with observation)3
Bendamustine-rituximab based regimen offers additional benefits
over R-CVP/R-CHOP4,5
2005
2011
2012
2013
Remission Duration after first-line therapy in FL
Median PFS (mos) ref
chlorambucil 12-15
CVP 15 Marcus, 2005
R-CVP 32 Marcus, 2005
R-chemo 48 Salles, 2011
R-chemo + maintenance 70* Salles, 2011
B-R 70 Rummel, Lancet 2013
B-R + maintenance ???
• 2 yrs maintenance added 30 months PFS in second-line (van Oers, 2006) • Projected 20-30 months PFS benefit in PRIMA • Could it also add 20 months PFS benefit to BR ?
???
8
Treatment Advances in FL
Chl Flud CVP/CHOP DHAP
R-bendamustine + maintenance R observation
time in years
Patient diagnosed in 1986
Patient diagnosed in 2008 ? 0 7 11
Better management of relapsed/ refractory disease has improved OS
Tan, Blood. 2013 Aug 8; 122(6): 981–987.
medn OS
Era 1 1960-75 pre-anthracycline 11.0 yrs
Era 2 1976-86 anthracycline 11.0 yrs
Era 3 1987-96 aggressive + purine analogues
18.5 yrs
Era 4 1997-03 Rituximab not reached
Follicular Lymphoma, Overall Survival, Stanford Experience 1960-2003
What is the best treatment for relapsed/refractory FL?
RCTs in rel/ref FL
• 280 studies reporting on efficacy and safety of treatments in rel/ref indolent NHL
• only 10 well designed RCTs in FL
• insufficient homogeneity to do meaningful meta-analysis
• The only significant result coming out of meta-analysis – bortezomib plus rituximab improves response rates compared to rituximab alone
so then, how to choose?
• Factors Influencing Treatment Choice: • Patient Factors
• Age, Co-morbidity, ECOG performance status, Symptoms
• Priority for Short-term vs Long-term Goals
• Acceptance of Risk/Benefit Ratio for treatment option
• Disease Factors • Stage, Sites, Bulk, Transformation
• Duration of last remission
• Specific Treatment Options • Prior therapy and associated response duration
• Reimbursement Gribben JG. Blood. 2007;109(11):4617-4626.
Stil-1: Salvage Treatments After BR and R-CHOP
Rummel M, et al. ASH 2014; Abstract 4407.
BR (n=261) N (%)
R-CHOP (n=253) N (%)
Overall 93 (36) 140 (55)
No treatment yet, n 27 19
BR 21 (22) 69 (49)
R-CHOP 29 (31) 4 (3)
Fludarabine-based 9 (10) 13 (9)
APBSCT 5 (5) 19 (13)
Radiation, n 9 8
Ibritumomab tiuxetan, n 1 5
Various, n 19 22
StiL NHL-2-2003: Trial Design
R
BR (n = 114) x 6 cycles (every 4 weeks)
• Bendamustine 90 mg/m2 days 1–2
• Rituximab 375 mg/m2 day 1
FR (n = 105) x 6 cycles (every 4 weeks)
• Fludarabine 25 mg/m2 day 1-3
• Rituximab 375 mg/m2 day 1
N=219 patients
Follicular lymphoma
Waldenström's lymphoma
Marginal zone lymphoma
Small lymphocytic lymphoma
Mantle cell lymphoma
Primary endpoint: • Non-inferiority of PFS at 1 year
Secondary endpoints: • ORR, TTNT, EFS, OS, and safety
*The protocol was amended in 2006 to allow rituximab maintenance therapy (rituximab 375 mg/m2 every 3 months for up to 2 years) in both arms, following regulatory approvals in this setting.
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
StiL NHL-2-2003: Prior therapies
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
BR (n=114)
FR (n=105)
Previous treatments (median) =1 =2 >2
1 68% 17% 15%
1 59% 23% 18%
Previous rituximab (n=90) 40% 43%
Last regimen • Bendamustine • Fludarabine/Cladribine • CHOP • Chlorambucil/CVP • Other • ASCT
12% 9%
54% 14% 6% 4%
19% 9%
51% 10% 12% 4%
Refractory to last regimen 4% 4%
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
BR (n = 109)
FR (n = 99)
p-value
Overall response rate 82% 49% <0.0001
Complete response 39% 16% 0.0004
Partial response 43% 33%
Stable disease 6% 16%
Progression 7% 30% <0.0001
Not evaluable 5% 4%
StiL NHL-2-2003: Response
StiL NHL-2-2003: PFS
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
StiL NHL-2-2003: Survival
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
StiL NHL-2-2003: Toxicities
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
Hematological Toxicities (Grade 3/4)
% of cycles*
BR (n = 585)
FR (n = 452)
Leukocytopenia 13.6 14.2
Neutropenia 14.0 14.5
Thrombocytopenia 2.2 2.8
Anemia 1.6 2.0
Non-hematological Toxicities (All Grades)
BR (n = 109)
FR (n = 99)
p-value
Alopecia, n – –
Paresthesias, n 4 8
Stomatitis, n 8 5
Nausea and emesis, n 29 27
Fatigue, n 14 13
Skin (erythema), n 10 7
Allergic reaction (skin), n 14 15
Infectious complications, n (%) 37 (34) 25 (25) 0.1765
Sepsis, n (%) 3 (3) 1 (1)
*86% of cycles were evaluable for toxicity.
StiL NHL-2-2003: Secondary Malignancies
Presented by Rummel MJ, et al. ASH 2014: Abstract 145.
BR (n = 114) FR (n = 105)
Secondary malignancies, n 16 16
Prostate – –
Colon/gastric 1 4
Bronchial – 1
Kidney/urothelial 4 3
Pancreatic – 1
Breast – –
Other carcinoma 9 4
MDS – 1
AML 1 2
CML 1 –
Median follow-up 96 months
GADOLIN: Trial Design
R 1:1
G-B
Obinutuzumab (1000 mg iv days 1,8 and 15 Cycle 1; Day 1 Cycles 2-6 (28 day cycles)
Bendamustine (90 mg/m2/kg iv days 1 and 2 Cycles 1-6; 28 day cycles)
B
Bendamustine (120 mg/m2/kg iv days 1 and 2 Cycles 1-6; 28 day cycles)
N=413 patients
Rituximab-refractory
CD+ iNHL
(incl. FL, MZL and SLL)
Primary endpoint: • IRF-assessed progression-free survival
Secondary endpoints: • PFS-assessed by investigator, OS, best overall response, duration of response, EFS, DFS, safety, PROs,
pharmacokinetic profile, pharmacoeconomics
Stratification Factors:
• NHL subtype (FL vs others) • Prior therapy (2 vs >2) • Refractory type (R-mono vs R-chemo) • Geographic region
G-Maintenance
Obinutuzumab (1000 mg iv every 2 months for 2 years or until progression)
CR PR SD
Presented by Sehn L, et al. EHA 2015; Abstract LB691.
GADOLIN Primary Outcome: IRF-assessed PFS
Presented by Sehn L, et al. EHA 2015; Abstract LB691. IRF, independent radiology facility.
GADOLIN: Adverse Events Grade 3-4
Non-hematological** G-B
(n=194) B
(n=198)
IRR*** 21 (10.8) 11 (5.6)
Vomiting 4 (2.1) 2 (1.0)
Decreased appetite 3 (1.5) 2 (1.0)
Fatigue 3 (1.5) 5 (2.5)
Nausea 2 (1.0) 6 (3.0)
Diarrhoea 2 (1.0) 5 (2.5)
Pyrexia 2 (1.0) 0
Headache 1 (0.5) 2 (1.0)
* Multiple occurrences of the same AE in an individual were counted only once;
** AEs with ≥15% incidence across all grades
*** AEs occurring during or within 24 hours after an infusion and considered to be related to any study drug
Hematological* G-B
(n=194) B
(n=198)
Neutropenia 64 (33.0) 52 (26.3)
Thrombocytopenia 21 (10.8) 32 (16.2)
Anemia 15 (7.7) 20 (10.1)
Febrile neutropenia 9 (4.6) 7 (3.5)
Leukopenia 2 (1.0) 3 (1.5)
Presented by Sehn L, et al. EHA 2015; Abstract LB691.
GADOLIN: Serious Adverse Events
Non-hematological* G-B
(n=194) B
(n=198)
IRR** 8 (4.1) 3 (1.5)
Sepsis 6 (3.1) 7 (3.5)
Pneumonia 5 (2.6) 10 (5.1)
Pyrexia 5 (2.6) 3 (1.5)
Multiple occurrences of the same AE in an individual were counted only once; * AEs with ≥2% incidence across all grades ** AEs occurring during or within 24 hours after an infusion and considered to be related to any study drug
Hematological* G-B
(n=194) B
(n=198)
Febrile neutropenia 8 (4.1) 6 (3.0)
Neutropenia 6 (3.1) 1 (0.5)
Thrombocytopenia 4 (2.) 0
Anemia 3 (1.5) 3 (1.5)
Leukopenia 0 1 (0.5)
Presented by Sehn L, et al. EHA 2015; Abstract LB691.
Phase II Study: Lenalidomide Plus Rituximab in Relapsed or Refractory iNHL
Tuscano JM, et al. Br J Haematol. 2014;165(3):375-381.
Eligibility (n=30*)
Stage III or IV, relapsed or refractory, biopsy-proven iNHL
* 27 patients
completed
1 cycle and were
evaluable for
response
Induction Phase: 56 Days
Oral lenalidomide:
(25 mg QD) days 1–21 of a 28-d cycle
Rituximab:
375 mg/m2 on day 15 of cycle 1, and then weekly for 4 doses.
Maintenance
Lenalidomide alone
Until disease progression
Specific Characteristics
Follicular lymphoma 22 (73.3%)
Prior therapies, median (range), 3 (1-11)
Refractory to rituximab 15 (51.7%)
Response Rates in Rel/Ref iNHL Treated with Lenalidomide Plus Rituximab
Tuscano JM, et al. Br J Haematol. 2014;165(3):375-381.
N ORR CR/CRu PR SD PD
iNHL 27 20 (74.1%) 12
(44.4%) 8 (29.6%) 4 (14.8%) 20 (11.1%)
Age > 65 years 11 9 (81.8%) 5 (45.5%) 4 (36.4%) 2 (18.1%) 0 (0.0%)
Follicular lymphoma 22 17 (77.3%) 9 (40.9%) 8 (36.4%) 2 (9.1%) 3 (13.6%)
Marginal zone lymphoma 3 2 (66.7%) 2 (66.7%) 0 (0.0%) 1 (33.3%) 0 (0.0%)
SLL/CLL 2 1 (50.0%) 1 (50.0%) 0 (0.01%) 1 (50.0%) 0 (0.0%)
Refractory to rituximab 13 8 (61.5%) 4 (30.8%) 4 (30.8%) 3 (23.1%) 2 (15.4%)
Heavily pretreated* 15 9 (60.0%) 6 (40.0%) 3 (20.0%) 3 (20.0%) 3 (20.0%)
At a median follow-up of 43 months: • Median DR: 15.4 months** • Time to next therapy: 37.4 months • PFS: 12.4 months
* Defined as ≥3 prior treatments
** Not reached for patients who achieved a CR
Safety of Lenalidomide Plus Rituximab in Relapsed or Refractory iNHL
• 20 pts (69%) had 1 lenalidomide dose reduction or treatment interruptions, mostly due to neutropenia or fatigue
• 6 patients discontinued therapy due to AEs (neutropenia, hyperviscosity, rash, deep vein thrombosis, pulmonary and skin infections)
Tuscano JM, et al. Br J Haematol. 2014;165(3):375-381.
Common Grade 3 and 4 AEs %
Lymphopenia 45%
Neutropenia 55%
Fatigue 23%
Hyponatremia 9%
*defined as ≥3 prior treatments **Not reached for patients who achieved a CR
• GS 101-09 (Phase 2) Gopal et al NEJM 2014 • Longer term date updated by Gopal at ASH 2014
N=125
Continuous therapy
Idelalisib 150 mg BID
Week 0 48
Long-term Follow-upStudy 101-09
Therapy maintained until progression
‡
Idelalisib monotherapy in double-refractory (alkylator and R) iNHL
Study 101-09 (Phase 2)
Baseline Patient Characteristics N=125
Male/female, n (%) 80/45 (64/36)
Median age, y (range) 64 (33–87)
Disease type, n (%)
FL 72 (58)
SLL 28 (22)
MZL 15 (12)
LPL/WM 10 (8)
Lactate dehydrogenase >ULN, n (%) 38 (30)
Bulky disease [>7 cm], n (%) 33 (26)
Neutropenia [ANC <1500 cells/μL], n (%) 17 (14)
Anemia [Hb <10 g/dL], n (%) 19 (15)
Thrombocytopenia [platelets <75,000/μL], n (%) 10 (8)
‡
Study Design and Patient Characteristics
Study 101-09 (Phase 2)
Prior Therapy Exposure at Baseline N=125
Median prior regimens, n (range) 4 (2–12)
Prior therapy, n (%)
Rituximab 125 (100)
Alkylating agent 125 (100)
Bendamustine 81 (65)
Anthracycline 80 (64)
Purine analog 42 (33)
Stem-cell transplantation 14 (11)
Median time from last regimen to study entry, mo 3.9
‡
Study Design and Patient Characteristics
Prior Therapy Refractoriness at Baseline N=125
Rituximab, n (%) 125/125 (100)
Alkylating agent, n (%) 124/125 (99)
Bendamustine-rituximab, n (%) 47/60 (78)
R-CHOP, n (%) 40/56 (71)
R-CVP, n (%) 29/36 (81)
Bendamustine, n (%) 61/81 (75)
Refractory to ≥2 regimens, n (%) 99 (79)
Refractory to last regimen, n (%) 112 (90)
Study 101-09 (Phase 2) ‡
Study Design and Patient Characteristics
Study 101-09 (Phase 2)
0% 20% 40% 60% 80% 100%
FLn=72
56% (43–67)
ORR, % (95% CI)
14%n=10
42%n=30
32%n=23
8%n=11
SLLn=28
MZLn=15
LPL/WMn=10
61% (41–79)
47% (21–73)
80% (44–98)
57%
n=16
40%n=6
70%n=7
10%n=1
36%
n=10
47%n=7
10%n=1
10%n=1
4%
n=1
1%n=1
4%
n=1
7%n=1
7%n=1
CompleteResponse
StableDisease
ProgressiveDisease
Notevaluable
PartialResponse
MinorResponse
‡
Overall Response Rate
Study 101-09 (Phase 2)
125 60 33 22 12 4 125 40 14 9 5 2 1
Patients at risk, n
On Study vs Last Prior Therapy
‡
Progression Free Survival
Study 101-09 (Phase 2)
AE Occurring in >15%, n (%) Any Grade Grade ≥3
Diarrhea/colitis 63 (50) 24 (19)
Cough 40 (32) 0
Nausea 39 (31) 2 (2)
Fatigue 38 (30) 2 (2)
Pyrexia 38 (30) 4 (3)
Dyspnea 23 (18) 6 (5)
Decreased appetite 23 (18) 1 (1)
Abdominal pain 21 (17) 3 (2)
Upper respiratory infection 21 (17) 0
Vomiting 20 (16) 3 (2)
Decreased weight 19 (15) 0
‡
Adverse Events
Grade ≥3 ALT/AST elevations occurred in 18 patients (14%) Drug was temporarily held in these pts, and 11/15 pts (73%) were re-treated
without recurrence of ALT/AST elevation
Study 101-09 (Phase 2)
Hematologic Lab Abnormalities Patients, n (%)
Any Grade
Baseline On Study Baseline On Study
Neutrophils decreased 29 (23) 71 (57) 7 (6) 35 (28)
Hb decreased 64 (51) 41 (33) 1 (1) 3 (2)
Platelets decreased 43 (34) 36 (29) 4 (3) 10 (8)
‡
Adverse Events
Idelalisib Indication
• Health Canada approval (NOC/C): • monotherapy for the treatment of patients with follicular
lymphoma who have received at least two prior systemic regimens and are refractory to both rituximab and an alkylating agent
Not funded in any province
Phase 2 Consortium Trial Ibrutinib monotherapy in R/R FL
• 40 patients with relapsed or refractory FL treated with ibrutinib, 560 mg daily, until disease progression or unacceptable toxicity
Characteristics No
Age, years, median (range) 64 (46-82)
FLIPI 3 21 (52.5%)
Elevated LDH 10 (25%)
B-symptoms 4 (10%)
GELF criteria 25 (63%)
Prior therapies, median (range) 3 (1-11)
Stem cell transplant 8 (20%)
Rituximab refractory 18 (45%)
Refractory to most recent treatment 14 (35%)
Bartlett NL, et al. ASH 2014. Abstract 800.
Ph2 Ibrutinib response rates
Median Follow-up
of
6.5 Months
All Subjects
Enrolled
(N=40)
Rituximab-
refractory
(N=18)
Rituximab-
relapsed
(N=19)
Rituximab +
Naïve
(N=3)
Overall response
rate
12 (30%) 2 (11%) 8 (42%) 2 (67%)
Complete response 1 (2.5%) NR NR NR
Partial response 11 (28%) NR NR NR
Bartlett NL, et al. ASH 2014. Abstract 800.
Median time to response was 2.4 (range 1.8-12.9) months
Ph2 Ibrutinib PFS
Median PFS 9.4 mos
Bartlett NL, et al. ASH 2014. Abstract 800.
Important toxicities of novel agents
Drug Toxicity Considerations
ibrutinib bleeding, atrial fibrillation, lymphocytosis, diarrhea
idelalisib colitis, pneumonitis, transaminitis
Novel agents and combinations
Ref
Therapy Class Phase N ORR Reference
Single Agent
Venetoclax BCL2-I Phase I 44 48% Davids MS, et al ASCO 2014. Abstract 8522
Copanlisib iv PI3k-I Phase IIA 33 53% Dreyling M, et. Al. ASH 2014. Abstract 1701
Duvelisib PI3K-I Phase I 31 65% Flinn I, et al. ASH 2014, Abstract 802
Combination therapies
Pidilizumab-R PD1-I Phase II 32 66% Westin JR, et al. Lancet Oncol.
2014;15(1):69-77.
Ibrutinib + R-CHOP BTK-I Phase I 32 94% Younes A, et al. Lancet Oncol.
2014;15(9):1019-1026
Ibrutinib + BR BTK-I Phase I 10* 90% Maddocks K, et al. Blood. 2014
Bortezomib +R-CHOP Proteasome
inhibitor Phase II 20* 75%
Jonathon B. et al. ASH 2014. Abstract 4432
Idelalisib +BR PI3k-I Phase I 79 81% De Vos S, et al. ASH 2014.
Abstract 3063
Maintenance
Obinutuzumab, maintenance Mab Phase Ib 72
CRR ~65%
Dyer MJS, et al. ASH 2014. Abstract 1743.
Rituximab, bendamustine and Ibrutinib: response by NHL subtype
Ref
Histology No. Evaluable
Patients** CR (%) PR (%) ORR (%)
Mantle cell lymphoma 17 13 (76) 3 (18) 16 (94)
Diffuse large B-cell lymphoma 16 5* (31) 1* (6) 6 (37)
Follicular lymphoma 10** 5 (50) 4 (40) 9 (90)
Marginal zone lymphoma 1 0 1 (100) 1 (100)
Transformed lymphoma 2 1 (50) 0 1 (50)
All Patients 46** 24 (52) 9 (20) 33 (72)
Maddocks K, et al. Blood. 2014 Oct 29. pii: blood-2014-08-597914. [Epub ahead of print]
* 3 Patients with DLCL with a CR and 1 patient with a PR had ABC DLCL by Hans’
immunohistochemical criteria. For the other two DLCL patients with a CR, one had
GCB DLCL and one was unclassifiable.
** 2 patients with FL and grade 3 rash during cycle 1 were not evaluable.
Phase 1/2 trial idelalisib with Rituximab, Bendamustine, or both in relapsed iNHL
All Subjects Enrolled (n=79)
Idelalisib + Rituximab
(N=32)
Idelalisib + Bendamustine
(N=33)
Idelalisib + Rituximab +
Bendamustine (N=14)
Overall response rate 64 (81%) 24 (75%) 29 (88%) 11 (79%)
Complete response 26 (33%) 8 (25%) 12 (36%) 6 (43%)
Partial response 38 (48%) NR NR NR
Stable disease 7 (9%) 4 (13% 3 (9%) 0
Progressive disease 4 (5%) NR NR NR
PFS at 24 months NR 55% 64% 71%
De Vos S, et al. ASH 2014. Abstract 3063.
iNHL: How I Treat
BR + maintenance R
F(R)
(R)CHOP
(R)CVP
BR
Refractory patients???
Clinical Trials in iNHL
• Maintaining a menu of clinical trials will provide individuals access to promising treatments
• Strive to have an active trial for front-line, for relapsed R-refractory, and for relapsed R-sensitive
• during the past decade, iNHL patients in NS have had access to bortezomib, lenalidomide, subcutaneous rituximab, galiximab, obinotuzumab, inotuzumab ozogomicin, idelalisib, and ibrutinib