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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


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%


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


StiL NHL-2-2003: Survival


StiL NHL-2-2003: Toxicities


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


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)


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)


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


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)


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


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

‡


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) ‡



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


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


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


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


Median time to response was 2.4 (range 1.8-12.9) months

Ph2 Ibrutinib PFS

Median PFS 9.4 mos


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

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