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Managing patients with relapsed follicular lymphoma

Managing patients with relapsed follicular lymphoma

John P Leonard M DJohn P Leonard M DJohn P. Leonard, M.D.Richard T. Silver Distinguished Professor of Hematology

and Medical OncologyProfessor of Medicine

Associate Director, Weill Cornell Cancer CenterChief, Lymphoma/Myeloma ServiceCenter for Lymphoma and Myeloma

John P. Leonard, M.D.Richard T. Silver Distinguished Professor of Hematology

and Medical OncologyProfessor of Medicine

Associate Director, Weill Cornell Cancer CenterChief, Lymphoma/Myeloma ServiceCenter for Lymphoma and Myeloma

Case

A 63-year-old male presented with follicular, grade 2 NHL with symptomatic diffuse LAN in the 5-cm range. He is treated with R-CHOP x 6 cycles and then observed.

2 ½ years later, he presents with progressive pelvic LAN in the 3-cm range on routine imaging.

Bl d t h i t i d LDH i th lBlood counts, chemistries, and LDH are in the normal range. Bone marrow biopsy is negative for evidence of lymphomatous involvement.

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Question

The preferred management for this patient is:A. Close observation and monitoringA. Close observation and monitoringB. Single agent rituximab x 4 dosesC. Single agent rituximab + maintenance RD. R-Fludarabine combination regimen E. BendamustineF. RadioimmunotherapyG. RICE or similar regimenH. RICE or similar regimen followed by AuSCTI. Other

Overall survival in follicular lymphoma by FLIPI

ity

Low risk

I di i k0.8

1.0No Nodal regions 4

L Elevated LDH

Surv

ival

pro

babi

l Intermediate risk

High risk

0

0.2

0.4

0.6

Years0 1 2 3 4 5 6 7

L Elevated LDH

A Age ≥60

S Stage III/IV

H Hemoglobin <120 g/L P<10-4

Adapted from Solal-Celigny et al. Blood. 2004;104:1258.

Risk Group No. of Factors % of Pts 5-y OS (%) 10-y OS (%)

Low 0-1 36 90.6 70.7

Intermediate 2 37 77.8 50.9

High 3-5 27 52.5 35.5

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Current treatment options in indolent lymphoma

• Observationl b /• Single agent rituximab +/- maintenance

– Can adding other biologics enhance activity without major toxicity?

• Chemotherapy + rituximab +/- maintenance– What is best chemotherapy?– What is role of maintenance rituximab?

• Radioimmunotherapy• Radioimmunotherapy– Alone or as consolidation

• SCT options in first (second, later) remission• Novel/investigational agents

Remission Duration of Patients Receiving AuSCT for FL in Second or Later RemissionSt. Barts and DFCI

Rohatiner et al. J Clin Oncol. 2007;25:2554-9.

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Comparison of novel anti-CD20s

Blood, Jul 2008; doi:10.1182/blood-2008-04-149161

Ofatumumab

• Human CD20 mAb that binds to membrane-proximal epitope

Ofatumumab binding site

Rituximab binding site

membrane proximal epitope encompassing both the small loop and large loop of CD201,2

• Approved in refractory CLL

• Phase I/II study in relapsed or refractory follicular lymphoma (FL)3

– ORR: 42% – Median duration of response: 30

months– ORR in prior rituximab-treated

patients: 64% 1. Teeling et al. J Immunol 2006;177:362; 2. Teeling et al. Blood 2004;104:1793; 3. Hagenbeek et al. Blood2008;111(12):5486–95

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Ofatumumab in R-Refractory FLTreatment Follow up

OFA 300 mgOFA 500 or 1000 mgResponse evaluation

0 1 2 3 4 5 6 7 3 mo 6 9 12 18 24

Study Week Month

• Open label, international, multicenter study in patients with FL who were refractory to rituximab alone or in combination

• Pre-medications prior to ofatumumab: – Paracetamol (acetaminophen) 1000 mg PO or eq.– Antihistamine (cetirizine) 10 mg PO or eq.– Prednisolone 100 mg IV or eq. prior to infusions 1 and 2; dose

could be reduced to <100 mg for other infusionsHagenbeek et al, ASH 2009

Ofatumumab in R-Refractory FL -Response Rates

80

100

nts

(%

)

ORR

0

20

40

60

Ofatumumab Ofatumumab All patients

Nu

mb

er

of

pa

tie

n

95% CI

13%10% 11%

• 87% and 91% of patients in the 500 mg group and 1000 mg group, respectively, completed all 8 infusions of ofatumumab

• No difference in primary endpoint (ORR) between 500 mg and 1000 mg group; hence, 2 groups were combined for secondary endpoint analyses

500 mg (N=30) 1000 mg (N=86) (N=116)

Hagenbeek et al, ASH 2009

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GA101: mechanisms of action type I versus type II antibodies

Increased direct cell deathUnique type II epitope & elbow hinge

Increased ADCC via increased affinity to the 'ADCC

B cell

Effectorcell

Unique type II epitope & elbow-hinge modification

via increased affinity to the ADCC receptor' FcgRIIIA

Lower CDC activityDue to recognition of type II epitope

CD20

FcgRIIIa

Complement

GA101 (Monotherapy)MaintenanceInduction

GA101 in recurrent B-NHL : Phase I dose escalation (3+3 design) 100-2000 mg/dose

Maintenance Dosing Schema

• Patients achieving PR or CR with induction eligible (allowance made for

months

RESPONSE ASSESSMENTS

241263 189 15 21

patients with “near PR” with clinical benefit)

• Administered every three months at cohort dose level

• Response assessed every 3 months by CT

Sehn et al, ASH 2009

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GA-101 in recurrent B-NHLOverall response following induction by dose cohort (13-week assessment)

CohortNo. of

patientsCR PR SD PD

Non evaluable

100/200 mg 3 1 2100/200 mg 3 1 2

200/400 mg 3 2 1

400/800 mg 3 2 1

800/1200 mg 3 3

1200/2000 mg 3 3

1000/1000 mg 7 4 2 11000/1000 mg 7 4 2 1

Total 22 5 13 3 1

24% 62% 14%

Sehn et al, ASH 2009

Subcutaneous humanized anti-CD20 Veltuzumabin B-cell NHL

80-320 mg/m2 every 2 weeks x 4 doses

Prior lines of therapy:5 T t t ï 6 ith 1 i 4 ith 2 i

Patients(n=15)

Overall response rate

All evaluable pts 8/15 (53%)

F lli l l h 7/12 (53%)

• 5 Treatment naïve, 6 with 1 prior rx, 4 with 2+ prior rx

Allen et al, J Clin Oncol 2009; 27(suppl): (abstract 8530).

Infections (3 pts): pneumonia, transient upper respiratory infections

Follicular lymphoma 7/12 (53%)

Non-Follicular lymphoma 1/3 (33%)

Chronic lymphocytic leukemia 0/8 (0%)

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Anti-lymphoma antibodies in the clinic

Cheson and Leonard, NEJM 2008

Multicenter Epratuzumab + RituximabStrauss, et al, JCO 2006

Duration of Response

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Radiolabeled anti-CD20 antibodies

• Yttrium 90 ibritumomab tiuxetan (Zevalin)

• Iodine 131 tositumomab (Bexxar)

• Pretargeted (investigational)S d lif di i d d– Secondary agent to amplify radiation dose and enhance specificity

Common themes regarding radiolabeled anti-CD20 antibodies

• Treatment done in a week (2 injections)• Gamma camera imaging or counts a g g

component• Manageable radiation safety issues• Toxicity is principally infusion-related and

hematologic– Baseline hematologic status relevant– Blood count monitoring required for 3 monthsBlood count monitoring required for 3 months

• Important long-term toxicity usually absent• RR 60-80%, CR 30%• Some patients have durable remissions• Myeloablative therapy promising

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Where should we consider the use of radioimmunotherapy in NHL?

• Current data clearly support use in:– Relapsed low-grade/transformed NHL

• Advantages over rituximab +/chemorx debatableAdvantages over rituximab +/chemorx debatable– Chemotherapy-refractory low-grade NHL– Rituximab-refractory low-grade NHL– Transformed NHL– Responsive disease but with short remissions

• Potential utility in:– Upfront therapy (alone or in sequence with chemotherapy)

Relapsed/refractory patients with other histologies– Relapsed/refractory patients with other histologies

IMIDs in lymphoid malignancies

• IMID effects– Inhibits TNF– Inhibits angiogenesis

• (bFGP, VEGF)– Stimulates T cells (CD8+)– Inhibits IL-12– Induces apoptosis– Alters cytokines– Affects stromal cells– Inhibits pro-survival factors (Akt)

Cool RM et al. Pharmacotherapy. 2002;22:1019; D’Amato RJ et al. Proc Natl Acad Sci USA. 1994;91:4082; Meierhofer C et al. BioDrugs. 2001;15:681; Thalidomide’s various effects in myeloma [figure]. Available at: http://www.multiplemyeloma.org/treatments/3.04.asp; Weber D et al. J Clin Oncol. 2003;21:16; Bartlett JB et al. Nature Reviews/Cancer. 2004;4:314

Inhibits pro survival factors (Akt)

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Lenalidomide for Relapsed/Refractory Indolent Lymphoma

StudyNo. of

PtsRegimen Efficacy

Witzig et al 43 Lenalidomide monotherapyORR: 23%, CR: 7%

PFS: 4.4 mos; DOR >16.5 mosPFS: 4.4 mos; DOR 16.5 mos

Dutia et al 16 Lenalidomide +R (R2)ORR: 75%, CR: 31%

PFS: 12 mos

Ahmadi et al 15 Lenalidomide, dexamethasone, and R

ORR: 53%, CR: 33%PFS: 86% at 10.9 mos

PFS for Patients Receiving Lenalidomide + R100

80

%)

Witzig. J Clin Oncol. 2009;27:5404; Dutia. ASH. 2009 (abstr 1679); Ahmadi. ASH. 2009 (abstr 1700).

Time (Months)0 5 10 15 20

60

40

20

0

Surv

ival

(%

Relapsed follicular NHLCALGB 50401

R Lenalidomide

RelapsedFollicular NHLafter ≥ 1 rituximabbased regimens

ANDOMI

Lenalidomide

Rituximab+Z

E

+Lenalidomide

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Single-Agent Bortezomib inRelapsed Indolent Lymphoma

Study SubtypeEvaluable

Patients (N)CR/CRu PR OR

FL 9 1/1 5 7 (77%)

O’Connor, 2005

FL 9 1/1 5 7 (77%)

MZL 2 0 2 2 (100%)

SLL 3 0 0 0

Goy, 2005

FL 5 0/1 0 1 (20%)

SLL 4 1/0 0 1 (25%)

WM 2 0 1 1 (50%)

Strauss, 2006FL 11 0 2 2 (18%)

WM 5 0 2 2 (40%)

O’Connor. J Clin Oncol. 2005;23:676; Goy. J Clin Oncol. 2005;23:667; Strauss. J Clin Oncol. 2006;24:2105.

CRu=unconfirmed CR; WM=Waldenström’s macroglobulinemia.

Phase III LYM-3001 Trial: Bortezomib Plus Rituximab in Relapsed/Refractory FL

BortezomibGrade 1/2 FL1.6 mg/m2 weekly on days 1,8,15, and 22

+Rituximab

375 mg/m2 once a week on days 1,8,15, and 22 of cycle 1, then 375 mg/m2 on day 1 of cycles 2 to 5

RANDOMIZE

Rituximab375 mg/m2 once a week on days 1,8,15, and 22 of cycle 1,

then 375 mg/m2 on day 1 of cycles 2 to 5

Documented relapse or progression following prior therapy

≥PR response to rituximabwith TTP ≥6 months

Accrual goal: N=670

US National Institutes of Health Web site. http://clinicaltrials.gov/ct2/show/NCT00312845?term=LYM-3001&rank=1. Accessed July 2, 2008.

Primary endpoint: PFS

g/ y y

5 35-day cycles

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Bendamustine in rituximab-refractory indolent NHL

• 100 pts (first 38 analyzed), rituximab-refractory indolent NHL (no response to R or response < 6 months)

• Median 3 prior regimens (range 1-10), 47% also chemoresistant

• Bendamustine administered 120 mg/m2 over 1 hr days 1, 2 every 21 days

• Toxicities primarily grade 3 and 4 hematologic, grade 1 and 2 nausea

• ORR 84% (29% CR), median PFS 9.7 monthsKahl, B, et al, ASH 2007, Abstract 1351

Bendamustine + rituximab in relapsed/refractory indolent and MCL: Efficacy

# of Patients (%)

FL SLL MCL Marginal Zone Total

Efficacy:

FL(n=24)

SLL(n=17)

MCL(n=16)

Marginal Zone(n=6)

Total(n=63)

ORR 23 (96%) 17 (100%) 12 (75%) 5 (83%) 57 (90%)

CR 17 (71%) 9 (53%) 8 (50%) 4 (67%) 38 (60%)

PR 6 (25%) 8 (47%) 4 (25%) 1 (17%) 19 (30%)

Median duration of progression-free survival: 30 months Median overall survival: 65 months

Rummel ASCO 2007, Abstract 8034

Grade 3 Grade 4 % of Grade 3/4

Leukocytopenia 32 3 16%

Thrombocytopenia 6 1 3%

Anemia 2 - 1%

Safety:

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Bendamustine, Bortezomib and Rituximab

• Phase II, multicenter study• Patient population: relapsed, indolent B-cell or mantle cell

NHL.• Exclusion: prior ASCT or RIT within 4 months; prior alloSCT

at any time .

• Schema: 28 day cycle

Day 1 Day 4 Day 8 Day 11

Bendamustine 90mg/m2 x xRituximab 375 mg/m2 xBortezomib 1.3 mg/m2 x x x x

Friedberg et al, ASH 2009

BVR – patient populationMedian 4 prior regimens

Category n (%)

IndolentIndolent

Follicular 16 (52)*

Small lymphocytic 3 (10)

Lymphoplasmacytic 2 (6)

Marginal zone 3 (10)

Mantle cell lymphoma 7 (23)

* FL grade 1 (N=7); FL grade 2 (N=3); FL grade 3 (N=5); FL NOS (n=1)

Friedberg et al, ASH 2009

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BVR - Response Rate*

% of ITT PopulationCategory

p(N = 29)

Overall response rate 79

Complete response 51

Partial response 28

Stable disease 10

Progressive disease 10

*One patient not evaluable for response; one patient not eligible and never received therapy

Friedberg et al, ASH 2009

BVR - Progression-free survival

PFS at 1 year=74%; PFS for responding pts at 1 year = 86%Friedberg et al, ASH 2009

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Bortezomib, Bendamustine, RituximabVERTICAL Study Design

Cycle 1

Days 1 2 8 15 22 35

Cycles 2–5 V

B

R

Patients received five 35-day treatment cycles When given on the same day, the order of administration was VBR

Days 1 2 8 15 22 35

Fowler et al, ASH 2009

Comparison with Other VR and BR Follicular Lymphoma Therapies

Study VERTICALRummel et al.

JCO 2005Robinson et al. JCO 2008

de Vos et al. JCO 2009†

Regimen VBR BR BR VR

P i th i diPrior therapies, median (range)

2 (1–11) 1 (1–3) 1 (1–4) 2 (0–3)

Prior rituximab, % 100 0 56 90

Median prior rituximab therapies (range)

2 (1–6) N/A 1 (1–3) NR

Refractory to last prior rituximab therapy, %

39 N/A NR NR

FLIPI risk, Low / Intermediate / High, %

30 / 33 / 37 17 / 25 / 58* 33 / 33 / 33* 33 / 33 / 33

>7 3 dBulky disease >7 cm: 21% 5 cm: 56% NR

>7 cm or 3 nodes from sites >3 cm: 18%

ORR, % 86 96* 93# 41*

CR, % 53 71* 41# 10‡

Gr 3/4 anemia, % 3 1§ 2 NR

Gr 3/4 neutropenia, % 27 NR 36 3

Gr 3/4 thrombocytopenia, % 6 3§ 9 0

*FL patients only; #indolent lymphoma patients only; †weekly regimen reported; ‡CR/Cru; §of assessable cycles

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Phosphatidylinositol 3-Kinase (PI3K) Signaling Pathway

CAL-101 Clinical Response RatePopulation No.

EvaluableNo. of PR Response

RateNo. of SD on study

Indolent NHL 15 9 60% 3

Aggressive NHL

MCL

DLBCL

12

7

5

6

6

0

50%

86%

0%

1

CLL 17 4 24% 7

AML 9 0 0% 1

PR=partial response; SD=stable disease

Flinn et al, ASH 2009

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Phase I study of the Btk inhibitor PCI-32765 in relapsed “aggressive NHL”

• Bruton’s tyrosine kinase (Btk) is a downstream mediator of B-cell receptor signaling

• Dosing: 1.25 mg/kg/day with escalation to 2.5, 5.0, 8.3, 12.5, 17.5 mg/kg12.5, 17.5 mg/kg

• 29 patients have been enrolled on cohorts 1-4 (12 FL, 7 CLL/SLL, 4 DLBCL, 4 MCL, 2 MZL)

• One DLT (neutropenia), most AEs have been < grade 2

Response Patients (n=19)

Advani et al. ASCO 2010, Abstract 8012

ORR 42%

CR 1 (SLL)

PR 7 (4 CLL/SLL, 2 MCL, 1 FL)

Summary

• Novel anti-CD20 antibodies are under evaluation but potential advantages relative to rituximab remainpotential advantages relative to rituximab remain unclear

• New antibodies with different targets are under exploration, largely in combination with rituximab

• “older-newer” drugs are under evaluation in NHL in combination regimens

• Various new agents are safe and activeVarious new agents are safe and active• Drug development in NHL is becoming more complex

due to disease and treatment heterogeneity