Post on 22-Oct-2018
12/16/2010
1
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.
12/16/2010
2
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
12/16/2010
3
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.
12/16/2010
4
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
12/16/2010
5
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
12/16/2010
6
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
12/16/2010
7
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%)
12/16/2010
8
Anti-lymphoma antibodies in the clinic
Cheson and Leonard, NEJM 2008
Multicenter Epratuzumab + RituximabStrauss, et al, JCO 2006
Duration of Response
12/16/2010
9
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
12/16/2010
10
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)
12/16/2010
11
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
12/16/2010
12
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
12/16/2010
13
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:
12/16/2010
14
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
12/16/2010
15
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
12/16/2010
16
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
12/16/2010
17
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
12/16/2010
18
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