Faculty Disclosures
The faculty reported the following relevant financial
relationships that they or their spouse/partner have with
commercial interests:
• Presenter, MD: Research: Pharma Company; Consultant:
Pharma Company TO BE FILLED IN BY
PRESENTING PHYSICIAN(S)
Off-label discussion disclosure:
This educational activity may contain discussion of published and/or investigational
uses of agents that are not indicated by the Food and Drug Administration. PCME does
not recommend the use of any agent outside of the labeled indications. Please refer to
the official prescribing information for each product for discussion of approved
indications, contraindications and warnings. The opinions expressed are those of the
presenters and are not to be construed as those of the publisher or grantors.
Steering Committee Disclosures
The Steering Committee reported the following relevant
financial relationships that they or their spouse/partner have
with commercial interests:
• John P. Leonard, MD: Advisor/Consultant: Abbott, Biotest, Calistoga
Pharmaceuticals/Gilead, Celgene, Cell Therapeutics, Cephalon,
GlaxoSmithKline, Hospira, Immunomedics, Johnson & Johnson,
Medimmune, Millennium Pharmaceuticals, Morphosys, Sanofi Aventis,
Seattle Genetics
• Julie Vose, MD, MBA: Research Grant: Allos Therapeutics, BristolMyers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte Corp.,
Millennium Pharmaceuticals, Onyx Pharmaceuticals, Pharmacyclics,
S*Bio Pte. Ltd, Sanofi-Aventis, US Biotest
Non-faculty Disclosures
Non-faculty content contributors and/or reviewers reported
the following relevant financial relationships that they or their
spouse/partner have with commercial interests:
Latha Shivakumar, PhD; Bradley Pine; Blair St. Amand;
Jay Katz; Paul M. Barr, MD: Nothing to Disclose
Educational Objectives
At the conclusion of this activity, participants should be able
to demonstrate the ability to:
• Review the current approaches for the treatment of
relapsed/refractory NHL
• Compare the various available treatments and choose the
optimal treatment based on patient characteristics and
recently presented data from ongoing clinical studies in
relapsed/refractory NHL
• Identify key investigational agents from ongoing clinical
studies in relapsed/refractory NHL
Paper Audience Response Questions
• During the course of the
program Audience
Response Questions will be
asked to determine the
current knowledge of the
audience
• These questions will not be
graded and are for
outcomes purposes only
• Please record your answers
on your evaluation form
located in your packet
Non-Hodgkin Lymphoma (NHL)
• Most common hematological cancer
• Seventh-most common cancer in United States
• Approximately 65,000 cases of NHL diagnosed in
2010
• More than 20,000 deaths from NHL reported in 2010
• As of 2007, approximately 430,000 people were living
with a history of NHL in the United States
American Cancer Society (ACS). http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf.
Flowers CR, et al. CA Caner J Clin. 2010;60(6):393-408.
National Cancer Institute (NCI). http://www.cancer.gov/cancertopics/types/non-hodgkin.
SEER Stats Fact Sheet: Non-Hodgkin Lymphoma. http://seer.cancer.gov/statfacts/html/nhl.html.
Frequency of NHL Subtypes In Adults
Mantle cell (6%)
Follicular lymphoma
(22%)
Peripheral T-cell (6%)
Other subtypes with a
frequency 2% (9%)
Small lymphocytic
lymphoma (6%)
Composite
lymphomas (13%)
Marginal zone
B-cell lymphoma
MALT type (5%)
Diffuse large
B-cell (31%)
MALT = mucosa-associated lymphoid tissue.
Armitage JO , Weisenberger DD. J Clin Oncol. 1998;16:2780-2795.
Marginal zone
B-cell lymphoma
nodal type (1%)
Lymphoplasmacytic
lymphoma (1%)
Two Major Lymphoma Clinical Paradigms
• Aggressive histologies—diffuse large B cell
– Practical objective of treatment: cure
– Reasonably good clinical prognostic tools
– Most patients treated the same (R-CHOP)
– Unmet need: one-third not cured; reduce toxicity of treatment
• Indolent histologies
– Practical objective of treatment: long disease control
– Fair clinical prognostic tools
– Treatment choice balances efficacy and toxicity
– Unmet needs: cures, rational treatment selection
R-CHOP = cyclophosphamide, doxorubicin, vincristine, and prednisolone, with rituximab.
Emerging Prognostic Tools for FL
• Clinical
– IPI, FLIPI, FLIPI-2
• Pathologic
• Molecular profiling
• Response-based
– MRD, CR vs PR, PET
– Duration of current/prior response
– Interesting potential, but limited data to date, indicating that
these should be used to guide therapy or drug development
FL = follicular lymphoma.; IPI = International Prognostic Index; FLIPI = Follicular Lymphoma International Prognostic Index;
FLIPI-2 = Follicular Lymphoma International Prognostic Index 2; MRD = minimal residual disease; CR = complete response;
PR = partial response; PET = positron emission tomography.
Overall Survival In FL by FLIPI
L Elevated LDH
A Age ≥60
S Stage III/IV
H Hemoglobin <120 g/L
Survival Probability
No Nodal regions 4
1.0
Intermediate risk
0.6
High risk
0.4
0.2
0
Risk Group
Low
Intermediate
A
High
No. of Factors
0-1
2
3-5
LDH = lactate dehydrogenase; OS = overall survival.
Adapted from Solal-Celigny et al. Blood. 2004;104:1258.
Low risk
0.8
P < 10-4
0
1
2
% of Patients
36
37
27
3
y
4
5
5-y OS (%)
90.6
77.8
52.5
6
7
10-y OS (%)
70.7
50.9
35.5
Current Treatment Options in
Indolent Lymphoma
• Observation
• Single-agent rituximab ± maintenance
– Can adding other biologics enhance activity without major toxicity?
• Chemotherapy + rituximab ± maintenance
– What is the best chemotherapy?
– What is the role of maintenance rituximab?
• RIT
– Alone or as consolidation
• SCT options in first (second, later) remission
• Novel/investigational agents
RIT = radioimmunotherapy; SCT = stem cell transplantation.
Managing Patients With
Relapsed and Refractory FL
Outcomes With Sequential
Chemotherapy in FL—1995
• 212 patients, newly diagnosed FL over 20 years
• Treated generally with chlorambucil, CVP, CHOP
CVP = cyclophosphamide, vincristine, and prednisone.
Johnson PWM et al. J Clin Oncol. 1995;13(1):140-147.
1st Line
Median
Response
Duration
(months)
31
Survival
From Response
(years)
9.6
2nd Line
13
4.9
3rd Line
13
3.5
4th Line
6
1.2
Limitations of These Data
• Retreatment with same agents versus different
approaches
• Pre-rituximab era
• New therapeutic options now available
• More rigorous monitoring/surveillance common now
– For better or worse
Case 1
• A 60-year-old male presented with follicular, grade 2 NHL
with symptomatic diffuse LAN in the 3- to 4-cm range; he is
treated with R-CHOP × 6 cycles and then observed.
• 2.5 years later, he presents with axillary and abdominal
LAN in the 3- to 4-cm range on routine imaging
• Blood chemistries, LDH, and complete blood counts are
normal, and bone marrow biopsy shows no evidence of
involvement with lymphoma
LAN = Lymphadenopathy
ARS Question 1
Please record your answer on your evaluation form now.
The preferred management for this patient is:
A.
Close observation and monitoring
B.
Single-agent rituximab × 4 doses
C.
Single-agent rituximab + maintenance rituximab
D.
Rituximab-fludarabine combination regimen
E.
Bendamustine-based regimen
F.
RIT
G.
RICE or similar regimen
H.
RICE or similar regimen, followed by ASCT
RICE = rituximab, ifosfamide, carboplatin, etoposide; ASCT = autologous SCT.
ARS Question 1
The preferred management for this patient is:
A.
Close observation and monitoring
B.
Single-agent rituximab × 4 doses
C.
Single-agent rituximab + maintenance rituximab
D.
Rituximab-fludarabine combination regimen
E.
Bendamustine-based regimen
F.
RIT
G.
RICE or similar regimen
H.
RICE or similar regimen, followed by ASCT
All the answers are reasonable choices for this patient.
RICE = rituximab, ifosfamide, carboplatin, etoposide; ASCT = autologous SCT.
Considerations in Choice of Therapy for
Second-line Treatment
•
•
•
•
•
Consider transformation
Symptoms
Bulk of disease
Age and performance status
Efficacy of last treatment
– Response, time since, tolerability
– Similar versus something different
• Patient preferences
Specific Considerations for This Patient
•
•
•
•
Transformation clinically unlikely
No symptoms
Nonbulky disease
Age and performance status
– SCT option, perhaps
• Last treatment
– Effective but would prefer more durability
Treatment Options for This patient
• Chemotherapy + rituximab
– Bendamustine favored over fludarabine
• Single-agent rituximab
– Asymptomatic, but unlikely to be durable
• RIT
– Well tolerated, chance at durability
• Combination chemotherapy + SCT
– Potentially durable, though toxicity
Rummel MJ et al. Blood 2010;116: Abstract 856.
Chemotherapy Data for
Recurrent Indolent NHL (Until Recently)
Regimen
N
RR
TTF/PFS (mo)
Rituximab monotherapy
166
48%
13
FCM
30
70%
21
Rituximab + FCM
35
94%
Not reached
(median follow-up: 3 y)
CHOP
231
72%
20
R-CHOP
234
85%
33
FCM = fludarabine, cyclophosphamide, mitoxantrone; RR = relative risk; TTF = time to treatment failure; PFS = progression-free survival.
McLaughlin P et al. J Clin Oncol. 1998;16:2825; Forstpointner R et al. Blood. 2004;104:3064; Van Oers. Blood. 2006;108:3295; Vose. J Clin Oncol.
2000;18:1316; Witzig. J Clin Oncol. 2002;20:2453; Witzig TE et al. J Clin Oncol. 2002;20:3262; Horning. J Clin Oncol. 2005;23:712.
Caveats From Data in This Population
• Heterogeneous prior therapies
• Heterogeneous prior use of rituximab
• Heterogeneous prior use of R-CHOP and rituximabbendamustine
• How much these data apply to an individual patient today
is unclear
• Expect that, with better upfront therapy, a “resistant”
patient will be “worse” with respect to prognosis
Phase II Trial of Bendamustine in Rituximabrefractory NHL: Results
Multicenter, nonrandomized, open-label, single-arm trial
Patient Subset
N
ORR
CR/CRu
PR
DOR (mo)
Evaluable patients
74
77%
34%
43%
6.67
Patients with ≥2 prior therapies
40
75%
30%
45%
5.3
Prior ASCT
6
67%
17%
50%
2.6
Alkylator-refractory patients
23
61%
13%
48%
7.7
Fludarabine-refractory patients
8
62%
FL
45
81%
37%
44%
SLL
11
63%
36%
27%
LPL
1
100%
100%
0
MZL
2
100%
50%
50%
Transformed
15
66%
13%
53%
Prior Therapies
NR
Histology
NR
Cru = unconfirmed complete response; DOR = duration of response; NR = not reported; ORR = overall response rate; SLL = small lymphocytic
lymphoma; LPL = lymphoplasmacytic lymphoma; MZL = marginal zone lymphoma..
Friedberg JW et al. J Clin Oncol. 2008;26:204-210.
Bendamustine in Rituximab-refractory NHL: PFS
PFS (All Treated Patients)
PFS (Indolent vs Transformed)
CI = confidence interval.
Friedberg JW et al. J Clin Oncol. 2008;26:204-210. Reprinted with permission. © 2008 American Society of Clinical Oncology.
Bendamustine + Rituximab in Relapsed/
Refractory Indolent and MCL: Efficacy
Efficacy:
FL
ORR
CR
PR
No. of Patients (%)
MCL
Marginal Zone
SLL
(n = 24)
(n = 17)
23 (96%)
Total
(n = 16)
(n = 6)
(n = 63)
17 (100%)
12 (75%)
5 (83%)
57 (90%)
17 (71%)
9 (53%)
8 (50%)
4 (67%)
38 (60%)
6 (25%)
8 (47%)
4 (25%)
1 (17%)
19 (30%)
 Median duration of PFS: 30 months
 Median OS: 65 months
Safety:
Grade 3
Grade 4
% of Grade 3/4
Leukocytopenia
32
3
16%
Thrombocytopenia
6
1
3%
Anemia
2
-
1%
MCL = mantle cell lymphoma.
Robinson KS, et al, J Clin Oncol 2008; 26: 4476-79; Rummel ASCO 2007, Abstract 8034.
Radiolabeled Anti-CD20 Antibodies
• Yttrium-90 ibritumomab tiuxetan (Zevalin®)
• Iodine-131 tositumomab (Bexxar®)
• Pretargeted (investigational)
– 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 component
Manageable radiation safety issues
Toxicity is principally infusion-related and hematologic
– Baseline hematologic status relevant
– Blood 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
ARS Question 2
Please record your answer on your evaluation form now.
Where should you consider the use of radioimmunotherapy
(RIT) in NHL?
A. Relapsed low-grade/transformed NHL
B. Chemotherapy-refractory low-grade NHL
C. Rituximab-refractory low-grade NHL
D. Transformed NHL
E. All of the above
ARS Question 2
Where should you consider the use of radioimmunotherapy
(RIT) in NHL?
A. Relapsed low-grade/transformed NHL
B. Chemotherapy-refractory low-grade NHL
C. Rituximab-refractory low-grade NHL
D. Transformed NHL
E. All of the above
Radioimmunotherapy (RIT) for NHL
• Current data clearly support use in:
– Relapsed low-grade/transformed NHL

Advantages over rituximab + chemotherapy 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
Remission Duration of Patients Receiving
ASCT for FL in Second or Later Remission
Case
Rohatiner AZ et al. J Clin Oncol. 2007;25:2554-2559.
Case Discussion Continued:
• Our patient (now 64 years old) with follicular, grade 2 NHL with
local disease status post R-CHOP × 6 cycles, relapsed 2.5
years later, and received bendamustine + rituximab; he had a
partial response for 15 months and now presents with 2-cm
diffuse LAN, asymptomatic
• Platelet count is 90,000, and bone marrow biopsy shows 30%
involvement of the intertrabecular space with FL cells; LDH is
normal, as are blood chemistries
• He is interested in nonchemotherapeutic and/or investigational
approaches
LAN = Lymphadenopathy
ARS Question 3
Please record your answer on your evaluation form now.
The preferred management for this patient is:
A.
Novel anti-CD20 antibody
B.
Lenalidomide
C.
Proteosome inhibitor
D.
PI3 kinase inhibitor
E.
Bruton’s tyrosine kinase (Btk) inhibitor
F.
RIT
G.
RICE or similar regimen, followed by ASCT
ARS Question 3
The preferred management for this patient is:
A.
Novel anti-CD20 antibody
B.
Lenalidomide
C.
Proteosome inhibitor
D.
PI3 kinase inhibitor
E.
Bruton’s tyrosine kinase (Btk) inhibitor
F.
RIT
G.
RICE or similar regimen, followed by ASCT
All the answers except RIT are reasonable options for the
management of this patient. RIT is not a reasonable option for a
Patient with a platelet count of 90,000 and 30% marrow involvement.
Comparison of Novel Anti-CD20s
Antibody
Specificity
Activity (vs Rituximab)
Additional Features
Type
Isotype
CDR
CDC
ADCC
Apoptosis
Ofatumumab
I
IgGI
Human
+++
=
=
Binds small extracellular part
of CD20; completely human;
slower off-rate
PRO131921
I
IgGI
Humanized
=
++
=
Enhanced affinity for
FcγRII
Veltuzumab
I
IgGI
Humanized
=/+
=
=
Slower off-rate
AME-133
I
IgGI
Humanized
=
+
=
Enhanced affinity for CD20
Tositumomab
II
IgG2a
Murine
-
=
++
Bound to radio-isotopes
GA-101
II
IgGr
Humanized
-
+++
+++
High affinity for FcγRII; strong
induction of apoptosis
Ig = immunoglobulin; CDC = complement-dependent cytotoxicity; ADCC = antibody-dependent cellular cytotoxicity.
Adapted from Van Meerten T, Hagenbeek A. Neth J Med. 2009;67:251-259.
Ofatumumab
Ofatumumab
binding site
Rituximab
binding site
• Human CD20 monoclonal antibody that
binds to 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 FL3
– 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 JL et al. Blood. 2004;104:1793-1800.
3. Hagenbeek A et al. Blood. 2008;111(12):5486-5495.
CLL = chronic lymphocytic leukemia.
Ofatumumab in Relapsed/Refractory FL—
Response Rates
Number of patients (%)
100
80
ORR
60
13%
40
10%
11%
20
95% CI
0
Ofatumumab 500 mg
(N=30)
Ofatumumab 1000 mg
(N=86)
All patients (N=116)
• 87% and 91% of patients in the 500-mg and 1000-mg groups, respectively, completed all 8
infusions of ofatumumab
• No difference in primary endpoint (ORR) between the 500-mg and 1000-mg groups; thus, 2
groups were combined for secondary endpoint analyses
Hagenbeek et al, ASH 2009.
GA101: Mechanisms Of Action—Type I
Versus Type II Antibodies
Increased direct cell death
Increased ADCC
Unique type II epitope and elbow-hinge
modification
Via increased affinity to the “ADCC
receptor” FcgRIIIA
Effector
cell
B cell
CD20
Lower CDC activity
FcgRIIIa
Due to recognition of type II
epitope
Complement
Open-label, Phase II, Randomized Study of
GA101 vs Rituximab
Rituximab
375 mg/m2
IV qwk × 4
GA101
1000 mg
IV qwk × 4
25 months
after C4D1
MAINTENANCE
Rituximab
375 mg/m2 IV q2mo × 12
End of maintenance visit
- Relapsed
CD20+ iNHL
- Prior
response ≥6
months to last
rituximab
regimen
R
A
N
D
O
M
I
Z
E
End of induction visit
INDUCTION
+28–42 days
after C4D1
GA101
1000 mg IV q2mo × 12
PD
discontinue
treatment
CT
Sehn et al. ASH 2011.
CT
CT
CT
1
3
6
CT
12
Time (mo)
CT
18
CT
25
GA101 Versus Rituximab: Best Overall
Response by in FL Patients
Response, n (%)
Rituximab
(n = 75)
GA101
(n = 74)
35 (46.7)
45 (60.8)
CR/CRu
15 (20.0)
20 (27.0)
PR
20 (26.7)
25 (33.8)
ORR
Difference in ORR, % [95% CI]
P value (1-sided, χ2 test)
Sehn et al. ASH 2011.
14.1 [–2.5; 30.8]
.04
PFS Assessed by Investigators in FL Patients
Survival probability
Randomized treatment
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Rituximab
GA101
Hazard ratio [95% CI]: 1.1 [0.6; 1.8]
0
3
6
9
12
15
18
21
24
27
3
4
0
2
0
0
0
0
Study month
Patients at risk, n
Rituximab 75
GA101 74
Patients with an event, n (%)
Median time to event, mo
95% CI for median time to event
Sehn et al. ASH 2011.
63
61
56
55
48
45
20
26
15
19
Rituximab (n = 75)
GA101 (n = 74)
26 (34.7)
29 (39.2)
17.4
17.3
[11.8; – ]
[13.0; – ]
IMIDs in Lymphoid Malignancies
Thalidomide’s Various Effects in Myeloma
• IMID effects
– Inhibits TNF
– Inhibits angiogenesis

(bFGP, VEGF)
– Stimulates T cells
(CD8+)
– Inhibits IL-12
– Induces apoptosis
– Alters cytokines
– Affects stromal cells
– Inhibits prosurvival
factors (Akt)
Cool RM et al. Pharmacotherapy. 2002;22:1019; D’Amato RJ et al. Proc Natl Acad Sci U S A. 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.
Lenalidomide for Relapsed/Refractory
Indolent Lymphoma
Study
No. of Pts
Regimen
Efficacy
Witzig et al
43
Lenalidomide monotherapy
ORR: 23%, CR: 7%
PFS: 4.4 mo; DOR >16.5 mo
Dutia et al
16
Lenalidomide + R (R2)
ORR: 75%, CR: 31%
PFS: 12 mo
Ahmadi et al
15
Lenalidomide, dexamethasone, and R
ORR: 53%, CR: 33%
PFS: 86% at 10.9 mo
PFS for Patients Receiving Lenalidomide + R
100
Survival
(%)
80
60
40
20
0
0
5
10
15
Time (mo)
20
Witzig. J Clin Oncol. 2009;27:5404; Dutia. ASH. 2009 (abstr 1679); Ahmadi. ASH. 2009 (abstr 1700).
Single-agent Bortezomib in Relapsed
Indolent Lymphoma
Study
O’Connor, 2005
Goy, 2005
Strauss, 2006
Subtype
Evaluable
Patients (N)
CR/CRu
PR
OR
FL
9
1/1
5
7 (77%)
MZL
2
0
2
2 (100%)
SLL
3
0
0
0
FL
5
0/1
0
1 (20%)
SLL
4
1/0
0
1 (25%)
WM
2
0
1
1 (50%)
FL
11
0
2
2 (18%)
WM
5
0
2
2 (40%)
WM = Waldenström’s macroglobulinemia.
O’Connor OA et al. J Clin Oncol. 2005;23:676-684.
Goy A. J Clin Oncol. 2005;23:667.
Strauss. J Clin Oncol. 2006;24:2105.
Promising New Agents in FL
• Antibodies
– New anti-CD20
– Anti-CD22, CD80, CD30, CD40, other targets
• Immunostimulatory molecules
• Other categories
– Proteosome inhibitors
– mTOR inhibitors
– PI3K inhibitors (CAL-101)
– IMIDs (lenalidomide)
– Btk inhibitors (PCI-32765)
mTOR = mammalian target of rapamycin; PI3 = phosphoinositide-3 kinase.
B-cell Receptor Signalling and Inhibition in
B-cell Malignancies
Stevenson FK et al. Blood. 2011;118:4313-4320.
CAL-101 Is an Orally Bioavailable Small
Molecule That Inhibits PI3K Delta Potently
and Selectively
CAL-101
Alpha
Beta
Gamma
Delta
Cell-based
Activity
PDGF-induced
pAKT
LPA-induced
pAKT
fMLP-induced
CD63+
FcR1-induced
CD63+
EC50 (nM)
>20,000
1900
3000
8
Class I
PI3K Isoform
• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions
• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK
• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)
Lannutti. Blood. 2011.
Single-agent CAL-101 Has Significant Antitumor
Activity in Patients With Indolent NHL and CLL
Best On-Treatment Change in Tumor Size
(ITT Analysis)
+100
% Change in Lymph Node Area
+75
+50
+25
iNHLa
CLLa
(N=30)
(N=54)
0
-25
-50b
-75
-100
a Patients receiving single-agent CAL-101 at starting doses ranging from 50 to 350 mg/dose BID
Inevaluable (patients without a follow-up tumor assessment)
b Criterion for nodal response [Cheson 2007, Hallek 2008]
Kahl, ASH 2010 (abstract 1777); Furman, ASH 2010 (abstract 55).
Combination Therapy Had Effects on Lymphadenopathy in All
Evaluable Patients With Indolent NHL Receiving CAL-101 + B or R
Change in Lymph Node Area, %
Best On-Treatment Change in Tumor Size
+100
+75
+50
+25
CAL-101 + B
(N=15)
0
CAL-101 + R
(N=12)
-25
-50a
-75
-100
Inevaluable (patients without a follow-up tumor assessment)
a Criterion for response [Cheson 2007]
Leonard et al. ICML Lugano 2011.
Phase I Study of the Btk Inhibitor, PCI-32765,
in Relapsed/Refractory B-cell Malignancies
• Btk is a downstream mediator of B-cell receptor signaling
• Dosing: 1.25 mg/kg/d, with escalation to 2.5, 5.0, 8.3, 12.5, 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 less than grade 2
Response
Patients (n = 19)
ORR
42%
CR
1 (SLL)
PR
7 (4 CLL/SLL, 2 MCL, 1 FL)
DLBCL = diffuse large B-cell lymphoma; DLT = dose-limiting toxicity; AEs = adverse events.
Advani et al. ASCO 2010 (abstract 8012).
One Approach to Treat a Patient With
Recurrent FL Post First-line Chemotherapy
Needing Treatment
• Late relapse (>2 years or so)
– Many options; decision based on tolerability/efficacy balance
• Early relapse (<2 years or so)
–
–
–
–
Chemotherapy
RIT
SCT
Novel/investigational agents
Managing Patients with Mantle
Cell Non-Hodgkin Lymphoma
Case 2
• 56-year-old male who presents with diffuse
lymphadenopathy and splenomegaly
• Biopsy shows diffuse MCL
• MIPI score: intermediate
• He received R-hyperCVAD/MTX/cytarabine, followed by
ASCT
• Relapse in same areas 8 years later
MIPI = Mantle Cell International Prognostic Index; R-hyperCVAD = rituximab–hyperfractionated
cyclophosphamide, vincristine, doxorubicin, dexamethasone; MTX = methotrexate.
CT Scan at Diagnosis
Case Study: Pathology
MCL showing germinal center overrun by
broadened mantle zone in lymph node
The MIPI
• 4 factors independently
associated with OS
Age
PS
LDH
WBC
• Risk distribution
– Low: 44% (score: <5.7)
– Intermediate: 35% (score:
5.7-6.2)
– High: 21% (score: >6.2)
1.0
0.8
Probability of OS
–
–
–
–
Survival After Diagnosis by MIPI
0.6
0.4
Low, median
not reached
Int, median: 51
High, median: 29
0.2
0
0
WBC = white blood count; ECOG = Eastern Cooperative Oncology Group;
ULN = upper limit of normal.
Hoster E et al. Blood. 2008;111:558-565.
12
24
36
48
60
72
84
96
mo
Formula for calculating MIPI:
[0.03535 x age (years)] + 0.6978 (if ECOG > 1) +
[1.367 × log10(LDH/ULN)] +
[0.9393 × log10(WBC count)]
Simplified MIPI
•
0-3 points applied for each prognostic factor; sum
reflects MIPI score
- Low risk: 0-3 points
- Intermediate risk: 4-5 points
- High risk: 6-11 points
Points
Age (y)
ECOG PS
LDH/ULN
WBC (cells/mm3)
0
<50
0-1
<0.67
<6700
1
50-59
--
0.67-0.99
6700-9999
2
60-69
2-4
1.00-1.49
10,000-14,999
3
≥70
--
≥1.50
≥15,000
Hoster E et al. Blood. 2008;111:558-565.
MCL
• 5%-10% of B-cell NHLs,
with moderately aggressive course
• 74% male; median age, 63 years
• >80% stage III/IV, including marrow
involvement
• Extranodal sites common: lymphomatous
polyposis, gastrointestinal, soft tissue,
or leukemic phase
• Prognosis poor: chemoresponsive, but
median survival 30 months with
CHOP-type chemotherapy
Fisher RI et al. Hematology Am Soc Hematol Educ Program. 2004;221-236.
Front-line Chemotherapy Options for
Patients With MCL
R-CHOP
Modified HyperCVAD
R-CHOP/RIT
R-Bendamustine
Less intensive
vs
R-CHOP/ASCT
R-HyperCVAD/MTX/Ara-C
R-HyperCVAD/MTX/Ara-C/ASCT
Nordic
More intensive
ARS Question 4
Please record your answer on your evaluation form now.
What second-line therapy would you choose for this patient
(now age 64 years)?
A. Purine analogue–based regimen
B. Bortezomib ± rituximab
C. Lenalidomide
D. Bendamustine-based regimen (BR, BVR)
E. Experimental therapy
BR= Bendamustine + rituximab; BVR= Bendamustine + bortezomib + rituximab
ARS Question 4
What second-line therapy would you choose for this patient
(now age 64 years)?
A. Purine analogue–based regimen
B. Bortezomib ± rituximab
C. Lenalidomide
D. Bendamustine-based regimen (BR, BVR)
E. Experimental therapy
All the answers are reasonable choices for this patient.
The patient was put on a bendamustine-based regimen.
BR= Bendamustine + rituximab; BVR= Bendamustine + bortezomib + rituximab
Recommendations for Second-line Therapy
• Suggested regimens or radiotherapy or clinical trial
Suggested Regimens
Bendamustine ± R
Bortezomib ± R
Cladribine + R
Fludarabine-based regimens: FC ± R, FCMR, FMR
Lenalidomide ± R
PCR
PEPC ± R
• Second-line consideration of allogeneic transplantation
F = fludarabine; C = cyclophosphamide’ M = mitoxantrone; R = rituximab; P = pentostatin; PEPC =
prednisone, etoposide, procarbazine, cyclophosphamide.
NCCN clinical practice guidelines: non-Hodgkin lymphomas. 2011.
Second-line Therapy for MCL
• Purine analogue–based regimen
– ORR: 50% to 70%
• Bortezomib ± rituximab
– ORR: 30% to 50%
• Lenalidomide
– ORR: 30% to 50%
• Bendamustine-based regimen (BR, BVR)
– ORR: 50% to 70%
• Experimental therapy
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
allogeneic SCT at any time
• Schema: 28-day cycle
Day 1
Day 4
Bendamustine 90 mg/m2
X
X
Rituximab 375 mg/m2
X
Bortezomib 1.3 mg/m2
X
Friedberg et al. Blood. 117 (10): 2801-12.
X
Day 8
Day 11
X
X
Response by Histology
Category
Response Rate % (95% CI)
Follicular NHL
93% (69-99%)
Mantle cell
71% (36-92%)
Friedberg et al. Blood. 117 (10): 2801-12.
ARS Question 5
Please record your answer on your evaluation form now.
What are the major acute toxicities associated
with the BVR regimen?
A. Anemia, thrombocytopenia, neutropenia
B. Peripheral neuropathy
C. Secondary malignancies
D. A and B
E. A, B, and C
ARS Question 5
What are the major acute toxicities associated
with the BVR regimen?
A. Anemia, thrombocytopenia, neutropenia
B. Peripheral neuropathy
C. Secondary malignancies
D. A and B
E. A, B, and C
Monitoring After BVR
• Major acute toxicities
– Anemia, thrombocytopenia, neutropenia
– Peripheral neuropathy
– Nausea/vomiting, diarrhea
• Long-term toxicities (>1 month off chemotherapy)
– Prolonged thrombocytopenia
– Peripheral neuropathy
Case Discussion Continued: Relapse #2
• The patient stays in partial remission for 9 months and
then has a progression in multiple lymph node sites
• He is considering several clinical trials
– Lenalidamide ± rituximab
– Cal-101
– PCI-32765
Rituximab in Combination With Lenalidomide
in MCL*
• Phase I/II study in relapsed/refractory MCL
• MTD: lenalidomide 20 mg plus rituximab 375 mg/m2
Objective Response
% (n/N)
Overall response
70% (7/10)
CR
PR
SD
30% (3/10)
40% (4/10)
10% (1/10)
Response duration
8 months
*Wang M et al. ASH 2009: Abstract 2719.
CAL-101 Is an Orally Bioavailable Small
Molecule That Inhibits PI3K Delta Potently
and Selectively
CAL-101
Alpha
Beta
Gamma
Delta
Cell-based
Activity
PDGF-induced
pAKT
LPA-induced
pAKT
fMLP-induced
CD63+
FcR1-induced
CD63+
EC50 (nM)
>20,000
1900
3000
8
Class I
PI3K Isoform
• Selectivity relative to Class I PI3K isoforms involved in insulin signaling and other physiological functions
• No off-target activity against Class II or III PI3K, mTOR, or DNA-PK
• No off-target activity seen in screen of >350 protein kinases (Ambit KINOMEscan™)
Lannutti. Blood. 2011.
Cal-101 in B-cell Lymphoma
Best Response
Best on-treatment change in tumor size
(ITT analysis)
% Change in Lymph Node Area
+100
+75
+50
+25
MCL
(n = 21)
iNHL
(n = 30)
0
-25
-50*
-75
-100
Inevaluable (patients without a follow-up tumour assessment; includes two patients with
LPL with no adenopathy)
* Criterion for response [Cheson 2007, Hallek 2008]
Kahl B et al. Blood (ASH Annual Meeting Abstracts). 2010;116:1777.
PCI-32765
Novel Small-molecule Btk Inhibitor
•
Forms a specific and irreversible
bond with cysteine-481 in Btk
•
Potent Btk inhibition
O
NH 2
–
N
N
N
IC50 = 0.5 nM
• Orally available
N
•
N
O
Once-daily dosing results in 24hour sustained target inhibition
Best Response
71%
69%
65%
CR
16%
16%
15%
PR
SD
PD
16%
20%
13%
55%
BTZ-naïve
(n = 31)
BTZ= Bortezomib
*Wang et al. ASH 2011; Abstract 442
18%
15%
50%
BTZ-exposed
(n = 20)
53%
Total
(n = 51)
Second-line Therapy Options for MCL
• Evaluate age and overall condition of the patient—
transplantation-eligible?
• Standard options
– Purine analogue
– Bendamustine
– Bortezomib
– Autologous or allogeneic SCT in CR2
• Investigational options
– Lenalidamide
– BCR pathway agents
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