waldenström’s macroglobulinemia: similar but different to myeloma? steve treon md, ma, phd dana...
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Waldenström’s macroglobulinemia:Similar but Different to Myeloma?
Waldenström’s macroglobulinemia:Similar but Different to Myeloma?
Steve Treon MD, MA, PhD
Dana Farber Cancer Institute
Harvard Medical School
Boston, Massachusetts, United States
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Advances in the Biology of Waldenstrom’s Macroglobulinemia
Closing Ceremony at the Acropolis, Athens, Greece 2002Closing Ceremony at the Acropolis, Athens, Greece 2002
Second Intl Workshop on Waldenstrom’s Macroglobulinemia
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Clinicopathologic Definition of WMClinicopathologic Definition of WM
• Pathologic diagnosis of lymphoplasmacytic lymphoma using REAL/WHO criteria.
• Presence of a monoclonal IgM protein, irrespective of serum level.
IWWM2, ATHENS 2002Owen RG, et al. Semin Oncol. 2003;30(2):110-115.
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Lack of relationship between serum IgM levels and BM involvement in WM.
Lack of relationship between serum IgM levels and BM involvement in WM.
BM Involvement (%)
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•Cells: lymphocytes, lymphoplasmacytoid cells, plasma cells excess mast cells in association with lymphoid aggregates
•BM: interstitial pattern with diffuse or nodular infiltrates excess mast cells in association with lymphoid aggregates
•LN/SP: diffuse pattern
**
LNBM BM
Lymphoplasmacytic Lymphoma
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• almost always expressed: sIgM, CD19,
CD20, CD22, CD79
• usually expressed: CD25, CD27, FMC7,
BCL-2, CD52
• variable expression: CD5, CD10, CD23
• small population: CD138 (plasma cells)
San Miguel et al, Semin Oncol 2003; Hunter et al, Clin Lymphoma 2005
Immunophenotypic expression of WMImmunophenotypic expression of WM
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Cytogenetics in WMCytogenetics in WM
•del 6q21-25 are commonly observed (30-50%) in WM; •Present in familial and sporadic WM cases; •Absent in IgM MGUS;•IgH (Chr.14) translocations are absent and help distinguish WM from IgM MM.
Schop, Blood 2002; Avet Loiseau , Semin Oncol 2003; Treon, Ann Oncol 2006; Ocio BJH 2007.
FISH for 6q21
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Advances in the Biology of Waldenstrom’s MacroglobulinemiaMicroenvironmental Support in WM by CD40L expressing mast cells.
H
I
J
Tryptase CD40 Ligand
WM-1
WM-2
Tournilhac et al, Ann Oncol 2006
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sCD27 in WM-Mast Cell InteractionssCD27 in WM-Mast Cell Interactions
Mast cells Lymphoplasmacytic cells
Soluble CD27CD70
APRIL
CD40L
TACI, BCMA
CD40
Tournilhac et al, Ann Oncol 2006; Ho et al, Blood 2008
MMP-8
CD27YSGN-70
YAlemtuzumab
CD52
Y
Alemtuzumab
CD52C-kit
Imatinib mesylateX
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Clinicopathologic Manifestations of WM
Clinicopathologic Manifestations of WM
Adenopathy, splenomegaly ≤15%
HCT, PLT, WBC HyperviscositySyndrome:Epistaxis, HA,Impaired vision >4.0 CP
IgM Neuropathy (22%)Cryoglobulinemia (10%)Cold Agglutinemia (5%)Fatigue, Constitutional Sxs
Cytokinemia?
Treon SP et al. Cancer Treat Res. 2008;142:211-242.
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From Dr. Marvin Stone
Funduscopic exam of a WM patient with hyperviscosity syndrome
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Pre
-Phe
resi
sP
ost
-Ph
ere
sis
Cryoglobulinemia in a patient with Waldenstrom’s macroglobulinemiaCryoglobulinemia in a patient with Waldenstrom’s macroglobulinemia
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IgM Related Neuropathies in WMIgM Related Neuropathies in WM
• Observed in about 22% of WM patients
• Most commonly is demyelinating and related to IgM neuropathic antibody.
• Usually sensory and related to antibodies targeting:– Myelin Associated Glycoprotein (MAG)
– Ganglioside M1 (GM1)
– Sulfatide
Courtesy Todd Levine, MD MAG antibody staining
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Genetic PredispositionGenetic Predisposition
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Familial disease predisposition in WMFamilial disease predisposition in WM
• N=1076 consecutive patients with clinicopathological diagnosis of WM
• 26.1% of WM patients have a first or second degree relative with a B-cell LPD.
0%
5%
10%
15%
20%
25%
30%
35%
40%
ALL CLL HCL HD MM MGUS NHL WM
Distribution of B-cell LPD in relatives of 281 Familial WM patients.
Treon et al, ICML 2011.
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Familial Associations in other B-cell LPD
Familial Associations in other B-cell LPD
• Prospective study of 1,948 pts with B-cell LPD
• First/Second Degree Relatives
• CLL (17.5%)
• NHL (12.6%)
• Hodgkin’s (11.9%)
Brown et al, BJH 2008DFCI
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Relative Risk of other B-cell LPD in patients with CLL, MM, and WM Relative Risk of other B-cell LPD
in patients with CLL, MM, and WM
Swedish Registry Data
1st degree Relatives
CLL WM/LPL MM
CLL 8.5 3.4 NS
NHL* 1.9 3.0 NS
MM NS NS 2.1
WM/LPL *Included 20.0 NS
MGUS NS 5.0 2.1
Kristinsson, Int J Cancer 2009; Blood 2009; Goldin, Haematologica 2009.
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GWAS: Copy Number Polymorphisms in GSTM1 and GSTT1 in WM Patients Varies by Family History
GWAS: Copy Number Polymorphisms in GSTM1 and GSTT1 in WM Patients Varies by Family History
* P <0.01 vs. Mixed B-Cell History
GSTM1(-/-) GSTT1(-/-) GSTM1(-/-) & GSTT1(-/-) GSTT1 CN >2WM Only 1/6 (17%)* 1/6 (17%) 1/6 (17%) 1/6 (17%)Mixed B-Cell 9/10 (90%) 4/10 (40%) 4/10 (40%) 0/10 (0%)Sporadic WM 2/5 (40%) 1/5 (20%) 1/5 (20%) 2/5 (40%)
Analysis of GSTM1/T1 Copy Number in WM Patients
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
GSTM1(-/-) GSTT1(-/-) GSTM1(-/-) & GSTT1(-/-) GSTT1 CN >2
WM Only
Mixed B-Cell
Sporadic WM
Hunter et al, ASH 2009
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Impact of familial status in rituximab-naïve patients receiving a rituximab containing regimen.
Impact of familial status in rituximab-naïve patients receiving a rituximab containing regimen.
Response to Therapy
93.974.8
23.2
7555.6
16.70
102030405060708090
100
Overall Major VGPR/CR
SporadicFamilial
p=0.032
P<0.001
p=0.029
Treon et al, ASH 2011
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Familial Disease Is Associated with shorter PFS and Time to Next Therapy
Familial Disease Is Associated with shorter PFS and Time to Next Therapy
0
10
20
30
40
50
60
70
80
90
100
Per
cen
t w
ith
ou
t p
rog
ress
ion
No familial diseaseFamilial disease
PFS
0 10 20 30 40 50 60 70 80 90 100Months
0
10
20
30
40
50
60
70
80
90
100
Per
cen
t w
ith
ou
t p
rog
ress
ion
No familial diseaseFamilial disease
TTNT
0 10 20 30 40 50 60 70 80 90 100Months
Treon et al, ASH 2011
p=0.015p=0.024
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Parameter DFParameterEstimate
StandardError Chi-Square Pr > ChiSq
HazardRatio
Fam Disease 1 -0.59016 0.27386 4.6438 0.0312 0.554
Age 1 -0.02276 0.01320 2.9712 0.0848 0.977
sIgM 1 0.0000498 0.0000573 0.7538 0.3853 1.000
sB2M 1 0.13171 0.05077 6.7293 0.0095 1.141
Hgb 1 0.08309 0.07579 1.2018 0.2730 1.087
Parameter DFParameterEstimate
StandardError Chi-Square Pr > ChiSq
HazardRatio
Fam Disease 1 -0.66490 0.26764 6.1717 0.0130 0.514
IPSS 1 0.20736 0.15232 1.8531 0.1734 1.230
Familial Disease Status in WM is an Independent Prognostic for PFS
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Does the type treatment impact response for familial patients?Does the type treatment impact response for familial patients?
71
100
48.4
100
6.5
80
0
20
40
60
80
100
120
Non-Bortezomib Bortezomib
ORR
Major
VGPR/CR
p=0.0006
p=0.05N=36
Treon et al, ASH 2011
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Impact of Bortezomib-based therapy on PFS in Familial and Sporadic WM Patients.
Impact of Bortezomib-based therapy on PFS in Familial and Sporadic WM Patients.
Familial WM Sporadic WM Familial WM Sporadic WM
Treon et al, ASH 2011
p=0.08p=0.68
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Consensus Panel Recommendations for Initiation of Therapy in WM
Consensus Panel Recommendations for Initiation of Therapy in WM
• Hb ≤10 g/dL on basis of disease
• PLT <100,000 mm3 on basis of disease
• Symptomatic hyperviscosity (>4.0 cp)
• Moderate to severe peripheral neuropathy
• Symptomatic cryoglobulinemia, cold agglutinemia, amyloidosis, or symptomatic autoimmune-related events on the basis of disease
Kyle RA, et al. Semin Oncol. 2003;30(2):116-120.
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Fab
Fc
Fc receptorNatural Killer Cell
CD20WM cell
CD20-Directed RituximabMonoclonalAntibody
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Serum IgM Levels Following Rituximab in Patients With WM
Serum IgM Levels Following Rituximab in Patients With WM
Treon SP, et al. Ann Oncol. 2004;15(10):1481-1483.
P denotes patient-required plasmapheresis for hyperviscosity.
14,000
12,000
00 2 4 6 8 10
Wks
Ser
um
IgM
(m
g/d
L)
10,000
8000
6000
4000
2000
12 14
WM 1WM 2WM 3WM 4WM 5WM 6WM 7WM 8WM 9WM 10WM 11
P
P
P
PP
P
P
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Bystander Release of IL-6 by Monocytes May Account for the Rituximab IgM Flare
1200
1400
1600
1800
2000
2200
2400
2600
IgM
(n
g/m
l)
+mon
ocyt
es+m
onoc
ytes
+
ritu
xim
ab+m
onoc
ytes
+ritu
xim
ab
+an
ti-IL
6 be
ads
IL-6IL-6
MonocytesMonocytes
FcγRIIAFcγRIIA
RituximabRituximab
WM-LPCWM-LPC
IL-6RIL-6R
IgMIgM
IVIgIVIg
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Primary Therapy of WM with Rituximab-Based Options
Regimen ORR CR
Rituximab x 4 25-30% 0%
Rituximab x 8 40-45% 0%
Rituximab/cyclophosphamide i.e. CHOP-R, CVP-R, CPR, RCD
70-80% 8-10%
Rituximab/nucleoside analoguesi.e. FR, FCR, CDA-R
70-90% 5-10%
Rituximab/thalidomide 70% 5%
Rituximab/bortezomib i.e. BDR, VR
70-90% 10-25%
Rituximab/bendamustine 90% NA
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Disease Transformation and MDS/AML Following Nucleoside Analogues in WM
Study Population N Median F/U (mo) Outcome
Leleu et al, JCO 20091
Prev treated with NA vs. non-NA or untreated
439 60 Histologic
Transformation (8%)MDS/AML (5%)
Tamburini et al, Leukemia 20052
Firstline with Fludara/Cyclo 49 41 Histologic
Transformation (10%)
Leblond, JCO 19983
Previously treated with
Fludara71 34 Histologic
Transformation (10%)
Rakkhit et al, ASH 20084
Untreated; 2CDA based
therapy111 NA Histologic
Transformation (9%)
1. Leleu X, et al.J Clin Oncol. 2009;27(2):250-255. 2. Tamburini J, et al. Leukemia. 2005;19(10):1831-1834. 3. Leblond V, et al. J Clin Oncol. 1998;16:2060-2064. 4. Rakkhit R, et al. Blood. 2008;112: Abstract 3065.
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Advances in the Biology of Waldenstrom’s Macroglobulinemia
Lenalidomide-Induced Anemia in WM
Decreased Hct observed in 10/12 pts following first week of lenalidomide monotherapy
Median Hct decrease: 3.9% (31.9% to 28.0%; P = .003)
No evidence for hemolysis; concurrent thrombocytopenia observed in 1 pt
4 patients hospitalized for anemia related complications (Afib, syncope, CHF)
Afib, atrial fibrillation, CHF, congestive heart failure, Hct, hematocrit.Treon SP, et al. Clin Cancer Res 2008
20
22
24
26
28
30
32
34
36
38
1 2 3 4 5 6 7 8 9 10 11 12
Pretherapy Posttherapy
Hem
ato
crit
(%
)
Patient
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Phase I Study of Pomalidomide, Dexamethasone, and Rituximab
(PDR) in WM
Agent Dose Schedule
Pomalidomide 1, 2, 3, 4 mg QD 52 weeks
Dexamethasone 40 mg wkly IV Pre-rituximab
Rituximab 375 mg/m2/wk W1-4; W12-15
•Aggravated Anemia less pronounced•IgM Flare potentiated•CR in Dose Level -1
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Proteasome Inhibitors
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Bortezomib Combination Therapy in WMBortezomib Combination Therapy in WM
• PrimaryBortezomib (1.3 mg/m2/biwkly)/Dexamethasone/Rituximab
ORR 95%; CR 22%; TTP >4 yrs; 30% Grade 3 PN
Bortezomib (1.6 mg/m2/wk)/Rituximab
ORR 92%; CR 8%; 80% 1 Y PFS; No Grade 3 PN
• SalvageBortezomib (1.6 mg/m2/wk)/Rituximab
ORR 81%; CR 5%; TTP 12 months; 5% Grade 3 PN.
Bortezomib (randomized wkly vs biwkly)/Rituximab
ORR 80%; CR 0%; TTP ?; 0% Grade 3 PN.
Treon SP, et al. J Clin Oncol. 2009;27(23):3830-383. Ghobrial IM, et al. Blood. 2010;116: Abstract 832. Ghobrial IM, et al. J Clin Oncol. 2010; 28(8):1422-1428. Agathocleous A, et al. Blood. 2007;110: Abstract 2559.Treon SP, et al. J Clin Oncol. 2009;27(23):3830-383. Ghobrial IM, et al. Blood. 2010;116: Abstract 832. Ghobrial IM, et al. J Clin Oncol. 2010; 28(8):1422-1428. Agathocleous A, et al. Blood. 2007;110: Abstract 2559.
vs. 10-12% in MM!
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Bortezomib-Based Rituximab TherapyBortezomib-Based Rituximab Therapy
Twice A Week Once A Week
CR/VGPR
PFS (?)
Time to Response
Rituximab IgM Flare
Neuropathy
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Primary Therapy of WM with Carfilzomib, Rituximab, Dex (CARD)
Primary Therapy of WM with Carfilzomib, Rituximab, Dex (CARD)
Induction Cycle 1 q21 daysDays 1,2,8,9 Carfilzomib 20 mg/m2 IV; Dexamethasone 20 mg IV.Days 2,9 Rituximab 375 mg/m2
Induction Cycle 2-6 q21 daysDays 1,2,8,9 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.Days 2,9 Rituximab 375 mg/m2
Maintenance Cycles 1-8 q 2 monthsDays 1,2 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.Days 2 Rituximab 375 mg/m2
2 months
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N
N
CH3
COOHN
ClH2C
ClH2C
BendamustineBendamustine
N
N
N
N
NH2
Cl
O
OH
HOCH2
CladribineCladribine
Benzimidazole ringBenzimidazole ring
NCl
Cl
N
P
OO
H
CyclophosphamideCyclophosphamide
Nitrogen mustardNitrogen mustard
Carboxylic acidCarboxylic acid
Bendamustine in WM
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CHOP plus Rituximab (CHOP-R)
Randomization
Bendamustine plus Rituximab (B-R)
B = Bendamustine 90 mg/m2 day 1+2 29+30 57+58 85+86 113+114 141+142 R = Rituximab 375 mg/m2 day 0 29 57 85 113 141
0 1 29 57 85 113 141
RB B-R B-R B-R
Tag
B-R B-R
0 1 22 43 64 85 106
RCHOP CHOP-R CHOP-R CHOP-R
Tag
CHOP-R CHOP-R
CHOP day 1 22 43 64 85 106 Rituximab 375 mg/m2 day 0 22 43 64 85 106
Rummel MJ, et al. Blood. 2008;112: Abstract 2596.Rummel MJ, et al. Blood. 2008;112: Abstract 2596.
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2020thth Aug 2008 Aug 2008 Bendamustine-RBendamustine-R CHOP-RCHOP-R
40 evaluable pts.40 evaluable pts. (n = 23) (n = 17)(n = 23) (n = 17)
Age (median)Age (median) 65 yrs65 yrs 64 yrs64 yrs
Stage IVStage IV 100 %100 % 100 % 100 %
Beta-2 Microglobulin Beta-2 Microglobulin 3,23,2 3,43,4
IgM (median, mg/dl)IgM (median, mg/dl) 2.7902.790 1.6901.690
Range IgM (mg/dl)Range IgM (mg/dl) 11.220 - 1.10011.220 - 1.100 8.510 - 900 8.510 - 900
Hb (median, g/dl)Hb (median, g/dl) 10,210,2 9,99,9
Toxicity treatment associatedToxicity treatment associated
Neuropathy (patients)Neuropathy (patients) 11 33
Waldenström Patient Characteristics: B-R vs CHOP-R
Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.
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PFS: Benda-R vs CHOP-R in Frontline WM
0 12 24 36 48 60 72
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
months
Pro
bab
ility
Bendamustine-R
CHOP-R
Rummel M, et al. Presented at: Third International Pt Physic Summit on WM; May 1-3, 2009; Boston, Massachusetts, United States.
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Advances in the Biology of Waldenstrom’s Macroglobulinemia
Bendamustine in Relapsed/Refractory WM
0
5
10
15
20
25
30
35
40
sIgM (g/L) Hematocrit (%)
Pre-Rx
Post-Rx
P<.0001 P = .0002P<.0001 P = .0002
Treon S, et al. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135.Treon S, et al. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135.
•ORR 83%•PFS 13.2 mos.
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PFS is impacted by Depth of Response in WM Pts Treated With Rituximab-Based Therapy.
CRCR
VGPRVGPR
PRPR
MRMR
NRNR
P < .00010.00
0.25
0.50
0.75
1.00
Wit
ho
ut
pro
gre
ss
ion
(%
)
0 10 20 30 40 50 60 70 80 90 100Time from treatment initiation (months)
CR/VGPRCR/VGPR
MR/PRMR/PR
P = 0.040.00
0.25
0.50
0.75
1.00
Wit
ho
ut
pro
gre
ss
ion
(%
)
0 10 20 30 40 50 60 70 80 90 100Time from treatment initiation (months)
Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].
Response Estimated PFS (mos)
CR >90
VGPR >75
PR 42.6
MR 30.8
NR/SD 10.6 N=159
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Treon S, et al. Clin Lymph Myeloma. 2010;10(5):347-352.
VAL/VAL 10-12%VAL/PHE 35-40%PHE/PHE 40-50%
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0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
Non-Responders Minor Responders Partial Responders VGPR/CR Responders
FcγRIIIA158-VV or VF
P = .03 P = .02
P = .04
P-values vs VGPR/CR
FcγRIIIA-158 Polymorphisms Predict Response in WM
Treon S, et al. Br J Haematol. 2011 May 12 [Epub ahead of print].
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•Glycoengineered Fc domain Enhanced ADCC effect
•Modified elbow hingeApoptosis induction
Mossner E, et al. Blood. 2010;115(22):4393-4402.
GA101: Novel Humanized CD20 MAB
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0
20
40
60
80
100
120
0.00001 0.00010 0.00100 0.01000 0.10000 1.00000
GA101
Rituximab
Log Ab concentration (ug/ml)
% T
ota
l C
yto
tox
icit
y
WM patient
FcγRIIIA-158 V/V
GA101
Rituximab
Log Ab concentration (ug/ml)
% T
ota
l C
yto
tox
icit
y
0
10
20
30
40
50
60
70
80
90
0.00001 0.00010 0.00100 0.01000 0.10000 1.00000
WM patient
FcγRIIIA-158 F/F
V/V
F/F
Yang G, et al. J Clin Oncol. 2010;28(15S): Abstract 8112.
ADCC Against WM Cells for GA101 is Greater Among Autologous NK Cells
Genotyped for FCGRIIIA-158 F/F
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GA101 Demonstrates Greater Direct Killing vs Rituximab in BCWM.1 WM Cells
Untreated
GA101
Rituximab
20.2% 31.4%
45.6% 77.6%
17.1% 23.6%
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To Maintain or Not to Maintain?
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Untreated, ObservationUntreated, MaintenancePrev Treated, ObservationPrev Treated, Maintenance
N=248
PFS in rituximab naïve WM patients who were observed or given maintenance rituximab therapy.
100
75
50
25
00 10 20 30 40 50 60 70 80 90 100 110 120
Time from treatment initiation (months)
Aliv
e o
r w
ith
ou
t p
rog
fres
sio
n (
%)
With Maintenance
No Maintenance
Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].
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Infectious Events in WM Patients Who Underwent Observation or Maintenance
Rituximab Therapy
0% 10% 20% 30% 40% 50%
Grade > 3
InfectiousEvents(Any
Grade)
Maintenance Rituximab
Observation
P = .0064
P = .718
Treon S, et al. Br J Haematol. 2011 May 25 [Epub ahead of print].
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Salvage OptionsSalvage Options
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• N = 50 (DFCI and Mayo)
• 10 mg QD
• Reduce to 5 mg for AE
• Median prior therapies: 3
• Median IgM: 3330 mg/dL
• ORR: 72%
• Median response:
• NR (3-22+ mos)
• Grade >3 thrombocytopenia, pneumonitis, mucositis, and hyperglycemia.
Everolimus in Relapsed/Refractory WM
Ghobrial IM, et al. J Clin Oncol. 2010;28(8):1408-1414.
RAD001RAD001
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RAD001 for Primary Therapy of WM
• N = 60
• Eligibility: symptomatic, untreated WM
• Dose: 10 mg QD
• Reduction to 7.5, 5.0 mg for AE
• Duration: 4 yrs to progression
• Primary endpoints: safety, ORR, and 2- and 4-yr PFS
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IgM Discordance to WM BM Disease Involvement is Common With RAD001
7 non-responders by serial BM biopsies despite reductions in sIgM.
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Advances in the Biology of Waldenstrom’s Macroglobulinemia
“Medicine is not only a science; it is also an art. It does not consist of compounding pills and plasters; it deals with the very processes of life, which must be understood before they may be guided.”
Phillipus Aureolus Paracelsus
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Advances in the Biology of Waldenstrom’s MacroglobulinemiaResponse Assessment can be complicated by differential impact of targeted therapies on WM clonal populations.
Varghese et al, Clin Lymph Myeloma 2009Varghese et al, Clin Lymph Myeloma 2009Post-Rituximab
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Alemtuzumab in WMAlemtuzumab in WM•CD52 widely expressed on WM and BM Mast cells.
•UK Study (n=7):
-ORR 86%; 1 CR;
-2 deaths due to Opportunistic Infections.
•Multicenter study by WMCTG (n=28):
-ORR 75%; Major RR: 36% (1 CR);
-TTP 14.5 months ;
-Cytopenias, CMV (3 deaths); Late ITP (1 death).
Owen et al, ASH 2003; Treon, Blood 2011.
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CharacteristicsCharacteristics No. availableNo. available No. of patients (%)No. of patients (%)
Sex: MaleSex: Male
Age at diagnosis, years [median (range)]Age at diagnosis, years [median (range)] ≥ 50 years ≥ 60 years ≥ 65 years
No. of prior therapiesNo. of prior therapies < 3 ≥ 3 IPSSWM - riskIPSSWM - riskIntermediate High
Interval diagnosis – ASCT, months [median Interval diagnosis – ASCT, months [median (range)](range)] ≤ 2 years 2 – 3 years ≥ 3years
158
158
153
158
158
99 (63%)
49 (20 – 67)74 (47%)10 (6%) 2 (1%)
104 (68%)104 (68%) 49 (32%)
58(37%)85(54%)85(54%)
20 (3 – 244)88 (88 (556%)6%)36 (23%)36 (23%)34 (21%)
Kyriakou et al, JCO 2010Kyriakou et al, JCO 2010
Autologous SCT in WM: EBMT
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ASCT IN WM RELAPSE RATE AND NON-RELAPSE MORTALITY
ASCT IN WM RELAPSE RATE AND NON-RELAPSE MORTALITY
1.0
0.0
0.2
0.4
0.6
0.8
0 1 2 3 4 5 6 7 8
Time after ASCT (years)
Cu
mu
lati
ve
Inci
den
ce
NRM
Relapse or Progression
52%
4.6% 5.6%3.8%
Kyriakou et al, JCO 2010
0.0
0.1
0.2
0.3
0.4
0.5
0 2 4 6 8 10
Time after ASCT (years)
Cu
m I
nc
Se
c M
alig
nan
cy8.4%
Secondary malignancies
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ADVERSE PROGNOSTIC FACTORS FOR POST ASCT OUTCOME: MULTIVARIATE ANALYSIS
ADVERSE PROGNOSTIC FACTORS FOR POST ASCT OUTCOME: MULTIVARIATE ANALYSIS
Adverse prognostic factorAdverse prognostic factor Relative riskRelative risk Confidence Confidence intervalinterval
P valueP value
Relapse / ProgressionRelapse / Progression ≥ 3 prior lines of therapy Refractory disease at ASCT
2.5 3.9
1.5 – 4.1 1.6 – 9.4
0.0010.003
Progression free survivalProgression free survival ≥ 3 prior lines of therapy Refractory disease at ASCT
2.4 4.1
1.5 – 3.9 1.8 – 9.2
0.001< 0.001
Overall survivalOverall survival Male sex ≥ 3 prior lines of therapy Age at ASCT > 60 years Refractory disease at ASCT
2.03.11.93.1
1.1 – 3.91.7 – 5.91.0. - 3.81.2 – 8.1
0.040.0010.050.03
Kyriakou et al, JCO 2010
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Novel DirectionsNovel Directions
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Burton’s Tyrosine Kinase (BTK)
Nat Rev Imm 2:945
• B-cell antigen receptor (BCR) signaling is required for tumor expansion and proliferation
• Bruton’s Tyrosine Kinase (Btk) is an essential element of the BCR signaling pathway
• Inhibitors of Btk block BCR signaling and induces apoptosis
IgM
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IKBα-(pS32)
total IKBα
Hogan Hogan + PCI-32765
MWCL1 MWCL1 + PCI-32765
ANBL6 ANBL6 + PCI-32765
INA6 INA6 + PCI-32765
Hogan Hogan + PCI-32765
MWCL1 MWCL1 + PCI-32765
ANBL6 ANBL6 + PCI-32765
INA6 INA6 + PCI-32765
ERK1/2 - (pT202/pY204)
total ERK1/2
NFkB signaling
MAPK signaling
Impact of BTK-I on NFKB and MAPK Signaling in WM and MM
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PCI-32765 Clinical Experience
N CR PR SD PD NE TETE
ORR %ITT
ORR %Eval
CLL/SLL 16 1 10 2 2 1 69% 85%
FL 16 1 3 5 4 3 25% 31%
MCL 9 3 4 1 1 78% 78%DLBCL 7 2 1 4 29% 29%
MZL/MLT 4 1 1 1 1 25% 33%
WM 4 2 1 1 50% 67%TOTAL 56 5 22 11 10 6 2 48% 56%
Advani et al. ASCO 2010
MCL (n=9)
CLL/SLL (n=13)
Indolent (n=20)
DLBCL (n=7)
Most Frequently Observed Toxicities: fatigue, diarrhea, nausea, myalgia, headache, and pneumonia. No apparent hepatic or renal toxicities. No evidence of cumulative hematologic toxicity.
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PCI 327625 in Relapsed/Refractory WMScreening
Registration
560 mg po qD PCI-32765
Progressive Disease (PD) or Unacceptable Toxicity
Stable Disease or ResponseContinue x 24 four week cycles
(maximum)
Stop PCI-32765
Event Monitoring
Event Monitoring
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WHOLE GENOME SEQUENCING IN WM
only 70 years
WM ===========*====
Paired Sequencingfrom same individuals
30 patients with WMIncluding familial and
sporadic patients
NORMAL ================
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WHOLE GENOME SEQUENCING IN WM
Treon et al, ASH 2011; Xu et al; ASH 2011 (Accepted).
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BCWM.1 BCWM.1 + control
agent
BCWM.1 + WM Inhibitory agent
Specific drug targeting of WM mutant protein
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Summary (I)Summary (I)
• WM has histological, immunophenotypic, clinical and molecular features which can distinguish it from MM.
• Familial predisposition is more common in WM, and impacts therapy.
• Bendamustine, bortezomib, cyclophosphamide, and thalidomide–based rituximab therapies are active, and can be used for symptomatic WM.
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Summary (II)Summary (II)•Use of nucleoside analogues should be carefully weighed against other options. Lenalidomide avoided. Bortezomib used with caution for neuropathy.
•Maintenance is an reasonable option for patients responding to a rituximab containing regimen.
•Genomic investigation has revealed novel targets for therapy of WM.
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Waldenström’s macroglobulinemia:Similar but Different to Myeloma.