5/12/2011
Advances in the Biology of Waldenstrom's Macroglobulinemia
Advances in the Therapy of
Waldenstrom's Macroglobulinemia.
Steve Treon MD, MA, PhD
Director, Bing Center for WM
Associate Professor
Dana Farber Cancer Institute
Harvard Medical School
Advances in the Biology of Waldenstrom's Macroglobulinemia
3rd International Workshop on
Waldenstrom's Macroglobulinemia
Paris, 2004
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Advances in the Biology of Waldenstrom's Macroglobulinemia
7th International Workshop on
Waldenstrom's Macroglobulinemia
Newport, RI, USA
www.wmworkshop.org
August 2012
Natural Killer Cell
CD20-
Fc receptor
Directed
Rituximab
Fc
Monoclonal
Antibody
Fab
CD20
WM cell
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Serum IgM Levels Following Rituximab
in Patients With WM
14,000
WM 1
P
12,000
WM 2
WM 3
10,000
WM 4
P
P
WM 5
P
(mg/dL)
8000
WM 6
P
P
WM 7
IgM
6000
WM 8
WM 9
4000
WM 10
Serum
WM 11
P
2000
0 02
4
6
8
10
12
14
Wks
P denotes patient-required plasmapheresis for hyperviscosity.
Treon SP, et al. Ann Oncol. 2004;15:1481-1483.
Advances in the Biology of Waldenstrom's Macroglobulinemia
Rituximab induced IgM flare occurs in
patients receiving combination therapy.
Monotherapy (60%)
Fludarabine/Rituximab (40%)
Cyclophosphamide/Rituximab (30%)
Thalidomide/Rituximab (50%)
Lenalidomide/Rituximab (75%)
Bortezomib/Dexamethasone/Rituximab (9%)
Bortezomib/Rituximab (20%)
Treon et al, Ann Oncol 2004; Nichols et al, ASH 2004; Ioakimidis et al, Clin Lymphoma Myeloma 2009; Treon et al,
Blood 2008; Treon et al, Clin Cancer Res 2008; Treon JCO 2009; Ghobrial et al, ASH 2009.
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Bystander release of IL-6 by Monocytes may
account for the Rituximab IgM flare.
IVIg
Rituximab
FcRIIA
2600
2400
Monocytes
2200
)
IL-6
ml 2000
(ng/ 1800
M
IL-6R
Ig 1600
1400
1200
WM-LPC
IgM
Advances in the Biology of Waldenstrom's Macroglobulinemia
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
70-80%
8-10%
i.e. CHOP-R, CVP-R, CPR, RCD
Rituximab/nucleoside analogues
70-90%
5-10%
i.e. FR, FCR, CDA-R
Rituximab/thalidomide
70%
5%
Rituximab/bortezomib
70-90%
10-25%
i.e. BDR, VR
Rituximab/bendamustine
90%
NA
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Disease transformation and MDS/AML
following nucleoside analogues in WM
Study
Population
N=
Median Outcome
F/U
(mo)
Leleu et al,
Prev treated
439 60
Histological Transformation
JCO 2009
with NA vs.
(8%)
non-NA or
MDS/AML (5%)
untreated
Tamburini
Firstline with
49
41
Histological Transformation
et al,
Fludara/Cyclo
(10%)
Leukemia
2005
Leblond,
Previously
71
34
Histological Transformation
JCO 1998
treated with
(10%)
Fludara
Rakkhit et
Untreated;
111 NA
Histological Transformation
al, ASH
2CDA based
(9%)
2008
therapy
Advances in the Biology of Waldenstrom's Macroglobulinemia
Thalidomide and Rituximab in WM
N=25
Thalidomide at 200 mg, increase to 400 mg and 8
infusions (375 mg/m2 per week) of rituximab.
ORR: 72%; CR/VGPR: 4%
Short-term toxicities included:
Sensory neuropathy (11); resolved grade 1 or less: 10.
Confusion (3), tremors (2), bradycardia (2).
Dose reduction in all pts. 50-100 mg/day tolerated.
Blood 2008; 112:4452
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Thalidomide and Rituximab in WM
Median PFS: 41.9 months
Median Follow-up: 40.4 months
Advances in the Biology of Waldenstrom's Macroglobulinemia
Lenalidomide (Revlimid)-Induced
Anemia in WM
Pretherapy
Posttherapy
Decreased Hct observed in
38
10/12 pts following first week
36
of lenalidomide monotherapy
34
Median Hct decrease: 3.9%
)
(31.9% to 28.0%; P = .003)
32
(%
No evidence for hemolysis;
30
concurrent thrombocytopenia
28
observed in 1 pt
Hematocrit 26
4 patients hospitalized for
anemia related complications
24
(Afib, syncope, CHF)
22
20
12345 6 789 10 11 12
Patient
Treon SP, et al. Clin Cancer Res 2008
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Phase I Study of Pomalidomide,
Dexamethasone, Rituximab (PDR) in WM.
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.
Advances in the Biology of Waldenstrom's Macroglobulinemia
Proteasome Inhibitors
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Bortezomib combination therapy in WM
Primary
Bortezomib (1.3 mg/m2/biwkly)/Dexamethasone/Rituximab
ORR 95%; CR 22%; TTP >3 yrs; 30% Grade 3 PN
Bortezomib (1.6 mg/m2/wk)/Rituximab
ORR 92%; CR 8%; 80% 1 Y PFS; No Grade 3 PN
Salvage
Bortezomib (1.6 mg/m2/wk)/Rituximab
ORR 81%; CR 5%; TTP 12 mos; 5% Grade 3 PN.
Bortezomib (randomized wkly vs. biwkly)/Rituximab
ORR 80%; CR 0%; TTP ?; 0% Grade 3 PN.
Treon et al, JCO 2009; Ghobrial et al, AJH 2010; Ghobrial et al, JCO 2010; Agathocleous et al, ASH 2007
Advances in the Biology of Waldenstrom's Macroglobulinemia
Bortezomib, Dexamethasone and Rituximab
in WM
Median PFS: >56.1 months
Median Follow-up: 43.3 months
IWWM6, Venice 2010
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Bortezomib-Based Rituximab Therapy
Twice A Week
Once A Week
CR/VGPR
Neuropathy
PFS (?)
Time to Response
Rituximab IgM Flare
Advances in the Biology of Waldenstrom's Macroglobulinemia
Proteasome: Cellular Recycling Plant
Bortezomib/Carfilzomib
MLNM4924
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Neuropathy Data for Carfilzomib in MM
Advances in the Biology of Waldenstrom's Macroglobulinemia
(Pooled Data from 003/004 Studies)
Advances in the Biology of Waldenstrom's Macroglobulinemia
Primary Therapy of WM with
Carfilzomib, Rituximab, Dex (CARD)
Induction Cycle 1 q21 days
Days 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 days
Days 1,2,8,9 Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.
Days 2,9
Rituximab 375 mg/m2
2 months
Maintenance Cycles 1-8 q 2 months
Days 1,2
Carfilzomib 36 mg/m2 IV; Dexamethasone 20 mg IV.
Days 2
Rituximab 375 mg/m2
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Advances in the Biology of Waldenstrom's Macroglobulinemia
MLNM 4924 /Dexamethasone in
Relapsed/Refractory WM
Induction Cycle 1 q21 days
Days 1,4,8,11 MLN 4924 20 mg/m2 IV; Dexamethasone 20 mg IV.
Induction Cycle 2-6 q21 days
Days 1,4,8,11 MLN 4924 20 mg/m2 IV; Dexamethasone 20 mg IV.
2 months
Maintenance Cycles 1-6 q 2 months
Days 1,4,8,11 MLN 4924 20 mg/m2 IV; Dexamethasone 20 mg IV.
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Advances in the Biology of Waldenstrom's Macroglobulinemia
Bendamustine
ClH2C
Bendamustine
N
Carboxylic acid
N
ClH2C
COOH
Nitrogen mustard
N
Benzimidazole ring
CH
NH
3
2
Cl
N
N
Cyclophosphamide
N
N
Cl
O O
N
P
HOCH
Cl
O
2
N
Cladribine
H
OH
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Advances in the Biology of Waldenstrom's Macroglobulinemia
PFS: Benda-R vs CHOP-R in frontline WM
Rummel et al, IWWM 2010
1.0
0.9
Bendamustine-R
0.8
0.7
0.6
0.5
Probability 0.4
0.3
0.2
CHOP-R
0.1
0.0
0
12
24
36
48
60
72
months
Presented on the Vth International Workshop on Waldenstrom´s Macroglobulinemia, Stockholm, Oct 15-19, 2008
Advances in the Biology of Waldenstrom's Macroglobulinemia
PFS in rituximab
CR
naïve WM pts
VGPR
treated with
PR
CR >90 mos.
rituximab based
MR
therapy (n=159).
NR
VGPR >75 mos.
p<0.0001
Response
Estimated
PFS (mo.)
PR 42.8 mos.
CR/VGPR
CR
>90
MR 30.8 mos.
VGPR
>75
MR/PR
PR
42.6 NR 10.1 mos.
MR
30.8
p=0.04
NR/SD
10.6
P<0.0001
Treon et al, BJH 2011
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VAL/VAL 10-12%
VAL/PHE 35-40%
PHE/PHE 40-50%
Treon et al, Clin Lymph Myeloma 2010
Advances in the Biology of Waldenstrom's Macroglobulinemia
FcRIIIA-158 polymorphisms predict response in WM
p-values vs. VGPR/CR
p=0.04
p=0.03
p=0.02
Treon et al, BJH 2011
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Advances in the Biology of Waldenstrom's Macroglobulinemia
GA101: Novel Humanized CD20 MAB
·Modified elbow
·Glycoengineered Fc
hinge
domain
Apoptosis induction
Enhanced ADCC
effect
Mossner et al, Blood 2010
Advances in the Biology of Waldenstrom's Macroglobulinemia
ADCC against WM cells for GA101 is greater among
autologous NK cells genotyped for FCGR3A-158 F/F
90
80
ity
GA101
ic
70
V/V
60
WM patient
Rituximab
totox
50
40
Cy
FcRIIIA-158 V/V
l
30
tao 20
T
10
%
0
0.00001
0.00010
0.00100
0.01000
0.10000
1.00000
Log Ab concentration (ug/ml)
120
ity
100
WM patient
ic
GA101
80
F/F
totox
60
FcRIIIA-158 F/F
Cyl
40
Rituximab
tao
20
T%
0
0.00001
0.00010
0.00100
0.01000
0.10000
1.00000
Log Ab concentration (ug/ml)
Yang et al, ASCO 2010
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Advances in the Biology of Waldenstrom's Macroglobulinemia
GA101 demonstrates greater direct killing
vs. rituximab in BCWM.1 WM cells.
Untreated
17.1%
23.6%
Rituximab
20.2%
31.4%
GA101
45.6%
77.6%
Advances in the Biology of Waldenstrom's Macroglobulinemia
To Maintain or Not to Maintain?
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Treon et al, BJH 2011
Advances in the Biology of Waldenstrom's Macroglobulinemia
PFS in rituximab naïve WM patients who underwent
observation or maintenance rituximab therapy.
N=248
With Maintenance
No Maintenance
Untreated, Observation
Untreated, Maintenance
Prev Treated, Observation
Prev Treated, Maintenance
Advances in the Biology of Waldenstrom's Macroglobulinemia
RAD001 in Relapsed/Refractory WM
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.
Ghobrial , Witzig et al, JCO 2010
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Advances in the Biology of Waldenstrom's Macroglobulinemia
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
Advances in the Biology of Waldenstrom's Macroglobulinemia
IgM changes following RAD001 in
untreated WM patients.
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Advances in the Biology of Waldenstrom's Macroglobulinemia
IgM discordance to WM BM disease
involvement is common with RAD001
7 non-responders by serial BM biopsies despite reductions in sIgM.
Advances in the Biology of Waldenstrom's Macroglobulinemia
Summary
Familial disease predisposition is common in WM and
effects treatment outcome.
Bendamustine,
Bortezomib
Cyclophosphamide,
and
Thalidomide based rituximab therapies are active and can
be considered in the upfront treatment of WM.
Use of nucleoside analogues should be carefully
considered due to potential long-term consequences.
Better categorical responses are associated with improved
progression free survival in rituximab naïve WM patients
receiving rituximab based therapy, and reflect FCGR3A
polymorphisms.
IgM discordance is common with RAD001, and BMBx are
important for serial response assessment.
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Advances in the Biology of Waldenstrom's Macroglobulinemia
Whole Genome Sequencing of WM Patients
· First 30 WM patients completed with tumor/normal pairing.
Sporadic and Familial patients included
·Deep sequencing (i.e. > 60 X average coverage used).
·Growth activating somatic mutation identified in 90% of WM
patients, vs. 0% of MM patients. Targetable for therapy!!
Manuscript in Review.
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 Macroglobulinemia
Acknowledgements
Dr. Irene Ghobrial (USA)
Prof. Pierre Morel (France)
Prof. Eva Kimby (Sweden)
Dr. Jeffrey Matous (Denver)
Dr. Herb Eradat (UCLA)
Dr. Stephanie Gregory (RUSH)
Dr. Ashraf Badros (UMD)
Dr. Ranjana Advani (Stanford Univ)
Dr. Leonard Heffner (Emory)
Dr. Sheeba Thomas (MD Anderson)
·Laboratory of Dr. Kenneth Anderson
Constantine Mitsiades, Douglas McMillin
·Laboratory of Dr. Nikhil Munshi
·Laboratory of Dr. Steve Treon
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