Novel insights into
Waldenström's Macroglobulinemia
Steven P. Treon, MD, MA, PhD
Bing Center for Waldenström's Macroglobulinemia
Dana Farber Cancer Institute
Harvard Medical School
Early Reports of Familial Waldenströms
Existence of "familial WM" was
first reported in 2 brothers by
Massari et al, in Nature 1962.
Subsequent reports confirmed
existence of familial cases of WM
and related B-cell disorders,
including MM, NHL, MGUS
among first degree kindred and
through multiple generations.
Prevalence of Familial WM
20
18.7
18
16
N=257
14
12
10
8
6
5.1
4
3.5
3.1
2.7
1.9
2
1.2
1.2
0 Any B-cell WM
NHL
MM
CLL
MGUS Hodgkin's
ALL
malignancy
Familial Waldenstrom's
Present at a younger age
Greater BM involvement
Higher serum IgM levels
Hunter et al, 3rd Intl Workshop on WM, 2004
Regulation of lymphoplasmacytic cell
differentiation.
"WM"
B-Cell
Lymphoplasmacytic Cell
Plasma Cell
PAX5
BLIMP1
PAX5
XBP1
IgM
IgA, IgG
BAC Analysis: Deletions in 6q21-22
Loss of hybridization in Cells using probes RP11-91c23
(red) and RP11-171J20 (green)
Blimp-1 transcript expression in BM LPC in
Waldenstrom's macroglobulinemia
Blimp1
Actin
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
WM Patients
Xavier et al, Ann Oncol 2005
PAX5 transcript expression in BM LPC in
Waldenstrom's macroglobulinemia
PAX5
Actin
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
WM Patients
Xavier et al, Ann Oncol 2005
XBP1 transcript expression in BM LPC in
Waldenstrom's macroglobulinemia
Xbp1
Actin
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
WM Patients
Xavier et al, Ann Oncol 2005
IgA and IgG hypogammaglobulinemia
in WM
Pre-
Post-
Pre-
Post-
N=
IgG
IgG
T-Test
IgA
IgA
T-Test
CR
8
644
472
0.05
75
37
0.08
PR
70
415
349
0.09
27
28
0.91
MR
14
474
394
0.01
38
26
0.02
Treon et al, ASH 2004
Third International Workshop on
Waldenström's macroglobulinemia
Paris 2004
Consensus Panel:
Update on Treatment Recommendations in
Waldenström's macroglobulinemia
Chairs:
Dr. Morie A. Gertz (USA)
Dr. Steve Treon (USA)
Response duration following standard
and extended Rituximab therapy in WM
Response
No. of
Median no. Major RR duration
patients of infusions
(%)
(months)
Byrd1 6
4
57
6.6+
Weber2 8
4
75
9.0
Foran3 7
4
29
NA
Treon4 30
4
27
8.4
Gertz 69
4
27 NR
Dimopoulos5 27
8
44
NR
WMCTG6 29 8
48 NR
1Byrd JC, et al. Ann Oncol 1999;10:15257; 2Weber DM, et al. Blood 1999;94:125a (Abstract 551);
3Foran JM, et al. J Clin Oncol 2000;18:31724; 4Treon SP, et al. J Immunother 2001;24:2729;
5Dimopoulos MA, et al. J Clin Oncol 2002;20:232733; 6Treon SP, et al. Ann Oncol 2005.
Pre-therapy IgM levels predict clinical
response to extended Rituximab in WM
18/21 patients (85.7%) with serum IgM
levels <6,000mg/dL responded
versus
1/5 patients (20.0%) with serum IgM levels
>6,000mg/dL responded (p=0.002)
No correlation with baseline bone marrow
tumor cell involvement
Treon SP, et al. Ann Oncol 2005
Serum IgM levels following Rituximab
in patients with WM.
12000
*
10000
*
*
)
*
8000
L
*
*
/
d
g
m
6000
(
M
Ig
4000
2000
0 1 2 3 4 5 6
* Denotes patient
7
8
underwent
9
Time (weeks)
plasmapheresis at
this time point for
Treon et al, Ann Oncol 2004
Combination Therapy with Rituximab
in WM
Major Response
No. of
RR
duration
patients
Regimen
(%) (months)
WMCTG1 43
Fludara/rituximab
82
NR
Weber2
Cladribine/cyclophosphamide/
17
rituximab 94
NR
Hensel3
Pentostatin/cyclophosphamide/
17
Rituximab 90
NR
Dimopoulos4
Dex/cyclophosphamide/
34
Rituximab 78
NR
Hunter5 13
CHOP/rituximab
77
NR
GLSG6
72
CHOP/rituximab (vs. CHOP)
94
NR
1Treon, et al. ASH 2004; 2Weber DM, et al. Semin Oncol 2003; 3Hensel et al, ASCO 2004;
4Dimopoulos MA, et al. ASH 2004; 6Hunter, et al. ASH 2004; 6Buske et al, ASH 2004.
Who should get
antibody monotherapy
vs.
chemotherapy or combined
chemotherapy and antibody?
Natural killer (NK) cell
FcRIIIa (CD16)
CD20
Tumor cell
FcRIIIa-158 Polymorphisms
and Response to Rituximab in WM
WM patients carrying at least
Responses
one valine
amino acid at
50
position 158 (V/V or V/F),
40
achieved a four-fold higher best
)
(% 30
overall response rate, p=0.03)
t
s
n
e
versus patients who were ti 20
a
P
homozygous for phenylalanine
10
(F/F).
0
158VV
158VF
158FF
Treon et al, ASH 2002; JCO 2005
mAb therapy
mAb plus CTX
alone?
or CTX?
158V/V
158F/F
or V/F patient
patient
CTX = chemotherapy
Use of immunomodulating
agents to augment Rituximab
activity in WM
Rituximab-induced ADCC of ARH-77 cells
is enhanced by Thalidomide and Revimid
40
*
35
Revimid
x
i
c
i
t
y
30
*
t
o
25
f
c
y
t
o
20
e
o
Thalidomide
15
t
a
g
10
e
r
c
e
n
P
5
Control
0
Rituximab (10µg/mL)
*p<0.02
Hayashi T, et al. Blood 2002;100:314b (Abstract 4800)
Thalidomide and Rituximab in WM
Thalidomide 200
400mg every day (weeks 152)*
Rituximab (weeks 25) Rituximab (weeks 1316)
*Liberal dose reduction to 50 mg po qD permitted
Responses
· N= 25 patients
· 24 patients evaluable for response
· CR= 1 ( 4.1%)
52.1%
· PR= 12
(48.0%)
60.1%
· MR= 2
( 8.0%)
· SD = 4
(16.0%)
· NR= 4
(16.0%)
· Median follow-up of 10 months
Cumulative Thalidomide Dose and
Response to Therapy
100000
90000
Responders: 38,850 mg
80000
Non-responders: 5,650 mg
70000
p=0.005
60000
mg
50000
40000
30000
20000
10000
0
CR
PR
MR
SD
NR
Revlimid (CC-5013) and Rituximab in WM
Revlimid 25 mg daily; 3 wks on; 1 wk off (48 weeks)*
Rituximab (weeks 25) Rituximab (weeks 1316)
*Dose reduction to 10 mg po qD permitted for toxicity
Alemtuzumab in Waldenström's
macroglobulinemia
FDA Approved for CLL
Responses in relapsed/
refractory WM patients
have been observed
Test dosing given over
1 week followed by 6-12
weeks of 3-times a week
IV therapy depending on
response
Phase II Study in WM
CD52
open by WMCTG in U.S.
WMCTG 02-079:
Alemtuzumab in WM
N=7; Median Prior Therapies: 2 (1-4)
Patients were relapsed or refractory to
fludarabine (4/7; 57%) and/or rituximab (7/7;
100%)
Overall 6/7 (85.7%) had at least a 25%
reduction in serum IgM with 3 PR; 3 MR;
No infectious complications.
Hematological toxicities common.
Hunter et al, ASH 2004
Survival of WM patient BM tumor cells following
ex vivo treatment with Bortezomib
120
100
80
of control)
%
60
rvival (
40
Su
20
0
WM-
WM-
WM-
WM-
WM-
WM-
WM-
pt#1
pt#2
pt#3
pt#4
pt#5
pt#6
pt#7
Mitsiades et al, Ann Oncology, 2002.
WMCTG 03-248:
Bortezomib in WM
N=27; Median Prior Therapies: 2 (1-4);
15 patients evaluable after 2 cycles of therapy; 8
relapsed and 7 refractory to previous therapy;
Overall 12/15 (80%) pts had at least a 25% reduction in
serum IgM with 5 PR; 7 MR;
Median IgM: 4050 to 2632 mg/dL after 2 cycles
(p=0.02)
>grade II adverse events: neuropathy (20%);
neutropenia (20%); thrombocytopenia (7%); rash (7%)
with therapy prematurely discontinued in one patient.
Hunter et al, Ann Oncol 2005
Clinical Response to Sildenafil in a
patient with WM
A. Serum IgM (mg/dL)
3
6000
A.
B. 2.5
5000
B. M-spike (g/dL)
4000
2
L
/d 3000
1.5
mg
C. Serum Viscosity (CP)
2000
1
1000
0.5
NA
NA
NA
NA
ND
D. Hematocrit (%)
0
0
0 3 5 7 9 13 15 33
0 3 5 7 9 13 15 33
Weeks
Weeks
3.5
C.
45
D.
3
40
35
2.5
30
P 2
25
C 1.5
p
e
r
c
ent
20
15
1
10
0.5
NA
NA
NA
5
NA
0
0
0 3 5 7 9 13 15 33
0 3 5 7 9 13 15 33
Weeks
Weeks
Treon et al, Clin Lymph 2004
Sildenafil induces apoptosis of
WM tumor cells
45
40
35
30
25
20
Media alone
15
Sil 0.01 ug/ml
10
5
0
Pt A
Pt B
Pt C
Pt D
Pt E
(1.24)
(1.25)
(1.31)
(1.92)
(4.80)
Treon et al, Clin Lymph 2004
Typical BM Biopsy Report in a patient with WM
BONE MARROW BIOPSY:
Variably cellular, overall mildly to moderately hypocellular
marrow (60-70% fat).
Approximately 30-40% of the cellularity and 10-20% of
intertrabecular space is comprised of a predominantly nodular
and interstitial population of small to intermediate sized
lymphocytes, plasma cells, and lymphoplasmacytoid forms.
Mast cells are seen in association with the lymphoid
aggregates.
CD40L expression on BM mast cells
in a patient with WM.
MK
MC
MCs
MC
Tryptase staining
CD40L staining
Mast Cell
WM cells
Mast Cell
Mast Cell Induced Proliferation of WM Cells is
inhibited by blocking CD40L signaling
6000
WM Cells
2000
WM Cells
1800
5000
HMC Mast
1600
Ku Mast
4000
Cells
1400
Cells
*
1200
3000
WM + HMC
1000
*
WM + Ku
Cells
*
*
800
Cells
2000
WM + HMC
600
WM + Ku +
1000
+ CD40 Fc
400
CD40 Fc (1
(1 ug/ml)
200
ug/ml)
0
WM + HMC
0
WM + Ku +
+ CD40 Fc
* p<0.006
CD40 Fc (10
* p<0.003
(10 ug/ml)
ug/ml)
Tournilhac et al, Proc ASCO 2004
Targeting mast cell support in
Waldenström's macroglobulinemia
BCMA, TACI, BAFF-R BLYS
Gleevec
Bortezomib X CD117
CD40L
CD40
CD52
CD52
WM Cell
Mast Cell
Summary
· Familial WM is common and loss of expression in
the PC differentiation genes BLIMP-1, PAX5, XBP1
is commonly observed.
· New agents under investigation include
Alemtuzumab
(Campath-1H), Bortezomib
(Velcade), Sildenafil (Viagra) and Imatinib Mesylate
(Gleevec).
· Mast cells appear to play a role in the
pathogenesis of WM by directly stimulating WM
growth through the CD40L-CD40 pathway. Mast
cells and MC-WM interactions therefore represent
a novel opportunity for WM therapy.
WM Clinical Trials Group (WMCTG)
Dana Farber Cancer Institute, MA
McMaster University, Canada
Mass General Hospital, MA
Cross Cancer Center, Canada
Beth Israel Hospital, MA
St Bartholomew's, UK
Roswell Park Memorial, NY
Karolinska Institut, Sweden
St Vincent's Hospital, NY
Hopital Schaffner, France
Long Island Jewish Memorial, NY
University of Salamanca, Spain
University of Maryland, MD
Niguarda Hospital, Italy
University of Miami, FL
Cleveland Clinic Foundation, OH
McCallum Cancer Center,
Australia
Northwestern University, IL
Rush Presbyterian, IL
Rocky Mountain Cancer Ctr, CO
Arizona Cancer Center, AZ
UCLA Medical Center, CA
Stanford University, CA
Fred Hutchinson, WA