TREATMENT STRATEGIES IN WALDENSTROM'S
MACROGLOBULINEMIA
Meletios A. Dimopoulos, MD
University of Athens School of Medicine
CLINICAL AND LABORATORY CONSIDERATIONS
FOR INITIATION OF THERAPY IN WM
· Hemoglobin 10 g/dL
· Platelet count < 100 x 109 /L
· bulky adenopathy
· significant organomegaly
· fever, night seats, weight loss, fatigue
· symptoms and signs of hyperviscosity
· symptomatic neuropathy
· nephropathy
· amyloidosis
· symptomatic cryoglobulinemia
· evidence of disease transformation
M.A. Dimopoulos, MD
PROGNOSTIC MARKERS IN WM
(Consensus Panel Recommendations)
· Factors Identifying Patients Likely to Require Treatment in
the Short Term
b2-microglobulin
hemoglobin
· Factors Predictive of Overall Survival
hemoglobin
b2-microglobulin
age
albumin
other cytopenias
M.A. Dimopoulos, MD
TREATMENT OPTIONS FOR WALDENSTROM'S
MACROGLOBULINEMIA
· Plasmapheresis
P
Alkylating agents
· Conventional
C
chemotherapy
Nucleoside analogues
· High
H
dose therapy
· Monoclonal Antibodies
Interferon-a
· Miscellaneous
Splenectomy
Thalidomide
M.A. Dimopoulos, MD
TREATMENT OF IgM-RELATED COMPLICATIONS
WITH PLASMAPHERESIS
· Continuous-flow centrifugation system
· 1 to 1.5 x plasma volume exchange per procedure
IgM by 60% to 75%
· Replacement fluid: 5% albumin + 0.9% saline
· Blood flow rates 80 mL/min
Hyperviscosity syndrome
Peripheral neuropathy
Cryoglobulinemia
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WM BASED ON
ALKYLATING AGENTS
Series
Regimen
Pt No Response % Median Survival
(years)
Kyle (2000)
Chl
46
70
5.4
Dimopoulos (1994) Chl Pred
77
57
5.0
Case (1991)
VMCBP
33
82
6.0
Annibali (2005)
MCP
72
77
5.5
Median time to response: 12 to 24 months
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WM WITH
FLUDARABINE
Series
Patient No
% Response
Foran (1999)
15
79
Thalhammer (2000)
7
85
Dhodapkar (2003)
118
40
Median time to response: 2.8 months
(range: 0.8 to 22.5)
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WM WITH CLADRIBINE
Series
Patient No
Response (%)
Dimopoulos (1994)
26
22 (85)
Fridrik (1997)
10
9 (90)
Delannoy (1999)
11
8 (73)
Lewandowski (2000)
11
7 (64)
Hampshire (2003)
14
9 (64)
Total
72
55 (76)
M.A. Dimopoulos, MD
SALVAGE TREATMENT OF WM WITH
FLUDARABINE
Series
Patient No
Response (%)
Dimopoulos (1993)
26
8 (31)
Zinzani (1995)
12
5 (42)
Leblond (1998)
71
21 (30)
Dhodapkar (2003)
64
22 (34)
Total
173
56 (32)
M.A. Dimopoulos, MD
SALVAGE TREATMENT OF WM WITH CLADRIBINE
Series
Patient No
Response (%)
Dimopoulos (1995)
46
20 (45)
Betticher (1997)
24
9 (38)
Delannoy (1999)
16
8 (50)
Lewandowski (2000)
14
9 (64)
Hampshire (2003)
19
12 (63)
Total
119
58 (49)
M.A. Dimopoulos, MD
HIGH DOSE THERAPY WITH AUTOLOGOUS SCT IN
WM
Series
Patient No
Disease
% Response (CR)
status
Desikan (1999)
8
Refractory
100 (13)
Anagnostopoulos (2001)
4
Refractory
75 (0)
Tournilhac (2003)
18
Chemosensitive (14)
95 (11)
Chemoresistant (4)
Dreger (2004)
10
First response
100 (14)
or primary resistant
Fassas (2004)
21
Various phases
100 (62)
M.A. Dimopoulos, MD
TREATMENT OF WM WITH RITUXIMAB (anti CD-20)
Series
No of Patients
Response Rate
Previously treated patients
Weber
8
75 %
Foran
7
29 %
Treon
23
30 %
Dimopoulos*
29
52 %
Treon*
29
48 %
Gertz
35
20 %
Untreated patients
Dimopoulos*
23
35 %
Gertz
34
35 %
* With extended rituximab: similar response rate but longer
duration of response
M.A. Dimopoulos, MD
TREATMENT OF WM WITH RITUXIMAB
· Non-myelosuppressive, no stem cell toxicity
· Median time to response: 3 to 5 months
· IgM flare in 40% of patients
· Some studies indicate that rituximab is less active when
m-protein >40 g/L
· Good choice for cytopenia, candidate for high-dose
therapy
· Avoid when high m-protein or when rapid disease control
is needed
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WALDENSTROM'S
MACROGLOBULINEMIA
Chlorambucil
Nucleoside
Rituximab
analogues
Response
50%
70-80%
40%
Time to response
>6
1.5-5
3-5
(months)
Duration of Rx
12-24
2-6
1
(months)
Cost
low
average
high
Myelosupression
moderate
significant
none
Opportunistic
no
yes
no
infections
Stem cell toxicity
yes
yes
no
Miscellaneous
secondary
IgM flare
leukemia
M.A. Dimopoulos, MD
COMBINATION THERAPY AS PRIMARY
TREATMENT OF WM
Series
Regimen
Pt Status %Response TTP
(months)
Dimopoulos
F+Cy
PreRx
55
24
Tamburini
F+Cy
PreRx, UnRx
77
25
Weber
Cl+Cy
UnRx
84
36
Treon
F+Rit
PreRx, UnRx
91
NR
Weber
Cl+Cy+Rit
UnRx
94
NR
Hensel
Pento+Cy+Rit PreRx, UnRx
90
NR
Dimopoulos
Cy+Dexa+Rit
UnRx
74
NR
M.A. Dimopoulos, MD
TREATMENT OF WALDENSTROM'S
MACROGLOBULINEMIA
· About 90% of patients
responded to 2-CdA/Cy
2-CdA/Cy
2-CdA/Cy/
Addition of rituximab did
(n = 35)
rituximab
not improve response
100
(n = 27)
90
83%
· Response better than
82%
80
reported with alkylating
70
agents (CHOP, CVP, CP)
60
55% response rate
50
40
· Addition of rituximab
30
associated with a trend
20
toward
11%
11%
10
6%
6%
Longer remission duration
0
Complete
Partial
No
Longer time to treatment
response
response
response
failure
M.A. Dimopoulos, MD
REGIMEN
· Dexamethasone 20 mg IV day 1
· Rituximab 375 mg/m2 IV day 1
· Cyclophosphamide 100 mg/m2 PO BID days 1-5
(total dose 1000 mg/m2)
DRC courses are repeated every 21 days for 6
courses
M.A. Dimopoulos, MD
RESPONSE AFTER DRC
CR: 1
74%
PR: 25
Early progression
: 6 patients
Less than 50% reduction
: 4 patients
Median Time to Response
: 4 months
Range
: 0.7-14 months
M.A. Dimopoulos, MD
TREATMENT OF RELAPSED/REFRACTORY WM
WITH BORTEZOMIB
Patient No
8
Male/Female
7/1
Median Age (years)
78
range
48-84
Median serum m-protein
2.7
range (g/dL)
0.8-8.3
Serum b2-microglobulin >3.5mg%
4
Prior treatments
alkylating agents
7
anthracyclines
2
nucleoside analogues
5
rituximab
8
thalidomide
6
Number of prior regimens
2
2
3
4
4
2
Median time to bortezomib (months)
60 (22-78)
M.A. Dimopoulos, MD
TREATMENT OF RELAPSED/REFRACTORY WM
WITH BORTEZOMIB
· 5 of 8 patients achieved 50% reduction of
m-protein
· median time to response: 1 month (0.7 to 2)
· Relatively well tolerated
fever, fatigue, thrombocytopenia, neuropathy
M.A. Dimopoulos, MD
10
9
8
7
(g/dl)
6
protein
5
4
monoclonal
3
serum
2
1
0
0
1,5
3
4,5
6
7,5
9
10,5
12
13,5
15
weeks
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WM
Patient is not potential candidate for auto SCT
Rapid disease control needed?
yes
no
ForCl + Rit
cytopenia(s)?
±
plasmapheresis
yes
no
Rituximab
Chlorambucil
or Rituximab
M.A. Dimopoulos, MD
PRIMARY TREATMENT OF WM
Patient is (or maybe) potential candidate for auto
SCT
Dexa + Cy + Rit ± plasmapheresis
Collect and cryopreserve stem cells
Treat according to risk factors
M.A. Dimopoulos, MD
FUTURE DIRECTIONS IN THE TREATMENT OF WM (I)
· Disease specific survival is a more accurate endpoint
· Monoclonal antibodies
rituximab:standard, extended, maintenance?
alemtuzumab, epratuzumab
immunophenotype screening customized
combination of monoclonal antibodies
· Rituximab ± nucleoside analogues ± alkylating agents
endpoints
response rate and especially CR
response duration
stem cell collection
immunosuppression
cause-specific survival
M.A. Dimopoulos, MD
FUTURE DIRECTIONS IN THE TREATMENT OF WM (II)
New agents
· Oblimersen (BCl2-antisense)
· Imatinib
· Vaccines
· Inhibitors of heat shock protein
· Histone deacetylase inhibitors
Early identification of patients with poor prognosis
High-dose therapy upfront
M.A. Dimopoulos, MD
GREEK MYELOMA STUDY GROUP
(Chairman: A. Maniatis)
Athens
Thessaloniki
G. Pangalis
C. Zervas
A. Anagnostopoulos
M. Papaioannou
N. Anagnostopoulos
I. Katodrytou
V. Grigoraki
Alexandroupolis
G. Kokkinis
C. Tsatalas
E. Vervessou
D. Margaritis
P. Roussou
Patras
M.C. Kyrtsonis
A. Symeonidis
M.A. Dimopoulos
Kriti
S. Delibasi
I. Xilouri
A. Poulis
Ioannina
P. Repousis
C. Bourantas
A. Zomas
A. Vassou
M.A. Dimopoulos, MD