Novel treatment options in
Waldenström macroglobulinaemia
Meletios A. Dimopoulos, MD
University of Athens School of Medicine,
Greece
Faculty disclosure information
Consultant: Celgene, Ortho Biotech, Roche
Grant/Research Support: Celgene,
Ortho Biotech
Speakers Bureau: Celg
pgene, Ortho Biotech
Major Stock Shareholder: No
Single-agent primary treatment of
Waldenström
ö
macroglobulinaemia
macroglobulinaemia
Nucleoside
Chlorambucil
Rituximab
analogues
Response rate, %
50
7080
40
Time to response, months
612
1.55
35
Duration of treatment,
1224
26
1
months
Cost
Low
Av
A erage
v
High
Myelosuppression
Moderate
Significant
None
Opportunistic infections
No
Yes
No
Stem cell toxicity
Yes
Yes
No
Miscellaneous
Secondary
Secondary
IgM "flare"
leukaemia
leukaemia
transformation
Long-term survival after fludarabine in WM:
10-
10 year follow-
follow up of SWOG S9003
S9003 trial
Patients received fludarabine i.v. 30 mg/m2 daily for 5 days
100
Median,
Events
years
N = 183
80
OS
115
6.8
(%) 60
EFS
147
3.0
tsn 40
Patie
OS
20
Estimated 10-year
y
OS 36%
EFS
Estimated 10-year PFS 19%
0
0
5
10
15
Time
Time from registration to treatment (years)
EFS = event-free survival;
PFS = progression-free survival;
SWOG = Southwest Oncology Group.
Dhodapkar MV, et al. Blood. 2009;113:793-96.
Long-term outcomes after
fludarabine and rituximab in
in WM
WM (1)
(1)
Individual changes in serum IgM concentration after
treatment with fludarabine
fludarabine and rituximab
rituximab (best response)
100
N = 43 (27 untreated)
80
l(%)
CR
2
60
CR: n =
VGPR: n = 14
leve
40
MRR 86%
ORR 95%
PR: n = 21
IgM
20
MR: n = 4
m
0
-20
seruin -40
-60
-80
Change
100
-
CR = complete response; MR = minor response; MRR = major
response rate; ORR = overall response rate; PR = partial
response; VGPR = very good partial response.
Treon SP, et al. Blood. In press 2009.
Long-term outcomes after
fludarabine and rituximab in
in WM
WM (2)
(2)
100
Median time to progression
(%)
(all patients) 51.2 months
nts
75
patie
free
50
f
25
ression-
Patients with no progression
g
at last follow-up
Pro
0
0
20
40
60
80
Time from treatment initiation (months)
Treon SP, et al. Blood. In press 2009.
Long-term outcomes after
fludarabine and rituximab in
in WM
WM (3)
(3)
Time to progression
pg
77.6 months (untreated patients)
100
38.4 months (previously treated patients)
(%)
p = 0.049
tsn 75
patie
free
50
f
25
No previous treatment
ression-g
Previous treatment
g
Patients with no progression at last follow-up
Pro
0
0
20
40
60
80
Time from treatment initiation (months)
Treon SP, et al. Blood. In press 2009.
Rituximab in combination with
nucleoside analogues (1)
· Rituximab with cladribine plus cyclophosphamide1
· Rituximab with cladribine plus cyclophosphamide
18 previously untreated patients
ORR 94%; CR
CR in
in 17% of patients
median time to response 2.4 months
median duration of response
p
58.6 months
· Rituximab with subcutaneous cladribine2
29 patients (
p(16 previousl
p
y untreated)
ORR 59%; MR in 24% of patients
1. Thomas SK, et al. Haematologica. 2007;92:[abstract 1227].
2. Laszlo D, et al. Blood. 2007;110:[abstract 1357].
Rituximab in combination with
nucleoside analogues (2)
· Rituximab with fludarabine plus cyclophosphamide (RFC)1
· Rituximab with fludarabine plus cyclophosphamide (RFC)
19 patients (5 previously untreated)
PR in 79% of patients
no patients developed IgM "flare"
delayed response
yp
in 10 patients
p
· RFC (oral fludarabine and cyclophosphamide)2
25 patients (
p(mainly pretreated
p
)
ORR 90%, VGPR in 35% of patients
median duration of response 8 months
1. Tedeschi A, et al. Blood. 2007;110:[abstract 1290].
2. Vargaftig J, et al. Haematologica. 2007;92:[abstract 1226].
DRC regimen
Day
12
3
4
5
D
Dexamethasone 20 mg i.v.
R
Rituximab 375 mg/m2
mg/m i.v.
i.v
Cyclophosphamide 100 mg/m2 p.o. b.i.d. (total 1,000 mg/m2)
DRC course repeated every 21 days × 6
Response, %
N = 72
ORR
83
CR
7
Median time to 50% IgM reduction
CR
7
4.1 (range 0.714) months
PR
67
MR
9
IgM "flare" in 32%
SD
8
25% IgM increase
increase in
in 11%
11%
PD
8
Dimopoulos MA, et al. J Clin Oncol. 2007;25:3344-49.
DRC regimen: time to progression
All patients
patients
Patients with a response
100
(%)
100
ents 75
75
pati
50
50
-freen
25
2-year PFS rate 67%
25
2-year PFS rate 80%
rogressio
0
0
P
0
20
40
0
20
40
Time from treatment initiation (months)
Without additional treatment, 2-year s r
u i
v a
v l
al rate
rate 78%
2-Year overall survival rate 81%
Dimopoulos MA, et al. J Clin Oncol. 2007;25:3344-49.
Standard R-CHOP in untreated WM
· 16 patients
median age 60 (range 4479) years
median 2-microglobulin 3 (range 2.17.6) g/mL
median haemoglobin 9 (range 7.710.9) g/dL
median IgM 6,389 (range 3,22913,300) mg/dL
· Objective response
response 91%
1 patient had an MR
· Median time to response 1 6
. months
months
· Median time to maximum response 2.1 months
· The main
main adverse event was myelosuppression
myelosuppression
CHOP = cyclophosphamide, hydroxydaunorubicin, Oncovin®
(vincristine), prednisone; R-CHOP = CHOP and rituximab.
Abonour A, et al. Blood. 2007;110:[abstract 3616].
CHOP versus R-CHOP in WM (1)
CHOP (n = 25)
N4
N = 8
48
R-CHOP (n = 23)
100
91
ORR
CR
)
75
%
60
ts(
50
ienatP 25
9
4
0
CO
CHOPR CO
-CHOP
Buske C, et al. Leukemia. 2009;23:153-61.
CHOP versus R-CHOP in WM (2)
Time to treatment failure after start of CHOP or R-CHOP therapy
10
1.0
0.8
0.6
robability 0.4
P
R-CHOP, median 5.2 years
CHOP, median 1.8 years
0.2
p = 0.0241
0 01
2
3
4
5
6
Time after start of induction therapy (years)
Number of patients at risk
R-CHOP
23
18
16
9
7
3
0
CHOP
25
14
10
5
1
0
Buske C, et al. Leukemia. 2009;23:153-61.
Thalidomide and rituximab in WM:
responses
· 25 patients, 23
23 of
of whom
whom received the intended
intended therapy
· Responses in evaluable patients
CR in 1 (4%)
(%)
64%
PR in 15 (60%)
MR in 2 (8%)
72%
SD in 1 (4%)
· Median follow-up 42 months
median TTP 35 months for all
all patients
median TTP 38+ months for patients with a response
MR = major response.
Treon SP, et al. Blood. 2008;112:4452-7.
Thalidomide and rituximab in WM:
time to progression
All evaluable patients
p
Patients with a response
p
100
100
(%)
ients 75
75
pat
50
50
n-freeo
25
25
Median TTP 34.8 (range 1.049.1) months
Median TTP 38.7 (range 10.349.1) months
rogressi
0
P
0
P
0
102030
4050
010
20
30
40
50
Time from treatment initiation (months)
Medi
ed an
a foll
o ow-
o up 47.1 mon
o th
t s; pr
p og
o r
g ess
ession in 10 of 18 pati
pat en
e ts
ts with
t a respo
e
n
spo se
se
For untreated patients, median TTP 36.04 (range 2.549.1) months
For pretreated patients, median TTP 15.25 (range 1.045.8) months (p = 0.36)
Treon SP, et al. Blood. In press 2009.
Bortezomib monotherapy in WM
Median
Study
Patients, N
ORR, %
PR, %
cycles, n
WMCTG1
27685
44
NCI-Canada2
27678
44
Dimopoulos3
10460
60
Gd
Grade 3t
3 sensory neuropa h
thy, seen in 20
2030% of patitients, was reversible
in most patients.
1. Treon SP, et al. Clin Cancer Res. 2007;13:3320-5.
2. Chen CI, et al. J Clin Oncol. 2007;25:1570-5.
3. Dimopoulos MA, et al. Haematologica. 2005;90:1655-8.
Twice-weekly BDR
as primary treatment
treatment in WM
· 23 patients
· Median 7 (range 38) cycles
Response
Patients, n (%)
(%)
CR or nCR
5 (22)
83%
PR
14 (61)
()
96%
MR
3 (13)
SD
1 (4)
· Median time to 25% decrease in IgM 1.1 months
· Median follow-up 22.8 (range 3.333.2) months
18 (78%) of 23 patients remain progression free
BDR = bortezomib, dexamethasone, and rituximab.
Treon SP, et al. J Clin Oncol. In press 2009.
BDR in WM: adverse events
Patients, %
Adverse event*
Grade 2Grade 3
Pt
Paraes h
thesia
69
30
Anaemia
83
4
Neutropenia
56
30
Thrombocytopenia
43
9
* 13 (81%) of 16 resolved at a median of 6 months.
Or grade 4.
Of the first 7 patients on study, 4 had a herpes zoster infection
necessitating treatment with valacyclovir 1 g/day p.o.
Treon SP, et al. J Clin Oncol. In press 2009.
Weekly bortezomib and rituximab
in relapsed/refractory WM
WM
· 37 patients enrolled; 30 evaluable
· Median number of prior treatments 3 (range 15)
Response
p
Patients, n (%)
()
CR
1 (3)
PR
16 (53)
ORR 89%
MR
10 (33)
SD
2 (7)
PD
1 (3)
· Median time to response 3 (range 27) months
· Rituximab "flare" occurred in 6 patients (20%)
· Median duration of response not reached (range 324+ months)
Ghobrial IM, et al. Blood. 2008;110:[abstract 832].
European Myeloma Network (EMN):
BDR protocol as primary treatment
treatment
21 days
35 days
35 days
35 days
35 days
Cycle 1
Cycle 2
Cycle 3
Cycle 4
Cycle 5
1 4 8 11
1 8 15 22
1 8 15 22
1 8 15 22
1 8 15 22
Cycle 1: bortezomib 1.3 mg/m2
Bortezomib Cycles 25: bortezomib 1.6 mg/m2
Rituximab (375 mg/m2
mg/m )
Dexamethasone (40 mg)
www.clinical trials.gov. NCT00832234.
EMN BDR protocol as primary treatment
(Greece, Spain, France
France, Netherlands)
Preliminary results
· 30 patients accrued so far
· 25 patients are
are evaluable for a response (5
(5 are
are early
for evaluation)
Response
Patients, n
CR
1
PR
10
MR
4
SD
8
PD
2
Alemtuzumab in WM (1)
· 28 patients
5 untreated
all previously treated patients had received rituximab
25 patients evaluable
Response
Patients, %
ORR
76
PR
32
MR
44
Hunter ZR, et al. J Clin Oncol. 2006;24:[abstract 752].
Alemtuzumab in WM (2)
· Haematological adverse events
grade 3 events most common in previously treated patients
(74% vs 20%; p = 0.041)
Haematological events (grade 3 and
and 4)
Patients, %
Neutropenia
39
Thrombocytopenia
18
Ai
Anaemia
7
Non-haematological events (grade 3 and 4)
Patients, %
Dermatitis
11
Fatigue
7
Infection
7
· After a median follow-up of 8.5+ months, 11 of 19
patients with a response remain free of progression
Hunter ZR, et al. J Clin Oncol. 2006;24:[abstract 752].
High-dose therapy for WM
Facts to
to consider
consider
· Patients' advanced age, and therefore comorbidity
· R l
e t
a il
tively b i
en gn l
c ili il
nical course f
o th
the di
disease
· Prior treatment with nucleoside analogues
· High risk of developing MDS or leukaemia
Autologous stem cell transplantation
Retrospective analyses
· EBMT registry1
201 patients
at time of transplant, 86% of patients had chemosensitive
disease and 14% had relapsed/refractory disease
transplant-related mortality
mortality rate
rate 8%
8%
5-year PFS 33%; 5-year OS 61%
· French registry2
32 patients
median EFS 32 (range 2119) months
5-year OS 58%
EBMT = European Group for Blood
1. Kyriakou C, et al. Haematologica. 2007;92:[abstract 1228].
and Marrow Transplantation.
2. Dhedin M, et al. Haematologica. 2007;92:[abstract 1229].
Allogeneic stem cell transplantation (1)
· EBMT registry
registry
106 patients
· at time of transplant, 70% had chemosensitive disease and
30% chemorefractory disease
disease
conventional conditioning was administered to 41% of patients
and RIC to 59%
1-year non-relapse mortality rate 27%
5-year PFS 48%; OS 63%
RIC = reduced intensity conditioning.
Kyriakou C, et al. Haematologica. 2007;92 Suppl 2:[abstract n. WM3.09].
Allogeneic stem cell transplantation (2)
· French registry
registry
22 patients; MA-allo in 11, RIC-allo in 11
transplant-related mortality rate
· 36% in MA-allo group
· 27% in RIC-allo group
median EFS
· 36 months in MA-allo group
· not reached in RIC-allo group
relapse rate
rate
· 36% in MA-allo group
· no relapses in RIC-allo group
MA = myeloablative.
Dhedin M, et al. Haematologica. 2007;92:[abstract 1229].
Allogeneic stem cell transplantation (3)
· Seattle experience
experience
12 patients underwent RIC-allo-SCT
transplant-related mortality rate 17%
10 of 11 evaluable patients had a response after the
transplant (4 CR, 6 PR)
5-year PFS rate 61%
median time to CR 12 months, thus supporting a
graft-versus-tumour effect
SCT = stem cell transplantation.
Anderson LD, et al. Blood. 2006;108:[abstract 3034].
Recommendations for
front-line treatment
treatment (1)
· Individual patient considerations in choosing a
first-line treatment
presence of cytopenia
need for rapid disease control
age
comorbidity
candidacy for an autologous transplant
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
Recommendations for
front-line treatment
treatment (2)
· Rituximab-based therapies may be
be the
the preferred initial
initial
treatment for most patients with WM
· When rapid disease control is needed,
p, R-CHOP or
NA-RC could be an appropriate choice
· Bortezomib-based combinations may emerge as a
choice for patients with hyperviscosity in whom rapid
reduction of the paraprotein is needed
· For patients who
who are, or
or may
may in the future
future be
be,
candidates for ASCT, appropriate primary therapies
include R-CHOP, DRC, and RT
DRC = dexmathasone, rituximab, and cyclophosphamide;
Dimopoulos MA, et al.
NA-RC = nucleoside analogues plus rituximib plus cyclophosphamide.
J Clin Oncol. 2009;27:120-6.
Recommendations for
front-line treatment
treatment (3)
· DRC or RT may be
be preferable
preferable for
for patients with
cytopenias, even for patients who are not candidates
for ASCT
· Rituximab with a nucleoside analogue with or without
cyclophosphamide may also be appropriate, especially
in patients with features
features of advanced disease
· Some selected patients with low-risk disease may
be appro
pp priate candidates for single-a
g
gent rituximab
or chlorambucil because of associated comorbid
conditions
RT = rituximab and thalidomide.
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
Recommendations for front-line treatment
in transplant candidates
Clinical condition
Recommended treatment
Ct
Cytopenia
DRC
Rituximab + thalidomide
High M-protein
R-CHOP
concentration
DRC
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
Recommendations for front-line treatment
in non-
non transplant candidates
Clinical condition
Recommended treatment
Cytopenia
DRC
Rit i
ux
b
ma + thalid
id
om e
High M-protein levels Nucleoside analogues + rituximab
Nucleoside analogues + rituximab +
cyclophosphamide
Low M-protein level
Rituximab
and cytopenia
Older age and slow
Chlorambucil
progression
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
Recommendations for
salvage treatment (1)
· The choice
choice of salvage therapy depends on
on
front-line treatment
quality and duration of previous response
patient's age
tolerance of initial therapy
candidacy for
for SCT
· Re-use of a front-line single agent or combination is
reasonable if a patient had an unmaintained response
that lasted for at least 12 months
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
Recommendations for
salvage treatment (2)
· For patients who
who have a short remission
remission or resistance
to a front-line regimen, second-line treatment may
include agents of a different class, alone or combined
· RFC or RCC regimen may be appropriate, but
should be avoided in younger patients and those
who are
are eligible for ASCT
· Bortezomib-based therapy may be an appropriate
second-line choice
· Alemtuzumab may represent a reasonable choice of
third-line therapy
RCC = rituximab, cladribine, and cyclophosphamide;
RFC = rituximab, fludarabine, and cyclophosphamide.
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.
The role of high-dose therapy
· The place
place of autologous or
or allogeneic
allogeneic SCT requires
requires
further evaluation in the context of prospective trials
· According to the IPSSWM,
g, one-third of patients belong
pg
to a high-risk group with a median survival of 3 years
· For younger patients with high-risk disease,
prospective trials should be considered that
incorporate high-dose therapy in the up-front treatment
strategy
· All new randomized trials should stratify patients
according to IPSSWM, and eventually specific
treatments may be evaluated for the different IPSSWM
risk groups
Dimopoulos MA, et al. J Clin Oncol. 2009;27:120-6.