5/12/2011
Purine analogs in Waldenström's
Macroglobulinemia
Véronique Leblond
Hôpital Pitié Salpêtrière
Therapeutic options
· Alkylating agents
· Purine analogs
· Monoclonal antibodies
· Bortezomib
Alone or in combination
· No large randomized trials
· Elderly patients (median age: 70 years) with comorbidities
· Treatments must be tailored to patient status
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5/12/2011
Chemotherapy
Overall
Randomized
CR
PFS
response
studies
Chlorambucil
Clb daily vs
(Facon 1993, Kyle 2000
40-80%
<5%
26m- 46m
Dimopoulos 1994 Garcia- Sanz
intermittent
2001)
Purine analogs
F vs Clb
38-79%
<5%
24- 40 m
WM1
(Foran 1999, Dhodapkar 2001)
Purine analogs +
27-36m
Cyclophosphamide
70-90%
<5%
(Tamburini 2006 Weber 2003)
A randomized trial of chlorambucil vs. fludarabine as initial
therapy in Waldenström's Macroglobulinemia (WM), non
MALT marginal zone lymphoma (MZL) and nonIgM
lymphoplasmacytic lymphoma (LPL) (WM1 trial)
V Leblond, J Lejeune , O Tournilhac, P Morel , MS Dilhuydy, C Dartigeas,
M Malphette, B Royer , M Ewings, S Chevret , S Johnson, R Owen
Hôpital Pitié Salpêtrière , Hôpital Saint Louis , CHU Clermont Ferrand, Hôpital
Schaffner Lens, CHU Bordeaux , CHU Tours, CHU Amiens
Department of Haematology, Taunton and Somerset NHS Foundation Trust, Taunton,
HMDS Laboratory, St James's Institute of Oncology, Leeds, UK.
NCRI Lymphoma Clinical Studies Group (UK)
Groupe coopérateur français LLC/MW (France)
GOELAMS
GELA
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5/12/2011
Inclusion criteria and end points
· WM, non MALT MZL, LPL in untreated
symtomatic patients (except splenectomy in
splenic MZL)
· Tumor population B CD5CD23 ( mandatory
immunophenotyping )
· PS<3
Primary endpoint: response rate and duration of
the response
Trial design.
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Rate of accrual 7/01 ­ 12/09 (n=418).
420
400
380
360
340
320
300
280
260
240
220
200
180
160
140
120
100
80
60
40
20
0
1
2
2
3
3
5
5
5
6
6
7
7
8
8
9
9
-0
t-01
02
03
06
07
09
v-
il-0
t-02
l-0
-03
v-04
-04
-04
t-04
v-0
il-0
t-05
l-0
-06
-0
l-0
t-07
v-08
-0
t-08
v-
il-0
-09
juil
oc
nv-
nv-
nv-
jan
avr-0
ju
oc
ja
avr-0
jui
oct
jan
avr
juil
oc
jan
avr-0
ju
oc
ja
avr-0
jui
oct
ja
avr
jui
oc
jan
avr-0
juil
oc
jan
avr-0
ju
oct
Inclusion N = 418
4 exclusions ( 2 errors of randomisation, 2 wrong diagnoses)
Fludarabine
Chlorambucil
(FAMP)
CHB
N = (50%)
N = (50%)
U.K.
France
N = 214
N = 200
WM: N = 339
MZL: N = 37
LPL: N = 38
FAMP: N=84
WM
FAMP: N=85
WM =
CHB: N=84
N = 171
CHB: N=86
168
FAMP: N=10
MZL
FAMP: N=9
MZL
CHB: N=9
CHB: N=9
N = 19
N = 18
LPL
FAMP: N=5
LPL
FAMP: N=14
CHB: N=5
CHB: N=14
N = 10
N = 28
FAMP
CHB
FAMP
CHB
N=107
N=107
N=100
N=100
(50%)
(50%)
(50%)
(50%)
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5/12/2011
Clinical and biological parameters
Fludarabine
Chlorambucil
Pvalue
Age (ans)
67.1 ± 9.6
67.3 ± 9.4
0.8
Sex (male. %)
67.1
66.7±
0.9
Hb (g/dl)
10.1 ± 2.1
10.2 ± 2.1
0.9
WBC (G/l)
9.2 ± 13.8
9.3 ± 14.8
0.3
Neutrophil (G/l)
3.6 ± 1.9
3.4 ± 1.9
0.9
Lymphocytes (G/l)
4.7 ± 13.3
4.9 ± 13.3
0.8
Platelets (G/l)
228 ± 128
220 ± 123
0.5
Creatinine (µmoles/l)
88 ± 23
93 ± 25
0.08
Albumin (g/l)
38 ± 837 ± 37
0.4
2M (mg/l)
3.7 ± 1.7
4 ± 2
0.08
IgM
30 ± 21
30 ± 20
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Response criteria
WM+ LPL
· PR : > 50% of tumor masses and monoclonal
component: 2nd international workshop (Weber
2003)
Marginal Zone Lymphoma
Cheson's criteria (1999)
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5/12/2011
Response Evaluation
Fludarabine
Chlorambucil
P
(N=207)
(N=207)
PR
88 (42.5%)
76 (36.7%)
P=0.06
CR
11 ( 5%)
4 (2%)
PR+CR
99 (47.8%)
80 (38.6%)
P=0.03
Stable
66 (32%)
68 (33%)
Failure
22 (10.5%)
37 (18 % )
Not evaluable
20
(9.7 %)
22 (10.7%)
Median duration of
42.1months
22.9 months
P=0.001
response
response rate at 5 y
30%
15%
Response Evaluation
Fludarabine
Chlorambucil
Entities
WM ( N=339)
N=168
N= 171
Response
77 (45.8%)
61 (35.7%)
Failure
76 (45.2%)
89 (52%)
NE
15(9%)
21 (12.2%)
MZL+LPL (N= 75)
N=38
N= 37
Response 22 (58%)
19 (51%)
Failure
12 (31.5%)
16 (43.2%)
NE
4 (10.5%)
2 (5.4%)
Age, hemoglobin , albumin and 2Microglobulin levels had no impact on the response rate
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Progression free survival
Median followup 36 months
Randomisation
Median (m)
95%C I
Fludarabine (N=207)
36.3 m
29.5; 44.5
Chlorambucil (N=207)
27.1 m
21.6;32.5
p= 0.015
Progression free survival
(Multivariate analysis)
Hazard Ratio
Parameter
p
[95%IC ]
Fludarabine
1
Chlorambucil
1.3 [1.0 ; 1.7]
0.03
Albumin 40 g/l
0.7 [0.5 ; 0,9]
0.03
Beta 2 microglobulin >3 mg/l
1.3 [0.5 ; 0.9]
0.04
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Disease free survival
Median
Randomisation
95%C I
(months)
Fludarabine ( N=99)
38.3 m
31; 46.4
Chlorambucil ( N=80)
19.9 m
16.1; 29.2
P=0.0005
Overall survival
P=0.055
CHB
FAMP
Overall survival at 5 y
62.1%
70.3%
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5/12/2011
Toxicity > grade II
(p=0.03)
Fludarabine
Chlorambucil
Number of cycles: 1017
Number of cycles: 1618
symptoms
Grade III
Grade IV
Grade III
Grade IV
N = 50
N = 45
N = 47
N = 25
Hemoglobin
24 (11.8)
25 (12.3)
25 (12.4)
14 (6.9)
Neutrophils
30 (14.8)
28 (13.8)
27 (13.4)
7 (3.5)
Platelets
6 (3.0)
11 (5.4)
10 (5.0)
8 (4.0)
Urea
1 (0.5)
5 (2.5)
3 (1.5)
4 (2.0)
Creatinine
0 (0.0)
0 (0.0)
0 (0.0)
3 (1.5)
ALT / AST
0 (0.0)
1 (0.5)
0 (0,0)
0 (0.0)
Infection
0 (0.0)
1 (0.5)
0 (0.0)
0 (0.0)
Lung toxicity
1 (0.5)
2 (0.9)
0 (0.0)
2 (1.0)
Neuropathy
0 (0.0)
0 (0.0)
1 (0.5)
0 (0.0)
Cardiac toxicity
0 (0.0)
0 (0.0)
1 (0.5)
0 (0.0)
Causes of death
65 UK, 46 France : 111 patients
· Progression: 35
· Infection: 18
· Large cell non Hodgkin lymphoma: 9 (7 Bcell and 2 Tcell)
· Solid tumors : 8 ( 1 mesothelioma, 2 lung K, 1 glioblastoma, 1 liver
K, 1 epidermoid carcinoma, 1 rectal carcinoma, 1 unknown)
· ALL: 1
· AML: 1
· Hemorrhage: 4
· Others: 13
· Unknown : 22
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Immunochemotherapy
Overall response
CR
PFS
Response duration 52 m
Rituximab + fludarabine
Treon Blood 2009
Median treated :38m
43 patients
95%
5%
Treated: 20
Median untreated: 77 m
Untreated: 23
Rituximab + purine
analogs
80% at 17m
82%
7%
(Treon 2004)
Rituxumab +
fludarabine+ cyclo
(Leblond 2011)
Median not reached at 45 months
62 patients
84%
VGPR/RC 30%
Response duration 41 months
Treated: 46
Untreated: 16
R- 2CDA
NA
(Lazlo 2008)
89.6%
28%
(29 pts)
Incidences of MDS/AML and Richter syndrome following Fludarabine, alone or combined
with Cyclophosphamide in 4 studies of the French Cooperative group on CLL/WM.
Previous
Study
S
FU
MDS
N
Study
Status
TTT
RS
treatment
treatment
(month)
(month)
AML
Retrospective Study
Alkylating
1
Relapse
Fluda IV x
1/71
5/71
71
5.9 yrs
based
23
34
Leblond (J Clin oncol
refractory
6
(1.4 %)
(7 %)
regimen
1998)
Randomized
First relapse
Alkylating
prospective Study 2
Fluda IV x
4/45
3/45
46
Primary
3.9 yrs
based
41
34
Leblond (Blood
6
(8.9 %)
(6.6 %)
refractory
regimen
2001)
Randomized
First relapse
Alkylating
prospective Study 2
2/45
2/45
46
Primary
3.9 yrs
based
CAP x 645
34
Leblond (Blood
(4.5 %)
(4.5%)
refractory
regimen
2001)
Retrospective Study
Alkylating
3
Untreated:14
based
Fluda + Cy
2/49
5/49
49
2.1 yrs
NR
42
(Tamburini
Relapse: 35
regimen,
IV x 6
(4 %)
(10 %)
Leukemia 2005)
fludarabine
Alkylating
Retrospective study
based
Rituximab
Untreated:16
2/62
3/62
62
4
4 yrs
regimen,
+ fluda+
NR
45
Relapse: 46
(3.2 %)
(4.8 %)
(Leblond 2011)
fludarabine
Cyx6
Rituximab
N: number of patients; TTT: Time To Treatment from diagnosis to study; Fluda IV: Fludarabine 40mg/m2 J1-J3 IV; CAP: Doxorubicine 25mg/m2 IV
D1, Cyclophophamide 750mg/m2 IV D1,
Prednisone 40mg/m2 D1-5; Fluda + Cy PO: Fludarabine 30mg/M2 D1-3
plus Cyclophosphamide
300mg/m2 D1-3; S: Survival; F-U: Follow-Up; MDS: myelodysplasic Syndrome; AML: Acute Myeloid Leukemia; RS: Richter's Syndrome.Rituximab
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Conclusions.
· Fludarabine is more effective than chlorambucil,
with acceptable toxicity
· Purine analogs are highly efficacious in WM ­
learn from CLL
·The impact of highly active regimens on the
incidence of therapy related complications
(MDS/AML, RS, long lasting cytopenia) must be
assessed in prospective trials
· Randomized phase III trials are possible in WM but
international collaboration (and patience!) is
essential
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