rituximab efficacy in other haematological malignancies
DESCRIPTION
Rituximab efficacy in other haematological malignancies. Christian Buske. CLL. Dose escalation of rituximab for CLL: response in patients with CLL. Response rate (%). (n=39)*. (n=24)*. (n=7)*. (n=9)*. Rituximab (mg /m 2 ). * Evaluable patients. - PowerPoint PPT PresentationTRANSCRIPT
Rituximab efficacy in other haematological malignancies
Christian Buske
CLL
Dose escalation of rituximab for CLL: response in patients with CLL
36
22
43
75
0
20
40
60
80
100
All Patients 500-825 1000-1500 2250
Rituximab (mg/m2)
Res
po
nse
rat
e (%
)
(n=24)* (n=7)* (n=9)*(n=39)*
* Evaluable patients O’Brien et al. J Clin Oncol. 2001;19:2165.
Evaluable patients(n=33)
Complete response
Partial response
Overall response rate
Response (%)
3
42
45
Byrd J, et al. J Clin Oncol 2001;19:2153–64
Median response duration – 10 months Fludarabine refractory patients – 6 months
Thrice weekly rituximab:overall response and outcome
Rituximab thrice weekly for CLL: median progression-free survival
Adapted from Byrd et al. J Clin Oncol. 2001;19:2153.
20 4 6 8 10 12 14 16 18 20
0
20
40
60
80
100
Months
Pat
ien
ts (
%)
Responders
All patients
Progression-free survival: rituximab plus fludarabine (9712) versus fludarabine arm of 9011
Rituximab + fludarabineCALGB 9712
FludarabineCALGB 9011
Retrospective analysis
1.0
0.8
0.6
0.4
0.2
00 20 40 60 80 100 120 140
Months
Pro
bab
ilit
y o
f p
rog
ress
ion
-fre
esu
rviv
al
p<0.0001
Byrd J, et al. Blood 2005;105:49–53
Overall survival: rituximab plus fludarabine (9712) versus fludarabine arm of 9011
Rituximab + fludarabineCALGB 9712
FludarabineCALGB 9011
Retrospective analysis
1.0
0.8
0.6
0.4
0.2
00 20 40 60 80 100 120 140
Months
p=0.0006
Pro
bab
ilit
y o
f p
rog
ress
ion
-fre
esu
rviv
al
Byrd J, et al. Blood 2005;105:49–53
MabThera + fludarabine/cyclophosphamide (FCR) for previously untreated CLL: protocol
MabThera 375mg/m2 (cycle 1) or 500mg/m2
(cycles 2–6)
Fludarabine 25mg/m28 15 22 291 2 3 4
Cycle 1 Start cycle 2
8 15 22 291 2 3
Cycles 2–6
Cycle repeats
Cyclophosphamide 250mg/m2
Days
Days
Keating M, et al. Blood 2005;106;599a (Abstract 2118)
FCR for previously untreated CLL: patient characteristics
Male (%) 70.3
Rai stage III-IV (%) 33
Median age (range) 57 (17–86)
Hemoglobin (range) 12.5G% (6.1–18.7)
White cell count (range) 76 x 103/μl (2.1–620)
Platelets (range) 154 x 103/μl (8–406)
Splenomegaly (%) 51
Patient characteristics
Keating M, et al. Blood 2005;106;599a (Abstract 2118)
FCR for previously untreated CLL: response rates
Response rate (%)
CR 72
nPR 10
PR 12
● The pretreatment characteristic most strongly associated with CR rate was β2-microglobulin level
Keating M, et al. Blood 2005;106;599a (Abstract 2118)
FCR for previously untreated CLL: 4-year analysis of previously untreated CLL patients
Response Patients (n) Response duration (%) Overall survival (%)
CR 217 83* 84*
nPR 31 64 84
PR 37 38 50
Overall 300 77 (CR + PR) 83
*p<0.01
● PCR for IgVH and flow responses were independently associated with duration of response
Keating M, et al. Blood 2005;106;599a (Abstract 2118)
FCR for previously untreated CLL: toxicity
Secondary cancers 17.7
AML 1
Myelodysplastic syndrome 1
AIHA 8.3
Red cell aplasia 2
Patients (%)
Keating M, et al. Blood 2005;106;599a (Abstract 2118)
Pro
po
rtio
n
1.0
0.8
0.6
0.4
0.2
0.0
Patients Failed Ex
202 185 F ± P
92 63 FC
224 53 FCR
0 12 24 36 48 60 72 84
p=0.004
p<0.001
Months
Time to failure by initial treatment:historical comparison of F+P vs FC vs FCR
Keating M, et al. Proc Am Soc Clin Onc 2004
FCR for previously treated CLL: response by prior therapy
Patients (%)
Fludarabine Fludarabine
sensitive resistant (n=108) (n=37)
OR 76 59
CR 31 5
PR 28 43
Nodular PR 17 11
Wierda et al., J Clin Oncol 2005;23:4070–8
Relapsed/refractory CLL: overall survival by treatment regimen
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6 7 8 9 10 11 12
Years
Pro
po
rtio
n s
urv
ivin
g
Wierda W, et al. Blood 2003;102:110a (Abstract 373)
Patients Died Protocol Median (months)
251 241 F ± P* 19
111 83 FC* 29
143 55 FC + rituximab 42+
p<0.01
p<0.04
*Historical controls
Pentostatin cyclophosphamide in previously treated CLL patients: response rates
0
20
40
60
80
100
OR CR
Patie
nts
(%)
All patients (n=23)
fludarabinerefractory (n=13)
74
8
17
77
Weiss M, et al. J Clin Oncol 2003;21:1278–84
CFAR: doses and schedule
Drug Dose Day of course
Cyclophosphamide 250mg/m2 3–5
Fludarabine 25mg/m2 3–5
Alemtuzumab 30mg 1, 3, 5
Rituximab 375–500mg/m2 2
(Allopurinol; TMP/SMX; Valacyclovir)
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Patient characteristics: CFAR (n=63)
Rai stage (int., high risk) 30, 33
Karyotype (n=53) complex (17p=15; 11q=10) 48% 11q del sole 5% 6q del sole
2% 13q del 5% Diploid 17% +12
8% Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Patient characteristics CFAR (cont.)
Median no. prior Rx 3 (1–14)
Alk refractory 35 (56%)
Flu refractory 28 (44%)
Prior FC 11 (17%)
Front-line 3
Salvage 8
Prior FCR 32 (51%)
Front-line 13
Salvage 19
Prior SCT 4 (6%)
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Response assessment (NCI-WG): CFAR (n=63)
Response Patients (%) ORR 42 (67)
CR 14 (22) nPR 1 (2) PR* 27 (43) NR 17 (27) Early death 3 (5) Not evaluable 1 (2)*10 PRs due to persistent cytopenia
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Response by patient characteristics:CFAR (n=63)
Characteristic CR OR
Rai Stage
I–II (n=30) 27 80
III–IV (n=33) 18 52*
Fludarabine sensitive (n=35) 37** 83
Fludarabine resistant (n=28) 4** 46**
Response (%)
*p<0.02**p<0.01
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Multivariate analysis: FCR and CFAR (n=231)
Variable CR TTP OS
Flu-Ref <0.001
2M 0.003 <0.001
No. prior Rx <0.001
ALB 0.03
Rai stage <0.001
Cytogenetics <0.01
PLT 0.03
Protocol 0.90 0.27 0.07
p-value
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Patients (%)
CFAR FCR n=63 n=177
Toxicity G3 G4 G3 G4
Neutropenia 17 71 15 66
Thrombopenia 24 35 16 18
Haematological toxicities: CFAR
Wierda W, et al. Blood 2005;106:213a (Abstract 719)
Waldenström’s macroglobulinaemia
Single-agent rituximab for the treatment of WM
Reference n OR (%) PR (%) Median
Dimopoulos et al. 20021
27 - 44 TTP: 16 months
Treon et al. 20022
29 73 46 TTF*: not reached
*Median follow-up of 20 months
1. Dimopoulos M, et al. J Clin Oncol 2002;20:2327–33
2. Treon S, et al. Blood 2002;100:813a (Abstract 3211)
Rituximab plus chemotherapy for the treatment of WM
Dimopoulos et al. 2004– previously untreated WM patients (n=34)
– treated with dexamethasone, rituximab and cyclophosphamide
– mean follow-up of 18 months 90% of pts progression free
Treon et al. 2002– previously treated WM patients (n=23)
– treated with rituximab plus fludarabine
– 85.7% of evaluable patients responded
Dimopoulos M, et al. Blood 2004;104:215a (Abstract 752)
Treon S, et al. Blood 2002;100;211a (Abstract 794)
R-CHOP vs CHOP in previously untreated LP-IC: patients
Patients (n=75) with previously untreated lymphoplasmocytoid/ic immunocytoma (LP-IC)
Lymphoplasmocytic 72%
Lymphoplasmocytoid 28%
Median age 61 years
IPI int/high or high 23%
Buske C, et al. Ann Onco 2005l;16:v110 (Abstract 250)
R-CHOP vs CHOP: response in patients with lymphoplasmocytoid/ic immunocytoma (LP-IC)
Buske C, et al. Ann Onco 2005l;16:v110 (Abstract 250)
0
20
40
60
80
100
OR CR
Pat
ien
ts (
%) R-CHOP
CHOP
TTF after 4 years: median not reached (R-CHOP) vs 1.8 years (CHOP); p=0.003
92*
70*
11* 5*
*p=0.035
PTLD
PTLD: response rates to single-agent rituximab and R-chemo
Reference Treatment n PR (%) CR (%) OR (%)
Choquet et al. 2002
Rituximab monotherapy
55 - 32.7 45.5
Trappe et al. 2005
Rituximab, CHOP + G-CSF
29 20.8 62.5 83.3
Choquet S, et al. Blood 2003;102:277a (Abstract 986)
Trappe R, et al. Blood 2005;106:274a (Abstract 932)
Front-line rituximab improves overall and event-free survival in patients with PTLD
108 patients with PTLD enrolled in the study – 33% treated with rituximab
In the whole group– CR: 46%
– PR: 13% Patients treated with rituximab had significantly
prolonged OS and EFS compared to the group as a whole (median follow-up of 15.2 months)– OS: 76% vs 21% (p=0.007)
– EFS: 70% vs 15% (p=0.02)
Gonzalez-Barca E, et al. Blood 2004;104:394a (Abstract 1406)
Rituximab efficacy in other haematological malignancies: conclusions
Rituximab in combination with fludarabine and cyclophosphamide is one of the most active regimens for the treatment of CLL– now being evaluated in phase III trials
Promising response rates in fludarabine refractory CLL patients have been achieved with rituximab containing regimens
Single-agent rituximab and rituximab/chemotherapy combinations have also demonstrated efficacy in LP-IC, WM and PTLD and warrant further investigation