Rituximab efficacy in other haematological malignancies Christian Buske

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

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60

80

100

Months

Pat

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%)

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

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-fre

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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

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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


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


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


FCR for previously untreated CLL: toxicity

Secondary cancers 17.7

AML 1

Myelodysplastic syndrome 1

AIHA 8.3

Red cell aplasia 2

Patients (%)


Pro

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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

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Years

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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

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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)


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%)


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


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


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


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


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

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OR CR

Pat

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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

Documents

Rituximab efficacy in other haematological malignancies Christian Buske