mabthera ® for chronic lymphocytic leukemia (cll)

MabThera® for Chronic Lymphocytic Leukemia (CLL)

Chronic Lymphocytic Leukemia

Staging CLL Characteristics Therapy Options MabThera in combination with chemotherapy for

CLL MabThera monotherapy for CLL

Rai Staging of Chronic Lymphocytic Leukemia

Stage

Criteria 0 I II III IV

Lymphocytosis (>15,000/mm3)

Lymphadenopathy

Splenomegaly

Hepatomegaly

Anemia (hemoglobin <11 g/dL)

Thrombocytopenia (<100,000/mm3)

+ +/-

CLL Characteristics

B-cell lineage 95%

Immunophenotype CD5+

CD19+

CD20+

CD23+ CD52+

Cytogenetic abnormalities Deletions at 13q14 Trisomy 12

Therapeutic Options for CLL

Chemotherapy– Single-agent: chlorambucil, fludarabine®

– Combination: FC, CVP

MoAbs– MabThera®

– Campath-1H®

SCT – Allogeneic– Mini-allogeneic– Autologous

Radiation (localized)

MabThera in combination with chemotherapy for CLL

MabThera + fludarabine for previously untreated CLL

Byrd et al

Blood 2003

MabThera + fludarabine for previously untreated CLL: protocol

RANDOMISED

RANDOMISED

Consolidation therapy

Patients with CR, PR, or stable disease received

MabThera (375mg/m2

weekly x 4)

Fludarabine 25mg/m2MabThera 375mg/m2

Sequential

1 5 9 13 17 21

Weeks

Concurrent

1 5 9 13 17 21Weeks

(2 months)

Byrd JC, et al. Blood 2003;101:6–14

MabThera + fludarabine for previously untreated CLL: patient characteristics


Sequential arm (n=53)

Concurrent arm (n=51)

Median age in years (range) 63 (36–79) 63 (36–86)

Male/female (%) 81/19 63/27

Rai stage (%) Intermediate High

58 42

61 39

CALGB performance status (%) 0 1 2

53 42 6

61 31 4

β2-microglobulin >3 (%) 47 38

Haemoglobin <11g/dL (%) 18 18

MabThera + fludarabine for previously untreated CLL: response


Concurrent arm (%) (n=53)

Sequential arm (%) (n=51)

ORR 90 77

CR 47 28

PR 43 49

MabThera + fludarabine in previously untreated CLL: progression-free survival


100

80

60

40

20

0

Per

cen

tag

ep

rog

ress

ion

-fre

e su

rviv

al

0 10 20 30 40 50

Concurrent arm

Sequential arm

Months

MabThera + fludarabine in previously untreated CLL: overall survival


Per

cen

tag

e o

vera

ll s

urv

ival

Concurrent arm

Sequential arm

0 10 20 30 40 50

100

80

60

40

20

0

Months

Induction toxicity

Concurrent arm (%)

Sequential arm (%)

Haematological

Neutropenia

Thrombocytopenia

76

20

39

10

Non-haematological

Infections

20

23

MabThera + fludarabine for previously untreated CLL: grade 3/4 adverse events

Consolidation therapy well tolerated in both treatment arms


MabThera + fludarabine for previously untreated CLL: comparison with fludarabine only

Byrd JC, et al. Blood 2003;102:73a (Abstract 245)

CALGB 9712 Fludarabine/

MabThera (%) (n=104)*

CALGB 9011 Fludarabine

only (%) (n=179)

p value

ORR 84 63 0.0003

CR 38 20 0.002

2-year PFS (CI) 67 (58–76) 45 (37–52) <0.0001

2-year OS (CI) 93 (88–98) 81 (75–87) 0.0009

* Combined sequential/concurrent arms

Similar patient eligibility criteria

MabThera + fludarabine for previously untreated CLL: summary

Higher ORR and CR rate in the concurrent arm (90% and 47%, respectively) than in the sequential arm (77% and 28%, respectively)

Response rates increased after consolidation therapy with MabThera

MabThera consolidation therapy well tolerated

There is a significant advantage for treatment with MabThera + fludarabine compared with fludarabine alone

Byrd JC, et al. Blood 2003;101:6–14;Byrd JC, et al. Blood 2003;102:73a (Abstract 245)

MabThera® +

Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL

Wierda et al

Ann Oncol 2003

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Protocol

8 15 22 291 2 3 4

Cycle 1 Start cycle 2

8 15 22 291 23

Cycles 2–6

Cycle repeats

MabThera® 375 mg/m2 (cycle 1) or 500 mg/m2

(cycles 2–6)

Fludarabine 25 mg/m2

Cyclophosphamide 250 mg/m2

Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

Days

Days

No. of patients 135

Age (y) Median 57(range) (24–86)

Sex Male 67%Female 33%

Rai stage 0–II 63%

III–IV 37%

Median 2-microglobulin (mg/dl) 3.9

Median WBC (x103/µl) 9.2

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Patient

Characteristics


MabThera® + Fludarabine/Cyclophosphamide (FCR) for

Previously Untreated CLL: Response

% of Patients (n=135)

ORR 95

CR 63

PR 17

Nodular PR 15

No response 4

Early death 1



Previously Untreated CLL: Response

% of Patients

MabThera® + FC Fludarabine* FC*(n=135) (n=82) (n=53)

ORR 95 85 91

CR 63 35 43

PR 32 50 48

* Historical controls


MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Molecular

Response

% PCR-negative

CR (n=55) 56

PR (n=10) 60

Nodular PR (n=8) 38


% of Cycles (n=721)

Hematologic (grade 3/4) Neutropenia 60

Thrombocytopenia 7

Non-hematologic (all grades) Nausea 20

Vomiting 6

Infections 14

Tumor lysis 1

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL:

Tolerability



Previously Untreated CLL: Summary

ORR and CR rate of 95% and 63%, respectively

CRs substantially higher after six versus three courses

MabThera® does not increase apparent toxicity of FC

Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.Keating et al. Blood. 2000;96(suppl 1):514a. Abstract 2214.

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL

Wierda et al

Blood 2003

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL:

treatment protocol

Allopurinol 300mg/day

Wierda W, et al. Blood 2003;102:110a (Abstract 373)

Dose (mg/m

2)

Cycle 1 (days)

Cycles 2–6 (days)

MabThera 375 1

500 1

Fludarabine 25 2–4 1–3

Cyclophosphamide 250 2–4 1–3

No. of patients (n=143) (%)

CR 40 (28)

Nodular PR 20 (14)

PR 43 (30)

No response 34 (24)

Early death 6 (4)


response

(72)



survival by response

1.0

0.8

0.6

0.4

0.2

00 1 2 3 4

Years

Pro

po

rtio

n s

urv

ivin

g


CR (median not reached)

Nodular PR (median not reached)

PR (median 41+ months)

No response (median 18 months)

Early death (median 2 months)

Percentage of patients

F ± P* (n=251)

FC* (n=111)

FC + MabThera (n=143)

CR 13 12 28

Nodular PR 25 16 14

PR 21 39 30

NR 28 24 24

Early death 11 7 4

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: response by

treatment regimen

59 67 72



Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: overall

survival by treatment regimen


1.0

0.8

0.6

0.4

0.2

0 0 1 2 3 4 5 6 7 8 9 10 1112 Years

Pro

po

rtio

n s

urv

ivin

g

Patients Died Protocol Median (months)

251 241 F ± P* 19

111 83 FC* 29

143 55 FC + MabThera 42+

p<0.01

p<0.04



conclusions

FC plus MabThera is well tolerated and produces the highest CR rate in previously treated patients to date

Improved survival with FC plus MabThera compared with historical F ± P and FC treated patients


MabThera® +

Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL

Garcia-Manero et al

Blood 2001

Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Eligibility Criteria

Performance status 3

Rai stage I–II with active disease (e.g., weight loss >10%, fever, fatigue)

Rai stage III–IV

Normal organ function

No. of patients* 136


Stage IV 38%Other 62%

Performance status 1 79%

No. of prior treatments Median 2.5

Prior treatment status Alkylating agents only 15%*Fludarabine sensitive 62%*Fludarabine refractory 23%*

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Patient

Characteristics

* Evaluable patients


% of Patients (n=136)*

ORR 71

CR 21

PR 37

Nodular PR 13

Median follow-up = 5 months


Previously Treated CLL: Response



% of Patients

Alkylators Fludarabine Fludarabine only sensitive resistant(n=20) (n=85) (n=31)

ORR 60 78 56

CR 15 27 6

PR 30 37 41

Nodular PR 15 14 9

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Response by

Prior Therapy



Previously Treated CLL: Tolerability

% of Courses (n=554)

Hematologic Neutropenia 46

Febrile neutropenia 2

Thrombocytopenia 5

Non-hematologic Nausea 19

Vomiting 5

Pneumonia 2


MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL:

Survival Compared with Historical Controls


0 6 12 18 24 30 36 41 48

1.0

0.8

0.6

0.4

0.2

0.0

Pro

po

rtio

n s

urv

ivin

g

Months

Fludarabine ± predisoneFludarabine/cyclophosphamideMabThera

® + fludarabine/cyclophosphamide

(n=136)

(n=117)

(n=252)

P <0.01


Previously Treated CLL: Summary

ORR of 71%– 21% CR– 37% PR– 13% nodular PR

Survival advantage of MabThera® + FC versus FC alone demonstrated at 13+ months median follow-up (P<0.01)

MabThera® does not increase the apparent toxicity of FC


Sequential fludarabine, high-dose cyclophosphamide and MabThera in

CLL

Lamanna et al

Blood 2003

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL:

protocol

Fludarabine(25mg/m2/day x 5 days

every 4 weeks x 6 cycles)

High-dose cyclophosphamide(3g/m2 every 2–3 weeks x 3 cycles)

MabThera(375mg/m2/week x 4)

Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)


patient characteristics


Number of patients 29

Median age in years (range) 59 (37–71)

Men (%) 79

Diagnosis (%) Intermediate-risk CLL High-risk CLL

45 55

Laboratory values Median white blood cells (1,000/µL) (range) Median haemoglobin (g/dL) (range) Median platelets (1,000/µL) (range) 2-microglobulin >3 (%) Trisomy 12 (%)

128 (5.4–541.1) 11.3 (7.6–16.4) 142 (60–363)

48 21


response


No. of patients (%) (n=21)

After fludarabine

After high-dose cyclophosphamide

After MabThera

Overall response rate

Complete response

16 (76)

3 (14)

18 (82)

7 (33)

18 (82)

12 (57)

Nodular response 0 (0) 1 (5) 2 (10)

Partial response 13 (62) 10 (48) 4 (19)

No response 5 (24) 3 (14) 3 (14)


grade 3/4 adverse events



Anaemia 3 (11)

Neutropenia 23 (85)

Thrombocytopenia 20 (74)

Infection 9 (33)

There were no treatment-related deaths

Consolidation therapy with high-dose cyclophosphamide improves quality of response over induction with fludarabine

A second consolidation with MabThera further improves quality of response in a significant proportion of patients


summary


MabThera® + Fludarabine in CLL

Schulz et al

Blood 2001

1 5 9 13 17 21

MabThera® + Fludarabine in CLL: Protocol

MabThera® 375 mg/m2/week i.v., weeks 9, 13, 17, 21

Fludarabine 25 mg/m2/day i.v. days 1–5, weeks 1, 5, 9, 13

Week

Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

MabThera® + Fludarabine in CLL:Patient Characteristics

No. of patients 30


Sex Male 70%Female 30%

Binet stage B 70%C 30%

B symptoms 50%

Prior therapy None 63%Chlorambucil/prednisone 37%


MabThera® + Fludarabine in CLL: Tolerability

Hematologic Neutropenia 37Leukopenia 27Thrombocytopenia 10Anemia 10

Non-hematologic Infections* 13Fever 3Pain 3Arrhythmia 3

* Nine patients (30%) experienced grade I/II infections


% of Patients (n=30) Grade 3/4

% of Patients

All Untreated Relapsed Stage B Stage C(n=29) (n=18) (n=11) (n=21) (n=8)

ORR 90 89 90 91 87

CR 24 22 27 29 12

CRu 10 6 18 14 –

PR 55 61 45 48 75

SD 3 – 9 5 –

MabThera® + Fludarabine in CLL: Response


MabThera® + Fludarabine in CLL:Time to Progression

1.0

0.8

0.6

0.4

0.2

0

Rat

e w

ith

pro

gre

ssio

n

0 3 6 9 12 15 18 21Months

Five progressions (n=30). Median not reached


MabThera Monotherapy for CLL

Standard Dose MabThera® in SLL (CLL-Type)

McLaughlin et al

J Clin Onc 1998

Standard Dose MabThera® in SLL (CLL-Type)

13

60

0

20

40

60

80

100

FL SLL (CLL-type)

Patients

OR

R (

%)

McLaughlin et al. J Clin Oncol. 1998;16:2825.

P=0.01

Low ORRs With MabThera® in Patients With CLL: Possible Explanations

Reduced CD20 expression

Rapid MabThera® clearance/low serum levels

High lymphocyte counts

MabThera® Serum Concentrations Correlate With Response

Adapted from McLaughlin et al. J Clin Oncol. 1998;16:2825.

Mab

Th

era®

Ser

um

Lev

els

(g

/mL

)

Hours

800

600

400

200

00 500 1000 1500

Infusion

Responders (CRs)

Non-responders

Strategies for Enhancing MabThera® Efficacy in CLL

Modify dosing regimen– Increase dose intensity (weekly x 4 with dose escalation)

– Increase dose density (thrice weekly x 4)

Combine with chemotherapy– fludarabine® +/- cyclophosphamide

Dose Escalation of MabThera® for CLL

O’Brien et al

J Clin Onc 2001

Dose 1Doses 2-4Cohorts n (mg/m2)(mg/m2)

A 19375 500

B 4375 650

C 3375 825

D 4375 1000

E 5375 1500

F 12375 2250

O’Brien et al. J Clin Oncol. 2001;19:2165.

Dose Escalation of MabThera® for CLL: Protocol


Dose Escalation of MabThera® for CLL: Eligibility Criteria

CLL or other mature B-cell leukemias

PS 3 (Zubrod)

Rai stage III-IV

Rai stage I-II with evidence of active disease (eg, weight loss, fever, fatigue)

Normal renal and hepatic function

Dose Escalation of MabThera® for CLL: Patient Characteristics

No. of patients 50

Age (y) Median 66(range) (44-87)

Histology CLL 80%MCL 8%MZL 8%PLL 4%

Stage I-II 20%III-IV 80%

No. of prior treatments Median 2(range) (0-6)

Patients refractory to fludarabine® 53%Alkylating agents 43%Both 33%


Dose Escalation of MabThera® for CLL: Response in Patients With CLL

36

22

43

75

0

20

40

60

80

100

All Patients 500-825 1000-1500 2250

MabThera® (mg/m2)

Res

po

nse

Rat

e (%

)

(n=24)* (n=7)* (n=9)*(n=39)*

* Evaluable patients.


Dose Escalation of MabThera® for CLL: Response

Characteristic

Histology CLL 36MCL 25MZL 75PLL 100

Stage I-II 60III-IV 35

Prior fludarabine® Sensitive 56 response Refractory 20

% of Patients

P=0.06

P=0.02


Dose Escalation of MabThera® for CLL: TTP in Responders

Adapted from O’Brien et al. J Clin Oncol. 2001;19:2165.

20 4 6 8 10 12 14 160

0.2

0.4

0.6

0.8

1.0

Months

Pro

po

rtio

n i

n R

emis

sio

n

Dose Escalation of MabThera® for CLL: Toxicity

Grade 3/4 toxicity (1st infusion) 12 CLL (n=40) 3Other (n=10) 50

MyelosuppressionNeutrophil count <109/L 27Neutrophil count <0.5 x 109/L 11

Tumor lysis 2

Infection 10

P=0.001

% of Patients(N=50)



Dose Escalation of MabThera® for CLL: Summary

Dose-response relationship

– ORRs up to 75% with 2250 mg/m2 MabThera®

Higher ORRs in patients with early-stage disease and fludarabine-sensitive patients

Elevated MabThera® doses well tolerated

MabThera® Thrice Weekly for CLL

Byrd et al

J Clin Onc 2001

MabThera® Thrice Weekly for CLL:Protocol

I 3 250 4 h, thrice weekly x 4

II 7 375 4 h, thrice weekly x 4

III 23 375 4 h (infusions 1 and 2) 1 h thrice weekly x 4

Byrd et al. J Clin Oncol. 2001;19:2153.

1st dose (all cohorts): 100 mg over 4 hours

CohortNo. of

PatientsSubsequent

Doses (mg/m2)Infusion Schedule


MabThera® Thrice Weekly for CLL: Eligibility Criteria

Histologically confirmed CLL or SLL Failed 1 prior therapy or were previously untreated with

positive antiglobulin test, history of autoimmune anemia, autoimmune thrombocytopenia, or were not candidates for chemotherapy based on comorbid illnesses

Recovered from toxicity of prior therapy Performance status 3 (ECOG) Life expectancy 3 months CD20+

Creatinine level 3.0 mg/dL No infection requiring IV or PO antibiotics Not pregnant No previous allergic reaction to MabThera®

No. of patients33

Age (y) Median 66(range) (50-80)

Histology CLL79%SLL21%

Stage I-II27%III-IV73%

No. of prior treatments Median2(range) (0-6)

Prior therapy None18%Alkylator/purine analog30%fludarabine® refractory52%


MabThera® Thrice Weekly for CLL: Patient Characteristics


ORR 52

CR 3

PR 48

* Evaluable patients.

% of PatientsResponse (n=29)*

MabThera® Thrice Weekly for CLL: Response

MabThera® Thrice Weekly for CLL: Response (cont’d)

Characteristic n % ORR

Histology SLL 7 43CLL 26 46

Stage I-II 9 56III-IV 24 42

Prior therapy None 6 83Alkylator/fludarabine® 10 30fludarabine® refractory 17 41


MabThera® 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


MabThera® Thrice Weekly for CLL: MabThera® Serum Concentrations

1 Before 0 0After 17.4 12.5

2 Before 7.7 10.7After 245.3 91.3

3 Before 159.5 144.7After 401.1 271.1

6 Before 418.8 259.1After 676.3 263.5

12 Before 686.4 283.7After 891.0 332.2

InfusionConcentration

(µg/mL)StandardDeviationEvaluation


MabThera® Thrice Weekly for CLL: Toxicity

Day Week

Hematologic (grade 3/4) 1 3 5 2-4

Neutropenia 18 18 9 15

Anemia 3 0 3 0

Thrombocytopenia 9 6 3 3

% of Patients (N=33)


MabThera® Thrice Weekly for CLL: Summary

ORR of 52%

Higher ORR in previously untreated patients

Median duration of response of 10 months

MabThera® serum levels continued to accumulate after dose 3– No patients experienced rapid clearance of MabThera®

Toxicity generally mild and transient

MabThera first-line and maintenance therapy for CLL and SLL

Hainsworth et al

J Clin Onc 2003

Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

MabThera first-line and maintenance therapy for CLL and SLL: protocol

MabThera(375mg/m2

weekly x 4)

Evaluation(week 6)

Patients with OR or SD:MabThera maintenance therapy(375mg/m2 weekly x 4, every6 months for up to four courses)

Patients with PD: off study

MabThera first-line and maintenance therapy for CLL and SLL: patient

characteristics


n (%)

Diagnosis CLL SLL

39 (89) 5 (11)

ECOG status 0 1 2

20 (45) 22 (50)

2 (5)

Stage I II III IV

2 (5) 11 (25)

7 (16) 24 (54)

No. of patients (%) (n=43)*

Response 6 weeks Best response

CR/CRu 2 (4) 5 (12)

PR 20 (47) 20 (46)

SD 21 (49) 18 (42)


MabThera first-line and maintenance therapy for CLL and SLL: response


MabThera first-line and maintenance therapy for CLL and SLL: PFS

Hainsworth J, et al. J Clin Oncol 2003;21:1746–51Hainsworth J, et al. Proc Am Soc Clin Oncol 2003;20:564 (Abstract 2332)

Median survival 19 months at 24-month follow-up Actuarial PFS 62% at 1 year and 49% at 2 years

100

80

60

40

20

0

PF

S (

%)

0 3 6 9 12 15 18 21 24 27 30Months

MabThera first-line and maintenance therapy for CLL and SLL: safety

No grade 3–4 adverse events during maintenance MabThera courses

No patient withdrew from treatment due to toxicity

First course

No. of patients (%)

Grade 3–4 toxicity 43

Fatigue 1 (2)

Headache 1 (2)


MabThera first-line and maintenance therapy for CLL and SLL: summary

Mabthera is an effective first-line treatment for patients with CLL/SLL

ORR of 51% (4% CR) increased to 58% (9% CR) after 28 patients had begun MabThera maintenance therapy

Treatment was well tolerated


MabThera consolidation in CLL for older patients in remission after first-

line chemotherapy

Mauro et al

Blood 2003

MabThera consolidation in CLL for older patients in remission after first-line chemotherapy:

protocol

Chlorambucil(10mg/m2/day x 5)

Prednisone(25mg/m2/day x 5)

every 28 days x 6 cycles

MabThera(375mg/m2/week x 4)

CR, PR

Mauro FR, et al. Blood 2003;102:674a (Abstract 2497)

MabThera consolidation in CLL for older patients in remission after first-line chemotherapy:

patient characteristics


No. of patients (n=19)

Male/female 9/10 Median age in years (range) 65.2 (61–81) Median months from diagnosis (range) 36.8 (7–111) Response to prior chlorambucil/prednisone Complete response Partial response

0 19

Rai stage 0 or I II

14 5

Median haemoglobin (g/dL) (range) 13 (11.1–16.0) Median peripheral blood lymphocytes x 109/L (range)

1.6 (0.9–9.3)

Median platelets x 109/L (range) 153 (91–231)

MabThera consolidation in CLL for older patients in remission after first-line

chemotherapy: response



Improved clinical response 13 (68)

Cytometric response 13 (68)

Complete response 10 (53)

Partial response 3 (16)

Molecular remission 1 (5)


chemotherapy: time to second-line therapy


100

80

60

40

20

0 0 5 10 15 20 25 3035 Months

2nd

ch

emo

ther

apy-

free

su

rviv

al (

%)

MabThera given as post-remission therapyin older patients with CLL achieves improved responses in many patients with a partial response to chlorambucil/prednisone

Post-remission MabThera is well tolerated


chemotherapy: summary


mabthera ® for chronic lymphocytic leukemia (cll)

Documents

cllmabthera fludarabine

fludarabine alonebyrd

responsebyrd jc

mabthera 375mgm2weekly

patient characteristicsbyrd

overall survivalbyrd

treatment armsbyrd jc

untreated cllbyrd et