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)  There are 2 commonly used systems for staging CLL: the Rai system and the Binet system.12 The Rai system was used in the studies presented here. The Rai system classifies CLL into 5 stages Stage 0: Absolute lymphocytosis with no lymphadenopathy, hepatosplenomegaly, anemia, or thrombocytopenia Stage I: Absolute lymphocytosis with lymphadenopathy, but no hepatosplenomegaly, anemia, or thrombocytopenia Stage II: Absolute lymphocytosis with or without lymphadenopathy, with either hepatomegaly or splenomegaly Stage III: Absolute lymphocytosis and anemia with or without lymphadenopathy, hepatomegaly, or splenomegaly Stage IV: Absolute lymphocytosis and thrombocytopenia with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia  +  +/-

CLL Characteristics B-cell lineage 95% Immunophenotype CD5+ CD19+ CD20+ CD23+ CD52+ Cytogenetic abnormalities Deletions at 13q14 Trisomy 12 CLL is one of the most common types of leukemia diagnosed in the Western Hemisphere, with 8100 projected new cases in the United States in the year 2000.9 The median age of patients at diagnosis is 65 years, and it is estimated that >4000 patients die from CLL each year.9,105 Virtually all CLL cells derive from a morphologically mature but immunophenotypically immature B cell. Immunophenotypic and cytogenetic markers are critical for distinguishing CLL from other B-cell malignancies such as MCL, which shares a similar antigenic profile. CLL cells are typically identified by expression of B-cell antigens CD19, CD20, CD23, and the T-cell antigen CD5.37 MCL is differentiated from CLL by the absence of CD23. The most common cytogenetic abnormalities associated with CLL include deletions at 13q14 and 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) To date, the most widely used therapy for patients with CLL has been the purine analogs, such as fludarabine®.62 In addition, combination chemotherapy regimens such as FC and CVP are also being investigated.62 Although these regimens result in high response rates initially, relapse is inevitable. Several recent studies have demonstrated the efficacy of MabThera® and Campath-1H® MoAbs in the treatment of CLL.9,105 These agents are particularly promising for patients with refractory or relapsed disease who have few therapeutic options. Until recently, aggressive therapies had not been used routinely because CLL was regarded as an indolent disease of the elderly.122 Promising results from studies with fludarabine®, however, have provided a rationale for disease consolidative therapies, and the efficacy of allogeneic, mini-allogeneic, and autologous SCT is currently being explored.26,122 Some patients with localized disease are treated with involved-field radiation.102

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 MabThera 375mg/m2 Fludarabine 25mg/m2 Concurrent R A N D O M I S E Consolidation therapy Patients with CR, PR, or stable disease received MabThera (375mg/m2 weekly x 4) 1 5 9 13 17 21 (2 months) Weeks A randomized phase II study was conducted to evaluate the relative efficacy of administering MabThera® + fludarabine®, either concurrently or sequentially, in patients with previously untreated CLL.8 Patients (N=104) were treated with fludarabine® (25 mg/m2 on days 1–5, every 4 weeks x 6) with or without MabThera®. Patients treated concurrently with fludarabine® + MabThera® initially received MabThera® on days 1 and 4 of the first fludarabine® cycle and on day 1 of fludarabine® cycles 2 through 6. The schedule was later altered, and MabThera® was administered at increasing doses during the first week of therapy (50 mg/m2 on day 1, 325 mg/m2 on day 5 [over 1 hour], and 375 mg/m2 [over 1 hour] for cycles 2–6). After 2 months of evaluation, all patients who had a CR, PR, or stable disease received consolidation therapy with MabThera® (375 mg/m2 weekly for 4 weeks). Sequential 1 5 9 13 17 21 Weeks Byrd JC, et al. Blood 2003;101:6–14

MabThera + fludarabine for previously untreated CLL: patient characteristics A total of 104 patients with previously untreated CLL were enrolled.8 The median age was 63. Byrd JC, et al. Blood 2003;101:6–14

MabThera + fludarabine for previously untreated CLL: response Interim results were originally presented on data from the first 42 patients at the 2001 annual meeting of the American Society of Clinical Oncologists.8 The combination of MabThera® and fludarabine® was active in previously untreated patients with CLL. Patients in the concurrent treatment arm had a higher ORR and CR rate (90% and 47%, respectively) than those in the sequential treatment arm (77% and 28%, respectively). Of note, patients in the sequential arm had not yet received MabThera® upon evaluation of induction response, suggesting that the combination of MabThera® and fludarabine® was more effective than fludarabine® alone. The ORR and CR rate with the combination of MabThera® plus fludarabine® were also higher than those reported with fludarabine® alone in a previous study of untreated patients with CLL (90% and 47% vs 80% and 38%, respectively).9 After a second course of MabThera®, response rates improved (PRs became CRs) in 1 of 4 (25%) evaluable patients in the concurrent arm and in 2 of 11 (18%) evaluable patients in the sequential arm. Byrd JC, et al. Blood 2003;101:6–14

Percentage progression-free survival MabThera + fludarabine in previously untreated CLL: progression-free survival 100 80 60 40 20 Sequential arm Percentage progression-free survival Concurrent arm 0 10 20 30 40 50 Months Byrd JC, et al. Blood 2003;101:6–14

MabThera + fludarabine in previously untreated CLL: overall survival Percentage overall survival Concurrent arm Sequential arm 0 10 20 30 40 50 100 80 60 40 20 Months Byrd JC, et al. Blood 2003;101:6–14

MabThera + fludarabine for previously untreated CLL: grade 3/4 adverse events Six patients in the concurrent arm and 1 patient in the sequential treatment arm had grade 3/4 infusion toxicity with the first treatment.8 Infusion reactions with subsequent treatments were uncommon. Induction toxicity in the concurrent and sequential treatment arms included grade 3/4 neutropenia (77% and 43%, respectively) and thrombocytopenia (24% and 20%, respectively), and grade 3 infection (33% and 29%, respectively). Whereas induction toxicity was relatively common, consolidation therapy with MabThera® was well tolerated in both treatment arms. Consolidation therapy well tolerated in both treatment arms Byrd JC, et al. Blood 2003;101:6–14

Similar patient eligibility criteria MabThera + fludarabine for previously untreated CLL: comparison with fludarabine only Similar patient eligibility criteria * Combined sequential/concurrent arms Byrd JC, et al. Blood 2003;102:73a (Abstract 245)

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 The ORR and CR rate were higher in the concurrent arm than in the sequential treatment arm. Because patients in the sequential treatment arm had not yet received MabThera®, these results suggest that the combination of MabThera® + fludarabine® was more effective than fludarabine® alone. The ORR and CR rate with the combination of MabThera® + fludarabine® were higher than those seen in a previous study in which patients with untreated CLL received fludarabine® alone (90% and 47% vs 80% and 38%, respectively).9 Consolidation therapy improved response rates in patients who had a CR, PR, or stable disease after an initial course of therapy. In general, the incidence of hematologic toxicity and infection were similar in both treatment arms, and consolidation therapy with MabThera® was well tolerated among all patients. 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 Cycle 1 Start cycle 2 MabThera® 375 mg/m2 (cycle 1) or 500 mg/m2 (cycles 2–6) 1 2 3 4 8 15 22 29 Days Fludarabine 25 mg/m2 Cycle repeats Cyclophosphamide 250 mg/m2 Cycles 2–6 In the study by Wierda and colleagues, patients with previously untreated chronic lymphocytic leukemia (CLL) received a total of 6 cycles of MabThera plus fludarabine/cyclophosphamide (FC).63 Cycles were administered every 4 weeks. During the first cycle, MabThera (375 mg/m2) was administered on day 1, and FC was given on days 2–4. During subsequent cycles (2–6), a higher MabThera dose (500 mg/m2) was administered on day 1, and FC was given on days 1–3. Allopurinol prophylaxis was recommended. 1 2 3 8 15 22 29 Days Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Patient Characteristics 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 b2-microglobulin (mg/dl) 3.9 Median WBC (x103/µl) 9.2 One hundred and thirty-five patients with CLL were enrolled. Patients were relatively young, with a median age of 57. The majority of patients had early-stage disease. Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

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 Analysis of all 135 patients on the study demonstrated a high ORR of 95%. Only five of 135 patients (4%) failed to respond to therapy. Responses included 85 CR (63%), 23 PR (17%) and 20 nodular PR (15%). Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for 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 The addition of MabThera® to FC (fludarabine/cyclophosphamide) produced the highest complete remission rate in first-line treatment of CLL of any other regimen tested thus far. In this study, 63% of patients achieved a CR. This compares with a CR rate of 35% with fludarabine alone and 53% with FC in historical controls. Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

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 Molecular remission, demonstrated by PCR-negativity for IgH gene rearrangement, was documented in 31 of 55 (56%) complete responders tested. Six of 10 (60%) patients with PR and three of eight (38%) patients with nodular PR also achieved molecular remission. After a median 24-month follow-up, all but two responders remained in CR or nodular PR. Eleven of the patients in CR were evaluated by PCR 6–12 months after treatment and eight remained PCR-negative in CR. Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Untreated CLL: Tolerability % 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 Neutropenia was the most common hematologic toxicity. Non-hematologic toxicity included nausea and vomiting. Infections occurred in 14% of the courses and included pneumonia, septicemia, fever of unknown cause, herpes, and soft tissue infections. Opportunistic infections were not observed. Tumor lysis was reported in three patients before allopurinol prophylaxis was initiated. Toxicity associated with the first infusion of MabThera primarily included fever, chills, and changes in blood pressure. Wierda et al. Ann Oncol. 2002;13(suppl 2):3. Abstract 008.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for 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 An ORR rate of 81% was seen after only three courses of therapy. After six courses of therapy, the CR rate increased substantially, exceeding that previously seen with FC therapy alone. The addition of MabThera did not increase the apparent toxicity of FC. Due to the increased incidence of infection, allopurinol prophylaxis is recommended. 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)

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: response (72) Wierda W, et al. Blood 2003;102:110a (Abstract 373)

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: survival by response 1.0 0.8 0.6 0.4 0.2 CR (median not reached) Nodular PR (median not reached) PR (median 41+ months) Proportion surviving No response (median 18 months) Early death (median 2 months) 0 1 2 3 4 Years Wierda W, et al. Blood 2003;102:110a (Abstract 373)

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: response by treatment regimen 59 67 72 * Historical controls Wierda W, et al. Blood 2003;102:110a (Abstract 373)

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: overall survival by treatment regimen 1.0 0.8 0.6 0.4 0.2 0 1 2 3 4 5 6 7 8 9 10 11 12 Years Proportion surviving 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 * Historical controls Wierda W, et al. Blood 2003;102:110a (Abstract 373)

Fludarabine, cyclophosphamide and MabThera in relapsed/refractory CLL: 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 Wierda W, et al. Blood 2003;102:110a (Abstract 373)

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL Garcia-Manero et al Blood 2001

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 Patients were eligible if they had previously treated CLL, a performance status of 3, and either Rai stage I–II with active disease or Rai stage III–IV disease.33 Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Patient Characteristics No. of patients* 136 Age (y) Median 59 (range) (36–81) 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%* One hundred and sixty-seven patients were registered, of whom 136 were evaluable for response and tolerability.33 Patients were relatively young, with a median age of 59. Thirty-eight percent of patients presented with stage IV disease, and the majority of patients (79%) had a low tumor burden (performance status score 1). Patients had received a median of 2.5 prior treatments. Among the evaluable patients (n=136), 15% had received alkylating agents only, whereas the majority of the remaining patients had received and were sensitive to fludarabine therapy (62%). * Evaluable patients Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Response % of Patients (n=136)* ORR 71 CR 21 PR 37 Nodular PR 13 Response was defined by the criteria of the NCI-Sponsored Working Group.12 Among the evaluable patients, the ORR was 71% and the CR rate was 21%.33 A further 37% and 13% of patients achieved either PR or nodular PR respectively. Molecular response was also assessed. Five of 14 patients (36%) in CR who were PCR-positive at diagnosis achieved PCR-negativity following MabThera® plus FC therapy. * Evaluable patients Median follow-up = 5 months Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Response by Prior Therapy % 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 Analysis of response according to prior therapy revealed that 27% of fludarabine-sensitive patients achieved a CR following MabThera® plus FC. A further three who had received alkylating agents only or two who were fludarabine-resistant also achieved a CR for an overall CR rate of 48%. Overall, 78% of fludarabine-sensitive patients responded to therapy (CR, PR or nodular PR). In addition, 60% of patients who had received alkylating agents only and 56% of fludarabine-resistant patients also responded to therapy. These results are of particular importance because patients with relapsed CLL typically have limited treatment options. Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for Previously Treated CLL: Tolerability % of Courses (n=554) Hematologic Neutropenia 46 Febrile neutropenia 2 Thrombocytopenia 5 Non-hematologic Nausea 19 Vomiting 5 Pneumonia 2 The most common hematologic toxicity was neutropenia, occurring in 46% of treatment courses.33 Febrile neutropenia and thrombocytopenia were rare (2% and 5% of courses, respectively). Pneumonia was reported in 2% of all treatment courses. Three of the seven deaths were attributed to progressive disease. Non-hematologic toxicity related to MabThera included fever, chills, and nausea, observed with the first course of therapy. Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

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 Proportion surviving Months Fludarabine ± predisone Fludarabine/cyclophosphamide MabThera® + fludarabine/cyclophosphamide (n=136) (n=117) (n=252) P <0.01 Overall survival was also analyzed for patients treated with MabThera® plus fludarbine/cyclophosphamide in this trial (n=136) and compared with data from similar patient populations treated with fludarabine ± prednisone (n=252) or FC alone (n=117) at the M.D Anderson Cancer Center. At a median 13+ month follow-up, MabThera® plus FC offered a survival advantage to this patient population compared to fludarabine/cyclophosphamide combinations. Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

MabThera® + Fludarabine/Cyclophosphamide (FCR) for 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 Heavily pretreated patients with CLL achieved an ORR of 71% with MabThera plus FC. At a median 13+ month follow-up, MabThera® plus FC offered a survival advantage to this patient population compared to FC alone. The addition of MabThera did not increase the apparent toxicity of FC. MabThera plus FC appears to be an effective and well-tolerated therapy for patients who historically have few treatment options. Garcia-Manero et al. Blood. 2001;98(suppl 1):633a. Abstract 2650.

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL Lamanna et al Blood 2003

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

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: patient characteristics Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: response Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: grade 3/4 adverse events There were no treatment-related deaths Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

Sequential fludarabine, high-dose cyclophosphamide and MabThera in CLL: summary 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 Lamanna N, et al. Blood 2003;102:440a (Abstract 1603)

MabThera® + Fludarabine in CLL Schulz et al Blood 2001

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 A phase II trial was conducted to evaluate the efficacy and safety of the standard MabThera® regimen (375 mg/m2 weekly) and fludarabine (25 mg/m2 days 1–5; 29–33; 57–61; 85–89). The first two infusions of MabThera® were given together with fludarabine on days 57 and 85 while the following doses were given on days 113 and 151. Week 1 5 9 13 17 21 Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

MabThera® + Fludarabine in CLL: Patient Characteristics No. of patients 30 Age (y) Median 59 (range) (30–70) Sex Male 70% Female 30% Binet stage B 70% C 30% B symptoms 50% Prior therapy None 63% Chlorambucil/prednisone 37% A total of 32 patients were recruited to the trial. Of 30 eligible patients, the median age was 59 years with 21 males and nine females. Nineteen patients were previously untreated, 11 had relapsed after prior chlorambucil and/or prednisone. Twenty-one patients had Binet stage B and nine stage C disease. Fifteen patients had B symptoms. The median number of prior regimens in relapsed patients was one (range 1–3). Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

MabThera® + Fludarabine in CLL: Tolerability % of Patients (n=30) Grade 3/4 Hematologic Neutropenia 37 Leukopenia 27 Thrombocytopenia 10 Anemia 10 Non-hematologic Infections* 13 Fever 3 Pain 3 Arrhythmia 3 * Nine patients (30%) experienced grade I/II infections Side effects consisting of fever, chills and exanthema of the skin were mild. Fever and chills were mainly related to the first infusion of MabThera® and the majority (47%) were grade I/II with only one patient (3%) experiencing grade IV infusion-related reactions. All other side effects were consistent with those observed with fludarabine alone and there was no apparent increase risk of infection associated with the addition of MabThera® to fludarabine. Nine patients (30%) experienced grade I/II infections and four (13%) grade III/IV infections. The most common hematologic toxicity was neutropenia (37% grade III/IV). No grade III/IV nausea was observed. Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

MabThera® + Fludarabine in CLL: Response % 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 – Of the 30 eligible patients, one died after the 2nd cycle of fludarabine during prolonged thrombocytopenia due to cerebral bleeding, thus response was evaluable in 29 patients. Twenty-six of the 29 evaluable patients responded to therapy for an ORR of 90% comprising 10 CR/CRu and 16 PRs. A further one patient had SD. The ORR was similar in both previously untreated and relapsed patients (89% vs 90%, respectively) as were CR rates (22% vs 27%, respectively). ORRs were also similar in patients with stage B or C disease (91% vs 87% respectively) although a greater proportion of patients with stage B disease achieved a CR compared with those with stage C disease (29% vs 12%). However, numbers of patients in these subgroups are relatively low. Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

MabThera® + Fludarabine in CLL: Time to Progression 1.0 0.8 0.6 0.4 0.2 Five progressions (n=30). Median not reached Rate with progression The median time to progression had not been reached after a median 6-month follow-up. At 9-month follow-up only five of 30 patients had progressed. 0 3 6 9 12 15 18 21 Months Schulz et al. Blood. 2001;98(suppl 1):364a. Abstract 1534.

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) ORR (%) In the pivotal trial, patients with SLL (CLL-type) who were treated with a standard dose of MabThera® had significantly lower ORRs than those with FL (13% vs 60%, respectively; P=0.01).79 These data underscore the inherent biologic differences between types of B-cell lymphomas, and suggest that protocol modifications may be needed for patients who are less sensitive to the standard MabThera® regimen. Patients McLaughlin et al. J Clin Oncol. 1998;16:2825.

Low ORRs With MabThera® in Patients With CLL: Possible Explanations Reduced CD20 expression Rapid MabThera® clearance/low serum levels High lymphocyte counts Results from the pivotal trial and other studies offer several possible explanations for the low ORRs seen in patients with SLL.1,81 The density of CD20 expression is lower on SLL (and CLL) cells than on cells of other B-cell lymphomas, such as FL.1 Lower expression of CD20 may result in reduced binding of MabThera® and, consequently, lower response rates. Pharmacokinetic studies from the pivotal trial demonstrated a strong correlation between serum MabThera® levels and response rates.81 Patients with SLL experienced a more rapid clearance of MabThera® than those with FL, possibly resulting in lower overall serum levels of the drug and, consequently, lower response rates. Pharmacokinetic studies in the pivotal trial showed a significant correlation between the number of circulating B cells at baseline and the rapidity of antibody clearance after the first infusion (P=0.01).81 Patients with SLL typically had higher circulating B-cell counts than those with FL, which may explain the rapid clearance of MabThera®, and thus lower therapeutic efficacy.

MabThera® Serum Concentrations Correlate With Response 800 600 400 200 Responders (CRs) Non-responders MabThera® Serum Levels (g/mL) Pharmacokinetic studies demonstrated that MabThera® serum levels were higher in patients who had CRs than in those who did not.79 For complete responders, MabThera® serum concentrations increased with each infusion, and high levels were maintained for several days after the fourth infusion. In contrast, MabThera® was rapidly cleared from the serum of patients who did not respond to MabThera®, and the absolute serum concentrations were substantially lower than in responders at all time points. 0 500 1000 1500 Infusion Hours Adapted from McLaughlin et al. J Clin Oncol. 1998;16:2825.

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 Recent studies have evaluated several strategies for enhancing MabThera® efficacy in patients with CLL. In single-agent trials, investigators evaluated the effects of increasing the dose intensity (weekly x 4 with dose escalation) and the dose density (thrice weekly x 4) of MabThera®.7,85 The efficacy of MabThera® was also evaluated in combination with fludarabine®, with and without cyclophosphamide.8,33,63

Dose Escalation of MabThera® for CLL O’Brien et al J Clin Onc 2001

Dose Escalation of MabThera® for CLL: Protocol Dose 1 Doses 2-4 Cohorts n (mg/m2) (mg/m2) A 19 375 500 B 4 375 650 C 3 375 825 D 4 375 1000 E 5 375 1500 F 12 375 2250 In the single-agent dose-escalation study, patients received 4 weekly doses of MabThera®.85 The first dose was the same for all patients (375 mg/m2), whereas the intensity of doses 2 to 4 varied from 500 mg/m2 to 2250 mg/m2. To limit the toxicity, the study followed the 3 + 3 rule of phase I trials: if grade 3 or 4 toxicity was seen in 0 of 3 patients, dosing was increased to the next level; if grade 3 or 4 toxicity was seen in 1 of 3 patients, 3 additional patients were enrolled at the same dose level; if grade 3 or 4 toxicity was seen in 2 of 3 to 6 patients, the maximum tolerated dose was reached. O’Brien et al. J Clin Oncol. 2001;19:2165.

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 Patients were eligible if they had CLL or another type of mature B-cell leukemia, a PS score 3, and either Rai stage I–II with evidence of active disease or Rai stage III–IV disease.85 O’Brien et al. J Clin Oncol. 2001;19:2165.

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% Fifty patients with a median age of 66 (range, 44–87) were enrolled in this study.85 The majority of patients presented with CLL (80%) and advanced-stage disease (III–IV; 80%). Patients had received a median of 2 prior treatments. Among the previously treated patients, 53% were refractory to fludarabine®, 43% were refractory to alkylating agents, and 33% were refractory to both fludarabine® and alkylating agents. O’Brien et al. J Clin Oncol. 2001;19:2165.

Dose Escalation of MabThera® for CLL: Response in Patients With CLL Response Rate (%) Response was assessed using the National Cancer Institute (NCI) Working Group criteria.12 Among the patients with CLL, the ORR was 36% (all responders had PRs), and significantly higher ORRs were seen in patients treated with the highest dose of MabThera® (75% [2250 mg/m2] vs 43% [1000 mg/m2–1500 mg/m2] vs 22% [500 mg/m2–825 mg/m2]; P=0.03).85 (n=39)* (n=24)* (n=7)* (n=9)* * Evaluable patients. MabThera® (mg/m2) O’Brien et al. J Clin Oncol. 2001;19:2165.

Dose Escalation of MabThera® for CLL: Response Characteristic Histology CLL 36 MCL 25 MZL 75 PLL 100 Stage I-II 60 III-IV 35 Prior fludarabine® Sensitive 56 response Refractory 20 % of Patients P=0.06 Historically, patients with heavily pretreated CLL do not respond well to therapy. A 36% response rate was, therefore, encouraging.85 The ORR for patients with other B-cell leukemias was 60%, with a range from 25% in MCL to 100% in PLL. Patients with stage I–II disease had higher ORRs than those with advanced-stage disease (P=0.06). Patients sensitive to prior fludarabine® therapy experienced significantly higher ORRs than did those who were refractory to fludarabine® (56% vs 20%, respectively; P=0.02). P=0.02 O’Brien et al. J Clin Oncol. 2001;19:2165.

Dose Escalation of MabThera® for CLL: TTP in Responders 1.0 0.8 0.6 Proportion in Remission 0.4 The median TTP in responders was 8 months, with the longest ongoing remission being 15+ months.85 The median survival time has not yet been reached; the estimated 1-year survival rate is 80%. 0.2 2 4 6 8 10 12 14 16 Months Adapted from O’Brien et al. J Clin Oncol. 2001;19:2165.

Dose Escalation of MabThera® for CLL: Toxicity % of Patients (N=50) Grade 3/4 toxicity (1st infusion) 12 CLL (n=40) 3 Other (n=10) 50 Myelosuppression Neutrophil count <109/L 27 Neutrophil count <0.5 x 109/L 11 Tumor lysis 2 Infection 10 P=0.001 Patients with CLL had a significantly lower incidence of grade 3/4 toxicity during the first infusion than those with other B-cell leukemias (3% vs 50%, respectively; P=0.001).85 Severe adverse events included fever, chills, dyspnea, and hypoxia. No grade 3/4 toxicity was seen during dose escalation, although the incidence of grade 1/2 adverse events increased at higher doses. Nine percent of patients who received doses of 500 mg/m2 to 1500 mg/m2 MabThera® had grade 1 toxicity vs 67% of those who received a dose of 2250 mg/m2. Myelosuppression was uncommon. Severe neutropenia, defined as a neutrophil count <0.5 x 109/L, was seen in 11% of patients. Minor infections were reported in 10% of patients and included bronchitis, gastroenteritis, urinary tract infection, and a local infection at the catheter site. O’Brien et al. J Clin Oncol. 2001;19:2165.

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 The ORR for patients with CLL was higher than that seen in patients with SLL in the pivotal trial (36% vs 12%, respectively). A clear dose-response relationship was seen, with greater response rates in patients treated with higher MabThera® doses. These results are particularly encouraging, considering the fact that these patients initially appeared to be less responsive to MabThera® and otherwise have limited therapeutic options. Higher ORRs were seen in patients with early-stage disease (vs advanced) and in those who were responsive to prior fludarabine® therapy (vs those who were refractory). Toxicity was generally mild to moderate, even at the highest MabThera® doses. Although a true maximum tolerated dose was not defined, further dose escalation was not pursued because treatment at the highest doses may be cost-prohibitive. O’Brien et al. J Clin Oncol. 2001;19:2165.

MabThera® Thrice Weekly for CLL Byrd et al J Clin Onc 2001

MabThera® Thrice Weekly for CLL: Protocol 1st dose (all cohorts): 100 mg over 4 hours No. of Patients Subsequent Doses (mg/m2) Infusion Schedule Cohort 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 A recent trial explored the potential efficacy of increasing the dose density of MabThera® in patients with CLL. For the first infusion, all patients were treated with a 100-mg dose of MabThera® given over 4 hours.7 Patients in cohorts I and II received subsequent infusions 3 x weekly for 4 weeks at doses of 250 mg/m2 and 375 mg/m2, respectively. These treatments were administered at an initial rate of 50 mg/h and were increased by 100-mg/h increments at 30-minute intervals to a maximum of 400 mg/h. Patients in cohort III received subsequent infusions 3 x weekly for 4 weeks at a dose of 375 mg/m2. The first 2 infusions were administered by the same method as in cohorts I and II; however, doses 3 through 12 were initiated at a rate of 50 mg/h for 15 minutes, and then increased to ensure that the full dose was received over a period of 1 hour. Allopurinol (300 mg) was given for the first 14 days of treatment. Byrd et al. J Clin Oncol. 2001;19:2153.

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® Patients were eligible for this trial if they had histologically confirmed CLL or SLL, and had failed 1 prior therapy or were untreated and had a positive antiglobulin test, a history of auto-immune anemia or thrombocytopenia, or were not candidates for chemotherapy because of comorbid illnesses.7 Patients were also required to have recovered from any toxicity related to prior therapy, to have a PS 3, a life expectancy 3 months, CD20+ lesions, a serum creatinine level 3.0 mg/dL, no infection requiring IV or oral (PO) antibiotics, and no previous allergic reaction to MabThera®. Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera® Thrice Weekly for CLL: Patient Characteristics No. of patients 33 Age (y) Median 66 (range) (50-80) Histology CLL 79% SLL 21% Stage I-II 27% III-IV 73% No. of prior treatments Median 2 (range) (0-6) Prior therapy None 18% Alkylator/purine analog 30% fludarabine® refractory 52% Thirty-three patients were enrolled with a median age of 66.7 The majority of patients presented with CLL (79%) and advanced-stage disease (III–IV; 73%). Patients had received a median of 2 prior treatments. Only 18% of patients were previously untreated; 30% had received an alkylator or purine analog therapy and approximately half of the patients were refractory to prior fludarabine® therapy (patients were considered refractory if they did not achieve a PR or CR after therapy or relapsed within 6 months of their last treatment). Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera® Thrice Weekly for CLL: Response % of Patients Response (n=29)* ORR 52 CR 3 PR 48 Response was evaluated using the criteria defined by the NCI-Sponsored Working Group.12 Among the 29 evaluable patients, the ORR was 52%, with CR and PR rates of 3% and 48%, respectively.7 Of note, significant reductions in complement levels (CH50 and C3) were seen in 12 patients after MabThera® treatments on days 1 and 3 (P<0.01), suggesting that CDC may contribute to the initial clearance of tumor cells in vivo. * Evaluable patients. Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera® Thrice Weekly for CLL: Response (cont’d) Characteristic n % ORR Histology SLL 7 43 CLL 26 46 Stage I-II 9 56 III-IV 24 42 Prior therapy None 6 83 Alkylator/fludarabine® 10 30 fludarabine® refractory 17 41 In this study, patients with CLL had higher ORRs than did patients with SLL in the pivotal trial (46% vs 13%, respectively).7 Patients who were previously untreated had higher ORRs (83%) than those who were previously treated with an alkylator or fludarabine® therapy (30%) and those who were refractory to fludarabine® (41%). Response was not significantly affected by histologic diagnosis, stage of disease, density of CD20 expression on tumor cells, cytokine levels (IL-6, IL-8, IFN gamma, and TNF alpha), and development of infusion-related reactions. Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera® Thrice Weekly for CLL: Median Progression-Free Survival 100 Responders All patients 80 60 Patients (%) 40 The median TTP was 6 months for all patients (range, 0–18+ months) and 11 months for responders (range, 3–18+ months).7 The median duration of response for all responders was longer than that for responders who were refractory to fludarabine® therapy (10 months vs 6 months, respectively). 20 2 4 6 8 10 12 14 16 18 20 Months Adapted from Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera® Thrice Weekly for CLL: MabThera® Serum Concentrations Concentration (µg/mL) Standard Deviation Infusion Evaluation 1 Before 0 0 After 17.4 12. 5 2 Before 7.7 10.7 After 245.3 91. 3 3 Before 159.5 144.7 After 401.1 27 1.1 6 Before 418.8 259.1 After 676.3 26 3.5 12 Before 686.4 283.7 After 891.0 33 2.2 Results from the pivotal trial demonstrated that patients who presented with SLL had lower ORRs and a more rapid serum clearance of MabThera®. These findings indicated that higher serum concentrations of MabThera® strongly correlated with increased response rates.79 MabThera® levels in this study began to accumulate after the third dose, with none of the patients experiencing a rapid clearance of the drug.7 (The data presented are from 3 patients who received 375 mg/m2 MabThera®; however, the identical pattern of accumulation was seen in patients who were treated with 250 mg/m2 MabThera®). These data demonstrate that a thrice weekly regimen resulted in high MabThera® serum levels, which may explain, at least in part, the higher response rates seen in this study as compared with those seen in patients with SLL in the pivotal trial. Byrd et al. J Clin Oncol. 2001;19:2153.

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) Twenty patients (61%) experienced adverse events during the first infusion (100 mg).23 Of these patients, 13 had transient hypoxemia, hypotension, or dyspnea that required cessation of treatment and supportive intervention. Only 2 patients (7%) had grade 3/4 events. Toxicity was less common with subsequent infusions. Hematologic toxicity was common during the first week of treatment, although it was generally mild and transient. Three of 6 patients who began treatment with a platelet count <50 x 109/L but >20 x 109/L had a decrease in platelets to <20 x 109/L with the first infusion. By the fifth day of treatment, all 3 patients returned to their baseline platelet count. After the first week of therapy, hematologic toxicity was minimal. Byrd et al. J Clin Oncol. 2001;19:2153.

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 Patients with CLL had a higher ORR with increasing density of MabThera® dosing (thrice weekly x 4 vs once weekly x 4). Higher ORRs were also seen in patients who were not previously treated vs those who relapsed after or who were refractory to prior therapy. The median duration of response was 10 months for all responders and 6 months for responders who were refractory to fludarabine® therapy. In contrast to results from the pivotal trial, rapid clearance and low serum levels of MabThera® were not observed. Pharmacokinetic results and response rates seen in this study suggest that administration of MabThera® thrice weekly may be more effective than the standard once weekly regimen for patients with CLL. Toxicity was generally mild, transient, and occurred during the first infusion. Serious infusion-related events appear to have been minimized by using a stepped-up dosing method that began with a 100-mg dose of MabThera®. Byrd et al. J Clin Oncol. 2001;19:2153.

MabThera first-line and maintenance therapy for CLL and SLL Hainsworth et al J Clin Onc 2003

MabThera first-line and maintenance therapy for CLL and SLL: protocol Patients with PD: off study MabThera (375mg/m2 weekly x 4) Evaluation (week 6) Patients with OR or SD: MabThera maintenance therapy (375mg/m2 weekly x 4, every 6 months for up to four courses) Hainsworth et al. conducted a study to evaluate the efficacy of MabThera for patients with previously untreated chronic lymphocytic leukaemia (CLL) and small lymphocytic lymphoma (SLL). Eligible patients had Rai stage II–IV (CLL) or Ann Arbor stage II–IV (SLL) disease, no prior therapy, ECOG performance status of 0–2 and no life-threatening signs/symptoms. Patients were treated with 4 weekly doses of MabThera 375mg/m2. Patients were evaluated at week 6, and those with objective responses or stable disease were treated with maintenance courses of MabThera (4 weekly doses of 375mg/m2 every 6 months, for a maximum of four courses). Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

MabThera first-line and maintenance therapy for CLL and SLL: patient characteristics Median age of the patients was 66 (range 38–85) years; 24 patients were male and 20 female. Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

MabThera first-line and maintenance therapy for CLL and SLL: response All 44 patients enrolled completed the first course and 43 were evaluable for response. Twenty patients (46%) completed four courses of MabThera treatment. With a median follow-up of 30 months, the median PFS for these patients is 18.9 months. Actuarial 1-year PFS = 64% (28 patients at risk); 2-year PFS = 50% (13 patients at risk). * Evaluable patients Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

MabThera first-line and maintenance therapy for CLL and SLL: PFS 100 80 60 40 20 PFS (%) 0 3 6 9 12 15 18 21 24 27 30 Months Median survival 19 months at 24-month follow-up Actuarial PFS 62% at 1 year and 49% at 2 years Hainsworth J, et al. J Clin Oncol 2003;21:1746–51 Hainsworth J, et al. Proc Am Soc Clin Oncol 2003;20:564 (Abstract 2332)

MabThera first-line and maintenance therapy for CLL and SLL: safety Toxicity was limited to typical, infusion-related reactions. No grade 3–4 adverse events during maintenance MabThera courses No patient withdrew from treatment due to toxicity Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

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 This study demonstrates that MabThera has significant and durable activity in previously untreated patients with CLL or SLL. These results are of particular importance because these conditions were previously thought to be only moderately responsive to MabThera treatment. Furthermore, this study suggests that untreated disease may be more susceptible to treatment with MabThera than later-stage disease. Hainsworth J, et al. J Clin Oncol 2003;21:1746–51

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 CR, PR MabThera (375mg/m2/week x 4) 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 Mauro FR, et al. Blood 2003;102:674a (Abstract 2497)

MabThera consolidation in CLL for older patients in remission after first-line chemotherapy: response Mauro FR, et al. Blood 2003;102:674a (Abstract 2497)

2nd chemotherapy-free survival (%) MabThera consolidation in CLL for older patients in remission after first-line chemotherapy: time to second-line therapy 100 80 60 40 20 0 5 10 15 20 25 30 35 Months 2nd chemotherapy-free survival (%) Mauro FR, et al. Blood 2003;102:674a (Abstract 2497)

MabThera consolidation in CLL for older patients in remission after first-line chemotherapy: summary MabThera given as post-remission therapy in older patients with CLL achieves improved responses in many patients with a partial response to chlorambucil/prednisone Post-remission MabThera is well tolerated Mauro FR, et al. Blood 2003;102:674a (Abstract 2497)