Illuminating Possibilities: Making Strides in the Treatment of B-cell Chronic Lymphocytic Leukemia (B-CLL)

Transcription

1 Illuminating Possibilities: Making Strides in the Treatment of B-cell Chronic Lymphocytic Leukemia (B-CLL) 1

2 Agenda Part 1: Chronic Lymphocytic Leukemia (CLL): A Brief Review Part 2: Campath (alemtuzumab) in Fludarabine-refractory B-CLL Part 3: Campath (alemtuzumab) in Previously Untreated Patients With B-CLL 2 2

3 Part 1 Chronic Lymphocytic Leukemia (CLL): A Brief Review Part 1 of this presentation provides an overview of CLL, including its diagnosis, staging, and prognosis 3

4 CLL Is the Most Common Leukemia in Western Society 35% of all leukemias; 15,340 new cases in ,2 Deaths 4500 in 2007 Median age at diagnosis is 65 years 3 Median survival of 10 years from diagnosis 3 Morbidity and mortality increase with disease progression 4 Bone marrow impairment Increased susceptibility to infection 1. Cancer Facts & Figures Leukemia & Lymphoma Society Facts Redaelli et al. Eur J Cancer Care. 2004;13: Byrd et al. Semin Oncol. 1998;25: % of all leukemias; 15,340 new cases in ,2 Deaths 4500 in 2007 Median age at diagnosis is 65 years 3 Median survival is 10 years from diagnosis 3 Morbidity and mortality increase as the disease progresses due to 4 : Bone marrow impairment Increased susceptibility to infection References: 1. Cancer Facts & Figures Leukemia & Lymphoma Society Facts Redaelli et al. Eur J Cancer Care. 2004;13: Byrd et al. Semin Oncol. 1998;25:

5 Clinical Course of CLL Diagnosis is often incidental Asymptomatic at diagnosis in ~50% of patients Initial findings: lymphocytosis/anemia Disease has a variable course; however, it often progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia Progression: bone marrow impairment, susceptibility to infection Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients Faguet. J Clin Oncol. 1994;12: Although CLL is predominantly an indolent disorder of late middleaged or elderly individuals, the disease may cause significant morbidity. In its least aggressive pattern, patients die of causes unrelated to CLL at a rate that closely follows actual norms for their age. In its most aggressive form, patients may die within 1 to 2 years after diagnosis At presentation, patients are often asymptomatic. Initial symptoms are generally secondary to lymphocytosis or anemia. As the disease advances, the following may appear: increasingly elevated lymphocyte counts; progressive lymphadenopathy and hepatosplenomegaly; and more severe anemia, granulocytopenia, or thrombocytopenia. Late in the course of the disease, hypogammaglobulinemia and progressive splenomegaly are prevalent. Infections are common with disease progression and are the leading cause of death in patients with CLL Most CLL patients die of infection or illness unrelated to the leukemia Long-term consequences of CLL include the development of autoimmune phenomena and/or transformation Faguet. J Clin Oncol. 1994;12:

6 Complications of CLL Severe systemic infections Recurrent bacterial infections, i.e. chest infections Autoimmune cytopenias AIHA ITP Bleeding Diffuse large B-cell lymphoma Richter s transformation EBV-associated LPD Secondary malignancies MDS/Acute myeloid leukemia Skin cancers Kalil et al. Drugs Aging. 2000;16: As previously mentioned, severe systemic infections represent the leading cause of death for patients with CLL. Increased susceptibility to infections is due both to intrinsic features of the pathogenesis of CLL as well as to therapy CLL evolves into a more aggressive lymphoid malignancy in about 10% to 15% of cases. Richter s transformation is the most common of these, in which patients develop a diffuse large cell immunoblastic lymphoma. Survival is poor Prolymphocytoid transformation occurs when the morphologic appearance of the CLL cells alters to somewhat larger cells with distinct nucleoli and less dense chromatin. This condition is refractory to typical chemotherapeutic agents Secondary malignancies may develop in patients with CLL, particularly carcinomas of the lung CLL may evolve into acute leukemia as a terminal event. When this occurs, the leukemia is myeloid in origin Kalil et al. Drugs Aging. 2000;16:

7 Traditional Prognostic Factors 1,2 Advanced stage at diagnosis Tumor load (WBC, LDH) Short lymphocyte doubling time Diffuse pattern of bone marrow infiltration Advanced age/male/ performance status High serum levels of β2-microglobulin and soluble CD23 Percentage of prolymphocytes WBC=white blood cells; LDH=lactic dehydrogenase. 1. Rozman et al. N Engl J Med. 1995;333: Cheson et al. Blood. 1996;87: In addition to clinical staging, the following prognostic factors provide information that may guide therapeutic decisions 1,2 : A short doubling time (<12 months) of the peripheral lymphocyte count indicates a poor prognosis Histologic patterns of bone marrow infiltration seem to correlate with clinical staging. In general, nondiffuse or nodular patterns are seen more frequently in early clinical stages with diffuse infiltration predominating in advanced disease. Patients with interstitial and nodular bone marrow involvement have a longer survival than those with mixed or diffuse patterns Older patients and males have a worse prognosis The presence of chromosomal abnormality on karyotype analysis is associated with a shortened survival. The effect is more marked in patients with multiple chromosomal aberrations and most severe when the chromosomal abnormality is associated with a high rate of proliferation of the neoplastic cell population. There is some correlation between chromosomal aberration and Rai stage: a normal karyotype occurs more frequently in patients at Rai stage 0, single chromosomal abnormalities are more common in intermediate-risk patients (Rai I/II), and complex karyotypes seem to be more common in high-risk individuals (Rai III/IV) High serum levels of β2-microglobulin and CD23 are associated with inferior survival CLL prolymphocytic leukemia has a worse prognosis than classic CLL References: 1. Rozman et al. N Engl J Med. 1995;333: Cheson et al. Blood. 1996;87:

8 Emerging Prognostic Factors in CLL 1-3 Abnormality IgV H mutation status 13q deletion Trisomy 12 11q deletion 17p deletion or p53 mutations Potential Impact on Disease Unmutated IgV H predicts for a poor outcome Suggests indolent disease progression May indicate a shorter treatment-free survival Suggests aggressive disease progression; often associated with bulky lymph nodes Results in resistance to alkylating agents or purine analogs and subsequent poor survival 1. Chiorazzi et al. N Engl J Med. 2005;352: Döhner et al. N Engl J Med. 2000;343: Catovsky et al. Blood. 2004;104:98. Abstract Chromosomal aberrations are proving to be useful prognostic indicators, 1,2 especially in CLL where approximately 80% of patients with active disease show genetic abnormalities. 3 While the Rai and Binet staging systems offer guidelines for initiating therapy, they cannot be used to predict (nor were they intended to predict) a patient s individual risk of disease progression or identify early stage patients who could benefit from aggressive treatment 2 Cytogenetic lesions are rare in early CLL; however, some alterations do appear as the disease progresses. 1 The most common is a deletion at 13q14.3, which occurs in more than 50% of cases over time. 1 The most ominous are deletions at 11q22-23, 17p13, and 6q21. 1 These abnormalities can significantly influence the patient s response to treatment and overall survival 2,3 References: 1. Chiorazzi et al. N Engl J Med. 2005;352: Döhner et al. N Engl J Med. 2000;343: Catovsky et al. Blood. 2004;104:98. Abstract 13. 8

9 Conventional Cytogenetics in CLL Juliusson et al. N Engl J Med. 1990;323: Cytogenetic analysis provides important information about CLL. This figure is from a study that Juliusson and colleagues published in They evaluated the karyotypes of 391 patients with CLL. As shown in this Kaplan-Meier curve, overall survival correlates with the number of chromosomal abnormalities detected Specific chromosomal aberrations have prognostic significance, as will be discussed. They may predict response to therapy In addition, malignancies evolve over time, acquiring additional mutations. Physicians can follow the clonal evolution of an individual s particular malignancy Juliusson et al. N Engl J Med. 1990;323:

10 Genetic Abnormalities Can Influence Survival (Döhner et al) in CLL Effects of genetic abnormalities on survival in patients with CLL (N=325) Döhner et al. N Engl J Med. 2000;343: Döhner et al evaluated 325 cases of CLL to assess the frequency and clinical relevance of genomic aberrations. Of the 325 patients, 248 had received no prior treatment, 39 had received 1 chemotherapeutic agent, and 38 had received 2 or more chemotherapeutic regimens before the cytogenetic analysis was conducted Of the 325 patients, 268, or 82%, exhibited abnormalities. The primary endpoint for this study was survival from time of diagnosis. All cases were evaluated by interphase cytogenetics. On the basis of regression analysis, the investigators constructed a hierarchical model of 5 genetic categories for evaluation as prognostic factors: 17p deletion; 11q deletion but not a 17p deletion; 12q trisomy but not a 17p or 11q deletion; normal genome; and 13q deletion as the sole aberration. Of the 325 patients, 300 could be assigned to one of these 5 subgroups; 25 with various chromosomal abnormalities could not This slide illustrates the percentage of surviving patients by genetic aberration over 168 months. Median survival times for the groups were: 17p deletion, 32 months; 11q deletion, 79 months; 12q trisomy, 114 months; normal genome, 111 months; and 13q deletion as the only abnormality, 133 months. As the slide shows, patients with 17p deletions had by far the worst prognosis Döhner et al. N Engl J Med. 2000;343:

11 CLL Treatment: a Likely Cause of p53 Gene Alteration Study Sturm et al 1 Pretreated patients* Number of patients by pretreatment status Percentage of patients with p53 gene alterations 80 25% Chemotherapynaïve patients 58 5% Lozanski et al 2 Pretreated 36 42% patients Chemotherapynaïve patients 0 0% *All but 18 patients were treated with alkylating agents. Patients had received a median of 3 prior therapies (range, 1-12). 1. Sturm et al. Cell Death Differ. 2003;10: Lozanski et al. Blood. 2004;103: DNA-damaging chemotherapy may be a cause of p53 inactivation and the resulting resistance to therapy 1,2 In a multicenter study, Sturm and colleagues investigated the p53 mutational status of 138 B-CLL samples and compared their findings with drug and γ-irradiation sensitivity profiles. Their results showed that treatment with alkylating agents correlated with the occurrence of p53 mutations 25% of patients who had been pretreated with chemotherapy (all but 18 with alkylating agents) showed p53 gene alterations as compared with only 5% of patients who had not received previous chemotherapy 1 In another study of 36 patients with refractory CLL who had received a median of 3 prior therapies (range from 1 to 12) including fludarabine, 15 patients, or 42%, had p53 mutations or chromosome 17p13.1 deletions 2 References: 1. Sturm et al. Cell Death Differ. 2003;10: Lozanski et al. Blood. 2004;103:

12 Part 2 Campath (alemtuzumab) in Fludarabine-refractory B-CLL In Part 2, we will briefly review the use of Campath in patients with relapsed or refractory B-CLL 12

13 Campath (alemtuzumab): Targeted Monoclonal Antibody (MAb) Campath is a recombinant DNA-derived humanized MAb directed against the cell-surface antigen, CD52 1 CD52 is a small glycoprotein (12 amino acids) 1 The proposed mechanism of action is antibodydependent cellular-mediated lysis following cell surface binding of Campath to CD52 1 CD52 vs CD20 expression on B-CLL cells 2 CD52: ~400,000 binding sites/cell CD20: ~8000 binding sites/cell 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Rossmann et al. Hematol J. 2001;2: Rossmann et al. Cytometry B Clin Cytom. 2007; [Epub ahead of print] 13 Campath is a recombinant DNA-derived humanized MAb directed against the cell-surface antigen, CD52 1 The proposed mechanism of action is antibody-dependent cellularmediated lysis following cell surface binding of Campath to CD52 1 CD52 expression is higher and less variable than CD20 expression 2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Rossmann et al. Hematol J. 2001;2:

14 Campath Pivotal Study (CAM211): Results 33% OR: CR 2%; PR 31%; 54% stable disease Median survival: 32 months in responders; 16 months for all patients LN <2 cm resolved in 64% of patients, not if >5 cm 53% of patients with B symptoms or fatigue at baseline experienced complete resolution of these symptoms Majority of patients had complete resolution or 50% reduction in organomegaly or lymphadenopathy LN=lymph nodes. Keating MJ, et al. Blood. 2002;99: % OR: CR 2%; PR 31%; 54% stable disease Median survival: 32 months in responders; 16 months for all patients LN <2 cm resolved in 64% of patients, not if >5 cm 53% of patients with B symptoms or fatigue at baseline experienced complete resolution of these symptoms Majority of patients had complete resolution or 50% reduction in organomegaly or lymphadenopathy

15 Campath (alemtuzumab) Pivotal Study (CAM211): Overall Survival 1,2 1. Keating et al. Blood. 2002;99: Keating et al. Leuk Lymphoma. 2002;43: One third of the patients in the study achieved an overall response. There was also a 6-month prolongation in survival in the intent-totreat population compared with fludarabine-refractory historical controls 1,2 Patients receiving Campath who responded had much better survival versus the intent-to-treat population 1 Median overall survival was 16 months for all patients and 32 months in responders 1 References: 1. Keating et al. Blood. 2002;99: Keating et al. Leuk Lymphoma. 2002;43:

16 Part 3 Campath (alemtuzumab) in Previously Untreated Patients With B-CLL On September 19, 2007, Campath was approved for use as a single agent for first-line treatment of B-CLL Part 3 of this presentation introduces the results of the pivotal trial comparing Campath with chlorambucil as a single agent for the treatment of B-CLL 16

17 Campath (alemtuzumab) in Previously Untreated B-CLL Patients: Study Objectives Evaluate Campath vs chlorambucil in a multicenter, randomized, open-label, phase 3 trial 1,2 Primary objective 1,2 Progression-free survival (PFS)* Secondary objectives 2 Safety Response rates according to 1996 NCIWG criteria Time to alternative treatment Time to treatment failure Overall survival Duration of response *PFS and response rates determined by an IRRP. 2 IRRP=independent response review panel; NCIWG=National Cancer Institute Working Group. 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 17 The primary endpoint of the study was to demonstrate that Campath alone significantly prolongs PFS compared with chlorambucil in the first-line treatment of B-CLL 1,2 Secondary efficacy endpoints included 2 : Response rates using the NCIWG criteria from 1996 Time to alternative treatment Time to treatment failure Overall survival Duration of response Safety was also evaluated as a secondary endpoint 2 Progression-free survival and response rates were reviewed by an IRRP 2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 17

18 Main Eligibility Criteria Inclusion criteria Histopathologically confirmed diagnosis of B-CLL Rai stage I-IV disease Progressive disease according to 1996 NCIWG criteria No previous chemotherapy for B-CLL Exclusion criteria ANC <0.5 x 10 9 /L or platelet count <10 x 10 9 /L Autoimmune thrombocytopenia Previous bone marrow transplant Active infection, positive for HIV Positive quantitative CMV by PCR ANC=absolute neutrophil count; CMV=cytomegalovirus; HIV=human immunodeficiency virus; PCR=polymerase chain reaction. Data on file, Bayer HealthCare Pharmaceuticals Inc. 18 Inclusion criteria were typical of first-line B-CLL studies. Patients were required to have: A confirmed diagnosis of B-CLL, Rai stage I to IV Progressive disease according to the 1996 NCIWG criteria Must not have received prior chemotherapy for B-CLL Exclusion criteria included: Severe pancytopenias due to previous bone marrow transplant or autoimmune thrombocytopenia Active infection at the time of study entry Positive for CMV, as determined by PCR Data on file, Bayer HealthCare Pharmaceuticals Inc. 18

19 Study Design 1,2 Previously untreated progressive B-CLL patients (N=297) Campath (alemtuzumab): 30 mg intravenously (IV) 3 times weekly (TIW) for up to 12 weeks (n=149) Chlorambucil: 40 mg/m 2 orally (PO) once every 28 days for a maximum of 12 cycles (up to 12 months) (n=148) 44 centers in 13 countries (US and Europe) participated 2 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 19 Two hundred ninety-seven treatment-naïve patients were entered into the study from 44 centers in 13 countries (US and Europe) 1,2 One-hundred forty-nine patients were randomized to receive Campath and 148 patients were randomized to the chlorambucil arm 2 The treatment schedules varied across the 2 treatment arms 2 : Patients in the Campath arm received the conventional dose of 30 mg administered as a 2-hour IV infusion 3 times a week for a total of 12 weeks. During the first week of therapy, the dose was escalated from 3 mg to 10 mg to 30 mg, and during the subsequent 11 weeks, patients received 30 mg 3 times per week 1,2 Patients in the chlorambucil arm received 40 mg/m 2 of the drug orally once a month for a maximum of 12 months, depending on the response 1,2 To ensure that the 2 study arms were balanced, the randomization was stratified by study center, the stage of the disease, performance status, age, gender, and the size of the largest lymph nodes 1,2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 19

20 Baseline Characteristics (ITT population; N=297) 1,2 Characteristics Campath (alemtuzumab) (n=149) Chlorambucil (n=148) Male/female 106/43 107/41 Median age (range) 59 (35-86) 60 (36-83) Rai stage (IRRP) I-II III-IV 93 (62.4%) 50 (33.6%) 96 (64.9%) 49 (33.1%) Maximum lymph node 5 cm 33 (22.1%) 34 (23.0%) WHO performance status (96.0%) 143 (96.6%) B symptoms Present 74 (49.7%) 87 (58.8%) Splenomegaly 53 (35.6%) 56 (37.8%) Hepatomegaly 43 (28.9%) 27 (18.2%) ITT=intent to treat; WHO=World Health Organization. 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 20 There were no significant differences in variables between the treatment arms Data on file, Bayer HealthCare Pharmaceuticals Inc. 20

21 Treatment Exposure (Safety Population*; N=294) 1,2 Drug regimen Median treatment duration (range) Median cumulative dose (range) Campath (alemtuzumab) (n=147) 30 mg IV TIW for 12 weeks 11.7 weeks (0-33) 956 mg (2-1645) Chlorambucil (n=147) 40 mg/m 2 PO once every 28 days for 12 cycles 28.3 weeks (4-59) 515 mg ( ) *3 patients withdrew from participation prior to the administration of study drug; 2 patients in the Campath arm and 1 patient in the chlorambucil arm. 2 Chlorambucil duration=7 cycles (1-12). 2 Campath TIW for 12 weeks (escalation period of 1 week assumed) 1033 mg Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 21 In this study, the maximum treatment durations were very different in the 2 treatment arms up to 12 weeks for Campath versus up to 12 months for chlorambucil and continued treatment was dependent upon response. Therefore, the treatment exposures in the 2 treatment arms were very different 1,2 Patients in the Campath arm received 30 mg of Campath by a 2-hour infusion, with a median duration of therapy just under 12 weeks 1,2 In the Campath arm, some patients had treatment durations that were longer than 12 weeks because of dose interruptions due to adverse reactions, such as infusion reactions or CMV. When the reactions were resolved, treatment was resumed to achieve a total of 12 weeks of therapy, exclusive of dose interruption 2 In contrast, patients receiving chlorambucil received the drug orally for a maximum of 12 cycles, with a median duration of therapy just over 7 months 1,2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 21

22 Premedication Campath (alemtuzumab) Diphenhydramine 50 mg IV 30 minutes prior to treatment Acetaminophen or paracetamol (500 mg to 1000 mg) PO Meperidine 25 mg or hydrocortisone 200 mg IV 1 hour before treatment, as clinically indicated Allopurinol 300 mg PO per day beginning 1 day before treatment and for the next 14 days, and as clinically indicated Chlorambucil Allopurinol 300 mg PO per day beginning 1 day before treatment to day 8 of therapy in each of the first 3 cycles, then as clinically indicated Adequate supportive care Data on file, Bayer HealthCare Pharmaceuticals Inc. 22 Premedication within the 2 treatment arms was different Because patients receiving Campath intravenously may have infusion reactions, patients in the Campath arm received an antihistamine and acetaminophen or paracetamol prior to each infusion Patients who did have reactions were treated with IV hydrocortisone or a pethidine, drugs known to reduce the reactions seen in patients All patients in the Campath arm also received allopurinol for at least the first 2 weeks of treatment Patients in the chlorambucil arm received allopurinol for the first 9 days, beginning 1 day prior to treatment and through day 8 of therapy for each of the first 3 cycles, and then as clinically indicated Data on file, Bayer HealthCare Pharmaceuticals Inc. 22

23 Concomitant Prophylactic Therapy Campath (alemtuzumab) arm 1,2 Trimethoprim/sulfamethoxazole DS (160 mg/800 mg) (co-trimoxazole) 1 tablet PO twice daily (BID) TIW Famciclovir 250 mg PO BID Equivalents can be used Both should be taken while on therapy and for a minimum of 2 months following the last dose or until CD cells/µl 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 23 All patients in the Campath arm received prophylaxis against Pneumocystis jiroveci pneumonia. Patients received the antibiotic combination trimethoprim/sulfamethoxazole, or an equivalent, during treatment 1,2 Patients also received prophylaxis against herpes virus reactivation, either famciclovir or its equivalent 1,2 These prophylactic therapies were continued for at least 2 months after the completion of Campath or until the CD4+ count reached 200 cells/µl References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 23

24 Response to First-line Therapy With Campath (alemtuzumab) vs Chlorambucil (N=297) OR=overall response; ORR=overall response rate. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; One of the secondary endpoints of the trial was response rate according to the NCIWG criteria 1 Significantly more patients treated with Campath achieved an overall response 83% with Campath versus 55% with chlorambucil 2 Significantly more patients treated with Campath versus chlorambucil achieved a complete response 2 A 24% complete response rate in the Campath arm compared favorably to the 2% complete response rate in the chlorambucil arm 2 References: 1. Data on file, Bayer HealthCare Pharmaceuticals Inc. 2. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;

25 Progression-free Survival Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; The primary endpoint of the study was PFS 1 Campath significantly prolonged PFS compared with chlorambucil 2 Median PFS was 14.6 months ( ) with Campath versus 11.7 months ( ) with chlorambucil 1,2 Median follow-up was about 25 months in both treatment arms 1 References: 1. Data on file, Bayer HealthCare Pharmaceuticals Inc. 2. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;

26 Time to Alternative Treatment Data on file, Bayer HealthCare Pharmaceuticals Inc. 26 A secondary endpoint of the study was time to alternative treatment, and this, again, was significantly longer for patients receiving Campath compared with chlorambucil The median time from entering the study to needing an alternative therapy was 23.3 months ( ) for patients receiving Campath compared with 14.7 months ( ) in the chlorambucil arm Data on file, Bayer HealthCare Pharmaceuticals Inc. 26

27 Treatment-free Interval Median duration of therapy 1,2 Median time to alternative treatment 2 Campath (alemtuzumab) (n=147) 12 weeks (0-33) 93 weeks ( ) Chlorambucil (n=147) 28 weeks (4-59) 59 weeks ( ) Treatment-free period 81 weeks 31 weeks 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 27 The median duration of therapy was very different between the two arms 12 weeks for Campath versus 28 weeks with chlorambucil. This must be taken into consideration when determining the treatment-free interval, which is the time from the end of treatment to the initiation of an alternative therapy 1,2 In this study, the treatment-free interval for patients receiving Campath was more than twice that for patients receiving chlorambucil, with an interval of treatment from the end of Campath to the next treatment that was 81 weeks versus 31 weeks for patients receiving chlorambucil 1,2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 27

28 Cytopenias Campath (alemtuzumab) (n=147) Chlorambucil (n=147) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Lymphopenia 97% 97% 9% 1% Neutropenia 77% 42% 51% 26% Anemia 76% 13% 54% 18% Thrombocytopenia 71% 13% 70% 14% Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; The high rate of lymphopenia is a direct result of effective treatment with Campath, as a result of the underlying disease process and the known antigen of Campath There are no dose modifications recommended for lymphopenia The incidences of grade 3/4 thrombocytopenia and anemia were comparable across the 2 arms Ten percent of patients received growth factor support The incidence of neutropenia was higher with Campath therapy, but this was generally manageable with growth factor support Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;

29 Infusion Reactions Campath (alemtuzumab) (n=147) Chlorambucil (n=147) All Grades % Grade 3/4 % All Grades % Grade 3/4 % Fever Chills Urticaria Rash Hypotension Dyspnea Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; As one would expect, infusion reactions were more common with Campath and the frequency of infusion reactions was highest in the first week of therapy Fever and chills were the most common infusion reactions, but most of these reactions were grade 1 or 2 Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;

30 Infections (All Grades) *Total infections is excluding patients with any CMV events. CMV viremia (without evidence of symptoms) includes both cases of single PCR-positive test results and of confirmed CMV viremia ( 2 occasions in consecutive samples 1 week apart). For the latter, ganciclovir (or equivalent) was initiated per protocol. 1. Data on file, Bayer HealthCare Pharmaceuticals Inc. 2. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; In this study of first-line Campath, when CMV reactivation was excluded, the incidence of the total number of infections between Campath and chlorambucil was similar, although greater in the Campath arm 1 The incidence of severe infections, such as grade 3/4 sepsis or febrile neutropenia, was also similar between Campath and chlorambucil 1,2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 30

31 Outcomes for Patients With CMV Infections 23 Campath (alemtuzumab)-treated patients had CMV infections* at any time during the study All but one were treated with antivirals and all recovered 91% of patients had study drug interrupted during the event 74% of patients resumed treatment with Campath after resolution of the event *CMV infections were defined as CMV positive by polymerase chain reaction with 1 symptom of CMV infection. Data on file, Bayer HealthCare Pharmaceuticals Inc. 31 Twenty-three patients within the Campath arm had CMV infections during the study. Per protocol, patients should have had an interruption of Campath, had the CMV infection treated, and then, if appropriate, could resume Campath therapy All but one were treated with antivirals and all recovered Most patients with symptomatic CMV infection had an interruption in their Campath treatment Almost three-quarters of patients restarted Campath when they became CMV-negative Data on file, Bayer HealthCare Pharmaceuticals Inc. 31

32 Conclusions: Campath (alemtuzumab) vs Chlorambucil in Previously Untreated B-CLL Campath is superior to chlorambucil for PFS Risk of disease progression or death was 42% less with Campath versus chlorambucil (P=.0001) 1 Campath is superior to chlorambucil for ORR ORR was 83% with Campath versus 55% with chlorambucil (P<.0001) 1 CR was 24% with Campath versus 2% with chlorambucil (P<.0001) 1 Treatment-free interval more than doubled with Campath 1,2 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 32 This study demonstrates that Campath is a more effective singleagent therapy than chlorambucil for first-line patients with B-CLL requiring treatment 1 The risk of disease progression or death was significantly less for patients receiving Campath than chlorambucil, and there was a significantly higher ORR and CR rate for Campath compared to chlorambucil 1 Patients receiving Campath experienced a significantly longer time to alternative treatment compared with those receiving chlorambucil, despite a shorter duration of therapy 1,2 The treatment-free interval more than doubled with Campath compared with chlorambucil 1,2 References: 1. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; Data on file, Bayer HealthCare Pharmaceuticals Inc. 32

33 Conclusions: Campath (alemtuzumab) vs Chlorambucil in Previously Untreated B-CLL Campath therapy was manageable and predictable No treatment-related deaths 1 Incidences of grade 3/4 anemia and thrombocytopenia and all infections, excluding CMV, were similar to chlorambucil 1,2 No increased risk of neutropenic infections with Campath 1 CMV infections occurred in 16% of patients treated with Campath 2 All patients recovered 1 The superior efficacy and proven safety of Campath as a single agent for B-CLL support its further development in the treatment of B-CLL. 1. Data on file, Bayer HealthCare Pharmaceuticals Inc. 2. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.; The adverse events seen in the Campath arm were manageable and predictable There were no treatment-related deaths with Campath 1 The rate of neutropenia was higher with Campath than with chlorambucil, but there was no increased risk of neutropenic infections with Campath. Rates of grade 3/4 anemia and thrombocytopenia were similar to chlorambucil 2 There was an increased risk of CMV infection. However, these infections were effectively managed with preemptive therapy 1 In summary, Campath is proven safe and effective as a single agent for first-line therapy in B-CLL References: 1. Data on file, Bayer HealthCare Pharmaceuticals Inc. 2. Campath [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;

34 Campath (alemtuzumab) is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). WARNING: CYTOPENIAS, INFUSION REACTIONS, and INFECTIONS Cytopenias: Serious, including fatal, pancytopenia/marrow hypoplasia, autoimmune idiopathic thrombocytopenia, and autoimmune hemolytic anemia can occur in patients receiving Campath. Single doses of Campath greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia [see WARNINGS AND PRECAUTIONS (5.1)]. Infusion Reactions: Campath can result in serious, including fatal, infusion reactions. Carefully monitor patients during infusions and withhold Campath for Grade 3 or 4 infusion reactions. Gradually escalate Campath to the recommended dose at the initiation of therapy and after interruption of therapy for 7 or more days [see DOSAGE AND ADMINISTRATION (2) and WARNINGS AND PRECAUTIONS (5.2)]. Infections: Serious, including fatal, bacterial, viral, fungal, and protozoan infections have occurred in patients receiving Campath. Administer prophylaxis against Pneumocystis jiroveci pneumonia (PCP) and herpes virus infections [see DOSING AND ADMINISTRATION (2.2) and WARNINGS AND PRECAUTIONS (5.3)]

35 Questions and Answers

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