CLL Quick Cards

CLL QUICK CARDS

Expand Your Knowledge!

The Chronic Lymphocytic Leukemia (CLL) Quick Cards are designed for use by Oncology Account Managers before and between sales calls as a quick, convenient educational tool on CLL to help you maximize your opportunities for dynamic, productive dialogue with customers.

Remember, these Quick Cards do not represent a complete CLL resource. For more detailed information, please consult the ARZERRA速 CLL Sales Training Modules and Resource Guide.

Information contained in this tool is beyond the scope of the FDA-approved indication for ARZERRA. Therefore, the efficacy and safety of ARZERRA cannot be inferred for the entire population of patients described in this tool or for specific subgroups identified herein. These cards discuss CLL in general, but you should only discuss CLL that is refractory to fludarabine and alemtuzumab with your customers.

ARZERRA速 (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14)]. No data demonstrate an improvement in disease related symptoms or increased survival with ARZERRA.

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

INTRODUCTION

Various topics are covered足足, such as CLL pathology, epidemiology, disease markers, diagnosis, staging, and guidelines. The back of these cards present possible discussions to help you facilitate a dialogue with your customers about a number of topics. You will receive new Quick Cards and/or updated cards regularly.

1

INTRODUCTION

1

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

© 2010 The GlaxoSmithKline Group of Companies.

All rights reserved. Printed in USA. AZA213R0 November 2010

Leukemia overview Major Types of Leukemia†

Background

LL is the most frequently diagnosed leukemia in adults C — In 2010, there will be an estimated 14,990 new cases of CLL compared to 12,330 for AML, 5330 for ALL, and 4870 for CML3 he CD20 antigen is expressed on almost all B cells T — In CLL, antibody-making B cells do not function normally and, ultimately, are less capable of fighting off infection5

Type

Characteristics

AML

Occurs in adults and children6 Fast growing6 Too many myeloblasts are found in blood and bone marrow7

ALL

Most common type in young children6 Fast growing6 Too many lymphoblasts found in blood and bone marrow8

CML

Mainly affects adults6 —Slowly progressing disease — Too many white blood cells (not lymphocytes) are made in the bone marrow Philadelphia chromosome is a characteristic feature9

CLL SLL

Mainly affects older adults6 Usually grows slowly6 oo many immature lymphocytes found mostly in the blood T and bone marrow

4

ARZERRA is not indicated in the above types of leukemia (except FA-ref CLL).

This table is included for your information only. If a customer asks about the use of ARZERRA in any population outside of FA-ref CLL, refer them to Medical Information (MI).

†

Peripheral smear from patient with CLL

* ARZERRA is only indicated in FA-refractory CLL. At present, no clear numbers on the prevalence of FA-ref CLL, the population in which ARZERRA is indicated, have been determined. Therefore, we have provided general population numbers for your reference only. The number of patients with FAref CLL will obviously be far smaller than that of the general population.

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CLL is a disorder of morphologically mature but immunologically less mature B cells — and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.10

OVERVIEW OF CLL PATHOLOGY/ETIOLOGY

I n leukemia, the bone marrow produces large numbers of abnormal white blood cells1 —These cells grow and survive longer than normal cells1 — Over time, these cells may accumulate and crowd out normal blood cells1 — According to the National Cancer Institute, more than 40,800 adults and 3500 children are diagnosed with leukemia each year2*

2

What this might sound like

OVERVIEW OF CLL PATHOLOGY/ETIOLOGY

Physician: I understand the patient population that ARZERRA was studied in, but does ARZERRA have any efficacy outside of FA-refractory CLL?

2

OAM: ARZERRA was studied in a single-arm, multicenter trial of 154 patients with relapsed or refractory CLL. Of these 154 patients, a subset of 59 patients with CLL refractory to fludarabine and alemtuzumab comprised the efficacy population for ARZERRA. I cannot speak to use outside of the indicated patient population for ARZERRA; however, I can refer you to MI to have the rest of your question addressed.

1. What you need to know about leukemia: what is leukemia? National Cancer Institute Web site. http://www.cancer.gov/cancertopics/what-is-cancer. Accessed August 6, 2010.

2. What you need to know about leukemia: about this booklet? National Cancer Institute Web site. http://www.cancer.gov/cancertopics/wyntk/leukemia. Accessed August 6, 2010.

3. Cancer Facts & Figures 2010. American Cancer Society Web site. Atlanta, GA: American Cancer Society; 2010.

4. Robak T. Novel monoclonal antibodies for the treatment of chronic lymphocytic leukemia.

Curr Cancer Drug Targets. 2008; 8(2):156-171.

5. Detailed guide: leukemia—chronic lymphocytic. American Cancer Society Web site. http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=62. Accessed August 6, 2010.

6. What you need to know about leukemia: types of leukemia. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/wyntk/leukemia/page3. Accessed August 6, 2010.

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

7. D efinition: acute myeloid leukemia. National Cancer Institute Web site. http://www. cancer.gov/Common/PopUps/definition.aspx?term=acute+myeloid+leukemia.

Accessed August 6, 2010.

8. Definition: acute lymphocytic leukemia. National Cancer Institute Web site. http:// www.cancer.gov/Common/PopUps/definition.aspx?term=acute+lymphocytic+leukemia.

Accessed August 6, 2010.

9. Philadelphia chromosome. Taber’s Cyclopedic Medical Dictionary. 20th ed. Taber’s Online Web site. http://www.tabers.com. Accessed June 27, 2008.

10. Chronic lymphocytic leukemia treatment (pdf): health professional version. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/ HealthProfessional/page2/print. Accessed August 25, 2010.

CLL accounts for 1 in 3 of all leukemias CLL fast facts (US data)

B-cell surface markers in CLL B cells express many surface molecules, some of which are unique to B cells7 — Cell surface molecules are also known as cluster of differentiation (CD) antigens8

M ainly affects older adults, occurring more often in males2 — Most prevalent in individuals in the 7th, 8th, and 9th decades of life3 —Median age at diagnosis is around 72 years4 —Rarely seen in people under 40 years of age2 —Few known risk factors5 —Average person’s lifetime risk of developing CLL is about 1 in 2002

C LL cells express CD19 and CD209 C D20 is present on >95% of B cells in both peripheral blood and lymphoid organs7 —May function as an ion channel important in B-cell activation7 C LL cells also co-express CD23 and CD59-11 In CLL, B cells express lower CD20 antigens in comparison to other B-cell malignancies12

Prognosis verall 5-year relative survival is 78% (SEER data: 1999-2006); O relative survival at 5 years by race and sex4: —77% for white males —81% for white females —62% for black males —68% for black females ost CLL patients survive 5 to 10 years,* with an initial M course that is relatively benign followed by a progressive, resistant, and terminal phase lasting 1 to 2 years6

B-cell Surface Markers†

CD20 on B Cells

I n 2010, CLL will account for about 4390 deaths2 Please note that this image is not inclusive of all B-cell surface markers.

†

During the later phase of CLL, morbidity is considerable, both from the disease and from complications of therapy.6 * You may not discuss this with customers. ARZERRA has no data demonstrating an impact on survival and to discuss survival may imply that ARZERRA had data demonstrating this effect. If a customer discusses survival data with you, you may listen, then transition back to the indicated patient population and the appropriate data supporting this.

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EPIDEMIOLOGY/STAGING OF CLL

M ost commonly diagnosed adult leukemia — Accounts for about one-third of all leukemias2 —About 14,990 new cases each year (2010 estimates)2 —Prevalence (as of 2005) is more than 90,000 cases3 1

3

What this might sound like Prognosis Discussion

EPIDEMIOLOGY/STAGING OF CLL

Physician: Overall survival and progression free survival are important factors in determining the therapies that I choose for my patients with refractory CLL. What kind of data does ARZERRA have to this end?

3

OAM: Good question. Let’s take a look at the pivotal study design for ARZERRA. PFS and OS were not primary endpoints in this interim analysis, and the main efficacy outcome was durable objective tumor response rate. The FDA agreed that the objective tumor response rate is reasonably likely to predict clinical benefit in this population for which there was an unmet medical need. In this patient population, with CLL refractory to both fludarabine and alemtuzumab, the overall response rate was 42% and the median duration of response was 6.5 months. All responses were partial responses.

Do you now have the information you need about the study design and efficacy outcomes for ARZERRA?

1. Cancer Facts & Figures 2010. American Cancer Society Web site. Atlanta, GA: American Cancer Society; 2010.

8. CD antigens. Philadelphia chromosome. Taber’s Cyclopedic Medical Dictionary, 21st ed.

Taber’s Online Web site. http://www.tabers.com. Accessed June 27, 2008.

2. What are the key statistics for chronic lymphocytic leukemia? American Cancer Society Web Site. http://www.cancer.org/Cancer/Leukemia-ChronicLymphocyticCLL/DetailedGuide/ leukemia--chronic-lymphocytic-key-statistics. Accessed August 6, 2010.

9. C hronic lymphocytic leukemia treatment (PDQ®): health professional version. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/ healthprofessional/allpages. Accessed August 9, 2010.

3. Facts 2008-2009. The Leukemia and Lymphoma Society Web site. http://www.leukemialymphoma.org/attachments/National/br_1182779969.pdf. Accessed August 6, 2010.

10. H allek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.

4. SEER stat fact sheets: chronic lymphocytic leukemia. National Cancer Institute Web site. http://seer.cancer.gov/statfacts/html/clyl.html#survival. Accessed August 6, 2010.

5. What are the risk factors for chronic lymphocytic leukemia? American Cancer Society Web site. http://www.cancer.org/Cancer/Leukemia-ChronicLymphocyticCLL/DetailedGuide/ leukemia--chronic-lymphocytic-risk-factors. Accessed August 6, 2010.

6. Chronic lymphocytic leukemia. eMedicine Web site. http://emedicine.medscape.com/ article/199313-overview. Accessed August 31, 2010.

7. B onilla FA. B cell development. UpToDate Web site. http://www.uptodate.com.

Accessed May 13, 2008.

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

11. C heson BD. Chronic lymphoid leukemias. In: Meloni D, Morrissey D, eds. Clinical Oncology.

3rd ed. Philadelphia, PA: Elsevier; 2004.

12. G inaldi L, Martinis MD, Matutes E, et al. Levels of expression of CD19 and CD20 in chronic B cell leukaemias. J Clin Pathol. 1998;51:364-369.

The precise cause(s) of the CLL lymphocyte are not known

Description

Deletion of 13q1,2

Present in 55% of cases. Most common cytogenetic abnormality in CLL; associated with a favorable prognosis

Trisomy 121,2

Detected in 15% to 20% of CLL cases

R ai staging system is used more often in the US3

Rai Staging System of CLL1,3 Stage Risk

Identified in 15% to 20% of cases, associated with bulky lymphadenopathy and poor prognosis

0

Deletion of 17p2

ccurs in <10% of patients at diagnosis, O associated with a poor prognosis

I

IgVH Mutational Status2

Unmutated IgVH status associated with poor prognosis

ZAP-70

ot normally found on B cells; high level of N expression associated with poor prognosis

Deletion of 11q

2

1,2

II

Low

Abnormality

Rai and Binet staging systems help clinicians evaluate patient prognosis and indications for treatment

Intermediate

Common cytogenetic abnormalities in CLL

High

Cytogenetic abnormalities can be identified via FISH in more than 80% of cases of CLL. In CLL, there is a lack of chromosomal translocations, and no single oncogene has been implicated in the pathogenesis.1

IV

Lymphocytosis is present (>10,000 cells/mm3).

Lymph nodes, spleen, liver not enlarged.

RBC and platelet counts near normal

Median Survival >10 Years

L ymphocytosis plus enlarged lymph nodes.

The spleen and liver are not enlarged. RBC and platelet counts near normal L ymphocytosis plus an enlarged spleen with or without enlarged liver, with or without enlarged lymph nodes. RBC and platelet counts near normal* L ymphocytosis plus anemia, with or without enlarged lymph nodes, spleen, or liver. Platelet counts near normal Lymphocytosis plus thrombocytopenia, with or without anemia, enlarged lymph nodes, spleen, or liver

7 Years

1.5 to 4 Years

* Your customers are likely to classify patients using the Rai staging system of CLL during your discussions. ARZERRA does not have data demonstrating efficacy in different RAI subroups. However, any patient that has FA-ref CLL is eligible for ARZERRA, and ARZERRA is indicated in this population regardless of staging. If your customer has further questions on the efficacy of ARZERRA based on a specific Rai stage, refer them to MI.

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

DISEASE MARKERS

III

Clinical Features

4

What this might sound like Efficacy Discussion

Rai Staging Discussion

Physician: Does ARZERRA have efficacy in patients with CLL that have a cytogenetic profile showing a deletion of 17p?

Physician: I have a patient with Rai stage III CLL. The patient is refractory to both fludarabine and alemtuzumab. Does ARZERRA have any data in this patient population?

OAM: The

pivotal trial for ARZERRA included patients with CLL refractory to both fludarabine and alemtuzumab. I can refer you to MI for specifics regarding the cytogenetic profiles of these patients, however, any patient with FA-refractory CLL is eligible for treatment with ARZERRA, and ARZERRA is indicated regardless of cytogenetic profile. Did I answer your question?

OAM: Thanks for your question. If I understand you correctly, you are asking if ARZERRA has data specific to Rai stage III patients with FA-refractory CLL? Physician: Yes, I am. Can I use ARZERRA in this patient?

DISEASE MARKERS

OAM: ARZERRA does not have data demonstrating efficacy in different RAI stage subgroups. However, any patient that has CLL refractory to fludarabine and alemtuzumab is eligible for ARZERRA, and ARZERRA is indicated regardless of staging. If you would like more information on this specific population, I can refer you to MI to address your question.

1. C heson BD. Chronic lymphoid leukemias. In: Meloni D, Morrissey D, eds. Clinical Oncology.

3rd ed. Philadelphia, PA: Elsevier; 2004.

2. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-197.

3. How is chronic lymphocytic leukemia staged? American Cancer Society Web site. http://www.cancer.org/Cancer/Leukemia-ChronicLymphocyticCLL/DetailedGuide/ leukemia-chronic-lymphocytic-staging. Accessed August 6, 2010.

4

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Certain disease markers may predict the prognosis or assess tumor burden of CLL patients Cytogenetic abnormalities (determined by FISH)*

CD38 immunophenotype

he most robust and reproducible of molecular profiling tests T — 17p deletion: a poor prognostic factor1-3 associated with rapid progression of disease,1 poor response to therapy,1,3-5 and short survival6 — 11q deletion: associated with a poor prognosis,1,2 poor response to therapy,4,5 and short survival6 — 13q deletion: associated with good-risk disease when it is the sole abnormality.1 Patients with 13q deletion generally have a longer median survival when compared with other chromosomal abnormalities commonly seen in CLL6

1

IgVH mutational status Unmutated IgVH status is a poor prognostic factor

1-3

A high level of CD38 expression is a poor prognostic factor1,3 D38 was initially found to correlate with IgVH mutation status, C but the relationship is not absolute1,3 xpression of CD38 is associated with significantly decreased E survival in some studies8,10

ß2 microglobulin high ß2 microglobulin serum level is considered to be a poor A prognostic factor,1 and may predict survival or progression-free survival3

Cytogenetic abnormalities are among the most important predictors of survival in CLL

IgVH mutational status correlates with disease progression7 and survival,4,7-10 and unmutated lgVH is associated with a worse clinical course1,11 and outcome when compared with patients with mutated IgVH3

60%

Probability of survival from date of diagnosis among CLL patients in 5 genetic categories

40%

20%

High level of expression is a poor prognostic factor1,3 L eukemia cell expression of ZAP-70 was found to correlate with the expression of unmutated IgVH genes; however, this association is not absolute1,3,12 ZAP-70 is also a strong predictor of time from CLL diagnosis to need for treatment1,13,14 and is associated with significantly decreased survival in some studies10,12

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0% 0

12

24 36

48 60 72 84 96 108 120 132 144 156 168 180 Months

Döhner H et al. N Engl J Med. 2000;343:1910-1916.

Prognostic markers described above may help to predict the prognosis or to assess tumor burden in CLL.3 * You may not discuss this with customers. ARZERRA has no data demonstrating an impact on cytogenetic abnormalities or survival and to discuss these may imply that ARZERRA had data demonstrating these effects. If a customer discusses these issues with you, you may listen, then transition back to the indicated patient population and the appropriate data supporting this.

PROGNOSTIC MARKERS

ZAP-70

17p deletion 11q deletion 12q trisomy Normal 13q deletion as sole abnormality

80%

Patients Surviving

Sequencing and analysis of IgVH rearrangements may not be routinely available in clinical laboratories and is not required in routine management of CLL1

100%

5

1. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-197.

PROGNOSTIC MARKERS

2. K röber A, Seiler T, Benner A, et al. VH mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood. 2002;100(4):1410-1416.

5

3. H allek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood.

2008;111(12):5446-5456.

4. B yrd JC, Gribben JG, Peterson BL, et al. Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol. 2006;24:437-443.

5. G rever MR, Lucas DM, Dewald GW, et al. Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol. 2007;25(7):799-804.

6. D öhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-1916.

7. C respo M, Bosch F, Villamor N, et al. ZAP-70 expression as a surrogate for immunoglobulinvariable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775.

8. D amle RN, Wasil T, Fais F, et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood. 1999;94(6):1840-1847.

FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

9. H amblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood.

1999;94(6):1848-1854.

10. O rchard JA, Ibbotson RE, Davis Z, et al. ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet . 2004;363:105-111.

11. R osenwald A, Alizadeh AA, Widhopf G, et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med. 2001;194(11):1639-1647.

12. K röber A, Bloehdorn J, Hafner S, et al. Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol. 2006;24:969-975.

13. R assenti LZ, Huynh L, Toy LT, et al. ZAP-70 compared with immunoglobulin heavy-chain g ene mutation status as a predictor of disease progression in chronic lymphocytic leukemia.

N Engl J Med. 2004;351:893-901.

14. R assenti LZ, Jain S, Keating MJ, et al. Relative value of ZAP-70, CD38, and immunoglobulin mutation status in predicting aggressive disease in chronic lymphocytic leukemia. Blood.

2008;112(5):1923-1930.

CLL diagnosis is often made incidentally during a routine blood test1 Patients with early CLL are often asymptomatic with slowly progressing symptoms

Common tests used in the diagnosis and management of CLL

F indings on physical exam are normal in 20% to 30% of patients1 W hen signs and symptoms do appear, they can include2*: —Weakness —Bruising/bleeding —Fatigue —Anemia —Weight loss —Fever —Infections —Night sweats

Test

Symptoms progress slowly in early CLL

Complete Blood Count (CBC)

atients may notice enlarged lymph nodes and/or pain or a sense P of “fullness” in the stomach (caused by an enlarged spleen)2 — Lymphadenopathy or splenomegaly present in 40% to 50% of patients; more common as CLL progresses1 — Involvement of other organs is unusual and suggests the possibility of Richter’s transformation1

— ≥5 x 109/L B lymphocytes in the peripheral blood for at least 3 months3 —Predominance of small, morphologically mature lymphocytes3 —Characteristic immunophenotype (CD5, CD19, CD20, CD23)4 — Bone marrow aspirate or biopsy not necessary at time of diagnosis4 A t diagnosis, approximately 9 of 10 CLL patients already have 1 or more comorbidities5 * ARZERRA has not shown an impact on symptoms of disease.

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I ncludes measure of white and red blood cells, hemoglobin, and hematocrit6 Normal values: — White blood cells (WBC): 4500 to 10,000 cells/mcL; also known as leukocyte count — Red blood cells (RBC): male 4.7 to 6.1 million cells/mcL; female 4.2 to 5.4 million cells/mcL; also referred to as erythrocyte count —H emoglobin: approximately 13.8 to 17.2 g/dL for men and 12.1 to 15.1 g/dL for women —H ematocrit: ratio of volume of RBCs to whole blood: 40.7% to 50.3% for men; 36.1% to 44.3% for women CLL diagnosis requires at least 5 x 109 B lymphocytes/L (5000/µL)4

Immunophenotyping

sed to identify cells based on the types of antigens U or markers on the surface of the cell. It is used to diagnose specific types of leukemia.7 CLL usually shows a characteristic immunophenotype: CLL cells express CD5, CD19, CD20, and CD231

Cytogenetic Analysis

etects changes in structure and number of D chromosomes in the lymphocytes8

FISH (Fluorescence In Situ Hybridization)

A type of cytogenetic test. Fluorescently labeled DNA probe used to detect chromosome changes7,8

Bone Marrow Aspiration/Biopsy

one marrow from hip or other bones evaluated for B abnormal lymphocytes. Generally not required for diagnosing CLL. Can provide prognostic information3

Other Tests

hest X-ray, MRI, CT scan, ultrasound, blood C chemistries, excisional lymph node biopsy, lumbar puncture (spinal tap)8

SYMPTOMS/DIAGNOSIS OF CLL

Diagnosis of CLL is established by the following criteria:

Description

6

What this might sound like Physician: Will ARZERRA help relieve the signs and symptoms of my CLL patients’ disease, like night sweats and weight loss?

SYMPTOMS/DIAGNOSIS OF CLL

OAM: ARZERRA is indicated for the treatment of patients with CLL refractory to fludarabine and alemtuzumab. ARZERRA is the only treatment specifically indicated for patient’s refractory to both these agents. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Although ARZERRA is the only product with this specific indication, there are other products, such as bendamustine and ritixumab, that have indications broad enough to include this patient population.

If you would like more specific information on symptom resolution, we can contact MI right now to get this for you.

1. C heson BD. Chronic lymphoid leukemias. In: Meloni D, Morrissey D, eds. Clinical Oncology.

3rd ed. Philadelphia, PA: Elsevier; 2004.

6. C BC. Medline Plus Web site. http://www.nlm.nih.gov/medlineplus/ency/article/003642.htm.

Accessed August 27, 2010.

2. D etailed guide: leukemia--chronic lymphocytic. American Cancer Society Web site. http://www.cancer.org/docroot/CRI/CRI_2_3x.asp?dt=62. Accessed August 6, 2010.

7. D ictionary of Cancer terms. National Cancer Institute Web site. http://www.cancer.gov/ dictionary/?CDr/D=341450. Accessed September 10, 2010.

3. H allek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.

8. L eukemia—chronic lymphocytic. American Cancer Society Web site. http://www.cancer.org/ Cancer/Leukemia-ChronicLymphocyticCLL/DetailedGuide/leukemia--chronic-lymphocyticdiagnosis. Accessed August 27, 2010.

4. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-197.

5. T hurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leukemia & Lymphoma.

2008;49(1): 49-56.

6 FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

Measurement of outcomes in CLL Goals of therapy

Minimal residual disease (MRD)

T reatment of CLL is generally not curative * (Do not discuss this information with customers. This is for your education only)

Defined as <1 CLL cell per 10,000 leukocytes4

T he traditional goal of therapy has been palliation; achievement of complete response (CR) is now possible for many patients2

I WCLL update of NCI-WG criteria now lists MRD negativity as a goal of therapy in clinical trials4

1

A chieving MRD*-negativity after therapy correlates with better progression-free and overall survival5

MRD as a treatment endpoint is only justified within a clinical trial setting5

Response definition after treatment for CLL patients

3

* There are no data in the ARZERRA label addressing MRD. This may not be discussed with customers. If a customer asks a question about MRD and ARZERRA, refer them to MI.

Complete Response (CR)

Partial Response (PR)

Progressive Disease (PD)

Stable Disease (SD)

Lymphadenopathy*

None above 1.0 cm

Decrease ≥50%

Increase ≥50%

Change of –49% to +49%

Liver and/or Spleen Size

Normal size

Decrease ≥50%

Increase ≥50%

Change of –49% to +49%

Constitutional Symptoms

None

Any

Any

Any

Leukocytes

>1500/µL

>1500/µL or >50% improvement

Any

Any

Circulating B Lymphocytes

Normal

Decrease ≥50% over baseline

Increase ≥50%

Change of –49% to +49%

Platelet Count

>100,000/mm3

>100,000/µL or increase ≥50% over baseline

Decrease ≥50% over baseline

Change of –49% to +49%

Hemoglobin

>11.0 g/dL (untransfused)

>11 g/dL or increase ≥50% over baseline

Decrease of >2 g/dL from baseline

Increase <11.0 g/dL or <50% over baseline, or decrease <2 g/dL

Marrow

Normocellular, <30% lymphocytes, no B-lymphoid nodules

Hypocellular, or ≥30% lymphocytes, or B-lymphoid nodules, or not done

Increase of lymphocytes to more than 30% from normal

No change of marrow infiltrate

CR: all of the criteria have to be met; PR: one of the criteria has to be met; PD: one of the above criteria has to be met; SD: all of the above criteria have to be met. * Sum of the products of multiple lymph nodes (as evaluated by CT scans in clinical trials or by physical exam or ultrasound in general practice).

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See reverse side for efficacy discussion

MEASUREMENT OF OUTCOMES

Parameter

7

What this might sound like Efficacy Discussion Physician: There were no complete responses in the ARZERRA trial.

Why is this?

OAM: You’re right, doctor. The overall response rate was 42% in the fludarabine and alemtuzumab refractory group with a median duration of response of 6.5 months. All responses were partial responses.

When you have a patient who has been treated with 5 prior therapies and is refractory to both fludarabine and alemtuzumab, what has been your experience with achieving a CR in those patients?

1. C hronic lymphocytic leukemia treatment (PDQ®): health professional version. National Cancer Institute Web site. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/ healthprofessional/allpages. Accessed August 9, 2010.

2. Gribben JG. How I treat CLL up front. Blood. 2010;115(2):187-197.

MEASUREMENT OF OUTCOMES

3. E ichhorst B, Hallek M. Revision of the guidelines for diagnosis and therapy of chronic lymphocytic leukemia (CLL). Best Pract Res Clin Haematol. 2007;20(3):469-477.

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FOR INTERNAL USE ONLY. NOT TO BE SHOWN TO OR LEFT WITH HEALTHCARE PROFESSIONALS. SALES TRAINING MATERIALS.

4. H allek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.

5. M oreno C, Ritgen M, Rawstron A. Is MRD eradication a desirable goal in CLL? Best Pract Res Clin Haematol. 2010;23:97-107.