Investigations Innovation Clinical Application New Frontiers

Investigations • Innovation • Clinical Application New Frontiers and Paradigm Changes in Optimizing Supportive Care in Cancer Focus on Thrombosis Prevention, CINV, and Hematologic Complications of Malignancy Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research

Program Faculty PROGRAM CHAIRMAN GARY H. LYMAN, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research Lee S. Schwartzberg, MD, FACP Supportive Oncology Services, Memphis Accelerated Community Oncology Research Network Clinical Professor of Medicine University of Tennessee Medical Center Memphis, Tennessee Jeffrey Crawford, MD George Barth Geller Professor for Research In Cancer Chief of Division of Medical Oncology Department of Medicine Duke University Medical Center Editor-in-Chief, Supportive Care Oncology Durham, North Carolina Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester, New York

Investigations • Innovation • Clinical Application An Evidence-Based Overview to Critical Issues in Supportive Care Overview Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research

Complications of Cancer Chemotherapy Myelosuppressive chemotherapy Neutropenia Febrile neutropenia (FN) Chemotherapy dose delays and dose reductions Complicated lifethreatening infection and prolonged hospitalization Decreased relative dose intensity (RDI) Reduced survival Kuderer NM et al. Cancer 2006; 106: 2258– 2266 Chirivella I et al. J Clin Oncol 2006; 24; abstract 668 Bosly A et al. Ann Hematol 2007, advance access published 20 October 2007; doi: 10. 1007/s 00277 -007 -0399 -y

Meta-analysis of Randomized Controlled Trials Relative risk of FN Febrile Neutropeonia (n = 3182) RR 95% CI p 0. 61 0. 53– 0. 72 <. 001 Combined filgrastim (n=9) 0. 62 0. 44– 0. 88 0. 007 Combined lenograstim (n=5) 0. 08 0. 03– 0. 18 <. 001 Combined pegfilgrastim (n=1) 0. 54 0. 43– 0. 67 <. 001 All G-CSF (n=15) 0. 1 0. 2 0. 5 1. 0 2. 0 5. 0 10 Favours G-CSF Kuderer et al. J Clin Oncol 2007; 25: 3158– 3167 Favours no G-CSF

Primary Prophylactic CSF Administration ► Required and recommended for “dose dense” regimens ► Recommended for the prevention of FN in patients who have a high risk of FN based on: • Age • Medical history • Disease characteristics • Myelotoxicity of the chemotherapy regimen ► Clinical trial data support the use of CSF when the risk of FN is in the range of 20% or higher

Primary Prophylactic CSF Administration: Special Circumstances ► When the following clinical factors are present, primary prophylaxis with CSF is often appropriate even with regimens with FN rates of <20% : ● ● ● ● ● Age >65 years Poor performance status Previous FN Poor nutritional status Open wounds or active infections More advanced cancer Extensive prior treatment, including large XRT ports Administration of combined chemoradiotherapy Cytopenias due to bone marrow involvement by tumor Other serious comorbidities

Evidence-based G-CSF Guidelines Key Recommendations Summary of Recommendations EORTC 1 ASCO 2 NCCN 3 G-CSF primary prophylaxis with ≥ 20% overall FN risk associated with chemotherapy Consider patient risk factors for overall FN risk G-CSF primary prophylaxis to maintain chemotherapy RDI Dose-dense chemotherapy regimens G-CSF for ongoing FN episode G-CSF formulation and dosing Secondary prophylaxis with G-CSF 1. Aapro et al. Eur J Cancer 2006; 42: 2433– 2453; 2. Smith et al. J Clin Oncol 2006; 24: 3187– 3205; 3. NCCN. Myeloid growth factors V. 1. 2009

Chemotherapy-Induced Acute Emesis Classes of Antiemetic ► Highest therapeutic index antiemetic agents • 5 -HT 3 Serotonin Receptor Antagonists • Corticosteroids (Dexamethasone) • NK 1 Receptor Antagonists (Aprepitant) ► These classes of antiemetic agents • Highly effective • Few significant side effects (when used appropriately) • Safe in combination Emetic Risk of IV Administered Antineoplastic Agents High (>90%) Carmustine Cisplatin Cyclophosphamide Dacarbazine Dactinomycin Mechlorethamine Streptozotocin >1500 mg/m 2 Moderate (30% to 90%) Carboplatin Cyclophosphamide<1500 mg/m Cytarabine >1 gm/m 2 Daunorubicin Doxorubicin Epirubicin Idarubicin Ifosfamide Irinotecan Oxaliplatin Low (10% to 30%) 2 5 -Fluorouracil Bortezomib Cetuximab Cytarabine <1000 mg/m 2 Docetaxel Etoposide Gemcitabine Methotrexate Mitomycin Mitoxantrone Paclitaxel Pemetrexed Topotecan Trastuzumab Minimal (<10%) 2 -Chlorodeoxyadenosine Bevacizumab Bleomycin Busulfan Fludarabine Rituximab Vinblastine Vincristine Vinorelbine

Chemotherapy-Induced Acute Emesis Antiemetic Agents Combinations of Antiemetics 5 -HT 3 Serotonin Receptor Antagonists Yields greatest antiemetic protection in randomizedmulticenter studies Dexamethasone Chemotherapy of high emetic risk Aprepitant Anthracycline + Cyclophosphamide 5 -HT 3 Serotonin Receptor Antagonists Dexamethasone Kris M et al, JCO 2006: 24: 2932 -2947 Indicated for patients receiving agents of moderate emetic risk other than anthracycline + cyclophosphamide

Antiemetic Regimens Based on Emetic Risk ASCO Guidelines ► Kris M et al, JCO 2006: 24: 2932 -2947 Aprepitant: days 1 -3 5 HT 3 SRA: day 1 ► Dexamethasone: day 1 (2, 3)* ► Low (10 -30%) Dexamethasone: days 1 -4 ► Moderate (30 -90%) ► ► High (> 90%) 5 -HT 3 SRA: day 1 (Aprepitant: days 1 -3 for AC) (AC- ► Dexamethasone: day 1 (may omit days 2, 3 s/p aprepitant) anthracycline + cyclophosphamide)

Investigations • Innovation • Clinical Application Optimizing Management of Cancer Patients at Risk for Venous Thromboembolism Program Chairman Gary H. Lyman, MD, MPH, FRCP (Edin) Editor-In-Chief, Cancer Investigation Professor of Medicine and Director Health Services, Effectiveness and Outcomes Research Division of Medical Oncology, Department of Medicine Duke University School of Medicine and the Duke Comprehensive Cancer Center Senior Fellow, Duke Center for Clinical Health Policy Research

Growth Invasion Metastases Angiogenesis Tumor Cells Hemostatic System Procoagulant Activity Cytokines Growth Factors Fibrinolytic Activity Kuderer NM et al J Clin Oncol 2009; 27: 4902 -4911

VTE Inpatient Risk and Mortality Hospitalized Cancer Patients* 7. 0 6. 5 6. 0 5. 5 5. 0 4. 5 4. 0 3. 5 3. 0 2. 5 2. 0 1. 5 1. 0 0. 5 0. 0 20 VTE- patients on chemo VTE-all patients DVT-all patients P<0. 0001 PE-all patients 1995 1996 1997 1998 1999 2000 2001 2002 2003 * n = 1, 015, 598 Khorana et al. Cancer 2007; 110: 2339 -2346 Inpatient Mortality (%) Rate of VTE (%) 133 U. S. academic medical centers, 1995 – 2003 18 16 14 12 10 8 6 4 2 0 VTE No VTE P<0. 0001 1995 1996 1997 1998 1999 2000 2001 2002 2003

Cancer and Venous Thromboembolism Risk of VTE Varies Over Natural History of Cancer 8 7 Hospitalization Chemotherapy Metastasis Relative Risk 6 5 End of life Diagnosis 4 Risk in cancer population 3 2 Remission 1 0 Risk in general population Time Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007

Risk Factors for VTE in Patients with Cancer Patient-related factors ► Older age ► Race Higher in AA ● Lower in Asians ► Major comorbidities ► History of VTE ● Treatment-related factors ► ► ► ► Cancer-related factors ► Major surgery Hospitalization Chemotherapy Central venous catheters Hormonal therapy Antiangiogenic agents ESAs ? Transfusions • Site of cancer • Advanced stage Rao MV, et al. In: Khorana and Francis, eds. Cancer-Associated Thrombosis; 2007

Important Consequences of VTE in Cancer Patients ► Increased morbidity ● ● ● Hospitalization Anticoagulation Postphlebitic syndrome ► Increased mortality ► Increased risk of recurrent VTE ► Bleeding complications ► Cancer treatment delays ► Increased healthcare costs

Ambulatory Cancer Patients Receiving Chemotherapy Prospective Study at 115 Randomly Selected US Practice Sites March 2002 – February 2006 [N = 4, 458] Cumulative Incidence of VTE HR = 4. 90 [2. 27 -10. 60], P<. 0001 All Cause Early Mortality Kuderer NM et al; J Clin Oncol 2008

Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer ASCO Clinical Practice Guidelines Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

Clinical Questions 1. Should patients with cancer receive anticoagulation for VTE prophylaxis while hospitalized? √ 2. Should ambulatory patients with cancer receive anticoagulation for VTE prophylaxis during systemic chemotherapy? √ 3. Should patients with cancer undergoing surgery receive perioperative VTE prophylaxis? 4. What is the best method for treatment of patients with cancer with established VTE to prevent recurrence? √ 5. Should patients with cancer receive anticoagulants in the absence of established VTE to improve survival? √ Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

ASCO Recommendations for VTE Prophylaxis in Patients with Cancer ► Hospitalized patients with cancer should be considered candidates for VTE prophylaxis in the absence of bleeding or other contraindications to anticoagulation. Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

Anticoagulant Prophylaxis to Prevent Screen -Detected VTE High Risk Hospitalized Medical Patients ► 3 large, randomized, placebo-controlled, double-blind trials in medical patients at high risk including cancer ● MEDENOX (enoxaparin)1 ~ 15% ● PREVENT (dalteparin)2 ~5% ● ARTEMIS (fondaparinux)3 ~15% ► Screening for asymptomatic DVT with venography or ultrasound 1 Samama MM, et al. N Engl J Med. 1999; 341: 793 -800 2 Leizorovicz A, et al. Circulation. 2004; 110: 874 -9 3 Cohen AT, et al. BMJ 2006; 332: 325 -329

Anticoagulant Prophylaxis to Prevent Screen. Detected VTE High Risk Hospitalized Medical Patients: VTE Study RRR MEDENOX 1 P < 0. 001 63% PREVENT 2 P = 0. 0015 Thromboprophylaxis Patients with VTE (%) Placebo Enoxaparin 40 mg 45% 5. 5 Placebo 5. 0 Dalteparin 5, 000 units 47% Fondaparinux 2. 5 mg MM, et al. N Engl J Med. 1999; 341: 793 -800 A, et al. Circulation. 2004; 110: 874 -9 3 Cohen AT, et al. BMJ 2006; 332: 325 -329 2 Leizorovicz 2. 8 10. 5 Placebo ARTEMIS 3 1 Samama 14. 9 5. 6

Incidence of Major Bleeding (%) Anticoagulant Prophylaxis to Prevent Screen-Detected VTE High Risk Hospitalized Medical Patients: Major Bleeding 1. 7% 1. 1% 0. 49% 0. 16% Study Samama MM, et al. N Engl J Med. 1999; 341: 793 -800 Leizorovicz A, et al. Circulation. 2004; 110: 874 -9 Cohen AT, et al. BMJ 2006; 332: 325 -329 0. 2%

ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Ambulatory Cancer Patients Routine prophylaxis with an antithrombotic agent in the ambulatory setting is not recommended. NOTE: Patients receiving thalidomide or lenalidomide with chemotherapy or dexamethasone are at high risk for thrombosis and warrant prophylaxis. LMWH or adjusted dose warfarin (INR~1. 5) is recommended. * * This recommendation is based on extrapolation from studies of prophylaxis in other high risk cancer settings. Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

Characteristics of Prophylaxis Studies VTE – Prophylaxis with LMWH Trial FAMOUS Solid Tumors TOPIC-I Breast Cancer TOPIC-2 NSCLC PRODIGE Glioma SIDERAS Solid Tumors PROTECHT Solid Tumors CONKO-04 Pancreatic Cancer FRAGEM Pancreatic Cancer Year Stage N LMWH / Dose Control Arm Duration Type of Pub Specific Chemo 2004 III/IV 385 Dalteparin Placebo 12 months Manuscript No 2005 III/IV 353 Certoparin Placebo 6 months Abstract+ No 2005 III/IV 547 Certoparin Placebo 6 months Abstract+ No 2007 Any 186 Dalteparin Placebo 6 -12 months Abstract No 2006 IV 141 Dalteparin Non. Placebo Indefinitely Manuscript No 2008 III/IV 1166 Nadroparin 2: 1 Placebo < 4 months with chemo Manuscript No 2009 Advanced 312 Enoxaparin Non. Placebo 3 months (to prog) Abstract 2009 Advanced 123 Dalteparin# Non. Placebo 3 months Abstract *Gemcitabine-based chemotherapy (1000 mg/m 2) Yes* # Higher dose than standard prophylactic dose

Systematic Review of LMWH Prophylaxis in Cancer Patients VTE Versus Major Bleeding: Absolute Risk Cancer Type Benefit Harm Venous Thromboembolism Major Bleeding 3. 1% 0. 9% 13. 0% 0. 8% 1. 4% 0. 8% Overall Pancreatic Non-Pancreatic Kuderer NM et al. ASH Oral Presentation 2009

Clinical Risk Model for Chemotherapy-associated VTE Risk Score Based on Pretreatment Risk Factors Risk score 1. Site of cancer a) Very high risk cancer (stomach, pancreas) 2 b) High risk (lung, lymphoma, gynecologic, bladder, testicular) 1 2. Platelet count >350, 000/mm 3 1 3. Hemoglobin level < 10 g/d. L or use of Red cell growth factors 1 4. Leukocyte count >11, 000 /mm 3 1 5. BMI > 35 kg/m 2 1 Khorana AA et al. Blood. 2008; 111: 4902 -4907

VTE Prediction Risk Score Chemotherapy – Associated Thrombosis 8% 7. 1% 7% Development cohort Validation cohort 6% Rate of VTE (%) 6. 7% 5% 4% 3% 1. 8% 2% 1% 0% RISK SCORE: 2. 0% 0. 8% 0. 3% n=734 n=374 Low (0) Khorana AA et al. Blood. 2008; 111: 4902 -4907 n=1, 627 n=842 Intermediate (1 -2) n=340 n=149 High (>3)

Mortality and Progression-Free Survival By VTE Risk Score Outcomes Low Risk N=1, 206 Intermediate Risk N=2, 709 High Risk N=543 All N=4, 458 1. 2% 5. 9% 12. 7% 5. 6% Mortality Risk (%) HR [+/- CI] 1. 0 3. 6 [1. 9 -6. 7] 6. 9 [3. 5 -13. 6] - Progression-free survival Risk (%) HR [+/- CI] Kuderer NM et al. ASH 2008 93% 82% 72% 84% 1. 0 2. 8 [2 -3. 9] 4. 3 [2. 9 -6. 3] -

ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Preventing Recurrence in Cancer Patients with Established VTE ► LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the patient with cancer with established VTE. ► LMWH for at least 6 months is also preferred for long-term anticoagulant therapy. ► After 6 months, indefinite anticoagulant therapy should be considered for patients with active cancer. NOTE: Vena cava filters are only indicated for patients with contraindications to anticoagulant therapy and in those with recurrent VTE despite adequate long-term therapy with LMWH. Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

Recurrent VTE and Bleeding During Anticoagulant Treatment Patients with cancer and venous thrombosis 30 30 Cancer 21% 20 10 No Cancer 7% Hazard ratio 2. 2 [1. 2 -4. 1] Major Bleeding, % Recurrent VTE, % Hazard ratio 3. 2 [1. 9 -5. 4] 20 Cancer 12% 10 No Cancer 5% 0 0 0 1 2 3 4 5 6 7 8 9 101112 Time (months) Prandoni P et al. Blood 2002; 100: 3484 -3488 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (months)

RCTs of Long-term Treatment in Cancer Patients with VTE RCTs of LMWH vs. Vitamin K Antagonists in Cancer Recurrent VTE, % Major Bleed, % Death, % Study No. Long-Term Treatment Meyer 1 2002 71 Warfarin 21. 1* 22. 7 67 Enoxaparin 1. 5 mg/kg 10. 5* 11. 3 Lee 2 2003 336 Warfarin 17* 4 41 336 Dalteparin 200/150 IU/kg 9* 6 39 30 Warfarin 10 2. 9 8. 8 29 Enoxaparin 1. 0 mg/kg 6. 9 6. 5 32 Enoxaparin 1. 5 mg/kg 6. 3 11. 1 19. 4 100 Warfarin 10* 7 19 100 Tinzaparin 175 IU/kg 6* 7 20 Deitcher 3 2006 Hull 4 2006 * P <. 05 1. Meyer G, et al. Arch Intern Med. 2002; 162: 1729 -1735. 2. Lee AY, et al. N Engl J Med. 2003; 349: 146 -153. 3. Deitcher SR, et al. Clin Appl Thromb Hemost. 2006; 12: 389 -396. 4. Hull RD, et al. Am J Med. 2006; 119: 1062 -1072.

The CLOT Trial Study Schema Control Group Randomization Dalteparin 200 IU/kg OD Vitamin K antagonist (INR 2. 0 to 3. 0) x 6 mo Experimental Group Dalteparin 200 IU/kg OD x 1 mo 5 to 7 days Lee AY, et al. N Engl J Med. 2003; 349: 146 -153. then ~150 IU/kg OD x 5 mo 1 month 6 months

The CLOT Trial: Results: Symptomatic Recurrent VTE risk reduction = 52% HR 0. 48 (95% CI 0. 30, 0. 77) log-rank p = 0. 002 Probability of Recurrent VTE, % 25 20 VKA, 17% 15 10 dalteparin, 9% 5 0 0 30 60 90 120 150 Days Post Randomization Lee AY, et al. N Engl J Med. 2003; 349: 146 -153. 180 210

ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Improving survival in absence of established VTE ► Anticoagulants are not recommended at this time as treatment to improve survival in patients with cancer without VTE. ► Participation in clinical trials designed to evaluate anticoagulant therapy as an adjunct to standard anticancer therapies is encouraged. Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505

Systematic Review of Anticoagulants as Cancer Treatment Impact on All Cause Mortality Kuderer, N. M. et al. J Clin Oncol; 27: 4902 -4911 2009 Kuderer NM, et al. Cancer. 2007; 110: 1149 -1161

Systematic Review of Anticoagulants as Cancer Treatment Impact on Major Bleeding Kuderer, N. M. et al. J Clin Oncol; 27: 4902 -4911 2009 Kuderer NM, et al. Cancer. 2007; 110: 1149 -1161

ASCO Recommendations for VTE Prophylaxis in Patients with Cancer Summary Patient Group Recommended Not Recommended Hospitalized VTE prophylaxis with anticoagulants patients with cancer If bleeding or contraindication to anticoagulation Ambulatory patients with cancer receiving chemotherapy Myeloma patients receiving thalidomide or Otherwise, no routine lenalidomide + chemotherapy/ dexamethasone. prophylaxis LMWH or adjusted dose warfarin. Patients with cancer undergoing surgery Prophylaxis with low-dose UFH or LMWH Prophylaxis with mechanical methods for patients with contraindications to pharmacologic methods Patients with cancer with established VTE Anticoagulation for at least 6 months. Consider continued anticoagulation beyond 6 months in those with active cancer. To improve survival Lyman GH et al: J Clin Oncol 2007; 25: 5490 -5505 - Consider mechanical methods when contraindications to anticoagulation. Not recommended

Recommendations for Primary Prevention of VTE in Patients With Cancer Comparisons of Guideline Panels Modified from Khorana AA et al J Clin Oncol 2009; 27: 4919 -4926

Unanswered Questions A Call to Action for Future Research ► Prevention of VTE in the ambulatory patient with cancer: A role for targeted prophylaxis? ► Prevention of VTE in the hospitalized patient with cancer: a need for cancer-specific studies? ► Optimal treatment of recurrent VTE ► Management of incidental or screen-detected VTE ► Impact of anticoagulation on survival of patients with cancer Khorana AA et al J Clin Oncol 2009; 27: 4919 -4926

Cancer and Venous Thromboembolism Conclusions ► VTE is a common complication of cancer and cancer treatment and is associated with considerable morbidity, mortality and costs. ► Hospitalized medical and surgical cancer patients are at increased risk for VTE and should be considered for pharmacologic prophylaxis if no contraindication to anticoagulation exists. ► Cancer patients treated for documented VTE should be considered for continued anticoagulation, preferably with LMWH, for up to 6 months or longer in patients with active malignancy. ► Routine thromboprophylaxis of ambulatory cancer patients is not currently recommended.

Cancer and Venous Thromboembolism Conclusions ► Prophylaxis may be considered in selective high risk settings such as multiple myeloma patients receiving thalidomide/lenalidomide. ► Consideration of prophylactic anticoagulation in cancer patients must always balance the risk of VTE with the increased risk of bleeding and other complications. ► Improved methods for the identification of cancer patients at high risk for VTE and candidates for targeted thromboprophylaxis are needed and under active investigation.

Investigations • Innovation • Clinical Application Chemotherapy-Induced Nausea and Vomiting (CINV) Optimizing Clinical Management Lee S. Schwartzberg, MD, FACP Supportive Oncology Services, Memphis Accelerated Community Oncology Research Network Clinical Professor of Medicine University of Tennessee Medical Center Memphis, Tennessee

Sun C et al. Support Care Cancer. 2005 P er fe ct H R ea em lt is h s C ur C ion re IN nt V H 1 e Ta Al alt s t op h e ec C D h a ia ep n r ge O e ss Se W tot ion xu e ox al igh icit D t. G y ys M fun ai n em c t C ory i on on l st os ip s a L e tio g n Pe p ri p Fa ain he t ig ra ue l. N eu F Fe ro l u br pa i le Th N C thy ro eu IN m tr V bo op 2 cy en to ia p D eni ia a M rrhe uc a os D itis ys u C ria IN V C 3 IN C V 4 IN V C 6 IN V D 5 ea th Median VAS Scores Chemotherapy Experienced Patients Rank Severe CINV Near Death Moderate Delayed Nausea Poorly Controlled Acute & Delayed CINV Complete Control Death Mucositis

Types of CINV: Definitions ► Acute (posttreatment) ● ► Delayed ● ● ► CINV that begins after first 24 hours May last for 120 hours Anticipatory ● ► Occurs within first 24 hours after administration of cancer chemotherapy Learned or conditioned response from poorly controlled nausea and vomiting associated with previous chemotherapy Breakthrough ● CINV that occurs despite prophylaxis and requires rescue

Emetogenic Potential of Single Antineoplastic Agents HIGH Risk in nearly all patients (> 90%) MODERATE Risk in 30% to 90% of patients LOW Risk in 10% to 30% of patients MINIMAL Fewer than 10% at risk

Patient-Specific Risk Factors for CINV ► Age <50 years ► Women > men ► History of light alcohol use ► History of vomiting with prior exposure to chemotherapeutic agents ► Other risks ● ● ● History of motion sickness History of nausea or vomiting during pregnancy History of anxiety ASHP. Am J Health Syst Pharm. 1999: 56: 729 -764; Balfour and Goa. Drugs. 1997: 54: 273 -298

Other Causes of Nausea and Vomiting in Cancer patients ► Brain metastases ► Electrolyte disturbances ► Gastoparesis ► Concurrent medications ► Bowel obstruction ► Vestibular dysfunction

Pathophysiology of Chemotherapy-Induced Emesis

Pharmacologic Agents for Prevention of CINV ► Corticosteroids ► Dopamine antagonists ► Serotonin (5 -HT 3) antagonists ► NK-1 receptor antagonists

Key Milestones in Antiemetic Treatment 1960 Phenothiazines: first agents to demonstrate antiemetic effect 1970 1980 1990 2002 2004 High-dose metoclopramide shown to enhance antiemetic effect Combination therapy: addition of a corticosteroid shown to improve antiemetic response First clinical studies of 5 -HT 3 antagonists Introduction of 5 -HT 3 antagonists into clinical practice for CINV New class of drug: NK-1 antagonists in clinical development for CINV Aprepitant: March 2003 Palonosetron: July 2003 Viale PH. Clin J Onc Nurs. 2005; 9(1): 77 -84 Hesketh PJ. Support Care Cancer. 2001; 9: 350 -4 Grunberg SM, Hesketh PJ. New Engl J Med. 1993; 329(24): 1790 -6 Hesketh PJ. Support Care Cancer. 2004; 12: 550 -4

Controlling Cisplatin-induced Emesis: Progress Over the Past 30 Years Complete Response: 100% - (24 hour control) 60% 75% - (120 hour control) 70% 50% 25% - 0% 1978 1988 1998 No Useful Rx HD-MCP/Dex 5 -HT 3/Dex 2008 5 -HT 3/Dex/NK 1

Patterns of Emesis Cisplatin vs Cyclophosphamide and Carboplatin Cisplatin Intensity of Emesis Cyclophosphamide/Carboplatin 0 1 2 3 Days Martin M. Oncology. 1996; 53(suppl 1): 26 -31 4 5

1 st Generation 5 HT 3 RAs are Therapeutically Equivalent ►Highest Level Evidence MASCC 2009 NCCN 2010 ASCO 2006 ► 1 st Generation Agents are therapeutically equivalent • • • Dolasetron Ondansetron Granisetron Pts receiving MEC* (N=1, 085) Complete Control (%) • • • Oral granisetron 2 mg IV ondansetron 32 mg 59. 0 58. 0 71. 0 72. 0 60. 0 58. 0 Emesis Total Nausea ► 1 st Generation oral, IV & 80% of pts received prophylactic steroids patch forms equally *Cyclophosphamide 500 - 1200 mg/m 2, carboplatin ≥ 300 mg/m 2 effective Perez et al. J Clin Oncol 1998; 16: 754

Palonosetron ► Second generation 5 -HT 3 antagonist ► Pharmacologic differences from older 5 -HT 3 antagonists ● ● ► FDA approved ● ● ► Prolonged half-life (~40 hours) Enhanced receptor binding affinity (30 -fold) IV formulation July 25, 2003 Oral formulation August 22, 2008 Regimens ● ● IV 0. 25 mg pre chemotherapy acute/delayed HEC/MEC PO 0. 50 mg pre chemotherapy acute MEC

Palonosetron vs. 1 st gen HT-3 RA: Complete Response on Day of Chemo & Beyond Palonosetron 0. 25 mg (n=378) Ondansetron/Dolasetron 32/100 mg (n=376) Complete Response (CR) (% of Patients) 100 80 60 * 72. 0 60. 6 * 64. 0 * 57. 7 46. 8 40 42. 0 20 0 Acute: 0 -24 (Day 1) Delayed: 24 -120 (Days 2 -5) Overall: 0 -120 (Days 1 -5) Time (hr) CR = no emetic episodes or use of rescue medications *p<0. 025 for pairwise difference (2 -sided Fisher’s exact test) between palonosetron and ondansetron/dolasetron. Gralla R et al. Ann Oncol. 2003; Eisenberg P et al. Cancer. 2003 Rubenstein EB et al. Proc Am Soc Clin Oncol. 2003. Abstract 2932

Palonosetron vs Ondansetron High Emetic Risk Chemotherapy Patients Also Receiving Dexamethasone N=447 (67%) * Aapro M Support Care Cancer 2003: 11: 391 *

Phase III Trial of IV Palonosetron vs. IV Granisetron with Cisplatin or AC-Based Chemotherapy ► 1114 patients ► Cisplatin (57%) or anthracycline/cyclophosphamide (43%) ► Single 0. 75 mg dose of palo vs. single 40 μg/kg dose of granisetron ► Dexamethasone 16 mg d 1; 4 mg/d d 2 -3 (AC/EC); 8 mg/d d 2 -3 CDDP ► Objective: demonstrate non-inferiority d 1 and superiority d 2 -5 of palonosetron ► Primary endpoint complete response (no emesis/no rescue) Saito M et al. Lancet Oncol. 2009; 10(2): 115 -24

Phase III Trial Palonosetron vs. Granisetron both with Dexamethasone in HEC Palo+ Dex (n=555) % Grani+ Dex (n=558) % P Complete Response, Acute (0 -24 h) 73. 7 72. 1 ND CR, Delayed (24 -120 h) 53. 0 42. 4 0. 0003 CR, Overall (0 -120 h) 47. 9 38. 1 0. 0007 No Nausea: 0 -120 hours 32 25 0. 01 No Emesis: 0 -120 hours 58 49 0. 006 Outcome Saito M et al. Lancet Oncol. 2009; 10(2): 115 -24

Palonosetron + Dexamethasone vs Granisetron + Dexamethasone in Japanese Patients Complete Response – AC/EC Subset 90 80 Complete Response (% of patients) 70 69. 0 Palonosetron 0. 75 mg IV (n=239) Granisetron 40 mcg/kg IV (n=236) 64. 8 60 61. 1 * 50. 0 50 52. 7 * 42. 8 40 30 20 10 0 Acute (0 -24 hrs) Please note that the EU approved dose is 0. 25 mg Data on file, Taiho/Helsinn 2008 Saito M, et al. Lancet Oncol 2009; 10: 115 -124 Delayed (24 -120 hrs) * p = 0. 0165 Overall (0 -120 hrs) † p = 0. 030 * Fisher’s exact test indicates a difference between PALO and GRAN † Chi-square test indicates a difference between PALO and GRAN

5 -HT 3 Treatment-Related Adverse Reactions Palonosetron 0. 25 mg IV (n=187) Palonosetron 0. 75 mg IV (n=188) n % n % Headache 9 4. 8 10 5. 3 Constipation 3 1. 6 6 3. 2 3 1. 6 Dizziness 1 0. 5 0 0. 0 6 3. 2 Adverse Reaction Ondansetron 32 mg IV (n=187) Adverse reaction = adverse event judged by the investigator to have a definite, probable, possible or unknown relationship to study medication n = number of patients with the adverse reaction *Reported in 2% of patients in any treatment group Gralla R, et al. Ann Oncol. 2003; 14: 1570 -1577

Palonosetron: 5 -HT 3 Antagonist of Choice? ► Palonosetron is a 5 -HT 3 antagonist with strong receptor binding affinity and an extended half-life ► Comparable tolerability ► Ease of use and trends towards superiority in delayed CINV favor palonosetron as the preferred 5 -HT 3 antagonist ► Definitive proof of superiority to first generation 5 -HT 3 antagonists would require trials with control arms utilizing corticosteroids, NK 1 antagonists and repetitive dosing of the first generation agents

Aprepitant ► Selective antagonist of the binding of Substance P to the neurokinin 1 (NK 1) receptor ► FDA approved ● Oral formulation: March 26, 2003 ● IV formulation (fosaprepitant): January 31, 2008 ► Regimen ● 125 mg PO day 1, 80 mg PO days 2 -3 acute/delayed HEC/MEC ● 115 mg IV day 1, 80 mg PO days 2 -3 acute/delayed HEC/MEC

Aprepitant in Anthracycline/ Cyclophosphamide Chemotherapy Complete Response (CR) (% of Patients) Complete Response (N=857) Aprepitant (n=433) Standard (n=424) 100 80 * 76 69 55 60 49 * 51 42 40 20 0 Acute: 0 -24 (Day 1) *p<0. 05 Delayed: 24 -120 (Days 2 -5) Time (hr) Complete response (CR): no emesis and no rescue medication. Warr DG et al. J Clin Oncol 2005; 23: 2822 -2830 Overall: 0 -120 (Days 1 -5)

Aprepitant in Moderately Emetogenic Chemotherapy Percent of Patients with No Emesis 100 Emesis-Free (% of Patients) 80 * Aprepitant (n=433) Standard (n=424) * 88 77 * 81 69 76 59 60 40 20 0 Acute: 0 -24 (Day 1) *p<0. 001 Delayed: 24 -120 (Days 2 -5) Time (hr) Warr DG et al. J Clin Oncol 2005; 23: 2822 -2830 Overall: 0 -120 (Days 1 -5)

Aprepitant in Moderately Emetogenic Chemotherapy Percent of Patients with No Nausea 100 Aprepitant (n=430) Standard (n=424) Nausea-Free (% of Patients) 80 60 61 59 37 40 36 33 33 20 0 Acute: 0 -24 (Day 1) Delayed: 24 -120 (Days 2 -5) Overall: 0 -120 (Days 1 -5) Time (hr) No nausea: score <5 mm on 0 -100 mm VAS. Warr DG et al. J Clin Oncol 2005; 23: 2822 -2830; Warr DG et al. Support Care Cancer. 2004. Abstract A 027

Phase III Aprepitant Study (801): Multiple-day Ondansetron • Initial cycle cisplatin > 70 mg/m 2 • 445 patients Group Day 1 O D Days 2 -3 A Aprepitant 32 12 125 Control 32 20 P O D P 8 80 16 A 16 P Day 4 O D P 8 16 16 O=ondansetron; D=dexamethasone; A=aprepitant; P=placebo Schmoll et al: Ann Oncol 17: 1000 -6, 2006

Phase III Aprepitant Study (801): Multiple-day Ondansetron ► Identical design to Protocols 052 and 054 except ondansetron dosed days 1 -4 ► Primary endpoint: complete response on days 1 5 after cisplatin ► Aprepitant regimen superior to control regimen of protracted ondansetron and dexamethasone dosing, CR 72% vs. 61% respectively Schmoll et al: Ann Oncol 17: 1000 -6, 2006

Perception vs Reality: Emetogenic Chemotherapy Highly Emetogenic Chemotherapy Moderately Emetogenic Chemotherapy Grunberg S. Cancer. 2004; 100: 2261 -2268

Optimizing Supportive Care in Cancer The best treatment of delayed CINV is to prevent it!

Are Oral Followup 5 -HT 3 RAs Really Effective for Delayed CINV? ► 671 pts receiving doxorubicin-based chemotherapy ● ► Pts then randomized for days 2 and 3: ● ● ● ► All treated w/ 1 st generation 5 HT 3 + Dex on Day 1 of CT Arm 1: Prochlorperazine 10 mg p. o. three times daily (q 8 h) Arm 2: Any oral 5 -HT 3 antiemetic, using standard dosing regimens Arm 3: Prochlorperazine 10 mg p. o. as needed for nausea Rescue medications for control of symptoms were allowed Hickock et al ASCO 2005 Final Results URCC-CCOP

Oral 5 HT 3 RAs: Majority of Patients Experience Nausea % Patients with Delayed Nausea 100 90 80 70 60 50 40 30 20 10 75 83 87 Prochlorperazine q 8 h* 5 HT 3* Prochlorperazine PRN* * p = 0. 002 (overall comparison); p = 0. 06 (Prochlorperazine q 8 h vs 5 -HT 3 ); ( p = NS (Prochlorperazine prn vs 5 -HT 3 ) ( • Patients randomized for days 2 and 3; rescue medications allowed Hickock et al ASCO 2005 Final Results URCC-CCOP

Oral 5 HT 3 RAs Not Effective for Delayed CINV ► Vomiting ● ► Significantly more patients vomited at least once during the delayed period (34%) than on the day of treatment (19%) p <0. 01 Nausea ● ● Nausea severity was significantly greater during the delayed period than on the day of treatment p < 0. 01 More patients getting oral 5 HT 3 RAs required rescue medications (45%) than patients getting Compazine® (27 -30%) p=0. 002 Hickock et al ASCO 2005 Final Results URCC-CCOP

Meta-Analysis of Efficacy of 5 -HT 3 RA in Prevention of Delayed Emesis from Chemotherapy ► ► Reviewed 5 studies, 1, 716 pts comparing 5 -HT 3 RA to placebo, 5 studies, 2, 240 pts comparing 5 -HT 3 RA + dexamethasone to dexamethasone alone 5 -HT 3 RA as monotherapy Absolute RR (95% CI) 8. 2% (3. 0 -13. 4) NNT 12. 2 Number of doses per protected pt: 74. 4 5 -HT 3 RA as adjunct to dexamethasone Absolute RR (95% CI) 2. 6% (-0. 6 -5. 8) NNT 38. 8 Number of doses per protected pt: 423 Geling and Eichler, JCO 2005; 23: 1289 -1294

Breakthrough Medications for CINV Consider other classes, alone or in combination ► Antipsychotics ► Cannabinoids ► Benzodiazepines ► Phenothiazines ► Dopamine Receptor Antagonists

NCCN Antiemesis Guidelines v. 2. 2010: HEC Recommendations Emetic risk group Acute prevention Delayed prevention >90% 5 -HT 3 RA DEX + aprepitant + DEX + aprepitant High and AC combinations Risk (% of patients) lorazepam H 2 blocker or proton pump inhibitor DEX, dexamethasone; AC, anthracycline-cyclophosphamide For more information see: http: //www. nccn. org

NCCN Antiemesis Guidelines v. 2. 2010: MEC Recommendations Emetic risk group Risk (% of patients) Acute prevention Delayed prevention 5 -HT 3 RA + DEX Moderate Low Minimal 30 -90% 10 -30% <10% 5 -HT 3 RA or DEX lorazepam H 2 blocker or proton pump inhibitor DEX, prochlorperazine, or metoclopramide lorazepam H 2 blocker or proton pump inhibitor No routine prophylaxis DEX, dexamethasone For more information see: http: //www. nccn. org No preventive measures

MASCC / ESMO Committees II-V Combined Statement #3 – Moderate* Prevention of nausea and vomiting following chemotherapy of moderate emetic risk: To prevent acute and delayed vomiting and nausea following chemotherapy of moderate emetic risk, we recommend a regimen of palonosetron and multiday dexamethasone beginning before chemotherapy * Does not include “AC” given its higher risk of nausea and vomiting, in which an NK 1 RA is added to Dex + 5 HT 3 RA Multinational Association for Supportive Care in Cancer. www. mascc. org June 2009

Summary ► 1 st generation 5 HT 3 RA’s therapeutically equivalent & major advance in supportive care for control of acute emesis ► Newer agents include 2 nd generation 5 -HT 3 RA palonosetron and NK-1 antagonist aprepitant ► Treatment guidelines have changed ● ● ► Degree of nausea incurred has been refined for many agents Delayed CINV recommendations are updated Prevention of CINV has improved, but challenges remain ● ● Improving detection of CINV, especially after 24 hours Educating patients and oncology healthcare givers The development and evaluation of clinically useful assessment tools Further development of regimens to treat delayed CINV

Investigations • Innovation • Clinical Application Risk Stratification Tools to Identify Patients for Primary and Secondary Prevention of VTE in the Setting of Malignancy Screening and VTE Risk Assessment Across the Complex Spectrum of Malignant Disorders—What Works? What Doesn’t? Alok A. Khorana, MD, FACP Vice-Chief, Division of Hematology/Oncology Associate Professor of Medicine and Oncology James P. Wilmot Cancer Center University of Rochester, New York

Optimizing Supportive Care in Cancer Risk Assessment for VTE In Cancer Patients Risk Factors for VTE Biomarkers Risk Assessment Models Implications for Study Design of Prophylaxis Trials Secondary Prophylaxis

Risk Factors for VTE Patient-related factors Older age Race, gender Comorbidities Cancer-related factors Site of cancer Advanced stage Initial period after diagnosis Rao et al. , in Cancer-Associated Thrombosis. (Khorana and Francis, Eds) 2007 Treatment-related factors Hospitalization Chemotherapy Anti-angiogenics Major surgery Erythropoiesis-stimulating agents Transfusions

VTE and Site of Cancer Type of cancer Hematologic Lung Adjusted OR (95% CI) 28 (4 -199. 7) 22. 2 (3. 6 -136. 1) GI 20. 3 (4. 9 -83) Breast 4. 9 (2. 3 -10. 5) Prostate 2. 2 (0. 9 -5. 4) Blom JW et al. JAMA 2005

VTE in the REAL-2 Study: Oxaliplatin vs Cisplatin P=0. 0003 HR for cisplatin 0. 51; 95% CI, 0. 34 to 0. 76; P =. 001 Starling et al JCO 2009

VTE With Bevacizumab RR=1. 29 (95% CI, 1. 03 -1. 63) Rate of VTE (%) 13% 9. 9% RR=1. 38 (95% CI, 1. 12 -1. 70) 6. 2% 4. 2% Bevacizumab (n=1, 196) Control (n=1, 083) All-Grade VTE (6 studies) Nalluri SR, et al. JAMA. 2008; 300: 2277 -2285. Bevacizumab (n=3, 795) Control (n=3, 167) High-Grade VTE (13 studies)

VTE in Myeloma Cumulative Percentage 0. 2 MPT 0. 1 MPT and Enoxaparin RMP and Aspirin 0 0 5 10 Months Palumbo et al. JTH 2006: 4 1842 -45 15 MP 20 25

Candidate Biomarkers ► Blood counts Platelet count Leukocyte count Hemoglobin ► Tissue factor ► Soluble P-selectin ► D-dimer ► C-reactive protein ► Factor VIII

Incidence Of VTE Over 2. 5 Months(%) Incidence of VTE By Quartiles Of Pre -Chemotherapy Platelet Count 6% 5% 4% 3% 2% • P =0. 005 1% 0% <250 250 -300 300 -350 Pre-chemotherapy Platelet Counts (x 1000) Khorana AA et al. Cancer 2005 >350

Incidence Of VTE Over 2. 4 Months (%) Incidence of VTE by Pre-Chemotherapy Leukocyte Count 6% 5% 4% 3% 2% • P =0. 0008 1% 0% <4. 5 (n=342) 4. 5 -11 (n=3202) >11 (n=513) 3 ) Pre-chemotherapy WBC Counts (x 1000/mm Khorana AA et al. Blood 2008

Incidence of VTE by Type of Leukocyte Absolute Neutrophil Count Absolute Monocyte Count Proportion with VTE P=0. 0001 P<0. 0001 Connolly et al ISTH 2009 Abs 1573

Independent Effect of Platelet & Leukocyte Counts In A Multivariate Analysis Variable Odds Ratio* (95% CI) P value Platelet count >350, 000/mm 3 1. 8 (1. 1 -3. 2) 0. 03 Leukocyte count >11, 000/mm 3 2. 2 (1. 2 -4. 0) 0. 008 *Adjusted for site of cancer, stage, hemoglobin < 10 g/dl or use of ESAs and obesity Khorana AA et al. Blood 2008

Effect of Leukocyte and Platelet Counts on VTE Risk In the Vienna CATS registry, platelet count >443, 000 was associated with VTE (HR 3. 5) Simanek et al, J Thromb Hemost 2009 In the RIETE registry, patients with leukocytosis had increased risk of recurrent VTE and death (OR 2. 7) Trujillo-Santos et al, Thromb Hemost 2008 In the REAL-2 study of advanced GEJ/gastric cancers, leukocytosis was associated with VTE during chemotherapy (HR 2. 0) Starling et al, J Clin Oncol 2009

Proportion Died Mortality by Pre-chemotherapy Leukocyte Count 0. 20 0. 18 0. 16 0. 14 0. 12 0. 10 0. 08 0. 06 0. 04 0. 02 0. 00 WBC>11 x 109/L WBC<11 x 109/L 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 Time (Days) MVA for early mortality: HR 2. 0, p = 0. 001 Kuderer et al ASH 2008 Connolly et al ISTH 2009 14. 0% (8. 9%-21. 6%) 4. 4% (3. 2%-6. 1%) P <0. 0001

Tissue Factor in Cancer: Lack of Standardized Assays ► Immunohistochemistry of tumor specimens ► TF ELISA ► TF MP procoagulant activity assay ► Impedance-based flow cytometry

Rate of VTE (%) Tissue Factor Expression and VTE P = 0. 04 Khorana AA, et al. Clin Cancer Res. 2007; 13: 2870 -2875.

Circulating Tissue Factor and VTE P l a s m a T F (p g / m L ) DVT Khorana AA, et al. J Thromb Haemost. 2008; 6: 1983 -1985. DVT Fatal PE P =. 04

Cumulative Incidence of VTE for Cancer Patients According to TF–bearing Microparticles 0. 6 Log Rank P=0. 002 0. 5 0. 4 0. 3 0. 2 0. 1 0. 0 0 5 Zwicker J I et al. Clin Cancer Res 2009; 15: 6830 -6840 10 15 Months 20 25

FRAGEM and TF Biomarker Data Boxplot of the percentage change of tissue factor antigen in the sera of pancreatic cancer patients in both the control and dalteparin groups 250 Control 200 150 100 50 0 -50 Maraveyas, et al. Blood Coagul Fibrinolysis 2010 Dalteparin

TF and Survival In Pancreatic Cancer Proportion surviving Median Survival in pts with TF MP-PCA >2. 5 and 2. 5 pg/m. L vs. 231 days for TF =2. 5 900 1000 N=117 patients with pancreaticobiliary cancers

Cumulative probability of VTE (%) Soluble P-Selectin and VTE in Cancer 0. 25 ► 687 cancer patients followed for median of 415 days 0. 20 0. 15 > 75 th percentile ► s. P-Selectin independent predictor of VTE 0. 10 < 75 th percentile 0. 05 0. 00 0 100 200 300 400 500 600 ► Cumulative 6 -mo probability of VTE was 12% vs 4% for levels < 75 th percentile 700 Observation time (days) Originally published in Ay C, et al. Blood. 2008; 112: 2703 -2708. Copyright © 2008 American Society of Hematology.

D-dimer, F 1/2 and VTE in Cancer Cumulative Risk (probability) 0. 25 Elevated D-d 0. 20 0. 15 Elevated D-d+F 1/2 0. 10 Elevated F 1/2 alone 0. 05 0 Nonelevated D-d and Noneleva F 1/2 100 200 300 400 500 Observation Time (Days) Ay, C. et al. J Clin Oncol; 27: 4124 -4129 2009 600 700

Optimizing Supportive Care in Cancer Risk Assessment for VTE In Cancer Patients Risk Factors Biomarkers Risk Assessment Models Implications for Study Design of Prophylaxis Trials

VTE in Cancer Outpatients ► The overwhelming majority of cancer patients are treated in the outpatient/ambulatory setting ► Which patients are most at risk? ► Which patients will benefit most from prophylaxis? How do you define “high” risk? ► Level of risk for which prophylaxis is considered acceptable by both patients and oncologists

Risk Model Patient Characteristic Site of Cancer Very high risk (stomach, pancreas) High risk (lung, lymphoma, gynecologic, GU excluding prostate) Score 2 1 Platelet count > 350, 000/mm 3 1 Hb < 10 g/d. L or use of ESA 1 Leukocyte count > 11, 000/mm 3 1 BMI > 35 kg/m 2 1 Khorana AA et al. Blood 2008

Rate of VTE over 2. 5 mos (%) Risk Model Validation 8% 7% Development cohort 6% 7. 1% 6. 7% Validation cohort 5% 4% 3% 1. 8% 2. 0% 2% 1% 0. 8% 0% 0. 3% n=734 n=374 n=1627 n=842 n=340 n=149 Risk Low (0) Intermediate(1 -2) High( >3) Khorana AA et al. Blood 2008

Vienna CATS Validation ► ► Full data available in 839 patients Median observation time/follow-up: 643 days Number of Patients Events n n (%) Score ≥ 3 96 16 (17%) Score 2 231 25 (11%) Score 1 17. 7% Score 1 233 14 (6%) Score 0 279 7 (3%) 9. 4% 3. 8% 1. 5% 6 months Ay et al ISTH 2009 Abs

Expanded Risk Score with D-Dimer and s. P-selectin Score ≥ 5 Number of Patients Events n n (%) 30. 3% Score 4 1. 0% 6 months Ay et al ISTH 2009 Abs 9 (29%) 52 10 (19%) Score 3 137 15 (11%) Score 2 Score 1 Score 0 31 Score 4 Score 3 Score ≥ 5 226 11 (5%) Score 1 192 13 (7%) Score 0 201 4 (2%)

Risk Model Is Highly Predictive of Short. Term Overall Survival By VTE Risk Score Categories Low P < 0. 0001 Intermediate High Kuderer NM et al. ASH 2008

Progression-Free Survival and Overall Survival by VTE Risk Category Outcomes Low Risk Intermediat e Risk High Risk All Patients (at 4 months) N=1, 206 N=2, 709 N=543 N=4, 458 1. 2% 5. 9% 12. 7% 5. 6% 1. 0 3. 56 [1. 916. 66] 6. 89 [3. 5013. 57] - 93% 82% 72% 84% 1. 0 2. 77 [1. 973. 87] 4. 27 [2. 90 -6. 27] - Mortality Risk (%) HR [+/- CI] PFS Risk (%) HR [+/- CI] Kuderer NM et al. ASH 2008

Optimizing Supportive Care in Cancer Risk Assessment for VTE In Cancer Patients Risk Factors Biomarkers Risk Assessment Models Implications for Study Design of Prophylaxis Trials

Rates of VTE in Recent Prophylaxis Studies N=1165 Agnelli et al Lancet Onc 2009 Palumbo et al ASH 2009 Riess et al ISTH 2009 Maraveyas et al ESMO 2009 N=930 N=312 N=123

VTE in Lung Cancer: PROTECHT and TOPIC studies s. VTE LMWH s. VTE Placebo All VTE LMWH All VTE Placebo 3. 5% 5% 4% 6. 2% 3% 5. 7% 4. 5% 8. 3% 3. 2% 5. 5% 4. 3% 7. 8% PROTECHT TOPIC-2 All Major Bleeding LMWH Major Bleeding Placebo 1% 0% TOPIC-2 3. 7% 2. 2% All 2. 5% 1. 7% PROTECHT Verso et al. JTH 2010 online NNT=50 (s. VTE) NNT=28 (all. VTE) RRR=46% NNH=125

International Myeloma Working Group Thromboprophylaxis Recommendations Individual risk factors: obesity (BMI ≥ 30), prior VTE, central venous catheter Comorbid risk factors: cardiac disease, chronic renal disease, diabetes, acute infection, immobilization Surgery risk factors: trauma, general surgery or any anesthesia Medications: erythropoietin Myeloma-related risk factors: diagnosis, hyperviscosity Myeloma therapy risk factors: multiagent chemotherapy, doxorubicin, high-dose steroids Patients with ≤ 1 VTE risk factor: Aspirin (81 -325 mg daily) Patients with ≥ 2 VTE risk factors: LMWH (enoxaparin 40 mg/d) or full-dose warfarin, although less existing supporting data for the latter Patients receiving thalidomide/lenalidomide concurrently with high-dose dexamethasone or doxorubicin should receive LMWH thromboprophylaxis Anticoagulant treatment can continue for 4 to 6 months or longer if additional risk factors are present Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide associated thrombosis in myeloma. Leukemia. 2008 Feb; 22(2): 414 -23.

PHACS : Prophylaxis in High-risk Ambulatory Cancer Patients Study Patients deemed high-risk for VTE starting chemotherapy Dalteparin prophylaxis x 12 weeks with 4 -weekly screening US and start/end CT chest R Observe x 12 weeks with 4 -weekly screening US and start/end CT chest R 01 HL 095109 -01, 9/2008

Ongoing Clinical Trials Study (Agent) Criteria for inclusion* N Endpoints PHACS (dalteparin x 12 wks) -Risk score >=3 404 Asymptomatic and symptomatic VTE SAVE-ONCO (semuloparin up to 4 mos) -Lung, bladder, GI, ovary -Metastatic or locally advanced 3200 DVT, PE, VTErelated death 227 VTE -Lung, colon, pancreas -Metastatic or Micro. TEC (enoxaparin x 6 mos) unresectable -Elevated TF MPs * All studies enroll patients initiating a new chemotherapy regimen

Treatment of VTE in Cancer: The CLOT Study Lee, A. Y. Y. et al. N Engl J Med 2003; 349: 146 -153

CLOT Study: Probability of Recurrent VTE, % Reduction in Recurrent VTE 25 Recurrent VTE 20 Risk reduction = 52% p-value = 0. 0017 OAC 15 10 Dalteparin 5 0 0 Lee et. al. N Engl J Med, 2003; 349: 146 30 60 90 120 150 Days Post Randomization 180 210

Summary of NCCN Guidelines Updates Summary of Major Changes in the 1. 2009 Version of the NCCN Venous Thromboembolic Disease Guidelines

Changes in 2009 NCCN Guidelines Stage 1 Immediate: ► “Stage 1 Immediate: Concomitant with diagnosis or while diagnosis and risk assessment (heparin phase)” changed to “Stage 1 Immediate: At diagnosis or during diagnostic evaluation” ► Low –molecular-weight-heparin: New footnote “ 6” was added that states, “Although each of the low molecular weight heparins (LMWH), have been studies in randomized control trials in cancer patients, dalteparin’s efficacy in this population is supported by the highest quality evidence and it is the only LMWH approved by the FDA for this indication. ” ► Unfractionated heparin (IV): target a. PTT range changed from “ 2. 0 -2. 9 x control) to “ 2. 0 -2. 5 x control…” (Also for VTE-H) in these patients.

Changes in 2009 NCCN Guidelines Stage 3 Chronic: ► “Third bullet: “Consider indefinite anticoagulation…. ” changed to “Recommend indefinite anticoagulation…. ” ► Fourth bullet: “For catheter associated thrombosis, anticoagulate as long as catheter is in place and for at least 3 months after catheter removal”.

Changes in 2009 NCCN Guidelines ► 6 Although each of the low molecular weight heparins (LMWH) have been studied in randomized controlled trials in cancer patients, dalteparin’s efficacy in this population is supported by the highest quality evidence and is the only LMWH approved by the FDA for this indication. Lee AYY, Levine MN, Baker RI, Bowden C, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism on patients with cancer. New Eng J Med 2003; 349(2): 146 -153.

(VTE-D): Therapeutic Anticoagulation Treatment for VTE ► The NCCN panel recommends VTE thromboprophylaxis for all hospitalized patients with cancer who do not have contraindications to such therapy, and the panel also emphasized that an increased level of clinical suspicion of VTE should be maintained for cancer patients. Following hospital discharge, it is recommended that patients at high-risk of VTE (e. g. cancer surgery patients) continue to receive VTE prophylaxis for up to 4 weeks post-operation. Careful evaluation and follow-up of cancer patients in whom VTE is suspected and prompt treatment and follow-up for patients diagnosed with VTE is recommended after the cancer status of the patient is assessed and the risks and benefits of treatment are considered.

Therapeutic Anticoagulation Failure Therapeutic INR Patient on warfarin Switch to heparin (LMWH preferred) or fondaparinux Check INR Subtherapeutic INR Increase warfarin dose and treat with parenteral agent until INR target achieved or consider switching to heparin (LMWH preferred) or fondaparinux

Therapeutic Anticoagulation Failure Therapeutic a. PTT Patient on heparin Increase dose of heparin or Switch to LMWH or Switch to fondaparinux and Consider placement of IVC filter and Consider HIT Check a. PTT levels Subtherapeutic a. PTT Increase dose of heparin to reach therapeutic level

Conclusions Cancer patients are clearly at increased risk for VTE but risk is highly variable TF is an emerging candidate biomarker predictive of VTE and survival ? generalizability to all cancers Lack of standardized assay A recently validated risk model can predict risk of VTE (and mortality) using 5 simple clinical and laboratory variables

Conclusions ►Thromboprophylaxis is safe and effective in certain high-risk settings ►LMWH-base prophylaxis is guideline-based standard of care ● ● Hospitalized and surgical patients Highly selected cancer outpatients (myeloma, ? pancreas, ? ? lung) ►Ongoing studies are adopting novel approaches to selecting patients for prophylaxis

Investigations • Innovation • Clinical Application Hematologic Complications of Chemotherapy Balancing Benefits and Risks of Intervention Jeffrey Crawford, MD George Barth Geller Professor for Research In Cancer Chief of Division of Medical Oncology Department of Medicine Duke University Medical Center Editor-in-Chief, Supportive Care Oncology Durham, North Carolina

APPRISE – Assisting Providers and Cancer Patients with Risk Information for the Safe Use of ESAs ► Doctors will be required to register and undergo training on risks and benefits of ESAs in order to continue prescribing. ► As part of the program, patients will be given a medication guide that outlines the risks and benefits of ESAs. ► Enrollment of providers begins March 24, 2010.

Biological Characteristics of Erythroid Stimulating Agents (ESAs) ► Epoetin alfa – FDA approval for chemotherapy induced anemia (CIA) - 1993 ● In vivo half-life 8. 5 h (IV) and 16 -19 h (SC) in healthy subjects 1 ► Darbepoetin alfa – FDA approval for CIA -2002 ● Higher proportion of sialic acid-containing carbohydrate, resulting in a 3 -fold longer half-life and a 4 -fold weaker binding affinity for the EPO receptor 2 ► Epoetin beta – Approved for CIA in Europe ● Less sialated than epoetin alfa and a slightly longer half-life when given SC (~24 h in healthy subjects)3 ► Despite pharmacodynamic differences, efficacy/safety of ESAs in CIA patients appear similar 1 Procrit prescribing information 2002; 2 Egrie JC et al. Oncology (Huntingt) 2002; 3 Halstenson CE et al. Clin Pharmacol Ther 1991

Rescue by Transfusion vs an Improvement/ Maintenance Strategy with ESAs: a Conceptual Model Hb Level Asymptomatic Zone ESA improvement/ maintenance strategy Transfusion Rescue Strategy Individualized patient trigger Weeks of Chemotherapy ODAC Meeting, 5/20/07

Modeled Probability of Receiving a Blood Transfusion as a Function of Baseline Hb Predicted Probability TFN 1 DA Placebo 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 OR=0. 41, 95%CI (0. 33, 0. 51) 0. 2 0. 1 0 15 14 13 12 11 10 9 8 7 6 Baseline Hb (g/d. L) 4 Phase 3, placebo-controlled CIA Studies, n=1641 (980297, 20000161, 20010145, 20030232) ODAC Meeting, 5/20/07 5

Summary of HRQo. L Data from Systematic Review of Randomized Placebo-controlled Trials Source Littlewood Boogaerts Iconomou Witzig Savonije Fixed-effects model Random-effects model Difference in Standardized Mean FACT-F Values (95% CI) 0. 23 (-0. 02 to 0. 48) 0. 11 (-0. 16 to 0. 38) 0. 44 (0. 07 to 0. 82) 0. 11 (-0. 12 to 0. 33) 0. 42 (0. 12 to 0. 71) 0. 076 0. 428 0. 021 0. 360 0. 005 0. 22 (0. 10 to 0. 34) 0. 22 (0. 10 to 0. 36) 0. 000 0. 001 QOL Scale (ESA vs control) P -1. 00 -0. 50 0. 00 Mean Change P-value FACT-F (5 studies, 1418 max pts) 3. 6 vs -0. 8 <0. 001 LASA (4 studies, 1076 max pts) 4. 8 vs -3. 6 <0. 001 1 Cella Difference in Standardized Means (95% CI) D et al, J Pain Symptom Manage. 2002; 24(6): 547 -561 Ross, S et al. Clin Ther. 2006; 28(6): 1 -31 Favors Control 0. 50 1. 00 Favors EPO/DARB 3 -point difference in FACT-F defined as clinically important 1

Higher Hb is Associated with Higher HRQo. L LASA Overall QOL Score 65 60 55 50 45 0 7 8 1 study (n=1580) Crawford J, et al. Cancer. 2002; 95(4): 888 -895. 9 10 11 Hb level (g/d. L) 12 13 14

When and Why do Physicians Transfuse? Data from 5 Phase 3 CIA Darbepoetin alfa Studies Across all studies, recommendation for transfusion was Hb <8 g/d. L (or signs & symptoms of anemia) (n=2286) Hb at Time of Transfusion Reasons Given for Transfusion (n=2185 transfusion episodes) (n=2227 CRF responses ) 10 -12 g/d. L ≥ 12 g/d. L (0. 7%) 9. 2% <8 g/d. L 35. 9% 8 – 10 g/d. L 54. 3% Hb Trigger 34. 7% Therapeutic 46. 0% Other 13. 7% Medically Indicated (4. 4%) Prophylactic (1. 2%)

Common Risks of Blood Product Infusions Some of the Risks of Transfusion ► Febrile nonhemolytic ► Acute transfusion reaction from mismatch ► Acute hemolytic ► Delayed hemolytic ► Allergic Anaphylactic Human leukocyte antigen sensitization Red blood cell allosensitization Graft-versus-host disease ► ► ► ► Clotting disturbances Electrolyte disturbances Volume overload in the young and elderly Transfusion-related acute lung injury Peri-operative infection susceptibility Blood borne infectoons – viral (HIV, hepatitis), bacterial, prions, parasites (malaria) Increased tumor recurrence from perioperative transfusion Worsensed cancer prognosis from perioperative transfusion Upile, T, et al. Clinical Advances in Hematology & Oncology Volume 7, Issue 10 October 2009

Patterns of Use and Risks Associated with Erythropoiesis. Stimulating Agents Among Medicare Patients with Cancer Background: Erythropoiesis-stimulating agents (erythropoietin and darbepoietin) have been approved to reduce the number of blood transfusions required during chemotherapy; however, concerns about the risks of venous thromboembolism and mortality exist. Methods: Study of patients aged 65 years or older in the Surveillance, Epidemiology and End Results-Medicare database; with colon, non-small cell lung or breast cancer or with diffuse large B-cell lymphoma from 1991 through 2001; and who received chemotherapy. The main outcome measures were claims for use of an erythropoiesis -stimulating agent, blood transfusion, venous thromboembolism (i. e. , deep vein thrombosis or pulmonary embolism), and overall survival. Hershman, D. JNCI 101 (23): 1 -9, 2009

Patterns of Use and Risks of ESAs Results ► 56, 210 patients received chemotherapy ► 15, 346 (27%) received an ESA ► 22% received transfusions ► 14. 3% of ESA patients had VTE ► 9. 8% of non. ESA patients had VTE ESA – erythroid stimulating agent VTE – venous thromboembolism Hershman, D. JNCI 101 (23): 1 -9, 2009

Trends in ESA and Transfusion Use in All Patients 70 % of Patients Receiving ESA % of Patients Receiving Blood Transfusion 60 % of Patients 50 40 30 20 10 0 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Hershman, D. JNCI 101 (23): 1 -9, 2009

Overall Survival Proportion alive 1. 00 0. 75 0. 50 EAS use 0. 25 ESA non-use 0 2 4 6 Time to death (years) Hershman, D. JNCI 101 (23): 1 -9, 2009 8 10

Blood Transfusions, Thrombosis and Mortality in Hospitalized Patients with Cancer Population 504, 208 pts with cancer admitted between 19952003 at 60 medical centers Khorana, Francis, Blumberg, Culakova, Refaai, Lyman. Arch Intern Med 2008; 168: 2377 -2381.

Blood Transfusions, Thrombosis and Mortality in Hospitalized Patients with Cancer Khorana, Francis, Blumberg, Culakova, Refaai, Lyman.

Community Oncology ESA Experience Mean hemoglobin levels at different time points Pre-NCD cohort Timepoint Post NCD cohort P Value Number Hb level (SD) Baseline 225 10. 7 (0. 9) 144 9. 7 (0. 8) <0. 0001 Week 4 206 11. 0 (1. 2) 138 10. 2 (1. 2) <0. 0001 Week 8 138 11. 2 (1. 3) 102 10. 3 (1. 1) <0. 0001 Feinberg, B. Community Oncology, June 2009, 257 -261

Community Oncology ESA Experience Feinberg, B. Community Oncology, June 2009, 257 -261

Focused ESA Safety Data Survival, Tumor Progression, TVE* ENHANCE 2003‡ BEST EPO-CAN-20 2007‡ 2005‡ 20000161 PREPARE 11/07† 20010103 GOG-191 1/07† 4/05, 4/07† 2007† DAHANCA 12/06† *8 trials selected by FDA for label inclusion out of 57 total, ‡ publication date, † = date data reported to FDA Lancet 2003; 632: 1255 -60. J Natl Cancer Inst 2006: 98: 708 -14. J Clin Oncol 2005; 23: 5960 -72. J Natl Cancer Inst 2005; 97: 489 -98. J Clin Oncol 2007; 25: 1027 -32. http: //www. fda. gov (accessed 3/20/08). JAMA 2008; 299: 914 -24

EPO CAN-20 ► 300 patients not on active treatment ► Primary endpoint: QOL at 12 weeks ► Target hemoglobin 12 -14 g/d. L ► Unplanned safety analysis 70 patients ► Result : Survival decrement HR 1. 84

EPO-CAN-20 (Advanced NSCLC) Reported Causes of Death Cause of Death Placebo (34 deaths) Epoetin Alfa (32 deaths) No. of Patients % Progressive lung cancer 31 91. 2 28 87. 5 Pneumonia 1 2. 9 1 3. 1 Myocardial infarction 1 2. 9 1 Renal failure 1 2. 9 - Hyponatremia - 1 3. 1 Bowel perforation - 1 3. 1 Unknown cause - 1 3. 1 Wright J et al. JCO 2007 Mar 20; 25(9): 1027 -32. Epub 2007 Feb 20

Meta-analysis: Lung Cancer Trials Study Name No. of Deaths/Total ESA Ao. C NSCLC Wright 2007 (EPO-CAN-20) CIA NSCLC EPO-GER-22 Vansteenkiste 2002 NSCLC Milroy 2003 (INT-49) Random Effects Model: NSCLC CIA SCLC Vansteenkiste 2002 SCLC Pirker 2007 (AMG 20010145) EPO-CAN-15 Thatcher 1999 Grote 2005 (N 93 -004) Random Effects Model: SCLC 32/33 95% CI Odds Ratio Lower Upper Control Limit 34/37 146/195 159/190 72/108 82/114 136/214 126/210 28/47 241/298 28/52 7/86 100/109 37/45 251/298 29/52 3/44 101/115 2. 82 0. 28 28. 56 0. 58 0. 78 1. 16 0. 83 0. 35 0. 44 0. 79 0. 96 1. 38 1. 72 0. 54 1. 27 0. 12 0. 52 0. 43 0. 30 0. 64 0. 83 1. 21 2. 00 4. 93 3. 72 0. 53 1. 28 0. 32 0. 79 0. 93 1. 21 1. 54 0. 83 0. 1 ODAC 2008 Supplement 0. 2 0. 5 Favors ESA 1 2 5 Favors Control 10

Cochrane Meta Analysis – Summary of Results N Hazard Ratio (95% CI) P-value All cancer pts 13, 933 1. 17 (1. 06, 1. 30) 0. 002 Chemotherapy trials 10, 441 1. 10 (0. 98, 1. 24) 0. 12 All cancer pts 13, 933 1. 06 (1. 00, 1. 12) 0. 05 Chemotherapy trials 10, 441 1. 04 (0. 97, 1. 11) 0. 26 Study population On-study mortality 1 Overall survival 2 Bohlius et al, (Lancet 2009) 1 deaths during active study phase; 2 deaths during longest follow-up available

Meta Analysis of Disease Progression Glaspy, Crawford, Vansteenkiste, Henry, Rao, Bowers, Berlin, Tomita, Bridges, Ludwig British Journal of Cancer 102, 301 -315 (5 January 2010)

Clinical Trials Identifier NCT 00858364 A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Long-Term Safety and Efficacy of Darbepoetin Alfa Administered at 500 µg Once-Every-3 -Weeks in Anemic Subjects With Advanced Stage Non-Small Cell Lung Cancer Receiving Multi-Cycle Chemotherapy

Clinical Trials Identifier NCT 00858364 ► Sponsor Amgen Inc. ► General Design Randomized, double-blind, placebo-controlled Phase 3, non-inferiority study intended to evaluate the long term safety and efficacy of darbepoetin alfa ► Intervention Aranesp or placebo administered Q 3 W (2: 1 randomization) ► Study population Subjects with advanced stage non-small cell lung cancer and anemia (Hb <=11 g/d. L) receiving or about to receive first-line chemotherapy ► Sample size 3000 subjects

Clinical Trials Identifier NCT 00858364 ► Primary outcome measure ● ► Overall Survival (OS) Secondary outcome measures ● ● ● ● Progression-free survival (PFS) Objective tumor response Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8. 0 g/d. L from week 5 (day 29) to end of efficacy treatment period Incidence of at least 1 RBC transfusion or hemoglobin less than or equal to 8. 0 g/d. L from study day 1 to end of treatment period Incidence of neutralizing antibody formation to darbepoetin alfa Change in hemoglobin from baseline to end of efficacy treatment period Incidence of adverse events (AEs) such as thrombovascular events (TVE), venous thromboembolic events (VTE), and AEs associated with RBC transfusions

Study Status as of June 2010 ► Study start date: June 2009 ► Currently recruiting subjects in North America, Europe, Asia and Latin America ● Study sites planned for a total of approximately 400 sites in over 30 countries

Chemotherapy-induced Neutropenia and Its Complications Myelosuppressive chemotherapy Neutropenia Febrile neutropenia (FN) Chemotherapy dose delays and dose reductions Complicated life-threatening infection and prolonged hospitalization Reduced survival Kuderer NM et al. Cancer 2006; 106: 2258– 2266 Chirivella I et al. J Clin Oncol 2006; 24; abstract 668 Bosly A et al. Ann Hematol 2008; 87: 277 -283 Decreased relative dose intensity (RDI)

100 (temperature >38. 2◦C and ANC <0. 5 x 109/L) Predicted probability of FN (%) Risk of FN Increases with Duration of Severe Neutropenia* 80 60 40 20 0 0 *ANC <0. 5 x 109/L 1 2 3 4 5 6 Days of severe neutropenia Adapted from Blackwell S, Crawford J. In: Morstyn G, Dexter TM. Filgrastim; (r-met. Hu. G-CSF) in Clinical Practice. New York: Marcel Dekker; 1994 p 103– 116 Crawford J et al. N Engl J Med 1991; 325: 164– 170 7 8 9

Most Initial FN Events Occur During the First Cycle of Chemotherapy Events in cycle 1 (%) Proportion of first FN events in cycle 1 by cancer type • FN events documented in 287/2692 (10. 7%) of adult cancer patients during the 1 st three cycles of chemotherapy NSCLC – non-small cell lung cancer; Adapted from Crawford J et al. JNCCN 2008; 6: 109– 118 SCLC – small cell lung cancer; NHL - non-Hodgkin’s lymphoma; HD – Hodgkin’s disease

Death as a Result of FN Hospitalization Inpatient mortality (percent patients admitted for FN) 25 Mortality following hospital admission of adult cancer patients with FN* 21. 4 20 15 10 10. 3 9. 5 5 0 2. 6 Overall (n=41, 779) No major comorbidity (n=21, 386) *Data based on a single admission per patient Kuderer NM et al. Cancer 2006; 106: 2258– 2266 One major comorbidity (n=12, 398) >one major comorbidity (n=7, 995)

Clinical Consequences of Neutropenia and Febrile Neutropenia 1. 0 + + 0. 8 + RDI 0. 6 + < 85% 0. 4 + +++ 85% + < 85%, censored 0. 2 + 85%, censored 0. 0 0 2 4 6 8 10 Disease-Free Survival (years) • Reduced RDI resulted in lower OS in ESBC receiving anthracyclinecontaining chemotherapy 1 Estimated Survival Cum Proportion Survival Suboptimal chemotherapy reduces survival 0. 8 0. 6 ARDI 0. 4 >90% 86–≤ 90% ≤ 85% 0. 2 0. 0 0 1 2 3 4 5 6 7 8 Years Post Chemotherapy • Reduced RDI resulted in lower OS in patients with DLBCL receiving CHOP-21 chemotherapy 2 OS, overall survival; ARDI, average relative dose intensity 1 Chirivella I, et al. Breast Cancer Res Treat 2009; 114(3): 479 -484 2 Bosly A, et al. Ann Hematol 2008; 87: 277– 283

Myelosuppression Predicts for Survival Benefit of Adjuvant Chemotherapy in Breast Cancer Patients Mayers C, Tannock IF. Cancer 2001; 91: 2253 Lyman G. JNCCN 2009; 7: 99 -108

Neutropenia as a Pharmacodynamic Endpoint of Clinical Benefit Analysis of 4626 Hodgkin’s Lymphoma patients on German HDSG Trials 1988 -1998 Results Female Male P value G 3/4 leukopenia 69. 90 52. 20 p<0. 0001 FFTF at 66 months 81% 74% Hypothesis: The better outcome of female HL patients is due to greater systemic chemotherapy exposure. Klimm B. J Clin Oncol 2005; 23: 8003 -8011

Overall Survival by Grade of Chemotherapy-Induced Neutropenia for Advanced NSCLC Patients Probability of Survival 1. 0 0. 8 No neutropenia Mild neutropenia Severe neutropenia 0. 6 Log-rank P=0. 0118 (stratified by treatment) 0. 4 0. 2 0 0 13 Patients at Risk No neutropenia 208 Mild neutropenia 138 Severe neutropenia 90 Di Maio M et al. Lancet Oncol 2005; 6: 669 26 39 52 65 78 91 104 Time From Landmark Day (Weeks) 150 98 69 102 74 50 68 54 28 43 38 21 29 33 14 20 21 14 13 13 8 10 11 4

Strategies For Management of Chemotherapy-Induced Neutropenia ► Prevention ● ● Chemotherapy Dose reduction/delay Myeloid growth factors • G-CSF (filgrastim, lenograstim) • GM-CSF (sargramostim, molgramostim) • Pegfilgrastim - Antibiotics ► Treatment ● ● ● Observation if afebrile Antibiotics Myeloid growth factors (limited benefit)

Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients ► 95 randomized controlled trials, 1973 -2004 (n=9283) ► 79 studies were on inpatients with hematologic malignancies and/or PSCT ► 52 trials involved quinolone prophylaxis ► 7 trials included CSFs Gafter-Gvili, A. Ann Intern Med. 2005: 142(12): 979 -995

Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients Results of Prophylaxis with Fluoroquinolones Outcome Relative Risk (CI) Fever . 67 (. 56 -. 81) Documented Infection . 50 (. 35 -. 70) Infection Related Death . 38 (. 21 -. 69) All cause mortality . 52 (. 35 -. 77) Adverse Events 1. 30 (. 61 -2. 76) Development of resistant bacteria 1. 69 (. 73 -3. 92) Gafter-Gvili, A. Ann Intern Med. 2005: 142(12): 979 -995

Meta-Analysis: Antibiotic Prophylaxis Reduces Mortality in Neutropenic Patients Limitations of Prophylactic Antibiotics ► Insufficient number of outpatient solid tumor/chemotherapy patients to be applicable ► Not recommended by IDSA guidelines because of concerns regarding antibiotic resistance ► Routine application limited to high risk inpatients with hematologic malignancies/stem cell transplants Gafter-Gvili, A. Ann Intern Med. 2005: 142(12): 979 -995

Role of Prophylactic Antibiotics in the Prevention of Infection after Chemotherapy SIGNIFICANT Trial ► Solid tumor/lymphoma patients (n-1565) receiving standard dose multicycle chemotherapy ► Randomized to levofloxacin 500 mg qd x 7 day vs placebo ► Primary endpoint – reduction in febrile episodes attributed to infection SIGNIFICANT Trial. Cullen, et al. NEJM 2005; 353: 988 -998

Role of Prophylactic Antibiotics in the Prevention of Infection after Chemotherapy SIGNIFICANT Trial Outcome In first cycle Febrile episode Probable infection Hospitalization In any Cycle Febrile episode Probable infection Hospitalization Severe Infection or Death RR Reduction Levofloxacin Placebo (95% CI) Number Needed to Treat (CI) 3. 5 14 6. 7 7. 9 19 10 56 (32 -72) 28 (10 -43) 36 (10 -54) 23 (15 -46) 19 (11 -58) 28 (16 -109) 11 34 16 15 41 22 29 (8. 1 -45) 18 (6. 3 -27) 27 (9. 9 -410) 23 (13 -91) 14 (9 -410 18 (11 -52) 1 2 50 (-14 to 78) Not significant Values are percentages unless otherwise specified. Moon, S. et al. Supportive Cancer Therapy, 2006 3(4): 207 -13

Primary Prophylaxis with MGFs Reduces Febrile Neutropenia RR = 0. 538 95% CI (0. 430 -0. 673) 46% reduction in risk of febrile neutropenia with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007; 25: 3158 -3167

Primary Prophylaxis with MGFs Reduces Infection-related Mortality RR = 0. 552 95% CI (0. 338 -0. 902) 45% reduction in risk of infectionrelated mortality with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007; 25: 3158 -3167

Primary Prophylaxis with MGFs Reduces Early Mortality RR = 0. 599 95% CI (0. 4330. 830) 40% reduction in risk of early mortality with primary prophylaxis Kuderer NM et al. J Clin Oncol. 2007; 25: 3158 -3167

What impact does pegfilgrastim have on early, allcause mortality in patients receiving chemotherapy? Design Community-based, prospective observational study Inclusion criteria Eligibility was not restricted on the basis of older age or major co-morbidities; 3 month life expectancy and 4 cycles chemotherapy planned Patient population 4, 458 consecutive adult patients initiating chemotherapy at 115 U. S. practice sites Endpoints Time to febrile neutropenia, progression-free and overall survival Lyman GH, et al. J Clin Oncol 2008; May 20 suppl: 6552

Pegfilgrastim Primary Prophylaxis Demonstrates Significant Impact on Early Overall and Progression-free Survival Pegfilgrastim Primary Prophylaxis Survival 0. 95 No Pegfilgrastim Prophylaxis 0. 90 0. 85 Hazard Ratio = 0. 412 [0. 210, 0. 211] P = 0. 010 0. 80 Pegfilgrastim Primary Prophylaxis 1. 00 Progression Free Survival 1. 00 0. 75 0. 90 No Pegfilgrastim Prophylaxis 0. 85 Hazard Ratio = 0. 554 [0. 453, 0. 923] P = 0. 015 0. 80 0. 75 0 10 20 30 40 50 60 70 80 90 Time (Days) Lyman GH, et al. J Clin Oncol 2008; May 20 suppl: 6552 0 10 20 30 40 50 60 70 80 90 Time (Days)

Impact of Pegfilgrastim on Overall and Disease Free Survival was Apparent in Major Prognostic Subgroups A 1. 00 0. 95 No Pegfilgrastim Planned RDI ≥ 85% N = 2, 623 0. 90 0. 85 Hazard Ratio = 0. 310 [0. 133, 0. 723] P = 0. 007 0. 80 10 20 30 40 50 60 Time (Days) 70 80 Lung Cancer N = 907 0. 90 0. 85 No Pegfilgrastim Hazard Ratio = 0. 346 [0. 125, 0. 954] P = 0. 040 0. 80 0. 75 0 Pegfilgrastim 0. 95 Survival B 1. 00 Pegfilgrastim 0. 75 90 0 10 20 30 40 50 70 80 90 Time (Days) D 1. 00 C 1. 00 Pegfilgrastim 0. 95 ECOG ≥ 1 N = 2, 024 0. 90 No Pegfilgrastim 0. 85 Hazard Ratio = 0. 383 [0. 192, 0. 761] P = 0. 006 0. 80 Survival 0. 95 Survival 60 Liver Dysfunction 0. 90 N = 1, 045 No Pegfilgrastim 0. 85 Hazard Ratio = 0. 274 [0. 110, 0. 684] P = 0. 006 0. 80 0. 75 0 10 20 30 40 50 60 Time (Days) 70 80 90 Lyman GH, et al. J Clin Oncol 2008; May 20 suppl: 6552 0 10 20 30 40 50 60 Time (Days) 70 80 90

Risk of Mortality in Patients with Cancer Experiencing Febrile Neutropenia Kaplan-Meier Survival Curve for Early Mortality 1. 00 Survival 0. 99 0. 98 0. 97 0. 96 Log rank test: Chi 2(1)=4. 79, p=0. 0287 0. 95 0 2 4 6 8 Length of Follow-up in Months 10 Non febrile neutropenia patients Febrile neutropenia patients Barron, R. Abstract 9561, ASCO 2009 12

Risk of Mortality in Patients with Cancer Experiencing Febrile Neutropenia Kaplan-Meier Survival Curve for Overall Mortality 1. 00 Log rank test: Chi 2(1)=23. 15, p<0. 0001 Survival 0. 95 0. 90 0. 85 0. 80 0. 75 0 10 20 30 40 50 Length of Follow-up in Months 60 Non febrile neutropenia patients Febrile neutropenia patients Barron, R. Abstract 9561, ASCO 2009 70

Guidelines at a Glance: Primary Prophylactic CSF Administration Neutropenic Event Risk EORTC 2006 ASCO 2006 NCCN 2007 Moderate to High Use CSF ≥ 20% Use CSF ~ 20% Use CSF > 20% Intermediate Consider CSF 10 - 20% with risk factors Recommend < 20% (with risk factors) Consider CSF 10 - 20% with risk factors Low CSF is not recommended < 10% Risk Factor Assessment +++ Not specified +++ CSF is not recommended for most patients < 10% ++ NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. v. 1. 2007. Available at: http: //www. nccn. org, accessed May 23, 2007 Smith TJ, et al. J Clin Oncol. 2006; 24(19): 3187 -3205 Aapro MS, et al. European J Cancer. 2006; 42: 2433 -2453

NCCN Practice Guidelines in Oncology v. 1. 2010 Myeloid Growth Factors Patient Risk Factors for Developing Febrile Neutropenia In addition to the risk of the chemotherapy regimen and the specific malignancy being treated, these factors need to be considered when evaluating a patient’s overall risk for febrile neutropenia. ► Older patient, notably patients age 65 and older (see NCCN Senior Adult Oncology Guidelines) ► Previous chemotherapy or radiation therapy ► Pre-existing neutropenia or bone marrow involvment with tumor ► Pre-existing conditions Neutropenia Infection/open wounds Recent surgery ► Poor performance status ► Poor renal function ► Liver dysfunction, most notably elevated bilirubin

Adverse Events Associated with Myeloid Growth Factors Filgrastim/Pegfilgrastim Common Bone/musculoskeletal pain (25 -50%) Less Common Splenomegaly (3%) Headache, nausea Fever (1%) Rare Allergic reaction Sweet’s syndrome Controversial Acute myeloid leukemia – epidemiologic association, but not confirmed in randomized prospective trials Myeloid Growth Factor Guidelines v. 1. 2008, www. NCCN. org

Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials Relative Risk for AML/MDS by Cancer Type Lyman, G. ASCO Abstract 9524, 2009

Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials AML/MDS by Planned CT Regimen Category Lyman, G. ASCO Abstract 9524, 2009

Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials All-Cause Mortality by Tumor Type Lyman, G. ASCO Abstract 9524, 2009

Acute Myeloid Leukemia or Myelodysplastic Syndrome and Overall Mortality with Chemotherapy and Granulocyte Colony-Stimulating Factor Meta-Analysis of Randomized Controlled Trials All-Cause Mortality by Regimen Category Lyman, G. ASCO Abstract 9524, 2009

Neutropenia / Management Summary ► Neutropenia is the major risk factor fever and infection, as well as reduced chemotherapy dose delivery; both of which can be associated with reduced survival of the cancer patient. ► In patients at significant risk of febrile neutropenia (>20%) prophylactic CSFs are warranted in the first and all subsequent cycles of chemotherapy. ► Prophylactic antibiotics may add to the benefit of CSFs in selected settings, but cannot replace them. ► Further prospective studies evaluating chemotherapy RDI and outcomes in cancer patients are needed.