Placebo (n = 467) Events occurring in 10% of Neulasta -treated patients and at a higher incidence as compared to placebo-treated patients b

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1 Start with support BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. CONTRAINDICATIONS Neulasta is contraindicated in patients with known hypersensitivity to E coli-derived proteins pegfilgrastim Filgrastim, or any other component of the product. WARNINGS General The safety and efficacy of Neulasta for peripheral blood progenitor cell (PBPC) mobilization has not been evaluated in adequate and well-controlled studies. Neulasta should not be used for PBPC mobilization. Splenic Rupture RARE CASES OF SPLENIC RUPTURE, INCLUDING SOME FATAL CASES, HAVE BEEN REPORTED FOLLOWING THE ADMINISTRATION OF NEULASTA. PATIENTS RECEIVING NEULASTA WHO REPORT LEFT UPPER ABDOMINAL AND/OR SHOULDER TIP PAIN SHOULD BE EVALUATED FOR AN ENLARGED SPLEEN OR SPLENIC RUPTURE. Adult Respiratory Distress Syndrome (ARDS) Adult respiratory distress syndrome (ARDS) has been reported in neutropenic patients with sepsis receiving Neulasta, and is postulated to be secondary to an influx of neutrophils to sites of inflammation in the lungs. Neutropenic patients receiving Neulasta who develop fever, lung infiltrates, or respiratory distress should be evaluated for the possibility of ARDS. In the event that ARDS occurs, Neulasta should be discontinued and/or withheld until resolution of ARDS and patients should receive appropriate medical management for this condition. Allergic Reactions Allergic reactions to Neulasta, including anaphylaxis, skin rash, and urticaria, have been reported in post marketing experience. The majority of reported events occurred upon initial exposure. In some cases, symptoms recurred with rechallenge, suggesting a causal relationship. In rare cases, allergic reactions including anaphylaxis, recurred within days after initial anti-allergic treatment was discontinued. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Neulasta should be permanently discontinued in patients with serious allergic reactions. Sickle Cell Disease Severe sickle cell crises have been associated with the use of Neulasta in patients with sickle cell disease. Severe sickle cell crises, in some cases resulting in death, have also been associated with Filgrastim, the parent compound of pegfilgrastim. Only physicians qualified by specialized training or experience in the treatment of patients with sickle cell disease should prescribe Neulasta for such patients, and only after careful consideration of the potential risks and benefits. PRECAUTIONS General Use With Chemotherapy and/or Radiation Therapy Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see DOSAGE AND ADMINISTRATION) because of the potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic chemotherapy. The use of Neulasta has not been studied in patients receiving chemotherapy associated with delayed myelosuppression (eg, nitrosoureas, mitomycin C). The administration of Neulasta concomitantly with 5-fluorouracil or other antimetabolites has not been evaluated in patients. Administration of pegfilgrastim at 0, 1, and 3 days before 5-fluorouracil resulted in increased mortality in mice; administration of pegfilgrastim 24 hours after 5-fluorouracil did not adversely affect survival. The use of Neulasta has not been studied in patients receiving radiation therapy. Potential Effect on Malignant Cells Pegfilgrastim is a growth factor that primarily stimulates neutrophils and neutrophil precursors; however, the G-CSF receptor through which pegfilgrastim and Filgrastim act has been found on tumor cell lines, including some myeloid, T-lymphoid, lung, head and neck, and bladder tumor cell lines. The possibility that pegfilgrastim can act as a growth factor for any tumor type cannot be excluded. Use of Neulasta in myeloid malignancies and myelodysplasia (MDS) has not been studied. In a randomized study comparing the effects of the parent compound of Neulasta, Filgrastim, to placebo in patients undergoing remission induction and consolidation chemotherapy for acute myeloid leukemia, important differences in remission rate between the two arms were excluded. Disease-free survival and overall survival were comparable; however, the study was not designed to detect important differences in these endpoints.* Information for Patients Patients should be informed of the possible side effects of Neulasta and be instructed to report them to the prescribing physician. Patients should be informed of the signs and symptoms of allergic drug reactions and be advised of appropriate actions. Patients should be counseled on the importance of compliance with their Neulasta treatment, including regular monitoring of blood counts. If it is determined that a patient or caregiver can safely and effectively administer Neulasta (pegfilgrastim) at home, appropriate instruction on the proper use of Neulasta (pegfilgrastim) should be provided for patients and their caregivers, including careful review of the Information for Patients and Caregivers insert. Patients and caregivers should be cautioned against the reuse of needles, syringes, or drug product, and be thoroughly instructed in their proper disposal. A puncture-resistant container for the disposal of used syringes and needles should be available. Laboratory Monitoring To assess a patient s hematologic status and ability to tolerate myelosuppressive chemotherapy, a complete blood count and platelet count should be obtained before chemotherapy is administered. Regular monitoring of hematocrit value and platelet count is recommended. Drug Interaction No formal drug interaction studies between Neulasta and other drugs have been performed. Drugs such as lithium may potentiate the release of neutrophils; patients receiving lithium and Neulasta should have more frequent monitoring of neutrophil counts. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. Carcinogenesis, Mutagenesis, and Impairment of Fertility No mutagenesis studies were conducted with pegfilgrastim. The carcinogenic potential of pegfilgrastim has not been evaluated in long-term animal studies. In a toxicity study of 6 months duration in rats given once weekly subcutaneous injections of up to 1000 mcg/kg of pegfilgrastim (approximately 23-fold higher than the recommended human dose), no precancerous or cancerous lesions were noted. When administered once weekly via subcutaneous injections to male and female rats at doses up to 1000 mcg/kg prior to, and during mating, reproductive performance, fertility, and sperm assessment parameters were not affected. Pregnancy Category C Pegfilgrastim has been shown to have adverse effects in pregnant rabbits when administered subcutaneously every other day during gestation at doses as low as 50 mcg/kg/dose (approximately 4-fold higher than the recommended human dose). Decreased maternal food consumption, accompanied by a decreased maternal body weight gain and decreased fetal body weights were observed at 50 to 1000 mcg/kg/dose. Pegfilgrastim doses of 200 and 250 mcg/kg/dose resulted in an increased incidence of abortions. Increased post-implantation loss due to early resorptions was observed at doses of 200 to 1000 mcg/kg/dose, and decreased numbers of live rabbit fetuses were observed at pegfilgrastim doses of 200 to 1000 mcg/kg/dose, given every other day. Subcutaneous injections of pegfilgrastim of up to 1000 mcg/kg/dose every other day during the period of organogenesis in rats were not associated with an embryotoxic or fetotoxic outcome. However, an increased incidence (compared to historical controls) of wavy ribs was observed in rat fetuses at 1000 mcg/kg/dose every other day. Very low levels (< 0.5%) of pegfilgrastim crossed the placenta when administered subcutaneously to pregnant rats every other day during gestation. Once weekly subcutaneous injections of pegfilgrastim to female rats from day 6 of gestation through day 18 of lactation at doses up to 1000 mcg/kg/dose did not result in any adverse maternal effects. There were no deleterious effects on the growth and development of the offspring and no adverse effects were found upon assessment of fertility indices. There are no adequate and well-controlled studies in pregnant women. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Nursing Mothers It is not known whether pegfilgrastim is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when Neulasta is administered to a nursing woman. Pediatric Use The safety and effectiveness of Neulasta in pediatric patients have not been established. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. ADVERSE REACTIONS (See WARNINGS, Splenic Rupture, Adult Respiratory Distress Syndrome (ARDS), Allergic Reactions, and Sickle Cell Disease.) Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of Neulasta cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to Neulasta use and for approximating rates. The data described below reflect exposure to Neulasta in 932 patients. Neulasta was studied in placebo- and active-controlled trials (n = 467, and n = 465, respectively). The population encompassed an age range of 21 to 88 years. Ninety-two percent of patients were female. The ethnicity of the patients was as follows: 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with solid tumors (breast [n = 823], lung and thoracic tumors [n = 53]) or lymphoma (n = 56) received Neulasta after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. In the placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta -treated patients as compared to placebo-treated patients. The incidence of other commonly reported adverse events were similar in the Neulasta - and placebo-treated patients, and were consistent with the underlying cancer diagnosis and its treatment with chemotherapy. The data in Table 1 reflect those adverse events occurring in at least 10% of patients treated with Neulasta in the placebo-controlled study. TABLE 1. Adverse Events Occurring in 10% a of Patients in The Placebo-Controlled Study Neulasta Event Placebo (n = 467) (n = 461) Alopecia 48% 47% Bone Pain b 31% 26% Diarrhea 29% 28% Pyrexia (not including 23% 22% febrile neutropenia) Myalgia 21% 18% Headache 16% 14% Arthralgia 16% 13% Vomiting 13% 11% Asthenia 13% 11% Edema Peripheral 12% 10% Constipation 10% 6% a Events occurring in 10% of Neulasta -treated patients and at a higher incidence as compared to placebo-treated patients b Bone pain is limited to the specified adverse event term, bone pain In the active-controlled studies, common adverse events occurred at similar rates and severities in both treatment arms (Neulasta, n = 465; Filgrastim, n = 331). These adverse experiences occurred at rates between 72% and 15% and included: nausea, fatigue, alopecia, diarrhea, vomiting, constipation, fever, anorexia, skeletal pain, headache, taste perversion, dyspepsia, myalgia, insomnia, abdominal pain, arthralgia, generalized weakness, peripheral edema, dizziness, granulocytopenia, stomatitis, mucositis, and neutropenic fever. Bone Pain The analysis of bone pain described below is based on a composite analysis using multiple, related, adverse event terms. In the placebo-controlled study, the incidence of bone pain was 57% in Neulasta -treated patients compared to 50% in placebo-treated patients. Bone pain was generally reported to be of mild-to-moderate severity. Among patients experiencing bone pain, approximately 37% of Neulasta - and 31% of placebo-treated patients utilized non-narcotic analgesics and 10% of Neulasta - and 9% of placebo-treated patients utilized narcotic analgesics. In the active-controlled studies, the use of non-narcotic and narcotic analgesics in association with bone pain was similar between Neulasta - and Filgrastimtreated patients. No patient withdrew from study due to bone pain. Laboratory Abnormalities In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. Leukocytosis was not associated with any adverse effects. In the placebo-controlled study, reversible elevations in LDH, alkaline phosphatase, and uric acid that did not require treatment occurred at similar rates in Neulasta - and placebo-treated patients. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Neulasta has not been adequately determined. While available data suggest that a small proportion of patients developed binding antibodies to Filgrastim or pegfilgrastim, the nature and specificity of these antibodies have not been adequately studied. No neutralizing antibodies have been detected using a cell-based bioassay in 46 patients who apparently developed binding antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. Therefore, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Cytopenias resulting from an antibody response to exogenous growth factors have been reported on rare occasions in patients treated with other recombinant growth factors. There is a theoretical possibility that an antibody directed against pegfilgrastim may cross-react with endogenous G-CSF, resulting in immunemediated neutropenia, but this has not been observed in clinical studies. OVERDOSAGE The maximum amount of Neulasta that can be safely administered in single or multiple doses has not been determined. Single subcutaneous doses of 300 mcg/kg have been administered to 8 healthy volunteers and 3 patients with non-small cell lung cancer without serious adverse effects. These patients experienced a mean maximum ANC of 55 x 10 9 /L, with a corresponding mean maximum WBC of 67 x 10 9 /L. The absolute maximum ANC observed was 96 x 10 9 /L with a corresponding absolute maximum WBC observed of 120 x 10 9 /L. The duration of leukocytosis ranged from 6 to 13 days. Leukapheresis should be considered in the management of symptomatic individuals. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. Neulasta should not be administered in the period between 14 days before and 24 hours after administration of cytotoxic chemotherapy (see PRECAUTIONS). The 6 mg fixed-dose formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg. No dosing adjustment is necessary for renal dysfunction (see CLINICAL PHARMACOLOGY, Special Populations). Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 4,810,643; 4,999,291; 5,582,823; 5,580,755, as well as other patents or patents pending. Reference *Heil G, Hoelzer D, Sanz MA, et al. A randomized, double-blind, placebocontrolled, phase III study of Filgrastim in remission induction and consolidation therapy for adults with de novo Acute Myeloid Leukemia. Blood. 1997;90: Issue Date: 01/03/2007 Manufactured by: Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, CA Amgen Inc. All rights reserved. MC36459

2 Help protect against febrile neutropenia before it strikes Neulasta (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Product Safety Information Rare cases of splenic rupture, adult respiratory distress syndrome, and sickle cell crises have been reported in postmarketing experience in patients receiving Neulasta. Allergic reactions, including anaphylaxis, have also been reported. The majority of these reactions occurred upon initial exposure. However, in rare cases, allergic reactions, including anaphylaxis, recurred within days after discontinuing anti-allergic treatment. In a placebo-controlled trial, bone pain occurred at a higher incidence in Neulasta -treated patients as compared to placebo-treated patients (31% vs 26%). The most common adverse events reported in either placebo- or active-controlled trials were consistent with the underlying cancer diagnosis and its treatment with chemotherapy, with the exception of bone pain. Please refer to the brief summary of Neulasta Prescribing Information Amgen. All rights reserved. MC Start with support

3 For Intravenous Use Only Rx Only. BRIEF SUMMARY Please see package insert for prescribing information. DESCRIPTION NovoSeven is recombinant human coagulation Factor VIIa (rfviia), intended for promoting hemostasis by activating the extrinsic pathway of the coagulation cascade. NovoSeven is a vitamin K-dependent glycoprotein consisting of 406 amino acid residues (MW 50 K Dalton). NovoSeven is structurally similar to human plasma-derived Factor VIIa. INDICATIONS AND USAGE NovoSeven is indicated for: treatment of bleeding episodes in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to Factor VIII or Factor IX and in patients with acquired hemophilia treatment of bleeding episodes in patients with congenital FVII deficiency prevention of bleeding in surgical interventions or invasive procedures in patients with congenital FVII deficiency NovoSeven should be administered to patients only under the supervision of a physician experienced in the treatment of bleeding disorders. CONTRAINDICATIONS NovoSeven Coagulation Factor VIIa (Recombinant) should not be administered to patients with known hypersensitivity to NovoSeven or any of the components of NovoSeven. NovoSeven is contraindicated in patients with known hypersensitivity to mouse, hamster, or bovine proteins. WARNINGS The extent of the risk of thrombotic adverse events after treatment with NovoSeven in patients with hemophilia and inhibitors is not known, but is considered to be low. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with apccs/pccs (activated or nonactivated prothrombin complex concentrates) may have an increased risk of developing thrombotic events due to circulating TF or predisposing coagulopathy. (See ADVERSE REACTIONS and Drug Interactions) The extent of the risk of arterial and venous thromboembolic adverse events after treatment with NovoSeven in patients without hemophilia is also not known. A clinical study in elderly non-hemophilia intracerebral hemorrhage patients indicated a potential increased risk of arterial thromboembolic adverse events with use of NovoSeven, including myocardial ischemia, myocardial infarction, cerebral ischemia and/or infarction. PRECAUTIONS General Patients who receive NovoSeven should be monitored if they develop signs or symptoms of activation of the coagulation system or thrombosis. When there is laboratory confirmation of intravascular coagulation or presence of clinical thrombosis, the rfviia dosage should be reduced or the treatment stopped, depending on the patient s symptoms. Due to limited clinical studies which clearly address the effect of posthemostatic dosing, precautions should be exercised when NovoSeven is used for prolonged dosing. (See DOSAGE AND ADMINISTRATION) Factor VII deficient patients should be monitored for prothrombin time and factor VII coagulant activity before and after administration of NovoSeven. If the factor VIIa activity fails to reach the expected level, or prothrombin time is not corrected, or bleeding is not controlled after treatment with the recommended doses, antibody formation may be suspected and analysis for antibodies should be performed. Information for Patients Patients receiving NovoSeven should be informed of the benefits and risks associated with treatment. Patients should be warned about the early signs of hypersensitivity reactions, including hives, urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis. Laboratory Tests Laboratory coagulation parameters may be used as an adjunct to the clinical evaluation of hemostasis in monitoring the effectiveness and treatment schedule of NovoSeven although these parameters have shown no direct correlation to achieving hemostasis. Assays of prothrombin time (PT), activated partial thromboplastin time (aptt), and plasma FVII clotting activity (FVII:C), may give different results with different reagents. Treatment with NovoSeven has been shown to produce the following characteristics: PT: As shown below, in patients with hemophilia A/B with inhibitors, the PT shortened to about a 7-second plateau at a FVII:C level of approximately 5 U/mL. For FVII:C levels > 5 U/mL, there is no further change in PT. FVII:C(U/mL) aptt: While administration of NovoSeven shortens the prolonged aptt in hemophilia A/B patients with inhibitors, normalization has usually not been observed in doses shown to induce clinical improvement. Data indicate that clinical improvement was associated with a shortening of aptt of 15 to 20 seconds. FVIIa:C: FVIIa:C levels were measured two hours after NovoSeven administration of 35 µg/kg and 90 µg/kg following two days of dosing at two hour intervals. Average steady state levels were 11 and 28 U/mL for the two dose levels, respectively. Drug Interactions The risk of a potential interaction between NovoSeven and coagulation factor concentrates has not been adequately evaluated in preclinical or clinical studies. Simultaneous use of activated prothrombin complex concentrates or prothrombin complex concentrates should be avoided. Although the specific drug interaction was not studied in a clinical trial, there have been more than 50 episodes of concomitant use of antifibrinolytic therapies (i.e., tranexamic acid, aminocaproic acid) and NovoSeven. NovoSeven should not be mixed with infusion solutions until clinical data are available to direct this use. Carcinogenesis, Mutagenesis, Impairment of Fertility Two mutagenicity studies have given no indication of carcinogenic potential for NovoSeven. The clastogenic activity of NovoSeven was evaluated in both in vitro studies (i.e., cultured human lymphocytes) and in vivo studies (i.e., mouse micronucleus test). Neither of these studies indicated clastogenic activity of NovoSeven. Other gene mutation studies have not been performed with NovoSeven (e.g., Ames test). No chronic carcinogenicity studies have been performed with NovoSeven. A reproductive study in male and female rats at dose levels up to 3.0 mg/kg/ day had no effect on mating performance, fertility, or litter characteristics. Pregnancy Pregnancy Category C. Treatment of rats and rabbits with NovoSeven in reproduction studies has been associated with mortality at doses up to 6 mg/ kg and 5 mg/kg. At 6 mg/kg in rats, the abortion rate was 0 out of 25 litters; in rabbits at 5 mg/kg, the abortion rate was 2 out of 25 litters. Twenty-three out of 25 female rats given 6 mg/kg of NovoSeven gave birth successfully, however, two of the 23 litters died during the early period of lactation. No evidence of teratogenicity was observed after dosing with NovoSeven. There are no adequate and well-controlled studies in pregnant women. NovoSeven should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery NovoSeven was administered to a FVII deficient patient (25 years of age, 66 kg) during a vaginal delivery (36 µg/kg) and during a tubal ligation (90 µg/kg). No adverse reactions were reported during labor, vaginal delivery, or the tubal ligation. Nursing Mothers It is not known whether NovoSeven is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of NovoSeven was not determined to be different in various age groups, from infants to adolescents (0 to 16 years of age). Clinical trials were conducted with dosing determined according to body weight and not according to age. Geriatric Use Clinical studies in hemophilia did not enroll geriatric patients. ADVERSE REACTIONS The most serious adverse reactions observed in patients receiving NovoSeven are thrombotic events, however the extent of the risk of thrombotic adverse events after treatment with NovoSeven in individuals with hemophilia and inhibitors is considered to be low. (See WARNINGS) The most common adverse reactions observed in clinical studies for all labeled indications of NovoSeven are pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema and rash. The following sections describe the adverse event profile observed during clinical studies for each of the labeled indications. Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in clinical trials of another drug, and may not reflect rates observed in practice. Hemophilia A or B Patients with Inhibitors The table below lists adverse events that were reported in 2% of the 298 patients with hemophilia A or B with inhibitors that were treated with NovoSeven for 1,939 bleeding episodes. The events listed are considered to be at least possibly related or of unknown relationship to NovoSeven administration. # of episodes # of unique Body System reported patients Event (n=1,939 treatments) (n=298 patients) Body as a whole Fever Platelets, Bleeding, and Clotting Hemorrhage NOS 15 8 Fibrinogen plasma decreased 10 5 Skin and Musculoskeletal Hemarthrosis 14 8 Cardiovascular Hypertension 9 6 Events which were reported in 1% of patients and were considered to be at least possibly or of unknown relationship to NovoSeven administration were: allergic reaction, arthrosis, bradycardia, coagulation disorder, DIC, edema, fibrinolysis increased, headache, hypotension, injection site reaction, pain, pneumonia, prothrombin decreased, pruritus, purpura, rash, renal function abnormal, therapeutic response decreased, and vomiting. Serious adverse events that were probably or possibly related, or where the relationship to NovoSeven was not specified, occurred in 14 of the 298 patients (4.7%). Six of the 14 patients died of the following conditions: worsening of chronic renal failure, anesthesia complications during proctoscopy, renal failure complicating a retroperitoneal bleed, ruptured abscess leading to sepsis and DIC, pneumonia, and splenic hematoma and GI bleeding. Thrombosis was reported in two of the 298 patients with hemophilia. Surgery Studies In Study C, six patients experienced serious adverse events: two of these patients had events which were considered probably or possibly related to study medication (acute post-operative hemarthrosis, internal jugular thrombosis). No deaths occurred during the study. In Study D, seven of 24 patients had serious adverse events (4 for bolus injection, 3 for continuous infusion). There were 4 serious adverse events which were considered probably or possibly related to rfviia treatment (2 events of decreased therapeutic response in each treatment arm). No deaths occurred during the study period. Congenital Factor VII Deficiency Data collected from the compassionate/emergency use programs, the published literature, a pharmacokinetics study, and the HTRS registry showed that at least 75 patients with Factor VII deficiency had received NovoSeven - 70 patients for 124 bleeding episodes, surgeries, or prophylaxis regimens; 5 patients in the pharmacokinetics trial. In the compassionate/emergency use programs, 28 adverse events in 13 patients and 10 serious adverse events in 9 patients were reported. Non-serious adverse events in the compassionate/emergency use programs were single events in one patient, except for fever (3 patients), intracranial hemorrhage (3 patients), and pain (2 subjects). The most common serious adverse event in the compassionate/emergency programs was serious bleeding in critically ill patients. All nine patients with serious adverse events died. One adverse event (localized phlebitis) was reported in the literature. No adverse events were reported in the pharmacokinetics reports or for the HTRS registry. No thromboembolic complications were reported for the 75 patients included here. Isolated cases of factor VII deficient patients developing antibodies against factor VII were reported after treatment with NovoSeven. These patients had previously been treated with human plasma and/or plasma-derived factor VII. In some cases the antibodies showed inhibitory effect in vitro. Acquired Hemophilia Data collected from four compassionate use programs, the HTRS registry, and the published literature showed that 139 patients with acquired hemophilia received NovoSeven for 204 bleeding episodes, surgeries and traumatic injuries. Of these 139 patients, 10 experienced 12 serious adverse events that were of possible, probable, or unknown relationship to treatment with NovoSeven. Thrombotic serious adverse events included cerebral infarction, cerebral ischemia, angina pectoris, myocardial infarction, pulmonary embolism and deep vein thrombosis. Additional serious adverse events included shock and subdural hematoma. Data collected for mortality in the compassionate use programs, the HTRS registry and the publications spanning a 10 year period, was overall 32/139 (23%). Deaths due to hemorrhage were 10, cardiovascular failure 4, neoplasia 4, unknown causes 4, respiratory failure 3, thrombotic events 2, sepsis 2, arrhythmia 2 and trauma 1. Postmarketing Experience The following post marketing adverse events are reported voluntarily from a population of uncertain size; hence, it is not possible to estimate their frequency or establish a causal relationship to exposure. The following additional adverse events were reported following the use of NovoSeven in both labeled indications and unlabeled indications that included individuals with situational coagulopathy and without known coagulopathy: high D-dimer levels and consumptive coagulopathy, thromboembolic events including myocardial infarction, myocardial ischemia, cerebral infarction and/ or ischemia, thrombophlebitis, arterial thrombosis, deep vein thrombosis and related pulmonary embolism, and isolated cases of hypersensitivity reactions including anaphylactic reactions. (See WARNINGS and PRECAUTIONS) Evaluation and interpretation of these post marketing events is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. A causal relationship has not been established for the above events. Additional data on the adverse event profile in general and regarding the frequency of thrombotic events in particular is being collected through a postmarket surveillance program. The Hemophilia and Thrombosis Research Society (HTRS) Registry surveillance program is designed to collect data on all uses of NovoSeven to expand the base of experience regarding the use of NovoSeven. All prescribers can obtain information regarding contribution of patient data to this program by calling OVERDOSAGE Dose limiting toxicities of NovoSeven Coagulation Factor VIIa (Recombinant) have not been investigated in clinical trials. The following are examples of accidental overdose. One hemophilia B patient (16 years of age, 68 kg) received a single dose of 352 µg/kg and one hemophilia A patient (2 years of age, 14.6 kg) received doses ranging from 246 µg/kg to 986 µg/kg on five consecutive days. There were no reported complications in either case. A newborn female with congenital factor VII deficiency was administered an overdose of rfviia (single dose: 800 µg/kg). Following additional administration of rfviia and various plasma products, antibodies against rfviia were detected, but no thrombotic complications were reported. A Factor VII deficient male (83 years of age, kg) received two doses of 324 µg/kg (10-20 times the recommended dose) and experienced a thrombotic event (occipital stroke). The recommended dose schedule should not be intentionally increased, even in the case of lack of effect, due to the absence of information on the additional risk that may be incurred. More detailed information is available on request. Manufactured by: Novo Nordisk A/S 2880 Bagsvaerd, Denmark NovoSeven is a registered trademark of Novo Nordisk Health Care AG. For Information contact: Novo Nordisk Inc. 100 College Road West Princeton, NJ 08540, USA NOVO-777 U.S. Patent No. 4,784,950 License Number: Novo Nordisk Inc. Date of issue: November

4 THE ONLY RECOMBINANT BYPASSING AGENT Resolve bleeds quickly. In effectively treated joint bleeds, a median of just 2 doses of NovoSeven was required 1* for many of your patients, that may mean a short time between start and finished. NovoSeven works at the source of a bleed and has been shown to resolve 91% of joint bleeds and 86% of muscle bleeds. 1 Administration is rapid as well, with extremely low-volume treatment (as low as 2.2 ml ) that takes just 2 to 5 minutes to infuse. Additionally, NovoSeven is the only recombinant bypassing agent, and no human serum or human proteins are used in production or formulation. From infants to adults, help patients with inhibitors resolve bleeds quickly and safely with recombinant NovoSeven. For the treatment of bleeding episodes in hemophilia A or B patients with inhibitors to FVIII or FIX; prevention of bleeding in surgical interventions or invasive procedures in hemophilia A or B patients with inhibitors to FVIII or FIX. IMPORTANT SAFETY INFORMATION Most common adverse events: pyrexia, hemorrhage, injection site reaction, arthralgia, headache, hypertension, hypotension, nausea, vomiting, pain, edema, and rash. Patients with disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia, or concomitant treatment with activated or nonactivated prothrombin complex concentrates (apccs/pccs) may have a potential risk of developing thrombotic events in association with NovoSeven treatment. Contraindicated in patients with known hypersensitivity to NovoSeven, its components, or mouse, hamster, or bovine proteins. The risk of potential interaction between NovoSeven and coagulation factor concentrates has not been evaluated. Simultaneous use of apccs/pccs should be avoided. Serious adverse events that may or may not have been related to the use of NovoSeven occurred in 14 of 298 patients with hemophilia A or B with inhibitors in the initial clinical program. *Includes excellent and effective responses; given at dosing intervals of 2 to 3 hours. Includes excellent, effective, and partially effective responses. Dosage based on 13-kg child. Please see brief summary of Prescribing Information at end of advertisement. Reference: 1. Lusher JM, Roberts HR, Davignon G, et al, and the rfviia Study Group. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhage in persons with haemophilia A and B, with and without inhibitors. Haemophilia. 1998;4: NovoSeven is a registered trademark of Novo Nordisk Health Care AG Novo Nordisk Inc January 2007

5 For patients 55 years and older with AML following induction chemotherapy... Which CSF is proven to help prevent early death by fighting fungal infections? LEUKINE Get More From Your CSF Goes beyond neutrophil recovery to reduce the incidence of fatal infections 1,2 Reduces the incidence of early death associated with fungal infections, including deaths due to Aspergillus and Candida* 1-3 Reduces the incidence of life-threatening, severe, and fatal infections 1,2 Shortens time to neutrophil recovery 1,2 Side effect profile similar to placebo 1 *During and within 30 days of study completion. 2 LEUKINE is indicated for use following induction chemotherapy in older adults with AML to shorten time to neutrophil recovery and to reduce the incidence of severe and life-threatening infections and infections resulting in death. Important Information In controlled clinical trials across all indications, no significant differences were observed between LEUKINE- and placebo-treated patients in the type or frequency of adverse events with the exception of an increase in skin-associated events in the LEUKINE group in the pivotal AML trial. There were occasional reports of fluid retention, dyspnea, supraventricular tachycardia, and laboratory abnormalities (increases in creatinine, bilirubin, and liver enzymes). Other adverse events have been reported. Please see adjacent brief summary of full Prescribing Information. References: 1. LEUKINE (sargramostim) [package insert]. Seattle, Wash: Bayer HealthCare Pharmaceuticals Inc.; Rowe JM, Rubin A, Mazza JJ, et al. Incidence of infections in adult patients (> 55 years) with acute myeloid leukemia treated with yeast-derived GM-CSF (sargramostim): results of a double-blind prospective study by the Eastern Cooperative Oncology Group. In: Hiddeman W, et al, eds. Acute Leukemias V: Experimental Approaches and Management of Refractory Diseases. Berlin, Germany: Springer-Verlag; 1996: Rowe JM. Treatment of acute myeloid leukemia with cytokines: effect on duration of neutropenia and response to infections. Clin Infect Dis. 1998;26: Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ All rights reserved Printed in USA April 2007

6 Rx only The following is a brief summary. Before prescribing, please consult full package insert. INDICATIONS AND USAGE Use Following Induction Chemotherapy in Acute Myelogenous Leukemia LEUKINE is indicated for use following induction chemotherapy in older adult patients with acute myelogenous leukemia (AML) to shorten time to neutrophil recovery and to reduce the incidence of severe and lifethreatening infections and infections resulting in death. The safety and efficacy of LEUKINE have not been assessed in patients with AML under 55 years of age. The term acute myelogenous leukemia, also referred to as acute non-lymphocytic leukemia (ANLL), encompasses a heterogeneous group of leukemias arising from various non-lymphoid cell lines which have been defined morphologically by the French-American-British (FAB) system of classification. Use in Mobilization and Following Transplantation of Autologous Peripheral Blood Progentior Cells LEUKINE is indicated for the mobilization of hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. Mobilization allows for the collection of increased numbers of progenitor cells capable of engraftment as compared with collection without mobilization. After myeloablative chemotherapy, the transplantation of an increased number of progenitor cells can lead to more rapid engraftment, which may result in a decreased need for supportive care. Myeloid reconstitution is further accelerated by administration of LEUKINE following peripheral blood progenitor cell transplantation. Use in Myeloid Reconstitution After Autologous Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients with non-hodgkin s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin s disease undergoing autologous bone marrow transplantation (BMT). After autologous BMT in patients with NHL, ALL, or Hodgkin s disease, LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, decreasing median duration of antibiotic administration, reducing the median duration of infectious episodes and shortening the median duration of hospitalization. Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential cell counts performed twice per week. Use in Myeloid Reconstitution After Allogeneic Bone Marrow Transplantation LEUKINE is indicated for acceleration of myeloid recovery in patients undergoing allogeneic BMT from HLAmatched related donors. LEUKINE has been found to be safe and effective in accelerating myeloid engraftment, reducing the incidence of bacteremia and other culture positive infections, and shortening the median duration of hospitalization. Use in Bone Marrow Transplantation Failure or Engraftment Delay LEUKINE is indicated in patients who have undergone allogeneic or autologous bone marrow transplantation (BMT) in whom engraftment is delayed or has failed. LEUKINE has been found to be safe and effective in prolonging survival of patients who are experiencing graft failure or engraftment delay, in the presence or absence of infection, following autologous or allogeneic BMT. Survival benefit may be relatively greater in those patients who demonstrate one or more of the following characteristics: autologous BMT failure or engraftment delay, no previous total body irradiation, malignancy other than leukemia or a multiple organ failure (MOF) score < two (see CLINICAL EXPERIENCE). Hematologic response to LEUKINE can be detected by complete blood count (CBC) with differential performed twice per week. CONTRAINDICATIONS LEUKINE is contraindicated: 1) in patients with excessive leukemic myeloid blasts in the bone marrow or peripheral blood (> 10%); 2) in patients with known hypersensitivity to GM-CSF, yeast-derived products or any component of the product; 3) for concomitant use with chemotherapy and radiotherapy. Due to the potential sensitivity of rapidly dividing hematopoietic progenitor cells, LEUKINE should not be administered simultaneously with cytotoxic chemotherapy or radiotherapy or within 24 hours proceeding or following chemotherapy or radiotherapy. In one controlled study, patients with small cell lung cancer received LEUKINE and concurrent thoracic radiotherapy and chemotherapy or the identical radiotherapy and chemotherapy without LEUKINE. The patients randomized to LEUKINE had significantly higher incidence of adverse events, including higher mortality and a higher incidence of grade 3 and 4 infections and grade 3 and 4 thrombocytopenia.11 WARNINGS Pediatric Use Benzyl alcohol is a constituent of liquid LEUKINE and Bacteriostatic Water for Injection diluent. Benzyl alcohol has been reported to be associated with a fatal Gasping Syndrome in premature infants. Liquid solutions containing benzyl alcohol (including liquid LEUKINE) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see PRECAUTIONSand DOSAGE AND ADMINISTRATION). Fluid Retention Edema, capillary leak syndrome, pleural and/or pericardial effusion have been reported in patients after LEUKINE administration. In 156 patients enrolled in placebo-controlled studies using LEUKINE at a dose of 250 mcg/m2/day by 2-hour IV infusion, the reported incidences of fluid retention (LEUKINE vs. placebo) were as follows: peripheral edema, 11% vs. 7%; pleural effusion, 1% vs. 0%; and pericardial effusion, 4% vs. 1%. Capillary leak syndrome was not observed in this limited number of studies; based on other uncontrolled studies and reports from users of marketed LEUKINE, the incidence is estimated to be less than 1%. In patients with preexisting pleural and pericardial effusions, administration of LEUKINE may aggravate fluid retention; however, fluid retention associated with or worsened by LEUKINE has been reversible after interruption or dose reduction of LEUKINE with or without diuretic therapy. LEUKINE should be used with caution in patients with preexisting fluid retention, pulmonary infiltrates or congestive heart failure. Respiratory Symptoms Sequestration of granulocytes in the pulmonary circulation has been documented following LEUKINE infusion12 and dyspnea has been reported occasionally in patients treated with LEUKINE. Special attention should be given to respiratory symptoms during or immediately following LEUKINE infusion, especially in patients with preexisting lung disease. In patients displaying dyspnea during LEUKINE administration, the rate of infusion should be reduced by half. If respiratory symptoms worsen despite infusion rate reduction, the infusion should be discontinued. Subsequent IV infusions may be administered following the standard dose schedule with careful monitoring. LEUKINE should be administered with caution in patients with hypoxia. Cardiovascular Symptoms Occasional transient supraventricular arrhythmia has been reported in uncontrolled studies during LEUKINE administration, particularly in patients with a previous history of cardiac arrhythmia. However, these arrhythmias have been reversible after discontinuation of LEUKINE. LEUKINE should be used with caution in patients with preexisting cardiac disease. Renal and Hepatic Dysfunction In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes. Dose reduction or interruption of LEUKINE administration has resulted in a decrease to pretreatment values. However, in controlled clinical trials the incidences of renal and hepatic dysfunction were comparable between LEUKINE (250 mcg/m2/day by 2-hour IV infusion) and placebotreated patients. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least every other week during LEUKINE administration. PRECAUTIONS General Parenteral administration of recombinant proteins should be attended by appropriate precautions in case an allergic or untoward reaction occurs. Serious allergic or anaphylactic reactions have been reported. If any serious allergic or anaphylactic reaction occurs, LEUKINE therapy should immediately be discontinued and appropriate therapy initiated. A syndrome characterized by respiratory distress, hypoxia, flushing, hypotension, syncope, and/or tachycardia has been reported following the first administration of LEUKINE in a particular cycle. These signs have resolved with symptomatic treatment and usually do not recur with subsequent doses in the same cycle of treatment. Stimulation of marrow precursors with LEUKINE may result in a rapid rise in white blood cell (WBC) count. If the ANC exceeds 20,000 cells/mm3 or if the platelet count exceeds 500,000/mm3, LEUKINE administration should be interrupted or the dose reduced by half. The decision to reduce the dose or interrupt treatment should be based on the clinical condition of the patient. Excessive blood counts have returned to normal or baseline levels within three to seven days following cessation of LEUKINE therapy. Twice weekly monitoring of CBC with differential (including examination for the presence of blast cells) should be performed to preclude development of excessive counts. Growth Factor Potential LEUKINE is a growth factor that primarily stimulates normal myeloid precursors. However, the possibility that LEUKINE can act as a growth factor for any tumor type, particularly myeloid malignancies, cannot be excluded. Because of the possibility of tumor growth potentiation, precaution should be exercised when using this drug in any malignancy with myeloid characteristics. Should disease progression be detected during LEUKINE treatment, LEUKINE therapy should be discontinued. LEUKINE has been administered to patients with myelodysplastic syndromes (MDS) in uncontrolled studies without evidence of increased relapse rates.13, 14, 15 Controlled studies have not been performed in patients with MDS. Use in Patients Receiving Purged Bone Marrow LEUKINE is effective in accelerating myeloid recovery in patients receiving bone marrow purged by anti-b lymphocyte monoclonal antibodies. Data obtained from uncontrolled studies suggest that if in vitro marrow purging with chemical agents causes a significant decrease in the number of responsive hematopoietic progenitors, the patient may not respond to LEUKINE. When the bone marrow purging process preserves a sufficient number of progenitors (>1.2 x 104/kg), a beneficial effect of LEUKINE on myeloid engraftment has been reported.16 Use in Patients Previously Exposed to Intensive Chemotherapy/Radiotherapy In patients who before autologous BMT, have received extensive radiotherapy to hematopoietic sites for the treatment of primary disease in the abdomen or chest, or have been exposed to multiple myelotoxic agents (alkylating agents, anthracycline antibiotics and antimetabolites), the effect of LEUKINE on myeloid reconstitution may be limited. Use in Patients with Malignancy Undergoing LEUKINE-Mobilized PBPC Collection When using LEUKINE to mobilize PBPC, the limited in vitro data suggest that tumor cells may be released and reinfused into the patient in the leukapheresis product. The effect of reinfusion of tumor cells has not been well studied and the data are inconclusive. Information for Patients LEUKINE should be used under the guidance and supervision of a health care professional. However, when the physician determines that LEUKINE may be used outside of the hospital or office setting, persons who will be administering LEUKINE should be instructed as to the proper dose, and the method of reconstituting and administering LEUKINE (see DOSAGE AND ADMINISTRATION). If home use is prescribed, patients should be instructed in the importance of proper disposal and cautioned against the reuse of needles, syringes, drug product, and diluent. A puncture resistant container should be used by the patient of the disposal of used needles. Patients should be informed of the serious and most common adverse reactions associated with LEUKINE administration (see ADVERSE REACTIONS). Female patients of childbearing potential should be advised of the possible risks to the fetus of LEUKINE (see PRECAUTIONS, Pregnancy Category C). Laboratory Monitoring LEUKINE can induce variable increases in WBC and/or platelet counts. In order to avoid potential complications of excessive leukocytosis (WBC >50,000 cells/mm3; ANC >20,000 cells/mm3), a CBC is recommended twice per week during LEUKINE therapy. Monitoring of renal and hepatic function in patients displaying renal or hepatic dysfunction prior to initiation of treatment is recommended at least biweekly during LEUKINE administration. Body weight and hydration status should be carefully monitored during LEUKINE administration. Drug Interaction Interactions between LEUKINE and other drugs have not been fully evaluated. Drugs which may potentiate the myeloproliferative effects of LEUKINE, such as lithium and corticosteroids, should be used with caution. Carcinogenesis, Mutagenesis, Impairment of Fertility Animal studies have not been conducted with LEUKINE to evaluate the carcinogenic potential or the effect on fertility. Pregnancy (Category C) Animal reproduction studies have not been conducted with LEUKINE. It is not known whether LEUKINE can cause fetal harm when administered to a pregnant woman or can affect reproductive capability. LEUKINE should be given to a pregnant woman only if clearly needed. Nursing Mothers It is not known whether LEUKINE is excreted in human milk. Because many drugs are excreted in human milk, LEUKINE should be administered to a nursing woman only if clearly needed. Pediatric Use Safety and effectiveness in pediatric patients have not been established; however, available safety data indicate that LEUKINE does not exhibit any greater toxicity in pediatric patients than in adults. A total of 124 pediatric subjects between the ages of 4 months and 18 years have been treated with LEUKINE in clinical trials at doses ranging from 60-1,000 mcg/m2/day intravenously and 4-1,500 mcg/m2/day subcutaneously. In 53 pediatric patients enrolled in controlled studies at a dose of 250 mcg/m2/day by 2-hour IV infusion, the type and frequency of adverse events were comparable to those reported for the adult population. Liquid solutions containing benzyl alcohol (including liquid LEUKINE ) or lyophilized LEUKINE reconstituted with Bacteriostatic Water for Injection, USP (0.9% benzyl alcohol) should not be administered to neonates (see WARNINGS). Geriatric Use In the clinical trials, experience in older patients (age >65 years), was limited to the acute myelogenous leukemia (AML) study. Of the 52 patients treated with LEUKINE in this randomized study, 22 patients were age years and 30 patients were age years. The number of placebo patients in each age group were 13 and 33 patients respectively. This was not an adequate database from which determination of differences in efficacy endpoints or safety assessments could be reliably made and this clinical study was not designed to evaluate difference between these two age groups. Analyses of general trends in safety and efficacy were undertaken and demonstrate similar patterns for older (65-70 yrs) vs younger patients (55-64 yrs). Greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Autologous and Allogeneic Bone Marrow Transplantation LEUKINE is generally well tolerated. In three placebo-controlled studies enrolling a total of 156 patients after autologous BMT or peripheral blood progenitor cell transplantation, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported at right: No significant differences were observed between LEUKINE and placebo-treated patients in the type or frequency of laboratory abnormalities, including renal and hepatic parameters. In some patients with preexisting renal or hepatic dysfunction enrolled in uncontrolled clinical trials, administration of LEUKINE has induced elevation of serum creatinine or bilirubin and hepatic enzymes (see WARNINGS). In addition, there was no significant difference in relapse rate and 24 month survival between the LEUKINE and placebo-treated patients. In the placebo-controlled trial of 109 patients after allogeneic BMT, events reported in at least 10% of patients who received IV LEUKINE or placebo were as reported at right: There were no significant differences in the incidence or severity of GVHD, relapse rates and survival between the LEUKINE and placebo-treated patients. Adverse events observed for the patients treated with LEUKINE in the historically-controlled BMT failure study were similar to those reported in the placebo-controlled studies. In addition, headache (26%), pericardial effusion (25%), arthralgia (21%) and myalgia (18%) were also reported in patients treated with LEUKINE in the graft failure study. In uncontrolled Phase I/II studies with LEUKINE in 215 patients, the most frequent adverse events were fever, asthenia, headache, bone pain, chills and myalgia. These systemic events were generally mild or moderate and were usually prevented or reversed by the administration of analgesics and antipyretics such as acetaminophen. In these uncontrolled trials, other infrequent events reported were dyspnea, peripheral edema, and rash. Reports of events occurring with marketed LEUKINE include arrhythmia, fainting, eosinophilia, dizziness, hypotension, injection site reactions, pain (including abdominal, back, chest, and joint pain), tachycardia, thrombosis, and transient liver function abnormalities. In patients with preexisting edema, capillary leak syndrome, pleural and/or pericardial effusion, administration of LEUKINE may aggravate fluid retention (see WARNINGS). Body weight and hydration status should be carefully monitored during LEUKINE administration. Adverse events observed in pediatric patients in controlled studies were comparable to those observed in adult patients. Acute Myelogenous Leukemia Adverse events reported in at least 10% of patients who received LEUKINE or placebo were as reported at right: Nearly all patients reported leukopenia, thrombocytopenia and anemia. The frequency and type of adverse events observed following induction were similar between LEUKINE and placebo groups. The only significant difference in the rates of these adverse events was an increase in skin associated events in the LEUKINE group (p=0.002). No significant differences were observed in laboratory results, renal or hepatic toxicity. No significant differences were observed between the LEUKINE and placebo-treated patients for adverse events following consolidation. There was no significant difference in response rate or relapse rate. In a historically-controlled study of 86 patients with acute myelogenous leukemia (AML), the LEUKINE treated group exhibited an increased incidence of weight gain (p=0.007), low serum proteins and prolonged prothrombin time (p=0.02) when compared to the control group. Two LEUKINE treated patients had progressive increase in circulating monocytes and promonocytes and blasts in the marrow which reversed when LEUKINE was discontinued. The historical control group exhibited an increased incidence of cardiac events (p=0.018), liver function abnormalities (p=0.008), and neurocortical hemorrhagic events (p=0.025).15 Antibody Formation Serum samples collected before and after LEUKINE treatment from 214 patients with a variety of underlying diseases have been examined for immunogenicity based on the presence of antibodies. Neutralizing antibodies were detected in five of 214 patients (2.3%) after receiving LEUKINE by continuous IV infusion (three patients) or subcutaneous injection (SC)(two patients) for 28 to 84 days in multiple courses. All five patients had impaired hematopoiesis before the administration of LEUKINE and consequently the effect of the development of anti-gm-csf antibodies on normal hematopoiesis could not be assessed. Antibody studies of 75 patients with Crohn s disease receiving LEUKINE by subcutaneous injection with normal hematopoiesis and no other immunosuppressive drugs showed one patient (1.3%) with detectable neutralizing antibodies. The clinical relevance of the presence of these antibodies are unknown. Drug-induced neutropenia, neutralization of endogenous GM-CSF activity and diminution of the therapeutic effect of LEUKINE secondary to formation of neutralizing antibody remain a theoretical possibility. Serious allergic and anaphylactoid reactions have been reported with LEUKINE but the rate of occurence of antibodies in such patients has not been assessed. Overdosage The maximum amount of LEUKINE that can be safely administered in single or multiple doses has not been determined. Doses up to 100 mcg/kg/day (4,000 mcg/m2/day or 16 times the recommended dose) were administered to four patients in a Phase I uncontrolled clinical study by continuous IV infusion for 7 to 18 days. Increases in WBC up to 200,000 cells/mm3 were observed. Adverse events reported were dyspnea, malaise, nausea, fever, rash, sinus tachycardia, headache and chills. All these events were reversible after discontinuation of LEUKINE. In case of overdosage, LEUKINE therapy should be discontinued and the patient carefully monitored for WBC increase and respiratory symptoms. Percent of AuBMT Patients Reporting Events LEUKINE Placebo LEUKINE Placebo Events by Body System (n=79) (n=77) Events by Body System (n=79) (n=77) Body, General Metabolic, Nutritional Disorder Fever Edema Mucous membrane disorder Peripheral edema 11 7 Asthenia Respiratory System Malaise Dyspnea Sepsis Lung disorder Digestive System Hemic and Lymphatic System Nausea Blood dyscrasia Diarrhea Cardiovascular System Vomiting Hemorrhage Anorexia Urogenital System GI disorder Urinary tract disorder GI hemorrhage Kidney function abnormal 8 10 Stomatitis Nervous System Liver damage CNS disorder Skin and Appendages Alopecia Rash Percent of Allogeneic BMT Patients Reporting Events LEUKINE Placebo LEUKINE Placebo Events by Body System (n=53) (n=56) Events by Body System (n=53) (n=56) Body, General Metabolic/Nutritional Disorders Fever Bilirubinemia Abdominal pain Hyperglycemia Headache Peripheral edema Chills Increased creatinine Pain Hypomagnesemia 15 9 Asthenia Increased SGPT Chest pain 15 9 Edema Back pain 9 18 Increased alk. phosphatase 8 14 Digestive System Diarrhea Respiratory System Pharyngitis Nausea Epistaxis Vomiting Stomatitis Anorexia Dyspepsia Hematemesis 13 7 Dysphagia 11 7 GI hemorrhage 11 5 Constipation 8 11 Skin and Appendages Rash Alopecia Pruritis Musculo-skeletal System Bone pain Arthralgia 11 4 Special Senses Eye hemorrhage 11 0 Cardiovascular System Hypertension Tachycardia 11 9 Percent of AML Patients Reporting Events LEUKINE Placebo LEUKINE Placebo Events by Body System (n=52) (n=47) Events by Body System (n=52) (n=47) Body, General Fever (no infection) Metabolic/Nutritional Disorder Metabolic Infection Edema Weight loss Respiratory System Weight gain 8 21 Pulmonary Chills Hemic and Lymphatic System Allergy Coagulation Sweats Digestive System 6 13 Cardiovascular System Hemorrhage Nausea Hypertension Liver Cardiac Diarrhea Vomiting Stomatitis Anorexia Abdominal distention 4 13 Skin and Appendages Skin Alopecia Dyspnea Rhinitis Hemic and Lymphatic System Thrombocytopenia Leukopenia Petechia 6 11 Agranulocytosis 6 11 Urogenital System Hematuria 9 21 Nervous System Paresthesia Insomnia 11 9 Anxiety Laboratory Abnormalities* High glucose Low albumin High BUN Low calcium 2 7 High cholesterol 17 8 Hypotension Urogenital System GU Nervous System Neuro-clinical Neuro-motor Neuro-psych Neuro-sensory 6 11 REFERENCES 11. Bunn P, Crowley J, Kelly K, et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the southwest oncology group. JCO 1995; 13(7): Herrmann F, Schulz G, Lindemann A, et al. Yeast-expressed granulocyte-macrophage colonystimulating factor in cancer patients: A phase Ib clinical study. In Behring Institute Research Communications, Colony Stimulating Factors-CSF. International Symposium, Garmisch- Partenkirchen, West Germany. 1988; 83: Estey EH, Dixon D, Kantarjian H, et al. Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with Ara-C and recombinant human granulocyte-macrophage colony-stimulating factor. Blood 1990; 75(9): Vadhan-Raj S, Keating M, LeMaistre A, et al. Effects of recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes. NEJM 1987; 317: Buchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood 1991; 78(5): Blazar BR, Kersey JH, McGlave PB, et al. In vivo administration of recombinant human granulocyte/macrophage colony-stimulating factor in acute lymphoblastic leukemia patients receiving purged autografts. Blood 1989; 73(3): HOW SUPPLIED Liquid LEUKINE is available in vials containing 500 mcg/ml (2.8 x 106 IU/mL) sargramostim. Lyophilized LEUKINE is available in vials containing 250 mcg (1.4 x 106 IU/vial) sargramostim. Each dosage form is supplied as follows: Carton of one multiple use vial; each vial contains 1 ml of preserved 500 mcg/ml liquid LEUKINE (NDC ); Carton of five vials of lyophilized LEUKINE 250 mcg (NDC ); Carton of five multiple use vials; each vial contains 1 ml of preserved 500 mcg/ml liquid LEUKINE (NDC ). Please see the full Prescribing Information for additional information, including dosage and administration guidelines. Manufactured by: Bayer HealthCare Pharmaceuticals Inc. Seattle, WA Revised December , Bayer HealthCare Pharmaceuticals Inc. All rights reserved BH

7 AML: A Study of CEP-701 in Patients with Relapsed Disease A Randomized, Open-label Study of Oral CEP-701 Administered in Sequence with Standard Chemotherapy to Patients with Relapsed Acute Myeloid Leukemia (AML) Expressing FLT-3 Activating Mutations Primary Objective Evaluate whether CEP-701 given in sequence with induction chemotherapy increases the proportion of patients who achieve a second complete remission (CR/CRp) Secondary Objectives Overall survival Event-free survival Remission duration (for patients with CR/CRp) Proportion of patients achieving an outcome of CR/CRp/PR (complete remission plus partial response) Proportion of patients maintaining an outcome of CR/CRp at day 113 Currently Enrolling Patients Eligibility Criteria 18 years old Cytological confirmation of AML Relapsed disease (initial CR of 1-24 months) FLT-3 activating mutation positive after point of initial relapse >3 months life expectancy ECOG performance status 0, 1, 2 For additional information, please visit Contact Information Call: usmedinfo@cephalon.com

8 Envisioning the future of cancer care...and turning it into today s innovative therapies Research at Genentech BioOncology that led to important breakthroughs: Original research on VEGF, one of the key mediators of angiogenesis Original research on the HER2 protein Collaborative efforts on the CD20 antigen Collaborative research on a HER1/EGFR TK inhibitor Key molecules now being investigated in our extensive clinical research program include: HER dimerization inhibitor Recombinant human Apo2L/TRAIL, a pro-apoptotic receptor agonist Systemic Hedgehog antagonist PARP inhibitor HER2 antibody-drug conjugate For more information, visit or call (800) Genentech, Inc. All rights reserved

9 A L P H A INVESTIGATING THE ORAL DAC* INHIBITOR LBH589 Now enrolling patients with advanced hematologic malignancies in the ALPHA trials TRIAL MALIGNANCY PHASE STATUS Cutaneous T-Cell Lymphoma (CTCL) After 2 prior systemic treatment regimens II ENROLLING Chronic Myeloid Leukemia (CML) Chronic Phase After imatinib and 1 other TKI* for Chronic Phase CML II ENROLLING Chronic Myeloid Leukemia (CML) Accelerated Phase/Blast Crisis After imatinib and 1 other TKI* for Accelerated Phase/Blast Crisis CML II ENROLLING Multiple Myeloma (MM) After 2 prior lines of therapy with bortezomib AND either thalidomide or lenalidomide II ENROLLING Contact Novartis Oncology for Enrollment Information Information about these clinical trials, including full inclusion/exclusion criteria, is available at by calling the Novartis Oncology Clinical Trials Hotline at (US residents only), or by visiting LBH589 is an investigational medicine. Efficacy and safety have not been established. There is no guarantee that LBH589 will become commercially available. *DAC = deacetylase; TKI = tyrosine kinase inhibitor. TRIALS Novartis 2007 June 2007 C-ONC A

10 Emerging Trends in the Treatment of Newly Diagnosed Chronic Myeloid Leukemia For complete program information and to participate in this CME/CE activity, log on to: Faculty: Neil P. Shah, MD, PhD Assistant Professor, Division of Hematology and Oncology University of California San Francisco School of Medicine San Francisco, CA Target Audience: This activity is intended for oncologists, hematologists, oncology/hematology nurses, oncology/hematology pharmacists, and other healthcare professionals involved in the treatment of patients with chronic myeloid leukemia. Learning Objectives: Upon completion of this activity, participants should be able to: Discuss the current standard of care for patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML) Interpret the results of clinical trials of patients with newly diagnosed chronic-phase CML and understand the clinical implications of this data Assess new treatment strategies for patients with newly diagnosed CML in the chronic phase Dr Physicians Up to 1.25 AMA PRA category 1 credits 1.25 N Nurses 1.25 Contact Hours 1.25 Ph Pharmacists 1.25 Contact Hours (0.125 CEUs) 1.25 Release date: June 1, 2007 Expiration date: May 31, 2008 Accreditation Physicians: This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of CME, Inc. and Transphorm Health Inc. The American Academy of CME is accredited by the ACCME to provide continuing medical education for physicians. The American Academy of CME designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. Nurses: The American Academy of CME is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center s Commission on Accreditation. The American Academy of CME designates this educational activity for 1.25 contact hours. Pharmacists: The American Academy of CME, Inc. (Academy) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. The Academy has assigned 1.25 contact hours (0.125 CEUs) of continuing pharmacy education credit to this activity. The ACPE universal program number is HO1. There are no fees for participating in or receiving credit for this activity. To successfully complete this activity and receive credit, you must review the CME/CE information, participate in the program, and complete a post-test (achieve a score of 80% or greater) and evaluation form. Upon successful completion an electronic document of credit will be ed to you. Jointly sponsored by the American Academy of CME, Inc. and Transphorm Health Inc. This activity is supported by an educational grant from Novartis Oncology. Oncology CME/CE for Physicians, Nurses, and Pharmacists

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15 Author guide Blood, the Journal of the American Society of Hematology, published in print and online, provides an international forum for the publication of original articles describing basic laboratory, translational, and clinical investigations in hematology. Acceptance of manuscripts is based on the originality and newness of the observation or investigation, the quality of the work described and validity of the evidence presented, the clarity of presentation, and the relevance to our readership. Authors submit a manuscript with the understanding that the manuscript (or its essential substance) has not been published other than as an abstract in any language or format and has not been submitted elsewhere for print or electronic publication consideration. Visit our complete Author Guide online at for information on the following topics: About Blood Journal scope Journal facts Article types Contact information Editorial Peer Review and Publication Peer review process Manuscript preparation Manuscript submission Editorial Policies for Authors Authorship criteria and contribution Copyright assignment Conflict of interest disclosure Funding and sponsorship Duplicate or prior publication Ethical principles for medical research involving human subjects Informed consent for patients Data sharing, distribution of reagents, and compound structure disclosure Deposition into public databases Guidelines for stem cell research Clinical trial registry Policy regarding NIH-sponsored authors Embargo policy Accepted Manuscripts Prepublication in First Edition Requirements for print Proofreading Publication fees Reprint requests Guidelines for Invited Reviews Blood Style Guide Forms and Checklists Checklist for revised online manuscripts Copyright transfer form Change of authorship form Article types Regular Articles. Manuscripts submitted as Regular Articles are expected to be concise, well organized, and clearly written. Acceptance of Regular Articles is based on the originality, definitiveness, and importance of the findings to the field of hematology. Regular Articles will be published under the following scientific categories: Chemokines, Cytokines, and Interleukins; Clinical Trials and Observations; Gene Therapy; Hematopoiesis; Hemostasis, Thrombosis, and Vascular Biology; Immunobiology; Neoplasia; Phagocytes; Red Cells; Stem Cells in Hematology; Transfusion Medicine; and Transplantation. Maximum length for a Regular Article is 5,000 words of text, not counting the abstract, tables, figure legends, and references; abstracts must not exceed 200 words and should be a single paragraph with no subheadings. Submissions are limited to a total of 7 figures and digital images are strongly preferred. Plenary Papers. Definitive manuscripts of exceptional scientific importance within the broad discipline of hematology will be considered for inclusion in the Plenary Papers category. The decision to highlight a article in this section rests entirely with the Editors. Review Articles. Review articles are highly desired and are generally solicited by the Editor-in-Chief. A review article should focus on a topic of broad scientific interest, on recent advances in diagnosis and therapy, or on another timely subject relevant to the field of hematology. Such articles must be concise and critical and include appropriate references to the literature. Reviews should not exceed 5,000 words in length, must include abstracts of 200 words or fewer, and must have no more than 100 references. The use of tables and color figures to summarize critical points is encouraged; the Journal offers a service to professionally draw illustrations, if requested. 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These brief capsules written by experts in the field present analyses of specific articles that are deemed particularly noteworthy. Invited by the Editors. Brief Reports. Short manuscripts definitively documenting either experimental results or informative patient presentations are considered for publication in this category. The authors are asked to document experimental results with a clear question in the introduction and then to present definitive proof in the body of the text. Keep the Materials and Methods section succinct, using primarily cited work, but sufficiently informative to allow reproduction of the data. Combine the Results and Discussion sections and do not repeat the introductory comments. Brief Reports should not exceed 1,200 words of text and 150 words in the abstract and should have no more than 2 figures/ tables and 25 references. How I Treat. Therapeutic recommendations for a specific hematological disorder written by an expert in the field. Controversies in Hematology. Expert analyses of the pros and cons on a hematological subject currently in ferment. Letters to the Editor. Comments on published articles or current topics in hematology are welcome and will be published if appropriate. Letters should stay in the range of words of text with 5-10 references and 1 figure or table (if needed). Please include a brief title succinctly stating the topic of your Letter. Submission fees and page charges do not apply to Letters. Letters to the Editor are always screened, but may also be peer reviewed or subjected to a Response by the authors of the initial article. Data Supplements. The Journal encourages the submission of Data Supplements, including videos and short movies, that enhance the understanding of the science discussed in the manuscript. Data Supplements must be submitted for peer review during the initial submission of the manuscript. The Editors will review the supplemental material along with the manuscript, but acceptance of the manuscript does not guarantee ultimate acceptance of the supplement. For more information, visit the online Author Guide. Contact information Please contact the Blood office if you cannot find an answer to your question(s) in our complete Author Guide at misc/ifora.dtl or in the Blood Bench>Press Manuscript Processing System at submit.bloodjournal.org: Blood, The American Society of Hematology, 1900 M Street, NW, Suite 200, Washington, DC 20036; phone: ; fax: Manuscript Submission: editorial@hematology.org (submission, peer review, First Edition) production@hematology.org (copyediting queries, proofs, printquality image requirements) bloodsubs@hematology.org (Blood subscriptions) BLOOD, 1 AUGUST 2007 VOLUME 110, NUMBER 3 xxii

16 14 16 SEPTEMBER 2007 HILTON LONDON METROPOLE, LONDON, UK SCIENTIFIC COMMITTEE F Caligaris-Cappio Università Vita-Salute San Raffaele, Milano, Italy D Catovsky Institute of Cancer Research, Sutton, UK G Dighiero Institut Pasteur, Paris, France H Döhner Universitätsklinikum Ulm, Ulm, Germany M Hallek Universität zu Köln, Köln, Germany P Hillmen Leeds Teaching Hospitals NHS Trust, Leeds, UK MJ Keating The University of Texas M. D. Anderson Cancer Center, Houston,TX, USA T Kipps University of California, San Diego, CA, USA E Montserrat Clínic Barcelona, Hospital Universitari, Barcelona, Spain KR Rai Long Island Jewish Medical Center, New Hyde Park, NY, USA Workshop Secretariat Darwin Grey Communications Sterling House, Oxford Road Kingston Bagpuize, Oxfordshire OX13 5AP, UK T: +44 (0) F: +44 (0) E: info@iwcll.org Register at

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18 Announcing a NEW Indication FRAGMIN the only LMWH approved for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT* and/or PE ), to reduce the recurrence of VTE in patients with cancer. FRAGMIN is available in the following single-dose, prefilled syringes: 7500 IU /0.3 ml, 10,000 IU/0.4 ml, 12,500 IU/0.5 ml, 15,000 IU/0.6 ml, and 18,000 IU/0.72 ml. Important Safety Information SPINAL/EPIDURAL HEMATOMAS When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions). FRAGMIN is contraindicated in patients with active major bleeding or with known hypersensitivity to the drug, heparin, or pork products, or with thrombocytopenia associated with a positive antiplatelet antibody test. It should be used with extreme caution in patients with a history of heparininduced thrombocytopenia. Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non Q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications. In a clinical trial of patients with cancer and acute symptomatic VTE treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of <100,000/mm 3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm 3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the oral anticoagulant arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm 3. FRAGMIN, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage; bleeding can occur at any site during therapy. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site. FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular-weight heparins. The most commonly reported side effect is hematoma at the injection site. *DVT=deep vein thrombosis. PE=pulmonary embolism. IU=international units. Please see brief summary of prescribing information for FRAGMIN on the following page. FRAGMIN is a registered trademark of Pfizer Health AB and is licensed to Eisai Inc. FR050216B 2007 Eisai Inc. All rights reserved. Printed in USA/May 2007 Marketed by

19 FRAGMIN (dalteparin sodium injection) For Subcutaneous Use Only BRIEF SUMMARY: For full prescribing information, see package insert. SPINAL/EPIDURAL HEMATOMAS When neuraxial anesthesia (epidural/spinal anesthesia) or spinal puncture is employed, patients anticoagulated or scheduled to be anticoagulated with low molecular weight heparins or heparinoids for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis. The risk of these events is increased by the use of indwelling epidural catheters for administration of analgesia or by the concomitant use of drugs affecting hemostasis such as non steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants. The risk also appears to be increased by traumatic or repeated epidural or spinal puncture. Patients should be frequently monitored for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. The physician should consider the potential benefit versus risk before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis (also see WARNINGS, Hemorrhage and PRECAUTIONS, Drug Interactions). INDICATIONS AND USAGE FRAGMIN Injection is indicated for the prophylaxis of ischemic complications in unstable angina and non-q-wave myocardial infarction, when concurrently administered with aspirin therapy (as described in CLINICAL TRIALS, Prophylaxis of Ischemic Complications in Unstable Angina and Non-Q-Wave Myocardial Infarction). FRAGMIN is also indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE): In patients undergoing hip replacement surgery; In patients undergoing abdominal surgery who are at risk for thromboembolic complications; In medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness. FRAGMIN is also indicated for the extended treatment of symptomatic venous thromboembolism (VTE) (proximal DVT and/or PE), to reduce the recurrence of VTE in patients with cancer. CONTRAINDICATIONS FRAGMIN Injection is contraindicated in patients with known hypersensitivity to the drug, active major bleeding, or thrombocytopenia associated with positive in vitro tests for antiplatelet antibody in the presence of FRAGMIN. Patients undergoing regional anesthesia should not receive FRAGMIN for unstable angina or non-q-wave myocardial infarction, and patients with cancer undergoing regional anesthesia should not receive FRAGMIN for extended treatment of symptomatic VTE, due to an increased risk of bleeding associated with the dosage of FRAGMIN recommended for these indications. Patients with known hypersensitivity to heparin or pork products should not be treated with FRAGMIN. WARNINGS FRAGMIN Injection is not intended for intramuscular administration. FRAGMIN cannot be used interchangeably (unit for unit) with unfractionated heparin or other low molecular weight heparins. FRAGMIN should be used with extreme caution in patients with history of heparin-induced thrombocytopenia. Hemorrhage: FRAGMIN, like other anticoagulants, should be used with extreme caution in patients who have an increased risk of hemorrhage, such as those with severe uncontrolled hypertension, bacterial endocarditis, congenital or acquired bleeding disorders, active ulceration and angiodysplastic gastrointestinal disease, hemorrhagic stroke, or shortly after brain, spinal or ophthalmological surgery. Spinal or epidural hematomas can occur with the associated use of low molecular weight heparins or heparinoids and neuraxial (spinal/epidural) anesthesia or spinal puncture, which can result in long-term or permanent paralysis. The risk of these events is higher with the use of indwelling epidural catheters or concomitant use of additional drugs affecting hemostasis such as NSAIDs (see boxed WARNING and ADVERSE REACTIONS, Ongoing Safety Surveillance). As with other anticoagulants, bleeding can occur at any site during therapy with FRAGMIN. An unexpected drop in hematocrit or blood pressure should lead to a search for a bleeding site. Thrombocytopenia: In FRAGMIN clinical trials supporting non-cancer indications, platelet counts of <100,000/mm 3 and <50,000/mm 3 occurred in <1% and <1% of patients, respectively. In the clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated for up to 6 months in the FRAGMIN treatment arm, platelet counts of <100,000/mm 3 occurred in 13.6% of patients, including 6.5% who also had platelet counts less than 50,000/mm 3. In the same clinical trial, thrombocytopenia was reported as an adverse event in 10.9% of patients in the FRAGMIN arm and 8.1% of patients in the OAC arm. FRAGMIN dose was decreased or interrupted in patients whose platelet counts fell below 100,000/mm 3. Thrombocytopenia of any degree should be monitored closely. Heparin-induced thrombocytopenia can occur with the administration of FRAGMIN. The incidence of this complication is unknown at present. In clinical practice, rare cases of thrombocytopenia with thrombosis have also been observed. Miscellaneous: Each multiple-dose vial of FRAGMIN contains benzyl alcohol as a preservative. Benzyl alcohol has been reported to be associated with a fatal Gasping Syndrome in premature infants. Because benzyl alcohol may cross the placenta, FRAGMIN preserved with benzyl alcohol should be used with caution in pregnant women and only if clearly needed. If anticoagulation with FRAGMIN is needed during pregnancy, preservative-free formulations should be used, where possible (see PRECAUTIONS, Pregnancy Category B, Nonteratogenic Effects). PRECAUTIONS General: FRAGMIN Injection should not be mixed with other injections or infusions unless specific compatibility data are available that support such mixing. FRAGMIN should be used with caution in patients with bleeding diathesis, thrombocytopenia or platelet defects; severe liver or kidney insufficiency, hypertensive or diabetic retinopathy, and recent gastrointestinal bleeding. If a thromboembolic event should occur despite dalteparin prophylaxis, FRAGMIN should be discontinued and appropriate therapy initiated. Drug Interactions: FRAGMIN should be used with care in patients receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because of increased risk of bleeding (see PRECAUTIONS, Laboratory Tests). Aspirin, unless contraindicated, is recommended in patients treated for unstable angina or non-q-wave myocardial infarction (see DOSAGE AND ADMINISTRATION). Laboratory Tests: Periodic routine complete blood counts, including platelet count, blood chemistry, and stool occult blood tests are recommended during the course of treatment with FRAGMIN. No special monitoring of blood clotting times (i.e., APTT) is needed. When administered at recommended prophylaxis doses, routine coagulation tests such as Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) are relatively insensitive measures of FRAGMIN activity and, therefore, unsuitable for monitoring the anticoagulant effect of FRAGMIN. Anti-Factor Xa may be used to monitor the anticoagulant effect of FRAGMIN, such as in patients with severe renal impairment or if abnormal coagulation parameters or bleeding should occur during FRAGMIN therapy. Drug/Laboratory Test Interactions: Elevations of Serum Transaminases: In FRAGMIN clinical trials supporting non-cancer indications where hepatic transaminases were measured, asymptomatic increases in transaminase levels (SGOT/AST and SGPT/ALT) greater than three times the upper limit of normal of the laboratory reference range were seen in 4.7% and 4.2%, respectively, of patients during treatment with FRAGMIN. In the FRAGMIN clinical trial of patients with cancer and acute symptomatic venous thromboembolism treated with FRAGMIN for up to 6 months, asymptomatic increases in transaminase levels, AST and ALT, greater than three times the upper limit of normal of the laboratory reference range were reported in 8.9% and 9.5% of patients, respectively. The frequencies of Grades 3 and 4 increases in AST and ALT, as classified by the National Cancer Institute, Common Toxicity Criteria (NCI-CTC) Scoring System, were 3% and 3.8%, respectively. Grades 2, 3 & 4 combined have been reported in 12% and 14% of patients, respectively. Carcinogenicity, Mutagenesis, Impairment of Fertility: Dalteparin sodium has not been tested for its carcinogenic potential in long-term animal studies. It was not mutagenic in the in vitro Ames Test, mouse lymphoma cell forward mutation test and human lymphocyte chromosomal aberration test and in the in vivo mouse micronucleus test. Dalteparin sodium at subcutaneous doses up to 1200 IU/kg (7080 IU/m 2 ) did not affect the fertility or reproductive performance of male and female rats. Pregnancy: Pregnancy Category B. Teratogenic Effects: Reproduction studies with dalteparin sodium at intravenous doses up to 2400 IU/kg (14,160 IU/m 2 ) in pregnant rats and 4800 IU/kg (40,800 IU/m 2 ) in pregnant rabbits did not produce any evidence of impaired fertility or harm to the fetuses. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Nonteratogenic Effects: Cases of Gasping Syndrome have occurred when large amounts of benzyl alcohol have been administered ( mg/kg/day). The 9.5 ml and the 3.8 ml multiple-dose vials of FRAGMIN contain 14 mg/ml of benzyl alcohol. Nursing Mothers: Limited data are available for excretion of dalteparin in human milk. One study in 15 lactating women receiving prophylactic doses of dalteparin detected small amounts of anti-xa activity in breast milk, equivalent to a milk/plasma ratio of < As oral absorption of LMWH is extremely low, the clinical implications, if any, of this small amount of anticoagulant activity on the nursing infant are unknown. Caution should be exercised when FRAGMIN is administered to nursing women. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Geriatric Use: Of the total number of patients in clinical studies of FRAGMIN, 5516 patients were 65 years of age or older and 2237 were 75 or older. No overall differences in effectiveness were observed between these subjects and younger subjects. Some studies suggest that the risk of bleeding increases with age. Postmarketing surveillance and literature reports have not revealed additional differences in the safety of FRAGMIN between elderly and younger patients. Careful attention to dosing intervals and concomitant medications (especially antiplatelet medications) is advised, particularly in geriatric patients with low body weight (<45 kg) and those predisposed to decreased renal function (see also CLINICAL PHARMACOLOGY and General and Drug Interactions subsections of PRECAUTIONS). ADVERSE REACTIONS Hemorrhage: The incidence of hemorrhagic complications during treatment with FRAGMIN Injection has been low. The most commonly reported side effect is hematoma at the injection site. The incidence of bleeding may increase with higher doses; however, in abdominal surgery patients with malignancy, no significant increase in bleeding was observed when comparing FRAGMIN 5000 IU to either FRAGMIN 2500 IU or low dose heparin. In a trial comparing FRAGMIN 5000 IU once daily to FRAGMIN 2500 IU once daily in patients undergoing surgery for malignancy, the incidence of bleeding events was 4.6% and 3.6%, respectively (n.s.). In a trial comparing FRAGMIN 5000 IU once daily to heparin 5000 U twice daily, the incidence of bleeding events was 3.2% and 2.7%, respectively (n.s.) in the malignancy subgroup. Unstable Angina and Non-Q-Wave Myocardial Infarction: Table 8 summarizes major bleeding events that occurred with FRAGMIN, heparin, and placebo in clinical trials of unstable angina and non-q-wave myocardial infarction. Table 8: Major Bleeding Events in Unstable Angina and Non-Q-Wave Myocardial Infarction Indication Dosing Regimen Unstable Angina and FRAGMIN Heparin Placebo Non-Q-Wave MI 120 IU/kg/12 hr. s.c. 1 i.v. and s.c. 2 every 12 hr s.c. n(%) (n(%) (n(%) Major Bleeding Events 3,4 15/1497 (1.0) 7/731 (1.0) 4/760 (0.5) 1Treatment was administered for 5 to 8 days. 2Heparin i.v. infusion for at least 48 hours, APTT 1.5 to 2 times control, then 12,500 U s.c. every 12 hours for 5 to 8 days. 3Aspirin (75 to 165 mg per day) and beta blocker therapies were administered concurrently. 4Bleeding events were considered major if: 1) accompanied by a decrease in hemoglobin of >2 g/dl in connection with clinical symptoms; 2) a transfusion was required; 3) bleeding led to interruption of treatment or death; or 4) intracranial bleeding. Hip Replacement Surgery: Table 9 summarizes: 1) all major bleeding events and, 2) other bleeding events possibly or probably related to treatment with FRAGMIN (preoperative dosing regimen), warfarin sodium, or heparin in two hip replacement surgery clinical trials. Table 9: Bleeding Events Following Hip Replacement Surgery FRAGMIN vs Warfarin Sodium FRAGMIN vs Heparin Indication Dosing Regimen Dosing Regimen Hip FRAGMIN Warfarin FRAGMIN Heparin Replacement 5000 IU once Sodium 1 oral 5000 IU once 5000 U three Surgery daily s.c. (n%) daily s.c. times a day s.c. n(%) n(%) n(%) Major Bleeding Events 3 7/274 (2.6) 1/279 (0.4) 0 3/69 (4.3) Other Bleeding Events 5 Hematuria 8/274 (2.9) 5/279 (1.8) 0 0 Wound Hematoma 6/274 (2.2) Injection Site Hematoma 3/274 (1.1) NA 2/69 (2.9) 7/69 (10.1) 1Warfarin sodium dosage was adjusted to maintain a prothrombin time index of 1.4 to 1.5, corresponding to an International Normalized Ratio (INR) of approximately Includes three treated patients who did not undergo a surgical procedure. 3A bleeding event was considered major if: 1) hemorrhage caused a significant clinical event, 2) it was associated with a hemoglobin decrease of >2 g/dl or transfusion of 2 or more units of blood products, 3) it resulted in reoperation due to bleeding, or 4) it involved retroperitoneal or intracranial hemorrhage. 4Includes two treated patients who did not undergo a surgical procedure. 5Occurred at a rate of at least 2% in the group treated with FRAGMIN 5000 IU once daily. Six of the patients treated with FRAGMIN experienced seven major bleeding events. Two of the events were wound hematoma (one requiring reoperation), three were bleeding from the operative site, one was intraoperative bleeding due to vessel damage, and one was gastrointestinal bleeding. None of the patients experienced retroperitoneal or intracranial hemorrhage nor died of bleeding complications. In the third hip replacement surgery clinical trial, the incidence of major bleeding events was similar in all three treatment groups: 3.6% (18/496) for patients who started FRAGMIN before surgery; 2.5% (12/487) for patients who started FRAGMIN after surgery; and 3.1% (15/489) for patients treated with warfarin sodium. Abdominal Surgery: Table 10 summarizes bleeding events that occurred in clinical trials which studied FRAGMIN 2500 and 5000 IU administered once daily to abdominal surgery patients. Table 10: Bleeding Events Following Abdominal Surgery FRAGMIN vs Heparin FRAGMIN vs Placebo FRAGMIN vs FRAGMIN Indication Dosing Regimen Dosing Regimen Dosing Regimen FRAGMIN Heparin FRAGMIN Heparin FRAGMIN Placebo FRAGMIN FRAGMIN Abdominal 2500 IU 5000 U 5000 IU 5000 U 2500 IU 2500 IU 5000 IU Surgery once daily twice daily once daily twice daily once daily once daily once daily once daily s.c. s.c. s.c. s.c. s.c. s.c. s.c. s.c. n(%) n(%) n(%) n(%) n(%) n(%) n(%) n(%) Postoperative 26/459 36/454 81/508 63/498 14/182 13/182 89/ /1033 Transfusions (5.7) (7.9) (15.9) (12.7) (7.7) (7.1) (8.7) (12.1) Wound 16/467 18/467 12/508 6/498 2/79 2/77 1/1030 4/1039 Hematoma (3.4) (3.9) (2.4) (1.2) (2.5) (2.6) (0.1) (0.4) Reoperation 2/392 3/392 4/508 2/498 1/79 1/78 2/ /1038 Due to Bleeding (0.5) (0.8) (0.8) (0.4) (1.3) (1.3) (0.2) (1.3) Injection Site 1/466 5/464 36/506 47/493 8/172 2/174 36/ /1035 Hematoma (0.2) (1.1) (7.1) (9.5) (4.7) (1.1) (3.5) (5.5) Medical Patients with Severely Restricted Mobility During Acute Illness: Table 11 summarizes major bleeding events that occurred in a clinical trial of medical patients with severely restricted mobility during acute illness. Table 11: Bleeding Events in Medical Patients with Severely Restricted Mobility During Acute Illness Indication Dosing Regimen Medical Patients with Severely FRAGMIN Placebo Restricted Mobility 5000 IU once daily s.c. once daily s.c. n(%) n(%) Major Bleeding Events 1 at Day 14 8/1848 (0.4) 0/1833 (0) Major Bleeding Events 1 at Day 21 9/1848 (0.5) 3/1833 (0.2) 1A bleeding event was considered major if: 1) it was accompanied by a decrease in hemoglobin of >2 g/dl in connection with clinical symptoms; 2) intraocular, spinal/epidural, intracranial, or retroperitoneal bleeding; 3) required transfusion of >2 units of blood products; 4) required significant medical or surgical intervention; or 5) led to death.

20 Three of the major bleeding events that occurred by Day 21 were fatal, all due to gastrointestinal hemorrhage (two patients in the group treated with FRAGMIN and one in the group receiving placebo). Two deaths occurred after Day 21: one patient in the placebo group died from a subarachnoid hemorrhage that started on Day 55, and one patient died on day 71 (two months after receiving the last dose of FRAGMIN) from a subdural hematoma. Patients with Cancer and Acute Symptomatic Venous Thromboembolism Table 12 summarizes the number of patients with bleeding events that occurred in the clinical trial of patients with cancer and acute symptomatic venous thromboembolism. A bleeding event was considered major if it: 1) was accompanied by a decrease in hemoglobin of >2 g/dl in connection with clinical symptoms; 2) occurred at a critical site (intraocular, spinal/epidural, intracranial, retroperitoneal, or pericardial bleeding); 3) required transfusion of >2 units of blood products; or 4) led to death. Minor bleeding was classified as clinically overt bleeding that did not meet criteria for major bleeding. At the end of the six-month study, a total of 46 (13.6%) patients in the FRAGMIN arm and 62 (18.5%) patients in the OAC arm experienced any bleeding event. One bleeding event (hemoptysis in a patient in the FRAGMIN arm at Day 71) was fatal. Table 12: Bleeding Events (Major and Any) (As treated population) 1 Study period FRAGMIN OAC 200 IU/kg (max. 18,000 IU) s.c. FRAGMIN 200 IU/kg (max 18,000 IU) s.c. once daily x 1 month, then 150 IU/kg once daily x 5-7 days and OAC (max 18,000 IU) s.c. once daily x 5 months for 6 months (target INR 2-3) Number Patients with Patients with Number Patients with Patients with at risk Major Bleeding Any Bleeding at Risk Major Bleeding Any Bleeding n(%) n(%) n(%) n(%) Total during study (5.6) 46 (13.6) (3.6) 62 (18.5) Week (1.2) 15 (4.4) (1.2) 12 (3.6) Weeks (2.7) 17 (5.1) (0.3) 12 (3.7) Weeks (3.0) 26 (8.8) (3.0) 40 (15.0) 1Patients with multiple bleeding episodes within any time interval were counted only once in that interval. However, patients with multiple bleeding episodes that occurred at different time intervals were counted once in each interval in which the event occurred. Thrombocytopenia: See WARNINGS: Thrombocytopenia. Other: Allergic Reactions: Allergic reactions (i.e., pruritus, rash, fever, injection site reaction, bulleous eruption) have occurred rarely. A few cases of anaphylactoid reactions have been reported. Local Reactions: Pain at the injection site, the only non-bleeding event determined to be possibly or probably related to treatment with FRAGMIN and reported at a rate of at least 2% in the group treated with FRAGMIN, was reported in 4.5% of patients treated with FRAGMIN 5000 IU once daily vs 11.8% of patients treated with heparin 5000 U twice daily in the abdominal surgery trials. In the hip replacement trials, pain at injection site was reported in 12% of patients treated with FRAGMIN 5000 IU once daily vs 13% of patients treated with heparin 5000 U three times a day. Ongoing Safety Surveillance: Since first international market introduction in 1985, there have been more than 15 reports of epidural or spinal hematoma formation with concurrent use of dalteparin sodium and spinal/epidural anesthesia or spinal puncture. The majority of patients had postoperative indwelling epidural catheters placed for analgesia or received additional drugs affecting hemostasis. In some cases the hematoma resulted in long-term or permanent paralysis (partial or complete). Because these events were reported voluntarily from a population of unknown size, estimates of frequency cannot be made. Post-Marketing Experience: Skin necrosis has occurred rarely. There have been isolated cases of alopecia reported that improved on drug discontinuation. OVERDOSAGE Symptoms/Treatment: An excessive dosage of FRAGMIN Injection may lead to hemorrhagic complications. These may generally be stopped by the slow intravenous injection of protamine sulfate (1% solution), at a dose of 1 mg protamine for every 100 anti-xa IU of FRAGMIN given. A second infusion of 0.5 mg protamine sulfate per 100 anti-xa IU of FRAGMIN may be administered if the APTT measured 2 to 4 hours after the first infusion remains prolonged. Even with these additional doses of protamine, the APTT may remain more prolonged than would usually be found following administration of conventional heparin. In all cases, the anti-factor Xa activity is never completely neutralized (maximum about 60 to 75%). Particular care should be taken to avoid overdosage with protamine sulfate. Administration of protamine sulfate can cause severe hypotensive and anaphylactoid reactions. Because fatal reactions, often resembling anaphylaxis, have been reported with protamine sulfate, it should be given only when resuscitation techniques and treatment of anaphylactic shock are readily available. For additional information, consult the labeling of Protamine Sulfate Injection, USP, products. A single subcutaneous dose of 100,000 IU/kg of FRAGMIN to mice caused a mortality of 8% (1/12) whereas 50,000 IU/kg was a non-lethal dose. The observed sign was hematoma at the site of injection. Rx only U.S. Patent 4,303,651 April 2007 FR Pfizer Inc All rights reserved. Printed in USA/May 2007 REMINDER TO AUTHORS An Important Category in Blood: Brief Reports When you consider submitting to Blood, don t forget Brief Reports. Short papers documenting either experimental result or informatve patient presentations are considered for publication in this category. Begin the Brief Report by documenting experimental results with a clear question in the introduction and then present definitive proof in the body of the text. Keep the Materials and Methods section succinct relying primarily on cited work but sufficiently informative to allow reproduction of the data. In the interest of conciseness, combine the Results and Discussion sections and do not repeat the introductory comments. Brief Reports, including figures, tables, and references, should fit on 2 printed pages. Therefore, when preparing your Brief Report, do not exceed 1200 words in the text,150 words in the abstract, 2 figures/ tables, and 25 references.

21 Thrombopoietin tertiary structure

22 Thrombocytopenia: Fewer Platelets, More Consequences Thrombocytopenia: The result of platelet destruction and/or impaired production 1 Thrombocytopenia is commonly encountered across a number of conditions, including immune (idiopathic) thrombocytopenic purpura (ITP). 1 Patients with thrombocytopenia are at increased risk for both minor and major bleeding events. 2 For instance, in ITP, there is a risk of fatal hemorrhage, due mainly to intracranial hemorrhage. 3 Thrombocytopenia has many causes. These causes include a deficiency in platelet production, excessive platelet destruction, sequestration of platelets by the spleen, or a combination of these. 4 Thrombopoietin: Essential in stimulating platelet production 5 Thrombopoietin (TPO) is the primary growth factor regulating platelet production and the proliferation of megakaryocytes. 5 TPO is produced primarily in the liver and binds to the TPO receptor on megakaryocytes. 6 New approaches for treating thrombocytopenia are being investigated. Increased understanding of hematopoiesis can lead to novel treatment approaches As a pioneer in hematopoietic research, Amgen has made significant contributions in the field of hematology/oncology and is now investigating the TPO pathway and its potential role in the treatment of thrombocytopenia. References: 1. Sekhon SS, Roy V. Thrombocytopenia in adults: a practical approach to evaluation and management. South Med J. 2006;99: Elting LS, Rubenstein EB, Martin CG, et al. Incidence, cost, and outcomes of bleeding and chemotherapy dose modification among solid tumor patients with chemotherapy-induced thrombocytopenia. J Clin Oncol. 2001;19: George JN, Woolf SH, Raskob GE, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for The American Society of Hematology. Blood. 1996;88: Puyo CA. Thrombocytopenia. Int Anesthesiol Clin. 2001;39: Kaushansky K. Thrombopoietin. N Engl J Med. 1998;339: Wolber E-M, Jelkmann W. Thrombopoietin: the novel hepatic hormone. News Physiol Sci. 2002;17: Amgen Inc. All rights reserved. P /07

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27 Blood Style Guide Online For the convenience of authors and readers, Blood is building an online style guide. It may be found online linked to the Blood Author Guide (or at Meanwhile, for answers to questions about aspects of Blood style not currently covered by the online style guide, please refer to a printed copy of the American Medical Association Manual of Style (9th edition) or contact the Blood Production Office at production@hematology.org. Blood in print ISSN Blood Online ISSN

28 CURRENTLY ENROLLING A Trial in Newly Diagnosed Multiple Myeloma An open-label, randomized, multicenter, phase 3b trial (Protocol C05009) comparing the efficacy and safety of 3 regimens containing VELCADE (bortezomib) for Injection in previously untreated multiple myeloma patients not eligible for high-dose chemotherapy and autologous stem cell transplantation (n=approximately 500) Study Schema R A N DO M IZ E Induction Therapy* Eight 21-day cycles VD VELCADE Dexamethasone VTD VELCADE Thalidomide Dexamethasone VMP VELCADE Melphalan Prednisone Maintenance Therapy VELCADE Five 35-day cycles Evaluation based on International Uniform Response Criteria for multiple myeloma. 1 *In an interim analysis after the first 70 patients in each arm have completed 4 cycles of therapy or discontinued treatment prior to 4 cycles of therapy, the most inferior arm (based on VGPR and toxicity) will be discontinued. Study Endpoints Primary endpoint: PFS Secondary endpoints: ORR, CR, VGPR, duration of response, OS, safety and tolerability, time to alternative therapy, quality of life Key Eligibility Criteria Measurable disease, symptomatic multiple myeloma or asymptomatic multiple myeloma with related organ or tissue damage No previous or current systemic therapy for multiple myeloma Not a candidate for high-dose chemotherapy and stem cell transplantation Karnofsky Performance Status score 50% Not a complete list of eligibility criteria. Before making a decision regarding trial enrollment, please consult the complete list in the trial summary. Reference: 1. Durie BG, Harousseau JL, Miguel JS, et al, for the International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006;20: For more information on VELCADE clinical trials, call VELCADE, and MILLENNIUM are registered trademarks of Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc., Cambridge, MA Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V0822 7/07

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30 PAID ADVERTISEMENT The first cycle of chemotherapy presents the greatest risk of neutropenia Chemotherapy-induced neutropenia Myelosuppression, including chemotherapy-induced neutropenia (CIN), is widely recognized as the primary dose-limiting toxicity in patients with cancer. 1-3 CIN can lead to febrile neutropenia and other neutropenic complications, such as fever and infection, which are frequently associated with increased morbidity, early mortality, increased medical costs, and the disruption of potentially curative treatment due to chemotherapy dose delays or reductions. 2,4-6 A cross-sectional retrospective analysis estimated that neutropenia hospitalization affects over 60,000 patients with cancer each year in the United States, with an average cost of $13,372 per hospitalization and an associated inpatient mortality rate of 6.8%; approximately 1 in 14 hospitalized patients dies. 7 Several studies have investigated the relationship between the risk of febrile neutropenia and the timing of neutropenic events (by cycle, across cycles, and in various tumor types). 1-3 In a retrospective analysis of 577 patients with intermediate-grade non-hodgkin s lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy, 58% of first-time febrile neutropenic events occurred during the first cycle, which was more than for the next 5 cycles combined. 1 Similar results on the high incidence of first-cycle febrile neutropenia have been reported in a large prospective registry, the Awareness of Neutropenia in Chemotherapy Registry. Awareness of Neutropenia in Chemotherapy Registry The Registry has collected data from more than 3,500 chemotherapy patients from 137 randomly selected community oncology practices across the United States. 8,9 Patients are representative of those typically treated in a community setting and are receiving several different chemotherapy regimens for a variety of malignancies, including breast, lymphoma, ovarian, and lung. Primary and secondary outcome measures include: 8,9 Neutropenia (absolute neutrophil count [ANC] < 1.0 x 10 9 /L) Severe neutropenia (ANC < 0.5 x 10 9 /L) Febrile neutropenia (fever or infection and ANC < 1.0 x 10 9 /L) Severe febrile neutropenia (fever or infection and ANC < 0.5 x 10 9 /L) Cycle 4{ Cycle 3 Cycle 2 Cycle 1{ {{ More than 50% of initial febrile neutropenia occurs in the first cycle across many tumor types 8 Incidence of initial febrile neutropenia (by select tumor type) 8 53% Absolute incidence (%) % 50% 53% 49% Overall Breast Lymphoma Ovarian Lung (N = 1,679) (n = 820) (n = 235) (n = 171) (n = 453) Adapted from Crawford, et al, for the Awareness of Neutropenia in Chemotherapy Study Group, ASH Poster The majority of each type of neutropenic outcome occurred during the first cycle. In only one instance, severe neutropenia in patients with ovarian cancer, did the proportion of events during the first cycle fall to less than half (44%). 8 The latest ASCO and NCCN neutropenia practice guidelines recommend proactively assessing the risk of febrile neutropenia in patients before they undergo chemotherapy treatment. Assessment should include the myelotoxicity of the chemotherapy regimen ( 20% risk of febrile neutropenia) and additional risk factors including age, medical history, and other disease characteristics. 10,11 Consider the risk. References: 1. Lyman GH, et al. Leuk Lymphoma. 2003;44: Lyman GH, et al. Cancer. 2003;98: Crawford J, et al, for the ANC Study Group. Blood. 2004;104(suppl):607a. Abstract Kuderer NM, et al. Proc Am Soc Clin Oncol. 2002;21:250a. Abstract Kuderer NM, et al. Cancer. 2006;106: Lyman GH, J Natl Compr Cancer Netw. 2005;3: Caggiano V, et al. Cancer. 2005;103: Crawford J, et al, for the ANC Study Group. Poster presented at: 46th Annual Meeting of the American Society of Hematology; December 4-7, 2004; San Diego, Calif. Poster Lyman GH, et al, for the ANC Study Group. Poster presented at: 41st Annual Meeting of the American Society of Clinical Oncology; May 13-17, 2005; Orlando, Fla. Poster Smith TJ, et al. J Clin Oncol. 2006;24: National Comprehensive Cancer Network. Clin Pract Guide Oncol [serial online]. Version Available at: PDF/myeloid_growth.pdf. Accessed December 19, 2006.

31 MULTIPLE MYELOMA INVESTIGATING THE ORAL DAC* INHIBITOR LBH589 Now enrolling adult patients with refractory Multiple Myeloma in a phase II, multicenter study of oral LBH589 For patients who: Have received at least 2 prior lines of therapy Have received bortezomib AND either thalidomide or lenalidomide Were refractory to the most recent line of therapy Oral LBH mg once daily Mon, Wed, Fri Primary endpoint: Response rate (CR/PR)* Information about this clinical trial, including full inclusion/exclusion criteria, is available at by calling the Novartis Oncology Clinical Trials Hotline at (US residents only), or by visiting LBH589 is an investigational medicine. Efficacy and safety have not been established. There is no guarantee that LBH589 will become commercially available. *DAC = deacetylase; CR = complete response; PR = partial response Novartis May 2007 C-ONC

32 Treatment issues in multiple myeloma Optimal treatment for patients with multiple myeloma should minimize peripheral neuropathy Peripheral neuropathy (PN) is characterized by damage to the motor and sensory fibers of the peripheral nerves. 1,2 This results in effects on nerve conduction that translate into painful bouts of tingling and burning sensations in the extremities. 3 In patients with multiple myeloma, peripheral neuropathy can result from the disease itself or from treatment. 4,5 Whereas lower grade toxicity can impact quality of life, severe forms of neuropathy are disabling. 6 Peripheral neuropathy, regardless of treatment, is a burden to patients Approximately 2.4% of the total U.S. population suffers from some form of peripheral neuropathy. 7 Patients with neuropathy (motor or sensory) can present with any combination of severe, sharp, shooting, stabbing, burning, hot, numbing, or tingling pain. 2,3 Patients with multiple myeloma are particularly susceptible because of lytic lesions, fractures and amyloid deposits dominant features inherent to the disease itself. 5,8 Early studies using nerve conduction tests demonstrated that impaired nerve function occurred in 39% of patients with multiple myeloma; these findings suggest that multiple myeloma may have a greater relationship with neuropathy than clinically shown. 9 More recently, it has been suggested that peripheral nerves can act as a sanctuary where malignant plasma cells continue to proliferate. 8 All grades of neurotoxicity can impact QoL 6,10 Although comparatively mild in its effects, neuropathic pain associated with Grade 1-2 level of toxicity is marked by a pathologic course that slowly damages peripheral nerve fibers. Patients with this degree of damage report diminished quality of life, at times measured by sleep deprivation, anxiety, and depression. 10 The consequences for patients with Grade 3-4 toxicity are even more devastating: from severe complications to neurologic damage. 2,6 Increased toxicity translates into an increase in burden 6 Grade 4 Motor: Life-threatening; disabling (eg, paralysis) Sensory: Disabling Grade 3 Motor: Weakness affecting daily living Sensory: Sensory alteration or paresthesia affecting daily living Grade 2 Motor: Symptomatic weakness, interfering with function but not daily living Sensory: Sensory alteration or paresthesia, including tingling, interfering with function but not daily living Grade 1 Motor: Asymptomatic Sensory: Loss of deep tendon reflexes or paresthesia, including tingling, but not interfering with function Current approaches to PN only curtail its toxicity 1,11 Damage resulting from treatment-related peripheral neuropathy can still be irreversible, despite timely dose reduction or discontinuation. 12 And the risk for patients with preexisting neuropathy runs high: administering neuropathy-inducing agents in these patients only increases the likelihood that such treatments will result in neuropathy. 2 Reversing to baseline neuropathy leaves a trail of neuronal damage 11 Some agents report neuropathy in as many as onethird of patients. 13,14 Clinical findings with these drugs show a reverse to baseline neuropathy levels once treatment is discontinued. 13 But even if agents are discontinued, and neuropathy subjectively returns to baseline, the neurons remain damaged. 11,15

33 So despite the ability of some agents to reverse neuropathy, patients may continue to experience pain and have signs of neuronal damage even after therapy is discontinued.4 Damage to peripheral nerve fibers (highlighted) can occur despite dose adjustment.4,11,13 Peripheral nerve fiber Dose adjustment including reduction or interruption may hamper the intended therapeutic benefits of the drug and limit the duration of treatment. Schwann cell nucleus Myelin sheath Neuron Dose adjustment for patients with peripheral neuropathy can create an additional concern for the physician. A dose reduction in patients even with lower grade neurotoxicity may limit the intended therapeutic impact of a drug. Rather than focusing on achieving measurable results, the clinician s efforts are diverted to increased patient management. And in some patients, treatment for neuropathic pain can lead to complications Current pharmacologic intervention for peripheral neuropathy includes a range of options, but each has its limitation: NSAIDs. This option is promising only for patients without hepatic or renal impairment a common concern in patients with multiple myeloma.2,16 Treatment should aim to achieve complete remission without compromising toxicity11,18 The burden of peripheral neuropathy is high for both patients and clinicians.6,10 As a dose-limiting toxicity with irreversibility factors,12 peripheral neuropathy should be avoided at all costs. Accordingly, treatment of multiple myeloma requires an option aimed at reducing tumor burden as well as the burden of neuropathy.11,18 Tricyclic antidepressants and opioids. These agents may be effective in treating pain, but they require additional management and monitoring.1,17 Gabapentin. This and other anticonvulsants may not be suitable for elderly patients.1 Optimal management of multiple myeloma and peripheral neuropathy should prevent the progression of both.11,18 References: 1. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Arch Neurol. 2003:60: Marrs J, Newton S. Updating your peripheral neuropathy know-how. Clin J Oncol Nurs. 2003;7: Thompson PD, Thomas PK. Differential diagnosis and epidemiology. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia. Elsevier Saunders; 2005: Ghobrial IM, Rajkumar SV. Management of thalidomide toxicity. J Support Oncol. 2003;1: Kyle RA, Dyck PJ. Neuropathy associated with the monoclonal gammopathies. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia. Elsevier Saunders; 2005: National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE). Version 3.0. Available at: Accessed February 12, Hughes RAC. Peripheral neuropathy. BMJ. 2002;324: Denier C, Lozeron P, Adams D, et al. Multifocal neuropathy due to plasma cell infiltration of peripheral nerves in multiple myeloma. Neurology. 2006;66: Walsh JC. The neuropathy of multiple myeloma. An electrophysiological and histological study. J Neurol Sci. 1971;25: McCarberg B, Billington R. Consequences of neuropathic pain: quality-of-life issues and associated costs. Am J Manag Care. 2006;12:S263-S Stillman M, Cata JP. Management of chemotherapy-induced peripheral neuropathy. Curr Pain Headache Rep. 2006;10: Chaudhry V, Chaudhry M, Crawford TO, Simmons-O Brien E, Griffin JW. Toxic neuropathy in patients with pre-existing neuropathy. Neurology. 2003;60: Velcade (bortezomib) for Injection Prescribing Information. 14. Thalomid (thalidomide) Prescribing Information. 15. Cata JP, Weng H-R, Burton AW, Villareal H, Giralt S, Dougherty PM. Quantitative sensory findings in patients with bortezomib-induced pain. J Pain. 2007;8: Motrin (ibuprofen) Prescribing Information. 17. Arbaiza D, Vidal O. Tramadol in the treatment of neuropathic cancer pain. Clin Drug Invest. 2007;27: National Comprehensive Cancer Network. Multiple myeloma. In: Clinical Practice Guidelines in Oncology. Version Provided as an educational service by Celgene Corporation Celgene Corporation 05/07 CELG07053

34 ASH STATE-OF-THE-ART SYMPOS I U M Recent Advances in the Treatment of HEMATOLOGIC MALIGNANCIES and CANCER-ASSOCIATED THROMBOSIS September 28-29, 2007 Philadelphia, PA SAVE THE DATE The 2007 ASH State-of-the-Art Symposium (SAS) will feature leading hematology experts exploring the latest research and treatment options for hematologic malignancies and cancer-associated thrombosis. Sessions will include in-depth discussions about developments in stem cell transplantation, best practices for pay-for-performance, and new treatment options for lymphoma, leukemia, multiple myeloma, and more. ADVANCE REGISTRATION RATES (available through September 25) ASH Associate Member $135 Non-Member Resident or Fellow $150 Allied Health Professional $175 ASH or PSOH Member $275 Non-Member $375 For more information or to register, visit Questions? Contact the ASH Education and Training Department at or cme@hematology.org. This meeting is presented by the American Society of Hematology (ASH ) in conjunction with the Pennsylvania Society of Oncology and Hematology (PSOH). American Society of Hematology 1900 M Street, NW Suite 200 Washington, DC 20036

35 Renewal instructions, claims, and other correspondence affecting the 2007 subscription year, including back copy and single issue orders, should be sent to: Blood Journal Subscription Office 1900 M Street, NW, Suite 200 Washington, DC USA 2007 SUBSCRIPTION RATES 2007 Subscription Rates for Blood, Volumes 109 & 110, are as follows: Individual Domestic $630 International $875 Institution Domestic (print/online) $1,145 Domestic (online only) $1,085 International (print/online) $1,375 International (online only) $1,085 Single Issues: Domestic $48, International $58 With your print subscription to Blood, you gain free online access to current issues and the entire online archive! Please visit our web site at For questions regarding your subscription or to place a subscription order, please call or send an message: (US & Canada) (Outside US & Canada) bloodsubs@hematology.org Blood in print ISSN Prescribing information for NovoSeven Eptacog alfa (activated) NovoSeven 1.2 mg (60 KIU) - powder and solvent for solution for injection NovoSeven 2.4 mg (120 KIU) - powder and solvent for solution for injection NovoSeven 4.8 mg (240 KIU) - powder and solvent for solution for injection Composition: Eptacog alfa (activated) 1.2 mg/vial (corresponds to 60 KIU/vial), eptacog alfa (activated) 2.4 mg/vial (corresponds to 120 KIU/vial), eptacog alfa (activated) 4.8 mg/vial (corresponds to 240 KIU/vial). 1 KIU equals 1000 IU (International Units). Eptacog alfa (activated) is recombinant coagulation factor VIIa with a molecular mass of approximately 50,000 Dalton produced by genetic engineering from baby hamster kidney cells (BHK Cells). After reconstitution 1 ml solution contains 0.6 mg eptacog alfa (activated). Pharmaceutical form: Powder for solution for injection with accompanying solvent for reconstitution (Water for Injections). Available in packs containing 1.2, 2.4 or 4.8 mg rfviia. Indications: Treatment of bleeding episodes and prevention of bleeding during surgery or invasive procedures in patients with: - congenital haemophilia with inhibitors to coagulation factors VIII or IX > 5 BU or who are expected to have a high anamnestic response to FVIII or FIX. -acquired haemophilia - congenital FVII deficiency - Glanzmann's thrombasthenia with antibodies to GP IIb-IIIa and/or HLA, and with past or present refractoriness to platelet transfusion. Posology: DOSAGE: The rfviia is dissolved in the accompanying solvent before use. After reconstitution the solution contains 0.6 mg rfviia/ml. Administer by intravenous bolus injection over 2-5 minutes; must not be mixed with infusion solutions or given in a drip. Haemophilia A or B with inhibitors or expected to have high anamnestic response. Initial dose of 90 µg/kg body weight. Duration of, and interval between, repeat injections dependent on severity of haemorrhage or procedure/surgery performed. For mild to moderate bleeding episodes (including home therapy): Two dosing regimens can be recommended: i) Two to three injections of 90 µg/kg body weight administered initially at 3-hour intervals. If further treatment is required, one additional dose of 90 µg/kg can be administered. ii) One single injection of 270 µg/kg body weight. Duration of home treatment should not exceed 24 hours. For serious bleeding episodes, initial dose 90 µg/kg body weight; dose every two hours until clinical improvement. If continued therapy indicated, dosage interval can be increased successively. Major bleeding episode may be treated for 2-3 weeks or longer if clinically warranted. For invasive procedures/surgery administer initial dose of 90 µg/kg body weight immediately before the procedure. Repeat dose at 2-3 hour intervals for first hours. In major surgery continue dosing at 2-4 hour intervals for 6-7 days. Dosage interval may then be increased to 6-8 hours for further 2 weeks. Treatment may be up to 2-3 weeks until healing has occurred. Acquired haemophilia Administer as early as possible after the start of the bleeding episode. Initial dose of 90 µg/kg body weight. Further injections may be given if required. Initial dose interval should be 2-3 hours. Once haemostasis achieved, the dose interval can be increased successively. Factor VII deficiency For bleeding episodes and for invasive procedures/surgery administer µg/kg body weight every 4-6 hours until haemostasis achieved. Adapt dose and frequency to individual. Glanzmann's thrombasthenia For bleeding episodes and for invasive procedures/surgery administer 90 µg (range µg)/kg body weight every 2 hours ( hours). At least three doses should be administered to secure effective haemostasis. For patients who are not refractory platelets are first line treatment. Contra-indications: Known hypersensitivity to active substance, excipients, or to mouse, hamster or bovine protein. Precautions: For severe bleeds NovoSeven should only be administered in hospitals specialised in the treatment of patients with coagulation factor VIII or IX inhibitors or in close collaboration with a physician specialised in treatment of haemophilia. No clinical experience with administration of single dose of 270 µg/kg body weight in elderly patients. Home therapy should not exceed 24 hours. Possibility of thrombogenesis or induction of DIC in conditions in which tissue factor could be expected in circulating blood, e.g. advanced atherosclerotic disease, crush injury, septicaemia, or DIC. Since NovoSeven may contain trace amounts of mouse, bovine and hamster proteins there is a remote possibility of the development of hypersensitivity. Monitor FVII deficient patients for prothrombin time and FVII coagulant activity; suspect antibody formation if FVIIa activity fails to reach expected level or bleeding not controlled with recommended doses. Avoid simultaneous use of prothrombin complex concentrates, activated or not. Use in pregnancy: Only administer to pregnant women if clearly needed. Not known if excreted in human milk; exercise caution when administering NovoSeven to nursing women. Side effects: Adverse reactions (serious and non-serious) reported during post-marketing period: Rare (>1/10,000, <1/1,000): Lack of efficacy. Very rare (<1/10,000): Coagulopathic disorders such as increased D-dimers and consumptive coagulopathy; myocardial infarction; nausea; fever; pain, especially at injection site; increase of ALT, ALP, LDH and prothrombin levels; cerebrovascular disorders including cerebral infarction and cerebral ischaemia; skin rashes; venous thrombotic events; haemorrhage. Serious adverse reactions include: Arterial thrombotic events (such as myocardial infarction or ischaemia, cerebrovascular disorders and bowel infarction); venous thrombotic events (such asthrombophlebitis, deep vein thrombosis and pulmonary embolism); thrombotic events in the liver. In the vast majority of cases patients were predisposed to such events. Isolated cases of hypersensitivity including anaphylactic reactions reported post-marketing. Patients with a history of allergic reaction should be carefully monitored. No reports of antibodies against FVII in haemophilia A or B patients. Isolated cases of FVII-deficient patients developing antibodies against FVII reported after treatment with NovoSeven. These patients previously treated with human plasma and/or plasma derived FVII. Monitor FVII deficient patients for FVII antibodies. One case angioneurotic oedema reported in patient with Glanzmann's thrombasthenia after administration of NovoSeven. The Summary of Product Characteristics should be consulted for a full list of side effects. Marketing Authorisation numbers: NovoSeven 60 KIU EU/1/96/006/001, NovoSeven 120 KIU EU/1/96/006/002, NovoSeven 240 KIU EU/1/96/006/003. Further information: Full prescribing information can be obtained from: Novo Nordisk A/S, Novo Allé, DK-2880 Bagsværd, Denmark. Date of last update of PI: March 2007.

36 49 th TM ASH Annual Meeting and Exposition December 8-11, 2007 Georgi ia World Congress Center Atlanta, Georgia EXPLORE EDUCATE DISCOVER NETWORK MARK YOUR CALENDAR The ASH annual meeting is the premier conference specifically designed for hematology professionals. ASH provides a superb educational program, cutting-edge scientific sessions, and numerous networking opportunities. Meeting Dates: December 8-11 Exposition Dates: December 8-10 Friday Satellite Symposia: December 7 Registration and Housing Early-Bird Registration and Housing ASH members only online only July 17 August 6 Advance Registration and Housing August 7 November 7 Abstract Submission Deadline Only electronic submissions will be permitted. August 21 Exhibits Application to Exhibit Deadline For companies with priority points only June 29 Exhibit Hall Placement Open to All Companies July 9 20 Experience ASH QUESTIO NS? Contact the American Society of Hematology Phone: meetings@hematology.org

37 The power of one Single Dose Management with NovoSeven Efficacy. 1 Convenience. 2,3 Safety. 1,2 In one NovoSeven is now indicated to stop bleeding in just one single 270 µg/kg dose. You can reduce multiple intravenous infusions thereby helping to preserve the status of the vein. Now patients with haemophilia and inhibitors can experience less disruption to their daily lives with efficacy, 1 convenience 2,3 and safety 1,2 in one. For further information visit or contact your local Novo Nordisk representative. 1. Kavakli K et al. Thromb Haemost 2006; 95: Santagostino E et al. J Thromb Haemost 2006; 4: Kenet G et al. J Thromb Haemost 2003; 1: Single Dose NovoSeven 270 µg/kg approved in EU. Pending approval in other countries. See overleaf for NovoSeven prescribing information. Date of preparation: June

38 Searching Blood and Beyond: THE NEW HIGHWIRE PORTAL HAS MORE TO OFFER THAN MEDLINE Researching the world s top scientific journals just got easier. HighWire Press created a single portal, which offers: More Content Access the full text of the 939 journals published online through HighWire Press as well as the abstracts in Medline s 4,959 journals. Content for the top journals can be searched on the day of publication (one day earlier than in Medline). Better Searching Search and browse full text by topic and keyword; gain instant access to a particular article just by typing year, volume, and page number. Easier Access Use ONE username/password to access all of your HighWire subscriptions. Access 1,333,015 full-text articles that are FREE. See instantly what you or your institution can access free of charge and what is available via pay-per-view. Broad-based Alerting Sign up for free alerts to new content matching your keywords, authors, citations, and topics in any of the HighWire-affiliated journals and in Medline. Next time you use Blood Online ( click on the HighWire Press logo next to the ASH logo and experience how the HighWire Press can make your searches easy. Or go directly to highwire.stanford.edu.

39 Announcements THE 22nd ANNUAL AL COURSE AND MEETING OF THE CLINICAL CYTOMETR OMETRY Y SOCIETY Hyatt Regency Capitol Hill Washington, DC Course dates: October 5-7, 2007 Meeting Dates: October 7-9, 2007 The Clinical Cytometry Society is pleased to announce its annual course and meeting to be held at the Hyatt Regency in Washington, DC, on October 5-9, The course, which precedes the meeting, provides in-depth training for practical analysis of clinical specimens by flow cytometry. The meeting provides supplemental training, as well as updates on topics of interest to clinical cytometrists and hematopathologists. Sessions at this meeting will include regulatory affairs, rare event analysis in the clinical laboratory, assessment of targeted therapy, hempath updates, and new developments in dendritic cells, as well as pratical case study interpretations, and luncheon workshops. The meeting and course may be registered for separately. For further information, please visit IMPERIAL COLLEGE LONDON 39th Annual Course-Advances in Haematology September 24-28, 2007 This course is designed to update both specialists and trainees on the scientific basis and clinical practice of hematology, including case presentations and slide seminars. This year, due to an extensive building programme at the Hammersmith, the course will be held at Imperial College in South Kensington. In addition, for the first time we are offering the opportunity of attendance for one or more days. The course organizers are Dr D. Milojkovic, Dr M. Laffan, and Professor J. Apperley. For further information, write to haematology.shortcourses@imperial.ac.uk. For further details including booking form, visit about/divisions/is/haemo/courses_haemo/. THE AMERICAN SOCIETY OF HEMATOLOGY 49th Annual Meeting, Call for Abstracts Electronic submission deadline: August 21, 2007 Abstracts for the 49th Annual Meeting and Exposition of the American Society of Hematology (ASH) are now being accepted. Abstracts must be submitted electronically through the ASH website, To be considered for presentation, abstracts must be submitted by Tuesday, August 21, using the electronic submission program found on the ASH website; paper abstract submissions, including those sent by fax or , will not be accepted. A $60 processing fee will be charged for each abstract submitted. All abstracts submitted by August 21 will be considered for presentation at the 2007 ASH Annual Meeting, being held December 8-11, 2007, in Atlanta, Georgia. Please visit the ASH website at for the most up-to-date information on the 49th ASH Annual Meeting and Exposition. BLOOD, 1 AUGUST 2007 VOLUME 110, NUMBER 3 ib

40 iib BLOOD, 1 AUGUST 2007 VOLUME 110, NUMBER 3 A COMPREHENSIVE BOARD REVIEW IN HEMATOLOGY AND MEDICAL ONCOLOGY The University of Texas xas M. D. Anderson Cancer Center and Baylor College ge of Medicine September 24-September 29, 2007 Edwin Hornberger Conference Center,, Houston, TX For information call or MOBR ( ); register@mdanderson.org; website:

41 Blood Classified ied Advertising Blood will accept advertisements for its Classified Advertising section only if they substantially relate to and further the American Society of Hematology s taxexempt purpose. ASH s purpose is to engage exclusively in charitable, scientific, and educational activities and endeavors, including promoting and fostering, among the many scientific and clinical disciplines, the exchange and diffusion of information and ideas relating to blood and blood-forming tissues and encouraging investigations of hematologic matters. Examples of advertisements that substantially relate to ASH s purposes include advertisements for hematologyrelated employment at academic institutions that involve a research and/or an educational component, and advertisements for symposia and meetings that relate to furthering the exchange of hematology-related information and ideas. To place an advertisement in Blood s Classified Advertising section, please contact Valerie Marvin at the following address: Blood, 180 Old Tappan Road, Old Tappan, NJ Phone: ; fax: ; vmarvin@cunnasso.com. Penn State College of Medicine Penn State Milton S. Hershey Medical Center DIRECTOR-HEMOSTASIS/THROMBOSIS PROGRAM We are seeking a full-time hematologist at the rank of associate professor/professor with an established track record of research in hemostasis, thrombosis or endothelial cell biology to head the Section of Hemostasis/Thrombosis in the Division of Hematology/Medical Oncology of the Department of Medicine in Hershey, PA. This is a tenure track clinician-scientist position supported by an endowed professorship in hematology. This individual will hold a joint appointment in the Department of Pathology and Laboratory Medicine as the Medical Director of the Special Hematology and Hemostasis Laboratories. The candidate will expand the existing federal and state funded Central Pennsylvania Hemophilia Center into a Hemophilia and Thrombophilia Center to provide comprehensive care, clinical research and education in disorders of hemostasis and thrombosis. The candidate is expected to develop a multi-disciplinary research program in the areas of hemostasis, thrombosis or endothelial cell biology. There are multiple opportunities for collaboration within the College of Medicine, other colleges at University Park, and the newly constructed Hershey Center for Applied Research adjacent to the Medical Center. Penn State Milton S. Hershey Medical Center is an Affirmative Action, Equal Opportunity Employer. Women and minorities are encouraged to apply. Interested individuals should send, or fax their CV to: Hamid Al-Mondhiry, MD, Chair, Search Committee, Division of Hematology/Oncology, Penn State Milton S. Hershey Medical Center, 500 University Drive (H046), Hershey, PA , Fax , halmondhiry@psu.edu Feist-Weiller Cancer Center LSU Health Sciences Center - Shreveport Section of Hematology-Oncology DIRECTOR BLOOD AND MARROW TRANSPLANTATION PROGRAM The Feist-Weiller Cancer Center at LSU Health Sciences Center, Shreveport, is seeking a Director of the Blood and Marrow Transplantation and Leukemia Program. The Directorship of Louisiana s most active BMT and Leukemia Program with established multidisciplinary teams of clinicians and scientists allowing the opportunity to create and build clinical or translational cancer research programs. In addition to performing both autologous and matched related allogeneic blood and marrow transplantation, the BMT Program at the Feist-Weiller Cancer Center is an active affiliate of the National Marrow Donor Program and routinely offers unrelated allogeneic transplantation to medically eligible patients. The Director is also in charge of the Stem Cell Laboratory which including apheresis and cryopreservation, and storage. The Feist-Weiller Cancer Center is the most active tertiary Cancer care and cancer research facility in Louisiana serving over 80% of the state. The FWCC has a state-of-the-art research facility, a new 60,000 square foot multidisciplinary out-patient clinical building, and a faculty of over 50 clinicians and scientists. The FWCC Divisions of Basic Cancer Research, Clinical Cancer Research, and Cancer Prevention and Control maintain active NCI-funded clinical research programs with strongly funded program in various aspects of the molecular biology of cancer with innovative translational research projects. Additional faculty slots are available with recruitment facilitated by generous start-up packages for basic and clinical research faculty and a mentored research development program is in place for junior faculty in both basic and clinical arenas. Shreveport is a progressive modern city with excellent school, numerous family activities, and a very low cost of living. Interested individuals who wish to participate in a unique, diverse, academically productive Cancer Center should send their curriculum vitae with three letters of reference to: Jonathan Glass, MD, Carroll W. Feist Professor of Cancer Research, Director, Feist-Weiller Cancer Center, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA , JGlass@LSUHSC.edu. Academic Bone Marrow Transplant Physician The Division of Hematology/Oncology at Loyola University Chicago, Stritch School of Medicine/Cardinal Bernardin Cancer Center seeks candidates with expertise in allogeneic and autologous bone marrow transplants for a faculty position as Assistant or Associate Professor in the expanding Bone Marrow Transplant Program. The focus of this position will be: allogeneic transplants, unrelated donor transplants, and cord blood ex-vivo expansion clinical trials. Current funded translational research includes mechanisms of GVHD development and therapy, trials of novel cytokines, cell based vaccine trials, and ex-vivo pre-clinical and clinical cord blood expansion trials using stromal based system. Cooperative studies through Southwest Oncology Group, CIBMTR, NMDP, and CTN are being conducted. The Cardinal Bernardin Cancer Center (CBCC) is a free standing facility that houses 40 oncology focused faculty, thirty-four basic research laboratories, and clinical treatment facilities that support over 85,000 patient visits per year. In addition, clinical patient services are provided at 3 satellite facilities. Clinical research activities interface with SWOG, RTOG, GOG, NSABP, and a Phase II network. Faculty are actively involved in the education of medical students, internal medicine residents, and hematology/oncology fellows. A competitive salary, benefits, and support package will be provided. Inquiries should be directed to: Patrick Stiff, MD, Director, Division of Hematology/Oncology, Loyola University Chicago, Cardinal Bernardin Cancer Center, 2160 South First Avenue, Maywood, IL FAX Loyola University Chicago is an Equal Opportunity/Affirmative Employer and Educator with a strong commitment to diversifying its faculty.

42 A S S I S T A N T /A S S O C I A T E P R O F E S S O R D i v i s i o n o f H e m a t o l o g y The Department of Medicine, Division of Hematology, at Stanford University invites applications for a faculty position at the Assistant/Associate Professor level to lead the clinical research program in multiple myeloma. Candidates should be hematology and/or oncology board certified or eligible and should have demonstrated ability to conduct clinical research. The position is in the Medical Center Line (MCL). The major criteria for appointment for faculty in the MCL shall be excellence in the overall mix of clinical care, clinical teaching, scholarly activity that advances clinical medicine, and institutional service appropriate to the programmatic need the individual is expected to fulfill. In addition to leading the multiple myeloma research program, the successful candidate will participate in the inpatient, outpatient, and consultation service of the Division. Stanford University is an equal opportunity employer and is committed to increasing the diversity of its faculty. It welcomes nominations of and applications from women and members of minority groups, as well as others who would bring additional dimensions to the university s research, teaching and clinical missions. Applicants should send a curriculum vitae, statement of clinical research interests, and the names and addresses of three references to: Linda Boxer, M.D., Ph.D. Chief, Division of Hematology Stanford University 269 Campus Drive CCSR Building, Room 1155 Stanford, CA lboxer@stanford.edu CLEVELAND CLINIC HEMATOLOGIC MALIGNANCIES The Department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic is seeking applicants for an Associate Staff or Staff physician position interested in Non-Hodgkin s Lymphoma. The successful candidate will be committed to clinical research and demonstrate an ability to develop independent clinical research projects. The Cleveland Clinic Department of Hematologic Oncology and Blood Disorders is rapidly expanding and has well established clinical and translational research programs. Excellent salary and benefit package available Please send letter and CV to: Brian J. Bolwell, M.D Chairman, Department of Hematologic Oncology and Blood Disorders Cleveland Clinic Taussig Cancer Center, R Euclid Avenue Cleveland, OH bolwelb@ccf.org The Cleveland Clinic Foundation is an Equal Opportunity Employer ACADEMIC HEMATOPATHOLOGIST UNIVERSITY OF PENNSYLVANIA SCHOOL OF MEDICINE The Department of Pathology and Laboratory Medicine at the University of Pennsylvania s School of Medicine seeks candidates for an Assistant, Associate, or Full Professor position in either the non-tenure clinician-educator track or the tenure track. Track and rank will be commensurate with experience. Applicants must have an M.D. or M.D./Ph.D. or equivalent degree and have particularly desired. The successful candidate will become part of a team of highly accomplished faculty. The candidate must demonstrate a strong record in translational, basic, or clinical research. Tenure track candidates must demonstrate a strong record/potential to garner extramural funding for basic research. Teaching and mentoring of medical students, biomedical graduate students, pathology residents and fellows and technologists will be integral components of the position. employer. Women and minority candidates are strongly encouraged to apply. Please submit by October 31, 2007 a curriculum vitae, a letter of interest, 3 reference letters, and a statement of research interests to: Guido Silvestri, M.D. University of Pennsylvania School of Medicine Department of Pathology and Laboratory Medicine 705 Stellar-Chance Laboratories, 422 Curie Blvd., Phila, PA gsilvest@mail.med.upenn.edu CLEVELAND CLINIC HEMATOLOGIC MALIGNANCIES The Department of Hematologic Oncology and Blood Disorders at the Cleveland Clinic is seeking applicants for an Associate Staff or Staff physician position interested in Multiple Myeloma. The successful candidate will be committed to clinical research and demonstrate an ability to develop independent clinical research projects. The Cleveland Clinic Department of Hematologic Oncology and Blood Disorders is rapidly expanding and has well established clinical and translational research programs. Excellent salary and benefit package available. Please send letter and CV to: Brian J. Bolwell, M.D Chairman, Department of Hematologic Oncology and Blood Disorders Cleveland Clinic Taussig Cancer Center, R Euclid Avenue Cleveland, OH bolwelb@ccf.org The Cleveland Clinic Foundation is an Equal Opportunity Employer

43 University of Louisville, Stem Cell Institute at James Graham Brown Cancer Center positions. The newly created Stem Cell Institute at James Graham Brown Cancer Center at the University of Louisville ( plans an expansion of research in the biology of normal and malignant stem cells, with an emphasis on tissue/organ regeneration and molecular mechanisms that govern trafficking, engraftment and expansion of normal stem cells and metastasis of malignant stem cells. Positions are available at open rank of Full Professor, Associate Professors and Assistant Professors (tenure track). Applicants must have M.D. Ph.D., or Ph.D. with postdoctoral research experience, a strong track record of publications, history of successful funding, and will be expected to establish an independently funded research program. We are looking for candidates in the areas of i) stem cell biology, ii) isolating, purification and expansion of human hematopoietic and non-hematopoietic cells, iii) molecular aspects of stem cell renewal/differentiation, iv) developmental embryology and v) animal in vivo models. The successful faculty candidates will be provided with laboratory space and generous start-up packages. The JGB Cancer Center houses excellent shared facilities for molecular and cellular biology, including flow cytometry and cell sorting, DNA sequencing, structural biology including molecular modeling, NMR, biophysics, crystallography, genomics and proteomics and facilities for transgenic mice. Please send curriculum vitae, with a bibliography, a synopsis of research interests, and the names and telephone/facsimile/ of at least three references to: Donald Miller MD, PhD Director, James Graham Brown Cancer Center University of Louisville 529 South Jackson Street Louisville, KY Donaldmi@ulh.org Mariusz Z. Ratajczak MD, PhD Stella & Henry Hoenig Endowed Chair Professor of Medicine Director of Stem Cell Institute at James Graham Brown Cancer Center University of Louisville 500 Floyd Street Louisville, KY mzrata01@louisville.edu UNIVERSITY OF SOUTHERN CALIFORNIA Keck School of Medicine HEMATOLOGIC ONCOLOGIST The USC/Norris Comprehensive Cancer Center and the Department of Medicine of the Keck School of Medicine at the University of Southern California (USC) seek an outstanding physician (M.D. or M.D./Ph.D.) to join the Division of Cancer Medicine and Blood Diseases. We are seeking candidates with a successful track record in patient care and clinical/translational research in hematologic malignancies. The successful candidate will be nominated for the Ronald H. Bloom Family Chair and recommended for appointment as Associate or Full Professor. We offer a highly competitive salary package with excellent benefits, outstanding infrastructural research support and high quality laboratory space in the new 175,000 sq ft Harlyne Norris Research Tower. Hematology and hematologic malignancy diagnostics and therapeutics have had a prominent history at USC. The patient population at USC/Norris Cancer Hospital, USC University Hospital and LAC+USC Medical Center is large, diverse and provides an outstanding resource for clinical research, including clinical trials and translational science. Significant growth in clinical, population-based, translational and basic research, in laboratory resources, and in faculty and support staff will occur in the next decade as a high priority of USC. Qualifications: Candidates must be board-certified (or equivalent) in Internal Medicine and board eligible/certified (or equivalent) in Hematology. A strong background in patient care and clinical/translational research in hematologic malignancy is essential, along with a track record of peer-reviewed clinical or laboratory funding and strong mentoring credentials. Please send letter of interest and curriculum vitae to: Search Committee - Ronald H. Bloom Family Chair Division of Cancer Medicine and Blood Diseases USC/Norris Comprehensive Cancer Center University of Southern California 1441 Eastlake Avenue, #3470 Los Angeles, CA Attn: Gloria Reyes ( gloriare@usc.edu) The University of Southern California is an EOE/AA

44 PEDIATRIC HEMATOLOGY/ONCOLOGY FACULTY POSITION The Division of Hematology/Oncology/BMT in the Department of Pediatrics at The Ohio State University College of Medicine and Public Health, located at Children s Hospital, Columbus, Ohio, is actively seeking a qualified individual at the Assistant to Associate Professor Level with an emphasis on Sickle Cell Disease and Hematology. The division currently consists of 13 faculty members; 3 of whom are dedicated to Hematology. The division also has an active fellowship program. The Hematology program at Columbus Children s Hospital currently provides comprehensive care for approximately 300 patients with sickle cell disease and thalassemia. The division has an active HTC and is actively involved in COG and PBMTC. The program is an Ohio Department of Health designated regional treatment center for patients with Sickle Cell Disorders. The Hemoglobinopathy Program is an active participant in ongoing NIHfunded multicenter trials in Sickle Cell Anemia and Thalassemia, and has ongoing independent investigations into quality of life and clinical outcomes. Opportunities exist for interdisciplinary academic collaboration between sub-specialists at Columbus Children s Hospital and The Ohio State University Hematology Program. Applicants should have strong administrative and clinical skills, interest or experience in clinical and translational research, and a commitment to teaching. The division has established laboratory research programs in vascular biology, molecular immunology, stem cell biology, and molecular oncology. Applicants must be BC/BE in pediatric hematology/ oncology. Send CV to Thomas Gross, MD/PhD, Chief, Division of Hematology/Oncology, Children s Hospital, 700 Children s Drive, Columbus, OH Telephone 614/ Fax 614/ GrossT@pediatrics.ohio-state.edu. The Ohio State University is an Equal Opportunity, Affirmative Action Employer. Women, minorities, veterans, and individuals with disabilities are encouraged to apply. Memorial Sloan Kettering Cancer Center Chair Department of Clinical Laboratories Memorial Hospital for Cancer and Allied Diseases Memorial Sloan-Kettering Cancer Center Memorial Sloan-Kettering Cancer Center seeks an individual of international stature to serve as the Chair of the Department of Clinical Laboratories. The Chair has responsibility for all clinical chemistry, microbiology, hematology, blood banking, and blood bank cytotherapy. The Department also provides laboratory services for clinical research programs at MSKCC and collaborates with the Sloan Kettering Institute in technology development and transfer. MSKCC is in a dynamic period of program expansion, creation of new programs, and construction of new facilities for clinical care and research. These include extensively renovated patient-care areas and significantly expanded laboratory research space. There are impressive opportunities for cross-institutional collaboration and program development with MSKCC s neighbors, the Weill Medical College of Cornell University, the New York Presbyterian Hospital, and the Rockefeller University. Interested applicants should send curriculum vitae and bibliography to: David R. Spriggs, M.D., Chair, Search Committee c/o Clara Irizarry, MPA Manager, Office of Academic Recruitment, MH Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY irizarrc@mskcc.org MSKCC is an Equal Opportunity / Affirmative Action Employer TRANSFUSION MEDICINE SPECIALIST The University of Texas Health Science Center at San Antonio The Department of Pathology at The University of Texas Health Science Center at San Antonio is seeking a pathologist with expertise in transfusion medicine. This position will carry a faculty appointment at an academic rank commensurate with education and experience. The applicant should have a M.D. degree or M.D./ Ph.D. degrees and be certified by the American Board of Pathology in Anatomic and/or Clinical Pathology and board certification or board eligibility in Transfusion Medicine (American Board of Pathology). A strong record of scholarship is preferred. Expertise in transfusion service, hospital donor services, therapeutic apheresis and hematopoietic precursor cells collection and processing is expected. Teaching responsibilities will include interactions with transfusion medicine fellows, pathology residents, School of Blood Banking students and medical students. A curriculum vitae, a letter briefly describing suitability and interests, and the name of three references for letters of recommendation should be sent to: Robert L. Reddick, M.D., Chairman, Department of Pathology, Mail Code 7750, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, Applications will be accepted until the position is filled. All faculty appointments are designated as security sensitive positions. The University of Texas Health Science Center at San Antonio is an Equal Opportunity Employment /Affirmative Action employer. ACADEMIC HEMATOLOGIST/ STEM CELL TRANSPLANT PHYSICIAN Dartmouth-Hitchcock Medical Center, Dartmouth Medical School and the Norris Cotton Cancer Center are seeking applications at the Assistant or Associate Professor level for an academic hematologist with a focus on Lymphoma and Transplantation. Minimum requirements include completion of an approved Fellowship program and board certification/eligibility in Hematology. Additional post-fellowship experience is preferred, but not necessary. Successful candidates will participate in the academic activities of a very active Lymphoma and Transplant Program within the Section of Hematology/Oncology. Integration with ongoing clinical and translational research programs are required. The Norris Cotton Cancer Center, is one of only thirtynine NCI-designated Comprehensive Cancer Centers, in the US. Please send letters of inquiry and CV to: Kenneth Meehan MD c/o Constance M. Goodrich Dartmouth-Hitchcock Medical Center Section of Hematology/Oncology One Medical Center Drive Lebanon, NH Phone: Fax: Constance.M.Goodrich@Hitchcock.ORG Dartmouth-Hitchcock Medical Center is an Equal Opportunity/Affirmative Action employer and encourages applications from women and members of minority groups.

45

46 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR PROCRIT IN THE TREATMENT OF ANEMIA IN CANCER PATIENTS ON CHEMOTHERAPY PROCRIT (epoetin alfa) FOR INJECTION FOR FULL PRESCRIBING INFORMATION FOR ALL INDICATIONS, REFER TO THE PHYSICIANS DESK REFERENCE WARNINGS: ERYTHROPOIESIS-STIMULATING AGENTS Use the lowest dose of PROCRIT that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid the need for red blood cell transfusion (see DOSAGE AND ADMINISTRATION in full Prescribing Information). PROCRIT and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events when administered to target a hemoglobin of greater than 12 g/dl (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Cancer Patients: Use of ESAs shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a hemoglobin of greater than 12 g/dl; shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin of greater than 12 g/dl; increased the risk of death when administered to target a hemoglobin of 12 g/dl in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population. (See WARNINGS: Increased Mortality and/or Tumor Progression) Patients receiving ESAs pre-operatively for reduction of allogeneic red blood cell transfusions: A higher incidence of deep venous thrombosis was documented in patients receiving PROCRIT who were not receiving prophylactic anticoagulation. Antithrombotic prophylaxis should be strongly considered when PROCRIT is used to reduce allogeneic red blood cell transfusions (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). INDICATIONS AND USAGE PROCRIT is indicated for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. PROCRIT is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months. PROCRIT is not indicated for the treatment of anemia in cancer patients due to other factors such as iron or folate deficiencies, hemolysis, or gastrointestinal bleeding, which should be managed appropriately. CONTRAINDICATIONS PROCRIT is contraindicated in patients with: 1. Uncontrolled hypertension; 2. Known hypersensitivity to mammalian cell-derived products; 3. Known hypersensitivity to Albumin (Human). WARNINGS Pediatrics Risk in Premature Infants The multidose preserved formulation contains benzyl alcohol. Benzyl alcohol has been reported to be associated with an increased incidence of neurological and other complications in premature infants which are sometimes fatal. Adults Increased Mortality, Serious Cardiovascular and Thromboembolic Events PROCRIT and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events in controlled clinical trials when administered to target a hemoglobin of greater than 12 g/dl. There was an increased risk of serious arterial and venous thromboembolic events, including myocardial infarction, stroke, congestive heart failure, and hemodialysis graft occlusion. A rate of hemoglobin rise of greater than 1 g/dl over 2 weeks may also contribute to these risks. To reduce cardiovascular risks, use the lowest dose of PROCRIT that will gradually increase the hemoglobin concentration to a level sufficient to avoid the need for RBC transfusion. The hemoglobin concentration should not exceed 12 g/dl; the rate of hemoglobin increase should not exceed 1 g/dl in any two week period (see DOSAGE AND ADMINISTRATION in full Prescribing Information). In a randomized prospective trial, 1432 anemic chronic renal failure patients who were not undergoing dialysis were assigned to Epoetin alfa (rhuepo) treatment targeting a maintenance hemoglobin concentration of 13.5 g/dl or 11.3 g/dl. A major cardiovascular event (death, myocardial infarction, stroke or hospitalization for congestive heart failure) occurred among 125 (18%) of the 715 patients in the higher hemoglobin group compared to 97 (14%) among the 717 patients in the lower hemoglobin group (HR 1.3, 95% CI: 1.0, 1.7, p = 0.03). Increased risk for serious cardiovascular events was also reported from a randomized, prospective trial of 1265 hemodialysis patients with clinically evident cardiac disease (ischemic heart disease or congestive heart failure). In this trial, patients were assigned to PROCRIT treatment targeted to a maintenance hematocrit of either 42 ± 3% or 30 ± 3%. Increased mortality was observed in 634 patients randomized to a target hematocrit of 42% [221 deaths (35% mortality)] compared to 631 patients targeted to remain at a hematocrit of 30% [185 deaths (29% mortality)]. The reason for the increased mortality observed in this study is unknown, however, the incidence of non-fatal myocardial infarctions (3.1% vs 2.3%), vascular access thromboses (39% vs 29%), and all other thrombotic events (22% vs 18%) were also higher in the group randomized to achieve a hematocrit of 42%. An increased incidence of thrombotic events has also been observed in patients with cancer treated with erythropoietic agents. In a randomized controlled study (referred to as the BEST study) with another ESA in 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly Epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when an ESA was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dl or hematocrit between 36% and 42%). The study was terminated prematurely when interim REMINDER TO AUTHORS An Important Category in Blood: Brief Reports When you consider submitting to Blood, don t forget Brief Reports. Short papers documenting either experimental result or informatve patient presentations are considered for publication in this category. Begin the Brief Report by documenting experimental results with a clear question in the introduction and then present definitive proof in the body of the text. Keep the Materials and Methods section succinct relying primarily on cited work but sufficiently informative to allow reproduction of the data. In the interest of conciseness, combine the Results and Discussion sections and do not repeat the introductory comments. Brief Reports, including figures, tables, and references, should fit on 2 printed pages. Therefore, when preparing your Brief Report, do not exceed 1200 words in the text,150 words in the abstract, 2 figures/ tables, and 25 references.

47 PROCRIT (epoetin alfa) results demonstrated that a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic events (1.1% vs. 0.2%) in the first 4 months of the study were observed among patients treated with Epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the Epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012). A systematic review of 57 randomized controlled trials (including the BEST and ENHANCE studies) evaluating 9353 patients with cancer compared ESAs plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. An increased relative risk of thromboembolic events (RR 1.67, 95% CI: 1.35, 2.06, 35 trials and 6769 patients) was observed in ESA-treated patients. An overall survival hazard ratio of 1.08, (95% CI: 0.99, 1.18; 42 trials and 8167 patients) was observed in ESA-treated patients. An increased incidence of deep vein thrombosis (DVT) in patients receiving Epoetin alfa undergoing surgical orthopedic procedures has been observed (see ADVERSE REACTIONS, Surgery Patients: Thrombotic/Vascular Events in full Prescribing Information). In a randomized controlled study (referred to as the SPINE study), 681 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, received either 4 doses of 600 U/kg Epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment, or SOC treatment alone. Preliminary analysis showed a higher incidence of DVT, determined by either Color Flow Duplex Imaging or by clinical symptoms, in the Epoetin alfa group [16 patients (4.7%)] compared to the SOC group [7 patients (2.1%)]. In addition, 12 patients in the Epoetin alfa group and 7 patients in the SOC group had other thrombotic vascular events. Antithrombotic prophylaxis should be strongly considered when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients (see BOXED WARNINGS and DOSAGE AND ADMINISTRATION in full Prescribing Information). Increased mortality was also observed in a randomized placebocontrolled study of PROCRIT in adult patients who were undergoing coronary artery bypass surgery (7 deaths in 126 patients randomized to PROCRIT versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all four deaths were associated with thrombotic events. ESAs are not approved for reduction of allogeneic red blood cell transfusions in patients scheduled for cardiac surgery. Increased Mortality and/or Tumor Progression Erythropoiesis-stimulating agents, when administered to target a hemoglobin of greater than 12 g/dl, shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy. ESAs also shortened survival in patients with metastatic breast cancer receiving chemotherapy when administered to target a hemoglobin of greater than 12 g/dl. The ENHANCE study was a randomized controlled study in 351 head and neck cancer patients where Epoetin beta or placebo was administered to achieve target hemoglobin of 14 and 15 g/dl for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving Epoetin beta, HR 1.62 (95% CI: 1.22, 2.14; p = ) with a median of 406 days Epoetin beta vs. 745 days placebo. The DAHANCA 10 study, conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy were randomized to darbepoetin alfa or placebo. An interim analysis in 484 patients demonstrated a 10% increase in locoregional failure rate among darbepoetin alfa-treated patients (p = 0.01). At the time of study termination, there was a trend toward worse survival in the darbepoetin alfa-treated arm (p = 0.08). The BEST study was previously described (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the Epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the Epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator assessed time to tumor progression was not different between the two groups. In a Phase 3, double-blind, randomized (darbepoetin alfa vs. placebo), 16-week study in 989 anemic patients with active malignant disease neither receiving nor planning to receive chemotherapy or radiation therapy, there was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. In addition, there were more deaths in the darbepoetin alfa treatment group [26% (136/515)] than the placebo group [20% (94/470)] at 16 weeks (completion of treatment phase). With a median survival follow up of 4.3 months, the absolute number of deaths was greater in the darbepoetin alfa treatment group [49% (250/515)] compared with the placebo group [46% (216/470); HR 1.29, 95% CI: 1.08, 1.55]. In a Phase 3, multicenter, randomized (Epoetin alfa vs. placebo), doubleblind study, patients with advanced non-small-cell lung cancer unsuitable for curative therapy were treated with Epoetin alfa targeting hemoglobin levels between 12 and 14 g/dl. Following an interim analysis of 70 of 300 patients planned, a significant difference in median survival in favor of the patients on the placebo arm of the trial was observed (63 vs. 129 days; HR 1.84; p = 0.04). Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin, have been reported in patients treated with PROCRIT. This has been reported predominantly in patients with chronic renal failure (CRF) receiving PROCRIT by subcutaneous administration. Any patient who develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, should be evaluated for the etiology of loss of effect, including the presence of neutralizing antibodies to erythropoietin (see PRECAUTIONS: LACK OR LOSS OF RESPONSE). If anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins. Contact ORTHO BIOTECH ( ASK OBI or ) to perform assays for binding and neutralizing antibodies. PROCRIT should be permanently discontinued in patients with antibody-mediated anemia. Patients should not be switched to other erythropoetic proteins as antibodies may cross-react (see ADVERSE REACTIONS: IMMUNOGENICITY). Albumin (Human) PROCRIT contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS The parenteral administration of any biologic product should be attended by appropriate precautions in case allergic or other untoward reactions occur (see CONTRAINDICATIONS). In clinical trials, while transient rashes were occasionally observed concurrently with PROCRIT therapy, no serious allergic or anaphylactic reactions were reported (see ADVERSE REACTIONS for more information regarding allergic reactions). The safety and efficacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. Hematology: Exacerbation of porphyria has been observed rarely in patients with CRF treated with PROCRIT. However, PROCRIT has not caused increased urinary excretion of porphyrin metabolites in normal volunteers, even in the presence of a rapid erythropoietic response. Nevertheless, PROCRIT should be used with caution in patients with known porphyria. In preclinical studies in dogs and rats, but not in monkeys, PROCRIT therapy was associated with subclinical bone marrow fibrosis. Bone marrow fibrosis is a known complication of CRF in humans and may be related to secondary hyperparathyroidism or unknown factors. The incidence of bone marrow fibrosis was not increased in a study of adult patients on dialysis who were treated with PROCRIT for 12 to 19 months, compared to the incidence of bone marrow fibrosis in a matched group of patients who had not been treated with PROCRIT. Cancer patients should have hemoglobin measured once a week until hemoglobin has stabilized, and measured periodically thereafter. Lack or Loss of Response: If the patient fails to respond or to maintain a response to doses within the recommended dosing range, the following etiologies should be considered and evaluated: 1. Iron deficiency: Virtually all patients will eventually require supplemental iron therapy (see IRON EVALUATION); 2. Underlying infectious, inflammatory, or malignant processes; 3. Occult blood loss; 4. Underlying hematologic diseases (ie, thalassemia, refractory anemia, or other myelodysplastic disorders); 5. Vitamin deficiencies: Folic acid or vitamin B12; 6. Hemolysis; 7. Aluminum intoxication; 8. Osteitis fibrosa cystica; 9. Pure Red Cell Aplasia (PRCA) or anti-erythropoietin antibody-associated anemia: In the absence of another etiology, the patient should be evaluated for evidence of PRCA and sera should be tested for the presence of antibodies to erythropoietin (see WARNINGS: PURE RED CELL APLASIA). Iron Evaluation: During PROCRIT therapy, absolute or functional iron deficiency may develop. Functional iron deficiency, with normal ferritin levels but low transferrin saturation, is presumably due to the inability to mobilize iron stores rapidly enough to support increased erythropoiesis. Transferrin saturation should be at least 20% and ferritin should be at least 100 ng/ml. Prior to and during PROCRIT therapy, the patient s iron status, including transferrin saturation (serum iron divided by iron binding capacity) and serum ferritin, should be evaluated. Virtually all patients will eventually require supplemental iron to increase or maintain transferrin saturation to levels which will adequately support erythropoiesis stimulated by PROCRIT. Drug Interactions: No evidence of interaction of PROCRIT with other drugs was observed in the course of clinical trials. Carcinogenesis, Mutagenesis, and Impairment of Fertility: Carcinogenic potential of PROCRIT has not been evaluated. PROCRIT does not induce bacterial gene mutation (Ames Test), chromosomal aberrations in mammalian cells, micronuclei in mice, or gene mutation at the HGPRT locus. In male and female rats treated intravenously (IV) with PROCRIT, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. Pregnancy Category C: PROCRIT has been shown to have adverse effects in rats when given in doses 5 times the human dose. There are no adequate and well-controlled studies in pregnant women. PROCRIT should be used during pregnancy only if potential benefit justifies the potential risk to the fetus. In studies in female rats, there were decreases in body weight gain, delays in appearance of abdominal hair, delayed eyelid opening, delayed ossification, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. In female rats treated IV, there was a trend for slightly increased fetal wastage at doses of 100 and 500 Units/kg. PROCRIT has not shown any adverse effect at doses as high as 500 Units/kg in pregnant rabbits (from day 6 to 18 of gestation). Nursing Mothers: Postnatal observations of the live offspring (F1 generation) of female rats treated with PROCRIT during gestation and lactation revealed no effect of PROCRIT at doses of up to 500 Units/kg. There were, however, decreases in body weight gain, delays in appearance of abdominal hair, eyelid opening, and decreases in the number of caudal vertebrae in the F1 fetuses of the 500 Units/kg group. There were no PROCRIT -related effects on the F2 generation fetuses. It is not known whether PROCRIT is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when PROCRIT is administered to a nursing woman. Pediatric Use: See WARNINGS: Pediatrics Pediatric Cancer Patients on Chemotherapy: The safety and effectiveness of PROCRIT were evaluated in a randomized, double-blind, placebocontrolled, multicenter study (see CLINICAL EXPERIENCE, WEEKLY (QW) DOSING, PEDIATRIC PATIENTS in full Prescribing Information). Geriatric Use: Insufficient numbers of patients age 65 or older were enrolled in clinical studies of PROCRIT for the treatment of anemia associated with cancer chemotherapy to determine whether they respond differently from younger subjects. Information for Patients Patients should be informed of the increased risks of mortality, serious cardiovascular events, thromboembolic events, and tumor progression when used in off-label dose regimens or populations (see WARNINGS). In those situations in which the physician determines that a patient or their caregiver can safely and effectively administer PROCRIT at home, instruction as to the proper dosage and administration should be provided. Patients should be referred to the full Information for Patients insert in the full Prescribing Information and that it is not a disclosure of all possible effects. Patients should be informed of the possible side effects of PROCRIT and of the signs and symptoms of allergic drug reaction and advised of appropriate actions. Hypertension: Hypertension, associated with a significant increase in hemoglobin, has been noted rarely in patients treated with PROCRIT. Nevertheless, blood pressure in patients treated with PROCRIT should be monitored carefully, particularly in patients with an underlying history of hypertension or cardiovascular disease. Seizures: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT three times weekly (TIW) and 2.9% (n = 2/68) of placebo-treated patients had seizures. Seizures in 1.6% (n = 1/63) of patients treated with PROCRIT TIW occurred in the context of a significant increase in blood pressure and hematocrit from baseline values. However, both patients treated with PROCRIT also had underlying CNS pathology which may have been related to seizure activity. In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT, 1.2% (n = 2/168) of safety-evaluable patients treated with PROCRIT and 1% (n = 1/165) of placebo-treated patients had seizures. Seizures in the patients treated with weekly PROCRIT occurred in the context of a significant increase in hemoglobin from baseline values however significant increases in blood pressure were not seen. These patients may have had other CNS pathology. Thrombotic Events: In double-blind, placebo-controlled trials, 3.2% (n = 2/63) of patients treated with PROCRIT TIW and 11.8% (n = 8/68) of placebo-treated patients had thrombotic events (eg, pulmonary embolism, cerebrovascular accident) (see WARNINGS: Increased Mortality, Serious Cardiovascular and Thromboembolic Events). In a placebo-controlled, double-blind trial utilizing weekly dosing with PROCRIT, 6.0% (n = 10/168) of safety-evaluable patients treated with PROCRIT and 3.6% (n = 6/165) (p = 0.444) of placebo-treated patients had clinically significant thrombotic events (deep vein thrombosis requiring anticoagulant therapy, embolic event including pulmonary embolism, myocardial infarction, cerebral ischemia, left ventricular failure and thrombotic microangiopathy). A definitive relationship between the rate of hemoglobin increase and the occurrence of clinically significant thrombotic events could not be evaluated due to the limited schedule of hemoglobin measurements in this study. The safety and efficacy of PROCRIT were evaluated in a randomized, double-blind, placebo-controlled, multicenter study that enrolled 222 anemic patients ages 5 to 18 receiving treatment for a variety of childhood malignancies. Due to the study design (small sample size and the heterogeneity of the underlying malignancies and of anti-neoplastic treatments employed), a determination of the effect of PROCRIT on the incidence of thrombotic events could not be performed. In the PROCRIT arm, the overall incidence of thrombotic events was 10.8% and the incidence of serious or life-threatening events was 7.2%. ADVERSE REACTIONS Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving PROCRIT (see WARNINGS: PURE RED CELL APLASIA) during post-marketing experience. There has been no systematic assessment of immune responses, i.e., the incidence of either binding or neutralizing antibodies to PROCRIT, in controlled clinical trials. Where reported, the incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading. Adverse Experiences Reported in Clinical Trials In double-blind, placebo-controlled studies of up to 3 months duration involving 131 cancer patients, adverse events with an incidence > 10% in either patients treated with PROCRIT or placebo-treated patients were as indicated below. Percent of Patients Reporting Event: Event followed by Patients Treated With PROCRIT (n = 63) first, Placebo-treated Patients (n = 68) second: Pyrexia 29%, 19%; Diarrhea 21%*, 7%; Nausea 17%*, 32%; Vomiting 17%, 15%; Edema 17%*, 1%; Asthenia 13%, 16%; Fatigue 13%, 15%; Shortness of Breath 13%, 9%; Paresthesia 11%, 6%; Upper Respiratory Infection 11%, 4%; Dizziness 5%, 12%; Trunk Pain 3%*, 16%. *Statistically significant. Although some statistically significant differences between patients being treated with PROCRIT and placebo-treated patients were noted, the overall safety profile of PROCRIT appeared to be consistent with the disease process of advanced cancer. During double-blind and subsequent open-label therapy in which patients (n = 72 for total exposure to PROCRIT ) were treated for up to 32 weeks with doses as high as 927 Units/kg, the adverse experience profile of PROCRIT was consistent with the progression of advanced cancer. Three hundred thirty-three (333) cancer patients enrolled in a placebocontrolled, double-blind trial utilizing Weekly dosing with PROCRIT for up to 4 months were evaluable for adverse events. The incidence of adverse events was similar in both treatment and placebo arms. OVERDOSAGE The expected manifestations of PROCRIT overdosage include signs and symptoms associated with an excessive and/or rapid increase in hemoglobin concentration, including any of the cardiovascular events described in WARNINGS and listed in ADVERSE REACTIONS. Patients receiving an overdosage of PROCRIT should be monitored closely for cardiovascular events and hematologic abnormalities. Polycythemia should be managed acutely with phlebotomy, as clinically indicated. Following resolution of the effects due to PROCRIT overdosage, reintroduction of PROCRIT therapy should be accompanied by close monitoring for evidence of rapid increases in hemoglobin concentration (>1 gm/dl per 14 days). In patients with an excessive hematopoietic response, reduce the PROCRIT dose in accordance with the recommendations described in DOSAGE AND ADMINISTRATION in full Prescribing Information. Manufactured by: Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA Distributed by: Ortho Biotech Products, L.P., Raritan, New Jersey OBPLP 2000 Revised March BC

48 PROCRIT Usage Oncology PROCRIT is indicated for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effect of concomitantly administered chemotherapy. PROCRIT is indicated to decrease the need for transfusions in patients who will be receiving concomitant chemotherapy for a minimum of 2 months. PROCRIT is not indicated in patients with active malignant disease not receiving chemotherapy. PROCRIT is also not indicated for the treatment of anemia due to other factors such as iron or folate defi ciencies, hemolysis or gastrointestinal bleeding, which should be managed appropriately. Important Safety Information From the Boxed WARNINGS Use the lowest dose of PROCRIT that will gradually increase the hemoglobin (Hb) concentration to the lowest level sufficient to avoid the need for red blood cell (RBC) transfusion. PROCRIT and other erythropoiesis-stimulating agents (ESAs) increased the risk for death and for serious cardiovascular events (including serious arterial and venous thromboembolic events, myocardial infarction, stroke, congestive heart failure) when administered to target a Hb of greater than 12 g/dl. A rate of hemoglobin rise of greater than 1 g/dl over 2 weeks may also contribute to these risks. Cancer patients: Use of ESAs: Shortened the time to tumor progression in patients with advanced head and neck cancer receiving radiation therapy when administered to target a Hb of greater than 12 g/dl. Shortened overall survival and increased deaths attributed to disease progression at 4 months in patients with metastatic breast cancer receiving chemotherapy when administered to target a Hb of greater than 12 g/dl. Increased the risk of death when administered to target a Hb of 12 g/dl in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population. Patients receiving PROCRIT pre-operatively for reduction of allogeneic RBC transfusions: A higher incidence of deep venous thrombosis was documented in patients receiving PROCRIT who were not receiving prophylactic anticoagulation. Antithrombotic prophylaxis should be strongly considered when PROCRIT is used to reduce allogeneic RBC transfusions. Contraindications PROCRIT is contraindicated in patients with uncontrolled hypertension or with known hypersensitivity to albumin (human) or mammalian cell-derived products. Additional Important Safety Information The rate of Hb increase should not exceed 1 g/dl in any two-week period and the Hb concentration should not exceed 12 g/dl. If the Hb approaches 12 g/dl or increases by more than 1 g/dl in a 2-week period, the dose should be reduced by 25%. Withhold the dose of PROCRIT if the Hb exceeds 12 g/dl until the Hb falls below 11g/dL; restart dose at 25% below the previous dose. Monitor Hb regularly during therapy, weekly until Hb becomes stable. Cases of pure red cell aplasia (PRCA) and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with PROCRIT; predominantly in patients with chronic renal failure receiving PROCRIT by subcutaneous administration. If any patient develops a sudden loss of response to PROCRIT, accompanied by severe anemia and low reticulocyte count, and anti-erythropoietin antibody-associated anemia is suspected, withhold PROCRIT and other erythropoietic proteins. Contact ORTHO BIOTECH ( ASKOBI or ) to perform assays for binding and neutralizing antibodies. If erythropoietin antibody-mediated anemia is confi rmed, PROCRIT should be permanently discontinued and patients should not be switched to other erythropoietic proteins. The safety and effi cacy of PROCRIT therapy have not been established in patients with a known history of a seizure disorder or underlying hematologic disease (eg, sickle cell anemia, myelodysplastic syndromes, or hypercoagulable disorders). In some female patients, menses have resumed following PROCRIT therapy; the possibility of pregnancy should be discussed and the need for contraception evaluated. Prior to and regularly during PROCRIT therapy monitor iron status; transferrin saturation should be 20% and ferritin should be 100 ng/ml. During therapy absolute or functional iron defi ciency may develop and all patients will eventually require supplemental iron to adequately support erythropoiesis stimulated by PROCRIT. Treatment of patients with grossly elevated serum erythropoietin levels (e.g., > 200 munits/ml) is not recommended. During PROCRIT therapy, blood pressure should be monitored carefully and aggressively managed, particularly in patients with an underlying history of hypertension or cardiovascular disease. Seizures in PROCRIT-treated patients have been reported in the context of a signifi cant increase in hemoglobin from baseline; increases in blood pressure were not always observed; and patients may have had other underlying central nervous system pathology. The most commonly reported side effects (>10%) for PROCRIT in clinical trials were pyrexia, diarrhea, nausea, vomiting, edema, asthenia, fatigue, shortness of breath, paresthesia, and upper respiratory infection. Please see adjacent page for Brief Summary of Prescribing Information, including Boxed WARNINGS. Manufactured by: Amgen Inc., Thousand Oaks, California Distributed by: Ortho Biotech Products, L.P., Bridgewater, New Jersey Ortho Biotech Products, L.P /07 08PCTC2367A