2008 Bristol-Myers Squibb Company 729US08AB /08

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1 2008 Bristol-Myers Squibb Company 729US08AB /08

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6 YOUR involvement OUR commitment Two opportunities for investigators to participate in further research with VELCADE in relapsed follicular lymphoma Two US-based trials are now recruiting in relapsed follicular lymphoma VERTICAL and VR-CAP. Both trials are evaluating the efficacy and safety of VELCADE in combination with novel and established regimens. VERTICAL VELCADE, Rituximab, and Bendamustine A phase 2, single-arm, open-label, multicenter study evaluating the efficacy and safety of VELCADE (bortezomib) for Injection in combination with bendamustine and rituximab in subjects with relapsed or refractory follicular lymphoma, who have received 4 or more doses of rituximab. ClinicalTrials.gov Identifier: NCT Patients with relapsed/ refractory follicular lymphoma. VELCADE (weekly) Rituximab Bendamustine Patients assessed for response rates, progression-free survival, duration of response, and safety. VR-CAP VELCADE, Rituximab, Cyclophosphamide, Prednisone Doxorubicin A phase 2, two-arm, nonrandomized, open-label, multicenter study evaluating the safety and efficacy of VELCADE (bortezomib) for Injection in combination with rituximab, cyclophosphamide, and prednisone doxorubicin in patients with relapsed or refractory follicular lymphoma. ClinicalTrials.gov Identifier: NCT Patients with relapsed/refractory follicular lymphoma. Investigator choice VELCADE (weekly) Rituximab Cyclophosphamide Prednisone VELCADE (weekly) Rituximab Cyclophosphamide Prednisone Doxorubicin Patients receive rituximab maintenance therapy for 2 years. Patients assessed for response rates, safety, progression-free survival, and duration of response. VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA Copyright 2009, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA 01/09 For more information about both trials, call Millennium at or visit

7 2008 Genzyme Corporation. All rights reserved

8 Don t Miss Myeloma Patients at the Initial Presentation New Guidelines recommend that serum free light chain assays be used in the initial evaluation of suspected myeloma 1 Guidelines published by the International Myeloma Working Group state that "serum FLC is recommended as part of screening for pathological monoclonal plasma proliferative disorders." Previous studies confirm this recommendation: The detection rate for plasma cell disorders increased from 48% for serum protein electrophoresis (spep/spe) alone to 100% when both spep and Freelite Serum Free Light Chain assays were used together. 2 Addition of the free κ/λ ratio to CZE increases the yield of lymphocyte and plasma cell proliferative processes detected by 56% Durie, et al. Hemat Meet. Report. 2008;2(2):19 2. Abadie, et al. Ann. Clin. Lab. Science. 2006;36: Bakshi, et al. Am. J. Clin. Pathol. 2005;124: Use Freelite Serum Free Light Chain assays in your initial evaluation of suspected myeloma. You can order Freelite assays at all major U.S. reference laboratories, myeloma centers and many hospital laboratories worldwide. Freelite is a trademark of The Binding Site Ltd, Birmingham, UK. THE BINDING SITE LTD United Kingdom Tel: +44 (0) Fax: +44 (0) info@bindingsite.co.uk THE BINDING SITE INC United States of America Tel: Fax: myeloma@thebindingsite.com us for your free copy of Serum Free Light Chain Analysis, 5th Edition.

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11 Take IV iron therapy to a proven place: Response with toleration! Please see brief prescribing information and references on following pages. Enriching lives of anemia patients. Venofer is manufactured under license from Vifor (International) Inc., Switzerland American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: Orders or information: venofer.com

12 The only first-line IV iron for pre-dialysis CKD patients... In treatment of iron deficiency anemia Raises hemoglobin levels and improves iron stores 1 Effective with or without erythropoietin With a demonstrated safety profile No test dose required; no black box warning Contains no dextran or modified dextran Greater tolerability than oral iron with fewer gastrointestinal symptoms IMPORTANT SAFETY INFORMATION: Venofer (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (CKD) patients receiving IV iron. Hypotension following administration of Venofer may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in non-dialysis dependent-ckd patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension. Reinvigorating anemia management. *100 mg vials and ampules worldwide from 1993 to 2007.

13 Reference: 1. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer ) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68: Data on file. American Regent, Inc., Shirley, NY. Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer (iron sucrose injection, USP) is indicated in the treatment of iron deficiency anemia in the following patients: non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer. No life-threatening hypersensitivity reactions were observed in the clinical studies.several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer. Venofer was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer. 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. Nursing Mothers: Venofer is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer in pediatric patients have not been established. In a country where Venofer is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer or any other drugs could be established. Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-ckd patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent- CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDD-CKD in the randomized clinical trials, whether or not related to Venofer administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Adverse Events Venofer Oral Iron (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal 0 0 Infusion site burning Injection site extravasation Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection 0 0 Nasopharyngitis Peritoneal infection 0 0 Sinusitis NOS Upper respiratory tract infection NOS Urinary tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Arthritis NOS 0 0 Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population) NDD-CKD Adverse Events 200 mg 500 mg (Preferred Term) (N=109) (N=30) % % Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal 0 0 Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection 0 0 Nasopharyngitis Peritoneal infection 0 0 Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia (Table 2 continued) NDD-CKD Adverse Events Venofer Oral Iron (Preferred Term) (N=139) (N=139) % % Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis 0 0 Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified (Table 3 continued) NDD-CKD Adverse Events 200 mg 500 mg (Preferred Term) (N=109) (N=30) % % Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis 0 0 Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS Drug related adverse events reported by 2% of Venofer (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population) NDD-CKD Adverse Events 200 mg 500 mg (Preferred Term) (N=109) (N=30) % % Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* 0 0 Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS *NOS=Not otherwise specified *NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer. Adverse events, whether or not related to Venofer, reported by 5% of the Venofer exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer group), three Venofer patients had events that were considered drug-related (hypotension, dyspnea and nausea). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer administration. OVERDOSAGE Dosages of Venofer (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation.venofer should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer is expressed in terms of mg of elemental iron. Each ml contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin,tsat). Administration: Venofer must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD):Venofer is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period.there is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 ml of 0.9% NaCl, over a period of hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS, Study D: Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer is supplied in 5 ml and 10 ml single dose vials. Each 5 ml vial contains 100 mg elemental iron (20 mg/ml) and each 10 ml vial contains 200 mg elemental iron (20 mg/ml). Contains no preservatives. Store in original carton at 25 C (77 F). Excursions permitted to C (59-86 F). [See the USP controlled room temperature]. Do not freeze. Sterile NDC mg/5 ml Single Dose Vial Individually Boxed NDC mg/10 ml Single Dose Vial Individually Boxed NDC mg/5 ml Single Dose Vial Packages of 10 NDC mg/10 ml Single Dose Vial Packages of 5 NDC mg/5 ml Single Dose Vial Packages of 25 NDC mg/10 ml Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, Am J Kidney Dis. 37: S182-S238, (suppl 1) BS2340 VENJA Rev. 10/08 Rev 10/2008 Venofer is manufactured under license from Vifor (International) Inc., Switzerland American Regent, Inc

14 NCI Clinical Trials at NIH Now at Your Fingertips It is easier than ever to find the right clinical trials for your patients. NCI clinical trials at the NIH Clinical Center are now online and fully searchable. NCI is currently conducting trials for many types of cancer including, but not limited to: Melanoma Hematologic Malignancies Brain Tumor Pediatric Cancers To learn whether your patients may be eligible or to refer patients, visit bethesdatrials.cancer.gov or call NCI-1937( ) The NIH Clinical Center in Bethesda, Md. 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 results or informative patient presentations are considered for publication in this category. Begin the Brief Report by documenting experimental results witha 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 Blood in print ISSN Blood Online ISSN 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.

15 VIDAZA (azacitidine for injection) The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE 1.1 Myelodysplastic Syndromes (MDS) VIDAZA is indicated for treatment of patients with the following French- American-British (FAB) myelodysplastic syndrome subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL). 4 CONTRAINDICATIONS 4.1 Advanced Malignant Hepatic Tumors VIDAZA is contraindicated in patients with advanced malignant hepatic tumors [see Warnings and Precautions (5.2)]. 4.2 Hypersensitivity to Azacitidine or Mannitol VIDAZA is contraindicated in patients with a known hypersensitivity to azacitidine or mannitol. 5 WARNINGS AND PRECAUTIONS 5.1 Anemia, Neutropenia and Thrombocytopenia Treatment with VIDAZA is associated with anemia, neutropenia and thrombo - cyto penia. Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each dosing cycle. After administration of the recommended dosage for the first cycle, dosage for subsequent cycles should be reduced or delayed based on nadir counts and hematologic response [see Dosage and Administration (2.3) in full prescribing information]. 5.2 Severe Preexisting Hepatic Impairment Because azacitidine is potentially hepatotoxic in patients with severe pre - existing hepatic impairment, caution is needed in patients with liver disease. Patients with extensive tumor burden due to metastatic disease have been rarely reported to experience progressive hepatic coma and death during azacitidine treatment, especially in such patients with baseline albumin <30 g/l. Azacitidine is contra indicated in patients with advanced malignant hepatic tumors [see Contraindications (4.1)]. Safety and effectiveness of VIDAZA in patients with MDS and hepatic impairment have not been studied as these patients were excluded from the clinical trials. 5.3 Renal Abnormalities Renal abnormalities ranging from elevated serum creatinine to renal failure and death have been reported rarely in patients treated with intravenous azacitidine in combination with other chemotherapeutic agents for non- MDS conditions. In addition, renal tubular acidosis, defined as a fall in serum bicarbonate to <20 meq/l in association with an alkaline urine and hypokalemia (serum potassium <3 meq/l) developed in 5 patients with CML treated with azacitidine and etoposide. If unexplained reductions in serum bicarbonate <20 meq/l or elevations of BUN or serum creatinine occur, the dosage should be reduced or held [see Dosage and Administration (2.4) in full prescribing information]. Patients with renal impairment should be closely monitored for toxicity since azacitidine and its metabolites are primarily excreted by the kidneys [see Dosage and Administration (2.4, 2.5) in full prescribing information]. Safety and effectiveness of VIDAZA in patients with MDS and renal impairment have not been studied as these patients were excluded from the clinical trials. 5.4 Monitoring Laboratory Tests Complete blood counts should be performed as needed to monitor response and toxicity, but at a minimum, prior to each cycle. Liver chemistries and serum cre atinine should be obtained prior to initiation of therapy. 5.5 Pregnancy Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine caused congenital malformations in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. There are no adequate and well-controlled studies in pregnant women using VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 5.6 Use in Males Men should be advised to not father a child while receiving treatment with VIDAZA. In animal studies, pre-conception treatment of male mice and rats resulted in increased embryofetal loss in mated females [see Nonclinical Toxicology (13)]. 6 ADVERSE REACTIONS 6.1 Overview Adverse Reactions Described in Other Labeling Sections: anemia, neutropenia, thrombocytopenia, elevated serum creatinine, renal failure, renal tubular acidosis, hypokalemia, hepatic coma [see Warnings and Precautions (5.1, 5.2, 5.3)]. Most Commonly Occurring Adverse Reactions (SC or IV Route): nausea, anemia, thrombocytopenia, vomiting, pyrexia, leukopenia, diarrhea, injection site erythema, constipation, neutropenia, ecchymosis. The most common adverse reactions by IV route also included petechiae, rigors, weak ness and hypokalemia. Adverse Reactions Most Frequently (>2%) Resulting in Clinical Intervention (SC or IV Route): Discontinuation: leukopenia, thrombocytopenia, neutropenia. Dose Held: leukopenia, neutropenia, thrombocytopenia, pyrexia, pneumonia, febrile neutropenia. Dose Reduced: leukopenia, neutropenia, thrombocytopenia. 6.2 Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to VIDAZA in 443 MDS patients from 4 clinical studies. Study 1 was a supportivecare controlled trial (SC administration), Studies 2 and 3 were single arm studies (one with SC administration and one with IV administration), and Study 4 was an international randomized trial (SC administration) [see Clinical Studies (14)]. In Studies 1, 2 and 3, a total of 268 patients were exposed to VIDAZA, including 116 exposed for 6 cycles (approximately 6 months) or more and 60 exposed for greater than 12 cycles (approximately one year). VIDAZA was studied primarily in supportive-care controlled and uncontrolled trials (n=150 and n=118, respectively). The population in the subcutaneous studies (n=220) was 23 to 92 years old (mean 66.4 years), 68% male, and 94% white, and had MDS or AML. The population in the IV study (n=48) was 35 to 81 years old (mean 63.1 years), 65% male, and 100% white. Most patients received average daily doses between 50 and 100 mg/m 2. In Study 4, a total of 175 patients with higher-risk MDS (primarily RAEB and RAEB-T subtypes) were exposed to VIDAZA. Of these patients, 119 were exposed for 6 or more cycles, and 63 for at least 12 cycles. The mean age of this population was 68.1 years (ranging from 42 to 83 years), 74% were male, and 99% were white. Most patients received daily VIDAZA doses of 75 mg/m 2. Table 1 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA (SC) in Studies 1 and 2. It is important to note that duration of exposure was longer for the VIDAZA-treated group than for the observation group: patients received VIDAZA for a mean of 11.4 months while mean time in the observation arm was 6.1 months. Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC VIDAZA Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class All VIDAZA b Observation c Preferred Term a (N=220) (N=92) Blood and lymphatic system disorders Anemia 153 (69.5) 59 (64.1) Anemia aggravated 12 (5.5) 5 (5.4) Febrile neutropenia 36 (16.4) 4 (4.3) Leukopenia 106 (48.2) 27 (29.3) Neutropenia 71 (32.3) 10 (10.9) Thrombocytopenia 144 (65.5) 42 (45.7) Gastrointestinal disorders Abdominal tenderness 26 (11.8) 1 (1.1) Constipation 74 (33.6) 6 (6.5) Diarrhea 80 (36.4) 13 (14.1) Gingival bleeding 21 (9.5) 4 (4.3) Loose stools 12 (5.5) 0 Mouth hemorrhage 11 (5.0) 1 (1.1) Nausea 155 (70.5) 16 (17.4) Stomatitis 17 (7.7) 0 Vomiting 119 (54.1) 5 (5.4) continued

16 Table 1: Most Frequently Observed Adverse Reactions ( 5.0% in All SC VIDAZA Treated Patients; Studies 1 and 2) Number (%) of Patients System Organ Class All VIDAZA b Observation c Preferred Term a (N=220) (N=92) General disorders and administration site conditions Chest pain 36 (16.4) 5 (5.4) Injection site bruising 31 (14.1) 0 Injection site erythema 77 (35.0) 0 Injection site granuloma 11 (5.0) 0 Injection site pain 50 (22.7) 0 Injection site pigmentation changes 11 (5.0) 0 Injection site pruritus 15 (6.8) 0 Injection site reaction 30 (13.6) 0 Injection site swelling 11 (5.0) 0 Lethargy 17 (7.7) 2 (2.2) Malaise 24 (10.9) 1 (1.1) Pyrexia 114 (51.8) 28 (30.4) Infections and infestations Nasopharyngitis 32 (14.5) 3 (3.3) Pneumonia 24 (10.9) 5 (5.4) Upper respiratory tract infection 28 (12.7) 4 (4.3) Injury, poisoning, and procedural complications Post procedural hemorrhage 13 (5.9) 1 (1.1) Metabolism and nutrition disorders Anorexia 45 (20.5) 6 (6.5) Musculoskeletal and connective tissue disorders Arthralgia 49 (22.3) 3 (3.3) Chest wall pain 11 (5.0) 0 Myalgia 35 (15.9) 2 (2.2) Nervous system disorders Dizziness 41 (18.6) 5 (5.4) Headache 48 (21.8) 10 (10.9) Psychiatric disorders Anxiety 29 (13.2) 3 (3.3) Insomnia 24 (10.9) 4 (4.3) Respiratory, thoracic and mediastinal disorders Dyspnea 64 (29.1) 11 (12.0) Skin and subcutaneous tissue disorders Dry skin 11 (5.0) 1 (1.1) Ecchymosis 67 (30.5) 14 (15.2) Erythema 37 (16.8) 4 (4.3) Rash 31 (14.1) 9 (9.8) Skin nodule 11 (5.0) 1 (1.1) Urticaria 13 (5.9) 1 (1.1) Vascular disorders Hematoma 19 (8.6) 0 Hypotension 15 (6.8) 2 (2.2) Petechiae 52 (23.6) 8 (8.7) a Multiple terms of the same preferred terms for a patient are only counted once within each treatment group. b Includes adverse reactions from all patients exposed to VIDAZA, including patients after crossing over from observations. c Includes adverse reactions from observation period only; excludes any adverse events after crossover to VIDAZA. Table 2 presents adverse reactions occurring in at least 5% of patients treated with VIDAZA in Study 4. Similar to Studies 1 and 2 described above, duration of exposure to treatment with VIDAZA was longer (mean 12.2 months) compared with best supportive care (mean 7.5 months). Table 2: Most Frequently Observed Adverse Reactions ( 5.0% in the VIDAZA Treated Patients and the Percentage with NCI CTC Grade 3/4 Reactions; Study 4) Number (%) of Patients Any Grade Grade 3/4 Best Best Supportive Supportive System Organ Class VIDAZA Care Only VIDAZA Care Only Preferred Term a (N=175) (N=102) (N=175) (N=102) Blood and lymphatic system disorders Anemia 90 (51.4) 45 (44.1) 24 (13.7) 9 (8.8) Febrile neutropenia 24 (13.7) 10 (9.8) 22 (12.6) 7 (6.9) Leukopenia 32 (18.3) 2 (2.0) 26 (14.9) 1 (1.0) Neutropenia 115 (65.7) 29 (28.4) 107 (61.1) 22 (21.6) Thrombocytopenia 122 (69.7) 35 (34.3) 102 (58.3) 29 (28.4) Gastrointestinal disorders Abdominal pain 22 (12.6) 7 (6.9) 7 (4.0) 0 Constipation 88 (50.3) 8 (7.8) 2 (1.1) 0 Dyspepsia 10 (5.7) 2 (2.0) 0 0 Nausea 84 (48.0) 12 (11.8) 3 (1.7) 0 Vomiting 47 (26.9) 7 (6.9) 0 0 General disorders and administration site conditions Fatigue 42 (24.0) 12 (11.8) 6 (3.4) 2 (2.0) Injection site bruising 9 (5.1) Injection site erythema 75 (42.9) Injection site hematoma 11 (6.3) Injection site induration 9 (5.1) Injection site pain 33 (18.9) Injection site rash 10 (5.7) Injection site reaction 51 (29.1) 0 1 (0.6) 0 Pyrexia 53 (30.3) 18 (17.6) 8 (4.6) 1 (1.0) Infections and infestations Rhinitis 10 (5.7) 1 (1.0) 0 0 Upper respiratory tract infection 16 (9.1) 4 (3.9) 3 (1.7) 0 Urinary tract infection 15 (8.6) 3 (2.9) 3 (1.7) 0 Investigations Weight decreased 14 (8.0) 0 1 (0.6) 0 Metabolism and nutrition disorders Hypokalemia 11 (6.3) 3 (2.9) 3 (1.7) 3 (2.9) Nervous system disorders Lethargy 13 (7.4) 2 (2.0) 0 1 (1.0) Psychiatric disorders Anxiety 9 (5.1) 1 (1.0) 0 0 Insomnia 15 (8.6) 3 (2.9) 0 0 Renal and urinary disorders Hematuria 11 (6.3) 2 (2.0) 4 (2.3) 1 (1.0) Respiratory, thoracic and mediastinal disorders Dyspnea 26 (14.9) 5 (4.9) 6 (3.4) 2 (2.0) Dyspnea exertional 9 (5.1) 1 (1.0) 0 0 Pharyngolaryngeal pain 11 (6.3) 3 (2.9) 0 0 Skin and subcutaneous tissue disorders Erythema 13 (7.4) 3 (2.9) 0 0 Petechiae 20 (11.4) 4 (3.9) 2 (1.1) 0 Pruritus 21 (12.0) 2 (2.0) 0 0 Rash 18 (10.3) 1 (1.0) 0 0 Vascular disorders Hypertension 15 (8.6) 4 (3.9) 2 (1.1) 2 (2.0) a Multiple reports of the same preferred term from a patient were only counted once within each treatment.

17 In Studies 1, 2 and 4 with SC administration of VIDAZA, adverse reactions of neutropenia, thrombocytopenia, anemia, nausea, vomiting, diarrhea, constipation, and injection site erythema/reaction tended to increase in incidence with higher doses of VIDAZA. Adverse reactions that tended to be more pronounced during the first 1 to 2 cycles of SC treatment compared with later cycles included thrombocytopenia, neutropenia, anemia, nausea, vomiting, injection site erythema/pain/bruising/reaction, constipation, petechiae, dizziness, anxiety, hypokalemia, and insomnia. There did not appear to be any adverse reactions that increased in frequency over the course of treatment. Overall, adverse reactions were qualitatively similar between the IV and SC studies. Adverse reactions that appeared to be specifically associated with the IV route of administration included infusion site reactions (e.g., erythema or pain) and catheter site reactions (e.g., infection, erythema, or hemorrhage). In clinical studies of either SC or IV VIDAZA, the following serious adverse reactions occurring at a rate of < 5% (and not described in Tables 1 or 2) were reported: Blood and lymphatic system disorders: agranulocytosis, bone marrow failure, pancytopenia, splenomegaly. Cardiac disorders: atrial fibrillation, cardiac failure, cardiac failure congestive, cardio-respiratory arrest, congestive cardiomyopathy. Eye disorders: eye hemorrhage. Gastrointestinal disorders: diverticulitis, gastro intestinal hemorrhage, melena, perirectal abscess. General disorders and administration site conditions: catheter site hemorrhage, general physical health deterioration, systemic inflammatory response syndrome. Hepatobiliary disorders: cholecystitis. Immune system disorders: anaphylactic shock, hypersensitivity. Infections and infestations: abscess limb, bacterial infection, cellulitis, blasto mycosis, injection site infection, Klebsiella sepsis, neutropenic sepsis, pharyngitis streptococcal, pneumonia Klebsiella, sepsis, septic shock, Staphylococcal bacteremia, Staphylococcal infection, toxoplasmosis. Metabolism and nutrition disorders: dehydration. Musculoskeletal and connective tissue disorders: bone pain aggravated, muscle weakness, neck pain. Neoplasms benign, malignant and unspecified: leukemia cutis. Nervous system disorders: cerebral hemorrhage, convulsions, intracranial hemorrhage. Renal and urinary disorders: loin pain, renal failure. Respiratory, thoracic and mediastinal disorders: hemop tysis, lung infiltration, pneumonitis, respiratory distress. Skin and subcutaneous tissue disorders: pyoderma gangrenosum, rash pruritic, skin induration. Surgical and medical procedures: cholecystectomy. Vascular disorders: orthostatic hypotension. 6.3 Postmarketing Experience Adverse reactions identified from spontaneous reports have been similar to those reported during clinical trials with VIDAZA. 7 DRUG INTERACTIONS No formal assessments of drug-drug interactions between VIDAZA and other agents have been conducted [see Clinical Pharmacology (12.3) in the full prescribing information]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D VIDAZA may cause fetal harm when administered to a pregnant woman. Azacitidine was teratogenic in animals. Women of childbearing potential should be advised to avoid pregnancy during treatment with VIDAZA. If this drug is used during pregnancy or if a patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Female partners of male patients receiving VIDAZA should not become pregnant [see Nonclinical Toxicology (13)]. Early embryotoxicity studies in mice revealed a 44% frequency of intra - uterine embryonal death (increased resorption) after a single IP (intra- peritoneal) injection of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 basis) azacitidine on gestation day 10. Developmental abnormalities in the brain have been detected in mice given azacitidine on or before gestation day 15 at doses of ~3-12 mg/m 2 (approximately 4%-16% the recommended human daily dose on a mg/m 2 basis). In rats, azacitidine was clearly embryotoxic when given IP on gestation days 4-8 (postimplantation) at a dose of 6 mg/m 2 (approximately 8% of the recommended human daily dose on a mg/m 2 basis), although treatment in the preimplantation period (on gestation days 1-3) had no adverse effect on the embryos. Azacitidine caused multiple fetal abnormalities in rats after a single IP dose of 3 to 12 mg/m 2 (approximately 8% the recommended human daily dose on a mg/m 2 basis) given on gestation day 9, 10, 11 or 12. In this study azacitidine caused fetal death when administered at 3-12 mg/m 2 on gestation days 9 and 10; average live animals per litter was reduced to 9% of control at the highest dose on gestation day 9. Fetal anomalies included: CNS anomalies (exencephaly/encephalocele), limb anomalies (micromelia, club foot, syndactyly, oligodactyly), and others (micro- gnathia, gastro schisis, edema, and rib abnormalities). 8.3 Nursing Mothers It is not known whether azacitidine or its metabolites are excreted in human milk. Because of the potential for tumorigenicity shown for azacitidine in animal studies and 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 consideration the importance of the drug to the mother. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Of the total number of patients in Studies 1, 2 and 3, 62% were 65 years and older and 21% were 75 years and older. No overall differences in effectiveness were observed between these patients and younger patients. In addition there were no relevant differences in the frequency of adverse reactions observed in patients 65 years and older compared to younger patients. Of the 179 patients randomized to azacitidine in Study 4, 68% were 65 years and older and 21% were 75 years and older. Survival data for patients 65 years and older were consistent with overall survival results. The majority of adverse reactions occurred at similar frequencies in patients < 65 years of age and patients 65 years of age and older. Azacitidine and its metabolites are known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be useful to monitor renal function [see Dosage and Administration (2.5) in full prescribing information and Warnings and Precautions (5.3)]. 8.6 Gender Differences There were no clinically relevant differences in safety and efficacy based on gender. 8.7 Race Greater than 90% of all patients in all trials were Caucasian. Therefore, no comparisons between Caucasians and non-caucasians were possible. 13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The potential carcinogenicity of azacitidine was evaluated in mice and rats. Azacitidine induced tumors of the hematopoietic system in female mice at 2.2 mg/kg (6.6 mg/m 2, approximately 8% the recommended human daily dose on a mg/m 2 basis) administered IP three times per week for 52 weeks. An increased incidence of tumors in the lymphoreticular system, lung, mammary gland, and skin was seen in mice treated with azacitidine IP at 2.0 mg/kg (6.0 mg/m 2, approximately 8% the recommended human daily dose on a mg/m 2 basis) once a week for 50 weeks. A tumorigenicity study in rats dosed twice weekly at 15 or 60 mg/m 2 (approximately 20-80% the recommended human daily dose on a mg/m 2 basis) revealed an increased incidence of testicular tumors compared with controls. The mutagenic and clastogenic potential of azacitidine was tested in in vitro bacte rial systems Salmonella typhimurium strains TA100 and several strains of trpe8, Escherichia coli strains WP14 Pro, WP3103P, WP3104P, and CC103; in in vitro forward gene mutation assay in mouse lymphoma cells and human lymphoblast cells; and in an in vitro micronucleus assay in mouse L5178Y lymphoma cells and Syrian hamster embryo cells. Azacitidine was mutagenic in bacterial and mammalian cell systems. The clastogenic effect of azacitidine was shown by the induction of micronuclei in L5178Y mouse cells and Syrian hamster embryo cells. Administration of azacitidine to male mice at 9.9 mg/m 2 (approximately 9% the recommended human daily dose on a mg/m 2 basis) daily for 3 days prior to mating with untreated female mice resulted in decreased fertility and loss of offspring during subsequent embryonic and postnatal development. Treatment of male rats 3 times per week for 11 or 16 weeks at doses of mg/m 2 (approximately 20-40%, the recommended human daily dose on a mg/m 2 basis) resulted in decreased weight of the testes and epididy - mides, and decreased sperm counts accompanied by decreased pregnancy rates and increased loss of embryos in mated females. In a related study, male rats treated for 16 weeks at 24 mg/m 2 resulted in an increase in abnormal embryos in mated females when examined on day 2 of gestation. 17 PATIENT COUNSELING INFORMATION Instruct patients to inform their physician about any underlying liver or renal disease. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with VIDAZA. For nursing mothers, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into consideration the importance of the drug to the mother. Advise men not to father a child while receiving treatment with VIDAZA. Manufactured for: Celgene Corporation Summit, NJ Manufactured by: Ben Venue Laboratories, Inc. Or Baxter Oncology GmbH Bedford, OH Halle/Westfalen Germany VidPlyPI.001 BS 08/08

18 2009 Pan Pacific Lymphoma Conference CALL FOR ABSTRACTS Deadline March 30, 2009 Claim your CME credit from the 2008 ASH Annual Meeting! The Fairmont Orchid The Big Island of Hawaii June 22-26, 2009 Nursing Component June 22-23, 2009 Recent Advances in Hematopathology Component June 23, 2009 Medical Component June 24-26, 2009 Corporate Symposia June 22-26, 2009 For More Information Call (402) or toll free (877) Facsimile (402) Brenda Ram, CMP at The deadline for claiming CME credits for the 2008 ASH Annual Meeting is March 31, To claim your CME credits, please visit ashcm08/ How do you get double the exposure for the same price? Your classified advertisement in Blood gives you more exposure than you think. When you place a print advertisement, you will also receive a free 30-day* posting on the American Society of Hematology s online Job Bank. This employment resource is located at and is free for all job seekers. For more information on submitting a classified ad in Blood, contact Valerie Marvin at vmarvin@cunnasso.com or at *Your 30-day online posting will start when your print advertisement first appears in Blood.

19 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 days. The average time from submission to publication is 7 weeks. Authors are invited to contact the Editor-in-Chief (bloodeditor@ hematology.org) prior to submission if they are uncertain whether their work falls within the general scope of the journal. Non-Englishspeaking authors are encouraged to contact the journal (editorial@ hematology.org) for reference to a professional editing service that may help improve the presentation of the paper. Regular Articles.The maximum length for a Regular Article is 5,000 references; abstracts must not exceed 200 words and should be a single paragraph with no subheadings. Submissions are limited to References should be limited to 50. The sections of a Regular Article should include Abstract, Introduction, Material and Methods, Results, Discussion, References, Figure Legends. Plenary Papers.Definitive original research articles of exceptional scientific importance may be considered for designation as Plenary Papers. The decision to highlight an article as a Plenary Paper rests entirely with the Editors. Review Articles. Review articles are welcomed by the journal and are generally solicited by the Editor-in-Chief. Authors wishing to submit a non-solicited Review Article should contact the Editor-in- Chief prior to submission. Review articles should focus on recent and should include appropriate references to the literature. Review articles should not exceed 5,000 words in length, must include an abstract of 200 words or fewer, and may not have more than critical points is encouraged; the Journal offers a service to professionally illustrate Reviews, once accepted, as appropriate. All Review Articles, even those solicited by the Editors, are Reviews in Translational Hematology. These critical reviews describe recent advances in basic science with direct future applications in patient diagnosis or treatment. Perspectives. and controversies relevant to hematology. Interested authors should correspond with the Editor-in-Chief prior to submission to discuss the suitability of the proposed subject matter. The length should not exceed 2,500 words; the abstract must not exceed 200 words; and references are limited to 50. Typically, Perspectives should state the topic and background information concisely, discuss opposing viewpoints, and make recommendations for further investigations or actions. Inside Blood. the same print issue of Blood. Brief Reports. Brief reports are short manuscripts definitively documenting either experimental results or informative clinical observations will be considered for publication in this category. Singlecase reports or case series can almost never be accommodated, unless they elucidate novel and important disease biology or approaches to therapy. Brief Reports are not intended to review process is equally rigorous as for Regular Articles. Brief included. The sections of a Brief Report should include Abstract, allow reproduction of the data, followed by a combined Results and Discussion section, References and Figure Legends. How I Treat. The journal welcomes articles written by expert clinicians offering up-to-date information and guidance regarding diagnosis and treatment of hematological diseases. Clear distinctions should be made between evidence-based versus experience-based recommendations. These pieces are generally solicited by the Editor-in-Chief, but any interested author is invited to correspond with the Editor-in-Chief prior to submission to discuss the suitability of the proposed subject matter. The length should not exceed 2,500 words; the abstract must not exceed 200 words; and references are limited to 50. Blood Work. Blood welcomes submissions of photo micrographs and brief case descriptions to serve as a comprehensive reference and teaching tool accessible to physicians and hematology students around the world. These images and cases will be published by the journal in a Blood Work section, in every a discussion of 250 words or less describing the clinical case will also be submitted for consideration to the ASH Image Bank. All other policies governing submissions to the journal apply to charges for publication if accepted. If you have questions, please Letters to the Editor. Constructive comments on published articles or current topics in hematology are welcome and will be published if appropriate. Letters can include no more than necessary. No abstract is required, but please include a brief title. Submission fees and page charges do not apply to Letters. Letters are screened by the Editor-in-Chief and, if deemed accompanied by a Response from the authors of the initial article. Data Supplements. The Journal encourages the submission of Data Supplements linked to primary research articles, 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. Public Access. is free to all online. Additionally, ASH has developed an agreement with the National Institutes of Health (NIH) that creates a new option to comply with the NIH policy on enhanced access. All Blood authors who published NIH-funded articles from May 2005 forward have no obligation to submit manuscripts to the NIH archive because Blood will do this on their behalf. The new option, the PMC(NIH Portfolio) Archive xxi

20 Author guide publishers to improve compliance with the current NIH public access policy while maintaining the publisher-mandated access embargoes. funded research for an internal use archive at NIH. ASH believes the PMC (NIH Portfolio) Archive program provides a better alternative for authors and journals than a mandated policy with a shorter embargo period. During implementation of this program over the course of the year, ASH hopes to continue to work with the NIH on ways to enhance access. ASH has implemented a public access policy in which Howard Hughes Medical Institute funded papers are deposited into PMC on payment of a public access fee of $2,000, in addition to the regular publication fees charged to authors. This public access option has now been extended to any author, for the same public access fee of $2,000. Upon payment of the fee, Blood will deposit the article into PMC and more information about the public access policy for Blood during the manuscript submission process. Contact information. question(s) in our complete Author Guide at hematologylibrary.org/authors/authorguide.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: For general inquiries: editorial@hematology.org (submission, peer review, First Edition) production@hematology.org (copyediting queries, proofs, print-quality image requirements) bloodsubs@hematology.org (Blood subscriptions) bloodpermissions@hematology.org (reprint and permission inquiries) Visit our complete Author Guide online at ifora.dtl for information on the following topics: About Blood Journal scope Journal facts Article types Original research articles Other article types Manuscript Preparation Manuscript Submission Peer Review Revised Manuscripts Accepted Manuscripts Prepublication in First Edition Online copyright transfer Requirements for print Cover illustrations Proofreading Publication fees Editorial Policies for Authors Authorship criteria Copyright assignment Duplicate or prior publication Principles for publication of medical research involving human subjects Data sharing, distribution of reagents, and compound structure disclosure Deposition into public databases Clinical trial registry Guidelines for stem cell research Public access options for authors Submission of NIH-funded accepted manuscripts to PubMed Central Press embargo policy Blood Style Guide Checklist for revised online manuscripts Change of authorship form Authors FAQs regarding manuscript submission xxii

21 Absolute identification of protein biomarkers? Absolutely. Did you know that autoantibodies can be useful indicators of many diseases including cancer? Now with 8,200 full-length proteins on every microarray, ProtoArray Human Protein MicroArrays deliver absolute identification of novel autoantibody markers for cancer, autoimmune, or other diseases. With sensitivity in the picogram range, you can profile diseased and healthy samples with as little as 1μL of crude sample in your own lab. Or if you prefer, our Immune Response Biomarker Profiling Service offers expert profiling, data analysis, and a comprehensive report that identifies your biomarker candidates. So there s no doubt, and no waiting, because you can get results in just one day. Pinpoint what you need at Invitrogen Corporation. All rights reserved. These products may be covered by one or more Limited Use Label Licenses (see the Invitrogen catalog or our website,

22 Free Blood PDA Downloads and How to Use Them What are PDA downloads? Blood PDA downloads are summaries of the latest Blood content sent directly to your Palm PDA or PocketPC PDA. The summaries consist of tables of contents, article abstracts, and full-text Inside Blood commentaries. Why use PDA downloads? Use Blood PDA downloads if it is more convenient to review the latest Blood content on your PDA than on your computer. Full text of articles can be read on Blood Online or in print. What are the requirements for PDA downloads? Blood PDA downloads work with the Palm operating system and the PocketPC 2002 operating system. They require a Macintosh or Windows computer with which you sync your PDA. You must register with HighWire Press (a free service), and you must download a small piece of software to your PDA via your desktop computer with which you sync your PDA. How do I set up my PDA? Once you have registered with HighWire Press, follow the instructions to download the HW View software. Then sync your PDA with your desktop computer to download your Blood content. How do I get future content? You must sync your PDA with your desktop computer each time you want the latest Blood content summaries. Then the summaries are on your PDA for your use away from your computer.

23 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.

24 Free Blood Content Alerts and How to Use Them What are content alerts? Blood content alerts are s sent to you notifying you that new content has been published on Blood Online. You can ask to be alerted about new issues (etoc alerts), about future article lists (ftoc alerts), about new articles in a particular online collection (collection alerts), about prepublication of manuscripts on First Edition Papers, or about customized bibliographic searches (CiteTrack alerts). What are CiteTrack content alerts? Blood CiteTrack alerts let you set up the parameters of your search before the content gets published. So if you want to be notified when we publish an article by a certain author, an article with a certain keyword in its title, abstract, or full text, or an article that cites a previously published article, you can set up a Blood CiteTrack alert to automatically notify you. Who can use content alerts? Anyone who is a registered user of Blood Online can set up any number of content alerts. You don t have to subscribe to be a registered user; so Blood content alerts are free to anyone. How do I set up a content alert? Go to and click Alerts to get started. If you aren t yet a registered user of Blood Online, you will be prompted to register. Registration is free.

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26 Blood First Edition Papers and How to Cite Them What are First Edition Papers? Blood First Edition Papers are accepted papers prepublished online in manuscript form. They have undergone full scientific review but no copyediting, typesetting, or proofreading; those processes occur after prepublication and result in final print and online publication in issue form. How often do new First Edition Papers appear? New manuscripts are prepublished every business day. How can I monitor new First Edition Papers? All current First Edition Papers are listed on Blood Online at the First Edition link. All papers are also indexed almost immediately on PubMed. You can also set up a Blood Online content alert that automatically s you when new First Edition Papers are posted. How do I cite a First Edition Paper? Because Blood First Edition Papers are prepublished before assignment to an issue, they lack a volume or page number and, therefore, cannot be cited in the traditional way. You should cite a First Edition Paper using its byline, title, prepublication date, and DOI. If you are citing it in Blood, use the following format: Lantner F, Starlets D, Gore Y, Flaishon L, et al. CD74 induces TAp63 expression leading to B cell survival. Blood. Prepublished on September 10, 2007, as DOI /blood What is a DOI? To aid citation, Blood assigns a DOI (digital object identifier) to each First Edition Paper. A DOI is a unique code that may be used to locate the article in perpetuity. The DOI is the best way to locate a First Edition Paper. Because Blood retains the DOI on the final print and online version of the article, it may also be used after final publication to locate an article via the Blood Online search page. Where do I find the DOI? It is at the top of each Blood First Edition Paper.

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28 To prevent and potentially reverse many of the symptoms of type 1 Gaucher disease 1,2 Cerezyme imiglucerase for injection leads the way Proven efficacy and safety for over 14 years 1 Used by more than 5200 patients and their doctors 3 The standard of care in treating type 1 Gaucher disease Reduces spleen and liver size 1 Improvement seen in bone mineral density with long-term treatment 4 Reductions in bone pain and bone crisis over time 5 To learn more about type 1 Gaucher disease, call TYPE1GAUCHER ( ), or visit Cerezyme is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of type 1 Gaucher disease that results in one or more of the following conditions: anemia, thrombocytopenia, bone disease, hepatomegaly, or splenomegaly. Important Safety Information Adverse reactions related to Cerezyme (imiglucerase for injection) administration have been reported in less than 15% of patients. Each of the following events occurred in less than 2% of the total patient population. Reported adverse events include nausea, vomiting, abdominal pain, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Adverse events associated with the route of administration include discomfort, pruritus, burning, swelling, or sterile abscess at the site of venipuncture. Symptoms suggestive of hypersensitivity include anaphylactoid reaction, pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Approximately 15% of patients have developed IgG antibodies; periodic monitoring is suggested. Side effects should be promptly reported to Genzyme Medical Information at , option 2. To learn more, please see full prescribing information at References: 1. Cerezyme [package insert]. Cambridge, MA: Genzyme Corporation; April Weinreb NJ, Charrow J, Andersson HC, et al. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113(2): Gaucher Registry, data on fi le, Wenstrup RJ, Kacena KA, Kaplan P, et al. Effect of enzyme replacement therapy with imiglucerase on BMD in type 1 Gaucher disease. J Bone Miner Res. 2007;22(1): Charrow J, Dulisse B, Grabowski GA, et al. The effect of enzyme replacement therapy on bone crisis and bone pain in patients with type 1 Gaucher disease. Clin Genet. 2007:71(3): Please see brief Prescribing Information on the next page Genzyme Corporation CZ-US-P036B Cerezyme is a registered trademark of Genzyme Corporation. All rights reserved.

29 Cerezyme (imiglucerase for injection) See package insert for full prescribing information. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Cerezyme (imiglucerase for injection) is indicated for long-term enzyme replacement therapy for pediatric and adult patients with a confirmed diagnosis of type 1 Gaucher disease that results in one or more of the following conditions: a. Anemia b. Thrombocytopenia c. Bone disease d. Hepatomegaly or splenomegaly CONTRAINDICATIONS There are no known contraindications to the use of Cerezyme (imiglucerase for injection). Treatment with Cerezyme should be carefully re-evaluated if there is significant clinical evidence of hypersensitivity to the product. WARNINGS Approximately 15% of patients treated and tested to date have developed IgG antibody to Cerezyme (imiglucerase for injection) during the first year of therapy. Patients who developed IgG antibody did so largely within 6 months of treatment and rarely developed antibodies to Cerezyme after 12 months of therapy. Approximately 46% of patients with detectable IgG antibodies experienced symptoms of hypersensitivity. Patients with antibody to Cerezyme have a higher risk of hypersensitivity reaction. Conversely, not all patients with symptoms of hypersensitivity have detectable IgG antibody. It is suggested that patients be monitored periodically for IgG antibody formation during the first year of treatment. Treatment with Cerezyme should be approached with caution in patients who have exhibited symptoms of hypersensitivity to the product. Anaphylactoid reaction has been reported in less than 1% of the patient population. Further treatment with imiglucerase should be conducted with caution. Most patients have successfully continued therapy after a reduction in rate of infusion and pretreatment with antihistamines and/or corticosteroids. PRECAUTIONS General In less than 1% of the patient population, pulmonary hypertension and pneumonia have also been observed during treatment with Cerezyme (imiglucerase for injection). Pulmonary hypertension and pneumonia are known complications of Gaucher disease and have been observed both in patients receiving and not receiving Cerezyme. No causal relationship with Cerezyme has been established. Patients with respiratory symptoms in the absence of fever should be evaluated for the presence of pulmonary hypertension. Therapy with Cerezyme should be directed by physicians knowledgeable in the management of patients with Gaucher disease. Caution may be advisable in administration of Cerezyme to patients previously treated with Ceredase (alglucerase injection) and who have developed antibody to Ceredase or who have exhibited symptoms of hypersensitivity to Ceredase. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies have not been conducted in either animals or humans to assess the potential effects of Cerezyme (imiglucerase for injection) on carcinogenesis, mutagenesis, or impairment of fertility. Teratogenic Effects: Pregnancy Category C Animal reproduction studies have not been conducted with Cerezyme (imiglucerase for injection). It is also not known whether Cerezyme can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Cerezyme should not be administered during pregnancy except when the indication and need are clear and the potential benefit is judged by the physician to substantially justify the risk. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Cerezyme (imiglucerase for injection) is administered to a nursing woman. Pediatric Use The safety and effectiveness of Cerezyme (imiglucerase for injection) have been established in patients between 2 and 16 years of age. Use of Cerezyme in this age group is supported by evidence from adequate and well-controlled studies of Cerezyme and Ceredase (alglucerase injection) in adults and pediatric patients, with additional data obtained from the medical literature and from long-term postmarketing experience. Cerezyme has been administered to patients younger than 2 years of age, however, the safety and effectiveness in patients younger than 2 have not been established. ADVERSE REACTIONS Since the approval of Cerezyme (imiglucerase for injection) in May 1994, Genzyme has maintained a worldwide postmarketing database of spontaneously reported adverse events and adverse events discussed in the medical literature. The percentage of events for each reported adverse reaction term has been calculated using the number of patients from these sources as the denominator for total patient exposure to Cerezyme since Actual patient exposure is difficult to obtain due to the voluntary nature of the database and the continuous accrual and loss of patients over that span of time. The actual number of patients exposed to Cerezyme since 1994 is likely to be greater than estimated from these voluntary sources and, therefore, the percentages calculated for the frequencies of adverse reactions are most likely greater than the actual incidences. Experience in patients treated with Cerezyme has revealed that approximately 13.8% of patients experienced adverse events which were judged to be related to Cerezyme administration and which occurred with an increase in frequency. Some of the adverse events were related to the route of administration. These include discomfort, pruritus, burning, swelling, or sterile abscess at the site of venipuncture. Each of these events was found to occur in <1% of the total patient population. Symptoms suggestive of hypersensitivity have been noted in approximately 6.6% of patients. Onset of such symptoms has occurred during or shortly after infusions; these symptoms include pruritus, flushing, urticaria, angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension. Anaphylactoid reaction has also been reported (see WARNINGS). Each of these events was found to occur in <1.5% of the total patient population. Pretreatment with antihistamines and/or corticosteroids and reduced rate of infusion have allowed continued use of Cerezyme in most patients. Additional adverse reactions that have been reported in approximately 6.5% of patients treated with Cerezyme include: nausea, abdominal pain, vomiting, diarrhea, rash, fatigue, headache, fever, dizziness, chills, backache, and tachycardia. Each of these events was found to occur in <1.5% of the total patient population. Incidence rates cannot be calculated from the spontaneously reported adverse events in the postmarketing database. From this database, the most commonly reported adverse events in children (defined as ages 2 12 years) included dyspnea, fever, nausea, flushing, vomiting, and coughing, whereas in adolescents (>12 16 years) and in adults (>16 years) the most commonly reported events included headache, pruritis, and rash. In addition to the adverse reactions that have been observed in patients treated with Cerezyme, transient peripheral edema has been reported for this therapeutic class of drug. OVERDOSE Experience with doses up to 240 U/kg every 2 weeks have been reported. At that dose there have been no reports of obvious toxicity. DOSAGE AND ADMINISTRATION Cerezyme (imiglucerase for injection) is administered by intravenous infusion over 1-2 hours. Dosage should be individualized to each patient. Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available. Disease severity may dictate that treatment be initiated at a relatively high dose or relatively frequent administration. Dosage adjustments should be made on an individual basis and may increase or decrease, based on achievement of therapeutic goals as assessed by routine comprehensive evaluations of the patient s clinical manifestations. Cerezyme should be stored at 2-8 C (36-46 F). After reconstitution, Cerezyme should be inspected visually before use. Because this is a protein solution, slight flocculation (described as thin translucent fibers) occurs occasionally after dilution. The diluted solution may be filtered through an in-line low protein-binding 0.2-μm filter during administration. Any vials exhibiting opaque particles or discoloration should not be used. DO NOT USE Cerezyme after the expiration date on the vial. On the day of use, after the correct amount of Cerezyme to be administered to the patient has been determined, the appropriate number of vials are each reconstituted with Sterile Water for Injection, USP. The final concentrations and administration volumes are provided in the following table: 200-Unit Vial 400-Unit Vial Sterile water for reconstitution 5.1 ml 10.2 ml Final volume of reconstituted product 5.3 ml 10.6 ml Concentration after reconstitution 40 U/mL 40 U/mL Withdrawal volume 5.0 ml 10.0 ml Units of enzyme within final volume 200 units 400 units A nominal 5.0 ml for the 200-unit vial (10.0 ml for the 400-unit vial) is withdrawn from each vial. The appropriate amount of Cerezyme for each patient is diluted with 0.9% Sodium Chloride Injection, USP, to a final volume of ml. Cerezyme is administered by intravenous infusion over 1-2 hours. Aseptic techniques should be used when diluting the dose. Since Cerezyme does not contain any preservative, after reconstitution, vials should be promptly diluted and not stored for subsequent use. Cerezyme, after reconstitution, has been shown to be stable for up to 12 hours when stored at room temperature (25 C) and at 2-8 C. Cerezyme, when diluted, has been shown to be stable for up to 24 hours when stored at 2-8 C. Relatively low toxicity, combined with the extended time course of response, allows small dosage adjustments to be made occasionally to avoid discarding partially used bottles. Thus, the dosage administered in individual infusions may be slightly increased or decreased to utilize fully each vial as long as the monthly administered dosage remains substantially unaltered. HOW SUPPLIED Cerezyme (imiglucerase for injection) is supplied as a sterile, nonpyrogenic, lyophilized product. It is available as follows: 200 Units per Vial NDC Units per Vial NDC Store at 2-8 C (36-46 F). Rx only US Patent Numbers: 5,236,838 5,549,892 Cerezyme (imiglucerase for injection) is manufactured by: Genzyme Corporation 500 Kendall Street Cambridge, MA USA Certain manufacturing operations may have been performed by other firms. Issued 4/ Genzyme Corporation. All rights reserved. Cerezyme and Ceredase are registered trademarks of Genzyme Corporation. CZ-US-PO

30 Help medical students get ahead; encourage them to apply for the ASH Minority Medical Student Award Program (MMSAP). Through the MMSAP, participants receive a stipend to complete an eight- to 12-week research project. This program is open to all minority medical students from the United States or Canada who are enrolled in a DO, MD, or MD/PhD program. MMSAP benefits include: A stipend of $5,000 to complete an eight- to 12-week research project An allowance of $2,000 for travel to the ASH annual meeting during the initial award year An allowance of $1,000 for travel to the ASH annual meeting awarded each subsequent year through medical school and residency Complimentary subscriptions to Blood and The Hematologist that continue through medical school and residency A research and a career-development mentor Encourage all eligible medical students to apply by March 12, To learn more about the MMSAP or to download an application, visit Questions? Contact Tiffanie Luckett, ASH Director of Development, at development@hematology.org or by phone at American Society of Hematology 1900 M Street, NW, Suite 200 Washington, DC

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35 2009 SUBSCRIPTION INFORMATION: Renewal instructions and remittance for the 2009 subscription year can be sent directly to us or through your preferred subscription agency. Payment may be made by check (drawn on a U.S. bank with U.S. funds) or by credit card (Visa, MC, Amex) and sent to: Blood Subscriptions Dept Washington, DC Subscription Rates for Blood, Volumes 113 & 114: Vol. 113 (24 issues) January-June / Vol. 114 (25 issues) July-December USA Outside USA Direct Direct Insitutional Subscriptions Single Site Tier 1 Online Only $1,160 $1,160 Online plus Print $1,290 $1,510 Tier 2 Online Only $1,220 $1,220 Online plus Print $1,350 $1,570 Tier 3 Online Only $1,310 $1,310 Online plus Print $1,440 $1,660 Individual Subscriptions*** Online plus Print $800 $1,020 ** Agented orders must include complete end user addresses. Otherwise regular rates will apply. *** We require payment via personal check and complete end user information for individual orders. For questions regarding your subscription order or to request a pro forma invoice, please contact us at: bloodsubs@hematology.org or Blood in print ISSN Blood Online ISSN Blood, Journal of the American Society of Hematology 1900 M Street, NW, Suite 200 Washington, DC Tel.: Fax: bloodsubs@hematology.org

36 For chronic lymphocytic leukemia (CLL) T REANDA Break away from expectations Dual structure TREANDA is a unique treatment that combines an alkylating group with a purine-like benzimidazole ring 1,2 Anti-tumor activity The exact mechanism of action of TREANDA remains unknown Dual cell-death effects via several pathways 1,3-5 Preclinical studies suggest that TREANDA may cause both apoptotic and nonapoptotic death of malignant cells TREANDA is active against both quiescent and dividing cells Superior clinical performance TREANDA tripled progression-free survival (PFS) and more than doubled overall response rate (ORR) vs chlorambucil Survival distribution function SUPERIOR PFS 73% risk reduction * HR =0.27 (95% CI : 0.17, 0.43) Months *Reduction in risk of progression of disease or death from any cause. HR=hazard ratio; CI=confi dence interval. Observed side-effect profile TREANDA (n=153) Chlorambucil (n=148) P<.0001 The most common non-hematologic adverse reactions (frequency 15%) are pyrexia (24%), nausea (20%), and vomiting (16%). The most common hematologic abnormalities (frequency 15%) are anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%). TREANDA is indicated for the treatment of patients with CLL. Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established. Please see accompanying brief summary of Prescribing Information, including references Cephalon, Inc. All rights reserved. TRE210 November TREANDA vs chlorambucil 59% ORR with TREANDA (95% CI: 51.03, 66.62) vs 26% (95% CI: 18.64, 32.71) (P<.0001) Complete response 8% vs <1% Median duration of response 19 mo with TREANDA (95% CI: 15.0, 24.2) vs 7 mo (95% CI: 5.8, 10.4) 1 Median PFS 18 mo with TREANDA (95% CI: 11.7, 23.5) vs 6 mo (95% CI: 5.6, 8.6) The effi cacy and safety of TREANDA were assessed compared with chlorambucil in a randomized, open-label, multicenter, Phase 3 trial in treatment-naïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were randomized to receive either single-agent TREANDA 100 mg/m 2 IV on Days 1 and 2 (n=153) or single-agent chlorambucil 0.8 mg/kg PO on Days 1 and 15 (n=148), up to six 28-day cycles. 1 Built for Action

37 References: 1. Data on fi le. Cephalon, Inc. 2. Hirschberg E, Gellhorn A, Gump WS. Laboratory evaluation of a new nitrogen mustard, 2-[Di-(2-chloroethyl)aminomethyl]benzimidazole, and of other 2-chloroethyl compounds. Cancer Res. 1957;17(9): Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res. 2008;14: Strumberg D, Harstrick A, Doll K, Hoffmann B, Seeber S. Bendamustine hydrochloride activity against doxorubicin-resistant human breast carcinoma cell lines. Anti-cancer Drugs. 1996;7: Schwänen C, Hecker T, Hübinger G, et al. In vitro evaluation of bendamustine induced apoptosis in B-chronic lymphocytic leukemia. Leukemia. 2002;16: TREANDA (bendamustine hydrochloride) for Injection Brief Summary of Prescribing Information INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established. TREANDA for Injection is indicated for the treatment of patients with indolent B-cell non-hodgkin s lymphoma (NHL) that has progressed during or within six months of treatment with rituximab or a rituximab-containing regimen. CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be 1 x 10 9 /L and the platelet count should be 75 x 10 9 /L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of allopurinol during the first few weeks of TREANDA therapy in patients at high risk. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m 2 ) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of premalignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 349 patients who participated in an actively-controlled trial (N=153) for the treatment of CLL and two single-arm studies (N=176) for the treatment of indolent B-cell NHL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m 2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients (continued) Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0 The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) Laboratory Abnormality All Grades Grade 3/4 All Grades Grade 3/4 n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Clinical Trials Experience in NHL. The data described below reflect exposure to TREANDA in 176 patients with indolent B-cell NHL treated in two single-arm studies. The population was years of age, 60% male, and 40% female. The race distribution was 89% White, 7% Black, 3% Hispanic, 1% other, and <1% Asian. These patients received TREANDA at a dose of 120 mg/m 2 intravenously on Days 1 and 2 for up to 8 21-day cycles. The adverse reactions occurring in at least 5% of the NHL patients, regardless of severity, are shown in Table 3. The most common non-hematologic adverse reactions ( 30%) were nausea (75%), fatigue (57%), vomiting (40%), diarrhea (37%) and pyrexia (34%). The most common non-hematologic Grade 3 or 4 adverse reactions ( 5%) were fatigue (11%), febrile neutropenia (6%), and pneumonia, hypokalemia and dehydration, each reported in 5% of patients. Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 176 (100) 94 (53) Cardiac disorders Tachycardia 13 (7) 0 Gastrointestinal disorders Nausea 132 (75) 7 (4) Vomiting 71 (40) 5 (3) Diarrhea 65 (37) 6 (3) Constipation 51 (29) 1 (<1) Stomatitis 27 (15) 1 (<1) Abdominal pain 22 (13) 2 (1) Dyspepsia 20 (11) 0 Gastroesophageal reflux disease 18 (10) 0 Dry mouth 15 (9) 1 (<1) Abdominal pain upper 8 (5) 0 Abdominal distension 8 (5) 0 General disorders and administration site conditions Fatigue 101 (57) 19 (11) Pyrexia 59 (34) 3 (2) Chills 24 (14) 0 Edema peripheral 23 (13) 1 (<1) Asthenia 19 (11) 4 (2) Chest pain 11 (6) 1 (<1) Infusion site pain 11 (6) 0 Pain 10 (6) 0 Catheter site pain 8 (5) 0 Infections and infestations Herpes zoster 18 (10) 5 (3) Upper respiratory tract infection 18 (10) 0 Urinary tract infection 17 (10) 4 (2) Sinusitis 15 (9) 0 Pneumonia 14 (8) 9 (5) Febrile Neutropenia 11 (6) 11 (6) Oral Candidiasis 11 (6) 2 (1) Nasopharyngitis 11 (6) 0 Investigations Weight decreased 31 (18) 3 (2) Metabolism and nutrition disorders Anorexia 40 (23) 3 (2) Dehydration 24 (14) 8 (5) Decreased appetite 22 (13) 1 (<1) Hypokalemia 15 (9) 9 (5) Musculoskeletal and connective tissue disorders Back pain 25 (14) 5 (3) Arthralgia 11 (6) 0 Pain in extremity 8 (5) 2 (1) Bone pain 8 (5) 0 Nervous system disorders Headache 36 (21) 0 Dizziness 25 (14) 0 Dysgeusia 13 (7) 0

38 Table 3: Non-Hematologic Adverse Reactions Occurring in at Least 5% of NHL Patients Treated With TREANDA by System Organ Class and Preferred Term (N=176) (continued) System organ class Number (%) of patients* Preferred term All Grades Grade 3/4 Psychiatric disorders Insomnia 23 (13) 0 Anxiety 14 (8) 1 (<1) Depression 10 (6) 0 Respiratory, thoracic and mediastinal disorders Cough 38 (22) 1 (<1) Dyspnea 28 (16) 3 (2) Pharyngolaryngeal pain 14 (8) 1 (<1) Wheezing 8 (5) 0 Nasal congestion 8 (5) 0 Skin and subcutaneous tissue disorders Rash 28 (16) 1 (<1) Pruritus 11 (6) 0 Dry skin 9 (5) 0 Night sweats 9 (5) 0 Hyperhidrosis 8 (5) 0 Vascular disorders Hypotension 10 (6) 2 (1) *Patients may have reported more than 1 adverse reaction. NOTE: Patients counted only once in each preferred term category and once in each system organ class category. Hematologic toxicities, based on laboratory values and CTC grade, in NHL patients treated in both single arm studies combined are described in Table 4. Clinically important chemistry laboratory values that were new or worsened from baseline and occurred in >1% of patients at grade 3 or 4, in NHL patients treated in both single arm studies combined were hyperglycemia (3%), elevated creatinine (2%), hyponatremia (2%), and hypocalcemia (2%). Table 4: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA in the NHL Studies Percent of patients Hematology Variable All Grades Grade 3/4 Lymphocytes Decreased Leukocytes Decreased Hemoglobin Decreased Neutrophils Decreased Platelets Decreased In both studies, serious adverse reactions, regardless of causality, were reported in 37% of patients receiving TREANDA. The most common serious adverse reactions occurring in 5% of patients were febrile neutropenia and pneumonia. Other important serious adverse reactions reported in clinical trials and/or post-marketing experience were acute renal failure, cardiac failure, hypersensitivity, skin reactions, pulmonary fibrosis, and myelodysplastic syndrome. Serious drug-related adverse reactions reported in clinical trials included myelosuppression, infection, pneumonia, tumor lysis syndrome, and infusion reactions. [See Warnings and Precautions] Adverse reactions occurring less frequently but possibly related to TREANDA treatment were hemolysis, dysgeusia/taste disorder, atypical pneumonia, sepsis, herpes zoster, erythema, dermatitis, and skin necrosis. Post-Marketing Experience. The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. OVERDOSAGE: The intravenous LD 50 of bendamustine HCl is 240 mg/m 2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m 2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m 2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant Grade 2 non-hematologic toxicity. Once non-hematologic toxicity has recovered to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) 1 x 10 9 /L, platelets 75 x 10 9 /L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m 2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m 2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. Dosing Instructions for NHL. Recommended Dosage: The recommended dose is 120 mg/m 2 administered intravenously over 60 minutes on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for NHL: TREANDA administration should be delayed in the event of a Grade 4 hematologic toxicity or clinically significant Grade 2 non-hematologic toxicity. Once nonhematologic toxicity has recovered to Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) 1 x 10 9 /L, platelets 75 x 10 9 /L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 4 toxicity, reduce the dose to 90 mg/m 2 on Days 1 and 2 of each cycle; if Grade 4 toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 90 mg/m 2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 60 mg/m 2 on Days 1 and 2 of each cycle. General Considerations for Tumor Lysis Syndrome. Consider using allopurinol as prevention for patients at high risk of tumor lysis syndrome for the first few weeks of treatment. Reconstitution/Preparation for Intravenous Administration. Aseptically reconstitute each 100 mg TREANDA vial with 20 ml of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/ml. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. Aseptically withdraw the volume needed for the required dose (based on 5 mg/ml concentration) and immediately transfer to a 500 ml infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 ml infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within mg/ml. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8 C or F) or for 3 hours when stored at room temperature (15-30 C or F) and room light. Administration of TREANDA must be completed within this period. DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing 100 mg of bendamustine HCl as white to off-white lyophilized powder. HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. 3-6 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons of 20 ml amber single-use vials containing 100 mg of bendamustine hydrochloride as a white to off-white lyophilized powder. NDC TREANDA (bendamustine hydrochloride) for Injection, 100 mg/vial. Storage. TREANDA may be stored up to 25 C (77 F) with excursions permitted up to 30 C (86 F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light. References 3-6: see full Prescribing Information. Manufactured by: Manufactured for: Pharmachemie B.V. Cephalon, Inc. The Netherlands Frazer, PA TREANDA is a registered trademark of Cephalon, Inc Cephalon, Inc. TRE148 November 2008 (Label Code: BS ) All rights reserved. This brief summary is based on TREANDA full Prescribing Information.

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41 ECOG E1A06 CURRENTLY ENROLLING A New Randomized Phase 3 Intergroup Study of Patients With Newly Diagnosed Multiple Myeloma Study Chair Keith Stewart, MBChB, Mayo Clinic, Scottsdale, AZ Primary Objective To compare progression-free survival with melphalan, prednisone, and thalidomide (MPT) versus melphalan, prednisone, and lenalidomide (REVLIMID ) (MPR) in patients with symptomatic, newly diagnosed multiple myeloma who are not candidates for high-dose therapy. Key Eligibility Criteria Newly diagnosed, symptomatic multiple myeloma Declined or ineligible for high-dose therapy Study Design Enrollment N=560 Treatment naïve no prior therapy except bisphosphonates or growth factors Creatinine <2.5 mg/dl ECOG performance status 2 Induction (Up to twelve 28-day cycles) Treatment A (MPT) Melphalan 9 mg/m 2 po a daily, days 1-4 each cycle b for 12 cycles Prednisone 100 mg po daily, days 1-4 each cycle for 12 cycles Thalidomide 100 mg po continuously until relapse Enteric-coated aspirin 325 mg po daily, continuously QOL assessments performed prior to, during, and following treatment Maintenance (Continues until disease progression) Treatment A Thalidomide 100 mg po Enteric-coated aspirin 325 mg po daily, continuously Treatment B (MPR) Melphalan 5 mg/m 2 po daily, days 1-4 each cycle b for 12 cycles Prednisone 100 mg po daily, days 1-4 each cycle for 12 cycles Lenalidomide 10 mg po continuously until relapse Enteric-coated aspirin 325 mg po daily, continuously QOL assessments performed prior to, during, and following treatment Treatment B Lenalidomide 10 mg po Enteric-coated aspirin 325 mg po daily, continuously a po, orally. b 1 cycle = 28 days. For more information, please contact: (NCT ) National Cancer Institute Cancer Trials Support Unit (ctsucontact@westat.com) (888) Note: This study is supported by the National Cancer Institute Cancer Trials Support Unit (CTSU). Institutions not aligned with ECOG will participate through the CTSU mechanism. Supplemental funding for this trial provided by Celgene Corporation. Supplemental funding for trial recruitment materials provided by Celgene Corporation. Investigational use of REVLIMID (lenalidomide). REVLIMID is a registered trademark of Celgene Corporation. 05/08 CELG08034