On November 5, 2015 Johnson & Johnson reported that at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting, Janssen Research & Development, LLC will present new data for both approved and investigational oncology and cardiovascular compounds across 10 disease areas (Press release, Johnson & Johnson, NOV 5, 2015, View Source [SID:1234508028]). More than 40 abstracts from company-sponsored studies have been accepted for presentation, including 17 oral presentations, the largest presence of company data to date. Oral presentations from five Janssen brands across two therapeutic areas will be presented at the meeting, including ibrutinib, daratumumab, siltuximab, imetelstat and rivaroxaban. Data and posters from bortezomib, decitabine and JNJ56022473 (formerly CSL362) will be presented as well.

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"The depth and breadth of data presented at ASH (Free ASH Whitepaper) 2015 demonstrate our deep passion for developing transformational medical solutions to treat and prevent disease in novel ways, with the goal of radically improving health for patients in need," said William N. Hait, M.D., Ph.D., Global Head, ​Janssen Research & Development, LLC.

Ibrutinib will be featured in 23 presentations sponsored by either Janssen or its collaboration partner, Pharmacyclics, seven of which are orals. Presentations include data evaluating its use as a single agent and in combination with other therapies across several disease states. IMBRUVICA is jointly developed and commercialized by Janssen Biotech, Inc. and Pharmacyclics LLC, an AbbVie company.

Daratumumab will be featured in 10 presentations sponsored or supported by Janssen, three of which are orals. The company will present data evaluating the fully human anti-CD38 monoclonal antibody as a single agent and in combination with standard therapies in multiple myeloma patients who are relapsed or refractory to standard therapies.

Siltuximab will be featured in one presentation sponsored by Janssen, reporting data from a Phase 2 study assessing the economic burden of relapsed or refractory multiple myeloma.

Imetelstat will be featured in two oral presentations sponsored by either Janssen or its licensing and collaboration partner, Geron Corporation.

Rivaroxaban will be featured in four oral presentations on anticoagulant use in venous thromboembolic disease sponsored by Janssen Pharmaceuticals, Inc. and its development partner for this medicine, Bayer HealthCare.

Ibrutinib Oral Presentations:

Chronic Lymphocytic Leukemia

Results from the International, Randomized Phase 3 Study of Ibrutinib Versus Chlorambucil in Patients 65 Years and Older with Treatment-Naïve CLL/SLL (RESONATE-2TM). (Abstract 495)
Outcome of Ibrutinib Treatment by Baseline Genetic Features in Patients with Relapsed or Refractory CLL/SLL With del17p in the RESONATE-17 Study. (Abstract 833)
Ibrutinib Plus Bendamustine/Rituximab (BR) is Associated with Greater Reductions in Fatigue Than Placebo Plus BR Among Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia and Fatigue. (Abstract 267)

Mantle Cell Lymphoma

Ibrutinib vs Temsirolimus: Results From a Phase 3, International, Randomized, Open-Label, Multicenter Study in Patients With Previously Treated Mantle Cell Lymphoma (MCL). (Abstract 469)

Multiple Myeloma

Combination Treatment with the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib and Carfilzomib in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Initial Results from a Multicenter Phase 1/2b Study. (Abstract 377)

Diffuse Large B-cell Lymphoma

The Role of PIM1 in Ibrutinib-Resistant ABC Subtype of Diffuse Large B-Cell Lymphoma. (Abstract 699)

Follicular Lymphoma

Ibrutinib Plus Rituximab in Treatment-Naïve Patients with Follicular Lymphoma: Results from a Multicenter, Phase 2 Study. (Abstract 470)

Daratumumab Oral Presentations:

Multiple Myeloma

Clinical Efficacy of Daratumumab Monotherapy in Patients with Heavily Pretreated Relapsed or Refractory Multiple Myeloma. (Abstract 29)
Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503). (Abstract 507)
Open-label, Multicenter, Phase 1b Study of Daratumumab in Combination with Pomalidomide and Dexamethasone in Patients with at Least 2 Lines of Prior Therapy and Relapsed or Relapsed and Refractory Multiple Myeloma. (Abstract 508)

Siltuximab Oral Presentation:

Multiple Myeloma

Economic Burden of Relapsed or Refractory Multiple Myeloma: Results from an International Trial. (Abstract 875)

Imetelstat Oral Presentations:

Telomerase Inhibitor Imetelstat Therapy in Refractory Anemia with Ring Sideroblasts with or without Thrombocytosis. (Abstract 55)
Dynamics of Mutations in Patients with ET Treated with Imetelstat. (Abstract 57)

Rivaroxaban Oral Presentations:

Deep Vein Thrombosis and Pulmonary Embolism

Safe and Effective Use of Rivaroxaban for Treatment of Cancer-Associated Venous Thromboembolic Disease: A Quality Improvement Initiative. (Abstract 431)
Current Practice Patterns and Patient Persistence on Anticoagulant Treatments for Cancer-Associated Thrombosis. (Abstract 626)
Xalia, a Non-Interventional Study Comparing Rivaroxaban with Standard Anticoagulation for Initial and Long-Term Therapy in Deep Vein Thrombosis. (Abstract 894)
Validation of the Inhospital Mortality for Pulmonary Embolism Using Claims Data (IMPACT) Prediction Rule within an All-Payer Inpatient Administrative Claims Database. (Abstract 747)

About IMBRUVICA (ibrutinib)

IMBRUVICA was one of the first therapies to receive U.S. approval after having received the FDA’s Breakthrough Therapy Designation. IMBRUVICA works by blocking a specific protein called Bruton’s tyrosine kinase (BTK).1 The BTK protein transmits important signals that tell B cells to mature and produce antibodies and is needed by specific cancer cells to multiply and spread.1, 2 IMBRUVICA targets and blocks BTK, inhibiting cancer cell survival and spread.1 For more information, visit www.IMBRUVICA.com.

Additional Information about IMBRUVICA

INDICATIONS

IMBRUVICA is indicated to treat people with:

Chronic lymphocytic leukemia (CLL) who have received at least one prior therapy
Chronic lymphocytic leukemia (CLL) with 17p deletion
Waldenström’s macroglobulinemia (WM)
Mantle cell lymphoma (MCL) who have received at least one prior therapy
Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

Hemorrhage – Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (subdural hematoma, gastrointestinal bleeding, hematuria, and post-procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA.

The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding.

Infections – Fatal and non-fatal infections have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 26% of patients. Cases of progressive multifocal leukoencephalopathy (PML) have occurred in patients treated with IMBRUVICA. Monitor patients for fever and infections and evaluate promptly.

Cytopenias – Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 19 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 9%) occurred in patients treated with IMBRUVICA. Monitor complete blood counts monthly.

Atrial Fibrillation – Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients treated with IMBRUVICA, particularly in patients with cardiac risk factors, acute infections, and a previous history of atrial fibrillation. Periodically monitor patients clinically for atrial fibrillation. Patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new-onset dyspnea should have an ECG performed. If atrial fibrillation persists, consider the risks and benefits of IMBRUVICA treatment and dose modification.

Second Primary Malignancies – Other malignancies (range, 5 to 14%) including non-skin carcinomas (range, 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 4 to 11%).

Tumor Lysis Syndrome – Tumor lysis syndrome has been reported with IMBRUVICA therapy. Monitor patients closely and take appropriate precautions in patients at risk for tumor lysis syndrome (e.g., high tumor burden).

Embryo-Fetal Toxicity – Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

ADVERSE REACTIONS

The most common adverse reactions (≥25%) in patients with B-cell malignancies (MCL, CLL, WM) were thrombocytopenia* (57%, 52%, 43%), neutropenia* (47%, 51%, 44%), diarrhea (51%, 48%, 37%), anemia* (41%, 36%, 13%), fatigue (41%, 28%, 21%), musculoskeletal pain (37%, 28%†, NA‡), bruising (30%, 12%†, 16%†), nausea (31%, 26%, 21%), upper respiratory tract infection (34%, 16%, 19%), and rash (25%, 24%†, 22%†).

*Based on adverse reactions and/or laboratory measurements (noted as platelets, neutrophils, or hemoglobin decreased).
†Includes multiple ADR terms.
‡Not applicable; no associated ADRs.

The most common Grade 3 or 4 non-hematological adverse reactions (≥5%) in MCL patients were pneumonia (7%), abdominal pain (5%), atrial fibrillation (5%), diarrhea (5%), fatigue (5%), and skin infections (5%).
Approximately 6% (CLL), 14% (MCL), and 11% (WM) of patients had a dose reduction due to adverse events.
Approximately 5% (CLL), 9% (MCL), and 6% (WM) of patients discontinued due to adverse events. Most frequent adverse events leading to discontinuation were infections, subdural hematomas, and diarrhea in CLL patients and subdural hematoma (1.8%) in MCL patients.

DRUG INTERACTIONS

CYP3A Inhibitors – Avoid co-administration with strong and moderate CYP3A inhibitors. If a moderate CYP3A inhibitor must be used, reduce the IMBRUVICA dose.

CYP3A Inducers – Avoid co-administration with strong CYP3A inducers.

SPECIFIC POPULATIONS

Hepatic Impairment – Avoid use in patients with moderate or severe baseline hepatic impairment. In patients with mild impairment, reduce IMBRUVICA dose.

Please see full Prescribing Information: View Source

About Daratumumab
Daratumumab is an investigational human monoclonal antibody (mAb) that binds with high affinity to the CD38 molecule, which is highly expressed on the surface of multiple myeloma cells. It is believed to induce rapid tumor cell death through multiple immune-mediated mechanisms, including complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity, as well as via induction of apoptosis.3, 4, 5 Five Phase 3 clinical studies with daratumumab in relapsed and frontline settings are currently ongoing. Additional studies are ongoing or planned to assess its potential in other malignant and pre-malignant diseases on which CD38 is expressed, such as smoldering myeloma and non-Hodgkin lymphoma. In August 2012, Genmab granted Janssen Biotech, Inc. an exclusive worldwide license to develop, manufacture and commercialize daratumumab.

About SYLVANT (siltuximab)
SYLVANT is an anti-interleukin-6 (IL-6) chimeric monoclonal antibody that binds to human IL-6.6 IL-6 is a multifunctional cytokine produced by various cells such as T cells, B cells, monocytes, fibroblasts and endothelial cells. Dysregulated overproduction of IL-6 from activated B cells in affected lymph nodes has been implicated in the pathogenesis of, or mechanism causing, MCD.7 Information about ongoing studies with siltuximab can be found at www.clinicaltrials.gov.

Additional Information about SYLVANT

INDICATION

SYLVANT (siltuximab) is indicated for the treatment of patients with multicentric Castleman’s disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative.

Limitation of Use. SYLVANT was not studied in patients with MCD who are HIV positive or HHV-8 positive because SYLVANT did not bind to virally produced IL‐6 in a nonclinical study.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS – Severe hypersensitivity reaction to siltuximab or any of the excipients in SYLVANT.

Concurrent Active Severe Infections – Do not administer to patients with severe infections until the infection resolves. SYLVANT may mask signs and symptoms of acute inflammation including suppression of fever and of acute phase reactants such as C-reactive protein (CRP). Monitor patients closely for infections. Institute prompt anti-infective therapy and do not administer further SYLVANT until the infection resolves.

Vaccinations – Do not administer live vaccines to patients receiving SYLVANT because interleukin-6 (IL-6) inhibition may interfere with the normal immune response to new antigens.

Infusion Related Reactions and Hypersensitivity – Stop the infusion if the patient develops signs of anaphylaxis. Discontinue further therapy.

Stop the infusion if the patient develops mild to moderate infusion reactions. If the reaction resolves, the infusion may be restarted at a lower infusion rate. Consider medicating with antihistamines, acetaminophen, and corticosteroids. Discontinue SYLVANT if the patient does not tolerate the infusion following these interventions. [see Adverse Reactions (6)].

Administer SYLVANT in a setting that provides resuscitation equipment, medication, and personnel trained to provide resuscitation.

Gastrointestinal (GI) Perforation – Use with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with symptoms that may be associated with or suggestive of GI perforation.

Adverse Reactions – The most common adverse reactions (>10% compared to placebo) in the MCD clinical trial were pruritus, increased weight, rash, hyperuricemia, and upper respiratory tract infection.

Drug Interactions – Cytochrome P450 (CYP450) Substrates – Upon initiation or discontinuation of SYLVANT, in patients being treated with CYP450 substrates with narrow therapeutic index, perform therapeutic monitoring of effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) as needed and adjust dose. Exercise caution when SYLVANT is co-administered with CYP3A4 substrate drugs where a decrease in effectiveness would be undesirable (e.g., oral contraceptives, lovastatin, atorvastatin).

For more information on SYLVANT, including the full prescribing information, visit www.SYLVANT.com.

About Imetelstat
Janssen entered into an exclusive worldwide license and collaboration agreement with Geron Corporation (Nasdaq: GERN) in November 2014 to develop and commercialize imetelstat, an investigational telomerase inhibitor. Imetelstat is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Imetelstat has not been approved for marketing by any regulatory authority.

About XARELTO (rivaroxaban)
XARELTO works by blocking the blood clotting Factor Xa. XARELTO does not require routine blood monitoring. XARELTO has a broad indication profile and is approved for six indications that include:

To reduce the risk of strokes and blood clots in patients with atrial fibrillation not caused by a heart valve problem. For patients currently well managed on warfarin, there is limited information on how XARELTO and warfarin compare in reducing the risk of stroke.
To treat patients with deep vein thrombosis (DVT).
To treat patients with pulmonary embolism (PE).
To reduce the risk of recurrence of DVT or PE following an initial six-month treatment for acute venous thromboembolism.
To reduce the risk of blood clots in the legs and lungs of patients who have just had knee replacement surgery.
To reduce the risk of blood clots in the legs and lungs of patients who have just had hip replacement surgery.

IMPORTANT SAFETY INFORMATION

WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

A. PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.
B. SPINAL/EPIDURAL HEMATOMA

Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include:
Use of indwelling epidural catheters
Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions
A history of traumatic or repeated epidural or spinal punctures
A history of spinal deformity or spinal surgery <
Optimal timing between the administration of XARELTO and neuraxial procedures is not known
Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.
Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

CONTRAINDICATIONS

Active pathological bleeding
Severe hypersensitivity reaction to XARELTO (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS

Increased Risk of Thrombotic Events After Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

Risk of Bleeding: XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage.

A specific antidote for rivaroxaban is not available. Because of high plasma protein binding, rivaroxaban is not expected to be dialyzable.

Concomitant use of other drugs affecting hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, other antithrombotic agents, fibrinolytic therapy, and NSAIDs.

Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in long-term or permanent paralysis. To reduce the potential risk of bleeding associated with the concurrent use of rivaroxaban and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of rivaroxaban. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of rivaroxaban is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An epidural catheter should not be removed earlier than 18 hours after the last administration of XARELTO. The next XARELTO dose is not to be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, the administration of XARELTO is to be delayed for 24 hours. Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.
Use in Patients With Renal Impairment:

Nonvalvular Atrial Fibrillation: Avoid the use of XARELTO in patients with creatinine clearance (CrCl) <15 mL/min, since drug exposure is increased. Discontinue XARELTO in patients who develop acute renal failure while on XARELTO.

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: Avoid the use of XARELTO in patients with CrCl <30 mL/min due to an expected increase in rivaroxaban exposure and pharmacodynamic effects in this patient population. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 30 to 50 mL/min. Patients who develop acute renal failure while on XARELTO should discontinue the treatment.

Use in Patients With Hepatic Impairment: No clinical data are available for patients with severe hepatic impairment. Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased.

Use With P-gp and Strong CYP3A4 Inhibitors or Inducers: Avoid concomitant use of XARELTO with combined P-gp and strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, lopinavir/ritonavir, ritonavir, indinavir/ritonavir, and conivaptan). Avoid concomitant use of XARELTO with drugs that are P-gp and strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort).

Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing and is not readily reversed. Promptly evaluate any signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

Patients With Prosthetic Heart Valves: The safety and efficacy of XARELTO have not been studied in patients with prosthetic heart valves. Therefore, use of XARELTO is not recommended in these patients.

Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

DRUG INTERACTIONS

Avoid concomitant use of XARELTO with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

XARELTO should not be used in patients with CrCl 15 to 80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A4 inhibitors unless the potential benefit justifies the potential risk.

USE IN SPECIFIC POPULATIONS

Pregnancy Category C: XARELTO should be used during pregnancy only if the potential benefit justifies the potential risk to mother and fetus. There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Use XARELTO with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery with an anticoagulant that is not readily reversible. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing.

Labor and Delivery: Safety and effectiveness of XARELTO during labor and delivery have not been studied in clinical trials.

Nursing Mothers: It is not known if rivaroxaban is excreted in human milk.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Females of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.
OVERDOSAGE

Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. A specific antidote for rivaroxaban is not available. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not expected to be dialyzable.

ADVERSE REACTIONS IN CLINICAL STUDIES

The most common adverse reactions with XARELTO were bleeding complications.

On November 5, 2015 CTI BioPharma Corp. (NASDAQ and MTA: CTIC) reported financial results for the third quarter ended September 30, 2015 (Press release, CTI BioPharma, NOV 5, 2015, View Source;p=RssLanding&cat=news&id=2107565 [SID:1234508027]).

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"We are focused on preparing our NDA submission for pacritinib and are on track to submit our application to the FDA this quarter," said James A. Bianco, M.D., CTI BioPharma’s President and CEO. "We also remain committed to completing the second Phase 3 trial of pacritinib, PERSIST-2, which we believe could serve as a post-approval confirmatory trial in the event our NDA application is accepted and approved under accelerated approval. Additionally, we look forward to upcoming data presentations of pacritinib and tosedostat studies at the ASH (Free ASH Whitepaper) Annual Meeting in December."

Third Quarter 2015 and Recent Highlights

In September 2015, announced plans to submit a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) with partner Baxalta Inc. for pacritinib, an investigational oral kinase inhibitor with specificity for JAK2, FLT3, IRAK1 and CSF1R for the treatment of patients with myelofibrosis, in the fourth quarter of 2015 and to request accelerated approval for the treatment of patients with intermediate and high-risk myelofibrosis with low platelet counts of less than 50,000 per microliter (< 50,000/uL) for whom there are no approved drugs. Priority review of the application will be requested at the time of NDA submission.
In September 2015, completed registered direct offering resulting in net proceeds of approximately $15.1 million and in October 2015, completed underwritten public offering resulting in net proceeds of approximately $46.5 million.
In November 2015, announced the upcoming presentations of data highlighting pacritinib and tosedostat at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (ASH) (Free ASH Whitepaper) to be held December 5-8, 2015, in Orlando, FL.

Third Quarter 2015 Financial Results

Total revenues for the third quarter and the nine months ended September 30, 2015 were $1.0 million and $4.8 million, respectively, compared to $39.5 million and $42.3 million for the same periods in 2014. The decrease in total revenue is primarily due to recognition of milestone payments in 2014, specifically a $20.0 million development milestone payment received from Baxalta for completion of enrollment in the PERSIST-1 Phase 3 clinical trial of pacritinib and $17.3 million from an upfront payment under the PIXUVRI collaboration agreement with Servier. Net product revenues of PIXUVRI for the third quarter and the nine months ended September 30, 2015 were $0.7 million and $2.4 million, respectively, compared to $2.0 million and $4.4 million for the same periods in 2014. The decrease in net product sales was primarily related to the pricing and volume variances between the periods presented as well as the decline in average exchange rate of the euro for our euro-denominated sales.

The non-GAAP operating loss, which excludes non-cash share-based compensation expense, for the third quarter and nine months ended September 30, 2015 was $26.1 million and $77.5 million, respectively, compared to non-GAAP operating income of $11.3 million and a non-GAAP operating loss of $29.8 million for the same periods in 2014. The GAAP operating loss for the third quarter and nine months ended September 30, 2015 was $32.0 million and $90.5 million, respectively, compared to a GAAP operating income of $7.5 million and operating loss of $46.9 million for the same period in 2014. The increase in operating loss for the nine-month period is predominantly associated with the Phase 3 development program for pacritinib and the PIX306 post-authorization Phase 3 trial for PIXUVRI as well as the milestone and the upfront payments received in the 2014 periods as mentioned above. Non-cash share-based compensation expense for the third quarter and nine months ended September 30, 2015 was $5.9 million and $13.0 million, respectively, compared to $3.8 million and $17.0 million for the same periods in 2014. For information on CTI BioPharma’s use of the aforementioned non-GAAP measure and a reconciliation of such measure to GAAP operating loss, see the section below entitled "Non-GAAP Financial Measures."

Net loss for the third quarter of 2015 was $32.6 million, or $(0.19) per share, compared to a net income of $4.6 million, or $0.03 per share, for the same period in 2014. Net loss for the first nine months of 2015 was $93.8 million, or $(0.54) per share, compared to a net loss of $51.8 million, or $(0.36) per share, for the same period in 2014.

As of September 30, 2015, cash and cash equivalents totaled $46.4 million, compared to $70.9 million as of December 31, 2014. Subsequent to September 30, 2015, we received approximately $46.5 million in net proceeds from an underwritten public offering in October 2015.

2015 Financial Outlook

CTI BioPharma now expects total revenues for 2015 will be approximately $30 million to $45 million, which are primarily based upon updated current expectations regarding license and contract revenues under the agreements with Baxalta and Teva and net product sales from PIXUVRI commercial operations. Non-GAAP operating loss for 2015 will be approximately $75 million to $85 million, which excludes non-cash share-based compensation expense. These financial projections are primarily based on our current expectations regarding patient enrollment, NDA submission timing and other factors previously outlined in the Company’s fourth quarter and full year 2014 financial results press release.

On November 5, 2015 Celldex Therapeutics, Inc. (NASDAQ:CLDX) reported business and financial highlights for the third quarter ended September 30, 2015 (Press release, Celldex Therapeutics, NOV 5, 2015, View Source [SID:1234508026]).

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"Celldex continues to advance one of the most robust, well-staged pipelines in immuno-oncology," said Anthony Marucci, President and Chief Executive Officer of Celldex Therapeutics. "As we move closer to final data from the ACT IV study in newly diagnosed glioblastoma, we continue to build on the potential promise of RINTEGA in the recurrent setting and look forward to presenting long-term survival data from the ReACT study at the SNO meeting later this month. In the third quarter we continued to execute on all fronts, including enrolling patients to seven ongoing Celldex-sponsored clinical trials. In addition, there are now numerous investigator initiated studies ongoing with additional concepts under discussion. We look forward to data in 2016 from several of these studies that we believe will further support the critical role of immunotherapy in oncology."

Program Updates:

RINTEGA ("rindopepimut"; "rindo"; CDX-110), an EGFRvIII(v3)-specific therapeutic vaccine for glioblastoma (GBM)

The ACT IV study is a randomized, double-blind, placebo controlled study of RINTEGA plus GM-CSF added to standard of care temozolomide in patients with newly diagnosed, surgically resected, EGFRvIII-positive glioblastoma. 745 patients were enrolled into ACT IV to reach the required 374 patients with minimal residual disease (assessed by central review) needed for analysis of the primary overall survival endpoint. All patients, including those with disease that exceed this threshold, will be included in a secondary analysis of overall survival as well as analyses of progression-free survival, safety and tolerability, and quality of life. The study design includes interim analyses conducted by an independent Data Safety and Monitoring Board (DSMB) at 50 and 75% of events (deaths). The first interim analysis occurred in June 2015, and the DSMB recommended continuation of the study as planned. The Company anticipates that the study will reach the required number of events to perform the second interim analysis in late 2015 and that the analysis will occur in early 2016.

As previously reported, data from the Phase 2 ReACT study in patients with recurrent glioblastoma were presented in an oral session at the 2015 ASCO (Free ASCO Whitepaper) Annual Meeting by David A. Reardon, M.D., Clinical Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, and the lead investigator of the ReACT study. Patients on the RINTEGA arm experienced a statistically significant overall survival (OS) benefit, and an impressive, emerging long-term survival benefit was observed. The primary endpoint of the study, progression-free survival at six months (PFS6), was met, and a clear advantage was demonstrated across multiple, clinically important endpoints including long-term progression-free survival, objective response rate (ORR) and need for steroids. The Company will present an update on overall survival and long-term survival in a podium presentation at the 20th Annual Scientific Meeting of the Society for Neuro-Oncology (SNO) on Friday, November 20th at 1:30 PM CT/2:30 PM ET.

Glembatumumab vedotin ("glemba"; CDX-011), an antibody-drug conjugate targeting gpNMB in multiple cancers

Enrollment continues in the Company’s Phase 2b randomized study (METRIC) of glembatumumab vedotin in patients with metastatic triple negative breast cancers that overexpress gpNMB, a molecule associated with poor outcomes for triple negative breast cancer patients and the target of glembatumumab vedotin. Enrollment is open across the United States, Canada and Australia. Trial expansion into the European Union (EU) is underway, and the Company plans to open enrollment in up to 50 sites in the EU in early 2016. Based on current projections, enrollment will be completed in the second half of 2016.

Patient enrollment continues in the Phase 2 study of glembatumumab vedotin in metastatic melanoma.

Celldex continues to advance plans to expand the study of glembatumumab vedotin in other cancers in which gpNMB is expressed.
A Phase 2 study in squamous cell lung cancer is expected to commence in Q1 2016.
Celldex and the National Cancer Institute have entered into a Cooperative Research and Development Agreement (CRADA) under which the NCI will sponsor two studies of glembatumumab vedotin—one in uveal melanoma and one in pediatric osteosarcoma.
Varlilumab ("varli"; CDX-1127), a fully human monoclonal agonist antibody that binds and activates CD27, a critical co-stimulatory molecule in the immune activation cascade

The Phase 1/2 study of varlilumab and nivolumab (Opdivo) in adult patients with advanced non-small cell lung cancer, metastatic melanoma, colorectal cancer, ovarian cancer, and head and neck squamous cell carcinoma is actively enrolling patients. This study is being conducted by Celldex under a clinical trial collaboration with Bristol-Myers Squibb. The companies are sharing development costs.

In April 2015, Celldex announced that it had entered into a clinical trial collaboration with Roche to evaluate the combination of varlilumab and atezolizumab (anti-PDL1) in a Phase 1/2 study in renal cell carcinoma. Under the terms of this agreement, Roche will provide study drug, and Celldex will be responsible for conducting and funding the study, which is expected to open to enrollment in Q4 2015.

Additional combination studies of varlilumab continue to enroll patients including:
A Phase 1/2 safety and tolerability study examining the combination of varlilumab and sunitinib (Sutent) in patients with metastatic clear cell renal cell carcinoma (CC-RCC); and,
A Phase 1/2 safety and tolerability study examining the combination of varlilumab and ipilimumab (Yervoy) in patients with Stage III or IV metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive Celldex’s CDX-1401.

Celldex will present a preclinical poster on the contribution of varlilumab’s immune stimulating properties versus regulatory T cell (Treg) depletion in multiple tumor models on Friday, November 6, 2015 at 6:15 PM ET at the 2015 Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) Annual Meeting.

Oncothyreon recently completed evaluation of two dosing cohorts in the Oncothyreon-led Phase 1b trial of ONT-10, a therapeutic vaccine targeting the tumor-associated antigen MUC1, in combination with varlilumab in patients with advanced breast and ovarian cancers. Preliminary data from these two cohorts did not demonstrate sufficient activity to move forward with the program, and Oncothyreon does not plan to enroll additional patients in the Phase 1b trial. Varlilumab biomarker analyses from peripheral blood samples from this study are consistent with prior experience including an increase in activated T cells and natural killer cells and a decrease in regulatory T cells.

Patient treatment in the Phase 1 dose-escalation study of varlilumab is complete. Any incremental data updates will be included in a future scientific presentation/publication.

Efforts are underway for additional Phase 2 studies of varlilumab, and the Company will provide updates on these studies as they are initiated.
CDX-1401, an antibody-based NY-ESO-1-specific therapeutic vaccine for multiple solid tumors

A Phase 1/2 study examining the combination of varlilumab and ipilimumab (Yervoy) continues to enroll patients with Stage III or IV metastatic melanoma. In the Phase 2 portion of the study, patients with tumors that express NY-ESO-1 will also receive CDX-1401, an off-the-shelf antibody-based dendritic cell targeted vaccine.

Celldex continues to support several external collaborations, including a National Cancer Institute sponsored Phase 2 study of CDX-1401 and CDX-301 for patients with metastatic melanoma, which recently completed enrollment.
CDX-301 (recombinant human Flt3L), a potent hematopoietic cytokine that uniquely expands dendritic cells and hematopoietic stem cells

CDX-301 is being developed as a combination product with other immuno-oncology agents in investigator-sponsored studies.

A pilot study of CDX-301 alone and in combination with Mozobil in hematopoietic stem cell transplantation was initiated in September 2014 and is currently enrolling patients and sibling-matched donors. The Company anticipates presenting early data from this study in Q1 2016.
Third Quarter and First Nine Months 2015 Financial Highlights and 2015 Guidance

Cash position: Cash, cash equivalents and marketable securities as of September 30, 2015 were $304.6 million compared to $334.0 million as of June 30, 2015. The decrease of $29.4 million was primarily driven by our third quarter net cash used in operating activities of $27.8 million. As of September 30, 2015 Celldex had 98.6 million shares outstanding.

Revenues: Total revenue was $1.0 million in the third quarter of 2015 and $3.7 million for the nine months ended September 30, 2015, compared to $1.1 million and $2.1 million for the comparable periods in 2014. The increase in the nine months ended September 30, 2015 was primarily due to our clinical trial collaboration with Bristol-Myers Squibb and our research and development agreement with Rockefeller University.

R&D Expenses: Research and development (R&D) expenses were $24.7 million in the third quarter of 2015 and $76.3 million for the nine months ended September 30, 2015, compared to $26.2 million and $77.4 million for the comparable periods in 2014.

G&A Expenses: General and administrative (G&A) expenses were $8.5 million in the third quarter of 2015 and $22.8 million for the nine months ended September 30, 2015, compared to $5.0 million and $14.4 million for the comparable periods in 2014. The increase in G&A expenses was primarily attributable to higher personnel-related expenses as we prepare for potential product launches and a $3.3 million increase year to date in RINTEGA and glembatumumab vedotin commercial planning costs over the $2.6 million spent in the comparable period in 2014.

Net loss: Net loss was $32.0 million, or ($0.32) per share, for the third quarter of 2015 and $94.5 million, or ($0.98) per share, for the nine months ended September 30, 2015, compared to a net loss of $28.1 million, or ($0.31) per share and $86.3 million, or ($0.97) per share for the comparable periods in 2014.

Financial guidance: Celldex expects that its cash, cash equivalents and marketable securities will be sufficient to fund our operating expenses and capital expenditure requirements through 2017; however, this could be impacted by our clinical data results from the RINTEGA program and their potential impact on our pace of commercial manufacturing and the rate of expansion of our commercial operations.

On November 5, 2015 Bio-Path Holdings, Inc., (NASDAQ: BPTH) ("Bio-Path"), a biotechnology company developing a liposomal delivery technology for nucleic acid cancer drugs, reported that Dr. Jorge Cortes, Deputy Chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center and Chair of Bio-Path’s Scientific Advisory Board, will present data from Bio-Path’s Phase I and Ib clinical trials of its lead product candidate BP-100-1.01 (Liposomal Grb-2 antisense) in the treatment of blood cancers during a poster session at the 57th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting in Orlando, Florida (Filing, 8-K, Bio-Path Holdings, NOV 5, 2015, View Source [SID:1234508025]).

Details for the poster presentation are as follows:

Title: "Safety, Pharmacokinetics, and Efficacy of BP-100-1.01 (Liposomal Grb-2 Antisense Oligonucleotide) in Patients with Refractory or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndrome (MDS)"

Session Name: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster III

Date: Monday, December 7, 2015

Presentation Time: 6:00 p.m. – 8:00 p.m. Eastern Time

Location: Hall A, Orange County Convention Center

The poster will highlight results from Bio-Path’s Phase I and Ib clinical trials in patients with blood cancers, notably the complete remission (CR) of one patient with advanced acute myeloid leukemia (AML) who was treated with BP-100-1.01 in combination with low-dose cytarabine (LDAC) chemotherapy and another patient with chronic myelogenous leukemia (CML) who showed significant reduction (81 percent to 5 percent) in bone marrow blasts. The results suggest possible disease inhibition with BP-100-1.01 treatment.

The full abstract can be found at View Source

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On November 5, 2015 ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) reported the schedule of several data presentations on Iclusig (ponatinib) that will take place at the 57th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) being held in Orlando, December 5 to 8, 2015 (Press release, Ariad, NOV 5, 2015, View Source;p=RssLanding&cat=news&id=2107604 [SID:1234508024]). A total of six abstracts were accepted at ASH (Free ASH Whitepaper). The schedule and meeting location for key sessions at ASH (Free ASH Whitepaper), together with the abstract information, are listed below:

Schedule your 30 min Free 1stOncology Demo!
Discover why more than 1,500 members use 1stOncology™ to excel in:

Early/Late Stage Pipeline Development - Target Scouting - Clinical Biomarkers - Indication Selection & Expansion - BD&L Contacts - Conference Reports - Combinatorial Drug Settings - Companion Diagnostics - Drug Repositioning - First-in-class Analysis - Competitive Analysis - Deals & Licensing

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Oral Presentation:

Title: The Impact of Ponatinib vs. Allogeneic Stem Cell Transplant (SCT) on Outcomes in Patients with Chronic Myeloid Leukemia (CML) or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL) with the T315I Mutation
Oral Session: Chronic Myeloid Leukemia – Therapy and Prognosis
Date & Time: Monday, December 7, 2015, 7:00 – 8:30 a.m., Presentation at 8:15 a.m.
Abstract No.: 480
Presenter: Franck E. Nicolini, M.D., PhD (Centre Hospitalier Lyon Sud, Pierre-Bénite, France)
Location: Orange County Convention Center, Orange County Convention Center, Valencia BC (W415BC)

Clinical Poster Presentations:

Title: Real-World Ponatinib Prescribing Patterns and Outcomes in US Patients
Poster Session: Chronic Myeloid Leukemia – Therapy: Poster I
Date & Time: Saturday, December 5, 2015, 5:30 – 7:30 p.m.
Abstract No.: 1591
Presenter: Michael J. Mauro, M.D. (Memorial Sloan Kettering Cancer Center)
Location: Orange County Convention Center, Hall A

Title: Relationship of Line of Therapy to Efficacy for Ponatinib in 3rd-Line vs. 4th-Line Chronic-Phase Chronic Myeloid Leukemia (CML)
Poster Session: Chronic Myeloid Leukemia –Therapy: Poster I
Date & Time: Saturday, December 5, 2015, 5:30 – 7:30 p.m.
Abstract No.: 1588
Presenter: Moshe Yair Levy, M.D. (Baylor University Med Center, Dallas, TX)
Location: Orange County Convention Center, Hall A

Title: A Multi-Institutional Retrospective Analysis of Tyrosine Kinase Inhibitor (TKI) Clinical and Preclinical Efficacy According to BCR-ABL Mutation Status in CP-CML Patients
Poster Session: Chronic Myeloid Leukemia – Therapy: Poster II
Date & Time: Sunday, December 6, 2015 at 6:00 – 8:00 p.m.
Abstract No.: 2790
Presenter: Victor M. Rivera, Ph.D. (ARIAD Pharmaceuticals, Inc.)
Location: Orange County Convention Center, Hall A

Title: Efficacy and Safety of Ponatinib in CP-CML Patients by Number of Prior Tyrosine Kinase Inhibitors: 4-Year Follow-up of the Phase 2 PACE Trial
Poster Session: Chronic Myeloid Leukemia – Therapy: Poster III
Date & Time: Monday, December 7, 2015, 6:00 – 8:00 p.m.
Abstract No.: 4025
Author: Andreas Hochhaus, M.D. (Jena University Hospital, Jena, Germany)
Location: Orange County Convention Center, Hall A

Preclinical Poster Presentation:

Title: Potent Preclinical Activity of Ponatinib in Germinal Center B-Cell-like Diffuse Large B-Cell Lymphoma (GCB-DLBCL) Models
Poster Session: Lymphoma: Pre-Clinical- Chemotherapy and Biologic Agents: Poster III
Date & Time: Monday, December 7, 2015, 6:00 – 8:00 p.m.
Abstract No.: 4000
Presenter: Joe Gozgit, Ph.D. (ARIAD Pharmaceuticals, Inc.)
Location: Orange County Convention Center, Hall A

About Iclusig (ponatinib) tablets

Iclusig is approved in the U.S., EU, Australia, Switzerland, Israel and Canada.

In the U.S., Iclusig is a kinase inhibitor indicated for the:

Treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.

These indications are based upon response rate. There are no trials verifying an improvement in disease-related symptoms or increased survival with Iclusig.

IMPORTANT SAFETY INFORMATION, INCLUDING THE BOXED WARNING

WARNING: VASCULAR OCCLUSION, HEART FAILURE, and HEPATOTOXICITY

See full prescribing information for complete boxed warning

Vascular Occlusion: Arterial and venous thrombosis and occlusions have occurred in at least 27% of Iclusig treated patients, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients less than 50 years old, experienced these events. Monitor for evidence of thromboembolism and vascular occlusion. Interrupt or stop Iclusig immediately for vascular occlusion. A benefit risk consideration should guide a decision to restart Iclusig therapy.
Heart Failure, including fatalities, occurred in 8% of Iclusig-treated patients. Monitor cardiac function. Interrupt or stop Iclusig for new or worsening heart failure.

Hepatotoxicity, liver failure and death have occurred in Iclusig-treated patients. Monitor hepatic function. Interrupt Iclusig if hepatotoxicity is suspected.

Vascular Occlusion: Arterial and venous thrombosis and occlusions, including fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures have occurred in at least 27% of Iclusig-treated patients from the phase 1 and phase 2 trials. Iclusig can also cause recurrent or multi-site vascular occlusion. Overall, 20% of Iclusig-treated patients experienced an arterial occlusion and thrombosis event of any grade. Fatal and life-threatening vascular occlusion has occurred within 2 weeks of starting Iclusig treatment and in patients treated with average daily dose intensities as low as 15 mg per day. The median time to onset of the first vascular occlusion event was 5 months. Patients with and without cardiovascular risk factors have experienced vascular occlusion although these events were more frequent with increasing age and in patients with prior history of ischemia, hypertension, diabetes, or hyperlipidemia. Interrupt or stop Iclusig immediately in patients who develop vascular occlusion events.

Heart Failure: Fatal and serious heart failure or left ventricular dysfunction occurred in 5% of Iclusig-treated patients (22/449). Eight percent of patients (35/449) experienced any grade of heart failure or left ventricular dysfunction. Monitor patients for signs or symptoms consistent with heart failure and treat as clinically indicated, including interruption of Iclusig. Consider discontinuation of Iclusig in patients who develop serious heart failure.

Hepatotoxicity: Iclusig can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in an Iclusig-treated patient within one week of starting Iclusig. Two additional fatal cases of acute liver failure also occurred. The fatal cases occurred in patients with blast phase CML (BP-CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Severe hepatotoxicity occurred in all disease cohorts. Iclusig treatment may result in elevation in ALT, AST, or both. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, reduce or discontinue Iclusig as clinically indicated.

Hypertension: Treatment-emergent hypertension (defined as systolic BP≥140 mm Hg or diastolic BP≥90 mm Hg on at least one occasion) occurred in 67% of patients (300/449). Eight patients treated with Iclusig (2%) experienced treatment-emergent symptomatic hypertension as a serious adverse reaction, including one patient (<1%) with hypertensive crisis. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. In 131 patients with Stage 1 hypertension at baseline, 61% (80/131) developed Stage 2 hypertension. Monitor and manage blood pressure elevations during Iclusig use and treat hypertension to normalize blood pressure. Interrupt, dose reduce, or stop Iclusig if hypertension is not medically controlled.

Pancreatitis: Clinical pancreatitis occurred in 6% (28/449) of patients (5% Grade 3) treated with Iclusig. Pancreatitis resulted in discontinuation or treatment interruption in 6% of patients (25/449). The incidence of treatment-emergent lipase elevation was 41%. Check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Dose interruption or reduction may be required. In cases where lipase elevations are accompanied by abdominal symptoms, interrupt treatment with Iclusig and evaluate patients for pancreatitis. Do not consider restarting Iclusig until patients have complete resolution of symptoms and lipase levels are less than 1.5 x ULN.

Neuropathy: Peripheral and cranial neuropathy have occurred in Iclusig-treated patients. Overall, 13% (59/449) of Iclusig-treated patients experienced a peripheral neuropathy event of any grade (2%, grade 3/4). In clinical trials, the most common peripheral neuropathies reported were peripheral neuropathy (4%, 18/449), paresthesia (4%, 17/449), hypoesthesia (2%, 11/449), and hyperesthesia (1%, 5/449). Cranial neuropathy developed in 1% (6/449) of Iclusig-treated patients (<1% grade 3/4). Of the patients who developed neuropathy, 31% (20/65) developed neuropathy during the first month of treatment. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Consider interrupting Iclusig and evaluate if neuropathy is suspected.

Ocular Toxicity: Serious ocular toxicities leading to blindness or blurred vision have occurred in Iclusig-treated patients. Retinal toxicities including macular edema, retinal vein occlusion, and retinal hemorrhage occurred in 3% of Iclusig-treated patients. Conjunctival or corneal irritation, dry eye, or eye pain occurred in 13% of patients. Visual blurring occurred in 6% of the patients. Other ocular toxicities include cataracts, glaucoma, iritis, iridocyclitis, and ulcerative keratitis. Conduct comprehensive eye exams at baseline and periodically during treatment.

Hemorrhage: Serious bleeding events, including fatalities, occurred in 5% (22/449) of patients treated with Iclusig. Hemorrhagic events occurred in 24% of patients. The incidence of serious bleeding events was higher in patients with accelerated phase CML (AP-CML), BP-CML, and Ph+ ALL. Most hemorrhagic events, but not all occurred in patients with grade 4 thrombocytopenia. Interrupt Iclusig for serious or severe hemorrhage and evaluate.

Fluid Retention: Serious fluid retention events occurred in 3% (13/449) of patients treated with Iclusig. One instance of brain edema was fatal. In total, fluid retention occurred in 23% of the patients. The most common fluid retention events were peripheral edema (16%), pleural effusion (7%), and pericardial effusion (3%). Monitor patients for fluid retention and manage patients as clinically indicated. Interrupt, reduce, or discontinue Iclusig as clinically indicated.

Cardiac Arrhythmias: Symptomatic bradyarrhythmias that led to a requirement for pacemaker implantation occurred in 1% (3/449) of Iclusig-treated patients. Advise patients to report signs and symptoms suggestive of slow heart rate (fainting, dizziness, or chest pain). Supraventricular tachyarrhythmias occurred in 5% (25/449) of Iclusig-treated patients. Atrial fibrillation was the most common supraventricular tachyarrhythmia and occurred in 20 patients. For 13 patients, the event led to hospitalization. Advise patients to report signs and symptoms of rapid heart rate (palpitations, dizziness). Interrupt Iclusig and evaluate.

Myelosuppression: Severe (grade 3 or 4) myelosuppression occurred in 48% (215/449) of patients treated with Iclusig. The incidence of these events was greater in patients with AP-CML, BP-CML and Ph+ ALL than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated, and adjust the dose as recommended.

Tumor Lysis Syndrome: Two patients (<1%) with advanced disease (AP-CML, BP-CML, or Ph+ ALL) treated with Iclusig developed serious tumor lysis syndrome. Hyperuricemia occurred in 7% (30/449) of patients overall; the majority had CP-CML (19 patients). Due to the potential for tumor lysis syndrome in patients with advanced disease, ensure adequate hydration and treat high uric acid levels prior to initiating therapy with Iclusig.

Compromised Wound Healing and Gastrointestinal Perforation: Since Iclusig may compromise wound healing, interrupt Iclusig for at least 1 week prior to major surgery. Serious gastrointestinal perforation (fistula) occurred in one patient 38 days post-cholecystectomy.

Embryo-Fetal Toxicity: Iclusig can cause fetal harm. If Iclusig is used during pregnancy, or if the patient becomes pregnant while taking Iclusig, the patient should be apprised of the potential hazard to the fetus. Advise women to avoid pregnancy while taking Iclusig.

Most common non-hematologic adverse reactions: (≥20%) were hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, and pyrexia. Hematologic adverse reactions included thrombocytopenia, anemia, neutropenia, lymphopenia, and leukopenia.