UP FRONT
2016 ASH Meeting on Hematologic Malignancies
September 16 – 17 , 2016 Chicago , IL World-class experts in hematologic malignancies discuss the latest developments in clinical care , and experts in the field discuss treatment options for their own patients based on the available data .
Advance Registration Open through August 22 , 2016 , at 11:59 p . m . Eastern time ( Note : Attendees who register after August 22 will be charged on-site registration rates .)
Serious adverse reactions In Study 3 , serious adverse reactions , regardless of causality , were reported in 25 % of ADCETRIS-treated patients . The most common serious adverse reactions were pneumonia ( 4 %), pyrexia ( 4 %), vomiting ( 3 %), nausea ( 2 %), hepatotoxicity ( 2 %) and peripheral sensory neuropathy ( 2 %).
Dose modifications Adverse reactions that led to dose delays in more than 5 % of ADCETRIS-treated patients in Study 3 were neutropenia ( 22 %), peripheral sensory neuropathy ( 16 %), upper respiratory tract infection ( 6 %), and peripheral motor neuropathy ( 6 %).
Discontinuations Adverse reactions led to treatment discontinuation in 32 % of ADCETRIS-treated patients in Study 3 . Adverse reactions that led to treatment discontinuation in 2 or more patients were peripheral sensory neuropathy ( 14 %), peripheral motor neuropathy ( 7 %), acute respiratory distress syndrome ( 1 %), paraesthesia ( 1 %) and vomiting ( 1 %).
Post Marketing Experience The following adverse reactions have been identified during post-approval use of ADCETRIS . 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 . Blood and lymphatic system disorders : febrile neutropenia . Hepatobiliary disorders : hepatotoxicity .
Infections : PML , serious infections and opportunistic infections . Metabolism and nutrition disorders : hyperglycemia . Gastrointestinal disorders : Pancreatitis ( including fatal outcomes ). Consider the diagnosis of pancreatitis for patients presenting with severe abdominal pain . Respiratory , thoracic and mediastinal disorders : noninfectious pulmonary toxicity including pneumonitis , interstitial lung disease , and ARDS ( some with fatal outcomes ). Skin and subcutaneous tissue disorders : Toxic epidermal necrolysis , including fatal outcomes .
Immunogenicity Patients with classical HL and sALCL Studies 1 and 2 were tested for antibodies to brentuximab vedotin every 3 weeks using a sensitive electrochemiluminescent immunoassay . Approximately 7 % of patients in these trials developed persistently positive antibodies ( positive test at more than 2 timepoints ) and 30 % developed transiently positive antibodies ( positive in 1 or 2 post-baseline timepoints ). The anti-brentuximab antibodies were directed against the antibody component of brentuximab vedotin in all patients with transiently or persistently positive antibodies . Two of the patients ( 1 %) with persistently positive antibodies experienced adverse reactions consistent with infusion reactions that led to discontinuation of treatment . Overall , a higher incidence of infusion related reactions was observed in patients who developed persistently positive antibodies .
A total of 58 patient samples that were either transiently or persistently positive for anti-brentuximab vedotin antibodies were tested for the presence of neutralizing antibodies . Sixty-two percent of these patients had at least one sample that was positive for the presence of neutralizing antibodies . The effect of anti-brentuximab vedotin antibodies on safety and efficacy is not known .
Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity , assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of incidence of antibodies to ADCETRIS with the incidence of antibodies to other products may be misleading .
DRUG INTERACTIONS In vitro data indicate that monomethyl auristatin E ( MMAE ) is a substrate and an inhibitor of CYP3A4 / 5 . In vitro data indicate that MMAE is also a substrate of the efflux transporter P-glycoprotein ( P-gp ).
Effect of Other Drugs on ADCETRIS CYP3A4 Inhibitors / Inducers : MMAE is primarily metabolized by CYP3A . Co-administration of ADCETRIS with ketoconazole , a potent CYP3A4 inhibitor , increased exposure to MMAE by approximately 34 %. Patients who are receiving strong CYP3A4 inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions . Co-administration of ADCETRIS with rifampin , a potent CYP3A4 inducer , reduced exposure to MMAE by approximately 46 %.
P-gp Inhibitors : Co-administration of ADCETRIS with P-gp inhibitors may increase exposure to MMAE . Patients who are receiving P-gp inhibitors concomitantly with ADCETRIS should be closely monitored for adverse reactions .
Effect of ADCETRIS on Other Drugs Co-administration of ADCETRIS did not affect exposure to midazolam , a CYP3A4 substrate . MMAE does not inhibit other CYP enzymes at relevant clinical concentrations . ADCETRIS is not expected to alter the exposure to drugs that are metabolized by CYP3A4 enzymes .
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D .
Risk Summary There are no adequate and well-controlled studies with ADCETRIS in pregnant women . However , based on its mechanism of action and findings in animals , ADCETRIS can cause fetal harm when administered to a pregnant woman . Brentuximab vedotin caused embryo-fetal toxicities in animals at maternal exposures that were similar to human exposures at the recommended doses for patients with classical HL and sALCL . If this drug is used during pregnancy , or if the patient becomes pregnant while receiving this drug , the patient should be apprised of the potential hazard to the fetus .
Animal Data In an embryo-fetal developmental study , pregnant rats received 2 intravenous doses of 0.3 , 1 , 3 , or 10 mg / kg brentuximab vedotin during the period of organogenesis ( once each on Pregnancy Days 6 and 13 ). Druginduced embryo-fetal toxicities were seen mainly in animals treated with 3 and 10 mg / kg of the drug and included increased early resorption ( ≥99 %), post-implantation loss ( ≥99 %), decreased numbers of live fetuses , and external malformations ( i . e ., umbilical hernias and malrotated hindlimbs ). Systemic exposure in animals at the brentuximab vedotin dose of 3 mg / kg is approximately the same exposure in patients with classical HL or sALCL who received the recommended dose of 1.8 mg / kg every three weeks . Nursing Mothers It is not known whether brentuximab vedotin is excreted in human milk . Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ADCETRIS a decision should be made whether to discontinue nursing or to discontinue the drug , taking into account the importance of the drug to the mother .
Pediatric Use The safety and effectiveness of ADCETRIS have not been established in the pediatric population . Clinical trials of ADCETRIS included only 9 pediatric patients and this number is not sufficient to determine whether they respond differently than adult patients .
Geriatric Use Clinical trials of ADCETRIS did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients . Safety and efficacy have not been established .
Renal Impairment Avoid the use of ADCETRIS in patients with severe renal impairment ( CLcr < 30 mL / min ).
The kidney is a route of excretion for monomethyl auristatin E ( MMAE ). The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg / kg of ADCETRIS to patients with mild ( CLcr > 50-80 mL / min ; n = 4 ), moderate ( CLcr 30-50 mL / min ; n = 3 ) and severe ( CLcr < 30 mL / min ; n = 3 ) renal impairment . In patients with severe renal impairment , the rate of Grade 3 or worse adverse
American Society for Radiation Oncology Annual Meeting
September 25 – 28 , 2016 Boston , MA This year , ASTRO invites more than 11,000 attendees to its 58th Annual Meeting to discuss the theme of “ Enhancing Value , Improving Outcomes .”
American Association of Blood Banks Annual Meeting
October 22 – 25 , 2016 Orlando , FL The AABB annual meeting brings together transfusion specialists , laboratory supervisors , cellular therapy and blood banking professionals , medical technologists , donor recruiters , physicians , and nurses to advance transfusion and cellular therapies worldwide .
Orlando , FL
reactions was 3 / 3 ( 100 %) compared to 3 / 8 ( 38 %) in patients with normal renal function . Additionally , the AUC of MMAE ( component of ADCETRIS ) was approximately 2-fold higher in patients with severe renal impairment compared to patients with normal renal function . Due to higher MMAE exposure , ≥Grade 3 adverse reactions may be more frequent in patients with severe renal impairment compared to patients with normal renal function .
Hepatic Impairment Avoid the use of ADCETRIS in patients with moderate or severe hepatic impairment .
The liver is a route of clearance for MMAE . The pharmacokinetics and safety of brentuximab vedotin and MMAE were evaluated after the administration of 1.2 mg / kg of ADCETRIS to patients with mild ( Child-Pugh A ; n = 1 ), moderate ( Child-Pugh B ; n = 5 ) and severe ( Child-Pugh C ; n = 1 ) hepatic impairment . In patients with moderate or severe hepatic impairment , the rate of ≥Grade 3 adverse reactions was 6 / 6 ( 100 %) compared to 3 / 8 ( 38 %) in patients with normal hepatic function . Additionally , the AUC of MMAE was approximately 2.2-fold higher in patients with hepatic impairment compared to patients with normal hepatic function .
OVERDOSAGE There is no known antidote for overdosage of ADCETRIS . In case of overdosage , the patient should be closely monitored for adverse reactions , particularly neutropenia , and supportive treatment should be administered .
NONCLINICAL TOXICOLOGY Carcinogenesis , Mutagenesis , Impairment of Fertility Carcinogenicity studies with brentuximab vedotin or the small molecule ( MMAE ) have not been conducted .
MMAE was genotoxic in the rat bone marrow micronucleus study through an aneugenic mechanism . This effect is consistent with the pharmacological effect of MMAE as a microtubule disrupting agent . MMAE was not mutagenic in the bacterial reverse mutation assay ( Ames test ) or the L5178Y mouse lymphoma forward mutation assay .
Fertility studies with brentuximab vedotin or MMAE have not been conducted . However , results of repeat-dose toxicity studies in rats indicate the potential for brentuximab vedotin to impair male reproductive function and fertility . In a 4-week repeat-dose toxicity study in rats with weekly dosing at 0.5 , 5 , or 10 mg / kg brentuximab vedotin , seminiferous tubule degeneration , Sertoli cell vacuolation , reduced spermatogenesis , and aspermia were observed . Effects in animals were seen mainly at 5 and 10 mg / kg of brentuximab vedotin . These doses are approximately 3 and 6-fold the human recommended dose of 1.8 mg / kg , respectively , based on body weight .
PATIENT COUNSELING INFORMATION
• Peripheral neuropathy Advise patients that ADCETRIS can cause a peripheral neuropathy . They should be advised to report to their health care provider any numbness or tingling of the hands or feet or any muscle weakness .
• Fever / Neutropenia Advise patients to contact their health care provider if a fever of 100.5 ° F or greater or other evidence of potential infection such as chills , cough , or pain on urination develops .
• Infusion reactions Advise patients to contact their health care provider if they experience signs and symptoms of infusion reactions including fever , chills , rash , or breathing problems within 24 hours of infusion .
• Hepatotoxicity Advise patients to report symptoms that may indicate liver injury , including fatigue , anorexia , right upper abdominal discomfort , dark urine , or jaundice .
• Progressive multifocal leukoencephalopathy Instruct patients receiving ADCETRIS to immediately report if they have any of the following neurological , cognitive , or behavioral signs and symptoms or if anyone close to them notices these signs and symptoms :
• changes in mood or usual behavior
• confusion , thinking problems , loss of memory
• changes in vision , speech , or walking
• decreased strength or weakness on one side of the body
• Pulmonary Toxicity Instruct patients to report symptoms that may indicate pulmonary toxicity , including cough or shortness of breath .
• Pancreatitis Advise patients to contact their health care provider if they develop severe abdominal pain .
• Pregnancy and Nursing ADCETRIS can cause fetal harm . Advise women receiving ADCETRIS to avoid pregnancy . Advise patients to report pregnancy immediately . Advise patients to avoid nursing while receiving ADCETRIS .
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MARK YOUR CALENDAR 58th ASH Annual Meeting & Exposition
December 3 – 6 , 2016 San Diego , CA Registration and housing for ASH members will open on Wednesday , July 20 , 2016 , at 11:00 a . m . Eastern time . Registration and housing for non-members will open on Wednesday , August 10 , 2016 , at 11:00 a . m . Eastern time .
Highlights of ASH ® North America
January 13 – 14 , 2017 Atlanta , GA Mexico City , Mexico
January 20 – 21 , 2017 Chicago , IL Dallas , TX
January 29 – 30 , 2017 New York , NY Seattle , WA
Highlights of ASH ® Asia - Pacific
March 10 – 12 , 2017 Hong Kong
Hong Kong Victoria Harbour
National Comprehensive Cancer Network Annual Conference
March 23 – 25 , 2017 Orlando , FL More than 1,500 health-care professionals involved in the care of patients with cancer are expected to attend the NCCN ’ s 22nd annual conference to discuss the conference ’ s theme : “ Improving the Quality , Effectiveness , and Efficiency of Cancer Care .”
ASH DEADLINES TO KEEP IN MIND July 15
2017 Honorific Awards nominations due www . hematology . org / awards
July 30
Translational Research Training in Hematology ( TRTH ) letter of intent due www . hematology . org / awards
August 1
Scholar Awards application deadline www . hematology . org / awards
August 1
ASH membership application deadline
( for consideration during the annual meeting in December ) www . hematology . org / membership
ASH Clinical News 3