CLINICAL NEWS
Long-Term Follow-Up Confirms Benefit of High-Dose Daunorubicin Across Molecular and Cytogenetic Groups of AML Patients
In a long-term follow-up of the Eastern Cooperative Oncology Group−American College of
Radiology Imaging Network Cancer Research Group ( ECOG- ACRIN ) E1900 study , researchers
Immunogenicity All clinical trial subjects were monitored for neutralizing antibodies ( inhibitors ) to Factor VIII by the modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY , at defined intervals during the studies and at the completion visit .
Clinical trials ( Phases 1 through 3 ) with KOVALTRY evaluated a total of 204 pediatric and adult patients diagnosed with severe hemophilia A ( Factor VIII < 1 %) with previous exposure to Factor VIII concentrates ≥50 EDs , and no history of inhibitors .
In the completed studies , no PTP developed neutralizing antibodies to Factor VIII . In an ongoing extension study , a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute infection and positive IgG anticardiolipin antibodies . The Factor VIII recovery was 2.2 IU / dL per IU / kg , annualized bleeding rate ( ABR ) was zero , and no change in therapy was required .
In an actively enrolling clinical trial in PUPs , 6 of 14 treated subjects ( 42.9 % with a 95 % Confidence Interval of 17.7-71.1 %) developed an inhibitor . Of these , 3 subjects ( 21.4 %) had high titer inhibitors , and 3 subjects ( 21.4 %) had transient low titer inhibitors for which no change in therapy was required .
The detection of antibody formation is dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , it may be misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to other products .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk . Animal reproduction studies have not been conducted using KOVALTRY . It is not known whether KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity . KOVALTRY should be given to a pregnant woman only if clearly needed . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively .
8.2 Lactation Risk Summary There is no information regarding the presence of KOVALTRY in human milk , the effects on the breastfed infant , or the effects on milk production . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for KOVALTRY and any potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal condition . found that treatment with high-dose daunorubicin ( 90 mg / m 2 ) resulted in increased overall survival ( OS ) and event-free survival ( EFS ; primary endpoints ) across a variety of subgroups of patients with acute myeloid leukemia ( AML ).
The original results of the ECOG-ACRIN E1900 study , published in 2009 , indicated that standard-dose daunorubicin ( 45 mg / m 2 ) led to increased rates of complete remission ( CR ) and improved OS . A subgroup analyses conducted at that time identified several factors associated
8.4 Pediatric Use Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs . Body weight adjusted clearance of Factor VIII in children ≤12 years of age is higher than in adults and adolescents . Consider higher or more frequent dosing in children to account for this difference in clearance [ see Clinical Pharmacology ( 12.3 )].
8.5 Geriatric Use Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or not they respond differently from younger patients . However , clinical experience with other Factor VIII products has not identified differences between the elderly and younger patients . As with any patient receiving recombinant Factor VIII , dose selection for an elderly patient should be individualized .
17 PATIENT COUNSELING INFORMATION
• Advise the patient to read the FDA-approved patient labeling ( Patient Information and Instructions for Use ).
• Hypersensitivity reactions are possible with KOVALTRY [ see Warnings and Precautions ( 5.1 )]. Warn patients of the early signs of hypersensitivity reactions ( including tightness of the chest or throat , dizziness , mild hypotension and nausea during infusion ) which can progress to anaphylaxis . Advise patients to discontinue use of the product if these symptoms occur and seek immediate emergency treatment with resuscitative measures such as the administration of epinephrine and oxygen .
• Inhibitor formation may occur at any time in the treatment of a patient with hemophilia A [ see Warnings and Precautions ( 5.2 )]. Advise patients to contact their physician or treatment center for further treatment and / or assessment , if they experience a lack of clinical response to Factor VIII replacement therapy , as this may be a manifestation of an inhibitor .
• Advise patients to discard all equipment , including any unused product , in an appropriate container .
• Advise patients to consult with their healthcare provider prior to travel . Advise patients to bring an adequate supply of KOVALTRY while traveling based on their current regimen of treatment .
Resources at Bayer available to the patient : For Adverse Reaction Reporting , contact Bayer Medical Communications 1-888-84-BAYER ( 1-888-842-2937 )
To receive more product information , contact KOVALTRY Customer Service 1-888-606-3780
Bayer Reimbursement HELPline 1-800-288-8374 For more information , visit www . KOVALTRY-us . com
Bayer HealthCare LLC Whippany , NJ 07981 USA
U . S . License No . 8 6907500BS with achieving clinical benefit ( including age < 50 years , intermediate cytogenetics , FLT3-ITDnegative type AML ), as well as other variables associated with poor response , including age ≥50 years , unfavorable cytogenetics , and the presence of FLT3-ITD mutations .
In the follow-up study , Marlise R . Luskin , MD , from the Division of Hematology and Oncology at the Abramson Cancer Center at the University of Pennsylvania in Philadelphia , and colleagues evaluated longer-term outcomes for the 657 patients ranging in age from 17 to 60 with de novo untreated AML who were enrolled in ECOG-ACRIN E1900 between December 2002 and November 2008 . Eligible patients received either standard or high-dose daunorubicin for three days in combination with cytarabine . The researchers examined the efficacy of high-dose daunorubicin based on patient age , cytogenetic risk , and genetic mutations .
The median patient age was 48 years , and 45.2 percent of patients were 50 years or older .
Patients ’ pre-treatment cytogenetic risks were classified as one of the following :
• Favorable : 13.6 %
• Intermediate : 40.9 %
• Unfavorable : 18.6 %
• Indeterminate : 26.9 %
Patients were also classified based on the presence of the following genetic mutations :
• FLT3-ITD ( previously examined in ECOG-ACRIN E1900 )
• MLL-PTD ( previously examined in ECOG-ACRIN E1900 )
• NPM1
• DNMT3A
After a median follow-up of 80.1 months ( range = 0.8-120.4 months ), the median OS was longer for patients in the high-dose cohort compared with the standard-dose cohort ( 25.4 months vs . 16.6 months ; p = 0.001 ; TABLE 1 , page 32 ).
In the younger patient cohort (< 50 years ), high-dose daunorubicin was associated with better OS compared with the standard dose ( 44.7 vs . 20.7 months ; p = 0.002 ), though a significant benefit of high-dose daunorubicin was not confirmed in the older patient population ( ≥50 years ).
Treatment with high-dose daunorubicin also benefited patients with favorable-risk and intermediate-risk cytogenetics , leading to a longer median OS than the standard dose in both
ASH Clinical News 31