CLINICAL NEWS
On Location ASH Annual Meeting
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a high-risk cytogenetic profile ( defined as having at least 1 of 5 chromosomal abnormalities , including t [ 4 ; 14 ], del17p , t [ 14 ; 16 ], amp [ 1q ], and del [ 1p ]), compared with 54 percent in the double-AHCT group .
After a median follow-up of 27 months from randomization ( range = 20-35 months ), PFS
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( the study ’ s primary endpoint ) was longer for patients in the double-AHCT group than for the single-AHCT group : Median PFS had not been reached in the double-AHCT group , compared with 45 months in the single-AHCT group ( p value not reported ).
The three-year estimate for PFS , though , was significantly
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greater in the double-AHCT group : 73 percent versus 60 percent in the single AHCT group ( hazard ratio [ HR ] = 0.66 ; 95 % CI 0.45-0.96 ; p = 0.030 ).
The results were consistent in subgroup analyses where , even among patients with greater bone marrow involvement , high lactate dehydrogenase
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( LDH ) levels , or highrisk cytogenetics , the HR for PFS was more favorable for patients in the double-AHCT group than for those in the single-AHCT group :
• β2-microglobulin > 3.5 mg / L : 0.59 ( 95 % CI 0.34-0.99 ; p = 0.005 )
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• bone marrow plasma cells > 60 %: 0.41 ( 95 % CI 0.22- 0.77 ; p = 0.006 )
• LDH values above the upper limits : 0.52 ( 95 % CI 0.28- 0.95 ; p = 0.034 )
• revised ISS stage II : 0.50 ( 95 % CI 0.31-0.80 ; p = 0.004 )
• high-risk cytogenetics : 0.57 ( 95 % CI 0.35-0.93 ; p = 0.024 )
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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 .
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 .
Double AHCT remained a significant independent predictor of PFS ( HR = 0.62 ; 95 % CI 0.40- 0.95 ; p = 0.027 ) in multivariate Cox regression analysis .
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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
“ In the age of novel therapies for multiple myeloma , the role of single versus double AHCT needs to be prospectively investigated .”
— MICHELE CAVO , MD
Investigators were unable to report on overall survival , as the data had not yet matured ; however , they did note that early indications showed no difference between the groups . Dr . Cavo also noted that a risk-adapted approach , which wasn ’ t studied in this trial , might identify patients who do not require additional treatment intensification after first AHCT . ●
REFERENCE
Cavo M , Petrucci MT , Di Raimondo F . Upfront single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma : an intergroup , multicenter , phase III study of the European Myeloma Network ( EMN02 / HO05 MM Trial ). Abstract # 991 . Presented at the 2016 ASH Annual Meeting , December 5 , 2016 ; San Diego , California .
February 2017