The child needs beta gene molecular testing to determine if he is also a carrier for beta thalassemia , as well as for one alpha gene loss . We also need to see the red blood cell and mean corpuscular volume values , as well as iron testing .
Geoffrey Wool , MD , PhD University of Chicago
Chicago , IL
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 .
The gene deletion confirms the alpha thalassemia heterozygosity , and the high Hgb A2 confirms the beta thalassemia heterozygosity , but the microcytosis suggests underlying iron deficiency . A beta thalassemia homozygosity can be excluded because the Hgb is within normal .
The combination between alpha and beta thalassemia heterozygosities is usually normocytic . A beta globin gene sequence and blood irons / ferritin can confirm the diagnosis .
Alex Felice , MD , PhD University of Malta
Msida
Single alpha chain deletion does not usually produce anemia or microcytosis unless something else is going on . I suspect the
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 described patient may have an abnormality in the beta-gamma gene complex , perhaps a deletion or non-functional fusion . Why not do genetic studies of this complex ?
Malcolm Vye , MD Retired Hematopathologist
Evanston , IL
Single gene alpha thalassemia mutation is not usually associated with either microcytosis or an elevation in either Hgb F or Hgb A2 . I would favor this patient having both alpha thalassemia – silent carrier and a beta-positive thalassemia trait .
James L . Harper , MD University of Nebraska Medical Center
Omaha , NE
The child has one single alpha gene deletion , and that doesn ’ t have much effect on hemogram . Though his Hgb electrophoresis is suggestive of beta trait , his Hgb F level is high . There may be coexistent Xmnl mutation . Again , he has normal reticulocyte count . In my opinion , this child should be considered as beta trait only .
Debmalya Bhattacharyya , MD Kolkata , India
I would answer yes , since the patient has an elevated Hgb A2 and a markedly decreased mean corpuscular volume . The latter is usually not that low – single gene deletion alpha thalassemia usually causes only a mild decrease in mean corpuscular volume .
Donald I . Feinstein , MD USC University Hospital , Keck Medical
Center of USC
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ASH Clinical News 9