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CLINICAL NEWS

TABLE 2 . MRD Status Determined by Peripheral-Blood Samples

Immunogenicity

Venetoclax-rituximab group ( n = 194 )

At 9 Months

The development of factor VIII inhibitors with the use of ADVATE was evaluated in clinical trials with pediatric PTPs (< 6 years of age with ≥50 factor VIII exposures ) and PTPs ( ≥10 years of age with ≥150 factor VIII exposures ). Of 276 subjects who were treated with ADVATE for at least 10 exposure days or on study for a minimum of 120 days , 1 adult developed a low-titer inhibitor ( 2 BU in the Bethesda assay ) after 26 exposure days . Eight weeks later , the inhibitor was no longer detectable , and in vivo recovery was normal at 1 and 3 hours after infusion of another marketed recombinant factor VIII concentrate . This event results in a factor VIII inhibitor frequency in PTPs of 0.4 % ( 95 % CI of 0.01 and 2 % for the risk of any factor VIII inhibitor development ). No factor VIII inhibitors were detected in the 53 treated pediatric PTPs .

In clinical trials that enrolled previously untreated subjects ( defined as having had up to 3 exposures to a factor VIII product at the time of enrollment ), 16 ( 29.1 %) of 55 subjects who received ADVATE developed inhibitors to factor VIII . Seven subjects developed high titer (> 5 BU ) and nine subjects developed low-titer inhibitors . Inhibitors were detected at a median of 13 exposure days ( min-max : 6−26 exposure days ) to the product .

Immunogenicity also was evaluated by measuring the development of antibodies to heterologous proteins . When assessed for anti-Chinese hamster ovary ( CHO ) cell protein antibodies , of 229 treated subjects , 3 showed an upward trend in antibody titer over time and 10 showed repeated but transient elevations of antibodies . When assessed for muIgG protein antibodies , of the 229 treated subjects , 10 showed an upward trend in anti-muIgG antibody titer over time and 2 showed repeated but transient elevations of antibodies . Four subjects who demonstrated antibody elevations to CHO cell or muIgG proteins , reported isolated events of urticaria , pruritus , rash , and slightly elevated eosinophil counts . All of these subjects had numerous repeat exposures to the product without recurrence of the events and a causal relationship between the antibody findings and these clinical events has not been established .

When assessed for the presence of anti-human von Willebrand Factor ( VWF ) antibodies , of the 228 treated subjects , none displayed laboratory evidence indicative of a positive serologic response .

The detection of antibody formation is highly 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 , comparison of the incidence of antibodies to ADVATE with the incidence of antibodies to other products may be misleading .

Post-Marketing Experience

The following adverse reactions have been identified during post-approval use of ADVATE . 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 .

Table 2 represents the most frequently reported post-marketing adverse reactions as MedDRA Preferred Terms .

Table 2 Post-Marketing Experience

Bendamustine-rituximab group ( n = 195 )

Venetoclax-rituximab group ( n = 194 )

At Any Time During Trial

Bendamustine-rituximab group ( n = 195 )

MRD = minimal residual disease

USE IN SPECIFIC POPULATIONS

Pregnancy

Pregnancy Category C . Animal reproduction studies have not been conducted with ADVATE . It is not known whether ADVATE can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity . ADVATE should be given to a pregnant woman only if clearly needed .

Nursing Mothers

It is not known whether this drug is excreted in human milk . Because many drugs are excreted in human milk , caution should be exercised when ADVATE is administered to a nursing woman .

Pediatric Use

Pharmacokinetic studies in children have demonstrated higher clearance , a shorter half-life and lower recovery of factor VIII compared to adults . This may be explained by differences in body composition and should be taken into account when dosing or following factor VIII levels in the pediatric population . Because clearance ( based on per kg body weight ) has been demonstrated to be higher in the pediatric population , dose adjustment or more frequent dosing based on per kg body weight may be needed in this population . In the ADVATE routine prophylaxis clinical trial , 3 children aged 7 to < 12 and 4 adolescents aged 12 to < 16 were included in the per-protocol analysis . The reductions in annualized bleeding rate per subject per year during any prophylaxis regimen as compared to during on-demand therapy were similar among children , adolescents , and adults .

Geriatric Use

Clinical trials of ADVATE did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently compared to younger subjects . Individualize dose selection for geriatric patients .

Nearly all patients ( n = 379 ; 99.2 %) experienced at least one adverse event ( AE ), including every patient in the venetoclax cohort and 185 in the bendamustine cohort ( 98.4 %). The most common AE in both cohorts was neutropenia ( 60.8 % and 44.1 %). Grade 3 / 4 AEs appeared to be more common among venetoclax-treated patients ( 82 % vs . 70.2 %; p value not provided ), which the authors noted was expected , “ given the longer duration of treatment with venetoclax [ median duration of exposure = 22.1 months ; range = 0.1-27.9 months ].” Neutropenia was the most common grade 3 / 4 AE and , again , this occurred more frequently in the venetoclax cohort ( 67.7 % vs . 38.3 %; p value not provided ). However , grade 3 / 4 febrile neutropenia and infections or infestations were more common in the bendamustine cohort ( 9.6 % vs . 3.6 %; p value not provided ).

Fatal AEs occurred in 5.2 percent of the venetoclax cohort and 5.9 percent of the bendamustine cohort , which included four fatal infections or infestations in each group . “ No new safety events were observed in either treatment regimen ,” the authors noted , and “ the relatively small number of patients in the venetoclaxrituximab group [ with ] tumor lysis syndrome shows the effectiveness of the risk-mitigation procedures that were implemented during the trial and the generally safe delivery of the treatment .”

The study is limited by short duration of follow-up and divergence between investigator-assessed and independent review committee – assessed outcomes . Longer follow-up is needed to assess the durability of responses , the authors noted .

Genentech and AbbVie supported the study . ●

The corresponding authors report no financial conflicts .

REFERENCE

Seymour JF , Kipps TJ , Eichhorst B , et al . Venetoclax – rituximab in relapsed or refractory chronic lymphocytic leukemia . N Engl J Med . 2018 ; 378:1107-20 .

Organ System [ MedDRA Primary SOC ]

Immune system disorders

Blood and lymphatic system disorders

Preferred Term

Anaphylactic reaction a

Hypersensitivity a

Factor VIII inhibition

General disorders and administration site conditions

Injection site reaction Chills Fatigue / Malaise Chest discomfort / pain Decreased therapeutic effect a

These reactions have been manifested by dizziness , paresthesias , rash , flushing , face swelling , urticaria , and / or pruritus .

© 2018 Shire US Inc ., Lexington , MA 02421 . All rights reserved . 1-800-828-2088 . SHIRE and the Shire Logo are registered trademarks of Shire Pharmaceutical Holdings Ireland Limited or its affiliates . ADVATE is a registered trademark of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .

Patented : see www . shire . com / legal-notice / product-patents /

Shire Lexington , MA 02421 USA Printed in USA Issued 11 / 2016

S38308 03 / 18

ASH Clinical News 47