Letters to the Editor

December 2017 Feature

In our December 2017 issue , “ Gun Violence : A Public Health Crisis ,” we spoke with experts about the complexities of treating gun control as a health-care issue and the varying opinions among hematologists about how – or whether – to approach firearm regulation as clinicians . A German hematologist wrote in to offer perspective on this uniquely American problem .

to the editor :

ADYNOVATE ® [ Antihemophilic Factor ( Recombinant ), PEGylated ] Lyophilized Powder for Solution For Intravenous Injection Brief Summary of Prescribing Information : Please see package insert for full Prescribing Information .

INDICATIONS AND USAGE

ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in children and adults with hemophilia A ( congenital factor VIII deficiency ) for :

• On-demand treatment and control of bleeding episodes

• Perioperative management

• Routine prophylaxis to reduce the frequency of bleeding episodes

Limitation of Use ADYNOVATE is not indicated for the treatment of von Willebrand disease . CONTRAINDICATIONS

ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ADVATE ® ( Antihemophilic Factor [ Recombinant ]), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions

Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .

Neutralizing Antibodies

Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .

Monitoring Laboratory Tests

• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .

• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .

ADVERSE REACTIONS The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .

Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice .

The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multicenter , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Table 1 lists the adverse reactions reported during clinical studies .

Table 1 : Adverse Reactions Reported for ADYNOVATE

MedDRA System Organ Class

Gastrointestinal Disorders Immune System Disorder Nervous System Disorders Skin and Subcutaneous Tissue Disorders Vascular Disorders

MedDRA Preferred Term

Number of Subjects n (%) ( N = 234 )

Rate of AEs per 100 Infusions ( N = 30865 )

Hypersensitivity a 1 ( 0.4 %) 0.003

Headache 5 ( 2.1 %) 0.026 Rash 1 ( 0.4 %) 0.003 Flushing 1 ( 0.4 %) 0.003 a

The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .

Two cases of acute pancreatitis , with no precipitating cause identified in one case , were reported in adults during an extension study of the clinical trial which evaluated 137 subjects . Administration of ADYNOVATE continued and both cases resolved .

Immunogenicity

The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .

Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), or PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .

The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .

Baxalta , Advate , Adynovate , and Baxject are trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .

Baxalta US Inc . Westlake Village , CA 91362 USA U . S . License No . 2020 Issued 12 / 2016 16I045-ADY-US S24588 01 / 17

I am an international ASH member and have just read the article about gun control . As a European citizen , I am concerned about the “ right ” to own guns in the United States . To be honest , I am deeply troubled as to whether it is in line with all we know about practicing humane and reasonable medicine ( primum nil nocere ).

Primary prophylaxis is key in medicine . To own a gun contradicts all we know about preventing homicides . Why , then , should a hematologist ask to preserve the right to own guns ?

As a foreigner , it is not my intention to criticize your country . When it comes to prevention , however , scientific reasoning is what should be discussed , and – from all we know – societies with gun control laws experience many fewer injuries and homicides , compared with countries that allow more access to guns .

If this was the case , why should physicians call for not restricting access to guns ? Could it be that there are other hidden agendas in play ?

Andreas Neubauer , MD Director , Department of Hematology ,

Oncology , and Immunology The University Hospital of Giessen and Marburg Marburg , Germany

Have a comment about an article ? Let us know what you think ; we welcome your feedback . Email the editor at ACNEditor @ hematology . org .

January 2018 Annual Meeting Edition