Personalizing the Management of HEMOPHILIA A CME SUPPLEMENT

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Table of Contents

CME Information ...... 2

Introduction ...... 6

Prophylactic Factor Replacement ...... 12

Case-Based Learning ...... 16

Personalizing Prophylaxis ...... 17

Adherence ...... 20

Managing the Level of Medication ...... 23

Case-Based Learning ...... 27

Emerging Therapies: Promise and Challenges ...... 29

Conclusions ...... 31

References ...... 32

Evaluation and Attestation Form ...... 78

Table of Contents 1 Personalizing the Management of HEMOPHILIA

CME Information AUTHORS Gynecology and Reproductive Sciences, Yale University School of Medicine Salley G. Pels, MD Assistant Professor of Pediatrics Patrick G. Gallagher, MD (Hematology/Oncology), Yale University Professor of Pediatrics (Neonatology), of School of Medicine; Associate Director, Genetics and of Pathology, Yale University Yale Hemostasis Center School of Medicine; Director, Yale Center for Blood Disorders Daniel U. Rabin, PhD Medical Director, The France Foundation Gary Kupfer, MD* Professor of Pediatrics (Hematology/ Jeanne Hendrickson, MD Oncology) and of Pathology, Yale University Associate Professor of Laboratory Medicine School of Medicine; Clinical Program Leader, and of Pediatrics, Yale University School of Pediatric Hematology & Oncology Program, Medicine; Associate Director, Transfusion Smilow Cancer Hospital; Section Chief, Medicine Service Pediatric Hematology/ Oncology; Clinical Research Program Leader, Pediatric Alfred Ian Lee, MD, PhD Hematology & Oncology Program, Yale Assistant Professor of Medicine (Hematology Cancer Center and FY15 Hematology), Yale University School of Medicine; Firm Chief, Inpatient Michael J. Paidas, MD* Hematology, Yale Cancer Center; Professor of Obstetrics, Gynecology, and Assistant Program Director, Traditional Reproductive Sciences, Yale University School Internal Medicine Residency Program, of Medicine; Vice Chair, Obstetrics; Program Yale University School of Medicine Director, Maternal Fetal Medicine Fellowship; Co-Director, Yale Women and Children's Christopher Anthony Tormey, MD Center for Blood Disorders; Co-Director, Assistant Professor of Laboratory Medicine National Hemophilia Foundation –Baxter and Lecturer in Molecular Biophysics and Clinical Fellowship Program at Yale; Division Biochemistry; Director, Transfusion Medicine of Maternal Fetal Medicine Fellowship, Yale University School of Medicine *Senior Authors Caroline Irma Cromwell, MD, MSCR Addresses Assistant Professor of Medicine Yale School of Medicine (Hematology), Yale University School of 333 Cedar St Medicine New Haven, CT 06510 Sara Ornaghi, MSCR The France Foundation Yale Women and Children’s Center for Blood 10 Vista Drive, Suite 100 Disorders, Department of Obstetrics, Old Lyme, CT 06371

2 CME Information Personalizing the Management of HEMOPHILIA

Corresponding Author TARGET AUDIENCE Daniel U. Rabin, PhD This activity is intended for hematologists 10 Vista Drive, Suite 100 who specialize in hemophilia. Old Lyme, CT 06371 Telephone: 860.598.2235 Fax: 860.434.5390 STATEMENT OF NEED email: [email protected] Hemophilia, an inherited bleeding disorder in which blood does not clot adequately, occurs in approximately 1 in 5000 males. 1 Great METHOD OF PARTICIPATION/ progress in hemophilia management has been HOW TO RECEIVE CREDIT achieved over the last several decades, with self-administered treatment of clotting factor **YYoouu m muusstt g goo t too wwwwww..YYaalleCME-Hemmoo..oorrg g concentrates becoming feasible in the 1970s. to request CtMo rEe cqrueedsit* C* ME credit The threat of blood-borne illness associated with treatment took center stage in the 1980s. 1. There are no fees for participating in and With this major safety issue addressed, the receiving credit for this activity. focus in hemophilia management is 2. Review the activity objectives and CME increasingly on prophylaxis with long-term information. substitution therapy of the missing clotting 3. Complete the CME activity. factor. 2 Go to www.YaleCME-Hemo.org 4. Complete the posttest. A score of at least Patients with severe hemophilia A or B who 75% is required to successfully complete experience recurrent joint bleeding are known this activity. The participant may take the to experience progressive hemophilic test until successfully passed. arthropathy, even with on-demand 5. Complete the CME evaluation/attestation replacement of appropriate factor form, which provides each participant with concentrates. 3 The frequency of bleeding the opportunity to comment on how episodes and the severity of joint disease and participating in the activity will affect their dysfunction are closely linked. 4 Thus, the professional practice; the quality of the approach to hemophilia has evolved so that instructional process; the perception of now primary prophylaxis, achieved with enhanced professional effectiveness; the long-term concentrate infusions, starting perception of commercial bias; and his/her after the first joint bleed or before the age of views on future educational needs. 2, is considered an evidence-based 6. Your CME certificate will be available for management strategy in severe hemophilia. It download. also appears to play a role in preventing inhibitor development, 3 a key side effect of PROVIDER treatment threatening patient health. 2 The use This activity is provided by Yale School of of long-term infusions with the goal of Medicine in collaboration with The France avoiding or delaying arthropathy is considered Foundation. secondary prophylaxis. 3

CME Information 3 Personalizing the Management of HEMOPHILIA

EDUCATIONAL ACTIVITY CREDIT DESIGNATION LEARNING OBJECTIVES Physicians: Yale School of Medicine designates Upon completion of this course, the this enduring material for a maximum of 2 participants should be able to: AMA PRA Category 1 Credit(s) ™. Physicians • Review data on barriers to optimal should claim only the credit commensurate prophylactic replacement of missing with the extent of their participation in the clotting factor activity. • Examine data on short- and long-term ramifications of a prophylactic (vs Release Date: November 30, 2015 episodic) treatment approach Expiration Date: November 29, 2016 • List factors to be considered when Estimated Time to Complete Activity: formulating a personalized prophylactic 2 hours approach for the individual patient • Identify aspects of new guidance that apply DISCLOSURES to a personalized prophylactic regimen It is the policy of Yale School of Medicine and • Determine how new data and agents fit The France Foundation to ensure balance, into the personalized prophylactic independence, objectivity, and scientific rigor approach in hemophilia in all its sponsored educational activities. All • Formulate a management plan that faculty, activity planners, content reviewers, anticipates, assesses, and addresses barriers and staff involved in the development of this to the prophylactic factor replacement activity have disclosed any significant approach financial interest or other relationship with • Summarize key factors that affect trough manufacturer(s) of any commercial levels product(s)/device(s) and/or provider(s) of • Evaluate current data and commercial services included in this recommendations on optimal clotting educational activity. The intent of this factor trough levels disclosure is not to prevent a person with a • Describe a detailed plan for assessing relevant financial or other relationship from treatment adherence in a patient with participating in the activity, but rather to hemophilia provide participants with information on • Design a plan for supporting treatment which they can base their own judgments. adherence that incorporates disease Yale School of Medicine and The France education, technical training needs, Foundation have identified and resolved any relevant psychosocial factors, and utilizes and all conflicts of interest prior to the release tools that the patient can easily of this activity. incorporate Activity Staff Disclosures ACCREDITATION STATEMENT The planners, reviewers, editors, staff, CME Yale School of Medicine is accredited by the committee, or other members at Yale School Accreditation Council for Continuing Medical of Medicine who control content have no Education (ACCME) to provide continuing relevant financial relationships to disclose. medical education for physicians.

4 CME Information Personalizing the Management of HEMOPHILIA

The planners, reviewers, editors, staff, CME research, interim analyses, and/or committee, or other members at The France unsupported opinion. Faculty in this activity Foundation who control content have no may discuss information about relevant financial relationships to disclose. pharmaceutical agents that is outside of US Food and Drug Administration approved Faculty Disclosures labeling. This information is intended solely The following faculty have indicated they have for continuing medical education and is not no relationships with industry to disclose intended to promote off-label use of these relavant to the content of this CME activity: medications. If you have questions, contact the • Salley G. Pels, MD medical affairs department of the • Daniel U. Rabin, PhD manufacturer for the most recent prescribing • Jeanne Hendrickson, MD information. • Caroline Irma Cromwell, MD, MSCR • Sara Ornaghi, MD COMMERCIAL SUPPORT • Patrick G. Gallagher, MD ACKNOWLEDGMENT • Gary Kupfer, MD This activity is supported by an educational The following faculty have indicated they have grant from Biogen Idec. relationships with industry to disclose relavant to the content of this CME activity: DISCLAIMER • Alfred Ian Lee, MD, PhD, has served as a Yale School of Medicine and The France consultant to Pfizer. Foundation present this information for • Christopher A. Tormey, MD, has received educational purposes only. The content is grant funding from the Termuo BCT provided solely by faculty who have been Corporation. In addition, he has received selected because of recognized expertise in honoraria for serving on the clinical their field. Participants have the professional advisory board of Avalon Healthcare. responsibility to ensure that products are • Michael J. Paidas, MD has participated in prescribed and used appropriately on the basis an advisory board and receives research of their own clinical judgment and accepted funding from CSC-Behring. He is an standards of care. Yale School of Medicine and unpaid consultant to Novo Nordisk. He The France Foundation assume no liability for receives research funding from rEVO the information herein. Biologics and Novo Nordisk. CONTACT INFORMATION UNAPPROVED USE DISCLOSURE If you have questions about this educational Yale School of Medicine and The France activity, please contact The France Foundation Foundation require CME faculty to disclose to at 860-434-1650 or [email protected]. the participants when products or procedures being discussed are off-label, unlabeled, experimental, and/or investigational (not FDA approved); and any limitations on the information that is presented, such as data that are preliminary or that represent ongoing

CME Information 5 Personalizing the Management of HEMOPHILIA

Introduction EPIDEMIOLOGY plasma components. 16 In high-income countries the life expectancy of a child with Hemophilia A and hemophilia B are related hemophilia is equivalent to one without the bleeding disorders that are most commonly disease. 17 Hemophilia public health programs inherited. When the term ‘hemophilia’ is have played a large role in this improvement used, it refers to factor VIII deficiency in survival. This effect is most evident in (hemophilia A) or factor IX deficiency developed countries, where patients seen in (hemophilia B, also called ‘Christmas Hemophilia Treatment Centers (HTC) show a disease’). The genes for factors VIII and IX are 60 to 70% reduction in mortality rates even located on the X chromosome, and thus are though they comprise the most severely generally inherited in an X-linked recessive affected patients. 11 manner. As such, they affect mostly males, with females often being healthy carriers. Hemophilia A and B are classified into 3 Approximately 1 in 5,000 to 10,000 males are categories by the International Society on born with hemophilia A, and 1 in 25,000 to Thrombosis and Haemostasis (ISTH): mild 30,000 males are born with hemophilia B. 5,6 (>5% to <40% of normal clotting factor in The incidence of hemophilia is similar for all circulation), moderate (1% to 5%), and populations and racial groups. 7,8,9,10 severe (<1%). 6 The range of clinical severity Hemophilia prevalence varies widely with the correlates well with assayed factor levels. 5,6 economic status of individual countries due Approximately two-thirds of patients with to the effect of premature deaths and hemophilia A and one half of individuals with shortened life-expectancy in poorer hemophilia B have severe disease. Bleeding countries. 11 varies with the severity of the disease. It Before the introduction of pharmaceutical occurs only in response to injury, trauma, or clotting factor preparations, the mean surgery in patients with mild hemophilia, to life-expectancy of patients with hemophilia intercurrent injury or surgery in moderate 12 was <30 years and patients mostly died of hemophilia, and spontaneously and at an intracranial, post-operative, or other severe early age in severe hemophilia. 5,18 Hemophilia 13,14,15 hemorrhages. Since the 1960s, factor VIII A and B of comparable severity bleed with and factor IX preparations have improved the similar frequency. 19 People with hemophilia A life-expectancy of patients with hemophilia. or B do not bleed harder or faster than people Mortality again increased during the 1980s without these disorders—they bleed longer. due to HIV and hepatitis C infection. Clotting Some patients with severe disease may have a factors became almost completely safe in milder clinical course, such as cases with developed countries since 1985 for HIV and hemophilia B Leyden. 20 or the pro-thrombotic since 1992 for hepatitis C due to new viral Leiden mutation of factor V. 21,22 Indeed, inactivation technologies and the concomitant pro-thrombotic conditions may introduction of recombinant products. New partially counteract the bleeding tendency of infectious agents and prion-related diseases hemophilia, resulting in fewer bleeding are of ongoing concern, as some episodes and a later onset of first bleeding. 22 manufacturing of recombinant products uses

6 Introduction Personalizing the Management of HEMOPHILIA

CLINICAL DISEASE Table 1. Bleeding Sites in Severe Hemophilia (adapted) 24

Bleeding Site Frequency

Joints 70-80% Most common: ankle, knee, elbow Others: shoulder, wrist, hip

Muscles 10-20% Most common: iliopsoas, calf, forearm

Other major bleeding sites: 5-10% Mouth, throat, neck, gastrointestinal tract, genitourinary tract

Central nervous system Less than 5%

Sites of Bleeding • Joint disorganization with hemosiderin Bleeding is the main clinical manifestation in deposition patients affected by hemophilia. The major • Joint space narrowing with cartilage bleeding sites in patients with severe destruction hemophilia are shown in Table 1 . • Marked joint destruction with severe Hemarthrosis is by far the predominant restriction in joint movement bleeding manifestation. Joint bleeding is more common in lower limbs, especially at the The extent of joint damage is directly related ankle. 23 This pattern is different from the to the number of joint bleeds. 25 While mucosal and cutaneous bleeding arthropathy typically becomes detectable characteristic of platelet dysfunction or von during school age years, joint pathology Willebrand disease (VWD) (Table 2). begins much earlier with initial bleeding episodes. The pathogenesis of hemophilic arthropathy begins with an inflammatory infiltrate that Initial Presentation follows acute joint hemorrhage. Repeated Newborns with severe hemophilia may bleeding into the joint leads to formation of a traverse delivery and the first few months of target joint, characterized by synovial life without clinically significant bleeding hypertrophy, articular cartilage destruction, episodes. Early bleeding symptoms are most bony changes, and a tendency towards more often associated with circumcision, frequent joint bleeding. 25,26 The classic model intracranial hemorrhage (ICH), and heel of hemophilic arthropathy, described almost sticks. 29 More frequently, children with severe four decades ago, consists of five radiographic hemophilia A or B become symptomatic after stages: 27,28 the newborn period but within the first two • Soft tissue swelling years of life, with a median age at diagnosis of • Subacute hemarthropathy

Introduction 7 Personalizing the Management of HEMOPHILIA

0.9 years. However, in those children carrying Diagnosis concurrent pro-thrombotic risk factors (e.g., The diagnosis of hemophilia typically begins factor V Leiden mutation), the first bleeding with a careful review of the family history, episode often occurs later, at a median age of particularly the maternal side. A negative 1.6 years. 30 family history is of little value in excluding hemophilia since one third of hemophilia Patients with moderate hemophilia present at cases are spontaneous. 34 Table 2 shows the a median age of 22 months. 31 Mild disease, in platelet defect and clotting factor defect the absence of an informative family history, associations with different bleeding may go undetected for significant periods of symptoms. time, 32 since as many as one-third of patients with mild disease have very few or no In patients presenting with a bleeding bleeding episodes. 18 Forehead hematomas diathesis of unknown etiology, three initial (‘goose-eggs’) are the characteristic tests should be performed: platelet count, presenting in children with mild and prothrombin time (PT), and activated partial moderate hemophilia. 33 thromboplastin time (aPTT). 35 Plasma PT measures extrinsic and common pathways of

Table 2. Clinical Manifestations of Bleeding Disorders

Bleeding Symptoms Bleeding Disorder Platelet Defects Clotting Factor Deficiencies Excessive bleeding Yes Not usually after minor cuts Petechiae Common Uncommon Ecchymosis Generally small and superficial; May develop large subcutaneous may be significant depending and soft tissue hematomas upon the defect or degree of thrombocytopenia Hemarthrosis, Uncommon Common in severe deficiency muscle hematomas states or in association with injury in those with mild to moderate deficiency states Bleeding with Often immediate, with degree of May be associated either with invasive procedures, bleeding depending upon the procedural bleeding or delayed including surgery severity of the defect, ranging bleeding, depending upon the from none (e.g., mild degrees of type and the severity of the thrombocytopenia or mild defect platelet function defect) to mild to severe (eg, Glanzmann thromboasthenia)

8 Introduction Personalizing the Management of HEMOPHILIA

Table 3. Causes of a Prolonged PT and/or aPTT

Inherited Acquired • Deficiency of factors VIII, IX, or XI • Heparin administration • Deficiency of factor XII, prekallikrein, • Inhibitor of factors VIII, IX, XI, or XII or HMW kininogen • Acquired von Willebrand disease • von Willebrand disease (variable) • Lupus anticoagulant coagulation, whereas aPTT measures intrinsic performed in the order of their statistical and common pathways. aPTT evaluates the frequency (factor VIII, IX, and finally XI). degree of heparin anticoagulation and is sensitive to inhibitors such as heparin and to Inhibitors deficiencies of all coagulation factors except An important complication of hemophilia factors VII and XIII. It is less sensitive than therapy is the development of antibodies, the PT to deficiencies of the common pathway primarily IgG, that inhibit the relevant (factors X and V, prothrombin, and factor. 40 Inhibitors develop in approximately fibrinogen). 34 A normal platelet count, 25% of patients with severe hemophilia A 41 normal PT, and a prolonged aPTT are but less frequently with mild or moderate characteristic of hemophilia A, hemophilia B, disease or hemophilia B. Young age at the and heparin therapy. time of initial replacement therapy, high treatment intensity, and early use of An abnormal test occurs in individuals who prophylaxis are characteristic of both severe have less than approximately 30 percent of deficiency and inhibitor formation. 42,43 the mean normal activity of factor VIII or IX. Plasma-derived and recombinant preparations However, patients with mild hemophilia B appear to be equivalent in their association may have normal or near normal aPTTs. Thus, with inhibitor development. 44 in undiagnosed mild bleeding disorders, a factor IX assay should be performed even if Inhibitors usually decrease responsiveness to the aPTT is normal. 36,37,38 factor concentrates and achieving hemostasis is more challenging in patients with Other disorders prolong the aPTT but not the inhibitors. They experience more bleeding PT (Table 3) . They include acquired inhibitors complications, especially at musculoskeletal to factor VIII or IX, and deficiency of factor sites. 45 An inhibitor should be suspected when XII, prekallikrein, or HK. However, abnormal any bleeding episode is refractory to usual bleeding does not occur with these therapy, particularly in patients with severe deficiencies. 39 A similar pattern of laboratory hemophilia. 46 Patients with factor IX results is seen in patients with inhibitors are also at risk for allergic and/or antiphospholipid antibodies (Lupus anaphylactic reactions. 47 These reactions are anticoagulant), who have a tendency to limited primarily to patients with gene thrombosis rather than bleeding. Specific deletions or major gene rearrangements. assays for the factors that can produce an isolated finding of prolonged aPTT should be Treatment of inhibitors typically requires a

Introduction 9 Personalizing the Management of HEMOPHILIA

combined approach with both immune Figure 1. Pro-Coagulant Complexes of the induction with specific factor product and Coagulation Cascade. 54 by-passing agent to treat or prevent acute bleeding episodes. 48 Various protocols for immune tolerance induction (ITI) exist, and inhibitors can be treated successfully in many patients. 47,49

CLOTTING CASCADE, DISEASE SUBTYPES Severe factor VIII or factor IX deficiency leads to bleeding because these factors play important roles in the coagulation pathway (Figure 1) . The interaction of clotting factors, cofactors, and proteolytic enzymes is the subject of several excellent reviews. 50,51,52 The cell-based model of coagulation refines the role of localization and cell surface interactions in regulating the clotting process. 53

Genetic Transmission and Disease Subtypes Hemophilia A and B are X-linked recessive disorders. Therefore, they occur almost exclusively in a male having one defective copy of the relevant gene on his X chromosome. 49 Because the affected male will transmit a normal Y chromosome to all his sons and an abnormal X chromosome HK: high molecular weight kininogen; PK: to all his daughters, his sons will not be prekallikrein; PL: phospholipid; PT: prothrombin; affected and all his daughters will be TH: thrombin. carriers. Approximately one-third of patients with hemophilia do not have a family history Approximately 40 percent of severe of the disease and appear to have novel hemophilia A is caused by a major inversion mutations. 34 of a section of the tip of the long arm of the X chromosome, one break point of which is Factor VIII Mutations situated within intron 22 of the gene. Five The genetic defects of hemophilia A percent of patients with hemophilia A have encompass point mutations, deletions, normal protein levels of a dysfunctional insertions, duplications, and transpositions. 55 factor VIII (“cross-reacting material The large size of the factor VIII gene and the positive”), often due to missense mutations presence of ‘hot spots’ are thought to make in the A2-domain. 56 the gene particularly sensitive to mutation.

10 Introduction Personalizing the Management of HEMOPHILIA

Factor IX Mutations Bleeding in Carriers Hemophilia B is a heterogeneous disorder A wide range of factor VIII and factor IX levels with a wide range of factor IX plasma levels has been observed in normal subjects as well and a variety of mutations such as complete as in heterozygous carriers of hemophilia A or gene deletions, small insertions/deletions, B. 60 Extreme degrees of X chromosome and, most commonly, point mutations. 57 inactivation (lyonization) and other genetic Similar to hemophilia A, approximately factors may lead to very low clotting factor one-third of hemophilia B cases have levels in heterozygous female carriers, with antigenic levels of factor IX that are near associated bleeding. Since factor levels of a normal, but they have much lower factor IX known carrier appear to be independent of activity levels. The clinical severity of these the severity of hemophilia within the family cases ranges widely from mild to severe. and vary from person to person 61 , clotting factor levels should be measured in all carriers Hemophilia B Leyden and Brandenburg preceding a medical or surgical intervention Hemophilia B Leyden is a rare form of in order to assess their risk of bleeding. hemophilia B caused by a mutation in the factor IX gene promoter. 58 In individuals with the Leyden phenotype, factor IX levels increase following puberty, likely due to an androgen responsive element (ARE) in the promoter. These individuals often convert from a severe to a mild clinical phenotype by adulthood. Hemophilia B Brandenburg results from a GàA mutation at the -26 position that disrupts the ARE and results in a severe clinical phenotype that does not resolve after puberty. 59

Introduction 11 Personalizing the Management of HEMOPHILIA

Prophylactic Factor Replacement

PROPHYLACTIC VS EPISODIC no bleeding and their joint scores remained TREATMENT unchanged throughout the study. Prophylaxis did not restore joint function or stop Traditionally, severe hemophilia was treated progression for boys who had joint defects after bleeding episodes. In recent years a before entering the study. A similar result was prophylactic approach has become the reported in 2006 by Feldman et al who used standard of care. Prophylaxis may be primary, an escalating prophylactic dose to treat 25 24 secondary, or tertiary. boys with severe hemophilia A. 63 Compared with an historical rate of 50% development of • Primary prophylaxis: initiation of a target joint in 44 months, the prophylaxis prophylaxis before 3 years of age, prior to group had a rate of 16% (4/25). Fischer et al the second bleeding episode involving a reviewed several studies with intermediate- large joint dose and high-dose prophylaxis and found • Secondary prophylaxis: initiation of that the high-dose group had less bleeding prophylaxis after 2 or more large joint over five years (median, 0 vs 1.3 joint bleeds prior to the onset of arthropathy bleeds/y, P < 0.01) and better joint health • Tertiary prophylaxis: initiation after (Haemophilia Joint Health Score > 10 of 144 arthropathy has already occurred points in 11% vs 46% of participants), although the quality of life measures were In 1992 Nilsson et al published a review of up similar in the two groups. Annual total costs to 25 years prophylaxis in a cohort of 60 were 66% higher for high-dose prophylaxis 62 Swedish boys with hemophilia A or B. Due (P < 0.01). 64 to a shortage of clotting factors in the early years of the study, only the youngest patients The advantage of prophylaxis over episodic were treated with high doses of factor VIII or treatment was confirmed in a trial by factor IX to maintain trough levels at 1-5% Manco-Johnson et al in 2007. 65 Sixty-five boys -1 (1-5 IU dL ). The patients experienced almost younger than 30 months with severe Table 4. Outcome Data in a Trial of Prophylaxis vs Enhanced Episodic Therapy with Factor VIII 65

Variable Prophylaxis Enhanced P Value (N = 32) Episodic Therapy (N = 33) Joint damage (MRI)—no. (%) 2 (7) 13 (45) 0.002 Joint damage (radiography)—no. (%) 1 (4) 5 (19) 0.10 Mean joint hemorrhages 0.63±1.35 4.89±3.57 < 0.001 (no./participant/yr) Mean total hemorrhages 3.27±6.24 17.69±9.25 < 0.001 (no./participant/yr)

12 Prophylactic Factor Replacement Personalizing the Management of HEMOPHILIA

hemophilia A were randomly assigned to The 2013 World Federation of Hemophilia prophylaxis (32 boys) or enhanced episodic guidelines found that there is level 2 therapy (33 boys). At age 6, 93% of those in (randomized trial) data supporting the the prophylaxis group and 55% of those in position that “Prophylaxis prevents bleeding the episodic-therapy group had normal and joint destruction and should be the goal index-joint structure on MRI ( P = 0.006). The of therapy to preserve normal musculoskeletal relative risk of MRI-detected joint damage function.” 24 The World Health Organization with episodic therapy compared with (WHO), 7 World Federation of Hemophilia prophylaxis was 6.1 (95% CI, 1.5 to 24.4). (WFH), 24 and the National Hemophilia Table 4 shows the joint damage results of this Foundation’s (NHF) Medical and Scientific trial. A clinical challenge is that many Advisory Council (MASAC) 72 all recommend patients receive treatment only on demand or initiation of prophylaxis where possible prior as secondary prophylaxis. Thus, orthopedic to the onset of frequent bleeding in severe complications remain a serious problem. hemophilia to keep trough levels >1% between doses. A number of additional clinical trials have demonstrated beneficial effects on outcomes, While the ideal prophylaxis regimen is particularly joint health, for patients who unknown at this time, several studies have have received prophylaxis versus on-demand evaluated various methods of administering therapy starting at a young age and prophylaxis: tailored low-dose, escalating continuing through adulthood. 66,67 The regimens, or pharmacokinetic-based Orthopedic Outcomes Study was a regimens. 73 Valentino and colleagues longitudinal study of 477 patients receiving compared two prophylaxis regimens versus secondary or tertiary prophylaxis. Patients on on-demand therapy in 66 severe Hemophilia prophylaxis had improved joint outcomes as A patients ages 7-59 years. Patients were well as fewer missed days of school, and fewer previously treated on-demand and were days hospitalized. 68 Another study randomized to receive standard every other demonstrated similar results in 45 children day dosing or pharmacokinetic (PK) derived with hemophilia A, with children randomized every third day dosing. Both prophylaxis to prophylaxis having significantly fewer regimens were superior to the on-demand hemarthrosis. 66 A Cochrane Review published therapy, and bleeding rates on both in 2011 concluded that there was strong prophylaxis arms were comparable. Patients evidence that prophylaxis was more effective on each prophylaxis regimen used the same than on-demand therapy in preserving joint amount of factor and had similar health function in children with hemophilia. 69 related quality of life measures. 74 A Studies have also shown that this benefit retrospective chart review of 58 patients extends to all age groups. In the Haemo-QoL receiving either “traditional” Swedish study, adolescents on prophylaxis reported (Malmo) protocol treatment or the Canadian higher quality of life scores, particularly in the tailored prophylaxis showed no difference in areas of academics and sports. 70 In a recent efficacy rates; the only major difference study of 84 male patients with severe between the two groups was the use of hemophilia A between the age of 12 and 50, implantable venous devices (75% versus prophylaxis led to a significant decrease in the 29%). 75 number of total bleeding episodes. 67

Prophylactic Factor Replacement 13 Personalizing the Management of HEMOPHILIA

Caracao compared three models: Swedish including access to factor products and their (Malmo), Canadian, and French, and cost, adequate venous access, and adherence outlined the challenges providers face when to recommended prophylaxis schedules. A choosing a regimen. 76 The Swedish (Malmo) survey of US physicians treating hemophilia model is a high-dose regimen utilizing 25-40 found that each of these perceived barriers led U/kg of factor two or three times per week for to decreased prescription rates. 81 Lack of hemophilia B or A, respectively, beginning venous access was reported as reducing before 3 years of age. 65,77 It serves as the basis prescription rates at least sometimes by 82% for the NHF recommendation, starting full of physicians. Adherence and financial dose prophylaxis after the first bleed. This concerns were also reported as a significant dosing regimen often requires early placement barrier by 87% and 71% of physicians of central lines. The Canadian and French respectively. Patient surveys have yielded approaches call for weekly dosing followed by similar results. Difficult venous access and step-wise escalation. While the Canadian the time required for dosing were the most protocol initiates treatment prior to the first commonly cited reasons for incomplete or second bleed, the French regimen starts compliance. Fewer patients and families after the second bleed, raising concerns about reported cost of therapy as a barrier. 82 what joint damage may have already occurred. Several studies show that early prophylaxis While prophylaxis is feasible in countries (prior to 3 years of age) has a clear where there is widespread access to factor advantage. 78,79,80 With relative equivalence products, only 54% of all patients with severe demonstrated between regimens, the optimal hemophilia A have access to on-demand choice should be determined for each patient therapy and only 37% receive regular in conversations with the patient and the prophylaxis. 83 Although access to product is family. not a widespread issue in the US, it is clear that the high cost of hemophilia care stems The adolescent and adult prophylaxis data are from expensive factor products, with the not as robust as the pediatric data. The highest costs incurred by those on prophylaxis SPINART trial showed significant differences regimens or with inhibitors. 84 Studies of factor in joint and other bleeding events in adult costs and healthcare use by patients with patients (12-50 years) who received hemophilia have found that 72-80% of prophylaxis or on-demand therapy. 67 The healthcare expenditures are for factor recommendations from NHF are therefore to concentrates and that the average cost of consider life-long prophylaxis for the hemophilia care in the US in 2008 was prevention of joint bleeds and subsequent $142,987 and $155,136 for Medicaid and arthropathy. private insurance, respectively. 85,86 These costs place a great burden on patients and payers BARRIERS alike, but routine prophylaxis brings significant benefits related to quality of life, While there is little expert debate that routine productivity, and complications (reduced factor prophylaxis starting in early childhood joint disease and hospitalization). reduces long term morbidity of patients with severe hemophilia, there are a number of Administering intravenous factor replacement potential barriers to universal treatment,

14 Prophylactic Factor Replacement Personalizing the Management of HEMOPHILIA

several times per week starting at a young age depressive symptoms, which significantly is a difficult task, and many families and impacts self-care. Multidisciplinary providers opt for central venous access devices patient-centered care teams are essential to (CVADs). A survey of 62 HTCs in the US address this condition as well as chronic pain revealed that 90.3% of centers use CVADs in and other illnesses of the aging population, their young patients, with 19 centers using including cardiovascular disease, urological CVADs for 100% of patients on prophylaxis, problems, and cancer. 90,91 while only 7 centers are not using them at all. 87 CVADs have potential complications, CLINICAL PEARLS including infection, thrombosis and device • Hemophilia A and B are classified as mild failure. A large meta-analysis of CVADs in (>5% to <40% of normal clotting factor in hemophilia patients found that the incidence circulation), moderate (1% to 5%), and of infection was only 0.66 per 1000 CVAD severe (<1%) days, however infection was reported as the most common reason for device removal at • The most common sites of bleeding are 69.9%. Thrombosis was cited in only 4.1% of joints (70-80%), muscle (10-20%), and cases where patients required central line digestive tract (5-10%) removal. 88 Because of these potential • A normal platelet count, normal PT, complications, implanted devices are typically and a prolonged aPTT are characteristic limited to early childhood with transition to of hemophilia A, hemophilia B, and peripheral infusions by the second decade of heparin therapy life. Self-infusion is challenging and requires • Inhibitor antibodies develop in 25% of family and patient education by the HTC and patients with hemophilia A and can nursing staff. decrease the efficacy of therapy • The median age of presentation is ~1 year, Medication adherence requires availability of frequently associated with circumcision, product, venous access, and a willing patient. ICH, and heel sticks Unfortunately, one third of patients with all • Approximately one third of patients severities of hemophilia A and B from the present without a family history of United States reported depressive symptoms, hemophilia with 18% reporting moderate to severe • Prophylaxis is superior to episodic therapy; symptoms of depression. 89 Seventy-six percent multiple protocols are available of those patients with depression reported functional impairment secondary to their

Prophylactic Factor Replacement 15 Personalizing the Management of HEMOPHILIA

Case-Based Learning

EB is a 2-year-old boy with severe hemophilia A. He has been on prophylaxis since age 14 months, when he was started on 50 U/kg once weekly per the Canadian protocol. His trough level of factor VIII today is <1%. He has never been positive for an inhibitor; however there is a family history of inhibitors in a maternal uncle. He has mild bruising, but has not had any joint bleeds since starting prophylaxis. He is in clinic today for his weekly infusion and education with his parents. They are anxious and not yet able to independently perform infusions at home. They have heard about central line placement and are wondering if it would be appropriate for EB.

Which option would you recommend and why? A. Place a central line B. Modify his dosing regimen C. Wait until he has a joint bleed and then modify his dosing regimen

______

______

If his trough level today were 2% how would your decision change?

______

______

Answer these questions at: www.YaleCME-Hemo.org

16 Case-Based Learning Personalizing the Management of HEMOPHILIA

Personalizing Prophylaxis

“Personalized prophylaxis” has emerged as Examination and Child PE scores. 97 The one of the most important and challenging Stockholm scoring system advocated by the mandates in the care of hemophilia patients. European Paediatric Network for Haemophilia While there is a clear benefit of early expanded upon the Gilbert score by including prophylaxis initiation in severe hemophilia, assessments of gait and pain. 98 In 2001 the how to treat the individual patient is often International Prophylaxis Study Group (IPSG) unclear. Many studies of prophylaxis report was formed with the goal of synthesizing all only a weak correlation between coagulation the different functional scoring systems, factor levels and prevention of bleeding, 92 and culminating in the Hemophilia Joint Health there is marked heterogeneity among patients Score (HJHS), which takes into account all in onset and progression of arthropathy. 68,80,93 the features of the original Gilbert score plus A successful plan takes into account medical duration of swelling, joint flexion and issues such as individual bleeding patterns, extension, strength, and gait. 99,100 The HJHS is musculoskeletal health, physical activity, body comprehensive and effective in monitoring mass, age, and inhibitors, while being joint changes in response to prophylaxis but sensitive to patient and parental concerns has not yet been validated in very young regarding costs, the discomfort of frequent children, adults, or patients with severe joint venipuncture and possible central venous disease. Radiographic scoring systems of catheter placement, and time commitments. arthropathy have also been developed based on X-ray (Pettersson score) 101 or magnetic MUSCULOSKELETAL ASSESSMENT resonance imaging. 102 Several studies have demonstrated abnormalities in gait, lower extremity muscle PHYSICAL ACTIVITY strength and size, and joint mobility in While older literature advised physical activity children and adolescents with severe restriction in hemophilia patients, many hemophilia. 94,95 Such differences may be seen investigators now encourage selective at a very early age, prior to radiographic participation in sports, physical exertion, and arthropathy and even before differences in fitness programs. 103 Children, adolescents, physical examination scores, suggesting that and young adult hemophilia patients on early adaptation occurs from the time of the prophylaxis who play high-impact sports do first joint bleeds. not appear to have a higher risk of bleeding than those involved exclusively in low-impact Musculoskeletal health in hemophilia may be sports. 104 Studies of the dynamics of evaluated using a number of different sports-related bleeding in hemophilia patients assessment tools. The World Federation of on prophylaxis reveal that a 1% increase in Haemophilia Physical Examination score factor levels via prophylaxis decreases the (Gilbert score) 96 was one of the first scoring bleeding risk by 2%, bleeding risk increases systems but was subsequently shown to be less transiently with escalating vigor of physical sensitive than other physical examination activity, and most bleeds occur within an tools, including the Colorado Physical hour after activity. 105

Personalizing Prophylaxis 17 Personalizing the Management of HEMOPHILIA

SPECIAL CONSIDERATIONS prophylaxis. Standard prophylaxis regimens are designed to maintain a trough level of Body Weight factor above 1%, converting severe Patients with hemophilia are obese or hemophilia to moderate hemophilia. Patients overweight at least as often as the general are monitored upon initiation of prophylaxis population. A greater body mass index (BMI) to ensure adequate exposure and to detect in hemophilia patients leads to limitations in inhibitors. Recommendations from the UK joint range-of-motion and worsened group include monitoring of trough levels at arthropathy, 106 particularly involving the clinic visits, considering PK studies if a hip. 107 While obesity itself does not cause patient’s trough level is at <1% in the absence increased bleeding, abnormalities in of an inhibitor, and optimizing dosing fibrinolysis have been described in obese regimen if bleeding is uncontrolled. 115 patients with hemophilia and may underlie Elements that negatively affect factor levels some of this pathology. 108 Guidelines do not include younger age, weight (obese or exist for factor replacement in obese patients, underweight), infection, comorbidities, and although some pharmacokinetic data suggests physical activity level. Additionally, there is that dosing by ideal rather than actual body some debate regarding the ideal trough level. weight in obese patients may be adequate, 109 perhaps due to decreased vascularity of Collins et al studied a cohort of 99 patients adipose tissue compared to muscle. 110 with severe hemophilia A. 116 Compared to patients who had no bleeds, patients who While overweight patients may be over experienced at least 1 bleed spent more than treated, underweight patients are frequently twice the amount of time with a factor VIII undertreated. Henrard and colleagues level <1%. In a study of 82 patients with observed factor VIII recoveries of 1.6, 2.14, standard prophylaxis in Sweden, there was a and 2.70 IU dL -1 /IU kg -1 in patients with weak but significant relationship between hemophilia A who were underweight, average, time below 1% factor VIII or factor IX level and obese, respectively. 111 Individualized and incidence of joint bleeding. However, therapy should be based on PK measurements there were some patients with trough levels rather than body weight. <1% who did not bleed and others >3% who did bleed. 117 Patients with milder phenotypes Osteopenia may also possess pro-thrombotic traits such Patients with severe hemophilia A have higher as Factor V Leiden which in some way rates of osteopenia in the lower lumbar spine compensate. 117,118,119 and femoral neck. 112 This appears to be independent of body size 113 and may be due to abnormalities in osteoblast function and GUIDELINES increased osteocalcin levels. 114 There are no strict guidelines for personalization of prophylaxis. While NHF, COAGULATION FACTOR WFH, WHO, and the UK Haemophilia Centre MEASUREMENT Doctor’s Organization recommend initiation of prophylaxis prior to the onset of significant Measurement of factor levels and individual bleeding and provide a general outline of PK are important for personalized infusions to maintain a factor trough level

18 Personalizing Prophylaxis Personalizing the Management of HEMOPHILIA

>1%, this may be optimized for the individual patient’s bleeding symptoms, activity level and lifestyle. 24,71,72,115 Full prophylaxis should consist of either three times a week or every other day dosing in hemophilia A and 2-3 times weekly in hemophilia B, using the minimum dose necessary to avoid significant breakthrough bleeding. Venous access devices are an important aid for treating young children. New longer half-life products should reduce the dosing burden on patients.

CLINICAL PEARLS • Multiple personal, medical, and lifestyle issues impact personalized prophylaxis, presenting the health care provider with frequent challenges • Selective physical activity should be part of the management plan • There is increasing evidence that dosing should be based on ideal body weight • Individual PK measurement should be performed to optimize dosing • Guidelines provide general recommendations, but therapy should be individualized

Personalizing Prophylaxis 19 Personalizing the Management of HEMOPHILIA

Adherence

Medication adherence in patients with itself, as well as the clinical impact of hemophilia is critical. In order to realize the prophylaxis. In a UK study of 65 patients, full potential of scientific advances and adherence to a prophylaxis regimen was prevent complications, barriers to prophylaxis correlated with belief in the need for must be identified and addressed. Patients treatment and belief in the efficacy of with chronic illnesses often do not take treatment. 122 Some patients on prophylaxis medications as prescribed. In hemophilia this who have not experienced severe symptoms can have devastating consequences. The are not aware of the natural course of their management paradigm has shifted away from disease. 123 But knowledge does not ensure the concept of the “non-compliant patient,” adherence; in a Scandinavian study of 108 and today’s models involve the patient, their patients, 41% acknowledged noncompliance environment, and the care team. Adherence with their prophylaxis regimen despite a high to prophylaxis has been associated with a degree of knowledge of their disease. 124 A reduced risk of intracranial hemorrhage. 120 cross sectional telephone survey queried 38 Patients on prophylaxis also report less pain patients with hemophilia who were advised to and improved quality of life. 121 (Table 5) . begin prophylaxis. Lack of initiation of Non adherence often leads to poor joint prophylaxis was generally found to be due to outcomes, more missed days of school or cost or disbelief regarding effectiveness. 125 work, and a poorer quality of life. Adherence also decreases with age. 81,123 For Lack of disease-specific education has been parents of young children with hemophilia, identified as a major barrier to prophylaxis child resistance can be a barrier to regular (Table 5) . Education should cover the disease prophylaxis. 126 The average age at which a

Table 5. Benefits and Barriers to Adherence

Benefits Barriers Decreased frequency of bleeding episodes Lack of awareness of consequences of non-adherence Improved joint function/prevention of Lack of education hemarthropathy Improved school attendance Fear of injection Decreased emergency room Lack of child cooperation visits/hospitalizations Improved academic performance Cost Improved quality of life Inconvenience Decreased pain Travel/Center hours

20 Adherence Personalizing the Management of HEMOPHILIA

young person with hemophilia begins to take records can be used to assess adherence. over his own care with self-infusions is 11.6 Evaluation has moved away from sole reliance years. 124 The adolescent experiencing chronic on patient self-report to more complex, illness may become less compliant with objective, and validated methods. 132 An treatment as he transitions to adulthood. Up example of this is a novel assessment known to 60% of patients will report a trial of as the VERITAS-Pro (Validated Hemophilia discontinuation of prophylaxis as young Regimen Treatment Adherence adults. 127 These patients often cite inadequate Scale-Prophylaxis). 105 VERITAS-Pro is a ten time/scheduling difficulties, as well as a lack minute 24 question tool that can accurately of understanding of the importance of assess a patient’s adherence rate and can also prophylaxis in prevention of both short and identify areas needing improvement. While it long term disability. 128 While historically is gaining use in clinical studies, this validated these actions have been attributed to teenage measure of adherence is not frequently used “angst,” research has clearly identified other in the HTC setting. Smart-phone and developmental factors. A study by Colver et computer-based applications can help patients al 129 describes the changes to the brain that keep a precise log of infusions and bleeds. 133 occur between the ages of 11 and 25. There is Some of these accept information such as an initial increase then a decrease in grey pain medications and activity levels and some matter, with synaptic proliferation in the web-based logs can be accessed by the HTC. pre-frontal area of the brain. This region is Other aids to adherence include electronic associated with emotional regulation and diary, internet dialogue page, reminder decision making. These brain changes are telephone calls, and home visits. associated with impulsive and risky behavior, highly valuing peer interactions, and Other supportive measures should be offered irrational decision making. 130 In the context to the patient (Table 6) . In one study of chronic illness, this can lead to increased challenges to comprehensive care. The Table 6. Strategies to Improve Adherence inconvenience and time required for prophylaxis has been noted in multiple • Assess adherence at every visit surveys as a hindrance to adherence. 124,125 Factors associated with high rates of • Use objective tools –infusion logs, adherence include longer time spent at HTC VERITAS-Pro visits and a good relationship with the • Educate patient and family physician and the hemophilia nurse. 123 – Use age-appropriate educational Assessment of adherence should occur at tools: CDs, DVDs, peer mentoring every patient visit, although historically • Individualize treatment plans for 131 physicians often do not assess adherence. lifestyle and activity level Patients should receive age-appropriate information on the risks and consequences • Engage HTC for close follow-up and of non-adherence. support • Plan transition of care, identify at-risk Self-reported logs, questionnaires, patients documentation of number of joint bleeds or • Identify financial barriers hospitalizations, and evaluation of pharmacy

Adherence 21 Personalizing the Management of HEMOPHILIA

frequent specialty pharmacy educator contact CLINICAL PEARLS with patients with hemophilia B significantly • Prophylaxis is a lifelong commitment decreased the annualized bleeding rate. 134 • Physical, social, emotional, and financial barriers must be continuously addressed A high rate of compliance is often found throughout the patient’s journey in clinical trials. 65 Patients are selected • Knowledge of disease and awareness of the according to strict inclusion criteria and importance of prophylaxis are key receive a high level of HTC contact, modifiable barriers to prophylaxis education, communication, and follow up. adherence The challenge for the health care provider as • Adolescence is a unique time during which the point of contact is how to translate these special strategies may be needed to keep lessons from clinical trials into daily clinical the patient engaged in their care practice. In addition to providing support that • Prophylaxis must continue to be encourages adherence the HTC staff can also individualized help the patient address financial barriers. • The comprehensive hemophilia treatment center is integral to supporting these Another approach derives from recent processes advances in therapy. Patients believe that a factor supplement with longer half-life will lead to improved quality of life, and patient adherence may improve with more convenient prophylaxis. 124,135

22 Adherence Personalizing the Management of HEMOPHILIA

Managing the Level of Medication MEDICATION TROUGHS trough levels 3 IU dL -1 and some do not ≥ bleed below 1 IU dL -1 ;137 a higher level might Factor VIII deficiency is classified as severe be needed to prevent all joint bleeds. 138 (< 1 IU dL -1 , < 1% of normal), moderate Multiple factors such as individual variation (1-5 IU dL -1 , 1-5% of normal) and mild in PK, adherence, inhibitors, suboptimal (5-40 IU dL -1 , 5-40% of normal). 24 Den Uijl dosing, and irregular dosing schedules can et al 136 reviewed historical data from a cohort influence how long a patient remains above of 377 patients with hemophilia A. They the bleeding threshold. Figure 3 illustrates observed that the patients with factor VIII less how the half-life of factor VIII in different than 1 IU dL -1 at any measurement suffered adults influences how rapidly they reach the approximately 6 joint bleeds per year while 1 IU dL -1 threshold following an infusion of patients with more than 12 IU dL -1 had none 30 IU kg -1 . (Figure 2). Time below threshold has clinical Pharmacokinetics is a crucial determinant of consequences. Each additional hour per week drug exposure and efficacy. After initial below threshold is calculated to increase the dosing and distribution, levels of plasma annual bleed rate by 2.2% for children and factor VIII are approximated by exponential 1.4% for adults (Figure 4) .116 While a detailed decay. When the drug concentration is at the PK profile is laborious, an individual patient’s lowest point, the trough value, patients are factor VIII PK can be estimated with data most susceptible to bleeding. While 1 IU dL -1 from two or three blood samples. 140 is generally accepted as a minimum threshold therapeutic goal some patients bleed with

Figure 2. Annual number of joint bleeds according to factor VIII activity. 136 The lowest recorded value for each patient was used for this analysis.

Managing the Level of Medication 23 Personalizing the Management of HEMOPHILIA

Figure 3. Effect of half-life on factor VIII level following a bolus infusion. The short half-life and long half-life lines represent the 5 th and 95 th percentiles of the normal half-life in a 70 kg man. An individual with a short half-life crosses the 1 IU dL -1 threshold 59 hours sooner than one with a long half-life. 139

Figure 4. The calculated probability of having no bleeds per year versus time per week spent with a factor VIII level less than 1 IU dL -1 .116 Open circles (o) and asterisks (*) represent hemarthroses in patients aged 1–6 years and 10–65 years, respectively.

24 Managing the Level of Medication Personalizing the Management of HEMOPHILIA

Figure 5 shows how the dosing schedule below the threshold for approximately 10 impacts trough levels. The upper panel hours during the week, while those with an illustrates the gap in factor VIII on Sunday. In 80% adherence rate on the same dosing the bottom panel an increased dose is given schedule would be below the threshold for on Friday to keep the patient above threshold approximately 16.5 hours. This translates into until Monday. A more cost-effective approach a sizeable increase in annual bleed rate and is to give a small dose on Sunday or to use can be especially risky for patients who are small daily doses. The large therapeutic physically active on Sundays. advantage conferred by the elevated trough with daily dosing must be balanced in clinical Another way to view the impact of PK and practice by considerations of inconvenience, dosing on factor VIII infusion dosage is to injection site reactions, adherence, and calculate the dose required to maintain a variable pharmacokinetics that could result in trough level above 1-1.5 IU dL -1 . Table 7 unsafe elevations in levels of factor VIII. presents the dose of factor VIII per infusion Collins et al 141 estimated the impact of required to maintain this level in a 70 kg man nonadherence on the time below 1 IU dL -1 . for daily, alternate day, and every third day Fully adherent adults on a Monday/ dosing. The estimations are given for short, Wednesday/Friday schedule of 30 IU kg -1 are median, and long half-lives.

Figure 5. Model of factor VIII levels with Monday, Wednesday, Friday dosing. The upper panel depicts a patient whose factor VIII reaches 1 IU dL -1 after 48 hours. Factor VIII is below 1 IU dL -1 on Sunday. The lower panel shows one method to sustain factor VIII above threshold: giving a fourfold dose on Friday. 140 I I I V

r o t c a F

a m s a l P

Managing the Level of Medication 25 Personalizing the Management of HEMOPHILIA

Table 7. Dose of factor VIII (IU) per infusion required to maintain trough level of 1–1.5 IU dL -1 in a 70 kg man, depending on dose schedule and half-life

Half-life Daily Alternate Day Every Third Dosing Dosing Day Dosing Short: 7.5 h (5 th percentile of normal 240 2420 22410* range) Median: 10.4 h 120 700 3570 Long: 16.5 h (95 th percentile of normal 50 200 600 range)

*The high dose required with every third day dosing for patients with a short factor VIII half-life is unrealistic and potentially harmful. 139

The standard of prophylaxis for hemophilia B PATIENT DIFFERENCES is to dose twice weekly to maintain trough The maintenance of trough levels greater than levels of factor IX above 1 IU dL -1 . There are 1% depends upon several key patient variables few outcomes data to support this choice and including age and weight. There are several the number is derived from experience with studies which have demonstrated reduced factor VII. 142 Two preparations of factor IX are clearance of factor VIII, increased recovery, available: plasma-derived factor IX (pdfactor and increased terminal half-life with increases IX) and recombinant factor IX (rFIX). They in age. 145,146 On the other hand, the terminal are similar in structure and function 143 but half-life of factor IX does not change with have different PK properties. rFIX has a higher age. 147 A patient’s PK cannot be predicted by clearance rate and shorter half-life than demographic information, and PK pdfactor IX 144 so rFIX requires a higher dose measurements should be a part of any than pdfactor IX with careful monitoring. individualized dosing regimen. Estimates for the increase in dose range from 25% 24 to 100%. 144

Bleeding episodes in spite of prophylaxis adherence and measured levels suggest the possibility of additional causes of bleeding. Given the high incidence of von Willebrand disease and assorted platelet disorders, such patients should undergo a workup that includes a VWD panel and a platelet aggregation assay. Patients should be regularly cautioned against the use of aspirin and other drugs with anticoagulation effects.

26 Managing the Level of Medication Personalizing the Management of HEMOPHILIA

Case-Based Learning

Mr. H is 37-years-old. He is in relatively good health and is able to lead a healthy lifestyle despite severe hemophilia A. He comes to clinic today for his annual comprehensive visit and to discuss his current prophylaxis regimen. He has 1-2 joint bleeds per year. Unfortunately, he has recently developed a target joint in his right knee.

He had a bleed after tripping on a rock when he was camping several months ago and he did not have his supplies with him. He had infused the prior day, but after the event was unable to infuse until the following day and did so daily for the remainder of that week. Since then, he has had several more bleeding episodes with and without minor trauma.

He works as an accountant and is not physically active during the week. He and his wife enjoy hiking and other activities on the weekends and he is not sure that his current infusion schedule of M-W-F is optimal. He rarely misses doses and has never had trouble with venous access.

Does Mr. H have adequate factor VIII on the weekend when he typically engages in physical activity?

______

______

Would you change his medication, his schedule, or both? Why?

______

______

How would you monitor his factor levels after changing his schedule?

______

______

Answer these questions at: www.YaleCME-Hemo.org

Case-Based Learning 27 Personalizing the Management of HEMOPHILIA

CLINICAL PEARLS • Prophylaxis should be used for patients with hemophilia to maintain a milder level of disease • A trough level greater than 1 IU dL -1 is the therapeutic standard for factor VIII but there is individual variation in patients’ bleeding at this level • PK measurements should be considered for individualizing therapy • Long-acting analogs of rFVIII and rFIX enable increased dosing intervals, higher interval trough levels, and equivalent prophylaxis compared to standard shorter acting factors. Clinical trials reveal no short term increase in the incidence of inhibitors

28 Case-Based Learning Personalizing the Management of HEMOPHILIA

Emerging Therapies: Promise and Challenges CLINICAL AND PATIENT BENEFITS half-lives. 148 Table 8 lists some of the OF FACTORS WITH PROLONGED approaches to extending factor in vivo HALF-LIVES stability. One significant promise of emerging REDUCED-IMMUNOGENICITY therapies is their extended half-lives and COAGULATION FACTOR associated ease of use. Modified forms of coagulation factors VIII and IX increase the CONCENTRATES interval between dosages for prophylaxis New recombinant factor VIII products should therapy and may be useful for patients with be minimally immunogenic, have coagulation new-onset bleeds. Such factors are predicted factor function, and bear a low infection risk. to markedly enhance quality of life measures One new product, turoctocog alfa for hemophilia patients, particularly when (NovoEight ®), 149 is a truncated factor VIII issues such as ease-of-use, complexity of molecule containing 21 amino acids of the dosing, maximum protection from bleeding, ß-domain. Site specific enzymatic and increased ability to participate in physical glycoPEGylation of the ß -domain extends the activities are taken into consideration. half-life but thrombin cleavage in vivo Greater efficacy and maintenance of removes the PEGylated peptide, resulting in a hemostasis should result from products with product that is similar to native factor VIII. 150 increased in vivo stability and extended Recently completed Guardian™ studies in

Table 8. New and emerging clotting factors with extended half-lives (adapted from 148 ) BDD: B-domain deletion, FL: full length

Modification Increase in Clinical t 1/2 Factor VIII BAY 94-9027 PEGylated rBDD 1.5X Turoctocog (NovoEight ®) PEGylated rBDD 1.6X 1.4-1.5X PEGylated rFL 1.4-1.5X Efraloctocog (Eloctate™) rBDD-Fc fusion 1.5-1.7X Factor IX Nonacog PEGylated 5X Fc fusion Fc fusion 2.5X CSL654 Albumin fusion 5X

Emerging Therapies: Promise and Challenges 29 Personalizing the Management of HEMOPHILIA

adult and pediatric populations have shown In addition to these biological obstacles, there turoctocog alfa to be effective and potentially are other challenges. One of the most less immunogenic than other recombinant significant questions is the optimal time to products. 151,152 A single chain rFVIII expressed transition a patient from an older factor in human embryonic kidney cells (human-cl concentrate to a new therapy. Some rhFVIII) is also in clinical development. 153 considerations include: 1) poor adherence to Posttranslational modification in human cells older therapies due to complex administration may decrease the generation of inhibitors. techniques or schedules; 2) lifestyle ACE910 is a bispecific antibody that limitations of an older therapy; and 3) a recognizes factors IXa and X and mimics the desire of a newly-diagnosed patient to use a cofactor function of factor VIII. Early clinical low-risk/low antigenicity product. Costs may results suggest that this molecule may be also be a significant concern for some effective for patients with hemophilia A with patients and the economics of new and old and without factor VIII inhibitors. 154-155 therapies must be considered.

A similar set of objectives exist for new factor Finally, the emergence of novel hemophilia IX products. Alprolix ®156 is an FDA-approved therapeutics will also have an impact on recombinant factor IX IgG Fc fusion product prescribing practices. Clinicians must that has a terminal half-life of 82 hours, an carefully consider not only the safety and increase of 2.5-fold over rFIX, 148 and has a efficacy of novel therapies but also how the low rate of inhibitor formation. Recombinant new regimens will impact adherence. One factor IX expressed in human hepatoma tool recommended by Witkop et al is a HuH-7 cells is also in development. 157 patient-provider agreement to enhance communication, adherence, and assessment CHALLENGES OF EMERGING of adherence. 159 Such a document sets clear THERAPIES: SCIENTIFIC guidelines and goals for patients. With OBSTACLES AND PRACTICAL adequate preparation and mindfulness of potential pitfalls, clinicians should be able to CONSIDERATIONS smoothly transition to prescribing novel When considering the biology and factor concentrates. pathophysiology of hemophilia disorders, new therapies face several challenges, including: • A low-risk profile, including both infectious and non-infectious complications • Inherent biological limitations (e.g., extending the half-life of factor VIII beyond that of von Willebrand factor) • Maintenance of coagulation function without augmented immunogenicity • Pushing the boundaries with “curative” therapies (e.g., FVIII gene therapy) 158

30 Emerging Therapies: Promise and Challenges Personalizing the Management of HEMOPHILIA

and medical problems such as inhibitory Conclusions antibodies to exogenous factor preparations. A key practice in personalizing therapy is Hemophilia A and B are X-linked recessive measuring a patient’s PK pattern. Though a bleeding disorders that typically affect males. complete PK workup is quite involved, Patients present most frequently in early simplified protocols can be very useful in childhood with bleeding after minor surgery individualizing care. or with intracranial hemorrhages. Depending on the level of clotting factor, hemophilia is Adherence plays a crucial role in maintaining categorized as mild, moderate, or severe. The the balance between using the minimal severity of bleeding depends on the paucity of effective dose and keeping the trough values clotting factor and therapeutic above 1%. Routine assessment, patient tools, supplementation is aimed at decreasing the family involvement, individualized treatment severity of factor deficiency and hence the plans, an HTC approach, and addressing severity of clinical disease. financial barriers should all be incorporated, The most serious chronic problem of with the recognition that a patient may have hemophilia is arthropathy subsequent to joint multiple barriers to adherence. New and bleeding. The extent of joint damage is related emerging factor VIII and factor IX to the number of bleeding events. This has led pharmaceuticals with longer half-lives and/or to a therapeutic strategy of prophylaxis rather reduced immunogenicity could have a huge than episodic treatment. Initiation and impact on patient lifestyle, help protect aggressiveness of prophylaxis varies among against low trough levels, and potentially different countries and different practitioners. improve adherence. The dose and timing of prophylactic supplementation depend on factors such as patient tolerance of infusion, age, physical activity, adherence, and treatment cost. The NHF, WFH, WHO and the UK Haemophilia Centre Doctor’s Organization support prophylaxis and maintaining factor trough levels > 1% but the details of the treatment plan are ultimately decided by the health care provider, patient, and family. Hemophilia Treatment Centers can be invaluable resources that provide experience and multidisciplinary support. The HTC can offer expert guidance and support for barriers such as education, design and transition of care,

Conclusion 31 Personalizing the Management of HEMOPHILIA

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