Optimal Approaches to Hemophilia Treatment: Insights and Strategies

Impact of monthly medication allowance for a hemophiliac patient Edited by: Gr. Bahoush, M.D. Pediatric Hematologist and Oncologist Iran University of Medical Sciences Senior Physician of ICHCC

Important points A patient with a severe inherited bleeding disorder is like a frontline combatant who is at risk of serious injury or death at any moment. Depending on the available resources, the treatment objectives can vary between countries and treatment centers.

The most important points of doing optimal CFC Prevention of disease complications, especially joint damage Creating a desirable lifestyle based on the patient's living conditions Improving life expectancy to almost the same level as the normal population

Treatment models in Hemophilia on-demand treatment: CFC infusion after bleeding development to control it Prophylaxis regimens: In prophylaxis the aim is to keep the blood factor level above 1% Prophylaxis may be started before any significant joint bleeds

The prophylaxis triangle If 1 determinant is changed, the other 2 will adjust. With resources, zero bleeds and normal physical activity targeted; with few only 2 substitutions per week may be given, thus accepting number of bleeds and limited activity. unlimited may be resources, low-dose a certain physical

ISTH prophylaxis definitions Primary prophylaxis: Begins in early childhood in the absence of documented joint disease and before the second clinically evident joint bleed and before the age of 3 years. Patients treated in this way have the potential of a life without joint arthropathy. Secondary prophylaxis: commences after 2 or more joint bleeds, but before the onset of joint disease as documented by physical examination and/or imaging studies. These patients may already have a significant risk of developing joint arthropathy. Tertiary prophylaxis is defined as treatment initiation after the onset of joint disease at any age of the patient

Early initiation of prophylaxis To prevent joint damage, prophylaxis should commence before joint disease starts and ideally before the first joint bleed occurs. As the average age of a first joint bleed in severe hemophilia is 1.5 years, and age at the start of prophylaxis older than 3 years has been found to significantly increase the risk of developing arthropathy, it is important that prophylaxis is initiated as early as possible

Home therapy (Pharmaceutical quota) Patients on home therapy receive regular shipments of CFC from their pharmacy providers, often on a monthly basis or as home supplies are depleted. Having an adequate supply of CFC at home to allow treatment over weekends and holidays, and to account for needs related to unexpected bleeding events, is critical to achieve safe patient care.

Home Therapy Moreover, natural disasters (hurricanes, tornadoes, floods, earthquakes) may occur, resulting in patients being cut off from delivery of CFCs for several days. During these periods of time, the need to continue regular care regimens, including prophylactic treatment and treatment of breakthrough bleeding episodes, requires continued access to an adequate supply of CFC to assure immediate treatment. Lack of an adequate supply of CFC to cover such situations might place patients at-risk for severe complications, including death.

The number of doses required for provision of home therapy varies greatly and is dependent upon the type of hemophilia (FVIII, FIX), the level of severity (severe, moderate, mild), the presence of an inhibitor, the prescribed regimen (on-demand, prophylaxis, immune tolerance), the number of bleeding episodes experienced regardless of the prescribed regimen, individual pharmacokinetics, the product utilized (standard half-life versus longer lasting products), and the level of physical activity. Therefore, a monthly supply may range from 15 doses in patients with FVIII deficiency on every other day prophylaxis using a standard half-life product to 2-4 doses for patients with FIX deficiency on prophylaxis with a longer- lasting product.

Points in home therapy In addition, the number of doses available for patients treated either on- demand or with a prophylactic regimen must take into account the number of breakthrough bleeding events anticipated based on number of such bleeds in the past.

Points in home therapy For those on prophylaxis, a minimum of one major dose and two minor doses should be available in addition to the prophylactic doses utilized monthly. For patients with severe or moderate hemophilia treated on-demand, the number of doses required to be available at home may be based upon historical bleeding patterns, with at least one major and two minor doses added to assure a level of safety.

Frequency of dosing in on-demand For early joint bleeds, muscle bleeding or oral bleeding: every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for at least 1 day until the bleeding episode, as indicated by pain, is resolved or healing is achieved For more extensive joint bleeds, muscle bleeding or haematoma (bruising): every 12 to 24 hours (8 to 24 hours for patients under the age of 6) for 3-4 days or more until pain and acute disability are resolved For life-threatening haemorrhages: every 8 to 24 hours (6 to 12 hours for patients under the age of 6) until the threat is resolved

On-demand therapy WHO dosage guidelines Site of bleed Optimal factor level (%) Dose (IU/kg bw) Duration (days) FVIII FIX Joint 30-50 20-30 30-50 1-2 Muscle 30-50 20-30 30-40 1-2 GI tract 40-60 30-40 40-60 7-10 Mouth 30-50 20-30 30-40 Until healing Epistaxis 30-50 20-30 40-60 Until healing Haematuria 30-100 25-50 70-100 Until healing CNS 60-100 50 80-100 7-10 Retro-peritoneal 50-100 30-50 60-100 7-10 Trauma or surgery 50-100 30-50 60-100 Until healing

Home Therapy for patients with inhibitor APCC (FEIBA) rFVIIa (Aryoseven) Emicizumab (Hemlibra) Status Licensed Licensed Licensed On-demand dose 50 100 U kg 1 q6 12 h until hemostasis 90 270 g kg 1 q2 3 h until hemostasis ---- Prophylaxis dose 85 U kg 90 g / kg 1 qd 1.5 mg kg 1 qw, 3 mg/kg :q2w; 6 mg kg 1 once monthly 1 3 5 times per week

Recommendations For all patients, the treating physician is best able to determine the number of doses required for each patient based upon their diagnosis, co-morbidities, clinical circumstances, product(s) utilized, and historical bleeding patterns.

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