MASAC Guidelines and Unmet Needs

Meera B. Chitlur, MD: The MASAC guidelines address the treatment of patients with hemophilia A with inhibitors who are on emicizumab. The primary focus is patients who are being treated with bypassing agents because the complications of TMA [thrombotic microangiopathy] as well as thrombosis were significant in these populations. Therefore, we wanted to make sure that we address the need for close monitoring, as well as offer advice on dosing and monitoring of these patients if such complications were to occur.

TMA and thrombosis were associated with the use of high doses exceeding 100 u/kg per day of aPCCs [activated prothrombin complex concentrates], and therefore, the recommendations are that we restrict the dose of aPCCs to less than 100 u/kg per day. We are also recommending that we try to avoid prolonged use of aPCCs with emicizumab; restrict the use to less than 24 hours; and if use is necessary for longer than a 24-hour period, consider close monitoring at an HTC [hemophilia treatment center] by a hematologist who’s well versed with the associated complications. It’s also important to recognize that the routine laboratory testing may not be helpful in this situation or in patients using emicizumab.

The MASAC guidelines also alluded to the fact that all aPTT [activated partial thromboplastin time]-based assays would not be useful in this situation. Monitoring of inhibitors would also require modification of the assay. We need to use human reagents to be able to detect the inhibitor. The CDC has given us an indication and provided us with reassurance that they would be able to run inhibitors, but they will need to know that the patient is on emicizumab to make sure that the assay is appropriately used. The MASAC guidelines alluded to the fact that all bleeds may not need to be treated in patients who are on emicizumab, but also ensured that major bleeds require treatment immediately. Minor bleeds may be monitored and not treated in patients with and without inhibitors in this situation.

The major unmet need in patients with hemophilia is our ability to prevent the development of inhibitors. If we can prevent the development of inhibitors, that would be a major complication in these patients that would be completely taken out of the equation. That would really change the management of patients with hemophilia.

Another major unmet need in our management of hemophilia with recombinant factor products is our inability to extend the half-life for hemophilia A patients. Hemophilia B patients have been very effectively managed with weekly and sometimes bimonthly treatments of factor products with extended half-life. That, in my mind, has effectively addressed the need to extend half-life. Unfortunately for the hemophilia A population, this has not been achievable with pegylated albumin-infused or Fc [fragment crystallizable] products, primarily because of the dependence of factor VIII on the von Willebrand factor. Therefore, the half-life extension is limited for these patients. In addition to that, in patients with inhibitors, our management of breakthrough bleeding is with the currently available bypassing agents, which is not acceptable.

There are also unmet needs with the new products that we have in place. For example, with emicizumab, there are things that we don’t necessarily know how to manage yet. In our very active patient population who want to play competitive sports, we are unsure if emicizumab will be able to provide effective coverage for bleeding that is associated with intense activity. We also do not know how we can use emicizumab in the neonatal population. Is it going to be effective in preventing intracranial hemorrhage? Is it going to be effective in the management of trauma-related bleeding that is seen in children when they learning to walk or run? We also do not know how we can use emicizumab with ITI [immune tolerance induction]. We hope that these are all going to be conducted very soon in our patients, and we will learn as we go.

With respect to what hasn’t been addressed from a patient perspective on quality of life, whatever we do so far is still a poke: It’s still something they have to remember to do on a regular basis. They cannot forget to take their medicine. They still have to take some factor for breakthrough bleeding. It has to be taken with them wherever they go. These are still unmet needs.

If gene therapy were to come into play and we could potentially cure the patient of their hemophilia, that would be a different question. We still don’t know how this will play out for the pediatric population. In the adult population, we’re still learning how gene therapy is going to work in the future.

As a hematologist, I think this is the most exciting time for providers as well as patients who have hemophilia. There has been a dramatic change in the last couple of years with products that have completely changed the lifestyle of and opportunities for our patients. We now have options that we never thought would be possible. Our patients with inhibitors have lives that have completely changed due to the drugs that they’re able to use now. As a physician, I think there’s so much more that I can offer to my patients than I could just a couple of years ago. This makes it a really exciting time for everybody in the field.

Transcript edited for clarity.