From the Journals

Elevated factor VIII troughs can lead to a higher proportion of zero bleeds in hemophilia



Rurioctocog alfa pegol prophylaxis was linked to fewer bleeding episodes in people with hemophilia A when it targeted higher levels of factor VIII (FVIII) troughs, according to a report published in Blood (2021;137[13]:1818-27).

Earlier studies demonstrated that the treatment effectively prevented bleeds with an acceptable safety profile in people with hemophilia A. The current prospective, randomized, open label PROPEL trial compared safety and efficacy of two target FVIII troughs in this population. Targeting 1%-3% and 8%-12% FVIII troughs was efficacious, with fewer bleeds in the latter arm and acceptable safety across both, according to Robert Klamroth, MD, of Vivantes Klinikum Friedrichshain, Berlin, and colleagues.

The PROPEL trial (NCT02585960) population comprised 155 patients with hepatitis A, aged 12-65 years, with severe disease and an annualized bleeding rate of at least 2 during the 12 months before enrollment in the study. All had previous FVIII treatment. Patients were randomized to 12 months’ pharmacokinetic rurioctocog alfa pegol prophylaxis targeting FVIII troughs of 1%-3% (reference arm) or 8%-12%.

The primary endpoint was absence of bleeds during the second 6-month period. A total of 95 patients completed the protocol.

Promising results

In the 1%-3% and 8%-12% arms, the proportions of patients who completed the protocol and had no bleeds were 40% and 67% respectively (P = .015). Serious adverse events occurred in 7 of 115 (6%) patients, including one treatment-related event in the 8%-12% arm. There were no deaths, serious thrombotic events, or adverse event-related discontinuations.

“Targeting 8% to 12% FVIII troughs resulted in a higher proportion of [patients] with no bleeds than prophylaxis that targeted 1% to 3% FVIII troughs. These results support the hypothesis that an elevated FVIII trough can benefit [patients]without changing the safety profile,” the researchers reported. Personalized treatment in this patient population should be considered, they added.

Problems remain

In an invited commentary, Christine L. Kempton, MD, of Emory University, Atlanta, pointed out that the study did not answer the question of what trough level is best, and that the target trough level may be up to a patient’s individual clinician to decide. “Many participants (42%) treated with the target trough level of 1% to 3% had no bleeding events during the study period, but some (38%) continued to have bleeding events despite higher target trough levels,” Dr. Kempton wrote. She added that, beyond this concern, the presence of subclinical bleeding is difficult to study and quantify, but its presence is supported in the literature by magnetic resonance imaging that demonstrated joint damage despite a lack of clinically evident bleeding.

“Thus, targeting zero clinical bleeding events does not mean that all joint disease, dysfunction, and pain will be eliminated. This reality underscores the need for better, not just more convenient, therapies,” she concluded.

The authors reported numerous relationships with a variety of pharmaceutical companies including grants, honoraria, and participation in speakers bureaus. Dr. Kempton reported honoraria from Takeda, Spark, Octapharma, and Pfizer, and research grants from Novo Nordisk.

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