Abstract
Introduction
Acquired hemophilia A (AHA) is a rare bleeding disorder in which acquired auto-antibodies to endogenous Factor VIII (FVIII) resulting in decreased FVIII activity. AHA can lead to life-threatening bleeding, with effective treatment requiring both immunosuppressive therapy (IST) and bypassing agents such as recombinant activated Factor VII (rFVIIa) or activated prothrombin complex concentrates (APCC) (Tiede et al. Haematologica 2020). Some, including our group, have begun using emicizumab as well (Knoebl et al. Blood 2020). IST is required for inhibitor eradication, but regimens are heterogenous and have not been systematically compared in the literature. While there is no standard of care IST in these patients, most patients in the literature receive multiple agents, including corticosteroids, mycophenolate mofetil, cyclosporine, and/or rituximab in combination.
We report in a prospective cohort that for IST, rituximab monotherapy is an effective strategy. An updated treatment algorithm is offered that has been effective for treatment of these patients at our institution, which adds emicizumab therapy after initial bleed control.
Methods
We analyzed clinical, pharmacy, and laboratory data from 24 patients treated with rpFVIII at the University of North Carolina for AHA from July 2015 to June 2021. All patients were initially treated according to our previously established dosing algorithm with recombinant porcine FVIII, and the last five patients have received emicizumab after initial factor dosing (see Figure 1). 17 of the patients who received rituximab and were followed at our center subsequently attained inhibitor eradication, six of those received only rituximab therapy. Investigational review board approval was obtained for our data collection and analysis.
Patients who did not receive rituximab, failed to reach an inhibitor level <0.5 BU, or who were lost to follow up were excluded from the analysis. For patients that fit the inclusion criteria, the time between date of the first rituximab infusion and the date of inhibitor eradication was calculated.
Results
All patients in our cohort who we followed until inhibitor eradication (17 of 24 patients) had eradication of inhibitors after a median of 143 days from initiation of immunosuppression. For patients treated with rituximab monotherapy for inhibitor eradication (6 of 17), this goal was reached in a median of 134.5 days (range 76-191 days). For those who received agents in addition to rituximab and have reached inhibitor eradication to date (9 of 17 patients), median days from initiation of immunosuppression to inhibitor eradication was 137.5 days (range 11-485) (P = 0.43 on Mann-Whitney test).
Patients were treated as previously reported by our group per an algorithm that starts recombinant porcine FVIII without waiting for a porcine inhibitor and at lower than FDA recommended dosing. Subsequent doses for bleed control are titrated according to one-stage, clot based FVIII activity. This report also includes 5 new patients who, after initial bleed control per our algorithm, were initiated on emicizumab while awaiting inhibitor eradication.
There was no correlation between time to rituximab initiation and time to inhibitor eradication in both those who received rituximab monotherapy and those who had multiple IST agents. There was also no significant difference in initial inhibitor titer between groups with median initial inhibitor titer of 104 BU in the rituximab monotherapy group, and 70 BU in the multiple IST agents group (see Figure 3).
Conclusions
Rituximab monotherapy appears to be an effective strategy for inhibitor eradication in acquired hemophilia A. In the context of bleed treatment with porcine factor, followed by emicizumab, a standardized, algorithmic approach can be effectively employed for these patients. Though any patients have inhibitor recurrence, as is described in the literature, with emicizumab available, bleeding can be avoided with regular monitoring. Emicizumab given while re-eradicating an inhibitor can prevent morbidity of this disease.
Figure 1 Figure 1.
Disclosures
Ellsworth: Takeda: Other: Salary supported as part of NHF-Takeda Clinical Fellowship Award. Key: Uniqure: Consultancy, Other: Participation as a clinical trial investigator; Grifols: Research Funding; Takeda: Research Funding; BioMarin: Honoraria, Other: Participation as a clinical trial investigator; Sanofi: Consultancy. Ma: Accordant: Consultancy; Takeda: Honoraria, Research Funding.
OffLabel Disclosure:
Emicizumab is not approved for use in Acquired Hemophilia A and this represents an OFF LABEL use of the drug.
Treatment of Acquired Hemophilia a with Rituximab and Emicizumab