Deferral of immunosuppression in acquired hemophilia Open Access

In this issue of Blood Advances, Schimansky et al¹ report the 2-year follow-up results of the GTH-AHA-EMI study, an open-label, single-arm study on the use of subcutaneous emicizumab as prophylaxis to delay immunosuppressive therapy (IST) in patients with acquired hemophilia (AHA). They compare outcomes with those of an earlier study (GTH-AH 01/2010) performed by the same research consortium, in which IST was given immediately upon diagnosis.² They report the key finding that delaying IST resulted in lower overall and infection-related mortality and a similar, although delayed, rate of complete remission from AHA.

The rationale for emicizumab prophylaxis in AHA (an off-label use of the drug in most countries) is that since infection is the major cause of death in this disease^3,4 and since IST predisposes patients to serious infections, deferring IST until the patient is better able to tolerate it might lead to reduced morbidity and mortality. The other agents available for prophylaxis, APCC and recombinant activated factor VII, are less-practical options owing to the need for frequent IV administration. The updated results of GTH-AHA-EMI and the comparison with those of GTH-AH 01/2010 add to the emerging literature supporting this strategy.^5,6 

There are inherent limitations in comparing even well-matched noncontemporaneous cohorts, and it cannot be concluded that delaying IST was the only or the main explanation for the differences in infectious complications and mortality. The authors acknowledge that evolving IST practices over the intervening years may have influenced outcomes in the 2 studies. In the earlier study, all of the 102 subjects (except 1, who suffered early death) received prednisolone, and 44 of them were given at least 1 additional line of IST therapy, most often cyclophosphamide. Rituximab was administered infrequently, to only about 20% of patients, as either second- or third-line IST. In contrast, upon completion of the 24-week emicizumab prophylaxis study only 29 of the 41 subjects had received first-line IST, and in more than half of them that therapy included rituximab. These patients received lower cumulative doses of corticosteroids, and they were less-frequently given cyclophosphamide. Overall, 23 of the 41 patients in this study (56%) received rituximab as first- or second-line IST. This reflects the trend to consider the earlier use of rituximab as a second or even first-line agent,⁷ thereby reducing exposure to IST drugs with substantial toxicity, especially in the typical older AHA patient population with comorbid illness.

When rituximab was used in GTH-AH 01/2010 it was given as 4 weekly doses of 375 mg/m², the regimen most commonly used in AHA. Other regimens that reduce total drug exposure have since been explored and are being adopted by some clinicians for patients with AHA.^7,8 In the GTH-AHA-EMI study, IST was at the discretion of local investigators, and it is not stated whether any of the patients in that study received less-intensive treatment.

Prophylaxis with emicizumab may also allow the consideration of lower intensity conventional IST agents. Although eradication of anti-factor VIII (FVIII) antibodies is the goal of treatment, IST is not necessarily an all or none strategy. If treatment that reduces but does not eliminate an inhibitor is accompanied by a clinically meaningful increase in FVIII activity that does not satisfy the criteria for partial remission, it may be possible to discontinue emicizumab and observe the patient for bleed control as the plasma level of the drug slowly declines over several months. The protocol in the emicizumab prophylaxis study specified a 12-week delay before considering IST, but in the real-world setting this stipulation should not be considered normative. The key concept is that effective prophylaxis renders IST nonurgent, and that it can be more safely introduced when bleeding is under control and the patient is ambulatory and at lower risk of nosocomial infections.

Optimal timing for withdrawing emicizumab in AHA is unclear. In the GTH-AHA-EMI study, most patients were maintained on treatment for longer than 12 weeks, ranging up to 108 weeks. The risk of bleeding in AHA remains somewhat elevated even after FVIII has recovered into the range of 30 to 50 IU/dL,³ levels at which the prophylactic efficacy of emicizumab is unknown. Schimansky et al stress that inhibitor eradication remains a critical therapeutic goal in AHA. This advice is sound in principle, but in selected patients long-term emicizumab prophylaxis with indefinite deferral of IST may be justifiable to enhance quality of life and avoid bleed-related hospital admissions. This option may be considered for patients in whom the risks of IST are judged to exceed those of breakthrough bleeding and in those with limited life expectancy, including patients with advanced cancer or selected chronic diseases. Deferral of IST may also benefit patients in whom spontaneous remission is considered more likely to occur, such as those with low-titer inhibitors or postpartum cases, sparing them unnecessary IST. Six patients in GTH-AHA-EMI had spontaneous remission before week 24; it is possible that additional patients would have achieved this status if IST had been withheld longer.

Emicizumab prophylaxis and deferral of IST in AHA have consequences including greater cost, the need for treatment of breakthrough bleeds, patient anxiety around bleeding risk, and the need for continued access to specialized medical care. There will also be increased risks associated with trauma or surgery in the presence of persistent FVIII inhibitors, although recombinant porcine FVIII concentrate provides an additional option for control of bleeding in many patients who require hemostatic therapy.

As Schimansky et al state, emicizumab is changing clinical practice in AHA, in no small part as a result of their own work in the field. This study makes a valuable contribution to the evolving approach to managing this rare but life-threatening disease. The questions raised by this new strategy will likely be revisited when the more potent FVIII-mimetic agents currently in clinical trials enter clinical practice.⁹ 

Conflict-of-interest disclosure: The authors declare no competing financial interests.