Eradication therapy

General aspects

Although spontaneous remission occurs, immunosuppressive therapy (IST) is recommended to eradicate the inhibitor as soon as possible to reduce the length of time the patient is at risk for severe bleeding. Factor VIII level and inhibitor titer at presentation are prognostic markers for remission rate and time to remission, and in frail low-risk patients, reduced intensity IST can be considered to reduce the risk of infections.

First line treatment

The prospective, observational UK surveillance study and EACH2 registry have compared outcomes for first line treatments. The UK surveillance study (2007) found no significant difference between monotherapy prednisone and combination therapy with mostly cyclophosphamid in terms of complete remission (CR) rate and time to remission [1]. In the EACH2 registry, patients on combination therapy were more likely to achieve stable CR, and time to CR was shorter. There was, however, a higher proportion of adverse events with combination therapy [2].

The German, Austrian and Swiss Thrombosis and Hemostasis Society (GTH) (2015) report a prospective observational study of 102 patients with AHA receiving IST according to the escalating protocol of the GTH [3]. Forty-eight patients achieved PR with prednisone monotherapy, 25 of them within 3 weeks. Forty-four patients were escalated to rituximab (9) or cyclophosphamid (35), and 12 received third line therapy with rituximab added to cyclophosphamid. Fourteen patients died before remission. Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with >1 IU/dL (89%, 24 days). Low FVIII:C was also associated with a lower rate of complete remission and decreased survival. Based on this observation, GTH suggest tailoring first line treatment intensity according to presenting FVIII-level [4].

A retrospective Dutch cohort study (2020) including 143 patients treated first line with monotherapy corticosteroids (67%), in combination with cyclophosphamide (12%) or rituximab (12%), reported remission rates of 33%, 80% and 67% respectively [5]. A high inhibitor titer was associated with lower CR rates. Infections occurred significantly more often with combination therapy than monotherapy corticosteroids, and mortality was mostly due to infections (19%) compared to fatal bleeds (7%) [2].

In a retrospective Nordic registry study of 181 patients with data from 6 haemophilia centres, the overall remission rate was 57% [6]. Corticosteroid monotherapy was the most frequently used first-line IST in 75% of cases (effective in 55%), followed by corticosteroids combined with cyclophosphamide in 13% (effective in 58%) and rituximab-based regimens in 9% (effective in 82%). Death from AHA related bleeding was reported in 12% of patients and IST related infectious death in 9%. The high rate of steroid monotherapy was considered related to the lower rate of overall CR.

In 2023, the first randomized study of IST in AHA was published. In a multicentre, open-label, randomized noninferiority trial by Wang et al, steroids combined with a single dose of rituximab 375 mg/m2 was compared to steroids combined with cyclophosphamide with daily dose of 2mg/kg until the inhibitor titre was negative [7]. The study included 63 patients and demonstrated noninferiority, with CR rate of 77.4% in the rituximab group and 68.8% in the cyclophosphamide group, without differences in treatment related adverse events.

In the recent GTH-AHA-EMI study, the group investigated a treatment strategy of subcutaneous emicizumab prophylaxis for 12 weeks without any IST [8]. After the study period of 12 weeks, one out of 47 enrolled patients had reached spontaneous remission while two had increased FVIII to 49 and 50 IU/dL, respectively with detectable inhibitor. Most patients (62%) received IST after the study period of 12 weeks as outpatients and at 24 weeks, 30% reached remission. The GTH AHA working group concluded that emicizumab is effective for bleed prophylaxis and should be considered from the time of diagnosis, and that IST should be offered to patients on emicizumab if they are eligible based on physical status [9].

Second line treatment

In parallel with the escalating GTH study from 2015 [3], second line therapy is considered when the patient does not show any sign of remission within 3 weeks.

Other treatment options

Azathioprine and ciclosporine

Other options for IST are azathioprine [10], ciclosporine or tacrolimus [11] that has been reported as successful first line treatment in combination with steroids.

Human immunoglobulin for intravenous use (IVIG)

Adding IVIG to other IST did not improve outcome in the UK surveillance study or EACH2 [1,12].

Factor VIII concentrate

Nemes [13] has been successful using a model for induction of tolerance in AHA with a combination of FVIII concentrate and cyclophosphamide 200 mg/day up to a total of 2-3 g and prednisolone 100 mg/day gradually tapering off. A complete remission was obtained in 24 of 26 patients, typically in 4 weeks. Another group reported 12 patients with CR rates of 92% after 3 weekly infusions of FVIII combined with vincristine, cyclophosphamide and steroids [14]. The same group later reported six patients who were treated with vincristine, cyclophosphamide, and steroids without FVIII and found 83% remission after 1–7 courses [15]. The role of FVIII co-administered with IST is not clear, and due to high cost, not recommended.

Immunoadsorption/MBMP

Zeitler et al. [16] presented 35 patients with high titre AHA and severe bleeding, treated according to the Modified Bonn/Malmö protocol (MBMP) combining immunoadsorption, IST, IVIG and FVIII infusions. Treatment cycles (days 1-7) were repeated until clinical and laboratory response were achieved. They underwent 1) large-volume adsorption 2.5 to 3 times the total plasma volume on days 1-5, 2) IVIG 0.3 g/kg on days 5-7, 3) prednisolone 1 mg/kg and cyclophosphamide 1-2 mg/kg daily until remission, and 4) FVIII concentrate infusion in a dosage of 100 up to 200 IU/kg every 6 h which was reduced when satisfactory response was achieved. With this regimen inhibitors were undetectable rapidly within 2-4 days, FVIII concentrate was stopped with a median of 12 days and the total treatment process was completed within 12-17 days. Guidelines generally recommend MBMP as third line treatment or in case of acute surgical intervention, situations of high bypassing agent consumption and life-threatening bleedings.

Based on a later report of 20 patients suffering from less severe AH, Goldman et al. [17] argue that immunoadsorption could be considered as first line therapy. The patients with residual FVIII >1 IU/dL and/or non-transfusion requiring bleedings at first presentation received first line IST consisting of cyclophosphamide 1 mg/kg/day and/or prednisolone 1 mg/kg /day. Despite the initial non-severe presentation and recommended first line treatment, bleeding was progressive in 5 patients. They switched to the full MBMP protocol, allowing FVIII recovery to normal after median 14 apheresis sessions. In contrast to IST treated patients, disease flares during immunosuppressive tapering were not seen.

Relapse

The relapse rate after first CR was about 20 % in the 90 patients with available data in the UK surveillance study [1]. The outcome was comparable in the EACH2, where relapse was reported in 15 (18%) patients who achieved a CR with steroids alone, translating to stable CR after first-line treatment with steroid monotherapy in 68 of 142 (48%) patients. The steroid and cyclophosphamide group had a 12% relapse rate, resulting in a stable CR in 58 of 83 (70%) patients. Of note, only 1(3%) of patients reaching CR with a rituximab regimen relapsed. In GTH, relapse occurred in 15 of 62 patients (24%).

In the EACH2 study relapses occurred up to 14 months after stopping IST, with a median of 4 months [2]. Most of these patients achieved a second CR although some needed a long-term maintenance immunosuppression. There are no studies to support choice of treatment in case of relapse.

Recommendations for eradication therapy

First line treatment

  • Start IST as soon as possible after diagnosis in patients eligible for treatment.

  • Corticosteroids in combination with rituximab or cyclophosphamide is recommended as first line therapy.

  • Corticosteroids as monotherapy can be considered in low-risk patients with FVIII > 0.01 IU/dL and low ( < 5 BU) inhibitor titer at presentation.

  • Rituximab monotherapy as first line treatment is not recommended due to longer time to remission.

Second line treatment

  • If the patient is not in responding within 3 weeks (ongoing bleeding, no increase in FVIII) consider adding second line treatment with rituximab or cyclophosphamide, whatever option not used as first line.

Relapse

  • Repeat first line treatment with corticosteroids and consider adding other IST.

See Table 2 for overview of eradication therapy.