Low-Dose Immune Tolerance Induction Therapy for Severe Hemophilia a Inhibitor Patients: Immunosuppressants Improve Outcomes but Are Generally Not Necessary for Inhibitor-Titer below 200 BU/Ml
Authors: Li Zhengping , Poon Man-Chiu , Wu Runhui 
Published: December 2023

Background
We previously showed that low-dose immune tolerance induction (ITI) incorporating immunosuppressants (IS) for severe hemophilia A patients with inhibitor titer ≥40 Bethesda Units (BU)/mL (LD-ITI-IS 40 regimen) had relatively high success rate with lower cost compared to those on high-dose ITI. Recent evidence suggested that patients with inhibitor titer &lt;200 BU/mL do not need high-dose ITI raising the question that IS may also not be necessary.
Objectives
To compare the efficacy of LD-ITI incorporating IS only for inhibitor titer ≥200 BU/mL (LD-ITI-IS 200 regimen) with that of LD-ITI-IS 40 regimen.
Methods
A prospective, single-arm, single-center cohort study on patients receiving LD-ITI-IS 200 beginning 2021, compared to those receiving LD-ITI-IS 40 before 2021.
The inclusion criteria were: (i) patients with an established diagnosis of SHA [FVIII clotting activity (FVIII: C) &lt;1% before inhibitor development]; (ii) patients ≤14 years age at the ITI-start; (iii) patients with high-titer inhibitors (≥5BU/mL).
All study patients received a LD-ITI with pd-FVIII/VWF (at 50 FVIII IU/kg) every-other-day. IS (rituximab + prednisone) were added for peak inhibitor-tier ≥40 BU/mL in LD-ITI-IS 40 regimen and ≥200 BU/mL in LD-ITI-IS 200 regimen. IS used for each regimen included rituximab 375 mg/m 2/week (maximum 600 mg) for 4 weeks, together with prednisone 2 mg/kg/day (maximum 60 mg) for one month, then tapered over 3 months. For patients receiving rituximab, intravenous immunoglobulin (200 mg/kg/month for 6 months) was administered for infection prophylaxis.
Success is defined as negative inhibitor plus FVIII recovery ≥66% of the expected. Partial success is defined as achieving inhibitor elimination but with persistently abnormal FVIII recovery.
Results
We enrolled 30 patients on LD-ITI-IS 200 and 64 patients on LD-ITI-IS 40, with similar baseline clinical characteristics (Table 1). Given that IS was initiated at a higher peak inhibitor-titer in the LD-ITI-IS 200 regimen, IS in the LD-ITI-IS 200 group was introduced at a significantly lower rate than that in the LD-ITI-IS 40 regimen group (30% vs. 62.5%, p = 0.003). The 2 regimens (LD-ITI-IS 200 vs.LD-ITI-IS 40) had similar success rate (66.7% vs. 79.7%), median time to success (7.4 vs. 10.6 months) (Figure 1), and ABR during ITI (3.7 vs. 2.8). The per kg treatment cost from ITI-start to ITI success in the LD-ITI-IS 200 (US$2167) was significantly lower than that in the LD-ITI-IS 40 (US$3349).
Among patients taking IS in the two regimens rituximab infusion-related side effects were similar, being 22.2% (2/9) for the LD-ITI-IS 200 patients and 22.5% (9/40) for the LD-ITI-IS 40 patients. All these side effects could be resolved and subsequently prevented by antihistamine drugs. No severe adverse events occurred.
Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS 200 regimen) and 28 IS-using (on LD-ITI-IS 40 regimen) had similar success rate (60% vs. 78.6%) and time to success (9.0 vs. 8.8 months). The per kg treatment cost from ITI-start to ITI partial success in the LD-ITI-IS 200 (US$891) was significantly lower than that in the LD-ITI-IS 40 (US$2819).
Between the two protocols, there were 12 patients with peak inhibitor-titer ≥200BU/mL (all using IS, 7 in LD-ITI-IS 200, 5 in LD-ITI-IS 40). Among them, 8 patients (66.7%, 4 on each regimen) achieved success over a median 10.1 months, and none relapsed at median 13.5 months follow-up since achieving success.
Between the 2 protocols, there were 44 patients (13 in LD-ITI-IS 200, 31 in LD-ITI-IS 40) with peak inhibitor-titer 5-39 BU/mL. Their overall success rate was 79.5%. Nine of the 44 patients (2 in LD-ITI-IS 200, 7 in the LD-ITI-IS 40) received IS because they failed to have adequate inhibitor titer decline in the first 3 months of ITI. All 9 achieved success at median 11.3 months from ITI-start with no relapsed after a median 22.6 months follow-up since success.
Conclusions
We have optimized the use of IS in our low-dose ITI protocol for SHA patients with high-titer inhibitors. We showed that more restrictive use of IS only for patients with peak inhibitor-titer ≥200 BU (instead of at a lower titer of ≥40 BU) maintained the same efficacy while decreasing the cost. Decreasing use of IS would decrease its potential side effects including infection risks.