-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

3988 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/MlClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 322. Disorders of Coagulation or Fibrinolysis: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Bleeding and Clotting, hemophilia, Clinical Research, pediatric, Diseases, real-world evidence, Therapies, therapy sequence, Study Population, Human
Monday, December 11, 2023, 6:00 PM-8:00 PM

Zhengping Li, MBBS1*, Man-Chiu Poon2 and Runhui Wu, MD3*

1Hematology Department, Beijing Children's Hospital, Affiliated to Capital Medical University, Beijing, AL, China
2University of Calgary, Calgary, AB, Canada
3Hematology Department, Beijing Children's Hospital, Affiliated to Capital Medical University, Beijing, China


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-IS40 regimen) had relatively high success rate with lower cost compared to those on high-dose ITI. Recent evidence suggested that patients with inhibitor titer <200 BU/mL do not need high-dose ITI raising the question that IS may also not be necessary.


To compare the efficacy of LD-ITI incorporating IS only for inhibitor titer ≥200 BU/mL (LD-ITI-IS200 regimen) with that of LD-ITI-IS40 regimen.


A prospective, single-arm, single-center cohort study on patients receiving LD-ITI-IS200 beginning 2021, compared to those receiving LD-ITI-IS40 before 2021.

The inclusion criteria were: (i) patients with an established diagnosis of SHA [FVIII clotting activity (FVIII: C) <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-IS40 regimen and ≥200 BU/mL in LD-ITI-IS200 regimen. IS used for each regimen included rituximab 375 mg/m2/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.


We enrolled 30 patients on LD-ITI-IS200 and 64 patients on LD-ITI-IS40, with similar baseline clinical characteristics (Table 1). Given that IS was initiated at a higher peak inhibitor-titer in the LD-ITI-IS200 regimen, IS in the LD-ITI-IS200 group was introduced at a significantly lower rate than that in the LD-ITI-IS40 regimen group (30% vs. 62.5%, p = 0.003). The 2 regimens (LD-ITI-IS200 vs. LD-ITI-IS40) 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-IS200 (US$2167) was significantly lower than that in the LD-ITI-IS40 (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-IS200 patients and 22.5% (9/40) for the LD-ITI-IS40 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-IS200 regimen) and 28 IS-using (on LD-ITI-IS40 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-IS200 (US$891) was significantly lower than that in the LD-ITI-IS40 (US$2819).

Between the two protocols, there were 12 patients with peak inhibitor-titer ≥200BU/mL (all using IS, 7 in LD-ITI-IS200, 5 in LD-ITI-IS40). 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-IS200, 31 in LD-ITI-IS40) with peak inhibitor-titer 5-39 BU/mL. Their overall success rate was 79.5%. Nine of the 44 patients (2 in LD-ITI-IS200, 7 in the LD-ITI-IS40) 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.


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.

Disclosures: Poon: University of Calgary: Current Employment; KVR Pharma, Novo Nordisk, Octapharma, Sobi, Takeda: Honoraria.

*signifies non-member of ASH