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Prediction Markers for Development of Persistent Inhibitors in Previously Untreated Patients with Severe Hemophilia A

1Università degli Studi di Milano, Department of Biomedical Sciences for Health, Milan, Italy, 2Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Milan, Italy, 3Università degli Studi di Milano, Department of Pathophysiology and Transplantation, Milan, Italy, 4Cairo University Pediatric Hospital, Pediatric Hematology Department, Cairo, Egypt, 5Faculty of Medicine, Ain Shams University, Department of Pediatrics, Cairo, Egypt, 6Jehangir Clinical Development Center, Department of Hematology, Jehangir Hospital Premises, Pune, India, 7Shahid Beheshti University of Medical Sciences, Pediatric Congenital Hematologic Disorders Research Center, Tehran, Iran, Islamic Republic of, 8Leiden University Medical Center, Department of Clinical Epidemiology, Leiden, the Netherlands

Abstract Number: PB0925

Meeting: ISTH 2020 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical

Background: Neutralizing antibodies (inhibitors) are the main complication of replacement therapy in hemophilia A. Some of these inhibitors disappear shortly after development (transient), while others remain (persistent), through a mechanism still unknown.

Aims: To investigate the predictive value of anti-FVIII IgG subclasses (IgG1, IgG2, IgG3, IgG4) within 6 months from inhibitor development on inhibitor persistence in previously untreated patients (PUPs) with severe hemophilia A.

Methods:

– Patients: Initially, we analyzed 43 PUPs from the SIPPET study who developed inhibitors, using samples taken within the first 60 days from inhibitor development. Subsequently, from the 43 PUPs we studied 14 (5 transient inhibitors and 9 persistent), at 5 time points over a course of 6 months post inhibitor development: T0: at inhibitor detection, T1: between 1-30 days following first inhibitor, T2: between 31-60 days, T3: between 61-120 days, T4: between 121-180 days.

– Laboratory methods: Anti-FVIII IgG subclasses were measured by ELISA assay as reported previously (Cannavò et al. Blood, 2017) with minor modifications.

– Statistical analysis: Logistic regression was applied to assess the association of “number of IgG subclasses” with “inhibitor persistence”.

Results: Relative Risks showed that within 60 days, the risk of inhibitor persistence increased with the rising number of IgG subclasses (Table 1). The analysis of IgG subclasses profiles over 6 months, showed a predominant presence of IgG1 and IgG4 in all inhibitor patients, regardless of transience/persistence. IgG3 antibodies were present in the early response and progressively reduced in both groups. IgG2 was the only subclass that had a differential tendency; disappeared in the transient group and increased in the persistent (Table 2).

Number of IgG subclass combinations Persistent anti-FVIII inhibitors (N=31) Transient anti-FVIII inhibitors (N=12) RR (95% CI)°
1
(only IgG1 – taken as reference)		 1 (3%) 2 (17%) 1
2
(combinations of 2 different IgG subclasses)		 8 (26%) 7 (58%) 1.71 (0.25 to 2.94)
3
(combinations of 3 different IgG subclasses)		 11 (35%) 2 (17%) 2.57 (0.73 to 3.01)
4
(all 4 IgG subclasses)		 11 (35%) 1 (8%) 2.81 (1.15 to 3.02)
°RR (95% CI): Relative Risk with 95% Confidence Interval.

[Table 1. Risk of inhibitor persistence according to the number of IgG subclass combinations.]

  IgG1
positive/total (%)		 IgG2
positive/total (%)		 IgG3
positive/total (%)		 IgG4
positive/total (%)
Time point Persistent Transient Persistent Transient Persistent Transient Persistent Transient
T0 9/9
(100%)		 5/5
(100%)		 2/9
(22%)		 1/5
(20%)		 9/9
(100%)		 5/5
(100%)		 7/9
(78%)		 3/5
(60%)
T1 9/9
(100%)		 5/5
(100%)		 5/9
(56%)		 1/5
(20%)		 9/9
(100%)		 3/5
(60%)		 8/9
(89%)		 4/5
(80%)
T2 9/9
(100%)		 4/5
(80%)		 6/9
(67%)		 1/5
(20%)		 9/9
(100%)		 4/5
(80%)		 9/9
(100%)		 4/5
(80%)
T3 8/8
(100%)		 5/5
(100%)		 7/8
(88%)		 1/5
(20%)		 6/8
(75%)		 4/5
(80%)		 8/8
(100%)		 5/5
(100%)
T4 8/8
(100%)		 4/5
(80%)		 4/8
(50%)		 0/5
(0%)		 5/8
(63%)		 2/5
(40%)		 8/8
(100%)		 5/5
(100%)
*14 PUPs: The 14 patients analyzed became 13 at time points T3 and T4, as subjects with persistent inhibitors reduced to 8 PUPs based on plasma availability.

[Table 2. Anti-FVIII IgG subclasses over 6 months post inhibitor in 14 PUPs* with inhibitors.]

Conclusions: Within 60 days from inhibitor formation, the presence of more than one anti-FVIII IgG subclass was associated with an increased risk of inhibitor persistence. Over a course of 6 months, IgG2 resulted as the only IgG subclass harboring predictive hallmarks of inhibitor persistence.

To cite this abstract in AMA style:

Miri S, Bucciarelli P, Valsecchi C, Schiavone L, Boscarino M, Palla R, El-Beshlawy A, Elalfy M, Ramanan V, Eshghi P, Mannucci PM, Rosendaal FR, Peyvandi F, on Behalf of the SIPPET Study Group . Prediction Markers for Development of Persistent Inhibitors in Previously Untreated Patients with Severe Hemophilia A [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/prediction-markers-for-development-of-persistent-inhibitors-in-previously-untreated-patients-with-severe-hemophilia-a/. Accessed September 24, 2023.

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