The Role of Therapy Regimen and Age at First Exposure on Inhibitor Development in Patients with Severe Hemophilia A

The Role of Therapy Regimen and Age at First Exposure on Inhibitor Development in Patients with Severe Hemophilia A

C. Escuriola Ettingshausen, R. Linde, I. Martinez Saguer, A. Zyschka, C. Kessel, H. Stoll and W. Kreuz

Introduction

Today the development of neutralizing antibodies is one of the most serious com- plications in the replacement therapy with Factor (F) VIII and IX concentrates.

Prospective studies with previously untreated patients (PUPs) demonstrated that severe hemophilia A patients are mostly affected (21-52%) within the first 50 expo- sure days (ED). Incidence is lower in patients with moderate or mild hemophilia A and hemophilia B [1].

Genetic risk factors as the patients´ ethnicity/race, the underlying gene mutati- on and to a lesser extent the HLA-type have an impact on the risk to develop inhi- bitors [2]. Recent publications indicate that early age at first exposure leads to an increased risk of inhibitor development in severe hemophilia A patients [3, 4]. In order to assess whether the risk of inhibitor development is associated with the age at first exposure and the treatment strategy during the initial phase of treatment with FVIII we are conducting a prospective PUP-study.

Patients and Methods

Over a 24-years-study period (start 1979) a total of 74 severely affected hemophilia A-PUPs have been consecutively recruited at the outpatient clinic of the Children’s University Hospital Frankfurt, Dept. of Hematology, Oncology and Hemo- staseology. They have been treated regularly with FVIII concentrates. The following parameters which may have impact on inhibitor development were prospectively investigated: Type and severity of hemophilia, reason for first ED (bleeds, surgery etc), age at first exposure and at inhibitor development, inhibitor titer (at start of ITI, peak titer), number of exposure days (ED) until inhibitor development, therapy regime (prophylaxis vs on demand), type and dosage of factor concentrate admini- stered, mutation type and HLA-type.

From 1976-1992 inhibitor testing according to the Bethesda method was perfor- med before the first exposure to FVIII and thereafter every 20th ED or in any situa- tion of suspected inhibitor formation. Since 1993 inhibitor testing was done more frequently: Before the first ED, every 3rd-4th exposure day (ED) for the first 20 EDs, thereafter until the 200th ED every 10th ED, after the 200th ED every 3 months.

Additional testing is recommended in any suspicion of inhibitor development.

I. Scharrer/W. Schramm (Ed.)

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Hemophilia Symposium Hamburg 2003

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Rarely exposed patients should be followed up every 3 months.

Definitions of inhibitors: Positive inhibitor = 0.6 Bethesda Units (BU). Low titer inhibitor (0.6–5 BU), high titer inhibitor >5BU.

Therapy Regimens

Primary prophylaxis: Regular prophylactic FVIII administration in order to prevent bleeds (25-40 IU FVIII/kg bw 3 times per week or every other day) started before or immediately after the first relevant bleeding episode.

A prophylactic treatment is defined as a secondary prophylaxis when started after 2 or more bleeds.

Results

Until January 2003, 23 out of 74 severe hemophiliacs developed an inhibitor (31%).

Preliminary evaluations over the years of this still ongoing study showed decreasing inhibitor incidences for patients with severe hemophilia A (Ehrenforth et al, Lancet 1992: 52% [5]; Kreuz et al, Sem Thromb Haemost 1999: 43% [6]; 2003:

31%). More than half of those patients developed high titer inhibitors (>5 Bethesda Units).

Age at First Exposure to FVIII and Inhibitor Development

No linear correlation was found between the age at first exposure to F VIII and inhi- bitor formation. However, in the group of very early exposed severe hemophiliacs (age at first ED <0.5 years) inhibitor incidence was remarkably high (62%, 5/8 pati- ents) (Table 1).

Table 1. Inhibitor incidence dependent on age at first exposure to FVIII (n.a.-data not available)

Age at 1st ED [years] Inhibitor/total patients

< 0.5 5/8 (62.5%)

0.5–1 7/32 (22%)

1–1.5 4/16 (25%)

> 1.5 4/13 (31%)

n.a. 3/5

total 23/74 (31%)

The Role of Therapy Regimen and Age at First Exposure on Inhibitor Development 39

Therapy Regimen and Inhibitor Development

Inhibitor incidence was 0% (1 transient inhibitor out of 23 patients) in those pati- ents who received prophylaxis before or immediately after the first relevant bleed and 42 % (18/43 patients) in case of delayed prophylaxis or on-demand treatment.

A significant difference in inhibitor incidence was found between the two groups (p=0.002) (Table 2).

Table 2. Inhibitor incidence dependent on the therapy regimen

Therapy regimen total (n=74)

Inh/total

Primary prophylaxis (start 0.8-2 yr) 0/23 (0%)*

(1 trans./23) Secondary prophylaxis or on-demand treatment (age >0.5 yr) 18/43 (42%)*

Inhibitor development during treatment of 1st bleed (age<0.5 yr) 5/8 (62.5%)

total 23/74 (31%)

*p=0.002 (Fisher’s exact test); trans (transient inhibitor); yr (year)

Discussion

Evaluations on inhibitor incidence over the years revealed a continuously decreas- ing incidence in our patient cohort. The decreasing inhibitor incidence might be explained by the changing therapeutic strategies over the years: In the 80ies patients were usually treated on-demand and long-term prophylaxis was started after sever- al bleeds. Since the early 90ies long-term prophylaxis was started earlier in severe hemophilia A patients. Accordingly the majority of those patients started prophy- laxis at the age of 1 year (before or immediately after the first relevant bleeding event).

Patients starting prophylaxis before or immediately after the first relevant bleed showed a significant lower inhibitor incidence than those treated on-demand in the initial phase of FVIII replacement therapy. In a group of Swedish patients who start- ed prophylaxis at early age, inhibitor incidence was also low for severe hemophilia A patients [7]. According to these observations a protective character of early pro- phylaxis can be discussed and should be investigated in a larger number of patients.

This evaluation should include the mutation type as well as the type of concentrate used.

Age at first exposure did not correlate with the occurrence of inhibitors.

However, we found a high rate of inhibitors in patients who were treated at very

early age (<0.5 years; 62.5%). All those patients received clotting factor concentrate

for treatment of severe bleeding or for surgical interventions. This observation con-

firms the hypothesis that early age at first exposure is associated with a high risk to

40 C. Escuriola Ettingshausen et al.

develop inhibitors. On the other hand we could not confirm, that severe hemophi- liacs, who get their first exposure at the age >1.5 years show a low inhibitor inci- dence as postulated by the Spanish and the Dutch group [3, 4].

In order to confirm the influence of age at first exposure and therapy regimen in the initial phase of treatment on inhibitor development in severe hemophiliacs a larger number of patients should be investigated.

References

1. Kreuz W, Ettingshausen CE, Auerswald G, Saguer IM; Becker S, Funk M, Heller C, Klarmann D, Klingebiel T and the GTH-PUP Study Group. Epidemiology of inhibitors and current tre- atment strategies. Haematologica 2003; 88 (6): 17-20

2. Oldenburg J, Schroder J, Brackmann HH, Müller-Reible C, Schwaab R, Tuddenham E.

Environmental and genetic factors influencing inhibitor development. Semin Hematol 2004;

41 (Suppl 1): 82-8

3. Lorenzo JI, Lopez A, Altisent C, Aznar JA. Incidence of factor VIII inhibitors in severe haemophilia: the importance of patient age. Br J Haematol 2001; 113(3): 600-3

4. Van der Bom JG, Mauser-Bunschoten EP, Fischer K, Van den Berg HM. Age at first treatment and immune tolerance to factor VIII in severe hemophilia. Thromb Haemostas 2003; 89:

475-79

5. Ehrenforth S, Kreuz W, Scharrer I, Linde R, Funk M, Güngör T, Kornhuber B. Incidence of development of factor VIII and factor IX inhibitors in haemophiliacs. Lancet 1992; 339:

594-8

6. Kreuz W, Ettingshausen CE, Zyschka A, Oldenburg J, Saguer IM, Ehrenforth S, Klingebiel T.

Inhibitor development in previously untreated patients with hemophilia A: A prospective long-term follow-up comparing plasma-derived and recombinant products. Semin Thromb Hemost 2002; 28 (3): 285-90

7. Petrini P. How to start prophylaxis. Haemophilia 2003; 9 (Suppl 1): 83-5

The Role of Therapy Regimen and Age at First Exposure on Inhibitor Development 41