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INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A

van Velzen, A.S.

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Citation for published version (APA):van Velzen, A. S. (2016). INSIGHT in risk factors and treatment of inhibitors in nonsevere hemophilia A.

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Download date: 10 Jan 2020

https://dare.uva.nl/personal/pure/en/publications/insight-in-risk-factors-and-treatment-of-inhibitors-in-nonsevere-hemophilia-a(bc61ebd0-42ef-4e85-8304-9eda17536ce8).html

CHAPTER 8

INHIBITORS IN NONSEVERE HEMOPHILIA A:OUTCOME AND ERADICATION STRATEGIES

Alice S. van Velzen, Corien L. Eckhardt, Daniel P. Hart, Marjolein Peters,Savita Rangarajan, Maria Elisa Mancuso, Frans J. Smiers, Kate Khair, Pia Petrini,

Victor Jimenez-Yuste, Charles R.M. Hay, Johanna G. van der Bom, Thynn T.Yee and Karin Fĳnvandraat , for the INSIGHT Study Group.

Thrombosis and Haemostasis 2015;114(1):46-55.

192

Inhibitors in nonsevere hemophilia A

Abstract

Background

In nonsevere hemophilia A (HA) patients the presence of an inhibitor may exacerbate

the bleeding phenotype dramatically. There are very limited data on the optimal

therapeutic approach to eradicate inhibitors in these patients.

Objective

We aimed to describe inhibitor eradication treatment in a large cohort of unselected

nonsevere HA patients with inhibitors.

Patients/Methods

We included 101 inhibitor patients from a source population of 2709 nonsevere HA

patients (factor VIII 2 – 40 IU/dL), treated in Europe and Australia (median age 37

years, interquartile range (IQR) 15 – 60; median peak titre 7 BU/mL, IQR 2 – 30).

Results: In the majority of the patients (71%; 72/101) the inhibitor disappeared; either

spontaneously (70%, 51/73) or after eradication treatment (75%, 21/28). Eradication

treatment strategies varied widely, including both immune tolerance induction and

immunosuppression. Sustained success (no inhibitor after rechallenge with factor

VIII concentrate after inhibitor disappearance) was achieved in 64% (30/47) of those

patients rechallenged with FVIII concentrate. In high titre inhibitor patients sustained

success was associated with eradication treatment (unadjusted relative risk 2.3, 95%

confidence interval 1.3 – 4.3), compared to no eradication treatment.

Conclusions

In nonsevere hemophilia A patients most inhibitors disappear spontaneously.

However, in 35% (25/72) of these patients an anamnestic response still can occur

when rechallenged, thus disappearance in these patients does not always equal

sustained response. Treatment for those requiring eradication has to be decided case

by case, as one single approach is unlikely to be appropriate for all.

193

CHAPTER 8

Introduction

Hemophilia A (HA) is an X-linked bleeding disorder caused by deficiency of

coagulation factor VIII (FVIII). FVIII concentrate is administered intravenously to treat

or prevent bleeding.1 The development of neutralizing FVIII antibodies (inhibitors) is

the most challenging and severe complication of clotting factor replacement in HA. In

severe HA this complication mainly occurs during childhood, however patients with

nonsevere HA (FVIII 2 – 40 IU/dL) are at a lifelong risk for inhibitor development as

they receive FVIII concentrates with irregular frequency due to the milder bleeding

phenotype and the use of desmopressin (DDAVP).2

Prior to inhibitor occurrence, patients with mild HA would normally only experience

bleeding episodes elicited by trauma.1 The inhibitor may aggravate the bleeding

phenotype dramatically, especially if it reduces the endogenous FVIII plasma levels

below 1 IU/dL. This is associated with an increase in morbidity.3-6

Subsequent clinical decisions become more challenging, particularly in the setting of

relevant co-morbidities such as cardio-vascular disease. Often FVIII bypassing agents

(FEIBA [Baxter] or recombinant FVIIa [Novoseven, Novonordisk]) are administered

with varying efficacy in achieving a satisfactory haemostasis.

Although previously the incidence of inhibitor development in nonsevere HA patients

was estimated to be between 3 – 13 %, recently certain F8 genotypes have been

identified that are associated with higher inhibitor rates.2-4 For some F8 genotypes the

inhibitor incidence approximates the rates observed in severe HA. Moreover, inhibitor

incidences in the nonsevere HA patients progressively increase with cumulative

number of FVIII exposure days apparently without reaching a plateau, which contrasts

with the observations in patients with severe HA. Inhibitor risk after 20, 50 and 100 ED

is estimated at 3.5 % (95% confidence interval (CI), 2.1 – 4.9), 6.7% (CI 4.5 – 8.9) and

13.3% (CI 9.6 – 17.0), respectively.2

Since inhibitor development in nonsevere HA is a substantial and relevant clinical

problem, there is a clinical imperative to know more about treatment regimens aimed

at inhibitor eradication in nonsevere HA.

Our current knowledge on inhibitor eradication treatment is largely based on studies

and clinical experience in severe HA patients with inhibitors.7 A common approach

to inhibitor eradication in severe HA is Immune Tolerance Induction (ITI). This was

194


first described in the 1970’s and in the past decades several treatment protocols

have been developed.8-13 These protocols consist of the administration of frequent

high doses FVIII concentrate with the aim of gaining tolerance to the FVIII protein.14

Less commonly, medication such as prednisolone, cyclophosphamide or anti-CD20

(Rituximab®) are administered to suppress the immune response.11,15,16

There are very limited data on the optimal therapeutic approach to eradicate

inhibitors in nonsevere HA patients.17 In these patients, losing and re-achieving

tolerance to therapeutic FVIII concentrate may be subject to different immunological

mechanisms compared to patients with severe HA.18 As patients with nonsevere HA

do have circulating endogenous FVIII, in contrast to patients with severe HA, the

allogeneic mismatch between endogenous and the exogenous therapeutic FVIII is

less than in severe HA. These nonsevere HA patients have continuous exposure to

their endogenous FVIII, which in most cases will only differ to infused wild type FVIII

by a single amino acid as a result of a F8 missense mutation. If an inhibitor occurs, the

anti-FVIII antibody is initially formed against the infused therapeutic (wild type) FVIII,

but can then cross-react with the endogenous FVIII. In contrast to severe HA, inhibitors

arising in nonsevere HA often have complex kinetics and a bleeding phenotype

similar to acquired HA. Consequently, immunosuppressive strategies are reported

more frequently to eradicate the inhibitor than in severe HA patients.3

Therefore, nonsevere HA patients may require a different approach than the traditional

immune tolerance induction applied in severe HA. Moreover, evidence to decide if

eradication treatment is needed in all nonsevere hemophilia A patients is scarce.

We studied the therapeutic approaches that have been used for inhibitor eradication

and their resultant outcome in the largest, unselected international cohort of patients

with nonsevere HA with inhibitors reported so far.

195

CHAPTER 8

Patients and methods

Subjects and study design

In this cohort study we included all nonsevere HA patients (FVIII:C 2 – 40 IU/dL) who

developed a clinically relevant inhibitor between 1980 and 2011 in one of the 34

participating centers of the INSIGHT study (investigators and centers are listed in

the appendix): an international, multicentre cohort study that included all nonsevere

HA patients who received at least one exposure to factor VIII concentrate during

the observation period. The institutional review boards of all participating centres

approved the study. The inhibitor patients were located in 28 European centres and

one centre in Australia.

For the present satellite study we collected data on inhibitor titers, inhibitor eradication

treatment and outcome. Detailed characteristics of the source population (genotype

and inhibitor risk) are described elsewhere.2

Definitions and features of variables

Patients were tested for inhibitors according to local practice and the results of all

inhibitor tests were reviewed to confirm the inhibitor status of the patients. Inhibitory

anti-FVIII antibodies were quantified at each local laboratory by the original Bethesda

method or the Nĳmegen modified assay from the nineties onwards.19,20 Protocols of

the inhibitor assay of all participating centers are available from the corresponding

author.2 Inhibitor titers were expressed in Bethesda Units per millilitre (BU/mL). A

clinically relevant inhibitor was defined as having at least two consecutive positive

Bethesda inhibitor assay titers of ≥1.0 BU/mL. Patients with inhibitor titers between

0.6 – 1.0 BU/mL had to fulfil one of the following two criteria to be classified as having

a clinically relevant inhibitor: 1.) a decrease in endogenous factor VIII plasma level to

at least 50% of the baseline level, or 2.) a reduced half-life of less than 6 hours after

FVIII concentrate administration. Patients who were not tested for inhibitors during

the follow-up period and who had no clinical features of inhibitor development (e.g.

increased bleeding tendency) were classified as negative for inhibitors.

A negative inhibitor titre was defined as a Bethesda inhibitor assay of <0.6 BU/mL

on two consecutive assays. Historical peak titre was defined as the highest inhibitor

titre available. A high titre inhibitor was defined as a historical peak titre >5.0 BU/mL

and a low titre inhibitor was defined as a historical peak titre of 0.6 – 5.0 BU/mL. Pre-

196


ITI titre (pre-titre) was defined as the most recent inhibitor titre available before the

start of inhibitor eradication therapy. We defined inhibitor eradication therapy as any

treatment with the objective to eradicate the inhibitor. Immune tolerance induction

(ITI) was defined as regular treatment with FVIII concentrate without adjunctive

medication.

Patients were classified into two mutually exclusive categories: ‘’Eradication’’, if

they ever had received eradication therapy during follow-up of this study and ‘’ No

eradication’’ if they never received any form of eradication therapy during follow-up.

Inhibitor disappearance was defined as: a) an endogenous FVIII:C level similar to the

pre-inhibitor baseline FVIII:C level and b) at least 2 consecutive Bethesda inhibitor

assays of < 0.6 BU/mL. Inhibitor disappearance was referred to as “spontaneous”

in the absence of eradication treatment. Sustained success was defined as lack of

anamnestic response ( i.e. a persistent negative inhibitor titre) upon rechallenge with

FVIII concentrate after disappearance of the inhibitor. Patients receiving prophylactic

treatment after inhibitor disappearance were not included when calculating the

number of patients with sustained success. Relapse of an inhibitor was defined as

the recurrence of the inhibitor upon rechallenge with FVIII concentrate after prior

inhibitor disappearance.

We classified all centres included in this study as a small or large hemophilia

treatment centre (HTC) using an arbitrarily chosen cut-off value of 30 patients; ‘small’

being HTC’s caring for ≤ 30 nonsevere HA patients that had ever been treated with

FVIII concentrates (n=7) and ‘large’ HTC’s caring for > 30 nonsevere HA patients ever

treated with FVIII concentrates (n=23).

Statistical analysis

Continuous variables were expressed as median values and interquartile ranges (IQR).

Categorical variables were expressed as frequencies and percentage values and

compared by Chi-square test or Fisher’s exact test, as appropriate. The relative risks

and 95% confidence intervals were calculated using a 2x2 table to compare treatment

and outcome between groups. All relative risks were reported as relative probability

as the occurred events that were analyzed (in an exposed group compared to a

non-exposed group) were ‘receiving eradication treatment’ or ‘attaining sustained

success’. All analyses were performed with SPSS software (IBM Corp. Released 2010.

IBM SPSS Statistics for Windows, Version 20.0. Armonk, NY: IBM Corp).

197

CHAPTER 8

Results

Patient characteristics

We identifi ed 107 nonsevere HA patients with an inhibitor within the total cohort of

2,709 consecutively treated patients that were exposed to clotting factor concentrates

between 1980 and 2011. Data on inhibitor eradication treatment and outcome were

available in 101 patients (Figure 1). The baseline characteristics of the 101 patients

are shown in table 1 and table 2. A high titre inhibitor was present in 56 patients,

45 patients had a low titre inhibitor. The endogenous FVIII:C level was decreased

at inhibitor detection in 58 patients (57%) with a median FVIII:C level at fi rst positive

inhibitor test of 1.4 IU/dL (interquartile range (IQR) 1.0 – 3.2). In 29 patients (29%) the

FVIII:C level was decreased ≤ 1 IU/dL.

Figure 1 Disposition fi gure of 101 nonsevere inhibitor patients

198


Table 1 Characteristics of 101 nonsevere inhibitor patients.

Low titre inhibitor pts(n=45)

High titre inhibitor pts(n=56)

Demographics: median (IQR) or n (%) median (IQR) or n (%)

Endogenous F VIII:C, IU/dL, before inhibitor development

9 (6 – 15) 9 (5 – 17)

Caucasian ethnicity 42 (93) 51 (91)

Cumulative ED to FVIII concentrates*, days 28 (17 – 65) 28 (12 – 72)

Cumulative ED to FVIII concentrates in 3months prior to inhibitor development, days

8 (2 – 14) 9 (4 – 15)

Age at inhibitor development, years 32 (11 – 55) 44 (19 – 64)

Clinical presentation:

Increased bleeding tendency at presentation†, no. patients

25 (56) 38 (68)

Treatment for bleeding episodes, no. patients

28 (62) 38 (68)

Endogenous FVIII:C level decreased†, no. patients

27 (69) 31 (72)

FVIII:C level at first inhibitor titre‡, IU/dL 2.6 (1.0 – 4.0) 1.0 (1.0 – 2.5)

Inhibitor titers:

First positive titre, BU/mL 1.1 (0.8 – 2.1) 6.0 (1.9 – 16)

Historical peak titre, BU/mL 1.8 (1.0 – 3.1) 20.0 (9.1 – 63.3)

* until inhibitor development† data not available for all patients, percentages are proportion of the total number of patients of whom data was available‡ in patients with decreased endogenous FVIII level

199

CHAPTER 8

Tab

le 2

Pat

ient

cha

ract

eris

tics

acco

rdin

g to

trea

tmen

t gro

ups.

No

era

dic

atio

n tr

eat-

men

t(n

=7

3)

ITI

(n=

16

)IT

I & im

mun

o-

sup

pre

ssiv

e m

edic

atio

n (n

=7

)

Imm

uno

sup

pre

ssiv

e m

edic

atio

n(n

=5

)

n (%

) or

med

ian

(IQ

R)

n (%

) or

med

ian

(IQ

R)

n (%

) or

med

ian

(IQ

R)

n (%

) or

med

ian

(IQ

R)

End

og

eno

us F

VIII

:C le

vel,

IU/d

L9

(6 –

16)

10(5

– 1

5)

7(4

– 1

1)12

(6 –

25)

Cau

casi

an e

thni

city

69(9

5)12

(75)

7(1

00)

5(1

00)

Ag

e at

inhi

bito

r d

evel

op

men

t,ye

ars

42(1

9 –

62)

13(7

– 3

3)

36(6

– 6

5)69

(50

– 79

)

Hig

h tit

re in

hib

itor

39(5

4)8

(50)

5(7

1)4

(80)

Dec

reas

ed e

ndo

gen

ous

FVIII

:C le

vel

40(6

6)*

9(8

2)†

4(8

0)‡

5(1

00)

Trea

ted

in la

rge

HTC

’s66

(90)

9(5

6)6

(86)

5(1

00)

Use

of b

ypas

sing

ag

ents

64(9

0)§

11(7

3) ¶

7(1

00)

5(1

00)

* va

riab

le a

vaila

ble

in 6

1 p

atie

nts

† va

riab

le a

vaila

ble

in 1

1 p

atie

nts

‡ va

riab

le a

vaila

ble

in 5

pat

ient

s§

vari

able

ava

ilab

le in

72

pat

ient

s¶

va

riab

le a

vaila

ble

in 1

5 p

atie

nts

200


Inhibitor eradication treatment

Eradication treatment was administered in total in 28 patients (28%) during follow-up.

The eradication treatment consisted of immune tolerance induction (ITI) exclusively in

16 patients, five patients were treated with immunosuppressive medication exclusively

and the other seven patients received a combination of ITI and immunosuppressive

medication. The characteristics of the treatment for these 28 patients are specified

in table 3. In the 23 patients receiving ITI (either exclusively or concomitant with

immunosuppressive medication), 10 patients were treated with recombinant FVIII

concentrates, 11 patients with plasma derived FVIII concentrates and in 2 patients the

type of FVIII concentrate was unknown. The following immunosuppressive drugs were

used: prednisone (n=8), cyclophosphamide (n=7) and rituximab (n=4).

For the patients that received inhibitor eradication treatment, the median time between

first positive inhibitor test and inhibitor disappearance was 9 months (IQR 3 – 16) and

for the patients that did not receive eradication treatment 15 months (IQR 7 – 38)

(p=0.087). Following the first positive inhibitor test, eradication treatment was initiated

after a median number of 27 days (IQR 4 – 97). During this period, between inhibitor

detection and start of treatment, 9 patients received treatment with FVIII concentrates

for bleeding episodes, 13 received bypassing agents and 4 did not receive any

treatment (in 4 patients information was not available). The median time between start

of eradication therapy and inhibitor disappearance was 7 months (IQR 3 – 15) and the

median time of follow-up after inhibitor disappearance was 91 months (IQR 48 – 161).

Patients in whom the inhibitor reduced the endogenous FVIII:C level to ≤ 1 IU/dL,

were treated more often with eradication therapy than the others (43% vs. 17%,

unadjusted relative probability, 2.6; CI, 1.3 – 5.3). In small HTC’s eradication treatment

was more frequently prescribed than in larger HTC’s (53% vs. 22%, unadjusted relative

probability, 2.3; CI, 1.2 – 4.2).

Age at inhibitor development was lower in patients that were treated with ITI

exclusively (median age 13 years, IQR 7 – 33) than in the patients that did not receive

any eradication treatment (median age 42 years, IQR 19 – 62). Treatment with

exclusively immunosuppressive medication was given to older patients (median age

69 years, IQR 50 – 79) in comparison to patients receiving other eradication treatment.

Eradication treatment was not administered before 1990 to the four patients that

developed an inhibitor between 1980-1989. Between 1990-1999 34 patients

developed an inhibitor and 10 (29%) of them received eradication treatment. Six

201

CHAPTER 8

of these patients were rechallenged after inhibitor disappearance and 5 (83%)

attained sustained success. In the last decade, 2000-2011, 18 of the 66 patients (27%)

with inhibitor development received eradication treatment. Also 6 patients were

rechallenged and 5 attained sustained success.

202


Tab

le 3

Tre

atm

ent c

hara

cter

istic

s er

adic

atio

n st

rate

gie

sPt

Age*

Peaktitre

FVIII:C level†IT

I reg

imen

Imm

uno

sup

pre

ssiv

e re

gim

en

Disappearanceinhibitor

Re-challenge

Prophylaxis

Final outcome

years

BU/mL

IU/dL

Pro

duc

tD

ose

‡R

egim

en‡

Dur

atio

n(m

ont

hs)

Typ

e p

rod

uct

Do

seR

egim

enD

urat

ion

Y/N

Y/N

Y/N

Sustainedsuccess/Relapse

152

390

1re

cFV

III50

IU/k

g3

d/w

k6

Ritu

xim

ab37

5 m

g/m

24

do

ses

4 w

ksN

NA

NA

NA

22

134

<1

recF

VIII

250-

500

IU/k

g3

d/w

k18

–

––

–Y

YN

S

325

130

1p

dFV

III30

00 IU

3 d

/wk

UK

––

––

NN

AN

AN

A

468

942

––

––

Cyc

lop

hosp

ham

ide

NS

NS

NS

NN

AN

AN

A

568

611

pd

FVIII

25 IU

/kg

3 d

/wk

10

Cyc

lop

hosp

ham

ide

150-

200

mg

7 d

/wk

9 m

onth

sY

YN

S

674

553

––

––

Pred

niso

neIV

Ig80

-40

mg

NS

dai

lyN

S3

wks

2 d

ays

NN

NA

NA

764

321

pd

FVIII

5000

IU3

d/w

kU

KY

YN

S

815

29<

1re

cFV

III50

IU/k

g3

d/w

k30

–

––

–Y

YY

S

203

CHAPTER 8

933

184

UK

2500

IU3

d/w

kU

KIV

IgC

yclo

pho

spha

mid

ePr

edni

solo

ne

60 g

1,5

g70

mg

§

dai

ly1

d/w

kd

aily

3 d

ays

6 w

ksU

KY

NU

KN

A

108

151

recF

VIII

250

IU/k

g7

d/w

k6

––

––

YY

NS

1184

131

––

––

Pred

niso

neN

SN

SN

SN

NN

AN

A

1245

10U

Kp

dFV

III60

00 IU

7 d

/wk

15

Ritu

xim

abIV

Ig T

acro

limus

UK

80 g

2 m

g

1 d

/wk

1 d

ayd

aily

2 w

ks1

day

5 m

ont

hsN

NN

AN

A

1337

101

––

––

NS

NS

NS

NS

YN

NN

A

1446

91

pd

FVIII

200

IU/k

g7

d/w

k3

––

––

YY

NS

157

9U

Kp

dFV

III25

0 IU

/kg

7 d

/wk

3 –

––

–Y

YU

KS

1618

8U

Kp

dFV

III10

0 IU

/kg

7 d

/wk

2,5

––

––

YY

NS

1719

69

pd

FVIII

100

IU/k

g7

d/w

k9¶

––

––

NN

AN

NA

1811

5U

KU

KU

KU

KU

K–

––

–Y

YU

KS

1952

45

pd

FVIII

1500

IU7

d/w

k5

––

––

YY

NR

2046

43

pd

FVIII

100

IU/k

g7

d/w

k8

––

––

YY

YS

2111

32

pd

FVIII

4000

IU7

d/w

k18

––

––

YY

NS

2235

3U

Kre

cFV

III25

IU/k

g7

d/w

k2

––

––

YY

NR

204


2361

34

--

--

Pred

niso

neC

yclo

pho

spha

mid

eN

SN

SN

SY

NN

NA

248

2U

Kre

cFV

III40

IU/k

g7

d/w

k6

––

––

YY

NS

255

21

recF

VIII

100

IU/k

g7

d/w

k3

Pred

niso

lone

Ritu

xim

ab1

mg

/kg

375

mg

/m2

2 d

/wk

1 d

/wk

4 w

ks4

wks

YY

YS

267

0.8

<1

recF

VIII

100

IU/k

g7

d/w

k11

**–

––

–Y

NN

NA

274

0.7

1re

cFV

III10

0 IU

/kg

7 d

/wk

9Pr

edni

sone

Cyc

lop

hosp

ham

ide

Ritu

xim

ab

50 m

gN

S24

5 m

g

1 d

/wk

1 d

/wk

1 d

/wk

4 w

ks4

wks

4 w

ksY

YY

S

281

0.6

5re

cFV

III15

00 IU

7 d

/wk

12–

––

–Y

YY

S

recF

VIII

= re

com

bin

ant F

VIII

co

ncen

trat

e, p

dFV

III=

pla

sma

der

ived

FV

III c

onc

entr

ate,

IU=

inte

rnat

iona

l uni

ts,

IU/k

g=

inte

rnat

iona

l uni

ts p

er k

g b

od

ywei

ght

, d/w

k= d

ays

per

wee

k, IV

Ig=

Intr

aven

ous

imm

uno

glo

bul

in,

NS=

no

t sp

ecifi

ed, U

K=

unk

now

n, N

A=

no

t ap

plic

able

, Y=

yes

, N=

no

, S=

sus

tain

ed s

ucce

ss, R

=re

lap

se

* ag

e at

inhi

bito

r d

evel

op

men

t †

end

og

eno

us F

VIII

:C le

vel d

urin

g in

hib

itor

per

iod

‡ d

ose

and

reg

imen

at t

he s

tart

of I

TI; d

ose

: if b

od

ywei

ght

was

unk

now

n d

ose

is to

tal I

U§

was

tap

ered

do

wn

by

dec

reas

ing

do

se e

very

2 w

eeks

, to

10

mg

, and

then

sto

pp

ed¶

at

tim

e o

f inc

lusi

on

ITI d

urat

ion

was

9 m

ont

hs b

ut IT

I was

stil

l ong

oin

g**

at

tim

e o

f inc

lusi

on

ITI d

urat

ion

was

11

mo

nths

but

ITI w

as s

till o

ngo

ing

205

CHAPTER 8

Outcome of inhibitor eradication treatment

The outcome of eradication management is presented in table 4a and 4b. The majority

of the patients receiving eradication treatment (83%; 10/12) attained sustained

success after inhibitor eradication, as they remained inhibitor free after rechallenge

with FVIII concentrate. Of the patients that did not receive any eradication treatment,

sustained success was observed in 21 patients (60%; 21/35).

The number of patients needing treatment for bleeding episodes during the inhibitor

episode was similar between the group that received eradication treatment and the

group that did not receive eradication treatment (85% vs. 90%, unadjusted RR, 0.88;

CI, 0.53 – 1.28).

Treatment with bypassing agents (FEIBA or recombinant FVIIa) after the first negative

inhibitor test occurred in 9 of the 72 patients with inhibitor disappearance.

206


Table 4a Eradication management total group

Totaln

Disappearancen (%)

Rechallengedn

Relapsen

Sustainedsuccess

n

No eradication 73 51 (71) 35 14 21

Eradication 28 21 (75) 12 2 10

ITI 16 14 (88)

Immunosuppressives 5 2 (40)

Both 7 5 (71)

Total group 101 72 (72) 47 16 31

207

CHAPTER 8

Tab

le 4

b E

rad

icat

ion

man

agem

ent H

T an

d L

T g

roup

Low

titr

e p

atie

nts

Hig

h ti

tre

pat

ient

s

To

tal

n)D

isap

pea

ranc

en

(%R

echa

lleng

edn

Rel

apse

n

Sust

aine

dsu

cces

sn

Tota

ln

Dis

-ap

pea

ranc

en

(%)

Rech

alle

nged

nR

elap

sen

Sust

aine

d

succ

ess

n

No

era

dic

atio

n34

27(7

9)21

615

3924

(63)

148

6

Erad

icat

ion

1111

(100

)5

23

1710

(59)

70

7

ITI

88

(100

)8

6(7

5)

Imm

uno

sup

pre

ssiv

es1

1(1

00)

41

(25)

Bo

th2

2(1

00)

53

(60)

Tota

l gro

up45

38(8

4)26

818

5634

(63)

218

13

Low

titr

e =

inhi

bito

r p

atie

nts

with

pea

k tit

re ≤

5 B

UH

igh

titre

= in

hib

itor

pat

ient

s w

ith p

eak

titre

> 5

BU

Sust

aine

d s

ucce

ss: n

umb

er o

f pat

ient

s w

ho m

aint

aine

d n

egat

ive

inhi

bito

r tit

re a

fter

trea

tmen

t with

FV

III c

onc

entr

ate

afte

r su

cces

sful

cle

aran

ce o

f inh

ibito

r

(rec

halle

nge)

208


Titre and outcome

The inhibitor disappeared in 72 of the 101 patients. After inhibitor disappearance 47

patients (47/72, 65%) were rechallenged with FVIII concentrate and 25 patients have

no documented rechallenge (25/72, 35%). In the patients with a low titre inhibitor,

inhibitor disappearance was more frequent than in patients with a high titre inhibitor

(84% vs. 62%, unadjusted RR, 1.4; CI, 1.1 – 1.7). However, there was no clear difference

in sustained success between these groups (69% vs. 62%, unadjusted relative

probability, 1.1; CI, 0.7 – 1.7). Rechallenge with FVIII concentrates was reported in 26

(26/38, 68%) of the low titre patients with inhibitor disappearance, compared with 21

(21/34, 62%) of the high titre patients with inhibitor disappearance.

In the group of patients with low titre inhibitors that received eradication treatment,

sustained success was attained in three (60%; 3/5) patients. In the low titre patients that

did not receive eradication treatment, fifteen (71%; 15/21) demonstrated sustained

success. Sustained success was not associated with eradication treatment in low titre

patients (unadjusted relative probability, 0.8; CI, 0.4 – 1.8).

In the high titre patients sustained success was attained in all seven patients (100%)

that were rechallenged after eradication treatment, compared to six (43%; 6/14)

patients without eradication that were rechallenged (unadjusted relative probability,

2.3; CI, 1.3 – 4.3). Thus, there seems to be a benefit of eradication treatment on

sustained success.

The outcome of eradication therapy did not differ in the subgroup of patients with a

decrease of their endogenous FVIII:C level to below 1 IU/dL in comparison to patients

that did not have a decrease of the FVIII:C level below 1 IU/dL. Also, there was no

correlation between baseline FVIII:C level before inhibitor development and success

of ITI.

209

CHAPTER 8

Discussion

This unique and unselected large cohort of 101 nonsevere hemophilia A patients

with inhibiting antibodies provides an insight into inhibitor management strategies

in Europe and Australia.

In 51 of the patients (51/73, 70%) the inhibitor disappeared spontaneously without

any eradication treatment. This may indicate that not all nonsevere inhibitor patients

need eradication treatment. In the majority of the remaining 28 patients that did

receive eradication treatment the inhibitor also disappeared (n=21, 75%), in these

patients the treatment strategy varied widely. Both high titre and low titre inhibitor

patients seemed to benefit from eradication treatment.

For the patients in whom the inhibitor disappears, with or without eradication

treatment, it is important to realize that an anamnestic response still may occur when

the patient is rechallenged. As inhibiting antibodies can become quiescent in the

absence of further challenges with FVIII concentrate, true tolerance is only present

when no anamnestic response occurs after rechallenge with FVIII concentrate.

Therefore, we have introduced this concept as the definition for “sustained success”.

In the absence of rechallenge, sustained success cannot be evaluated. In this case,

disappearance of the inhibitor might be due to an extinguished immune response

in absence of the antigen and thus outcome of eradication treatment cannot be

evaluated. In our cohort, sustained success was attained in 100% (7/7) of the high

titre and in 60% (3/5) of the low titre patients receiving eradication treatment. Due to

the very small numbers in these groups, we have to interpret the findings with care.

However, it is worth noting that eradication treatment failed in 2 low titre patients. Yet,

the dose of FVIII for ITI in those two patients was relatively low. Other patients treated

with similar dosages received immunosuppressive medication concurrently.

Significant time intervals between exposure to FVIII concentrate and inhibitor

screening might lead to oversight of inhibitor relapse after minor exposure. Inhibitor

testing does not always occur shortly after a patient is rechallenged with FVIII

concentrate, especially when there are no clinical signs of inhibitor development.

When the time interval between rechallenge and inhibitor testing is too long, a low

titre relapsing inhibitor might be missed. This may be dangerous when a patient

subsequently receives a high dose of FVIII concentrate, e.g. for a surgical procedure

and demonstrates an anamnestic response with a fast and strong increase in the

210


inhibitor titre, accompanied by a fall in endogenous FVIII levels. The decision to

rechallenge a patient with FVIII concentrate after spontaneous disappearance

of an inhibitor must therefore be taken with care and may prevent clinicians from

rechallenging an inhibitor patient with FVIII concentrate. This may partly explain why

25 of the 72 patients in whom the inhibitor disappeared in our study were never

rechallenged with FVIII concentrate. This potentially reflects compromises in the

medical management of these patients.

Patients that were rechallenged with FVIII concentrate may consist of a subgroup with

more favourable prognostic factors. In the analysis this may invoke bias, overestimating

the occurrence of sustained success. The risk of relapse may depend on the reason

for rechallenge, e.g. minor spontaneous bleeding versus major surgery. This implies

that a patient that has been rechallenged for a minor bleed cannot necessarily be

treated safely with FVIII concentrates for several days for a major surgery. To properly

assess the risk of relapse, future studies should also take into account the frequency

of and time to rechallenge.

The median time between first positive inhibitor test and inhibitor disappearance

seems nearly twice as long in the patients without eradication treatment (18 months)

compared to the patients with eradication treatment (10 months). Presumably, the

timing of inhibitor testing will have been ad hoc in patients without eradication

treatment and patients with eradication treatment had more structured inhibitor

screening. Therefore, a valid comparison between these two groups for time to

inhibitor disappearance is not possible.

A recent study of Kempton and colleagues reported a better effect of treatment with

rituximab on inhibitor eradication in 32 mild and moderate HA patients than ITI.21

We could neither confirm nor refute this observation in our study as only four patients

were treated with rituximab, and all of them received it in combination with immune

tolerance induction.

Besides the treatment regimen and clinical determinants, it is important to obtain

more knowledge on the genetic determinants of the outcome of inhibitor eradication

in nonsevere patients. Unfortunately, we were not able to analyse the effect of F8

genotype in our study since there were only 4 mutations that occurred in three or

more subjects (i.e. Arg593Cys, Tyr2105Cys, Arg2150His and Trp2229Cys).

Only patients with a clinically relevant inhibitor were classified to be positive for

an inhibitor in our analysis (see ‘’Patients and methods’’). Patients who were not

211

CHAPTER 8

tested for inhibitors during the follow-up period and who had no clinical features of

inhibitor development (e.g. increased bleeding tendency) were classified as negative

for inhibitors. This may have underestimated inhibitor occurrence resulting in a

conservative assessment of inhibitor outcome, as the mildest cases, with expectedly

the highest success rates, may have not entered the study. Although the inhibitor

disappearance rate was similar in patients treated or observed (75% versus 71%) this

does not mean that these strategies are equally effective, since patients were not

randomized. It is likely that inhibitor eradication was administered to more severe

patients, and therefore the effect of this strategy may be underestimated in our study.

In this context “severe” patients are those with an increased bleeding tendency and/

or a decrease in endogenous FVIII:C level below 1 IU/dL and/or a high titre inhibitor.

The number of patients needing treatment for bleeding episodes during the inhibitor

episode was similar between patients that did and did not receive eradication

treatment. This could be due to the fact that more severe patients received eradication

treatment and less severe patients did not receive eradication treatment. Possibly the

patients receiving eradication treatment would have experienced more bleeding

complications if this treatment had been withheld from them.

Also, the heterogeneity of the patients in characteristics and in management, due to

national differences and the large time span of the study, limit the conclusions that

can be drawn regarding the effectiveness of eradication treatment.

For future studies addressing the determinants of successful inhibitor eradication in

nonsevere HA it is important that uniform definitions of true tolerance are used that

take the effect of rechallenge with FVIII concentrates into account.

This observational study was designed to describe the therapeutic approaches that

have been used to eradicate inhibitors in nonsevere HA patients. Due to the nature

of this study, we cannot formulate any general recommendations for treatment

of nonsevere HA inhibitor patients yet. This study shows that some patients may

benefit from eradication treatment; however one single approach is unlikely to be

appropriate for all patients. Consequently, clinicians will need to continue to make

these decisions on a case-by-case basis. Often the severe bleeding complications and

related morbidity of the inhibitor seems to be the most important reason for clinicians

to start eradication treatment.

Further research is needed to determine factors that can predict which nonsevere

212


HA patients require treatment to eradicate their inhibitor. Recommendations should

be based on patient and inhibitor characteristics, and may be different from the

recommendations in severe HA patients.22 Specifically for patients with nonsevere

hemophilia there may be a role for DDAVP in preventing inhibitor development and/

or relapse.17 Since a fair proportion of the nonsevere HA patients can be effectively

treated with DDAVP for bleeding episodes and minor surgery, this seems a feasible

and safe objective for patients without cross-reacting inhibitors.

This study is an advance over registry-type and single institution studies and provides

a solid summary of the overall outcome of both low and high titre inhibitors in

nonsevere HA patients. With the stringent definitions that were employed, this study

may provide input for prospective studies that aim to identify predictors for successful

inhibitor eradication. However, given that this data required collection over 31 years,

this highlights the challenges in executing such studies in this rare patient group.

213

CHAPTER 8

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215

CHAPTER 8

Acknowledgements

This study was supported in part by a grant from The Netherlands Organization for Health Research and

Development (ZonMw Grant no 40-00703-98-8570) to C.L.E and K.F., and an unrestricted research grant from

CSL Behring to M.P. and K.F. The sponsors had no role in the choice of members of the steering committee

and the participating centers nor the design and conduct of the study; collection, management, analysis, and

interpretation of the data; and preparation, review and approval of the manuscript.

The authors would like to thank N. Streefkerk, A. van Eĳkelenburg, B. van Tienoven and C. Kruĳt for their help

with the data collection.

Author contributions

A.S. van Velzen and K. Fĳnvandraat have full access to all of the data in the study and take responsibility for the

integrity of the data and the accuracy of the data analysis;

A.S. van Velzen helped to design the study, collected, interpreted and analysed the data, and wrote the

manuscript;

C.L. Eckhardt helped to design the study, collected and interpreted the data andreviewed, edited and

approved the final version of the manuscript;

D.P. Hart designed the study, supervised the interpretation of the data, and reviewed and approved the final

version of the manuscript;

J.G. van der Bom designed the study, supervised the interpretation and statistical analysis of the data, and

reviewed and approved the final version of the manuscript;

T.T. Yee designed the study, supervised the interpretation of the data, and reviewed and approved the final

version of the manuscript;

K. Fĳnvandraat designed and supervised the study, wrote the protocol, and wrote and edited the manuscript;

the other authors collected the data or supervised data collection, and reviewed and approved the final

version of the manuscript.

216


Conflict-of-interest disclosure:

A.S.v.V. has given lectures at educational symposiums sponsored by Baxter, Novo Nordisk and Pfizer. C.L.E.

has received an unrestricted grant from The Netherlands Organization for Health Research and Development

(ZonMW) and has given lectures at educational symposiums organized by Novo Nordisk and Baxter.

D.P.H. has received a Bayer Early Career Investigator Award, and has received payment for lectures from Baxter,

Bayer, Pfizer and Octapharma. He has received consultancy honoraria from Novonordisk. C.R.M.H. is board

member of the Baxter recombinant IX Data Safety monitoring Board, has received payment for consultancy

meetings with Baxter, Pfizer, Inspiration and Novo Nordisk, has received unrestricted grants supporting

research from Baxter, Pfizer, Bayer and CSL Behring, has received payment for lectures from Baxter, Bayer,

Pfizer, Novo Nordisk, CSL Behring, Grifols, and LFB, and received payment to travel to scientific meetings.

R.L. has received payment for consultancy meetings with Baxter and Bayer, has received payment for lectures

from Pfizer and Bayer, and has received payment for development of educational presentations by Pfizer and

Bayer. P.P. is a board member of the Medical Advisory Board Pfizer, has received payment for lectures from

Bayer, Baxter and Pfizer, and has received travel expenses for hemophilia meetings. V. J-Y. is a member of

the European Hemophilia Treatment and Standardisation Board sponsored by Baxter, had received payment

for consultancy meetings with Pfizer, Grifols, Novo Nordisk and Bayer, has received grants from Octapharma

and Novo Nordisk, and has received payment for lectures from Baxter, Novo Nordisk, Pfizer, Grifols and

Octapharma. J.A. has received honorarium for advisory boards and lectures from Pfizer, CSL Behring, SOBI,

Novo Nordisk, Baxter and Bayer, and has received grants from Baxter, Grifols and Bayer. G.C. has received

payment for lectures from Baxter, Pfizer, CSL Behring, Novo Nordisk and Kedrion. S.H. is board member of the

European Coagulation Disorders Advisory Council of CSL Behring, has received payment for lectures from

Baxter, Pfizer, Novo Nordisk, CSL Behring and Grifols, and received payment to travel to scientific meetings.

C.H. has received grants/ research support from Baxter, Bayer, CSL Behring, Novo Nordisk and Pfizer, and

received honoraria/consultation fees from Baxter, Bayer, CSL Behring, LFB, Novo Nordisk, Octapharma, Pfizer

and Sobi. M.H. has participated in an advisory board from Bayer, and has received payment to institution for

lectures from Baxter, CSL and NovoNordisk. R.K. has participated in advisory boards for Baxter, Bayer, CSL

Behring, Pfizer and Novo Nordisk, and has received payment for lectures from Bayer, Baxter, CSL Behring,

Novo Nordisk, SOBI and Pfizer. F.W.G.L has received unrestricted research grants of CSL Behring and Baxter

and has participated in the past in scientific advisory boards for CSL Behring and Baxter. C.M. has received

an unrestricted grant from CSL Behring, has received payment for lectures from CSL Behring, Wyeth, Bayer,

Baxter, Biotest, and Novo Nordisk, and has received travel expenses paid by CSL Behring, Wyeth/Pfizer,

Bayer, Baxter, Biotest, and Novo Nordisk. E.P.M.B. received unrestricted educational/research support from

CSL Behring, Bayer, Baxter, Novo Nordisk, Pfizer and Sanquin. M.G.M. has received payment for consultancy

meetings with Baxter, Novo Nordisk, Bayer, Pfizer, Amgen, Glaxo and Shire, and received payment for lectures

217

CHAPTER 8

from Baxter, Novo Nordisk, Bayer, Pfizer, Amgen, Glaxo and Shire. K.M. has received unrestricted research

grants from Bayer and Baxter, and has received payment for travel expenses by Wyeth, CSL Behring, Baxter

and Bayer, and participatedin an advisory board for CSL Behring. M.M. has participated in advisory boards for

Novo Nordisk, Pfizer and CSL Behring, has received payment for consultancy meetings with Bayer and Biotest,

and has received payment for lectures from Bayer and Novo Nordisk.

K.P. has participated in advisory boards for Pfizer, Baxter and Bayer, has received payment for lectures by Novo

Nordisk, has received travel grants from Baxter, Bayer and CSL Behring, and has an unrestricted chair to the

University for research in Haemophiliapaid by Pfizer, Baxter and CSL Behring. S.E.R-P. has received the Bayer

HaemophiliaClinical Training Award, has received payment for lectures from Bayer and Novo Nordisk, and has

received payment for travel expenses for participation in variouscongresses. P.S. is a board member of Bayer

International Advisory Board, hasreceived payment for consultancy meetings with Baxter, Novo Nordisk and

Pfizer and received payment for lectures from Bayer, Baxter and Amgen. J.G. vd B. hasreceived payment for

consultancy meetings with Bayer and Wyeth, has received grants from Bayer Schering Pharma, Baxter, CSL

Behring, Novo Nordisk and Wyeth and hasreceived payment for lectures from Bayer. K.F. is a member of the

European HemophiliaTreatment and Standardization Board sponsored by Baxter has received unrestricted

research grants from CSL Behring, Pfizer and Bayer and has given lectures ateducationalsymposiums

organized by Pfizer, Baxter and Bayer.

The remaining authors declare no competing financial interests.

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