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Prepublished online as a Blood First Edition Paper on July 12, 2002; DOI 10.1182/blood-2002-03-0765.
 Previous Article | Table of Contents | Next Article 
Blood, 1 November 2002, Vol. 100, No. 9, pp. 3426-3428
BRIEF REPORT
Rituximab in the treatment of acquired factor VIII inhibitors
Adrian Wiestner,
Hearn J. Cho,
Adam S. Asch,
Mary Ann Michelis,
Jack A. Zeller,
Ellinor I. B. Peerschke,
Babette B. Weksler, and
Geraldine P. Schechter
From the Hematology Branch, National Heart, Lung, and
Blood Institute, National Institutes of Health, Bethesda, MD; Weill
Medical College, Cornell University, New York, NY; Hackensack
University Medical Center, Hackensack, NJ; and Veterans Affairs Medical
Center and George Washington University, Washington, DC.
 |
Abstract |
Autoantibodies against factor VIII (FVIII) are rare but can cause
life-threatening bleeding requiring costly factor replacement and
prolonged immunosuppression. We report 4 consecutively treated patients
whose acquired FVIII inhibitors responded rapidly to immunosuppressive
regimens that included rituximab, a monoclonal antibody against
CD20+ B cells. Three patients had spontaneously
occurring inhibitors. The fourth, a patient with mild hemophilia A,
developed both an autoantibody and an alloantibody following
recombinant FVIII treatment. Pretreatment FVIII activities ranged
from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who
developed the inhibitor while receiving prednisone responded to single
agent rituximab. The hemophilia patient had rapid resolution of the
autoantibody, whereas the alloantibody persisted for months. Responses
continue off treatment from more than 7 to more than 12 months.
This report adds to the growing evidence that rituximab has efficacy in
immune disorders resulting from autoantibody formation.
(Blood. 2002;100:3426-3428)
© 2002 by The American Society of Hematology.
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Introduction |
Autoantibodies against factor VIII (FVIII) develop
in less than one individual per million per year and have a reported
mortality between 6% and 22%.1-3 Most cases are
idiopathic; up to 50% are associated with autoimmune diseases,
malignancies, drugs, or the postpartum period.1,4 Human or
porcine FVIII, prothrombin complex concentrates, or recombinant human
FVIIa may be required to control bleeding.2,5,6 To
suppress inhibitor formation most patients receive immunosuppressive
drugs,1,3,7 such as prednisone,8
cyclophosphamide,9-11 azathioprine, or
cyclosporine.12,13
The anti-CD20 monoclonal antibody rituximab rapidly eliminates most
circulating B cells, suggesting that it could be beneficial in
autoantibody-mediated diseases by targeting the autoreactive B
cells.14 Early reports of responses in immune
thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) appear to
confirm this notion,14-16 prompting consideration of its
use for FVIII inhibitors.
| |
Study design |
Four consecutive patients diagnosed with acquired FVIII
inhibitors at our institutions received either 4 (patients 1-3) or 2 (patient 4) weekly infusions of rituximab, 375 mg/m2.
Except for patient 3, each patient received a brief course of prednisone at 1 mg/kg/d that was rapidly tapered (Figure
1 and 2).
All patients gave informed consent. FVIII inhibitors were titered by
the Bethesda assay.17 The STACLOT LA test by
Diagnostica Stago (Asnieres-sur-Seine, France) was used to detect lupus
anticoagulants.
View larger version (16K):
[in this window]
[in a new window]
| Figure 1.
Response to treatment in 3 patients with acquired FVIII
inhibitors.
Upper half of the figure shows percentages of FVIII activity (FVIIIc).
Lower half shows inhibitor titer in Bethesda units. Rituximab 375 mg/m2 (open arrows) was started at week 0 and repeated
weekly for 4 doses. Prednisone at 1 mg/kg/d is indicated by a solid
line; broken line indicates prednisone taper. Solid arrow indicates
cyclophosphamide 1 g intravenously. In patient 3, azathioprine (A)
was stopped, and prednisone 30 mg every day was continued
unchanged as indicated by the broken line.
|
|
View larger version (10K):
[in this window]
[in a new window]
| Figure 2.
Response to treatment in a patient with mild hemophilia
A and an acquired FVIII inhibitor.
Upper half of the figure shows percentage of FVIII activity (FVIIIc).
Lower half shows inhibitor titer in Bethesda units. Rituximab 375 mg/m2 (open arrows) was given at week 0 and week 1. Prednisone at 1 mg/kg/d is indicated by a solid line; broken line
indicates prednisone taper.
|
|
Patient 1, a 69-year-old man with chronic renal failure, presented with
melena, bleeding from an arthrocentesis site, hemoglobin of 5.6 g/dL,
partial thromboplastin time (PTT) of 94 sec, FVIII activity
(FVIIIc) of 4%, and inhibitor titer of 5 Bethesda units (BU). He
required 7 units of red cells. Bleeding resolved following treatment
with recombinant human FVIII (100 U/kg loading, 10 U/kg/h maintenance),
desmopressin acetate (DDAVP), and conjugated estrogen. Prednisone was started on day 1 and rituximab on day 3. Pretreatment serum electrophoresis revealed a very small monoclonal immunoglobulin G
(IgG)  paraprotein. Total  -globulin level was 0.92 g/dL (normal range, 0.6-1.6 g/dL).
Patient 2, a 38-year-old man with ascites and lymphadenopathy of
unknown etiology, PTT of 67 sec, FVIIIc less than 1%, inhibitor titer
of 23 BU, and a lupus anticoagulant, developed a large hematoma at a
venepuncture site and a 2 g/dL fall in hemoglobin. One week after treatment with FVIII inhibitor bypassing activity (FEIBA) 50 IU/kg four times a day, 1 g cyclophosphamide intravenously, and
prednisone, FVIIIc was 3%, and treatment with rituximab was initiated
because of lack of clinical improvement. FEIBA was safely discontinued
1 wk after rituximab was initiated.
Patient 3, a 79-year-old woman on prednisone and azathioprine for
polymyalgia, developed spontaneous giant ecchymoses; the largest was
20 × 25 cm. Investigations revealed a PTT of 58 sec, FVIIIc of 2%,
inhibitor titer of 8 BU, and a lupus anticoagulant. Azathioprine was
discontinued, prednisone maintained, and weekly rituximab initiated.
Within 1 week, the ecchymoses resolved.
Patient 4, a 39-year-old man with mild hemophilia A and FVIIIc level of
15% because of an Arg2150His mutation received recombinant human FVIII perioperatively. Six days after the operation, on a regimen
of FEIBA and DDAVP, an inhibitor of 60 BU was detected, but FVIIIc was
unchanged at 15%. Two weeks later FVIIIc fell to 2% with only a
minimal increase following DDAVP prompting treatment with rituximab and prednisone.
| |
Results and discussion |
Our patients who presented with bleeding had rapid clinical
improvement following initiation of immunosuppressive treatment that
included rituximab. This improvement was most striking in patient 3 whose giant ecchymoses resolved rapidly following the first dose of
rituximab, her sole treatment. In patients 1 to 3, FVIIIc normalized,
and the inhibitor became undetectable between 3 and 12 weeks from the
start of rituximab (Figure 1). Patient 1 had a normal FVIIIc within 2 weeks and resolution of the inhibitor at 3 weeks. The antigenic
stimulation by the FVIII infusions patient 1 received may have had a
role in his rapid response.10 In patient 4 (Figure 2),
endogenous FVIIIc returned to baseline within 1 week, indicating
resolution of the autoantibody, whereas antibody directed against
wild-type FVIII persisted for more than 2 months. All patients remain
in remission from more than 7 to more than 12 months off treatment.
Spontaneous resolution of FVIII inhibitors occurs in up to 30% of
patients, most frequently when the inhibitors develop in the postpartum
period.18 Because the median time to spontaneous resolution is 21 months, most patients are treated with
immunosuppressive drugs to induce more rapid
resolution.1,3,7 Single-agent prednisone has a reported
response rate of 30%8,9 and could have accounted for the
responses seen in 3 of our patients. However, patients who respond to
prednisone frequently require long-term maintenance therapy to prevent
relapse.8 In contrast, we were able to taper prednisone
rapidly without relapse in our patients.
The combination of prednisone with cyclophosphamide is effective in
70% to 100% of patients, and inhibitors resolve within 3 to 37 weeks.10,11 The time to response in our patients treated with rituximab appears shorter, and potential complications associated with combination prednisone and cyclophosphamide therapy such as
neutropenic fever, herpes zoster, myelodysplasia, and
cataracts10,11 were avoided.
Inhibitor titers in our patients were of intermediate strength and
comparable to those reported in many studies.3,10 Although patients with low-level inhibitors respond more easily to
immunosuppressive treatment, inhibitor titer is not directly related to
bleeding complications, and even patients with low titer inhibitors can have fatal bleeding.
The addition of short courses of prednisone to rituximab may have
enhanced the response in our patients. A preliminary report found only
partial remissions in 3 patients with FVIII inhibitors treated with
rituximab alone and a complete remission in a patient who also received
prednisone.19 However, the complete response of our
patient 3 indicates that single-agent rituximab can suffice. Two of our
patients (patients 1 and 2) may have had an underlying lymphoproliferative disorder, possibly accounting for a better response.
Rituximab was well tolerated in our study. -Globulin levels
decreased by 16% at 3 months in patient 1 and returned to pretreatment levels by 7 months. In the context of recent reports on viral infections following rituximab,20-22 it is noteworthy that
we observed no worsening of pre-existing hepatitis C in patient 4, who
was on a course of ribavirin and interferon when rituximab was started.
FVIII inhibitors have been reported in several kindreds with mild
hemophilia because of missense mutations, usually arising after factor
replacement and causing a bleeding pattern similar to acquired
hemophilia.23 Patient 4's course was similar to these
previously reported experiences (Figure 2). Consistent with an
alloresponse, the high titer inhibitor initially spares the endogenous
FVIII, but a subsequent drop in the FVIII level indicates the formation
of autoantibodies. In our patient, prednisone and rituximab led to a
rise in FVIIIc back to his baseline level within a week. However,
measurable antibody against wild-type FVIII persisted for
more than 2 months, suggesting that rituximab eliminated autoreactive B
cells more effectively than alloreactive B cells.
Rituximab has been used with varying success in other
autoantibody-mediated disorders. Reported response rates range from 30% in ITP15 to 100% in childhood AIHA.16
Different response rates may be due to differences in pathogenesis or
expression levels of CD20 on the antibody-producing B-cell
population.14 During maturation of B cells to plasma
cells, CD20 expression is down-regulated. Therefore, timing may be
critical for response because rituximab may not be effective if a
CD20 plasma cell population has become established. The
patients with ITP received rituximab a median of 15 months from
diagnosis,15 whereas patients in our study were treated
within weeks of diagnosis. Early reports also suggest that rituximab
may have efficacy in rheumatoid arthritis24 and Wegener
granulomatosis.25 Our patient's polymyalgia unfortunately
did not improve following treatment with rituximab. However, the lupus
anticoagulants in patients 2 and 3 and the monoclonal gammopathy in
patient 1 resolved after treatment.
We conclude that rituximab appears to be an effective and safe
treatment for patients with FVIII inhibitors and merits further study.
Early treatment and combination with prednisone may be required for
maximal benefit.
| |
Footnotes |
Submitted March 11, 2002; accepted June 17, 2002.
Prepublished online
as Blood First Edition Paper, July 12, 2002; DOI
10.1182/blood-2002-03-0765.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
Reprints: Geraldine P. Schechter, Hematology Section, Room
4D113, Veterans Affairs Medical Center, 50 Irving St NW, Washington, DC
20422; e-mail: g.p.schechter{at}med.va.gov.
| |
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Top
Abstract
Introduction