Rituximab in the Treatment of Postpartum Acquired Hemophilia A

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					                 JOURNAL OF COAGULATION DISORDERS                                                          REVIEW ARTICLE



Rituximab in the Treatment of Postpartum Acquired
Hemophilia A
Maria Gabriella Mazzucconi, Francesca Biondo and Cristina Santoro
Affiliation: Haematology Institute, Dipartimento di Biotecnologie cellulari ed Ematologia, ‘‘Sapienza’’ University of Rome,
Rome, Italy

Submission date: 10th July 2009, Revision date: 2nd September 2009, Acceptance date: 14th September 2009




                                                        A B S T R A C T

   Acquired hemophilia A is a rare disorder caused by the development of autoantibodies against coagulation factor VIII:
it is often characterized by severe bleeding tendency. Its incidence is 0.2–1 per million persons per year. It may be
associated with malignancies, autoimmune disorders, or pregnancy but, in about 50% of cases, no cause can be
identified. Postpartum acquired hemophilia A represents 7–21% of all cases, with an incidence of about 1/350 000
deliveries. The aim of the management of acquired hemophilia A and, in particular of postpartum acquired hemophilia
A, is the control of bleeding, if present, and the eradication of the inhibitor. The latter can be obtained with
immunosuppressive drugs. However, cyclophosphamide and other alkylating agents should not be used in young women
with postpartum inhibitor because of the risk of infertility. Complete remission rate obtained with these agents is about 80%
or more but, in some cases, persistence of the inhibitor despite treatment or relapse after response represent an actual risk
of recurrent bleedings. Therefore, alternative therapeutic approaches are advisable. Rituximab has been used in
acquired hemophilia A since 2001 either as first-line therapy or in resistant/relapsed patients. Its efficacy is very high (about
90% eradication rate); it is safe and well tolerated, especially in young people. For these reasons, Rituximab can play a
role in the therapeutic approach to postpartum acquired hemophilia A. Few cases have been treated up to now, but the
results are very promising. Inhibitor eradication was obtained in all cases. No relevant side-effects were noted, nor did
infections occur. Cytotoxic immunosuppressive drugs can compromise fertility in young female patients, whereas
Rituximab can be a valid and safe alternative treatment.

  Keywords: acquired hemophilia A, inhibitor to factor VIII, immunosuppressive therapy, postpartum factor VIII inhibitor,
Rituximab

  Correspondence: Maria Gabriella Mazzucconi, Associate Professor, Dipartimento di Biotecnologie cellulari ed
Ematologia, ‘‘Sapienza’’ University of Rome, via Benevento n. 6, 00161, Roma, Italy. Tel: +39-06-857951-85795778; fax: +39-06-
44241984; e-mail: mazzucconi@bce.uniroma1.it



INTRODUCTION                                                           symptoms, in acquired hemophilia, the most common
                                                                       sites of bleeding are skin, mucosa, muscles, and
  Acquired hemophilia A is a rare disorder caused by
                                                                       retroperitoneum. The severity of bleeding is not
the development of autoantibodies directed against
                                                                       proportional to the inhibitor titer [5].
coagulation factor VIII (FVIII). Often, it is character-
ized by a severe bleeding tendency. An estimated                         In some cases (postpartum, drug-induced inhibitors),
incidence of 0.2–1 per million persons per year has                    the inhibitors tend to disappear spontaneously within
been reported. The incidence increases with age: 50–                   a few months after delivery or drug discontinuation
60% of the cases occur over the age of 50 years, and the               [4]. Treatment or cure of the underlying disease causes
incidence is higher in men (about 53%), but in the                     the disappearance of the inhibitor [6].
youngest patients, the incidence is higher in women,                     The aims of the therapeutic approach are the control
because of the relationship with pregnancy [1–3].                      of bleeding and the eradication of the inhibitor auto-
  This disorder may be associated with pregnancy,                      antibodies. With regard to the treatment of bleeding,
malignancies, and autoimmune disorders, but in a                       the main tools are bypassing agents (activated pro-
consistent proportion of cases, about 50%, no cause                    thrombin complex concentrates (APCC), recombinant
can be identified at diagnosis [1]. Risk of mortality                  activated FVII (rFVIIa), human and recombinant
varies from 8% to 22%, usually from fatal bleedings                    FVIII concentrates and desmopressin (DDAVP)).
[4]. At variance from congenital hemophilia, in which                  Although up to 36% of all patients affected by
joint hemorrhages are the most common bleeding                         acquired hemophilia A, who do not receive therapy


JCD 2009; 000:(000). Month 2009                                    1                                       www.slm-hematology.com
Journal of Coagulation Disorders



for inhibitor eradication, experience a spontaneous                In recent years, many reports have suggested a
disappearance of their autoantibodies, this occurrence           significant role for Rituximab (RTX) in the treatment
is unpredictable, and the patients remain at risk of             of patients with acquired FVIII inhibitors. Rituximab
bleeding as long as autoantibodies persist, especially if        is a chimeric murine/human monoclonal antibody of
very low levels of FVIII are detected [7]. Thus, a               immunoglobulin G1 kappa type directed against CD20,
therapeutic approach aimed at inhibitor eradication is           a transmembrane protein expressed on the surface of
mandatory, as recommended recently by Huth-Kuhne   ¨             premature and mature B lymphocytes. It depletes B
et al [8]. Treatments for inhibitor eradication include          cells from the blood, lymph nodes, and bone marrow
immunosuppression with corticosteroids, cyclopho-                and has demonstrated efficacy in the treatment of
sphamide, cyclosporine, and other cytotoxic drugs.               CD20-positive lymphoproliferative diseases. It blocks
Treatment with high-dose immunoglobulin (HDIg), as               the proliferation of normal B cells, thus interfering
first-line therapy without concomitant immunosup-                with antibody production of the IgG type. In fact,
pressive agents, achieved only a 12% success rate [9],           several studies have reported therapeutic efficacy of
and the recent study by Collins et al [3], comparing             RTX in a number of autoimmune diseases, such as
patients who either did or did not receive HDIg,                 systemic lupus erythematosus, rheumatoid arthritis,
showed no benefit for those taking HDIg. So, the use of          autoimmune hemolytic anemia, autoimmune thrombo-
HDIg, as a single agent is not recommended in                    cytopenic purpura, thrombotic thrombocytopenic pur-
acquired hemophilia A [8].                                       pura, and acquired hemophilia A [14–16]; RTX may
                                                                 induce immune tolerance in congenital hemophilia
  Corticosteroids and cyclophosphamide are regarded
                                                                 with inhibitor alloantibodies to FVIII or FIX [17].
as the most effective therapeutic approach. Cortico-
steroids given at standard doses (e.g., prednisone 1 mg/           Figure 1 reports the characteristics and structure of
kg daily for 3–6 weeks) eradicate the inhibitor in about         the RTX molecule and its target (CD20 protein).
30–50% of cases [10]. In general, responder patients               Since the description of the first three cases treated
have low inhibitor titers and no underlying diseases             in 2001 by Karwal et al [18], RTX has been used in adult
[11]. Cyclophosphamide (at doses of 1–2 mg/kg daily)             patients (aged 18–94 years) with acquired hemophilia
alone or in combination with steroids may eradicate              A, both as first-line therapy and as salvage treatment
the inhibitor in patients resistant to corticosteroid            in cases refractory to conventional immunosuppres-
[10]. Numerous authors also consider this drug as                sive drugs. In most studies, the therapy schedule was
initial treatment in combination with prednisone in              375 mg/m2 per dose, once a week for 4 weeks.
patients with very high inhibitor titers [12]. Moreover,         Rituximab has been used either as a single agent or
a meta-analysis by Delgado et al [4] concerning a                in association with corticosteroids or other immuno-
review of 20 reports showed that the higher response             suppressive drugs; the latter course is used in patients
rate obtained with cyclophosphamide/prednisone com-              with very high inhibitor titer in whom combined
bination therapy did not translate to lower mortality.           therapy improved the response [19]. In some relapsed
This is probably due to the toxicity of the combination          patients, retreatment with RTX was also effective [7].
therapy in elderly patients, specifically for neutropenia-       The response rate was very high: in the review by
related infections [13]. Recently, in a non-randomized           Franchini [20] involving 65 treated patients, complete
study, Collins et al [3] compared patients treated with
corticosteroids alone (n534) vs corticosteroids plus
cytotoxic drugs (n545): response rates were 76% and
78% respectively. However, about 20–30% of the
patients are refractory to these treatments, and up
to 20% of patients responding to immunosuppressive
treatments relapse and require additional treatment
[13]. In order to eradicate the inhibitor, recently
published international recommendations on the
diagnosis and treatment of patients with acquired
hemophilia A suggested corticosteroids as first-line
therapy, at a dose of 1 mg/kg/day p.o. (prednisone) for
4–6 weeks, either alone or in combination with
cyclophosphamide at a dose of 1.5–2 mg/kg/day for a
maximum of 6 weeks. However, the potential risks
and benefits of immunosuppressive therapy should be
considered in individual patients: women with post-              Figure 1. Characteristics and structure of Rituximab chimeric
                                                                 antibody molecule and of CD20 transmembrane protein of B
partum inhibitor should not be treated with cyclopho-
                                                                 lymphocyte surface. Mouse (V): murine anti-CD20 variable
sphamide or other alkylating drugs because of the                sequence regions (in red wine); Human (C): human constant
risk of infertility [8].                                         sequence regions (in blue)


JCD 2009; 000:(000). Month 2009                              2                                   www.slm-hematology.com
response was achieved in 57, partial response in 2,            particular for patients for whom prednisone or
minimal response in 2, and no response in 5 only.              cytotoxic drugs are unsuitable [19].
Similar results were reported in the review by Garvey            In the recently published international recommenda-
[19], who described 47 patients (44 of them were the           tions, RTX has been suggested as second-line therapy
same as Franchini reported): complete response was             if first-line immunosuppressive therapy fails or is
reached in 37, partial response in 8, complete/partial         contraindicated [8].
response in 1, no response in 1. Time to achieve a
response ranged from 1 to 106 weeks (median                      Definition of the response to immune therapy,
11.5 weeks), in the review by Franchini [20], and from         according to Baudo and de Cataldo [26] is as follows.
1 to 65 weeks (median 10 weeks) in that of Garvey [19],        Complete remission (CR) is defined as normal level of
in comparison with the time taken to reach a response          FVIII and no detectable inhibitor; partial remission
with corticosteroids (median 8 weeks), with cortico-           (PR) is defined as an inhibitor titer , 10 BU/mL or a
steroids plus cyclophosphamide (median 7 weeks), and           decrease of 50% if the baseline titer was ,10 BU/mL ;
with cyclophosphamide alone (median 30 weeks) [19].            failure is defined as no change, or an inhibitor titer
Sperr et al [21] compared the efficacy of RTX in 43            .10 BU/mL, or a decrease less than 50% of the
patients with that of cyclophosphamide/prednisone              baseline values. Complete and partial response must
in 44 patients. Complete remission with RTX was                be combined with clinical improvement and disappear-
obtained in 78.6% of treated cases, median time to             ance of the bleeding tendency.
response was 8.3 weeks and, during follow-up, 66% of
responders were still in complete remission after              SEARCH STRATEGY
2 years. Among the 44 patients treated with immuno-
                                                                 We performed a search on MEDLINE without
suppressive drugs, complete remission was reached in
                                                               temporal limits, but with special attention to the last
84.1% of cases, median time to response was 6.3 weeks,
                                                               10 years.
and the probability of continuous complete remission
was 94% [21]. Rituximab treatment was safe in the                The keywords we used were: acquired hemophilia,
majority of cases, but Onitilo et al [22] reported that        postpartum inhibitors, postpartum acquired hemophi-
two patients (75 and 73 years old, respectively, both          lia, Rituximab, immunosuppression, immunosuppres-
with cancer) died from sepsis in remission. Moreover,          sive therapy, FVIII inhibitors, and autoantibodies.
they described a rebound elevation of FVIII activity
(FVIII:C) after successful therapy with RTX [22]. This         POSTPARTUM ACQUIRED HEMOPHILIA A
elevation may be associated with increased risk of
                                                                 With regard to postpartum FVIII inhibitors, they
venous thrombosis [23], and therefore periodic mon-
                                                               represent 7–21% of all cases of acquired hemophilia A,
itoring of FVIII:C levels is mandatory in the post-
                                                               for an estimated incidence of about 1/350 000 deliveries
remission follow-up. Furthermore, RTX has been
                                                               [3]. Its pathogenesis remains unclear but, because
rarely associated with cases of progressive multifocal
                                                               autoantibodies develop more often in the postpartum
encephalopathy, hepatitis B reactivation, and other
                                                               period, one hypothesis may be that the mother was
viral infection in non-Hodgkin’s lymphoma (NHL) and
                                                               exposed to fetal FVIII during delivery. However, in
in autoimmune diseases [19].
                                                               subsequent pregnancies, a reappearance of the inhibitor
  In summary, the efficacy rate of RTX is very high: in        is very rare, which would exclude an anamnestic
fact, more than 90% of treated patients responded              response [1]. Until now, more than 100 cases of post-
positively. However, patients with very high inhibitor         partum acquired hemophilia A have been described.
titer may require additional courses of RTX and/or             Such a disease may occur after any pregnancy, but it is
concomitant administration of other immunosuppres-             reported more frequently in primigravidas and most
sive drugs, such as cyclophosphamide. With these               commonly between 1 and 4 months after delivery.
considerations in mind, Aggarwal et al [24] proposed           Delgado et al [4], in their meta-analysis, reported that,
an algorithm incorporating RTX, based on inhibitor             in the majority of cases (about 60%) of pregnancy-
titer. In patients with low inhibitor titer ,5 Bethesda        associated inhibitors, these inhibitors spontaneously
units (BU)/mL) and minimal or absent bleeding,                 disappear after a mean time of 30 months, but in this
prednisone is the first-line treatment; in patients with       review, the median inhibitor titer was not so high, that is
inhibitor titer .5,30 BU/mL and serious bleeding, or           20 BU/mL. Moreover, they recorded only one death out
without response to prednisone, RTX is added; in               of 34 reported cases [4]. In the analysis of Hauser et al [27]
patients with inhibitor titer >30 BU/mL, combined              concerning 51 cases of postpartum acquired hemophilia
therapy with prednisone, cyclophosphamide, and RTX             A, a considerable variability emerged in the titer of
has been proposed [24]. On the contrary, some authors          inhibitors (range between 5 and 200 BU/mL) and the
considered that RTX may be a useful salvage treat-             severity of bleeding symptoms. They reported three
ment in patients who have failed first-line therapy [21,       deaths but, in 76.5% of cases, the inhibitor disappeared
25] or a useful alternative to existing treatments, in         spontaneously [27]. Solymoss also described a variable


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Journal of Coagulation Disorders



severity of bleeding symptoms: indeed, no fatal episodes       not appear to be correlated with the inhibitor titer or
occurred over a total of 80 bleeding episodes [28].            the bleeding severity. Presently, however, interna-
                                                               tional recommendations advise against the use of
THERAPEUTIC APPROACH TO POSTPARTUM                             cyclophosphamide and other alkylating agents in
                                                               women with postpartum inhibitor because of the risk
ACQUIRED HEMOPHILIA A
                                                               of infertility [8].
  The aim of management of postpartum acquired
hemophilia A is the control of bleeding and the                  Mazzucconi et al [31] used combined therapy with
eradication of the inhibitors. In some cases, a ‘‘wait         dexamethasone and HDIg in four cases of postpartum
and see’’ approach can be justified by the absence of          inhibitor: in three cases, a rapid decrease and sub-
                                                               sequent eradication of inhibitor was obtained, without
hemorrhagic symptoms and low inhibitor titer: in fact,
                                                               relevant side-effects.
a spontaneous disappearance of inhibitor is possible.
Mannucci and Peyvandi [30] have recently suggested               However, the question arises whether the immuno-
that, even though it may take several weeks after              suppressive therapy can really change the natural
delivery for inhibitor disappearance, a conservative           course of the postpartum acquired hemophilia A: in
approach based upon the prompt treatment of bleeding           fact, the clinical course of this disease is mostly
is warranted in these women, whereas inhibitor                 benign, and a spontaneous disappearance of inhibitor
eradication with immunosuppressive agents should               is possible. Hauser et al [27] reported that the
be deferred and implemented only in the rare cases of          probability of remission is about 100%, while immu-
persisting antibodies [30]. On the contrary, the recent        nosuppressive therapy may induce only faster eradica-
international recommendations state that ‘‘all patients        tion of the inhibitor.
diagnosed with acquired hemophilia A receive immu-               On the contrary, in some cases, persistence of high-
nosuppressive therapy immediately following diagno-            titer inhibitor, despite several lines of therapy,
sis’’ [8].                                                     represents an actual risk of recurrent bleedings, so
  However, treatment is mandatory when bleeding                other therapeutic approaches are advisable that could
occurs, which can become a life-threatening event in           possibly eradicate the autoantibodies without further
the postpartum period. Treatment of bleeding episodes          toxicity.
depends on the inhibitor titer, whether low, ,5 BU/
mL, or high, .5 BU/mL, and on the level of residual            ROLE OF RITUXIMAB (RTX) IN POSTPARTUM
FVIII:C (undetectable or detectable). In the presence          ACQUIRED HEMOPHILIA A
of low inhibitor titer and detectable residual FVIII:C,          Rituximab is considered a safe therapeutic approach
desmopressin (DDAVP) or human or recombinant                   in acquired hemophilia A and can be a valid alter-
FVIII concentrates can be used, whereas if FVIII:C is          native for patients unable to receive cytotoxic immu-
undetectable, human or recombinant FVIII concen-               nosuppressive drugs: in particular, in young female
trates at adequate dosages must be used. In case of            patients, treatment with cytotoxic drugs can compro-
high inhibitor levels, bypassing agents, such as APCC          mise fertility [19, 32]. On the contrary, RTX is well
and rFVIIa, constitute the treatment of choice [1, 8,          tolerated with few side-effects, especially in young
16].                                                           people with acquired hemophilia A. For these reasons,
 In rare cases that do not respond to these therapeutic        RTX can also have a role in the therapeutic approach
agents, a reduction in inhibitor titer can be obtained         to postpartum acquired hemophilia A, especially when
by plasmapheresis with or without extracorporeal               first-line therapy has failed, according to the recent
immunoadsorption [29].                                         international recommendations [8]. Until now, only a
                                                               few cases of postpartum acquired hemophilia A treated
  The eradication of persistent autoantibodies can
                                                               with RTX have been reported, with promising results.
be obtained by the immunosuppressive therapeutic
approach. Corticosteroids represent first-line therapy,         From 2004 to the present, eight cases have been
while other immunosuppressant drugs such as cyclo-             completely described in the literature, either as single
phosphamide or, less frequently, azathioprine, cyclo-          case reports or as case/cases among series regarding
sporine, and 6-mercaptopurine have been used as a              patients with acquired inhibitors to FVIII associated
second-line therapeutic approach or in combination             with various conditions.
with corticosteroids (mainly cyclophosphamide).                  In Table 1, the main characteristics of patients are
Solymoss reported that, with steroids alone or in              described. Age at diagnosis ranged between 18 and
combination with cyclophosphamide, it is possible to           40 years (mean 29 years, median 27.5 years); three women
obtain inhibitor eradication in 86% of cases [28].             were primigravidas, two have had previous pregnancies
Similar results were also observed by Baudo and de             (one of them a first trimester spontaneous abortion), and
Cataldo [26]: 78% successful eradication when steroids         in the other three, the number of pregnancies was not
with or without cyclophosphamide, azathioprine, or             specified. In two patients, lupus anticoagulant (LA) and
HDIg were given. The response to treatment did                 multiple sclerosis were associated conditions. The


JCD 2009; 000:(000). Month 2009                            4                                 www.slm-hematology.com
                                                                                                                                                                          Bilateral limb amputation
interval from delivery to diagnosis ranged between 0.6




                                                                                                                                                                                                      Post-infusion headache,
and 34.4 weeks (mean 14.1 weeks, median 8.6 weeks);




                                                                                                                                                                             for compartment
inhibitor titer (BU/mL) ranged from 1.7 to 3075 ( mean




                                                                                                                                                 SE/AE
525.2, median 13); in three patients, it was very high,




                                                                                                                                                                             syndrome
whereas in the other five it was ,5 BU/mL in three and
.5 and ,20 BU/mL in two; FVIII:C levels were ,1% in




                                                                                                                                                                                                        chills
all but one patient, in whom it was detectable (13.5%). In




                                                                                                                                                                          None




                                                                                                                                                                                                                                                     None
                                                                                                                                                                                                                                                                    None
                                                                                                                                                                                                                                                                                    None
                                                                                                                                                                                                                                n.d.
                                                                                                                                                              n.d
four patients, RTX was given after the failure of two or




                                                                                                                                                                                                                                                                                                   AZA, azathioprine; CR, complete remission; CYCLO, cyclophosphamide; HDIg, high-dose immunoglobulin; PDN, prednisone; n.d., not done; VCR, vincristine.
more immunosuppressive treatments, whereas in the




                                                                                                                                   Duration

                                                                                                                                   (months)
other four, no previous therapy had been given.




                                                                                                                                     of CR



                                                                                                                                                                          12+
                                                                                                                                                                          36+


                                                                                                                                                                                                      29+

                                                                                                                                                                                                                                24+
                                                                                                                                                                                                                                                     24+
                                                                                                                                                                                                                                                                    24+
                                                                                                                                                                                                                                                                                    8+
                                                                                                                                                              n.d
Rituximab was administered according to a standard
single weekly dose for 4 weeks in four patients, for
9 weeks in one patient, and only once in three patients




                                                                                                                                               Time* to CR
[7, 22, 32–35]. In the patients reported by Stasi et al [7]




                                                                                                                                                 (weeks)




                                                                                                                                                                                                                                n.d.
                                                                                                                                                              n.d.
and by Maillard et al [32], no concurrent therapy was




                                                                                                                                                                                                                                                                    2.6
                                                                                                                                                                          48
                                                                                                                                                                          43


                                                                                                                                                                                                      39



                                                                                                                                                                                                                                                     3


                                                                                                                                                                                                                                                                                    2
given, whereas in those described by Onitilo et al [22], by
Santoro et al [33], and by Machado et al [34], cyclopho-
sphamide, prednisone, and azathioprine plus cyclopho-




                                                                                                                                      Response
sphamide were associated with RTX, respectively; in the




                                                                                                                                                              CR
                                                                                                                                                                          CR
                                                                                                                                                                          CR


                                                                                                                                                                                                      CR

                                                                                                                                                                                                                                CR
                                                                                                                                                                                                                                                     CR
                                                                                                                                                                                                                                                                    CR
                                                                                                                                                                                                                                                                                    CR
remaining three patients reported by Dedeken et al [35],
in whom RTX was given as a single dose, at the onset of
the disease, prednisone was concurrently administered

                                                                                                                                      Concurrent
                                                                                                                                      treatments




                                                                                                                                                                                                                                CYCLO AZA
                                                                                                                                                                                                                                                     PDN HDIg
and in one patient HDIgs were also given.




                                                                                                                                                                          CYCLO
  Complete remission, that is disappearance of inhibi-
                                                                                                                                                              None
                                                                                                                                                                          None




                                                                                                                                                                                                      PDN




                                                                                                                                                                                                                                                                    PDN
                                                                                                                                                                                                                                                                                    PDN
tor and complete recovery of FVIII:C, was reached in
all cases, with variable times to response: in six
                                                                                                                                   (375 mg/m2/
                                                                                                                                    RTX doses




patients, in whom these data were reported, the time
                                                                                                                                      week)




to response ranged from 2 to 48 weeks (mean 23 weeks,
                                                                                                                                                              4
                                                                                                                                                                          4
                                                                                                                                                                          9


                                                                                                                                                                                                      4

                                                                                                                                                                                                                                4
                                                                                                                                                                                                                                                     1
                                                                                                                                                                                                                                                                    1
                                                                                                                                                                                                                                                                                    1
median 21 weeks). No patient relapsed: duration of
persistent CR (reported in seven patients) ranged from

                                                                                                                                                                                                                                PDN CYCLO HDIg AZA
                                                                                                                                                                          AZA VCR CYCLO PDN




8 to 36 months (mean 22.4 months, median 24 months).
No relevant side-effects related to the drug were
                                                                                                                                      treatments
                                                                                                                                       Previous




                                                                                                                                                                                                      PDN DXM HDIg



recorded, but in one patient [22] with LA, bilateral
limb amputation, due to compartment syndrome, was
                                                                                                                                                                          PDN HDIg




                                                                                                                                                                                                        CYCLO




performed. No infections occurred in any case.
                                                                                                                                                                            HDIg




 As far as bleeding symptoms at presentation or
                                                                                                                                                              None




                                                                                                                                                                                                                                                     None
                                                                                                                                                                                                                                                                    None
                                                                                                                                                                                                                                                                                    None


during follow-up were concerned, these varied from
                                                                  Table 1. Features of Postpartum Acquired Hemophilia A patients




ecchymoses, easy bruising, and epistaxis to large
                                                                                                                                                    FVIII:C




                                                                                                                                                                                                                                13.5
                                                                                                                                                                                                                                                     0.3
                                                                                                                                                                                                                                                                    0.5
                                                                                                                                                                                                                                                                                    0.8




muscle hematomas, abdominal shedding of blood, and
                                                                                                                                                     (%)
                                                                                                                                                              ,1
                                                                                                                                                                          ,1
                                                                                                                                                                          ,1


                                                                                                                                                                                                      ,1




hemorrhagic shock post delivery. In three cases,
bleeding symptoms were successfully treated with
                                                                                                                                      titer (BU/mL)




rFVIIa, followed in one case by infusion of porcine
                                                                                                                                         Inhibitor




                                                                                                                                                                                                                                1.7




FVIII.
                                                                                                                                                                          3075
                                                                                                                                                                           470




                                                                                                                                                                                                      621
                                                                                                                                                              16




                                                                                                                                                                                                                                                     10
                                                                                                                                                                                                                                                                    4
                                                                                                                                                                                                                                                                                    4


                                                                                                                                                                                                                                                                                                   {Associated condition: lupus anticoagulant.




  Behavior of CD19/20 peripheral positive B cells
                                                                                                                                                                                                                                                                                                   {Associated condition: multiple sclerosis.




during RTX treatment was reported in the case
described by Santoro et al [33]: the levels were detected
                                                                                                                                   (yes/no)
                                                                                                                                   gravida




at baseline (205 6 106/L), at the first week after
                                                                                                                                    Primi


                                                                                                                                                              n.d.

                                                                                                                                                                          n.d.




                                                                                                                                                                                                                                n.d.
                                                                                                                                                                          yes




                                                                                                                                                                                                      yes




                                                                                                                                                                                                                                                                                    yes
                                                                                                                                                                                                                                                     no
                                                                                                                                                                                                                                                                    no




stopping therapy (level 0/L), at the fifth month (0/L), at
the ninth month (56 6 106/L) and at the twelfth month,
                                                                                                                                                                                                                                                                                                   *From the last RTX infusion.




when a complete recovery was recorded (212 6 106/L).
                                                                                                                                      (years)




There were no changes in the serum immunoglobulin.
                                                                                                                                        Age

                                                                                                                                                              30
                                                                                                                                                                          18
                                                                                                                                                                          24


                                                                                                                                                                                                      25

                                                                                                                                                                                                                                40
                                                                                                                                                                                                                                                     36
                                                                                                                                                                                                                                                                    34
                                                                                                                                                                                                                                                                                    25




COMMENTS AND DISCUSSION
                                                                                                                                                                                                                                                                    Dedeken{ [35]
                                                                                                                                                                                                                                Machado [34]
                                                                                                                                                                          Maillard [32]




                                                                                                                                                                                                                                                     Dedeken [35]


                                                                                                                                                                                                                                                                                    Dedeken [35]
                                                                                                                                                                          Onitilo{ [22]


                                                                                                                                                                                                      Santoro [33]




  Among the above-described cases of postpartum
acquired hemophilia, four were treated with RTX as
                                                                                                                                                              Stasi [7]




first-line therapy, associated with prednisone in three. In
                                                                                                                                                 Case




the other four cases, more than two previous therapeutic


www.slm-hematology.com                                        5                                                                                                                               JCD 2009; 000:(000). Month 2009
Journal of Coagulation Disorders



approaches had been given without success. In four               the recovery of peripheral CD20-positive B cells began
patients, four doses of RTX were administered, while in          months after stopping therapy: in the case described by
the others, nine doses were given in one patient and only        Santoro et al [34], it was completed by the 12th month.
one dose in three. Inhibitor titer was very high in three        It seems to be advisable to monitor the behavior of
patients and at low–intermediate levels in the other five.       peripheral CD20-positive B cells at baseline and then
Concurrent treatments were given in all but two                  serially until a complete recovery is reached.
patients. All patients achieved a CR; the time to response         In conclusion, RTX is a new drug in acquired hemo-
was very short in the cases described by Dedeken et al           philia and, in particular, in the setting of postpartum
[35] (2–3 weeks) and very long (39–48 weeks) in the              cases. Available data are thus limited and may carry a
others, who were also characterized by highest inhibitor         bias in reporting only positive outcomes. However, it
titers. No relapses occurred during follow-up, which             may be a useful alternative or addition to existing
ranged from 8 to 36 months (Table 1).                            therapies. While bleeding symptoms usually disap-
  In these cases, RTX seems to be very effective, but the        peared early during the course of therapy with RTX, a
response delay seems to be related to the highest                CR occurred later after the beginning of therapy.
inhibitor titer. Moreover, no relevant side-effects were         Nevertheless, RTX can be considered a valid second-
recorded and, in spite of the suppression of CD20-               line therapy after the failure of corticosteroids,
positive B lymphocytes, no infections occurred. It is            sparing the use of cytotoxic drugs.
interesting that the patient described by Santoro et al           Disclosure: The authors have no funding disclosure to
[33] experienced a clinical improvement just after the           declare.
first infusion of RTX, as she never presented with
further hemorrhagic events, while the inhibitor titer            REFERENCES
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