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Blood, 15 June 2001, Vol. 97, No. 12, pp. 3995-3997
BRIEF REPORT
Anti-CD20 monoclonal antibody for the treatment of severe,
immune-mediated, pure red cell aplasia and hemolytic anemia
Marco Zecca,
Piero De
Stefano,
Bruno Nobili, and
Franco Locatelli
From Pediatric Hematology/Oncology, IRCCS
Policlinico San Matteo, University of Pavia, Italy, and the Department
of Pediatrics, University of Naples, Italy.
 |
Abstract |
Immune-mediated, acquired pure red cell aplasia (PRCA) is a
rare disorder frequently associated with other autoimmune phenomena. Conventional immunosuppressive treatment is often unsatisfactory. Rituximab is a monoclonal antibody against the CD20 antigen, highly effective for in vivo B-cell depletion. An 18-month-old girl
with both severe PRCA and autoimmune hemolytic anemia, refractory to immunosuppressive treatment, received 2 doses of rituximab, 375 mg/m2 per week. The drug was well tolerated. After
anti-CD20 therapy, substitutive treatment with intravenous
immunoglobulin was started. The treatment resulted in marked depletion
of B cells; a striking rise in reticulocyte count ensued, with
increasing hemoglobin levels, finally leading to transfusion
independence. The child is now 5 months off-therapy, with normal
hemoglobin and reticulocyte levels. This case suggests a role of
anti-CD20 monoclonal antibody for treatment of patients with
antibody-mediated hematologic disorders.
(Blood. 2001;97:3995-3997)
© 2001 by The American Society of Hematology.
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Introduction |
Acquired pure red cell aplasia (PRCA) is rare
in infancy, median age of onset being usually between 50 and 60 years.1-3 The pathogenesis of the disease is
immune-mediated in most cases, soluble serum inhibitors or inhibitory T
cells, able to impair in vitro growth of erythroid progenitors
(burst-forming unit [BFU-E], and colony-forming unit [CFU-E]),
having been demonstrated in several series of patients.1-3
PRCA is frequently associated with other autoimmune phenomena, that is,
production of autoantibodies directed against erythrocytes,
acetylcholinesterase, smooth muscle, and so on.2 PRCA
associated with autoimmune hemolytic anemia (AIHA) has been previously
reported.4
Treatment of PRCA usually employs steroids and/or other
immunosuppressive drugs (ie, cyclosporine-A and cyclophosphamide), or
immunomodulating agents such as immunoglobulin, with response rates to
these therapies ranging from 30% to 55%.2,3
Rituximab is a humanized, murine, monoclonal antibody (MoAb)
directed against the CD20 antigen, expressed on pre-B lymphocytes and
on mature B lymphocytes.5,6 Rituximab has been
demonstrated to be highly effective for in vivo B-cell depletion, B
lymphocytes becoming undetectable in peripheral blood after a single
infusion, and recovering only 6-9 months after discontinuation of
treatment.5,6 The antibody has been recently introduced
for treatment of B-cell lymphomas.7-10
We describe the case of an 18-month-old child with immune-mediated PRCA
and AIHA, refractory to first- and second-line immunosuppressive therapy, who was successfully treated with anti-CD20 MoAb.
| |
Study design |
An 18-month-old Caucasian girl was hospitalized due to
recent onset of pallor and listlessness. Physical examination at
admission was unremarkable, with the exception of pallor and mild
jaundice; the patient did not present either spleen or liver
enlargement. Full blood count at admission showed
normochromic-normocytic anemia (hemoglobin = 5.6 g/dL) with
reticulocytopenia (absolute reticulocyte count = 7 × 109/L) and normal white blood cell and platelet
counts. Total and unconjugated bilirubin levels were increased (2.31 mg/dL and 1.77 mg/dL, respectively), and serum haptoglobin was
undetectable. Tests for hereditary hemolytic anemias, as well as direct
and indirect Coombs tests, were negative. Evaluation of the blood film
revealed the presence of spherocytes, whereas erythrocyte fragments
were not detectable. Serologic tests for parvovirus B19, human
cytomegalovirus, and Epstein-Barr virus were negative. Chest x-ray was
normal. A blood count performed 6 months earlier had shown normal
hemoglobin (12 g/dL).
A bone marrow aspirate performed at admission demonstrated normal
representation of myeloid and megakaryocyte precursors, but nearly
absent erythroid precursors. In vitro cultures of patient light-density
bone marrow cells, performed in triplicate as described previously,11 demonstrated that, compared with 3 healthy
bone marrow donors, a significant reduction of colonies from erythroid progenitors was present, with patient and controls BFU-E and CFU-E being 20 ± 4 versus 88 ± 11 and 32 ± 3 versus 67 ± 5,
respectively. By contrast, growth of the patient's
granulocyte-macrophage progenitors (CFU-GM) was normal. The patient's
plasma profoundly inhibited growth of BFU-E from healthy controls
(93 ± 16 and 24 ± 6 without and with patient's plasma),
suggesting the existence of soluble serum factors responsible for both
PRCA and hemolysis.
Due to a steadily decreasing hemoglobin level, the child was
transfused. Repeated administration of red blood cell concentrates was
required in order to maintain hemoglobin above 6 g/dL (Figure 1). In the following weeks, she remained
transfusion-dependent, with erythrocyte consumption much higher than
that compatible with hyporegenerative anemia (transfusion of 15-20 mL/kg of packed red blood cells every 5-7 days was necessary). In
detail, during a period of 10 weeks, 13 erythrocyte transfusions were
administered. Serum bilirubin levels remained above normal levels,
whereas serum haptoglobin was constantly undetectable. Despite clinical
and biochemical signs of continuing hemolysis, the direct antiglobulin test (DAGT), repeatedly performed during this time, remained negative. In AIHA the DAGT is positive, but patients with AIHA and PRCA in whom the DAGT has been persistently negative have been occasionally reported.4 Because other causes of persistent hemolysis
could reasonably be excluded, a diagnosis of AIHA with PRCA was made in
our patient and immunosuppressive treatment was started.
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| Figure 1.
Clinical course of the patient and response to
treatment.
Reticulocyte count and hemoglobin levels are reported in the graph.
Black circles represent red blood cell transfusion, tick marks
represent immunoglobulin infusions, and rectangles treatment with
corticosteroids and cyclosporine-A. Arrows show the 2 infusions of
anti-CD20 monoclonal antibody.
|
|
Methylprednisolone, first at conventional doses (2 mg/kg per day), then
at high doses (5 mg/kg per day), together with intravenous immunoglobulin infusions, were administered, both proving ineffective in increasing reticulocyte count and in reducing erythrocyte
consumption. Concomitant treatment with cyclosporine-A during 6 weeks
was equally ineffective (Figure 1). Because a case of immune-mediated
thrombocytopenia successfully treated with anti-CD20 monoclonal
antibody (rituximab) had been published,12 we reasoned
that selective destruction of B cells producing antibodies responsible
for both PRCA and hemolysis might be effective. Rituximab was
administered intravenously at the dose of 375 mg/m2 as a
4-hour infusion, once weekly for a total of 2 doses. Before each
infusion, the child received pre-medication with methylprednisolone and
diphenhydramine. The drug was well tolerated and the child did not
present any adverse reaction or side effects. Substitutive treatment
with intravenous immunoglobulin (400 mg/kg every 3 weeks) was given, in
order to prevent treatment-induced hypogammaglobulinemia.
| |
Results and discussion |
Treatment with rituximab resulted in marked depletion of B cells
in peripheral blood, as demonstrated by the percentage of CD19+ and CD20+ cells dropping from the
pretreatment values of 12% and 11%, respectively, to values less than
0.5% for both antigens 2 days after the first infusion.
Shortly after the first anti-CD20 MoAb infusion, the patient showed a
striking rise in reticulocyte count, with a maximum value of
347 × 109/L achieved 2 weeks after starting the
treatment. Progressive increase of hemoglobin level and achievement of
transfusion independence (Figure 1) followed the rise in reticulocytes.
Bilirubin and haptoglobin levels normalized, as well. The course of the
response was as expected and gave further support to a diagnosis of
AIHA with concomitant antibody-mediated PRCA.
The child, 5 months after MoAb therapy, is transfusion-independent,
with normal hemoglobin and reticulocyte levels. She is no longer
receiving immunosuppressive treatment. The percentage of the patient's
B lymphocytes is still below 1%. During the observation period, the
child did not develop any significant infectious complication.
As mentioned, so far only one case of immune-mediated
thrombocytopenia, successfully treated with anti-CD20 MoAb, has been extensively reported in the literature.12 In that patient,
the administration of 4 doses of rituximab induced complete and
long-lasting normalization of platelet count. Treatment of
patients with AIHA using rituximab has been preliminarily reported
with variable response.13-15
In our experience, response to anti-CD20 infusion occurred 4 days after
the first administration, and it was sustained, allowing discontinuation of all other immunosuppressive therapies. The rapid
response and disappearance of B cells from peripheral blood suggested
that 2 doses of monoclonal antibody might be sufficient, thus saving costs.
Recovery of B lymphocytes after treatment with rituximab has been
described to start from 6 to 9 months after the last administration; a
normal B-lymphocyte number is usually achieved only 12 months after
treatment discontinuation.5 As a consequence, a
significant reduction in immunoglobulin M (IgM) and IgG serum levels is
to be expected,16 with a possible risk of infectious
complications, as recently reported.17,18 For this reason,
we gave replacement therapy with intravenous immunoglobulins.
The outcome of childhood severe, immune-mediated, hematologic cytopenia
with conventional immunosuppressive approaches is sometimes
unsatisfactory.1-3 For this reason, the recent
introduction of new immunomodulating agents, such as MoAbs approved for
in vivo use, represents an appealing and promising treatment modality for patients with the most severe and/or refractory forms of disease. In refractory or chronic disease, use of rituximab is attractive also
because it could reduce or avoid some side effects of prolonged therapy
with steroids (eg, fluid retention, severe catabolic damage, hyperglicemia, avascular necrosis of bone, growth impairment) and/or
other aspecific immunosuppressive drugs.
In conclusion, even though a longer follow-up is required to assess the
long-term efficacy of this treatment, this case provides a basis for
future prospective trials aimed at defining the role of anti-CD20 MoAb
for antibody-mediated hematologic disorders.
| |
Acknowledgments |
We would like to thank Rita Maccario for the immune-phenotype study
of peripheral blood lymphocytes and Patrizia Comoli for help in
revising the manuscript.
| |
Footnotes |
Submitted January 16, 2001; accepted February 20, 2001.
Supported in part by grants to F.L. from AIRC
(Associazione Italiana per la Ricerca sul Cancro), CNR (Consiglio
Nazionale delle Ricerche), and IRCCS (Istituto di Ricovero e Cura
a carattere Scientifico) Policlinico San Matteo, Pavia.
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: Franco Locatelli, Oncoematologia Pediatrica, IRCCS
Policlinico San Matteo, P.le Golgi 2, I-27100 Pavia, Italy; e-mail:
f.locatelli{at}smatteo.pv.it.
| |
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Abstract
Introduction