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Blood, Vol. 96 No. 3 (August 1), 2000:
pp. 1184-1186
BRIEF REPORT
Pure red cell aplasia due to parvovirus B19 in a patient treated
with rituximab
Vivek R. Sharma,
Donald R. Fleming, and
Stephen P. Slone
From the Division of Medical Oncology/Hematology, the
Department of Pathology, and the James Graham Brown Cancer Center,
University of Louisville, Louisville, KY.
 |
Abstract |
Rituximab is a chimeric monoclonal antibody directed
against CD20 and used in the treatment of B-cell non-Hodgkin's
lymphoma. Due to its ability to deplete B lymphocytes, rituximab can
interfere with humoral immunity, causing it to be suppressed for
several months after treatment. The reported case depicts a serious
consequence of this effect of rituximab therapy: pure red cell aplasia
resulting from chronic parvovirus B19 infection. The point of interest
in this case is not only the association between rituximab therapy and
pure red cell aplasia, but the diagnostic and therapeutic utility of
the knowledge of parvovirus B19 as the likely etiologic link between
the two. Given the known efficacy of intravenous immunoglobulin (IVIg)
in the treatment of chronic parvovirus B19 infection, this therapy
can cure some of these patients and successfully render most others
transfusion-independent until recovery of their own humoral immune system.
(Blood. 2000;96:1184-1186)
© 2000 by The American Society of Hematology.
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Introduction |
Pure red cell aplasia is a type of anemia that results
from an isolated depletion of erythroid precursors from the bone
marrow. There are well-described associations of this disorder with
thymomas, lymphoproliferative disorders, autoimmune disorders, certain
drugs, and infectious agents.1 Among the infectious agents,
parvovirus B19 is the most significant and is notorious for producing
the great majority of aplastic crises in patients with chronic
hemolytic states. Infection with this virus generally tends to be brief and self-limited in healthy persons, but it can become chronic and
persistent in patients with impaired humoral
immunity.2,3
Rituximab (Rituxan; Genentech, South San Francisco, CA) is
a chimeric monoclonal antibody (mAb) directed against the B-cell receptor, the CD20 antigen, and used in the treatment of non-Hodgkin's lymphomas. It acts by depleting both malignant and normal pre-B and
mature B lymphocytes by a variety of mechanisms after first binding to
the CD20 antigen expressed on their surfaces. The pharmaceutical product profile on Rituxan mentions a case of pure red cell aplasia in
a patient treated with Rituxan; however, no further information on the
underlying mechanism is available.4
We report here a case of pure red cell aplasia due to chronic
persistent parvovirus B19 infection in a patient treated with Rituxan
for non-Hodgkin's lymphoma. To our knowledge, this is the first case
report of pure red cell aplasia associated with the use of rituximab
therapy, which implicates parvovirus B19 as the etiologic factor
linking the two. Aspects of this case may provide leads into diagnostic
and therapeutic decision making for similar patients encountered in the future.
| |
Study design |
A 45-year-old white male was diagnosed with stage IV follicular
mixed non-Hodgkin's lymphoma in December 1998. In addition to
extensive lymphadenopathy, the patient had bone marrow involvement by
the lymphoma, both morphologically and by flow cytometric analysis. A
polymerase chain reaction (PCR) test demonstrated the presence of
the bcl-2 gene translocation. He was treated with
a combination of CHOP (cyclophosphamide, doxorubicin, vincristine
(Oncovin), and prednisone) chemotherapy and Rituxan, and the therapy
was recycled every 21-28 days. By May 1999, he had received 5 cycles of
the above regimen with excellent clinical response (complete remission
by imaging studies).
In mid-May 1999, the patient presented with symptoms of anemia and was
found to have a hemoglobin of 73 g/L (7.3 g/dL). He was
transfused with packed red cells. Due to the microcytic, hypochromic nature of his anemia, the patient underwent a complete endoscopic evaluation of his gastrointestinal tract, which failed to reveal an
obvious bleeding source. He presented 3 weeks later with similar symptoms of anemia and a hemoglobin of 63 g/L (6.3g/dL), and he required another red cell transfusion. The corrected reticulocyte count
was less than 1%. At this time, a bone marrow aspiration was
performed, which revealed findings consistent with pure red cell
aplasia. Also visualized were large pronormoblasts with nuclear inclusion bodies that were very suggestive of parvovirus infection (Figure 1). There was no evidence of
lymphoma by flow cytometry, and PCR analysis failed to demonstrate the
bcl-2 gene mutation.
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| Fig 1.
A giant pronormoblast with prominent nuclear inclusion
bodies dwarfs the granulocyte precursor cells.
Evaluation of the bone marrow aspirate revealed maturing granulopoiesis
and thrombopoiesis but severely suppressed erythropoiesis, which was
arrested at the pronormoblast stage. The myeloid:erythroid ratio
was 72:1, with pronormoblasts comprising 1.2% of total bone marrow
cells.
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The above findings prompted testing for parvovirus B19 by both
serologic and PCR tests. The serologic test was negative, but the PCR
returned positive for parvovirus B19 DNA. With this information, he was
treated with 30 g intravenous immunoglobulin (IVIg) weekly for 3 weeks.
His hemoglobin increased to 99 g/L (9.9g/dL) by the time of the third
dose and continued to improve over the next 2 months without further
need for transfusion or IVIg. His most recent hemoglobin from September
1999 was 143 g/L (14.3 g/dL). A PCR test for parvovirus B19 was still
positive in August 1999.
| |
Results and discussion |
The causal association of parvovirus B19 with pure red cell aplasia
is well established.3,5 Parvovirus B19 is a single-stranded DNA virus that produces a wide spectrum of clinical manifestations, but
the destruction of erythroid precursors constitutes the main source of
morbidity and mortality associated with it.2,3 Clearance of
viremia and hence recovery of erythropoiesis are contingent upon an
adequate antibody response to the virus, which occurs within about 1-2 weeks in most healthy persons.2 Patients who are unable to
mount an adequate humoral immune response to the virus, however, fail
to clear it from their circulation. They are consequently left with
persistent ongoing destruction of their erythroid precursors, which
leads to a chronic transfusion-dependent anemic
state.6-10
Rituximab is a monoclonal antibody directed against CD20, which
depletes both normal and malignant CD20+ pre-B and mature B
lymphocytes from circulation by a variety of mechanisms including
complement-dependent cytotoxicity, antibody-dependent cell-mediated
cytotoxicity, and induction of apoptosis. Recovery of B lymphocytes
after treatment with rituximab typically starts about 6 months later
and may take up to a year to return to pretreatment levels.4 As a consequence of this, there are sustained
reductions in both IgM and IgG serum levels, which in fact, drop below
the normal range in up to 14% of patients.4 This results
in chronically impaired humoral immunity, thereby providing an
opportunity for parvovirus B19 to establish persistent infection and
produce chronic red cell aplasia.
In determining the cause of the pure red cell aplasia in our patient,
the morphologic findings in his bone marrow were compelling enough to
direct attention primarily toward an infectious etiology and away from
other considerations. Lymphoma was felt unlikely to be a contributing
factor as he was in complete remission by radiographic and bone marrow
criteria, the latter being confirmed by highly sensitive techniques.
Also, he was not receiving any medication associated with pure red cell
aplasia. Therefore, parvovirus B19 emerged as the most likely cause and
was further verified by PCR analysis. Although it is impossible to
definitively ascribe the B19 infection in our patient to any one of his
potential predispositions, his lymphoma was in complete remission at
the time of presentation, and in its long history of extensive use,
CHOP chemotherapy has never been implicated in causing chronic B19
viremia. We therefore feel that rituximab, with its efficient and
prolonged depletion of B lymphocytes, was the most likely explanation.
IVIg has been found to be an effective therapy for chronic parvovirus
B19 infection. Commercial IVIg is known to contain IgG antibodies to
parvovirus B19, which can control and may even eradicate B19
infection.11-13 This therapy was successful in bringing
about a resolution of anemia in our patient. The detection of viral DNA
in circulation after clinical improvement following IVIg therapy merely
reflects the qualitative nature of the PCR test for B19, which is not
designed to accurately identify a quantitative drop in the viral load
reflected clinically by the increment in hemoglobin level. The test,
however, besides being highly sensitive, is also very specific, and a
positive result has been shown to predict true infection with great
accuracy, even in asymptomatic mass-screened blood
donors.14-16
In conclusion, this case is the first one to be reported depicting an
association between rituximab therapy and pure red cell aplasia.
Parvovirus B19 infection appears to be the linking factor in this
association, as described above. The development of chronic pure red
cell aplasia in a patient treated with rituximab should prompt a search
for parvovirus B19 infection. If detected, treatment with IVIg may cure
the infection in some patients and allow adequate control of viremia in
others, enabling them to become transfusion-independent. Such therapy
may need to be given intermittently for several months to these latter
patients until their humoral immunity recovers from the effects of
rituximab and clears the virus from circulation. Finally, with regard
to diagnosis, it is worth noting that B19 infection in these patients
may not be detected by serologic testing due to their impaired antibody
response, as was the case with our patient. A PCR study to detect viral
DNA in serum should be performed. Indeed for any patient with chronic
pure red cell aplasia, parvovirus B19 infection should be ruled out by
PCR prior to embarking on immunosuppressive therapy aimed at treating
idiopathic or autoimmune forms of the disorder. Morphologic changes in
the bone marrow, if found, also help with the diagnosis. When in doubt,
a therapeutic trial of IVIg may be appropriate if definitive testing
for parvovirus B19 is not immediately available.
| |
Acknowledgment |
We are grateful to Dawn Grant for her valuable assistance in the
preparation of the manuscript.
| |
Footnotes |
Submitted February 15, 2000; accepted March 27, 2000.
Reprints: Vivek R. Sharma, James Graham Brown Cancer Center,
529 South Jackson St, Louisville, KY 40202; e-mail:
vrshar01{at}gwise.louisville.edu.
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.
| |
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Top
Abstract
Introduction