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Blood, 15 February 2003, Vol. 101, No. 4, pp. 1654-1654
CORRESPONDENCE
To the editor:
Pure red-cell aplasia due to parvovirus B19 infection in a
patient treated with alemtuzumab
A 56-year-old woman was diagnosed with mycosis fungoides 10 years earlier. Her cutaneous manifestations were widespread patches, plaques, and ultimately tumor nodules. Her disease was refractory to
standard therapies, and she had no histocompatible sibling. She subsequently entered a phase 2 clinical trial of alemtuzumab
(Campath-1H) for cutaneous T-cell lymphoma (CTCL). After 2 weeks'
treatment, she became mentally obtunded with a fever of 40°C. A
septic workup including computed tomographic (CT) scan and magnetic
resonance imaging (MRI) brain scan, lumbar puncture, and
testing for HIV, herpes simplex virus, cryptococcal meningitis, and
Mycobacterium tuberculosis were unrewarding. She failed to respond to empirical broad spectrum antibiotics. Twenty-three days after commencing alemtuzumab, the patient developed a
severe, transfusion-refractory anemia (hemoglobin level, 77 g/L),
and reticulocytopenia (reticulocyte count, 3 × 109/L),
with bone-marrow biopsy revealing features of pure red-cell aplasia (PRCA). Erythropoiesis was markedly reduced, with normal myelopoiesis and megakaryocytes. Giant pronormoblasts were
demonstrated, and the myeloid-erythroid ratio was 23:7. (Of note:
marrow 8 days prior to commencing alemtuzumab demonstrated normal
erythropoiesis.) She had a T-cell lymphopenia of
0.31 × 109 lymphocytes per liter affecting both her
CD4+ and CD8+ T-cell subsets. Parvovirus IgM
and polymerase chain reaction (PCR) were positive. Intravenous
immunoglobulin (1.5g/kg over 4 days) was administered. Twelve days
later, there was a reticulocytosis (reticulocyte count,
226 × 109/L), and the patient became afebrile, alert,
and transfusion independent. A repeat bone-marrow biopsy 1 month
later was normal. Pure red-cell aplasia is characterized by severe anemia,
reticulocytopenia, and selective deficiency of erythroblasts in an otherwise normal marrow aspirate. Etiologies of PRCA include primary (autoimmune, preleukemic, or idiopathic) and secondary causes such as (a) paraneoplastic ones (thymoma, hematologic malignancies, solid tumors), (b) infections (parvovirus B19, HIV, HTLV, and others),
drugs (azathioprine, isoniazid, etc), (d) collagen vascular diseases,
(e) chronic haemolytic disorders, and (f) a range of other causes
(pregnancy, severe uremia, and nutritional deficiencies).1 Human parvovirus B19 is a small nonenveloped single-stranded DNA virus.
It is transmitted via respiratory droplets or, rarely, by blood
products.2 Infection is common: 15% of young children, 50% to 60% of young adults, and up to 90% of the elderly population show IgG seropositivity. Parvovirus binds to the blood group P antigens (globoside),2 destroying erythroid
precursors. In childhood, it can cause erythema infectiousum ("fifth
disease"), hydrops fetalis, an acute polyarthropathy, or a transient
aplastic crisis.2 The normal immune system clears the
infection before there is prolonged symptomatic anemia. Patients with
lymphopenia secondary to HIV, or after transplantation,
chemotherapy, or chronic immunosuppressive therapy have the same
incidence of this common infection but may fail to clear parvovirus,
and may suffer from a chronic aplastic state and severe anemia.
Patients with reduced red-cell survival (eg, the chronic hemolytic
anemias) may suffer an acute aplastic crisis related to parvovirus B19.
Initial treatment of parvoviral PRCA usually consists of intravenous
immunoglobulin (IVIG) at doses equivalent to those used for immune
thrombocytopenic purpura. Alemtuzumab is a humanized IgG monoclonal antibody directed against the
CD52w antigen, present on normal and malignant B and T lymphocytes and
monocytes but not on human hemopoietic stem cells.3
Alemtuzumab is effective for the treatment of B-cell chronic
lymphocytic leukemia (B-CLL) and T-CLL4 and, in one small
study, CTCL,5 prompting our current trial. Alemtuzumab causes prolonged, severe CD4 and CD8 lymphopenia.7 There
have been no other reported cases of parvovirus B19 causing PRCA in patients receiving alemtuzumab. The severe CD4 lymphopenia induced by
alemtuzumab and other monoclonal therapies such as
rituximab7 for lymphoproliferative diseases is a risk
factor for opportunistic infections. Consideration of parvovirus
infection as a possible cause of anemia in these patients is important.
Treatment with IVIG should be used.
Kirsten E. Herbert, H.
Miles Prince, and David A. Westerman
Correspondence: Miles Prince, Department of
Hematology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett
St, Melbourne, Victoria 8006, Australia; e-mail:
miles.prince{at}petermac.org
References
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Dessypris E.
Pure red cell aplasia. In:
Hoffman R,Benz EJ Jr,Shattil SJ, et al., eds.
Hematology: Basic Principles and Practice. 3rd ed. New York: Churchill Livingstone; 2000:342-354.
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Fisch P, Handgretinger R, Schaefer HE.
Pure red cell aplasia.
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Willis F, Marsh JC, Bevan DH, et al.
The effect of treatment with Campath-1H in patients with autoimmune cytopenias.
Br J Haematol.
2001;114:891-898[CrossRef][Medline]
[Order article via Infotrieve].
4.
Foon KA.
Monoclonal antibody therapies for lymphomas.
Cancer J.
2000;6:273-278[Medline]
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5.
Lundin J, Osterborg A, Brittinger G, et al.
CAMPATH-1H monoclonal antibody in therapy for previously treated low-grade non-Hodgkin's lymphomas: a phase II multicenter study. European Study Group of CAMPATH-1H treatment in low-grade non-Hodgkin's lymphoma.
J Clin Oncol.
1998;16:3257-3263[Abstract].
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Keating MJ, Flinn I, Jain V, et al.
Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study.
Blood.
2002;99:3554-3561[Abstract/Free Full Text].
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Sharma VR, Fleming DR, Slone SP.
Pure red cell aplasia due to parvovirus B19 in a patient treated with rituximab.
Blood.
2000;96:1184-1186[Abstract/Free Full Text].
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Related Letter in Blood Online:
-
No clinical evidence for CD4+ cell depletion caused by rituximab
- M. Wayne Saville, Mark C. Benyunes, Pratik S. Multani, H. Miles Prince, Kirsten Herbert, and David Westerman
Blood 2003 102: 408-409.
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This article has been cited by other articles:
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M. W. Saville, M. C. Benyunes, P. S. Multani, H. M. Prince, K. Herbert, and D. Westerman
No clinical evidence for CD4+ cell depletion caused by rituximab
Blood,
July 1, 2003;
102(1):
408 - 409.
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