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Blood, 1 September 2002, Vol. 100, No. 5, pp. 1922-1923
CORRESPONDENCE
To the editor:
Severe cold hemagglutinin disease (CHD) successfully treated
with rituximab
Autoimmune hemolytic anemia results from an IgM antibody
(Ab)-red cell interaction and is referred to as cold hemagglutinin disease (CHD). CHD is most commonly associated with infectious or
lymphoproliferative diseases but may also be coupled with malignancies or autoimmune or immunodeficiency syndromes. Cold agglutinin-mediated hemolysis occurs at low temperatures, may be severe, and is notoriously difficult to treat. CHD patients with infections often have a short
clinical course, whereas those with lymphoma require therapy. Therapeutic maneuvers successful in patients with warm Ab-associated autoimmune hemolytic anemia such as corticosteroids, intravenous immunoglobulin G (IgG), and splenectomy are usually ineffective in
CHD.1,2 Novel treatment approaches of CHD are based on a
better understanding of the immunologic abnormalities associated with
this disorder, as well as the availability of sophisticated biotechnology products.1-5 Rituximab is a genetically
engineered chimeric monoclonal antibody that targets the CD20 antigen
on B cells currently used for the treatment of non-Hodgkin lymphoma. In
vitro studies have demonstrated that the antibody binds human C1q and
induces complement-dependent cytotoxicity, antibody-dependent, cell-mediated cytotoxicity, and apoptosis. In clinical trials of
patients with malignant lymphoma, rituximab depleted circulating B
cells with the first doses, leading to ongoing remissions and remaining
effective for several months.3-5 In these diseases, as in
autoimmune thrombocytopenia (ITP), rituximab presumably acts by
elimination of CD20+ clonotypic precursor B cells and/or
CD20+ plasma cells, applying to immunoglobulin-mediated
diseases of B lymphocytes.6 Here we report on 2 patients
with severe CHD, who were both successfully treated with the chimeric
anti-CD20 monoclonal Ab rituximab. The patients' disease course and
response to rituximab are displayed in Figure
1. Both patients were seronegative for
HIV-1 and HIV-2, and other infections were ruled out by appropriate diagnostic procedures.
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| Figure 1.
Changes in biologic variables before and after rituximab
therapy.
(A) First patient; (B) second patient. Pred indicates
prednisone; PP, plasmapheresis; Cy, cyclophosphamide; and
MMF, mycophenolate mofetil.
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The first patient, a 50-year-old female, was admitted to our hospital
in February 2001 because of severe anemia (hemoglobin level,
7.3g/dL), jaundice, weakness, and dyspnea. Respiratory sounds
were normal, and the spleen and liver were not enlarged. Laboratory
data showed marked reticulocytosis (7.54%) and bilirubinemia (7.8 mg/dL), positive direct Coombs test, a high cold agglutinin titer of
1:256 (normal, 1:32), and low haptoglobin level (21 mg/dL). A bone
marrow (BM) biopsy revealed a markedly hyperplastic erythropoiesis and
agglutination of erythroid precursors. Immune phenotyping showed only
polyclonal B cells and no cytogenetic abnormalities. Initially,
prednisone (2 mg/kg/d) was administered and slowly tapered (Figure 1A).
But 5 months later the direct Coombs test became positive again, with a
concomitant increase in cold agglutinins (1:1024), impressive decrease
of hemoglobin level to 5.9 g/dL, elevated reticulocyte
percentage (10.1%), elevated lactate dehydrogenase (LDH) level (458 U/L), elevated bilirubin level (6.8 mg/dL), and haptoglobin level below
5 mg/dL. Cyclophosphamide (1000 mg/m2) was given but did
not improve the clinical course. Therefore, mycophenolate
mofetil (MMF; 1 g/d, then 2 g/d) was started, which has been described
as beneficial in autoimmune hematolytic anemia.2 Nevertheless, the above parameters did not improve; on the contrary, severe illness of the patient persisted with daily worsening of the
clinical condition. Emergency plasmapheresis was carried out, resulting
in only brief clearance of cold agglutinins. Since the effect of
plasmapheresis did not lead to a marked improvement in the clinical
course, rituximab was given (375 mg/m2, intravenously,
weekly for 4 courses). Already with the first infusion, this led to a
marked improvement of the patient's clinical condition and to a
continuously rising hemoglobin level and marked decrease of
reticulocyte percentage and bilirubin and LDH levels (Figure 1A). MMF
was discontinued with the first rituximab infusion, and only the latter
continued for 3 additional weeks. Tolerance to treatment was excellent,
with no side effects. At last follow-up, 9 months after rituximab
therapy, the hemoglobin level is 12.6 g/dL, bilirubin level, 1.6 mg/dL,
and LDH level, 188 U/L, indicating continuing remission of CHD. The second patient, a 60-year-old woman, presented to our hospital in
March 2001. In 1990, laboratory studies had shown a positive direct
Coombs test, and an idiopathic CHD was diagnosed. Initially, only mild
signs of hemolysis with normal hemoglobin level did not require
specific therapy. During the year 2000, however, pre-existing
Raynaud phenomenon worsened and the hemoglobin level decreased
to 10.0 g/dL, reticulocyte percentage was 5.7%, haptoglobin level was
below 20 mg/dL, and LDH level was 583 U/L. Physical examination showed
neither adenopathy nor liver or spleen enlargement. The direct Coombs
test was positive, attributable to complement (C3d, 4+). Serum protein
electropheresis revealed a monoclonal protein (IgM kappa). The BM
aspirate and biopsy showed erythroid hyperplasia and lymphoplasmocytic
infiltrates (10%), with abnormal B cells by immunophenotyping. Since
this patient refused cyclophosphamide chemotherapy, she was treated
with rituximab (4 × 375 mg/m2). No infusion-related side
effects were observed. Five weeks and 11 months after the last
rituximab infusion, the hemoglobin level had increased to,
respectively, 12.1 g/dL and 12.9 g/dL, reticulocyte percentage
had decreased to, respectively, 2.5% and 2.0%, and LDH level had
decreased to, respectively, 335 U/L and 253 U/L (Figure 1B). Our report demonstrates that both CHD patients were successfully
treated with rituximab. No side effects occurred, and no additional
immunosuppressive or chemotherapeutic agents had to be administered to
maintain the response. The effect of the elimination of B cells by this
anti-CD20 therapy is novel and has rarely been described. One small
trial and only 2 case reports have reported on the use of rituximab in
patients with autoimmune hemolytic anemia.7-9 The largest
report comprises 6 children, showing an ongoing complete remission (CR)
with rituximab, but with warm reactive Ab (IgG)-associated autoimmune
hemolytic anemia, which is vastly better to treat than
CHD.7 The 2 case reports describe a CR to rituximab each
in a single patient with refractory CHD, including the diagnosis of an
indolent clonal lymphoproliferative disease similar to our second
patient.8,9 Nevertheless, these patients
received a combination of rituximab plus cyclophosphamide and
corticosteroids,8 or rituximab plus
 -interferon,9 whereas in our patients previous
nonresponsive medication was stopped with the beginning of rituximab in
the first patient, and, even more striking and not reported to date, a
complete remission was rapidly achieved with rituximab alone in the
second patient. Moreover, in these previous reports8,9 the
follow-up was shorter, the disease course milder,8,9 and
recurrence of CHD arose 7 months later, with the patient dying from a
stroke 14 months after the treatment initiation.9 In our 2 patients treatment response is ongoing 9 and 11 months after the start
of rituximab, with no CHD recurrence either in the first patient, with
no underlying primary lymphoma, or in the second patient, with no
further treatment necessity for the lymphoplasmocytic lymphoma. Of interest is, finally, that pure red cell aplasia (PRCA), as a rare
complication in chronic lymphocytic leukemia (CLL), has
recently been demonstrated in 2 B-cell CLL patients to also dramatically respond to rituximab,9 and its action in
Waldenström macroglobulinemia, immune thrombocytopenic purpura
(ITP), and cryoglobulinemia has clearly been
verified.10-12 The mechanism of action of rituximab seems
to be that of an immune modulation, presumably in Waldenström
macroglobulinemia due to the elimination of either CD20+
clonotypic precursor B cells or CD20+ plasma cells. The
same rationale may well apply to other immunoglobulin-mediated diseases
of B lymphocytes, such as cryoglobulinemia, ITP, and CHD. In summary,
our report strongly suggests that rituximab can successfully control
refractory CHD. With the increasing interest in Ab-based therapies,
rituximab appears to be a promising alternative to the conventional
medication in CHD. In view of its mild toxicity and the lack of
effective alternative treatments, it should be strongly considered in
severely affected patients who do not respond to standard therapy.
Monika Engelhardt, Andreas Jakob, Björn Rüter, Martin Trepel, Friedrich Hirsch, and Michael Lübbert
Correspondence: Monika Engelhardt, University of Freiburg
Medical Center, Hugstetterstr 55, D-79106 Freiburg, Germany; e-mail:
engelhardtm{at}mm11.ukl.uni-freiburg.de
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