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Blood, 1 February 2002, Vol. 99, No. 3, pp. 1092-1094
BRIEF REPORT
Successful treatment of pure red cell aplasia with rituximab in
patients with chronic lymphocytic leukemia
Hassan Ghazal
From the Kentucky Cancer Clinic, Hazard, KY.
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Abstract |
Pure red cell aplasia (PRCA) is a rare complication in patients
with chronic lymphocytic leukemia (CLL). It is characterized by
reticulocytopenia and by an absence of red cell precursors in the bone
marrow. Unlike autoimmune hemolytic anemia, which is characterized by
an increased number of reticulocytes, positive Coombs test findings,
and a high serum level of lactate dehydrogenase. Two patients with
B-cell CLL are reported to have developed PRCA, one while on
chemotherapy with fludarabine and one seeking treatment for de
novo PRCA. Both responded dramatically to therapy with monoclonal
antibody rituximab (Rituxan) in a short period of time and continued to
be transfusion-independent. These are the first 2 reported patients for
whom rituximab treatment for PRCA in CLL was successful, and
this treatment deserves further investigation.
(Blood. 2002;99:1092-1094)
© 2002 by The American Society of Hematology.
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Introduction |
Pure red cell aplasia (PRCA) is a severe type of
anemia, characterized by an absence of red blood precursors in the bone
marrow and by reticulocytopenia while normal platelet and neutrophil production levels are maintained.1,2 PRCA is a rare
disorder and is a known complication in some (6%) patients
with chronic lymphocytic leukemia (CLL).1 It can also be
associated with autoimmune disorders, lymphoma, Hodgkin disease,
myeloproliferative disorders, acute and chronic hepatitis, thymomas,
and with drug-induced and other infections, particularly viruses such
as human parvovirus B19.1,2 In patients with CLL, anemia
can result from severe bone marrow infiltration and progression of the
disease or it can be the result of an autoimmune hemolytic process,
characterized by positive Coombs test findings, high lactate
dehydrogenase (LDH) level, and high reticulocyte count in peripheral
blood, in contrast to patients with PRCA. Therefore, it is important to
rule out hemolytic anemia in any patient with CLL anemia.
Rituximab (Rituxan; Genentech, San Francisco, CA) is a genetically
engineered chimeric monoclonal antibody designed to target CD20 antigen
on B cells. In vitro studies have demonstrated that the antibody binds
human C1q and induces complement-dependent cytotoxicity,
antibody-dependent, cell-mediated cytotoxicity, and
apoptosis.3,4 In clinical trials of patients with
lymphoma, rituximab depleted circulating B cells with the first few
doses and remained as effective for up to 6 to 9 months.5
We describe 2 patients with B-cell CLL and PRCA, one detected during de
novo presentation without any prior therapy and one during therapy with
fludarabine (Fludara; Berlex, Richmond, CA), a drug that can be
associated with autoimmune hemolytic anemia (AIHA). The first patient
did not respond to known therapeutic measures for 6 months and then
responded dramatically to rituximab in a short period of time. After
the second patient completed fludarabine therapy, rituximab treatment
was begun and produced a dramatic response in PRCA and a normalization
of blood counts in a short period of time. To our knowledge, this is
the first published report of the use of rituximab for the treatment of PRCA in patients with CLL, and it warrants further investigation. Recently, an infant with AIHA and PRCA was reported to have responded well to rituximab at 375 mg/m2 weekly for
two weeks and became transfusion-independent.6
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Study design |
Patient 1
The first patient was a 79-year-old man who sought treatment for
severe anemia in April 2000. He had an elevated white blood cell (WBC)
count of 25 × 109/L with 80% lymphocytes. A diagnosis
of B-cell CLL was made based on flow cytometry analysis showing 90%
CD20 and 97% CD5 positivity. Bone marrow aspiration and biopsy
specimen showed a diffuse pattern of lymphocytic involvement, and
chromosomal analysis revealed trisomy 12. His hemoglobin level dropped
to 7.0 g/dL, and he required blood transfusions every 3 weeks or so.
There was no evidence of hemolysis by virtue of negative Coombs test
results, normal serum LDH level, and reticulocyte count of 0.1% with
near-absent red cell precursors in the marrow. He had normal serum
vitamin B12 and folate levels, elevated ferritin level, normal platelet count, and no evidence of blood loss. In addition, human parvovirus B19
immunoglobulin (Ig)G and IgM findings were negative, and his erythropoietin level was elevated at 647 IU/L.
He received cyclosporin A to maintain serum level of more than 100 ng/mL. After 4 weeks, prednisone (40 mg/d) was added because treatment
elicited no response thus far. His course afterward was complicated by
the development of steroid-induced diabetes mellitus and rising WBC
counts up to 75 × 109/L, 4 months after he initially
sought treatment, and by transfusions every 3 weeks or so. At
that point (September 2000), intravenous immunoglobulin was initiated
at 1 g/kg per day for 2 days, again without much change in his anemia.
In October 2000, 6 months after cyclosporin-prednisone therapy,
rituximab was administered at 375 mg/m2 per week for 8 consecutive weeks, based on some data on its efficacy in CLL with
AIHA6-10 and based on results in our second patient. He
tolerated this treatment extremely well and did not have side effects.
His WBC count was 45 × 109/L, and that decreased in a
week to 12 × 109/L and to 3.6 × 109/L in
only 2 weeks. His hemoglobin count was 8.1 g/dL during the second week
of rituximab therapy, and he needed 2 U blood. This was the last
transfusion he needed. Dramatically, his reticulocyte count rose to
2.5%, and by the eighth week on rituximab, his hemoglobin count was
12.1 g/dL, and for the first time in 8 months he did not need a
transfusion. Repeat bone marrow aspiration and biopsy specimen showed
resolution of the PRCA with normal maturation of his erythroid series
and near resolution of lymphocytic infiltration. At last follow-up
(August 2001), his WBC count was 6.1 × 109/L, his
lymphocyte count was 2.6 × 109/L, his hemoglobin count
was 13.5 g/dL, and his platelet count was 170 × 109/L,
indicating continuing remission of CLL and PRCA.
Patient 2
The second patient is a 47-year-old woman with a 7-year history
of B-cell CLL, initial WBC count of 43 × 109/L,
hemoglobin level of 13.5 g/dL, and normal platelet count (findings in
January 1994), and clinically she remained in stage 0 disease. In late
1999, her WBC count began to rise rapidly and reached 160 × 109/L in February 2000 with a high
 2 microglobulin level (2.4 mg/L). Fludarabine was
administered at that time at 25 mg/m2 day for 5 days every
3 to 4 weeks. After 5 cycles, her WBC count was
22 × 109/L, and her hemoglobin level dropped to 7.1 g/dL, and she became transfusion-dependent. Her reticulocyte count was
0.1%, and she had no evidence of hemolysis based on negative direct
Coombs test, normal serum LDH level, and normal bilirubin level.
Vitamin B12 and folate levels were normal, ferritin level was elevated,
and human parvovirus B19 titers were negative. She declined bone marrow biopsy at that time. In July 2000, after 6 cycles of fludarabine therapy, her WBC remained slightly elevated at
14 × 109/L with 80% lymphocytes, normal platelet count,
and blood transfusion dependence in spite of erythropoietin (Procrit,
Ortho Biotech Products, Raritan, NJ) injections for more than 4 months.
Anemia could not be attributed to overcrowded bone marrow because
before therapy with fludarabine, her WBC was
160 × 109/L. At that time her hemoglobin level and
reticulocyte count were normal, and now her WBC count is only
14 × 109/L, indicating major shrinkage of the lymphocyte
population. Given that fludarabine failed to achieve complete response
and that there was a possibility of inducing immune modulation to
change her transfusion dependency combined with reports of rituximab inducing responses in patients with AIHA and
CLL6-10rituximab was tried as a consolidation therapy 6 weeks after her last cycle of fludarabine treatment. The patient
tolerated rituximab (375 mg/m2 per week for 8 weeks)
extremely well and had no side effects. Her WBC count dropped to
approximately 5 × 109/L with 50% lymphocytes. More
important, her reticulocyte count increased gradually from 0.1% to
approximately 10% by the eighth week of rituximab therapy, and she
became transfusion-independent after the fourth week of treatment. As
of August 2001, a year after the initiation of rituximab treatment, her
hemoglobin level is normal at 14.2 g/L, WBC is
2.5 × 109/L, absolute lymphocyte count is
1.2 × 109/L, platelet count is
209 × 109/L, and reticulocyte count is 2.3% (Figure
1).
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| Figure 1.
Hemogram and treatment sequence of patient 2.
Arrow ( ) represents fludarabine cycle, and ( ) represents
rituximab treatment.
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Results and Discussion |
As stated, anemia in patients with CLL can be attributed to many
factors, notably overcrowding of the marrow with leukemia cells,
hypersplenism, and auto-immune hemolysis. Rarely is it attributed to
PRCA. The pathogenesis of the latter is not well understood, but
abnormal T cells were found to inhibit the growth of erythroid
progenitor burst-forming and colony-forming units.12-14 These T cells included IgG-Fc receptor, and levels were higher in
patients with CLL-PRCA than in patients with stage III
CLL.12-14 In addition, the T cells decreased markedly
with effective therapy for PRCA.12-14 Rituximab is a
monoclonal antibody designed to target the CD20 antigen on B cells,
inducing apoptosis.3,4 Small uncontrolled trials and case
studies have reported the use of rituximab for the
treatment of patients with AIHA.6-11 PRCA can coexist with
AIHA in some patients,6 although both our patients had no
evidence of hemolysis. To our knowledge, this is the first published
report of rituximab use for the treatment of PRCA in CLL. The article
by Zecca et al6 of AIHA and PRCA in a infant reports one
of the rare combinations in the same patient. Even though the factors
are different than they are for our 2 patients with CLL and PRCA, it is
interesting that the infant responded to rituximab as well after only 2 weekly treatments. Perhaps this confirms that the rituximab mechanism
of action is that of an immune modulatory effect. A note of caution:
although our patients tolerated therapy well, cytokine release syndrome
and tumor lysis have been reported after the administration of
rituximab to patients with CLL whose lymphocyte counts were elevated.
Rare cytopenias have been observed, and PRCA associated with rituximab
therapy developed in a single patient with chronic human
parvovirus B19 infection.15
T-cell dysfunction has been proposed as the etiology of PRCA in
patients with CLL. Our results using rituximab, which primarily depletes B cell stores, challenges that idea and points to a possible role for B cells' dysfunction as well. Whether rituximab
also induces an immune modulatory effect on those T cells
remains to be seen. The other issue is the addition of rituximab, in
our second patient, after fludarabine therapy. Chemotherapy such as chlorambucil may select for those abnormal T lymphocytes and may increase their number, inducing PRCA. It remains a mystery how
rituximab, which depletes B cells, cleared PRCA after fludarabine therapy. Perhaps B cells are the final messengers by which T cells
relay the message.
Clearly, there is still a lot to be learned on this subject, and we are
far from a breakthrough, but at least we have documented positive
results using rituximab for treating PRCA in patients with CLL. Further
investigation is definitely warranted.
| |
Footnotes |
Submitted July 30, 2001; accepted September 27, 2001.
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: Hassan Ghazal, Kentucky Cancer Clinic, 200 Medical
Center Dr, Suite 3-0, Hazard, KY 41701; email: hassan{at}tgtel.com.
| |
References |
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Abstract
Introduction