Blood, 15 November 2000, Vol. 96, No. 10, pp. 3644-3646
BRIEF REPORT
Lymphoproliferative disease of granular T lymphocytes
presenting as aplastic anemia
Ronald S. Go,
Ayalew Tefferi,
Chin-Yang Li,
John A. Lust, and
Robert L. Phyliky
From the Divisions of Hematology and Hematopathology,
Mayo Clinic and Foundation, Rochester, MN.
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Abstract |
Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also
known as T-cell large granular lymphocyte leukemia, is a clonal
disorder of cytotoxic T lymphocytes that is clinically manifested as
chronic neutropenia and anemia. Association with autoimmune disorders
is common. In 9 patients, T-LDGL is reported as presenting as aplastic
anemia. The clinical characteristics were similar to acquired aplastic
anemia. Morphologic evidence of increased granular lymphocytes in the
peripheral blood and an excess of
CD3+/CD8+/CD57+ cells in the bone
marrow were found in most cases. Cyclophosphamide was ineffective, but
noncytotoxic immunosuppressive agents generally produced a good
response. After a median follow-up of 49 months, 5 patients had died
from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL,
and T-LDGL should be considered in the differential diagnosis of
acquired aplastic anemia.
(Blood. 2000;96:3644-3646)
© 2000 by The American Society of Hematology.
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Introduction |
Lymphoproliferative disease of granular T
lymphocytes (T-LDGL), also referred to as T-cell large granular
lymphocyte leukemia, is a disorder of cytotoxic T lymphocytes,
characterized by the presence of clonal proliferation of granular
lymphocytes in the peripheral blood or bone marrow and clinically
associated with cytopenias, lymphocytosis, frequent infections, and
autoimmunity.1 The natural history of the disease is
usually prolonged and the prognosis relatively favorable. In many
patients, the disease is mild and requires little or no
therapy.2 The cytopenia is usually manifested as
neutropenia or anemia and much less frequently as thrombocytopenia.
Although not well described, pancytopenia can be the presenting finding
at diagnosis. Of the patients in our series of 203 T-LDGL patients,
14% had pancytopenia at presentation.3 A subset of these
patients fit the diagnostic criteria for aplastic anemia. Here, we
describe 9 cases of T-LDGL presenting as aplastic anemia.
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Study design |
After approval was obtained from the institutional review board,
our database of T-LDGL patients was reviewed for presentation of
aplastic anemia at diagnosis. Criteria for T-LDGL include unexplained abnormal blood counts (cytopenias, macrocytosis, and/or lymphocytosis) and expression of a clonal T-cell-receptor gene rearrangement. Detection of an increase of granular lymphocytes in the peripheral blood or bone marrow and supportive immunophenotypic studies by flow
cytometry or histochemistry were considered relevant but not essential.
The diagnosis of aplastic anemia was made according to the criteria
published by the International Agranulocytosis and Aplastic Anemia
Study group.4 We prepared a Wright-Giemsa-stained blood
smear for each patient and counted the absolute number and percentage
of granular lymphocytes as previously reported.2 Multiparametric flow cytometry of the peripheral blood or bone marrow
was used to study lymphocytic immunophenotype.
T-cell-receptor gene rearrangement study was performed by means of
either Southern analysis or polymerase chain reaction. Complete
response (CR) was defined as normalization of blood counts, including
granular lymphocytes. Partial response (PR) was defined as more than
50% improvement in the deviation of blood counts from normal, but less
than a CR, and by symptomatic improvement or, in the case of
transfusion dependency, a 50% reduction in transfusion
requirements. Any response less than partial was considered no
response (NR).
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Results and discussion |
Nine patients with T-LDGL presented with aplastic anemia. Of
these, 6 patients were males and the median age was 61 years (range,
39-72). Pertinent associated medical conditions were rheumatoid arthritis in one patient and concurrent inflammatory bowel disease and
giant cell arteritis in another. Presenting symptoms included fatigue,
easy bruising, mucosal bleeding, and fever. Lymphadenopathy, hepatomegaly, or splenomegaly were not observed. Laboratory findings are summarized in Tables 1 and
2. Three patients had severe aplastic anemia. None of the patients had absolute lymphocytosis. The
absolute granular lymphocyte count, percentage of granular lymphocytes
in the peripheral blood, and bone marrow granular lymphocytes were
increased in 7, 8, and 6 cases, respectively. One patient did not have
morphologic evidence of increased granular lymphocytes in the
peripheral blood or bone marrow. Immunohistochemical staining showed
interstitial marrow involvement by CD3+, CD8+,
and CD57+ cells in most cases. Rheumatoid factor and
antiplatelet antibody were tested in only 1 patient each, and were both
negative. Antineutrophil antibody was not tested in any
patient.
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Table 1.
Median laboratory findings in 9 patients with
lymphoproliferative disease of granular T lymphocytes presenting as
aplastic anemia
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Table 2.
Test results for selected patients with
lymphoproliferative disease of granular T lymphocytes presenting as
aplastic anemia
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Two patients died before specific treatment was instituted (1 and 12 weeks after diagnosis). Initial treatment consisted of prednisone in 5 patients, resulting in 1 unmaintained CR, 1 steroid-dependent PR, 1 transient PR, and 2 NR. The 2 remaining patients received a combination
of oral cyclophosphamide and prednisone. Both did not have a response.
After initial prednisone failure, 2 patients received cyclophosphamide
as second-line therapy without benefit. One of them subsequently
received antithymocyte globulin with cyclosporine and achieved a
transient PR. This patient, however, died of complications from
allogeneic bone marrow transplantation. The other patient received
cyclosporine and then azathioprine but did not have a response.
Prednisone was tried again, and a PR was achieved for 2.75 years. Other
second-line therapies included methotrexate (1 of 1 unmaintained PR)
and antithymocyte globulin with cyclosporine (1 of 1 unmaintained CR).
Time to treatment response varied from 1 to 3 months. For those
patients who achieved CR, treatment was generally continued for 6 months to a year. After a median follow-up of 49 months (range, 15-106 or higher), 5 patients had died from the disease or treatment-related
complications. Two patients died of sepsis, 1 of intracranial bleed,
and 1 of hepatic veno-occlusive disease after allogeneic bone marrow
transplantation. One other patient died of progressive disease, but the
terminal event was unclear. The treatment results are summarized in the Figure 1. The median survival for the
group was 40 months.
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| Figure 1.
Treatment outcomes of patients with aplastic anemia
associated with lymphoproliferative disease of granular T lymphocytes.
CR indicates complete response; PR, partial response; NR, no response;
ATG, anti-thymocyte globulin; BMT, bone marrow transplantation; and y,
years. aUnmaintained, btreatment dependent,
ctransient, and *duration of treatment
responses until last follow-up.
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Most patients with idiopathic aplastic anemia are now known to have an
immune-mediated destruction of hematopoietic cells.5 Cytotoxic T cells play an important role in this regard by release of
cytokines, which leads to inhibition of hematopoiesis and expression of
Fas receptors on progenitor cells. The interaction of Fas receptor with
the Fas ligand present in cytotoxic T cells triggers apoptosis. While
the exact pathophysiology of T-LDGL is not clear, it may be similar to
aplastic anemia.1
Compared with patients with idiopathic aplastic anemia, patients with
T-LDGL-associated aplastic anemia have similar demographic characteristics, presenting symptoms, and physical findings. Evidence of autoimmunity was observed in about half of all the patients. All but
one patient had evidence of granular lymphocytosis, either relative or
absolute, in the peripheral blood or bone marrow. We did not use
granular lymphocyte count as an absolute criteria for diagnosis because
some patients may have low granular lymphocyte count. This is
consistent with a recent report updating the criteria for
LDGL.6
Because of limited antibody panels studied with the use of flow
cytometry, we were not able to further characterize the immunophenotype of the granular lymphocytes. The presence of a clonal T-cell receptor gene rearrangement in all cases, however, pointed to a T-cell origin.
The diagnosis of T-LDGL can easily be missed if peripheral blood smear
and bone marrow are not carefully reviewed for granular lymphocytes,
because absolute lymphocytosis is usually not observed in an automated
blood count report.
With the exception of increased interstitial infiltration by
CD3+/CD8+/CD57+ cells, the bone
marrow findings were not different from acquired aplastic anemia. In
our experience, bone marrow cellularity in T-LDGL was normal in 41%,
increased in 39%, and decreased in 20% of the cases.3 It
is likely that when T-cell-mediated suppression of hematopoietic cells
is the dominant pathology, bone marrow will be hypocellular. When
B-cell dysfunction predominates, then a more cellular marrow may be
observed. We did not find any characteristic abnormality in the
analysis of bone marrow cytogenetics.
Three patients had loss of Y chromosome, and another patient had
translocation (1;7). Loss of Y chromosome is considered a normal
age-related phenomenon.7 Translocation (1;7) has been associated with myeloproliferative and myelodysplastic
disorders.8 The patient with translocation (1;7) did not
have any evidence of these disorders at diagnosis and at subsequent
follow-up. The use of cyclophosphamide, which is one of the preferred
treatments of T-LDGL, was not associated with a clinical response,
while noncytotoxic immunosuppressive agents being used for aplastic anemia produced a response in most cases. Further follow-up is necessary to assess the long-term outcome of these patients.
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Acknowledgments |
We thank Janice Hodnefield, Barb Todd, and Bill Wittrock for their
laboratory assistance.
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Footnotes |
Submitted March 30, 2000; accepted July 12, 2000.
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: Robert L. Phyliky, Mayo Clinic, Division of
Hematology, 200 First St SW, Rochester, MN 55905; e-mail:
phyliky.robert{at}mayo.edu.
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Abstract
Introduction
