Download Lymphoproliferative disease of granular T

From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
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
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 CD3ⴙ/CD8ⴙ/CD57ⴙ 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
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.
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
From the Divisions of Hematology and Hematopathology, Mayo Clinic and
Foundation, Rochester, MN.
Submitted March 30, 2000; accepted July 12, 2000.
Reprints: Robert L. Phyliky, Mayo Clinic, Division of Hematology, 200 First St
SW, Rochester, MN 55905; e-mail: [email protected].
3644
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).
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.
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
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.
© 2000 by The American Society of Hematology
BLOOD, 15 NOVEMBER 2000 䡠 VOLUME 96, NUMBER 10
From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
BLOOD, 15 NOVEMBER 2000 䡠 VOLUME 96, NUMBER 10
T-CELL LARGE GRANULAR LYMPHOCYTE LEUKEMIA
3645
Table 1. Median laboratory findings in 9 patients with lymphoproliferative
disease of granular T lymphocytes presenting as aplastic anemia
Median (range)
Normal
values
Hemoglobin (g/dL)
9.5 (5.0-10.5)
12.0-17.5
White cell count (⫻ 109/L)
2.4 (1.0-3.4)
3.5-10.5
Platelet count (⫻ 109/L)
46 (1-128)
150-450
Mean corpuscular volume (fL)
97.1 (90.0-117.0)
81.2-98.3
Absolute neutrophil count (⫻ 109/L)
0.65 (0.16-0.92)
1.70-7.0
Absolute lymphocyte count (⫻ 109/L)
1.58 (0.79-2.31)
0.90-2.90
Absolute granular lymphocyte count (⫻ 109/L)
0.61 (0.43-1.04)
0.10-0.50
Percentage granular lymphocytes (%)
43 (13-54)
5-25
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.
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
Table 2. Test results for selected patients with lymphoproliferative disease of
granular T lymphocytes presenting as aplastic anemia
No. of patients
Direct antiglobulin test (n ⫽ 5)
Positive
1
Antinuclear antibody test (n ⫽ 6)
Positive
2
Cytogenetic studies (n ⫽ 8)
Normal
4
Loss of Y chromosome
3
Translocation (1;7)
1
Peripheral blood flow cytometry (n ⫽ 6)*
Inverted CD4:CD8 ratio
2
Normal
4
Bone marrow immunohistochemistry (n ⫽ 8)
Increase in CD3⫹ cells and CD8⫹ cells
8
Increase in CD57⫹ cells
7
*Immunophenotypes studied include CD2, CD3, CD5, CD7, CD3/CD8,
CD3/CD4.
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.
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
From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
3646
BLOOD, 15 NOVEMBER 2000 䡠 VOLUME 96, NUMBER 10
GO et al
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.
Acknowledgments
We thank Janice Hodnefield, Barb Todd, and Bill Wittrock for their
laboratory assistance.
References
1.
Lamy T, Loughran TP Jr. Current concepts: large
granular lymphocyte leukemia. Blood Rev. 1999;
13:230-240.
2.
Dhodapkar MV, Li CY, Lust JA, Tefferi A, Phyliky
RL. Clinical spectrum of clonal proliferation of Tlarge granular lymphocytes: a T-cell clonopathy of
undetermined significance? Blood. 1994;84:
1620-1627.
3.
Go RS, Tefferi A, Li CY, Lust JA, Morice WG, Phyliky RL. Lymphoproliferative disease of granular T
lymphocytes: a single institution experience with
203 cases [abstract]. Blood. 1999;94:515a.
4.
International Agranulocytosis and Aplastic Anemia Study. Incidence of aplastic anemia: the relevance of diagnostic criteria. Blood. 1987;70:
1718-1721.
5.
Young NS, Maciejewski J. The pathophysiology
of acquired aplastic anemia. New Engl J Med.
1997;336:1365-1372.
6.
Semenzato G, Zambello R, Starkebaum G, Os-
7.
8.
himi K, Loughran TP Jr. The lymphoproliferative
disease of granular lymphocytes: updated criteria
for diagnosis. Blood. 1997;89:256-260.
United Kingdom Cancer Cytogenetics Group.
Loss of the Y chromosome from normal and neoplastic bone marrows. Genes Chromosomes
Cancer. 1992;5:83-88.
Scheres JM, Hustinx TW, Geraedts JP, Leeksma
CH, Meltzer PS. Translocation 1;7 in hematologic
disorders: a brief review of 22 cases. Cancer
Genet Cytogenet. 1985;18:207-213.
From www.bloodjournal.org by guest on August 12, 2017. For personal use only.
2000 96: 3644-3646
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
Updated information and services can be found at:
http://www.bloodjournal.org/content/96/10/3644.full.html
Articles on similar topics can be found in the following Blood collections
Brief Reports (1945 articles)
Clinical Trials and Observations (4598 articles)
Neoplasia (4182 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.