|
|
 Previous Article | Table of Contents | Next Article 
Blood, 15 July 2001, Vol. 98, No. 2, pp. 483-485
BRIEF REPORT
Acquired pure red cell aplasia associated with
lymphoproliferative disease of granular T lymphocytes
Ronald S. Go,
Chin-Yang Li,
Ayalew Tefferi, and
Robert L. Phyliky
From the Divisions of Hematology and Hematopathology,
Mayo Clinic and Foundation, Rochester, MN.
 |
Abstract |
Acquired pure red cell aplasia (PRCA) can be associated with
lymphoproliferative disease of granular T lymphocytes (T-LDGL), also
known as T-cell large granular lymphocyte leukemia. Fifteen adult
patients with PRCA associated with T-LDGL comprise this study.
Neutropenia and rheumatoid arthritis were uncommon. All patients
responded to immunosuppressive therapy. The 2 most commonly used
treatments were prednisone and cyclophosphamide ± corticosteroids, producing overall response rates of 50% and 60%,
respectively. Treatment with cyclophosphamide was associated with a
more durable remission (median, 60 versus 7.5 months). After a median
follow-up of 67 months, 2 patients died of treatment-related
complications, one from myelodysplasia and another from
cyclosporine-induced renal failure. The clinical course and
treatment responses of PRCA associated with T-LDGL in this series were
similar to the general group of PRCA. Because T-LDGL is frequently
underdiagnosed, it is likely that a significant proportion of
idiopathic or primary PRCA is in fact secondary to T-LDGL.
(Blood. 2001;98:483-485)
© 2001 by The American Society of Hematology.
| |
Introduction |
Common to the pathophysiology of bone marrow
failure syndromes, including aplastic anemia, pure red cell aplasia
(PRCA), and a subset of myelodysplastic diseases, is an immune-mediated
suppression of marrow progenitor cells by cytotoxic T
lymphocytes.1-5 Lymphoproliferative disease of granular T
lymphocytes (T-LDGL) is a clonal disorder of cytotoxic T lymphocytes
that usually manifests as neutropenic infections and is associated with
autoimmune disorders, most commonly rheumatoid arthritis. T-LDGL can
present as failure of hematopoiesis or immune-mediated destruction in
any one or a combination of the several myeloid cell lines, including
red cells, neutrophils, and platelets. The frequent associations of
these bone marrow failure syndromes with T-LDGL and recent findings on
pathogenic mechanisms of T-LDGL suggest that T-LDGL may share a similar
pathology to these other syndromes.6,7 We have previously
reported that T-LDGL is a disorder frequently associated with
PRCA.8 In our institutional series of 203 patients with
T-LDGL, 15 (7%) patients presented as PRCA.6 This report
reviews our clinical experience in 15 patients with PRCA in the setting
of T-LDGL. This series included an update on 9 patients previously
reported.8
| |
Study design |
After receiving the approval of the institutional review board
of the Mayo Foundation, our database of patients with T-LDGL was
reviewed for associated PRCA. A diagnosis of PRCA was made on the basis
of clinical and bone marrow findings. Anemia with reticulocyte count of
less than 1% had to be present. On bone marrow examination, there was
almost complete absence of erythropoietic precursors or maturation
arrest at the pronormoblastic stage. Maturation of other hematopoietic
cell lines was normal. Other known causes of PRCA were excluded.
Published criteria for T-LDGL was used.9 Complete response
(CR) was defined as normalization of hemoglobin. Partial response
(PR) was defined as an increase in hemoglobin level by 2 g/dL or
more or by a 50% reduction in transfusion requirements. Any
response less than partial was considered no response (NR). The
percentage and absolute counts of granular lymphocytes in the
peripheral blood were calculated as previously reported.7 Multiparametric flow cytometry of the
peripheral blood or bone marrow and immunohistochemical staining of
bone marrow biopsy was used to study lymphocytic immunophenotype.
T-cell receptor gene rearrangement study was performed by using either the Southern blot analysis or polymerase chain reaction.
| |
Results and discussion |
We found 15 patients having PRCA associated with T-LDGL. In
all cases, the diagnosis of PRCA was made concurrently with T-LDGL. Of
those 15 patients, 8 were women. The median age at diagnosis was 66 years (range, 28-88 years). Associated medical conditions included
B-cell non-Hodgkin lymphoma (2), B-cell chronic lymphocytic leukemia
(1), thymoma (1), porphyria cutanea tarda (1), rheumatoid arthritis
(1), inflammatory bowel disease (1), and polyendocrine failure (1). In
the patient with a history of thymoma, thymectomy was performed 6 years
before the diagnosis of T-LDGL and PRCA. All patients presented with
symptoms because of anemia and were transfusion dependent. Except for
pallor, there were no other physical findings. Laboratory findings are
shown in Table 1. Absolute lymphocytosis
in the peripheral blood was noted in only 6 patients. In the rest of
the patients without absolute lymphocytosis, increase in granular
lymphocytes could be identified by examination of the peripheral blood
or the bone marrow.
View this table:
[in this window]
[in a new window]
|
Table 1.
Laboratory findings of 15 patients with pure red cell
aplasia associated with lymphoproliferative disease of granular T
lymphocytes
|
|
Seven patients were initially treated with prednisone (3 CR, 4 NR), and 5 patients received a combination of cyclophosphamide and
corticosteroids (4 CR, 1 NR). Other initial treatments included chlorambucil/prednisone (1/1 NR), methotrexate (1/1 NR), and
cyclophosphamide/doxorubicin/vincristine/prednisone (1/1 CR). The
treatment outcome from initial therapy until a response was obtained is
outlined in Figure 1. In patients who
initially responded to cyclophosphamide (5), the remission
duration ranged from 22 to 120 months. All responded again to
cyclophosphamide. In contrast, all prednisone responders (3) relapsed
within 5 to 10 months of treatment. They were retreated with either
oral cyclophosphamide (1 CR, 1 NR) or prednisone (1 CR). Salvage
treatments used included cyclosporine, methotrexate, fluoxymesterone,
antithymocyte globulin, or combination chemotherapy. The usual dosages
of immunosuppressive agents used were prednisone, 1 mg/kg/d;
cyclophosphamide, 50-100 mg/d; cyclosporine, 10 mg/kg/d; and
methotrexate, 7.5-15 mg/wk. In general, a specific treatment was tried
for at least 2 to 3 months unless side effects were not tolerated. The
use of cytotoxic agents was limited to a total of 6 to 12 months after
a response was achieved, whereas noncytotoxic immunosuppressive agents
were given as long as necessary to control the disease. After a median follow-up of 67 months (range, 22-113 months), 13 patients were alive;
10 patients had PR, and 3 patients were in unmaintained CR. Continued
therapy was necessary in all of the patients in PR. The clinical course
was characterized by frequent relapses, although durable responses
could be achieved. Two patients died of treatment-related
complications, one from acute myeloid leukemia arising from
myelodysplasia after cyclophosphamide treatment and another from
cyclosporine-induced renal failure.
View larger version (16K):
[in this window]
[in a new window]
| Figure 1.
Treatment outcomes of patients with PRCA associated with
T-LDGL from diagnosis until first response.
CR indicates complete response; PR, partial response; NR, no response;
DNT, did not tolerate; CHOP,
cyclophosphamide/doxorubicin/vincristine/prednisone; CVP,
cyclophosphamide/vincristine/prednisone; pt, patient.
|
|
It is now evident that a close association exists between T-LDGL
and PRCA.8,11,12 In our experience, PRCA is the second most common hematologic disease found in T-LDGL patients, exceeded only
by autoimmune hemolytic anemia.2 In this subset of T-LDGL with concomitant PRCA, it is notable that rheumatoid arthritis and
neutropenia were infrequently associated (1 and 2 patients, respectively). A careful examination of the peripheral blood is always
necessary as lymphocytosis was observed in less than half of our cases.
Similarly, bone marrow involvement by granular lymphocytes was mostly
subtle. Peripheral blood flow cytometry detected an abnormal T-cell
population in only 8 of the 12 patients studied. This finding was
probably because of the limited antibody panel we used (Table
1) for routine T-cell analysis. A more detailed analysis of the
CD8+ subset, including determinations of CD16, CD56, and
CD57, might have provided us more information. Initial case reports and
series of T-LDGL included only cases that were obvious on clinical
grounds, ie, those with evident lymphocytosis and symptoms, features
consistent with a later diagnosis.13,14 As is true when
there is a better awareness of a newly described disease, T-LDGL
earlier in its natural history is being recognized in a more recent
reported series.10 In fact, the diagnostic criteria for
T-LDGL were modified to reflect this
recognition.15 Nevertheless, we believe that T-LDGL remains a disease that is underdiagnosed.
The 2 most commonly used treatments in our series were prednisone
alone and cyclophosphamide with or without concurrent low-dose corticosteroids. As initial therapy, cyclophosphamide ± corticosteroids produced a better overall response rate (CR + PR)
than prednisone alone (80% versus 43%). When uses such as initial and
salvage therapies were considered together, the overall response rates for cyclophosphamide ± corticosteroids and prednisone were
similar (60% and 50%, respectively). Treatment with cyclophosphamide
was, however, associated with a longer duration of response, 60 months (range, 22-117 months) versus 7.5 months (range, 5-43 months). Cyclosporine and methotrexate were used in the setting of treatment failure from other agents, with responses noted in 2 of 3 and 1 of 3 patients, respectively. These responses were durable, but, in each
case, the treatment had to be maintained to achieve continued remission. All patients achieved remission after sequential
immunosuppressive therapy. This finding suggests that T-LDGL
association may be prognostic of a good response to immunosuppression.
Considering that the clinical course and treatment responses of PRCA
associated with T-LDGL are similar to the general group of PRCA and
that T-LDGL is probably an underdiagnosed disorder, it is likely that a
significant proportion of idiopathic or primary PRCA is, in fact,
secondary to T-LDGL.
| |
Acknowledgments |
We thank Janice Hodnefield, Barbara Todd, and William Wittrock for
their laboratory assistance.
| |
Footnotes |
Submitted November 14, 2000; accepted March 21, 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: Robert L. Phyliky, Mayo Clinic, Division of
Hematology, 200 First St, SW, Rochester, MN 55905; e-mail:
phyliky.robert{at}mayo.edu.
| |
References |
1.
Kagan WA, Ascensao JA, Pahwa RN, et al.
Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis.
Proc Natl Acad Sci U S A.
1976;73:2890-2894[Abstract/Free Full Text].
2.
Maciejewski JP, Hibbs JR, Anderson S, Katevas P, Young NS.
Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure.
Exp Hematol.
1994;22:1102-1110[Medline]
[Order article via Infotrieve].
3.
Abkowitz JL, Kadin ME, Powell JS, Adamson JW.
Pure red cell aplasia: lymphocyte inhibition of erythropoiesis.
Br J Hematol.
1986;63:59-67[Medline]
[Order article via Infotrieve].
4.
Akard LP, Brandt J, Lu L, Adamson JW.
Chronic T cell lymphoproliferative disorder and pure red cell aplasia.
Am J Med.
1987;83:1069-1074[CrossRef][Medline]
[Order article via Infotrieve].
5.
Knox SJ, Greenberg BR, Anderson RW, Rosenblatt LS.
Studies of T-lymphocytes in preleukemic disorders and acute nonlymphocytic leukemia: in vitro radiosensitivity, mitogenic responsiveness, colony formation, and enumeration of lymphocytic subpopulations.
Blood.
1983;61:449-455[Abstract/Free Full Text].
6.
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.
7.
Lamy T, Loughran TP Jr.
Current concepts: large granular lymphocyte leukemia.
Blood Rev.
1999;13:230-240[CrossRef][Medline]
[Order article via Infotrieve].
8.
Lacy MQ, Kurtin PJ, Tefferi A.
Pure red cell aplasia: association with large granular lymphocyte leukemia and the prognostic value of cytogenetic abnormalities.
Blood.
1996;87:3000-3006[Abstract/Free Full Text].
9.
Go RS, Tefferi A, Li CY, Lust JA, Phyliky RL.
Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia.
Blood.
2000;96:3644-3646[Abstract/Free Full Text].
10.
Dhodapkar MV, Li CY, Lust JA, Tefferi A, Phyliky RL.
Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance?
Blood.
1994;84:1620-1627[Abstract/Free Full Text].
11.
Mamiya S, Itoh T, Miura AB.
Acquired pure red cell aplasia in Japan.
Eur J Haematol.
1997;59:199-205[Medline]
[Order article via Infotrieve].
12.
Kwong YL, Wong KF.
Association of pure red cell aplasia with T large granular lymphocyte leukaemia.
J Clin Pathol.
1998;51:672-675[Abstract].
13.
McKenna RW, Parkin J, Kersey JH, Gajl-Peczalska KJ, Peterson L, Brunning RD.
Chronic lymphoproliferative disorder with unusual clinical, morphologic, ultrastructural and membrane surface marker characteristics.
Am J Med.
1977;62:588-596[CrossRef][Medline]
[Order article via Infotrieve].
14.
Pandolfi F, Loughran TP, Starkebaum G, et al.
Clinical course and prognosis of the lymphoproliferative disease of granular lymphocytes: a multicenter study.
Cancer.
1990;65:341-348[CrossRef][Medline]
[Order article via Infotrieve].
15.
Semenzato G, Zambello R, Starkebaum G, Oshimi K, Loughran TP.
The lymphoproliferative diseases of granular lymphocytes: updated criteria for diagnosis.
Blood.
1997;89:256-260[Abstract/Free Full Text].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. R. Mohan, M. J. Clemente, M. Afable, H. N. Cazzolli, N. Bejanyan, M. W. Wlodarski, A. E. Lichtin, and J. P. Maciejewski
Therapeutic implications of variable expression of CD52 on clonal cytotoxic T cells in CD8+ large granular lymphocyte leukemia
Haematologica,
October 1, 2009;
94(10):
1407 - 1414.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Fujishima, K.-i. Sawada, M. Hirokawa, K. Oshimi, K. Sugimoto, A. Matsuda, M. Teramura, M. Karasawa, A. Arai, Y. Yonemura, et al.
Long-term responses and outcomes following immunosuppressive therapy in large granular lymphocyte leukemia-associated pure red cell aplasia: a Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group
Haematologica,
October 1, 2008;
93(10):
1555 - 1559.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K.-i. Sawada, M. Hirokawa, N. Fujishima, M. Teramura, M. Bessho, K. Dan, H. Tsurumi, S. Nakao, A. Urabe, M. Omine, et al.
Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA Collaborative Study Group
Haematologica,
August 1, 2007;
92(8):
1021 - 1028.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Sokol and T. P. Loughran Jr.
Large granular lymphocyte leukemia.
Oncologist,
March 1, 2006;
11(3):
263 - 273.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Sloand, P. Scheinberg, J. Maciejewski, and N. S. Young
Brief Communication: Successful Treatment of Pure Red-Cell Aplasia with an Anti-Interleukin-2 Receptor Antibody (Daclizumab)
Ann Intern Med,
February 7, 2006;
144(3):
181 - 185.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Ravandi and S. O'Brien
Chronic Lymphoid Leukemias Other Than Chronic Lymphocytic Leukemia: Diagnosis and Treatment
Mayo Clin. Proc.,
December 1, 2005;
80(12):
1660 - 1674.
[Abstract]
[PDF]
|
|
|
|
|
|
|
M. G. Rose and N. Berliner
T-Cell Large Granular Lymphocyte Leukemia and Related Disorders
Oncologist,
June 1, 2004;
9(3):
247 - 258.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. O'Keefe, M. Plasilova, M. Wlodarski, A. M. Risitano, A. R. Rodriguez, E. Howe, N. S. Young, E. Hsi, and J. P. Maciejewski
Molecular Analysis of TCR Clonotypes in LGL: A Clonal Model for Polyclonal Responses
J. Immunol.,
February 1, 2004;
172(3):
1960 - 1969.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction