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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3372-3378
Neutropenia Associated With T-Cell Large Granular Lymphocyte
Leukemia: Long-Term Response to Cyclosporine Therapy Despite
Persistence of Abnormal Cells
By
Raman Sood,
Carleton C. Stewart,
Peter D. Aplan,
Hiroyuki Murai,
Pamela Ward,
Maurice Barcos, and
Maria R. Baer
From the Departments of Hematologic Oncology and Bone Marrow
Transplantation, the Division of Medicine, Laboratory of Flow
Cytometry, the Department of Pediatrics, the Department of Neurology,
Laboratory of Molecular Diagnostics, and the Department of Pathology,
Roswell Park Cancer Institute, Buffalo, NY.
 |
ABSTRACT |
T-cell large granular lymphocyte (T-LGL) leukemia is clinically
indolent, but is associated with severe neutropenia in approximately 50% of cases. The pathogenesis of the neutropenia is unclear. We
report reversal of severe neutropenia associated with T-LGL leukemia in
five patients treated with cyclosporine (CSA). All five had persistent
neutrophil counts below 0.5 × 109/L, two had
agranulocytosis, and four had recurrent infections. Increased
populations of LGL were present in blood and marrow, with a T-LGL
immunophenotype
(CD3+CD8+CD16±CD56±CD57+)
shown by multiparameter flow cytometry, and clonal T-cell receptor (TCR) gene rearrangements in two of two pretreatment blood samples studied. CSA was initiated at doses of 1 to 1.5 mg/kg orally every 12 hours, with subsequent dose adjustments based on trough serum levels.
Four patients attained normal neutrophil counts with CSA alone; one
required addition of low-dose granulocyte-macrophage colony-stimulating
factor. Time to attainment of 1.5 × 109/L neutrophils
ranged from 21 to 75 days. Attempts to taper and withdraw CSA resulted
in recurrent neutropenia. Three patients have maintained normal
neutrophil counts on continued CSA therapy for 2, 8, and 8.5 years. Two
patients died 1.7 and 4.6 years after initiation of CSA despite normal
neutrophil counts one of metastatic melanoma and one of complications
after aortofemoral bypass surgery. Despite resolution of neutropenia,
increased populations of T-LGL cells have persisted in all patients
during CSA therapy, as shown by morphology and flow cytometry and by
the presence of clonal TCR gene rearrangements in four patients'
posttreatment blood samples. We conclude that CSA is an effective
therapy for neutropenia associated with T-LGL leukemia, and that
resolution of neutropenia despite persistence of abnormal cells implies
that CSA may inhibit T-LGL secretion of yet unidentified mediators of
neutropenia.
| |
INTRODUCTION |
LARGE GRANULAR lymphocytes (LGL) are a
morphologically distinct subset of lymphocytes which constitute 10% to
15% of normal peripheral blood mononuclear cells.1 LGL
include two phenotypically distinct populations of cells, T-cell LGL
(T-LGL), which express the T-cell antigen CD3, and natural killer cell
LGL (NK-LGL), which lack CD3 expression.2 LGL leukemias are
rare but well characterized.1 NK-LGL leukemia presents as
an acute systemic illness which pursues a fulminant course. In
contrast, T-LGL leukemia is generally clinically indolent.
Nevertheless, approximately 50% of patients with T-LGL leukemia have
severe neutropenia, which renders them susceptible to potentially
lethal infectious complications.1
The pathogenesis of severe neutropenia associated with T-LGL leukemia
is unclear, and its treatment has generally been
unsatisfactory.1 Therapy with corticosteroids and cytotoxic
agents is usually ineffective,3-5 splenectomy does not
generally produce sustained increases in neutrophil
counts,6 and colony-stimulating factor (CSF) therapy has
not yielded consistent results.7-10 Weekly oral
low-dose methotrexate was reported to be effective in reversing
neutropenia in 6 of 10 patients; LGL counts normalized in 5 of the 6, and abnormal clones identified by T-cell receptor (TCR) gene
rearrangements disappeared in 3.11 A response of T-LGL
leukemia with severe neutropenia to 2-chlorodeoxyadenosine has also
been reported.12
We report the use of cyclosporine (CSA) to successfully treat severe
neutropenia associated with T-LGL leukemia in a series of five
patients. Our patients have had long-term responses to CSA, but
maintenance CSA therapy has been required to sustain responses.
Neutrophil counts have normalized despite persistence of increased
populations of T-LGL, suggesting that CSA may inhibit T-LGL secretion
of yet unidentified mediators of neutropenia. CSA appears to represent
effective therapy for neutropenia associated with T-LGL leukemia.
| |
MATERIALS AND METHODS |
Patients.
Six patients with T-LGL leukemia were seen at Roswell Park Cancer
Institute (Buffalo, NY) between 1989 and 1995. The diagnosis of T-LGL
leukemia was established by the presence of increased populations of
LGL in the peripheral blood with T-LGL immunophenotypes (see below).
One patient had maintained absolute neutrophil counts (ANC) between 0.8 and 1.2 × 109/L for 20 years without any therapy, and has
continued to be observed with stable neutrophil counts without
therapeutic intervention. The other five patients had persistent ANCs
below 0.5 × 109/L. These five patients were treated with
CSA.
CSA therapy.
Patients were treated with daily oral CSA (Sandimmune, Sandoz, East
Hanover, NJ). CSA was initiated at a dose of 1 to 1.5 mg/kg orally
every 12 hours. Doses were gradually increased until ANCs rose above
1.5 × 109/L, while maintaining trough cyclosporine levels
in therapeutic range (250 to 400 ng/mL). One patient did not respond to
CSA alone, and recombinant human granulocyte-macrophage CSF (GM-CSF;
Schering-Plough, Kenilworth, NJ) was added at a dose of 1.5 µg/kg
subcutaneously daily. After resolution of neutropenia, CSA doses were
tapered to the lowest doses at which therapeutic responses were
maintained.
Multiparameter flow cytometry.
Peripheral blood mononuclear cell expression of the CD3, CD8, CD16,
CD57, and CD56 antigens was studied by multiparameter flow
cytometry13 using the Leu4, Leu2, Leu11, Leu7 (Becton
Dickinson, San Jose, CA), and NKH1 (Coulter, Hialeah, FL) monoclonal
antibodies. A mononuclear gate was created by gating out granulocytes
in the forward versus side scatter display. Populations of T-LGL,
defined by coexpression of CD3 and CD57, were measured in pretreatment and posttreatment blood samples. For Patient 4, in whom CD57 was not
studied pretherapy and whose T-LGL cells coexpressed CD3 and CD56,
CD3+56+ counts were compared in pretherapy and
posttherapy samples. To determine a normal range for
CD3+CD57+ cells, cells coexpressing these two
antigens were measured by multiparameter flow cytometry in peripheral
blood samples from 10 normal donors. A normal range of 0.128 ± 0.118 × 109/L (mean ± SD) was established. The normal range
for CD3+CD56+ cells in the same 10 donors was
0.098 ± 0.098 × 109/L.
Southern blot analysis.
Rearrangement of the TCR- subunit gene was studied by Southern blot
analysis using a probe for the constant region. Ten-microgram aliquots
of genomic DNA extracted from peripheral blood mononuclear cells were
digested with Hind III, EcoRI, and BamHI (New England Biolabs, Beverly,
MA). Digested DNA was size-separated by electrophoresis in 0.8%
agarose gels (Seakem GTG; FMC Bioproducts, Rockland, ME), transferred
to Zetabind (Cuno, Meridien, CT), and hybridized with a radiolabeled
400-bp Bgl II/Pst I CT genomic probe.14
Autoradiograms were interpreted according to Cossman et
al.14
To detect TCR- gene rearrangements, DNA digested with HindIII,
EcoRI, and BamHI was hybridized with a C1 probe.15 For TCR- gene rearrangement analysis, DNA digested with EcoRI, BamHI, and SstI was hybridized with a J1 probe.16
Polymerase chain reaction (PCR).
PCR was performed using a panel of 24 TCR- chain variable region
(TCR-V) and generic TCR- chain joining region (TCR-J) primers.17 TCR-V primers were fluorescently labeled.
Amplification reagents included 300 ng of DNA template; 1.5 mmol/L
MgCl2; 20 mmol/L Tris-HCl, pH 8.4; 50 mmol/L KCl; 0.2 mmol/L dNTPs; 7% dimethyl sulfoxide; and 0.1 µmol/L of each primer
in a total volume of 100 µL, to which 1 U of Taq polymerase (GIBCO,
Grand Island, NY) was added. Thermal cycling was performed in a DNA
thermal cycler (Perkin-Elmer Cetus, Norwalk, CT) as follows: an initial
denaturation for 5 minutes at 94°C, then 1 minute at 94°C, 1 minute
at 60°C, and 2 minutes at 72°C for 35 cycles. One microliter of
each PCR product was loaded on a 6% denaturant polyacrylamide gel,
electrophoresed, and scanned on a Genescanner 373 (Applied Biosystems,
Foster City, CA).
| |
RESULTS |
Pretreatment clinical data for the five patients with severe
neutropenia associated with T-LGL leukemia are shown in Table 1. Age at presentation ranged from 45 to 76 years (median, 62 years). Three patients were men and two were women.
All five patients had persistent neutrophil counts below 0.5 × 109/L; two of the five had agranulocytosis. Four patients
had had recurrent infections, including pneumonia, sinusitis, cutaneous abscesses, and urinary tract infections. One patient (Patient 3) was
also anemic, with a hemoglobin level of 8.8 g/dL, a mean corpuscular
volume of 101 µ, a low reticulocyte count, and absence of red blood
cell antibodies. The other four patients had normal hemoglobin values.
All five patients had normal platelet counts. Two patients had
splenomegaly at presentation. Two patients had rheumatoid factor; one
of the two (Patient 4) had a polyarthritis that was consistent with
rheumatoid arthritis, but the other (Patient 5) had minimal symptoms
and signs of arthritis.
Pretreatment bone marrow biopsies were hypocellular in three patients,
normocellular in one, and hypercellular in one. Granulocytic hypoplasia
was present in all cases, with myeloid to erythroid ratios ranging
between 1:1 and 1:16. Myeloid maturation was normal, without dysplasia
or maturation arrest. Erythroid maturation was also normal in all
patients. Patient 3, the patient with anemia, had 63% erythroblasts in
his pretreatment marrow, with normal maturation. LGL were seen in
marrow aspirates in all cases. Lymphoid nodules were present in four
patients' pretreatment bone marrow biopsies.
All five patients had increased populations of LGL shown in peripheral
blood smears. Immunophenotyping performed by multiparameter flow
cytometry showed T-LGL immunophenotypes in all five cases (Table
2). CD3, CD8, and CD57 were coexpressed on
T-LGL cells in all five. CD16 was also expressed on the abnormal
population in two cases, and CD56 in one.
Southern blot analyses of T-cell receptor genes performed on
pretreatment blood samples from Patients 3 and 5 showed TCR- gene
rearrangements. PCR analysis showed clonal expansion of the TCR-V24
and TCR-V4 families in Patients 3 and 5, respectively. The other
three patients did not have pretreatment material available for study.
Only one patient (Patient 1) had received previous therapy for severe
neutropenia associated with T-LGL leukemia before treatment with CSA.
Her initial treatment had consisted of splenectomy 6 years previously,
with a partial response for 3 years. She had then been treated with
prednisone, cyclophosphamide, antithymocyte globulin, plasmapheresis,
lithium, and interferon- , all without response. The other four
patients received CSA as their initial therapy.
Responses to CSA therapy are summarized in Table
3. Neutrophil counts normalized in all five
patients. The time to attainment of ANC  1.5 × 109/L
ranged between 21 and 75 days, with a median of 60 days. CSA doses
required to achieve a therapeutic response ranged between 100 and 300 mg every twelve hours. Four patients responded to CSA alone, and one
(Patient 3) to the combination of CSA and low-dose GM-CSF. All five
patients tolerated cyclosporine therapy well. The only toxicities were
mild hypertension in one patient and reversible renal dysfunction in
another.
Despite normalization of neutrophil counts, increased populations of
T-LGL persisted in all five patients' blood during CSA therapy.
Posttreatment peripheral blood smears continued to show increased
populations of LGL. Pretreatment and posttreatment T-LGL counts
determined by multiparameter flow cytometry are compared in Table
4. Post-CSA T-LGL counts were lower than
pretreatment counts in two patients (Patients 1 and 5), but were
similar to pretreatment counts in the other three. Figure
1 shows populations of T-LGL cells
demonstrated by multiparameter flow cytometry in Patient 5's blood
before initiation of CSA therapy and after response to CSA.
View larger version (26K):
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| Fig 1.
T-LGL cells
(CD3+CD8+CD16+CD56 )
shown by multiparameter flow cytometry in Patient 5's peripheral blood
before and after CSA therapy. The cells also expressed CD57 (not
shown).
|
|
TCR gene rearrangement studies were performed on posttreatment blood
samples from all five patients both by Southern blot analysis and by
PCR. Clonal TCR- gene rearrangements were shown in posttreatment
samples from four patients both by Southern blot analysis and by PCR.
Figure 2 shows TCR- gene rearrangements demonstrated by Southern blot analysis in Patient 5's peripheral blood
cells before and after CSA therapy, and Fig
3 shows clonal rearrangement of the
TCR-V4 demonstrated by PCR in Patient 5's blood cells after CSA
therapy. Patient 1's posttreatment blood cells did not show convincing
evidence of a TCR- gene rearrangement by Southern blot analysis or
by PCR, and neither TCR- nor TCR- gene rearrangement was shown by
Southern blot analysis. A pretreatment sample from Patient 1 was not
available for study.
View larger version (50K):
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[in a new window]
| Fig 2.
TCR- gene rearrangements shown by Southern blot
analysis in Patient 5's peripheral blood cells before and after CSA
therapy. The abnormal band is indicated by an arrow. Molt-4 and
DHL-4 cells are shown as positive and negative controls,
respectively.
|
|
View larger version (22K):
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| Fig 3.
Clonal rearrangement of TCR-V4 shown by the PCR in
Patient 5's blood cells after cyclosporine therapy (B). Shown as
negative controls are Patient 5's blood cells studied with V1
primers (A) and blood cells from a normal donor studied with V4
primers (C). The image in (A) is magnified 60-fold in relation to the images in (B) and (C). (A) and (C) show multiple small peaks produced by polyclonal rearrangements, whereas (B) shows a discrete tall peak
produced by a clonal rearrangement and superimposed on a polyclonal
background.
|
|
Pre-CSA and post-CSA bone marrow aspirate smears and biopsy sections
were compared in three patients (Table 5).Although the lymphocyte mass (the percentage of lymphocytes in the bone
marrow aspirate smear multiplied by the average cellularity of the bone marrow biopsy) decreased after treatment with CSA, the percentage of
lymphocytes remained elevated in all three patients, as did the
proportion of lymphocytes with LGL morphology (20% to 60%). All three
patients' bone marrow samples showed marked absolute granulocytic
hypoplasia before CSA therapy. There was a modest increase in
granulocyte mass (the percentage of granulocytes in the bone marrow
aspirate smear multiplied by the average cellularity of the bone marrow
biopsy) in posttherapy samples, but granulocytic hypoplasia persisted
in all three patients. Thus, despite normalization of ANCs, bone marrow
samples, like peripheral blood samples, showed evidence of persistent
involvement by LGL leukemia.
After attainment of responses in all five patients, attempts were made
to taper CSA doses to the lowest levels at which therapeutic responses
were maintained. The maintenance dose of CSA was lower than the
induction dose in all but one patient (Table 3). Although CSA doses
could be decreased, attempts to progressively taper and withdraw CSA
resulted in recurrent neutropenia. Of note, neutropenia recurred when
CSA therapy was tapered and withdrawn in Patient 3, the patient who had
required the addition of low-dose GM-CSF to CSA to achieve a response.
Recurrence of neutropenia when CSA was withdrawn showed that this
patient had in fact responded to CSA as well as GM-CSF.
The duration of follow-up ranges from 1.7 to 8.5 years (median, 4.6 years). Three of the five patients are alive, with normal neutrophil
counts. Patient 3 died of metastatic melanoma 1.7 years after
initiation of CSA. Patient 4 died of postoperative complications following aorto-femoral bypass surgery 4.6 years after initiation of
CSA, despite a normal neutrophil count.
| |
DISCUSSION |
We report sustained reversal of neutropenia associated with T-LGL
leukemia in five patients treated with CSA. Our report represents the
largest series of patients with LGL leukemia treated with CSA and has
the longest follow-up. This report highlights the relatively low doses
of CSA required to treat this disorder, the favorable toxicity profile
of CSA therapy, and the rapid onset of clinical response. We have also
shown the persistence of T-LGL cells despite resolution of neutropenia,
and the need for ongoing maintenance CSA therapy to sustain responses.
The diagnosis of T-LGL leukemia was established in our patients by
morphological demonstration of increased populations of LGL in
peripheral blood and by demonstration of the
CD3+CD8+CD57+ immunophenotype by
multiparameter flow cytometry. LGL counts in normal peripheral blood
have been reported as 0.198 ± 0.112 × 109/L,2 0.210 + 0.020 × 109/L,18 and 0.223 + 0.099 × 109/L,19 although higher values of 0.630 ± 0.261 × 109/L in men and 0.350 ± 0.176 × 109/L in women were found in one study.5 Using
coexpression of CD3 and CD57 to identify T-LGL, we established a normal
range of 0.128 ± 0.118 × 109/L. An LGL count of 2 × 109/L was used as the criterion for diagnosing LGL leukemia
in some earlier studies.4,5 It has subsequently been
recognized that otherwise typical LGL leukemia patients may have LGL
counts below 2 × 109/L.20 The updated
criterion for the diagnosis of LGL leukemia is the demonstration of
clonal expansion of a population of granular lymphocytes.20
Three of our patients had LGL counts of 2 × 109/L or
greater. The other two had LGL counts below 2 × 109/L,
but had flow cytometric evidence of T-LGL expansion, and also exhibited
TCR- gene rearrangements, albeit in posttreatment samples. Patient 1 in our series had an LGL count of 2 × 109/L and
had expansion of CD3+CD8+CD57+
cells shown by multiparameter flow cytometry, but did not have convincing evidence of a TCR gene rearrangement in a posttreatment blood sample, despite persistence of increased numbers of T-LGL shown
by morphology and flow cytometry. A pretreatment sample was not
available for study. The apparent absence of a TCR gene rearrangement
in this patient's cells was surprising, but rare cases of otherwise
typical T-LGL leukemia without TCR gene rearrangements have been
reported.1 Of particular note is a report of a patient with
T-LGL leukemia who had a clonal cytogenetic abnormality, but did not
have a clonal TCR gene rearrangement.21
Clonal disorders of T-LGL have an indolent clinical course. Neutropenia
is generally the most significant clinical problem in these patients.
Neutropenia has been reported in approximately 85% of patients, and
severe neutropenia (<0.5 × 109/L) is present in
approximately 50%.1 Recurrent bacterial infections resulting from severe neutropenia are the presenting feature in the
majority of cases. Anemia and thrombocytopenia are less common (approximately 50% and 20% of patients, respectively), and, when present, are generally mild. Rheumatoid arthritis is diagnosed in
approximately 30% of patients with LGL leukemia, but its
manifestations are generally mild.22 Thus, neutropenia
represents a life-threatening complication of what is otherwise an
indolent disease, and is the major indication for therapy.3
The mechanism by which severe neutropenia develops in patients with
T-LGL leukemia is not well understood.1 Neutropenia does
not appear to be caused by marrow infiltration, as the extent of bone
marrow infiltration by LGL cells is usually not sufficient to explain
the severity of the neutropenia, and neutropenia is more common and
more severe than anemia and thrombocytopenia.1 Moreover,
neutropenia does not appear to be caused by direct immune suppression.
Normal LGL have been shown to suppress GM colony formation,23-25 but this phenomenon has not been observed
when LGL cells from patients with LGL leukemia have been cocultured with bone marrow from normal donors,26,27 nor with
autologous marrow.28
Immune destruction mediated by granulocyte antibodies may play a role
in the neutropenia associated with T-LGL leukemia because anti-granulocyte antibodies are common,27,29 shortened
neutrophil survival has been shown,30 and both complement
fixation by the IgG fraction29 and antibody-dependent
cell-mediated cytotoxicity26 have been
observed. Nevertheless, peripheral destruction of
granulocytes cannot be the only operative mechanism because
granulocytic hypoplasia, as was noted in our patients, is a common
finding and anti-neutrophil-reactive IgG persists when neutrophil
counts normalize in response to methotrexate therapy.11
LGL from patients with T-LGL leukemia produce a variety of lymphokines
which may play a role in the genesis of neutropenia. Production of
interferon- has been shown, as has inhibition of myeloid colony
growth by interferon-.31 Interleukin-2 (IL-2) synthesis
has been demonstrated in T-LGL cells from patients with T-LGL leukemia,
and IL-2-mediated autocrine proliferation has been
suggested.32 Finally, tumor necrosis factor- (TNF-)
synthesis has been shown, and TNF- synthesis was stimulated by
incubation with IL-2.33
Neutropenia may arise by more than one mechanism in patients with T-LGL
leukemia. Baker et al34 showed both humoral and cellular
suppression of granulopoiesis in a patient with neutropenia associated
with a CD3+CD8+CD57+ population.
Marrow colony forming unit-GM (CFU-GM) growth was markedly reduced, but
normalized after T-cell depletion in the absence of autologous plasma.
Addition of either autologous T cells or autologous plasma to cultures
caused marked growth inhibition. Humoral suppression of CFU-GM was
shown to be mediated by the IgG fraction and seemed to be
complement-independent. The patient did not respond to plasmapheresis,
aimed at reversing humoral suppression of granulopoiesis, nor to
prednisone, cyclophosphamide, or vinblastine therapy, aimed at treating
cellular suppression. CSA therapy was initiated based on the idea that
it might be effective in inhibiting both cellular immune mechanisms and
synthesis of immunoglobulins (see below). Single-agent CSA therapy
produced rapid normalization of the neutrophil count, and in vitro
studies showed reversal of both humoral and cellular suppression, but only when CSA was present in the culture medium. This in vitro observation suggested the need for ongoing CSA therapy.
CSA is an immunosuppressive agent which inhibits activation of
CD4+ lymphocytes, thereby suppressing both cellular and
humoral immunity.35 CSA also inhibits expression of the
genes coding for IL-2 and the IL-2 receptor, as well as other
cytokines. Our use of CSA to treat neutropenia associated with T-LGL
leukemia was predicated on these properties, as well as on earlier
reports of the successful use of CSA to treat other immunologically
mediated cytopenias, including severe aplastic anemia,36
pure red cell aplasia,37 and amegakaryocytic
thrombocytopenia.38
There are five previous reports of successful CSA therapy of
neutropenia associated with LGL leukemia,39-43 including
our own 1989 abstract reporting the early results of treatment of
Patients 1 and 2 in the present report.38 Three other
patients successfully treated with CSA alone have been
reported.40-42 Two had previously been unsuccessfully
treated with other agents, including prednisone, cyclophosphamide,
vincristine, and lithium. All three patients received ongoing CSA
therapy after resolution of neutropenia. Numbers of T-LGL were
unchanged in one patient, but decreased markedly in the other two.
Jakubowski et al43 reported a patient with T-LGL leukemia
whose neutropenia, previously unresponsive to prednisone and
cyclophosphamide, did not respond to G-CSF alone but responded to the
combination of G-CSF and CSA, and who was then able to be receive
maintenance therapy consisting of G-CSF alone. T-LGL cells were not
detectable in this patient during maintenance therapy. CSA has also
been used to successfully treat adult-onset cyclic
neutropenia,44 an entity associated with clonal T-LGL
proliferation45; increased numbers of T-LGL persisted
during maintenance CSA therapy. Of interest also is a report of
successful CSA therapy of severe anemia in two patients with T-LGL
leukemia.46 As with CSA therapy of neutropenia, expanded
populations of T-LGL persisted despite successful therapy of anemia,
and maintenance CSA therapy was needed to sustain responses.
The mechanism of response of T-LGL leukemia to CSA is poorly
understood. We postulate that CSA reverses neutropenia associated with
T-LGL leukemia by inhibiting T-LGL secretion of inhibitory cytokines as
well as synthesis of anti-granulocyte antibodies. Based on our
experience with unsuccessful withdrawal of CSA therapy and based on in
vitro observations,34 it seems that maintenance of normal
neutrophil counts is dependent on ongoing CSA therapy, albeit in
reduced doses. Of note, increased populations of T-LGL persisted in all
of our patients despite resolution of neutropenia. Of interest are the
cases in the literature in which T-LGL decreased in number or became
undetectable coincident with CSA-induced resolution of neutropenia. CSA
likely interrupted an autocrine loop in these cases by inhibiting
synthesis of IL-2 and possibly other cytokines. It is unclear whether
ongoing CSA therapy is needed in cases in which T-LGL cells become
undetectable.
Successful CSA therapy of neutropenia associated with T-LGL leukemia in
a series of five patients, reported here, suggests that the response
rate to CSA is high. Nevertheless, additional, larger prospective
trials are needed to define the true rate of response to CSA in this
rare disorder. Additionally, mechanisms of response remain to be
defined.
| |
FOOTNOTES |
Submitted August 15, 1997;
accepted December 17, 1997.
Supported in part by National Institutes of Health Grant No. CA73773.
P.D.A. is a scholar of the Leukemia Society of America.
Address reprint requests to Maria R. Baer, MD, Division of Medicine,
Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The authors thank Dr William Lawrence (Buffalo, NY), Dr Alan Baer
(Buffalo, NY), and Dr Loren Rosenbach (Pittsburgh, PA) for referring
patients for this study.
| |
REFERENCES |
1.
Loughran TP:
Clonal disorders of large granular lymphocytes.
Blood
82:1,
1993[Abstract/Free Full Text]
2.
Chan WC,
Link S,
Mawle A,
Check I,
Brynes RK,
Winton EF:
Heterogeneity of large granular lymphocyte proliferations: Delineation of two major subtypes.
Blood
68:1142,
1986[Abstract/Free Full Text]
3.
Loughran TP,
Starkebaum G:
Large granular lymphocyte leukemia: Report of 38 cases and review of literature.
Medicine
66:397,
1987[Medline]
[Order article via Infotrieve]
4.
Semenzato G,
Pandolfi F,
Chisesi T,
de Rossi G,
Pizzolo G,
Zambello R,
Trentin L,
Agostini C,
Dini E,
Vespignani M,
Cafaro A,
Pasqualetti D,
Giubellino MC,
Migone N,
Foa R:
The lymphoproliferative disease of granular lymphocytes: A heterogeneous disorder ranging from indolent to aggressive conditions.
Cancer
60:2971,
1987[Medline]
[Order article via Infotrieve]
5.
Oshimi K:
Granular lymphocyte proliferative disorders: Report of 12 cases and review of the literature.
Leukemia
2:617,
1988[Medline]
[Order article via Infotrieve]
6.
Loughran TP,
Starkebaum G,
Clark E,
Wallace P,
Kadin ME:
Evaluation of splenectomy in large granular lymphocyte leukaemia.
Br J Haematol
67:135,
1987[Medline]
[Order article via Infotrieve]
7.
Thomssen C,
Nissen C,
Gratwohl A,
Tichelli A,
Stern A:
Agranulocytosis associated with T-gamma-lymphocytosis: No improvement of peripheral blood granulocyte count with human-recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF).
Br J Haematol
71:157,
1989[Medline]
[Order article via Infotrieve]
8.
Lang DF,
Rosenfeld CS,
Diamond HS,
Shadduck RK,
Zeigler ZR:
Successful treatment of T- lymphoproliferative disease with human-recombinant granulocyte colony stimulating factor.
Am J Hematol
40:66,
1992[Medline]
[Order article via Infotrieve]
9.
Mudler AB,
de Wolf JTM,
Smit JW,
Oostveen JW,
Vellenga E:
Correction of neutropenia by GM-CSF in patients with large granular lymphocyte proliferation.
Ann Hematology
65:91,
1992[Medline]
[Order article via Infotrieve]
10.
Lamy T,
LePrise P-Y,
Amiot L,
Drenou B,
Fauchet R,
Genetet N,
Semana G:
Response to granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to G-CSF in a case of agranulocytosis associated with large granular lymphocyte (LGL) leukemia.
Blood
85:3352,
1995[Free Full Text]
11.
Loughran TP,
Kidd PG,
Starkebaum G:
Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate.
Blood
84:2164,
1994[Abstract/Free Full Text]
12.
O'Brien S,
Kurzrock R,
Duvic M,
Kantarjian H,
Stass S,
Robertson LE,
Estey E,
Pierce S,
Keating MJ:
2-Chlorodeoxyadenosine therapy in patients with T-cell lymphoproliferative disorders.
Blood
84:733,
1994[Abstract/Free Full Text]
13. (Suppl 1)
Stewart CC:
Clinical applications of flow cytometry: Immunologic methods for measuring cell membrane and cytoplasmic antigens.
Cancer
69:1543,
1992[Medline]
[Order article via Infotrieve]
14.
Cossman J,
Uppenkamp M,
Sundeen J,
Coupland R,
Raffeld M:
Molecular genetics and the diagnosis of lymphoma.
Arch Pathol Lab Med
112:117,
1988[Medline]
[Order article via Infotrieve]
15.
Murre C,
Waldmann RA,
Morton CC,
Bongiovanni KF,
Waldmann TA,
Shows TB,
Seidman JG:
Human -chain genes are rearranged in leukemic T-cells and map to the short arm of chromosome 7.
Nature
316:549,
1985[Medline]
[Order article via Infotrieve]
16.
Chervinsky DS,
Grossi M,
Kakati S,
Block AMW,
Aplan PD:
Concurrent presence of inv(14)(q11q32) and t(4;11)(q21;q23) in pre-B acute lymphoblastic leukemia.
Genes Chrom Cancer
12:229,
1995[Medline]
[Order article via Infotrieve]
17.
Beers T,
Du T-L,
Rickert M,
Overturf P,
Choi Y,
Greenberg SJ:
Ex vivo clonotype primer-directed gene amplification to identify malignant T cell repertoires.
J Leukoc Biol
54:343,
1993[Abstract]
18.
Kelmen E,
Gergely P,
Lehoczky D,
Triska E,
Demeter J,
Vargha P:
Permanent large granular lymphocytosis in the blood of splenectomized individuals without concomitant increase of in vitro natural killer cell cytotoxicity.
Clin Exp Immunol
63:696,
1986[Medline]
[Order article via Infotrieve]
19.
Loughran TP,
Draves KE,
Starkebaum G,
Kidd P,
Clark CA:
Induction of NK activity in large granular lymphocyte leukemia: Activation with anti-CD3 monoclonal antibody and interleukin 2.
Blood
69:72,
1987[Abstract/Free Full Text]
20.
Semenzato G,
Zambello R,
Starkebaum G,
Oshimi K,
Loughran TP:
The lymphoproliferative disease of granular lymphocytes: Updated criteria for diagnosis.
Blood
89:256,
1997[Abstract/Free Full Text]
21.
Brito-Babapulle V,
Matutes E,
Foroni L,
Pomfret M,
Catovsky D:
A t(8;14)(q24;q32) in a T-lymphoma/leukemia of CD8+ large granular lymphocytes.
Leukemia
1:789,
1987[Medline]
[Order article via Infotrieve]
22.
Wallis WJ,
Loughran TP,
Kadin ME,
Clark EA,
Starkebaum GA:
Polyarthritis and neutropenia associated with circulating large granular lymphocytes.
Ann Intern Med
103:357,
1985
23.
Spitzer G,
Verma DS:
Cells with Fc Gamma receptor from normal donors suppress granulocyte macrophage colony formation.
Blood
60:758,
1982[Abstract/Free Full Text]
24.
Hansson M,
Beran M,
Andersson B,
Keissling R:
Inhibition of in vitro granulopoeisis by autologous allogeneic human NK cells.
J Immunol
129:126,
1982[Abstract]
25.
Barlozzari T,
Herberman RB,
Reynolds CW:
Inhibition of pluripotent hematopoietic stem cells of bone marrow by large granular lymphocytes.
Proc Natl Acad Sci USA
84:7691,
1987[Abstract/Free Full Text]
26.
Reynolds CW,
Foon KA:
T-lymphoproliferative disease and related disorders in human and experimental animals: A review of the clinical, cellular, and functional characteristics.
Blood
64:1146,
1984[Abstract/Free Full Text]
27.
Loughran TP,
Kadin ME,
Starkebaum G,
Abkowitz JL,
Clark EA,
Disteche C,
Lum LG,
Slichter SJ:
Leukemia of large granular lymphocytes: Association with clonal chromosomal abnormalities and autoimmune neutropenia, thrombocytopenia, and hemolytic anemia.
Ann Intern Med
102:169,
1985
28.
Grillot-Courvalin C,
Vinci G,
Tsapis A,
Dokhelar M-C,
Vainchenker W,
Brouet J-C:
The syndrome of T8 hyperleukocytosis: Variation in phenotype and cytotoxic activities of granular cells and evaluation of their role in associated neutropenia.
Blood
69:1204,
1986[Abstract/Free Full Text]
29.
Rustagi PK,
Han T,
Ziolkowski L,
Farolino DL,
Currie MS,
Logue GL:
Granulocyte antibodies in leukaemic chronic lymphoproliferative disorders.
Br J Haematol
66:461,
1987[Medline]
[Order article via Infotrieve]
30.
Starkebaum G,
Martin PJ,
Singer JW,
Lum LG,
Price TH,
Kadin ME,
Raskind WH,
Fialkow PJ:
Chronic lymphocytosis with neutropenia: Evidence for a novel, abnormal T-cell population associated with antibody-mediated neutrophil destruction.
Clin Immunol Immunopathol
27:110,
1983[Medline]
[Order article via Infotrieve]
31.
Hooks JJ,
Haynes BF,
Detrick-Hooks B,
Diehl LF,
Gerrard TL,
Fauci AS:
Gamma (immune) interferon production by leukocytes from a patient with a TG cell proliferative disease.
Blood
59:198,
1982[Abstract/Free Full Text]
32.
Koizumi S,
Seki H,
Tachinami T,
Taniguchi M,
Matsuda A,
Taga K,
Nakarai T,
Kato E,
Taniguchi N,
Nakamura H:
Malignant clonal expansion of large granular lymphocytes with a Leu-11+, Leu-7 surface phenotype: In vitro responsiveness of malignant cells to recombinant human interleukin 2.
Blood
68:1065,
1986[Abstract/Free Full Text]
33.
Zambello R,
Trentin L,
Bulian P,
Cassatella M,
Raimondi R,
Chisesi T,
Agostini C,
Semenzato G:
Role of tumor necrosis factor- and its specific 55-kd and 75-kd receptors in patients with lymphoproliferative disease of granular lymphocytes.
Blood
80:2030,
1992[Abstract/Free Full Text]
34.
Baker BL,
Hendricks JB,
Shahidi NT,
Woodson RD,
Schultz JC,
Norback DH:
Humoral and cellular immunosuppression of granulopoiesis in a patient with neutropenia.
Am J Med
85:264,
1988[Medline]
[Order article via Infotrieve]
35.
Kahan BD:
Cyclosporine.
N Engl J Med
321:1725,
1989[Medline]
[Order article via Infotrieve]
36.
Stryckmans PA,
Dumont JP,
Velu TH,
Debusscher L:
Cyclosporine in refractory severe aplastic anemia.
N Engl J Med
310:655,
1984[Medline]
[Order article via Infotrieve]
37.
Totterman TH,
Nisell J,
Killander A,
Gahrton G,
Lonnqist B:
Successful treatment of pure red cell aplasia with cyclosporine.
Lancet
2:693,
1984[Medline]
[Order article via Infotrieve]
38.
Hill W,
Landgraf R:
Successful treatment of amegakaryocytic thrombocytopenia with cyclosporine.
N Engl J Med
312:1060,
1985[Medline]
[Order article via Infotrieve]
39. (suppl 1)
Baer MR,
Martinez JY,
Dadey B,
Han T:
Cyclosporine reverses agranulocytosis associated with large granular lymphocyte proliferation.
Blood
74:68a,
1989
40.
Pastor E,
Sayas MJ:
Severe neutropenia associated with large granular lymphocyte lymphocytosis: Successful control with cyclosporin A.
Blut
59:501,
1989[Medline]
[Order article via Infotrieve]
41.
Garipidou V,
Tsatalas C,
Sinacos Z:
Severe neutropenia in a patient with large granular lymphocytosis: Prolonged successful control with cyclosporin A.
Haematologica
76:424,
1991[Medline]
[Order article via Infotrieve]
42.
Gabor EP,
Mishalani S,
Lee S:
Rapid response to cyclosporine therapy and sustained remission in large granular lymphocyte leukemia.
Blood
87:1199,
1995[Free Full Text]
43.
Jakubowski A,
Winton EF,
Gencarelli A,
Gabrilove J:
Treatment of chronic neutropenia associated with large granular lymphocytosis with cyclosporine A and filgrastim.
Am J Hematol
50:288,
1995[Medline]
[Order article via Infotrieve]
44.
Selleri C,
Catalano L,
Alfinito F,
De Rosa G,
Vaglio S,
Rotoli B:
Cyclosporin A in adult-onset cyclic neutropenia.
Br J Haematol
68:137,
1988[Medline]
[Order article via Infotrieve]
45.
Loughran TP,
Hammond WP:
Adult-onset cyclic neutropenia is a benign neoplasm associated with clonal proliferation of large granular lymphocytes.
J Exp Med
1164:2089,
1986
46.
Bible KC,
Tefferi A:
Cyclosporine A alleviates severe anaemia associated with refractory large granular lymphocytic leukaemia and chronic natural killer cell lymphocytosis.
Brit J Haematol
93:403,
1996[Medline]
[Order article via Infotrieve]
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Abstract
Introduction
Abstract