1. No category

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Pure Red Cell Aplasia: Association With Large Granular Lymphocyte
Leukemia and the Prognostic Value of Cytogenetic Abnormalities
By Martha Q. Lacy, Paul J. Kurtin, and Ayalew Tefferi
From 1980 through 1994, we identified 47 adult patients
netic abnormalities. Therewas a trend toward superior rewith acquired pure red cell aplasia (median age, 64 years;
sponse to immunosuppressive agents in the patients with
range, 22 to 84 years). Associated clinical disorders included T-cell LGL leukemia.Cyclophosphamide, with or without
T-cell large granular lymphocytic(LGL)leukemia, thymoma,
corticosteroids, was the mostuseful
treatment agent.
chronic lymphocytic
leukemia,
and
non-Hodgkin‘s
lymCyclosporine A was effective for refractory disease,Neither
phoma. Review of bone marrow findings in 40 patients
the presence of an associated clinical disorder northe exisshowed absence of erythroid precursors in 14 patients and
surtence ofdetectableerythroid precursors affected overall
rare pronormoblasts in 26. None had morphologic evidence
vival. We conclude that (l) T-cell LGL leukemia isthe disorof myelodysplasia. T-cell receptor gene rearrangement stud-der most commonly associated with pure red cell aplasia,
ies with Southern blot technique in 14 patients showed
(2) the presence of clonal cytogenetic abnormality predicts
clonalrearrangements in nine.Karyotypicanalysesperpoor response to immunosuppressive therapy, and (3) oral
formed in 28 patients showed clonal abnormalities in four.
cyclophosphamideandcyclosporineAareeffective
treatOverall, 28 of 47 patients (60%) responded to immunosupment regimens.
pressive therapy, but none were the patients with cytoge0 7996 by The American Society of Hematology.
P
URE RED CELL aplasia (PRCA)is a rare hematologic
syndrome characterized by anemia, reticulocytopenia,
and severe erythroid hypoplasiaof the bone marrow associated with quantitatively and qualitatively normal megakaryocytic and myeloid cell lines. In children, the syndrome is
often congenital and referred to as Diamond-Blackfan anemia. Acquired PRCA in children is usually self-limited and
referred to as “transient erythroblastopenia of childhood.”
In adults, most of the cases are idiopathic, and the rest have
been associated with lymphoproliferative disorders, parvovirus infections, and thymomas.
When PRCAmarrow cells areassayed in semisolid media,
60% have a normal number of assayable erythroid progenitors.’ Increased erythropoietic proliferative capacity in vitro
is correlated with therapeutic response to immunosuppressive
The ability to proliferate in vitro, but not in
vivo, is a notable feature of PRCA and suggests aninhibitor
in vivo that blockserythropoiesis.Humoralmechanisms
havebeen demonstrated in vitro,includingsuppression of
heme synthesis, inhibition of colony-forming units-erythroid
(CFU-E) and burst-formingunits-erythroid (BFU-E), and direct cytotoxicity to pronormoblasts.’-’
For the patients with PRCA in whom an IgG inhibitor
cannot be demonstrated, lymphocyte-mediated inhibition of
erythropoiesis isthoughttobe
themajor mechanism of
pathogenesis.Earlyinvestigations
of apatientwithT-cell
chronic lymphocytic leukemia showed that blood lymphocytes inhibited normal marrow CFU-E growth,an effect that
could be abolished by marrow treatment with antithymocyte
globulin and complement.’ Subsequently, T cells with recepFrom the Division of Hematology and Internal Medicine and the
Division of Patholog.y, Mayo Clinic and Mayo Foundation, Rochester,MN.
Submitted June 20, 1995; accepted November 15, 1995.
Address reprint requests to Ayalew Tefferi, MD, Mayo Clinic,200
First St SW, Rochester, MN 5.5905.
The publication costs of this article were defrayed
in part by page
chargepayment. This article must thereforebeherebymarked
“advertisement” in accordance with 18 U.S.C. .section 1734 sole1.v lo
indicate this fact.
0 1996 by The Americun Society of Hematology.
0006-4971/96/8707-00I9$3.00/0
3000
tors for the Fc portion of IgG molecule (Ty) were shown to
have an inhibitory effect on CFU-E.” A similar inhibition
of erythropoiesis in vitro by large granular lymphocytes has
also been demonstrated.”.” In patients with B-cell chronic
lymphocytic leukemia and PRCA, an increased percentage
of Ty cells wasfound in marrowaspirates and shown to
inhibitthe growth of erythroid colonies in vitro. CFU-E
growth markedly increased after removal of the Ty cells by
E-rosetting.”
PRCA secondary to parvovirus B 19 is thought to be due
to a direct toxic effect of the virus on pronormoblasts. Serum
that contains this DNAvirus inhibits CFU-E growth in vitro,
an effect that can be inhibited by antibody to the virus.“.”
Also, virus has been identified in proliferating CFU-E.
The aforementioned observations suggest a heterogeneous
pathogenetic mechanism in adult PRCA. Clinically,the natural history of the disease, the associated conditions, and its
response to treatment are incompletely understood, mainly
because most published series
are small. Also, few reports
include long-term follow-up information. The report of the
largest series to date has suggested that in most patients the
disease responds to immunosuppressive therapy, and that
PRCA is a chronic, relapsing disease with a median survival
time greater than I O years.“ Nevertheless, in a substantial
number of patients, the disease fails to respond to therapy,
with long-term survival less than the median. Identification
of prognostic factors would be useful in counseling patients
and in planning treatment.
We reviewed the 14-year-long experience at our institution with adultPRCA. Giventhe known associations of
PRCA with thymomaandchroniclymphocytic
leukemia,
we were particularly interested in looking for an association
with lymphoproliferative disorders. We also sought to identify potential prognostic factors and toreview response rates
to various treatment regimens.
MATERIALS AND METHODS
We identified 47 patients who were evaluated at
our institution
between 1980 and 1994 for acquired PRCA. The cases of five of
these patients have been included
in previous report^.""^ Patients
with Diamond-Blackfan anemia or transient erythroblastopenia of
childhood were excluded. The medical histories of the patientswere
reviewed retrospectively, and pertinent clinical and laboratory data
Blood, Vol 87, No 7 (April l ) , 1996: pp 3000-3006
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3001
PURE RED CELL APLASIA
Table 1. Conditions Associated With PRCA in 47 Patients
PR, no.
Overall
Response
Rate%
2
56
88
50
No. of
Clinical Association
Idiopathic 12
T-cell large granular
leukemia
lymphocytic
Thymoma
Chronic lymphocytic
leukemia
Non-Hodgkin‘s
lymphoma
Abnormal cytogenetics
Patients
CR. no.
25
9
6
2
4*
1
l
4
3
1
0
2
4
0
0
0
75
50
Abbreviations: CR. complete response; PR, partial response.
* One of the patients also had large granular lymphocytic leukemia.
were abstracted. Cytogenetic analysis and T-cell receptor (TCR)
gene rearrangement studies with Southern blot technique are offered
as routine clinical tests at our institution, and whenever available,
the results of these investigations were recorded. Follow-up data
were obtained by contacting the patient or his or her personal physician. All the patients had bone marrow aspirates and biopsies performed, and the findings were reviewed by one of our hematopathologists at the time of evaluation. Bone marrow specimens from 40
of the patients were available for rereview by a single hematopathologist (P.J.K.). The diagnosis of PRCA was made if the patient presented with a severe anemia and reticulocytopenia, the bone marrow
aspirate and biopsy showed absence of erythrocyte precursors on
maturation arrest atthe pronormoblastic stage, and the leukocyte
and platelet counts were normal. A diagnosis of large granular
lymphocytic (LGL) leukemia was made if the patient had evidence
of a clonal TCR gene rearrangement and lymphocyte phenotyping,
either by immuohistochemical techniques or flow cytometry, confirmed the LGL phenotype. In three cases, patients with clonal TCR
gene rearrangements did not have lymphocyte phenotyping available. In these patients, the diagnosis wasmade by finding large
granular lymphocytes in the peripheral blood smear and by excluding
other T-cell malignancies on clinical grounds. Patients with morphologic evidence of dysmyelopoiesis were excluded. A “complete response” was defined as a hemoglobin concentration greater than 11
g/dL sustained without transfusions. A “partial response” was defined as a hemoglobin concentration less than 11 g/dL in a patient
who became transfusion independent. Two-sided x* tests were used
to determine significance levels among different groups of patients
with regard to treatment outcome. Survival data were estimated with
the Kaplan-Meier method.
RESULTS
Patient Characteristics
Forty-seven patients who met the pathologic criteria for
the diagnosis of PRCA were identified. All these patients
were profoundly anemic for at least 1 month, and all required
transfusions of packed erythrocytes at some time. There were
28 malesand 19 females, the median age was 63 (range,
22 to 88 years). The median hemoglobin concentration at
presentation was 6.3 g/dL (range, 3.0 to 8.4 g/dL), with a
median retriculocyte count of 0.1 % (range, 0.1% to 0.6%).
All patients had radiographic examination or computed tomographic (CT) scans of the chest to look for thymoma. The
median follow-up periodwas 4.5 years (range, 0.5 to 13
years). Nine patients had T-cell LGL leukemia, four had
chronic lymphocytic leukemia, two had non-Hodgkin’s
lymphoma, and four had thymoma (Table 1). One of the
patients with thymoma also had LGL leukemia and, for the
purposes of this review, was grouped with the LGL leukemia
patients. Four patients had abnormal karyotypes. The karyotypic abnormalities are listed in Table 2. The 25 other patients were classified as having idiopathic PRCA. Acute leukemia did not develop in any of the patients. In one patient,
the onset of PRCA coincided with the resection of the thymoma. In two other patients, PRCA coincided with recurrences of unresectable invasive thymomas. Thymoma was
discovered in a fourth patient when he presented with PRCA.
Although his thymoma was resected, his PRCA did not improve. One year later, he underwent peripheral blood lymphocyte phenotyping and was found to have a preponderance
(86%) of CD3+/CD8+ lymphocytes. Subsequent TCR gene
rearrangement studies confirmed clonality.
Laboratory and Pathologic Review
Bonemarrow specimens from 40 of the patients were
available for review. Fourteen patients had an absence of
erythroid precursors (Fig 1). Twenty-six patients had maturation arrest at the level of pronormoblasts (Fig 2). Three
patients had giant pronormoblasts and vacuolations suggestive of parvovirus infection, and eight hadbonemarrow
eosinophilia. None of the patients had morphologic evidence
of myelodysplasia, as defined by the French-American-British Cooperative Group.’’ Furthermore, on the basis of bone
marrow morphology alone, it was difficult to identify prospectively those patients withLGL leukemia. The clonal
LGLs were always a minor bone marrow cell population,
accounting for 5% or less of the bone marrow cellularity.
The median hemoglobin concentration at presentation was
6.9 g/dL (range,3.0 to 8.4 g/dL). The median reticulocyte count
was 0.1% (range, 0.0% to0.6%).Themedianplateletand
leukocyte countswere normal. The patients who had abnormalities involving platelets or leukocytes had chronic lymphocytic
leukemia or LGL leukemia. Bloodor bone marrow specimens
(or both) from14 patients were tested for TCR gene rearrangements. The specimens from nine patients showed clonal rearrangementof TCR-P (Fig 3 and Table3).Peripheralblood
lymphocyte phenotyping, either with immunohistochemistry or
flow cytometry, was available in six
of the patients with
rearranged TCR gene and confirmed the LGL phenotype. Five
patients had lymphocytes positive for CD2 or CD3. Four
of
these patients were also positivefor CD8, and one was positive
for CD57. The lymphocytes from one patient expressed CD57,
but were not typed for CD2 or CD3. Twenty-eight patients had
cytogenetic analyses,and four had clonal karyotypic abnormali-
Table 2. Cytogenetic Abnormalities Detected in Four
of 28 Patients Tested who had PRCA
~
Cytogenetic Abnormality’
de1(20)(q11.2q13.1)
delX~pll.2),-2;der(5),t~5;?)(q13;?~,+rnar(l8~
t(1;5)(p36;q35)
-5,de1(5)(q15),+21
* In one patient each.
~___
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LACY, KURTIN, AND TEFFERI
3002
I
. i f
Fig l. Bonemarrowaspirate
fromone of 14 patients with
PRCA and absence of erythroid
precursors.
ties. Eght patients had serologic studies for parvovirus IgM,
and none were positive.
Results of Treatment
Because this was a retrospective review, the patients did
notreceiveuniformtreatment.Mostpatientsinitiallyreceived treatment with corticosteroids followed by various
forms of immunosuppressive therapy until a response was
achieved. Doses varied, but a typical starting dose was 0.5
to 1mgikg prednisone or its equivalent. Among the patients
receiving cytotoxic therapy, most received cyclophospha-
Fig 2. Bone marrow aspirate
from patient with PRCA. Note
ram pronormoblast$.
I
mide with or without prednisone. The doses of cyclophosphamide varied from 25 to 100 mg daily. One patient receivedcombinationchemotherapyconsistingofcyclophosphamide, vincristine, and prednisone. One other patient
receivedchlorambucilwithprednisone.Fivepatientsin
whom corticosteroids or cytotoxic therapy failed, received
cyclosporineA. Of these five patients, four had starting doses
of 12 mgkg in divided doses. The other patient had an initial
dose of 150 mg twice daily. The dose
of cyclosporineA was
tapered as tolerated.
Overall, 28 patients (60%) had a responseto immunosup-
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PUREREDCELLAPLASIA
l 2 3 4 5 6
Fig 3. Autoradiographs of the TCR gene rearrangements digested
with Ecom and hybridized with the JP, probe. Lane 1 shows the
pattern of a normal control subject. The arrow indicates that 11-kb
germline fraction. Lanes 2 through 6 demonstrate rearrangements in
five of the patients with PRCA. Similar rearrangements were found
in another four patients.
pressive therapy. After the patients with cytogenetic abnormalities were excluded, the response rate in the group was
65%. Among the 25 patients who received corticosteroids
as first-line therapy, responses were seen in nine. The median
time to response was 1.4 months (range, 1 to 3 months).
Four other patients were given corticosteroids after having
no response to other modalities; none of these patients had
a response. Cytotoxic agents with or without corticosteroids
were used as first-line therapy in IO patients, five of whom
had a response. Also, 15 other patients received cyclophosphamide after having no response to corticosteroids or other
therapies, and eight of these patients had a response to cyclophosphamide. The mediantime to response in this group
was 2.1 months (range, 1 to 3 months). All the patients who
had treatment with cyclosporine A received it as second- or
third-line therapy after failing to respond to corticosteroids
or cytotoxic agents. Three of these patients had a response
to cyclosporine A given initially at doses of 12 mgkg, and
one had a response to a dose of 150 mg twice daily. In all
the patients who had a response, cyclosporine A was tapered
as tolerated, and three patients have required ongoing maintenance therapy with low doses of the drug. All the patients
whohad a response to cyclosporine A hadit in thefirst
month of treatment. Two spontaneous remissions occurred,
both in patients with idiopathic PRCA. The PRCA in these
patients was not thought to be drug-induced, and the remissions were not associated with drug withdrawal. Six of the 28
patients who had a response, including the five who initially
received treatment with corticosteroids alone, had a relapse
when treatment was discontinued. Five of these six patients
wenton to achieve a second remission. The sixth patient
refused further therapy. None of the patients with a response
to cytotoxic agents had relapse. Fourteen patients achieved
3003
a response to their first therapy; most of the patients required
more than one type of treatment. The responses by various
clinical groups are listed in Table 1, and the results of all
the regimens used are listed in Table 4. The median survival
time for the group was 12 years. Amongthe 47 patients,
there were 13 deaths. Eight of these resulted from failure of
the PRCA, torespond to therapy, with resultant iron overload
and organ dysfunction. Two patients died of progressive
CLL. One patient died of progressive malignant thymoma.
Two patients died of unrelated medical problems.
The patients with LGL leukemia had a better response
to therapy than those with idiopathic PRCA (88% v 56%).
However, this result does not reach statistical significance
( P = .07), and the difference in survival time between the
two groups was not statistically significant. There wasno
difference when comparing the response rates and median
survival times between the patients who had an absence of
erythroid precursors and those withrare pronormoblasts
(57% v 50%; P = NS). None of the patients with karyotypic
abnormalities achieved remission.
DISCUSSION
Our data and those in the literature support the concept
that PRCA is pathogenetically heterogeneous. The blood and
bone marrow findings are the final common pathway ofat
least four different disease processes: ( I ) humoral inhibition
of erythropoiesis, (2) suppression of erythropoiesis by clonal
T cells, as in LGL leukemia, or by nonclonal T cells, as in
chronic lymphocytic leukemia and thymoma, (3) karyotypic
abnormalities of bone marrow stem cells that probablyrepresent a form of myelodysplastic syndrome, and (4)a direct
toxic effect of parvovirus B19 on erythroid precursors.
The association of PRCA with lymphoproliferative disorders is of interest because of the growing evidence that in a
subset of patients withPRCAthe disease ismediated by
clonal T-cell proliferations. The results of Mangan et all3
suggest that PRCA associated with chronic lymphocytic leukemiaismediated
by T lymphocytes. Abkowitz et all2
clearly demonstrated T-cell-mediated inhibition of erythropoiesis in marrow culture systems from patients with PRCA.
Sivakumaran et aIz0 reported two patients with PRCA who
Table 3. TCR Gene Rearrangements
Patient
F
G
H
I
Specimen
J01
Jbz
Studied
(EcoFiI or BarnHI)
(EcoRI)
BM
PB
PB
PB
BM
PB
PB
PE
PB
PB
+
+
+
+
+
+
TY
(EcoRI)
+
+
E
t
+
G
+
+
+
ND
ND
ND
G
+
G
ND
ND
ND
Abbreviations: BM, bone marrow aspirate; E, equivocal results; G,
germline; ND, not done; PE, peripheral blood; +, rearrangement
noted.
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3004
LACY, KURTIN, AND TEFFERI
Table 4. Treatment Regimens for Patients With PRCA
Response (no. of
patients)
Treatment Regimen
RR
Corticosteroids
9/29 5
CTX ? corticosteroids
13/25
(no.
Associated Conditions
of patients)
Complete
Partial
Response
No Response
6
3
Idio(5)
LGL(3)
NHL(1)
11
2
LGL(4)
Idio(6)
Idio(l1)
LGL(4)
Thy(2)
Abn Cyto(3)
Idio(4)
LGL(3)
Abn CytO(3)
CLL(2)
Abn cyto(1)
CsA
415
Plasmapheresis
1l6
Androgens
0113
ATG
Azathioprine
011
013
0
0
0
0
Methotrexate
Splenectomy
IVlG
Erythropoietin
Spontaneous
Ill
011
112
o/ 1
2
1
0
1
0
1
0
0
0
0
1
Relapse
(no. of patients)
to Time
Response
lmo)
3
Thy(1)
CLL(1)
LGL(1)
Idio(1)
Thy(1)
CLL(1)
Idio(1)
1
-
-
-
Idio(3)
NHL(1)
Abn cyto(1)
Idio(8)
LGL(1)
NHL(1)
Abn cyto( 1 )
Thy(1)
Abn cyto(1)
Idio(2)
LGL( 1)
Idio(1)
LGL(1)
1
Idio(2)
LGL(1)
Idio(1)
LGL(1)
-
Abbreviations: Abn cyto, clonal karyotypic abnormalities; ATG, antithymocyte globulin; CLL, chronic lymphocytic leukemia; CsA, cyclosporine
A; CTX, cyclophosphamide; Idio, idiopathic; WIG, intravenous immune globulin; LGL, T-cell large granular lymphocytic leukemia; NHL, nonHodgkin’s lymphoma; RR, overall response rate; Thy, thymoma
had TCR gene rearrangements that indicated T-cell clonality.
Motoji et a12’ reported a case of LGL leukemia associated
with PRCA. The TCR gene rearrangement could not be detected after the PRCA was treated successfully with cyclophosphamide. Hara et a12’ reported on a patient with PRCA
and type I autoimmune polyglandular syndrome whohad
rearrangement of TCRyS on Southern blot analysis and demonstrated that the TCRyS+ lymphocytes inhibited BFU-E
in culture. Oshimi et alZ3reported on a series of 33 patients
with LGL leukemia, four of whom metthe criteria (proposed
by D e ~ s y p r i s for
~ ~ )the diagnosis of PRCA. Eight other patients in that series had clinical presentations identical to
PRCA, but did not meet the pathologic criteria for PRCA.
Dhodapkar et a l l 7 identified five patients with PRCA among
68 patients with T-cell LGL leukemia.
In our series, LGL leukemia was the disorder most commonly associated with PRCA. Nine of the 14 patients tested
showed clonal TCR gene rearrangements. It is possible that
the association with LGL leukemia is even stronger than our
data suggest, because most of our patients were examined
before the Southern blots for TCR gene rearrangements were
routinely available at our institution.
In our experience, a clonal cytogenetic abnormality predicts a poor response to immunosuppressive therapy. It is
raretofind a cytogenetic abnormality in association with
PRCA, and nolarge series of such patients has been reported
that might help to assess its clinical significance. There have
been reports of two patients with PRCA associated with 5qkaryotypes, andneither of themhad a response to treatment.25.26Dessypris et a127reported a series of 31 patients
with PRCA in whom chromosome analyses were performed
and found one patient with an abnormal karyotype (47 +
G). The patient had no response to immunosuppressive therapyand subsequently developed acute leukemia.” It is of
interest to note that three of our four patients had abnormalities involving chromosome 5 and that the other patient had
a 20q- abnormality, an abnormality associated with disorders
of the erythroid series.28None of our patients and none of
those described in the literature had a response to immunosuppressive therapy. We postulate that the PRCA seen in
these patients is actually a form of myelodysplasia rather
than secondary to autoimmune or lymphoproliferative disease and that such patients are unlikely to have a response
to immunosuppressive therapy.
Our data do little to elucidate the role of parvovirus B19
in the pathogenesis of PRCA. Only eight of our patients had
IgM serologic studies for parvovirus, and none were positive.
The data of Frickhofen et alZ9suggest that as many as 15%
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3005
PURE RED CELL APLASIA
of cases of acquired PRCA are associated with parvovirus
infection. This distinction is important because the treatment
of choice for these patients would be immunoglobulin given
intravenously rather than immunosuppressive therapy.
Our data are consistent with those of Clark et all6 with
regard to treatment regimens. In our experience, treatment
with corticosteroids alone was of limited value. Only 30%
of the patients had a response, and most of these were not
durable responses. Three of nine patients who responded to
corticosteroids were able to maintain remissions after corticosteroid therapy was stopped. The others either had a relapse and required cytotoxic agents or became dependent on
corticosteroids. Thus, corticosteroids may still have a useful
role in the treatment of PRCA, particularly in young people
who may be spared the long-term consequences of cytotoxic
therapy or treatment with cyclosporine A. However, most
patients will require additional agents to achieve or to maintain remission. Treatment with cytotoxic agents, generally
a combination of cyclophosphamide and prednisone, was
effective in 50% of our patients. Of more importance, none
of these patients had relapse. In our experience, androgens
were of no benefit. On the basis of our data, plasmapheresis
is seldom justified. The experience with antithymocyte globulin (ATG) presented here was very limited. However, Abkowitz et a1” found six of nine patients with PRCAimproved
with use of ATG. Despite our small number of patients, we
found the most effective agent was cyclosporine A. Four of
the five patients who received this agent had a response. All
of those who had treatment with cyclosporine A received it
as second- or third-line therapy after not having a response
to corticosteroids or cytotoxic agents. The only patient who
did not have a response to cyclosporine A had a cytogenetic
abnormality. Means et a13’ used a combination of
cyclosporine A and corticosteroids and obtained responses
in six ofnine heavily pretreated patients. Raghavacha?* summarized the experience reported in the literature with treating
PRCAwith cyclosporine A and reported that the overall
response rate was 65%. Therefore, consideration should be
given to using cyclosporine A earlier to treat PRCA.
In conclusion, we found that LGL leukemia is the disease
most commonly associated with PRCA.This association predicts superior response to immunosuppressive therapy, but
is not correlated with improved survival. We found that a
cytogenetic abnormality predicts poor response to immunosuppressive therapy and that such patients may be better
served by treatment strategies suitable for clonal myeloid
disorders. The presence or absence of erythroid precursors
in the bone marrow does not correlate with clinical outcome.
Various immunosuppressive agents are effective in the treatment of PRCA.
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Pure red cell aplasia: association with large granular lymphocyte
leukemia and the prognostic value of cytogenetic abnormalities [see
comments]
MQ Lacy, PJ Kurtin and A Tefferi
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