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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 93 No. 3 (February 1), 1999:
pp. 1032-1037
Primary Plasma Cell Leukemia: Clinical, Immunophenotypic, DNA
Ploidy, and Cytogenetic Characteristics
By
R. García-Sanz,
A. Orfão,
M. González,
M.D. Tabernero,
J. Bladé,
M.J. Moro,
J. Fernández-Calvo,
M.A. Sanz,
J.A. Pérez-Simón,
A. Rasillo, and
J.F. San Miguel
From the Castellano-Leonés Cooperative Group for the Study of
the Monoclonal Gammopathies, Centro de Investigacion del
Cáncer de Salamanca, Institut d'Investigacions Biomédiques
August Pi y Sunyer de Barcelona (IDIBAPS) and the Spanish Cooperative
Group for the Treatment of the Hematological Malignancies (PETHEMA),
and the Department of Hematology, University Hospital of Salamanca,
Salamanca, Spain.
 |
ABSTRACT |
We report on a series of 26 patients diagnosed with primary (de
novo) plasma cell (PC) leukemia (PCL) in whom we analyzed the
clinicobiologic characteristics of the disease together with the
immunophenotype, DNA cell content, proliferative index, and numeric
chromosomal aberrations of the neoplastic PC, and compared them with
664 multiple myeloma (MM) patients at diagnosis. The median age, sex
ratio, and bone lesion extension were similar, but PCL cases displayed
a higher prevalence of clinical stage III, extramedullary involvement,
and Bence Jones cases, with fewer IgA cases than for MM patients. In
addition, according to several prognostic indicators
( 2-microglobulin serum level, proportion of S-phase PCs,
proteinuria, calcium serum level, lactate dehydrogenase [LDH] and
renal function), the incidence of adverse prognostic factors was
significantly higher in PCL versus MM. Immunophenotypic expression was
similar for CD38, CD138, CD2, CD3, CD16, CD10, CD13, and CD15, but PCL
differed from MM in the expression of CD56, CD9 HLA-DR, CD117, and CD20
antigens. Twenty-two PCL cases were diploid and one was hypodiploid,
while most MM cases (57%) showed DNA hyperdiploidy. With the
fluorescent in situ hydridization (FISH) technique, 12 of 13 PCL cases
displayed the numeric aberrations,  13 (86%), ±1 (57%), +18
(43%), and X in women (25%), but they lacked several numeric
aberrations usually found in MM such as +3, +6, +9, +11, and
+15. PCL cases had a lower overall response to therapy than MM cases
(38% v 63%, P = .01332). Among PCL patients, a
trend for a worse response was observed in cases treated with melphalan
and prednisone (MP) versus polychemotherapy. Overall survival was
significantly worse in PCL versus MM patients (8 v 36 months,
P < .0001), but it was significantly better in PCL patients
treated with polychemotherapy versus MP (18 v 3 months, P = .0137). By contrast, MM patients did not show
significant differences in overall survival according to the treatment
used, MP or polychemotherapy. Ten variables seemed to predict survival in PCL patients, but only the 2-microglobulin level and
S-phase PCs retained an independent value in multivariate analysis. In summary, our study illustrates that PCs from PCL display singular phenotypic, DNA cell content, and cytogenetic characteristics that lead
to a different disease evolution versus MM.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
MONOCLONAL GAMMOPATHIES comprise a wide
range of entities characterized by the proliferation of a clonal
population of terminally differentiated B cells, plasma cells
(PCs).1 When the number of circulating PCs is significant,
the term plasma cell leukemia (PCL) is usually used. The
French-American-British group2 has suggested that this term
should be restricted to a de novo presentation in leukemic phase, but
others have used it more generally.3,4 To obtain uniform
criteria for the diagnosis of PCL, Kyle et al3 proposed an
absolute PC count greater than 2 × 109/L, with PCs also
comprising greater than 20% of peripheral blood cells, although
according to others, these criteria are arbitrary.5 Due to
the low frequency of this entity, most publications on PCL are based on
case reports, and only two series with more than 20 patients can be
found in the literature.4,6 Moreover, information about the
intrinsic biology (immunophenotype, proliferative rate, and cytogenetic
aberrance) of tumor cells present in primary PCL and possible
differences versus myelomatous PCs is still scanty.
We now report on a series of 26 patients diagnosed with primary (de
novo) PCL in whom we have analyzed the clinicobiologic characteristics
of the disease together with the immunophenotype, DNA cell content,
proliferative index, and numeric chromosomal aberrations of the
neoplastic PCs, comparing them with 664 multiple myeloma (MM) patients
at diagnosis previously reported in part.7,8 Our results
show that primary PCL is associated with several biologic features
different from MM and follows an aggressive course with a poor response
to standard MM therapy.
| |
SUBJECTS AND METHODS |
Patients.
Between January 1982 and December 1996, we studied 26 patients with
primary PCL who were registered in our laboratory among 690 consecutive
untreated patients with MM (3.8%). The criteria for a diagnosis of PCL
required greater than 2 × 109/L blood PCs. The diagnosis
of MM was based on criteria from the Chronic Leukemia-Myeloma Task
Force.9 Patients were treated according to the protocols of
the Spanish cooperative group Programa Español de Tratamiento de
Hemopatías Malignas (PETHEMA), which include
melphalan and prednisone (MP) or alternating cycles of vincristine,
cyclophosphamide, melphalan, and prednisone/vincristine, bleomycin,
adriamycin, and prednisone (VCMP/VABP) at standard or high
doses.10 Patients with primary PCL received the same treatment as contemporary MM patients. Twelve received the standard MP
regimen, and the remaining 14 patients received polychemotherapy (VCMP/VBAP at standard dose, n = 5; VCMP/VBAP at high dose, n = 9).
In each patient, the most relevant clinical and laboratory disease
characteristics documented at diagnosis were evaluated for biologic and
prognostic significance. These included clinical features (age, sex,
performance status, bone pain and lesions, hepatosplenomegaly, and
plasmocytomas), hematologic parameters (hemoglobin level, white blood
cell count, platelet count, and erythrocyte sedimentation rate), serum
biochemical data (creatinine, urea, calcium, lactate dehydrogenase
[LDH], and 2-microglobulin levels), electrophoretic
characteristics (total protein, albumin, type of monoclonal [M]
component, and presence of urine Ig light chains), the percentage of
bone marrow (BM) PCs, and the presence or absence of bone lesions. The
performance status and bone lesions were scored according to previously
described criteria.10 In addition, patients were grouped
into clinical stages according to the Durie and Salmon
criteria.11
The response was considered to be complete, objective (OR), partial
(PR), or a failure (FR) according to the standard criteria of the
PETHEMA group.8,10 Patients who died before completion of
the therapy were considered as early deaths. Overall survival was
considered from the moment of diagnosis to the moment of death, and
response duration from the moment at which the response was obtained
until relapse.
Immunophenotypic studies.
Immunophenotypic characterization of BM PCs was performed as previously
described.12-14 The following panel of monoclonal
antibodies (MoAbs) whose specificity has been described
elsewhere12,15were used: Leu 17 (CD38), Leu M7 (CD13),
anti-CALLA (CD10), anti-HLA-DR (Ia), Leu 16 (CD20), Leu M1 (CD15),
FMC56 (CD9), Leu 19 (CD56), Leu 4 (CD3), Leu 5b (CD2), Leu 11c (CD16),
c-kit (CD117), and B-B4 (CD138). These MoAbs were used in triple
staining, with CD38 included in all combinations for specific
identification of PCs.16 Irrelevant isotype-matched mouse
Igs were used as negative controls.
Analysis of cell reactivity with the different combinations of MoAbs
was performed on a FACScan flow cytometer (Becton Dickinson, San Jose,
CA). Results were analyzed for at least 10,000 cells per
test using the PAINT-A-GATE-PRO software program (Becton Dickinson). An
antigen was considered positive when at least 15% of the PCs displayed
reactivity for this marker. A complete immunophenotype of the PCs was
available in 21 PCL and 290 MM cases.
DNA measurements.
DNA measurements were performed with previously described
methods.15,17 The DNA index was calculated as the ratio of
the modal channel obtained for PCs (CD38+++) and the
remaining normal cells (CD38 or CD38+)
present in the sample; in addition, the proportion of cells in the
different cell-cycle phases for both subsets (PCs and residual normal
cells) was calculated according to previously described criteria8,17 using the MODFIT software (Verity Software
House, Topsham, ME) after excluding cell doublets and
separately gating PCs and residual normal cells. Information about cell
DNA content from PCs and normal residual hematopoietic cells was
available for 22 PCL and 404 MM cases.
Analysis of numeric chromosomal aberrations.
The analysis of numeric chromosomal aberrations was performed using
interphase fluorescent in situ hybridization (FISH) with probes for 15 different human chromosomes according to previously described
methods.18 The following panel of probes were used for the
analysis of numeric aberrations: chromosomes 1 (pUC1.77; Boehringer
Mannheim, Mannheim, Germany), 3 (pAE0.68; Boehringer), 6 (D6Z1; Oncor, Gaithersburg, MD), 7 (pZ7.6B; Boehringer), 8 (pZ8.4; Boehringer), 9 (D9Z1; Oncor), 10 (CEP10; Vysis, Framingham, MA), 11 (CEP11; Vysis), 12 (D12Z3; Oncor), 15 (pMC15; Boehringer), 17 (pZ17-1.6A; Boehringer), 18 (pZXba; Boehringer), X (pDMX1; Boehringer), and Y (pHY2.1; Boehringer). In addition, a locus-specific DNA probe for the Rb gene sequence in chromosome 13 was used (LSI13; Vysis). Hybridization spots were evaluated by fluorescence microscopy, counting the hybridization spots per cell in at least 200 cells per
sample. In all slides analyzed, the number of unhybridized cells in the
assessed areas was less than 1%, and only spots with a similar size,
intensity, and shape were counted. The mean percentage of
trisomic/monosomic cells in control samples (BM cells from 20 healthy
individuals) was 0% to 2% for trisomies and 0% to 5% for
monosomies. A patient was considered to be carrying a numeric chromosomal abnormality when the percentage of cells displaying a
proportion of events with an abnormal number of spots was higher than
the mean ± 2 SD for the percentage obtained for that specific chromosome in normal controls. FISH analysis for numeric aberrations was available in 13 PCL and 56 MM patients.
Statistical methods.
To estimate the statistical significance of differences observed
between mean values for PCL and MM patients for continuous variables,
the Mann-Whitney U and Kruskal-Wallis tests were used with SPSS
statistical software (SPSS Inc, Chicago, IL).19 The chi-square test (crosstabs; SPSS) was used for comparison of
dichotomous variables between groups.19 Survival curves
were plotted according to the method of Kaplan and Meier and compared
using the log-rank test (survival; SPSS). The variables considered for
possible inclusion in a regression analysis (Coxreg; SPSS) were those
displaying a significant association with survival in the univariate
analysis (P < .05) or for which prior studies suggested a
possible prognostic value. The stepwise regression method was
discontinued when the P value for entering an additional factor
was greater than .05. The model was tested by including the variables
in a continuous manner.
| |
RESULTS |
Clinical features.
Twenty-six (3.8%) of 690 patients with PC malignancies referred to our
institution between 1983 and 1996 were identified as having primary
PCL. The most relevant clinical features of all 26 primary PCL patients
and the remaining MM patients are presented in Table 1. Upon comparing
the tumor burden according to the Durie and Salmon criteria, a higher
incidence of clinical stage III was found (P = .00093) in
primary PCL versus MM. In the PCL group, there was a higher prevalence
of Bence Jones protein cases and fewer IgA cases than in the MM group
(Table 1). Although the prevalence of Bence Jones protein cases was
higher in PCL, the degree of proteinuria was similar in PCL and MM
(3.7 ± 4.0 v 4.3 ± 5.2 g/d, P > .05). The
median age, sex ratio, and bone lesion extension were similar in both
groups of patients. Extramedullary involvement was noted in 4% of MM
cases and 23% (n = 6) of primary PCL cases (P < .05).
The six cases of extramedullary involvement were subcutaneous nodes
(n = 3), peritoneal plasmacytoma, meningeal infiltration, and
parapleural mass. In addition, according to several prognostic
indicators such as the 2-microglobulin serum level,
proportion of S-phase PCs, proteinuria, calcium serum level, LDH serum
level, and renal function, the incidence of adverse prognostic features
was significantly higher in PCL versus MM (P < .01).
Residual BM function was poorer in PCL cases, as assessed by both the
hemoglobin level and platelet count (Table
1), as well as the percentage of normal
residual BM cells in S phase (see Table 3).
Immunophenotypic characteristics and DNA cell content.
The immunophenotypic characteristics of PCs from both PCL and MM cases
are listed in Table 2. CD38 and CD138
antigens were excellent PC markers in both groups of patients, while
CD2, CD3, and CD16 were consistently negative in all cases. In
addition, the frequency of CD10+, CD13+, and
CD15+ cases was similar in both groups. By contrast,
statistically significant differences were observed between PCL and MM
for the expression of CD20, CD56, CD9, CD117, and HLA-DR antigens: the CD20 antigen displayed higher reactivity in PCL, whereas the other four
antigens were more frequently present in MM. These findings indicate
that although PCL has a characteristic immunophenotype that differs
from the pattern for MM, there is some overlap in antigenic expression.
All except one PCL cases analyzed were diploid (DNA index, 1), with the
remaining case displaying a DNA index less than 1. In contrast, most MM
cases (57%) showed a DNA index greater than 1 (Table 3). It should be
noted that in one PCL case, two PC subpopulations were found, one
diploid (DNA index, 1) and the other tetraploid (DNA index, 2). The
distribution of cells along the cell cycle was also different between
PCL and MM, with the former showing a higher percentage of S-phase PCs
and a lower percentage of S-phase residual normal cells (Table
3).
Numeric chromosomal aberrations.
Although only one of 13 PCL cases in which FISH studies were available
showed an abnormal DNA cell content by flow cytometry (DNA index,
0.88), FISH analysis revealed that 12 cases displayed numeric
aberrations (Table 4). In these cases with
a DNA index of 1, the abnormalities were not detected by flow
cytometry, due to the low sensitivity of the technique for detection of
balanced chromosomal gains and losses (eg, coexistence of one trisomy
and one monosomy) or single numeric chromosomal abnormalities (monosomy 13 and trisomy 18). The specific chromosomal abnormalities detected were monosomy 13 (85% of cases), chromosome 1 changes (57%), trisomy 18 (43%), and monosomy X in women (25%). In MM cases, a higher frequency of numeric abnormalities were detected, most corresponding to
trisomies 1, 6, 9, 11, and 15. Statistically significant differences between PCL and MM were observed for the following chromosomal aberrations: 13 (26% in MM and 84% in PCL, P = .00038),
+9 (0% in PCL and 52% in MM, P = .00835), and +6 (0% in
PCL and 32% in MM, P = .04231). Conventional cytogenetic
analysis was available in only three PCL patients, and no discrepancies
were observed versus the FISH analysis.
The PCL patient in whom two PC subsets with different DNA content were
identified had a complete FISH study, and two subpopulations of clonal
PCs were also found, one displaying tetrasomy for all chromosomes
analyzed and another one in which monosomy 13 and trisomy 18 were detected.
Response to treatment and outcome.
Within the PCL group, 29% of cases achieved an OR to treatment and 8%
a PR, while 50% showed progressive disease and 13% died before the
response could be evaluated. In contrast, in MM patients, there was a
complete response (negative immunofixation) in 4%, OR in 37%, PR in
22%, and stable disease in 9%, with only 13% of patients displaying
progressive disease. The remaining MM patients died before the response
was evaluated. Overall, patients with primary PCL achieved a
significantly lower response rate than patients with MM (38% v
63%, P = .01). Nevertheless, the frequency of complete
response plus OR was not significantly different between the two groups
of patients (41% v 29%, P > .05). Among primary PCL patients, the response tended to be worse in cases treated with MP
(17% of responses OR + PR, with only 8% OR) versus cases that
received polychemotherapy (OR + PR, 50%; OR, 47%), although these
differences did not reach statistical significance, probably due to the
low number of patients.
Overall survival was significantly worse in PCL versus MM patients
(median survival, 8 v 36 months, respectively,
P < .0001; Fig 1).
Interestingly, survival was significantly better in patients with
primary PCL treated with polychemotherapy versus MP (18 v 3 months, P = .0137; Fig 2a). In
MM, although survival was also better with polychemotherapy, the
differences were not statistically significant (Fig 2b). However, this
difference in therapeutic results between MM and PCL patients could be
due to the existence of different prognostic features within both
groups. To assess this aspect, we selected a group of 28 MM patients
matched with patients from the PCL group (high percentage of PCs in S
phase, high 2-microglobulin, anemia, hypercalcemia, and
stage III). No differences in survival were observed between these two
groups of patients (Fig 1). Moreover, in analyzing the influence of the type of treatment in 28 poor-prognosis MM patients (MP, n = 11; polychemotherapy, n = 17), it was found that the percentage of ORs
was also higher in those treated with polychemotherapy (56%) versus
the MP group (9%, P < .05), although this does not
translate into a significantly different survival.
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| Fig 1.
Survival differences between MM and primary PCL: (A) 664 MM patients (mean survival, 36 months), (B) 28 MM patients with poor
prognostic features (S-phase PCs >3%, 2-microglobulin
>6 mg/mL, and stage III) (mean survival, 13 months), and (C) 26 PCL
patients (mean survival, 8 months). 664 MM versus 26 PCL, P < .0001; 28 poor-prognosis MM versus 26 PCL, P = .2989.
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The response duration was slightly shorter in PCL versus MM patients (9 v 20 months, P = .0613). Due to the low number of patients with primary PCL who achieved a response with MP (n = 2), it
was not possible to compare its duration with the duration observed in
primary PCL patients treated with polychemotherapy.
Only one PCL patient received intensive therapy followed by stem cell
transplantation as first-line therapy. She was 45 years old and
achieved an OR after six courses of VCMP/VBAP, and then she received high-dose (200 mg/m2) melphalan followed by
autologous stem cell transplantation. At the time of the data
collection, this patient was alive and free from progression 18 months
after diagnosis.
Analysis of prognostic factors.
Ten variables were identified as having an unfavorable prognostic
influence (P < .05) on the survival of primary PCL cases (serum 2-microglobulin  6 mg/L, S-phase BM PCs 4.5%,
ECOG 2, serum LDH 460 U/L, serum creatinine 2 mg/mL, calcemia
11.0 mg/mL, serum C-reactive protein 6 mg/dL, platelet count
100 × 109/L, MP therapy, and absolute peripheral
blood PC count 4 × 109/L). Cox regression in 21 primary PCL patients showed that the 2-microglobulin
serum level and percentage of S-phase PCs were the only parameters with
independent prognostic value for predicting the outcome in these
patients (Table 5).
| |
DISCUSSION |
The data presented in this report show that patients with primary PCL
display a wide range of clinical and biologic differences compared with
MM patients, some of which concern the intrinsic characteristics
(immunophenotype, DNA cell content, and cytogenetics) of PCs and are
probably responsible for the variability in the treatment response and
the clinical behavior pattern.
PCs from PCL displayed a more immature phenotype than MM as assessed by
the expression of the CD20 antigen, which is usually absent in
MM.20 In addition, PCs from PCL frequently lacked the CD56
antigen, which has been considered to have an important role in
anchoring PCs to the BM stroma.21,22 Nevertheless, the
phenotypic differences do not allow a complete discrimination between
PCL and MM. The phenotypic characteristics could also help to explain
the differences in survival, since CD56 antigen expression has been
associated with a good prognosis21 while the CD20 antigen
has been associated with a shorter survival.7
To the best of our knowledge, only a few cases have been reported with
data for DNA cell content.17,23 Our study shows that all
PCL patients have a DNA index of 1 or less. This clinical picture is
completely different from that found in MM, which usually displays
hyperdiploidyDNA index greater than 1.1 Moreover, MM
patients with a DNA index of 1 or less usually have a poor prognosis.17,24,25 With the same laboratory approach used to assess DNA cell content, the distribution of PCs along the different
cell-cycle phases can also be measured,15 and clonal PCs
from primary PCL cases displayed a higher proliferative capacity (S-phase cells) versus MM. There are no other reports in which the
proliferative rate of PCs from PCL has been analyzed, but our
observation would explain why previous reports showed that PCL is
frequently associated with high serum LDH and aggressive behavior.4,6 In addition, we have also found in PCL that the proliferation of normal BM cells (residual cells in S phase) is
markedly blunted. This could explain why the degree of anemia and
thrombocytopenia is much higher in PCL versus MM, which would be
difficult to explain based only on the tumor burden.
We have detected a very high incidence of chromosome 13 monosomies
(85%) in PCL, in contrast to the low incidence observed in MM (26%).
This chromosomal abnormality has been associated with a short survival
in MM treated with either conventional chemotherapy26 or
high-dose therapy.27 In this PCL series, trisomies of
chromosomes 6 and 9 were absent, whereas they were frequent in MM
cases, with statistically significant differences. Other chromosomal
aberrations repeatedly found in MM, like trisomies for many chromosomes
(3, 7, 11, 15, and 17),18,28-30 were not present in our PCL
cases. Interestingly, some of these trisomies have been found to be
associated with a good prognosis in MM, such as trisomies 6, 9, and
17.26 Dimopoulos et al6 have reported nine PCL
cases in which conventional cytogenetic analysis was available, and
showed similar data for the presence of monosomy 13 (45% in nine
cases), numeric chromosome 1 changes (45%), and +18 (22%). However,
conventional cytogenetics showed that, apart from these results, many
other chromosomal aberrations can be observed in PCL cases that form
highly complex karyotypes.
The clinical data observed in our series are concordant with previous
reports3,31-33 showing that primary PCL patients usually have more extramedullary disease, anemia, thrombocytopenia,
hypercalcemia, increased LDH and 2-microglobulin serum
levels, and impaired renal function. These findings can be easily
explained not only by the presence at presentation of more extensive
disease in primary PCL versus MM, but also by the presence of a high
proliferative ratio of neoplastic cells and adverse cytogenetic data.
All of these data represent a unique array of adverse prognostic
factors that explain the poor outcome generally described for patients with primary PCL. An additional observation in concordance with previous reports4,6 is the poor response to MP compared
with polychemotherapy. Although such a difference has not been observed in MM, it should be noted that in MM, treatment comparisons have generally not been restricted to a cohort of patients with such adverse
prognostic features. In the present study, we selected a group of MM
patients with prognostic features matched to the group of PCL patients,
but the therapeutic results in the former group did not differ
according to the treatment administered. These findings indicate that
upon comparing different treatment approaches, PCL patients seem to
display a real difference in chemosensitivity compared with MM patients.
In summary, our study illustrates that PCs from PCL display a singular
phenotype, a DNA cell content and cytogenetic characteristics that are
responsible for a different disease evolution versus MM. In addition,
our data confirm that primary PCL requires not only different clinical
management but also different treatment.
| |
ACKNOWLEDGMENT |
The authors thank Mark Anderson for technical assistance.
| |
FOOTNOTES |
Submitted February 3, 1998; accepted September 25, 1998.
Supported in part by grants from the Spanish Fondo de Investigaciones
Sanitarias de la Seguridad Social (FIS-SS 96/1233), Dirección General de Investigación Científica y
Tecnológica (DGICYT PB93-0614), Areces Foundation (1997),
Dirección General de Enseñanza Superior (DGES PM97-0161),
and a grant from the LAIR Foundation (1998 to J.A.P.-S.).
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.
Address reprint requests to Prof J.F. San Miguel, MD,
PhD, Department of Hematology, University Hospital of
Salamanca, Paseo de San Vicente, 58-182, Salamanca, 37007 Spain;
e-mail: <sanmigiz{at}gugu.usal.es>
| |
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Abstract
Introduction