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Clinical Profile of Plasma Cell
Leukemia at Tertiary Care Hospital in
Kashmir, India
Javvid Muzamil, Shiekh A. Aziz, Gull M. Bhat, Abdul R. Lone, Shuaeb Bhat
1
,
Firdousa Nabi
2
Abstract:
INTRODUCTION: Plasma cell dyscrasias represent 1.4–2% of all malignancies and among
hematologic malignancies; it constitutes 10% of the tumors. Plasma cell dyscrasias are composed
of multiple myeloma (MM), and primary and secondary plasma cell leukemia.
MATERIALS AND METHODS: Primary plasma cell leukemia (pPCL) is a rare and aggressive
disease, representing 1–4% of plasma cell dyscrasias.
RESULTS: The prognosis of this is very poor with median survival of 8–11 months in different reported
series.
DISCUSSION: We are reporting a study from our hospital over a period of 8 years and 9 months, in
which pPCL was found in 1.8% of MM patients, with slight male predominance and earlier age than
MM, and all had high disease burden with high lactate dehydrogenase (LDH), β2-microglobulin, and
plasmacytosis.
CONCLUSION: This disease had very aggressive behavior, especially with light chain lambda
disease, and all patients succumbed within 8 months of treatment.
Keywords:
Lactate dehydrogenase (LDH), multiple myeloma (MM), per iodic acid schiff (P.A.S.), peripheral
blood film (PBF), primary plasma cell leukemia (pPCL), secondary plasma cell leukemia (sPCL),
Sudan black stain (S.B.)
Introduction
Primary plasma cell leukemia (pPCL) is
arareandaggressivediseasewitha
prevalence of only 1–4% of all plasma cell
malignancies.
[1-3]
It is defined by the
presence of >2×10
9
/l peripheral blood
plasma cells or plasmacytosis accounting
for >20% of the white cell count.
[1]
The
prognosis of pPCL is very poor with a
median overall survival (OS) of 8–11
months.
[1,4]
However, the outcome of
pPCL has improved by the introduction
of autologous stem cell transplantation as
well as novel agents like bortezomib.
[1,4-7]
Compared to multiple myeloma (MM), the
presenting signs and symptoms of pPCL
have a more rapid onset with higher
tendency of hyper-metabolic symptoms
(weight loss, fever, sweating, fatigue, and
weakness), extra-medullary manifestations,
hypercalcemia, renal involvement, bone
marrow failure, and higher β2-
microglobulin but rarely osteolytic bone
lesions.
[7]
Furthermore, the presence of
poor-risk cytogenetic alterations known
from MM is markedly higher.
[1,4,8]
PCL is
classified as primary when it presents “de
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DOI:
10.4103/1658-5127.192988
Departments of Medical
Oncology
1
Clinical Hematology,
Sher I Kashmir Institute of
Medical Sciences, Soura
2
Department of
Prosthodonsia, Govt.
Dental College, Srinagar,
Jammu and Kashmir,
India
Address for
correspondence:
Dr. Javvid Muzamil, MD
(Internal Medicine), DM
(Scholar), Department of
Medical Oncology, Married
Hostel, Room Number
F16, Sher I Kashmir
Institute of Medical
Sciences, Soura, Srinagar
- 190 011, Jammu and
Kashmir, India.
E-mail:
Javvidmd@gmail.com
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of the Creative Commons Attribution-NonCommercial-
ShareAlike 3.0 License, which allows others to remix,
tweak, and build upon the work noncommercially, as
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For reprints contact: reprints@medknow.com
How to cite this article: Muzamil J, Aziz SA, Bhat
GM, Lone AR, Bhat S, Nabi F. Clinical profile of
plasma cell leukemia at Tertiary Care Hospital in
Kashmir, India. J Appl Hematol 2016;7:95-101.
©2016 Journal of Applied Hematology | Published by Wolters Kluwer - Medknow 95
Original Article
[Downloaded free from http://www.jahjournal.org on Wednesday, October 26, 2016, IP: 14.139.59.178]
novo”in patients with no evidence of previous MM and
as secondary when it is observed as a leukemic
transformation of relapsed or refractory disease in
patients with previously recognized MM.
[9]
60–70%
of PCL are primary, and the remaining 30–40% are
secondary.
[10]
More recent data suggest that there is an
increasing incidence of secondary PCL, now
accounting for about 50% of the cases.
[4]
We are
reporting our experience about primary plasma cell
leukemia for almost 10-year period and found
different biology in our patients and very poor
prognosis.
Clinical study: It is discussed under following headings.
Materials and Methods
A study was conducted at our hospital with hemto-
oncological setup for the past 28 years. A cancer registry
is maintained for the past 15 years. Clinical survey was
conducted on plasma cell leukemia for the last 8 years
beginning from 2007 till September 2015. The first
patient was enrolled in January 2007 and the last
patient was enrolled in December 2014. All patients
of MM and de-novo plasma cell leukemia were enrolled
in the study. Patient characteristics were noted down
and all patients underwent complete hemogram with
peripheral blood film (PBF) examination. If PBF was
abnormal with presence of plasma cells with either 2000
cells/μl or 20% of total cell count, diagnosis of PCL was
established. Rest of the patients of MM were excluded
from the study with normal PBF. These patients further
underwent investigations like complete liver function
and kidney function tests, lactate dehydrogenase
(LDH), uric acid, acid base with electrolytes, β2-
microglobulin, skeletal survey, serum and urinary
electrophoresis with immunofixiation, light chain
assay in urine and serum, bone marrow aspiration
with biopsy, immunophenotyping, and cytogenetic.
Patients were treated with borteozomib-based
chemotherapy, and clinical outcome and OS were
noted down.
Study and Observation (Results)
In this study, a total of 441 patients with plasma cell
dyscrasias were enrolled, out of which 433 patients had
MM and eight patients had pPCL. The median age of
patients with MM observed was 50 years, with the
youngest patient being 35 years and the oldest being
70 years. The median age of patients with pPCL was
53 years, with the youngest patient being 45 years and
the oldest being 60 years. The male to female ratio in
MM was 4:1 and in pPCL it was 1.7:1. So the percentage
of pPCL was 1.89% among all plasma cell dyscrasias.
Further study was concentrated on patients with
pPCL.
Fifty percent of patients were hypertensive on
treatment and 25% were diabetic on oral
hypoglycemic agents. There was no other co-
morbidity observed in this series. These patients
presented with multiple symptoms and signs, which
are outlined in Table 1. The most common symptom
reported was fever followed by bone pain, which are in
contrary to MM and the most common sign observed
was pallor followed by hepato-splenomegaly and
lymphadenopathy, which are again rarely seen
in MM.
All patients were subjected to laboratory tests
in the form of complete hemogram, full chemistry,
acid base, and electrolytes, as depicted in Table 2. On
peripheral blood examination, all patients were
anemic with median HB of 9.2 g/dl, had lower total
leucocyte count (TLC) with median of 4.15 × 10
3
/μl,
and had very low platelet count with median of
20 × 10
3
/μl. On peripheral blood examination,
different degree of plasmacytosis was observed in
blood ranging from 22 to 38% and many were
having plasmablastic appearance [Figure 1], with
median plasma cell percentage of 28% and median
peripheral plasma cell count of 1162 per μl.
Skeletal survey was having multiple lytic lesions
[Figure 2] in every patient, with atypical finding in
one patient having splenic hypo-echoic lesions
[Figure 3], finding confirmed by aspiration having
plasma cell infiltration. On serum chemistry
examination, they all had normal kidney and liver
functions with lower serum proteins and
albumin, and raised LDH and gamma globulins
[Table 2].
Table 1: Symptomatology of pPCL
Symptom Percentage
Fever 100
Bone pain 40
Weight loss 30
Recurrent vomiting 25
Malaise 25
Cough 20
Dysuria 10
Sweating 10
Signs Percentages
Pallor 100
Hepatomegaly 60
Splenomegaly 50
Lymphadenopathy 45
Ascites 20
Jaundice 20
Petechie 10
Consolidation 10
Fracture 10
Muzamil, et al.: Clinical profile of plasma cell leukemia at tertiary care hospital
96 Journal of Applied Hematology | Vol 7, Issue 3, Jul-Sept 2016
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Then the patients were subjected to MM profile, which
is tabulated as Table 3. All patients had very high β2-
microglobulin with median value of 5.8 mg/l and
positive serum M spike with undetectable M spike in
urine on protein electrophoresis. But urine
immunofixation was positive for M spike in λregion.
On immunoglobulin assay, all immunoglobulins’like
Ig G, Ig A, and Ig M were markedly suppressed with
very high levels of lambda (λ) free light chains in serum.
The median value of lambda (λ) free light chains in
serum was 3250 mg/l. All our patients had significant
light chain disease and that too lambda chain.
Serum immune flow-cytometry of peripheral blood
revealed the plasma cell leukemia phenotype, which
is also depicted in flow diagrams [Figure 4]. It
showed high expression and positivity of CD38,
CD138, and its co-expression but it was having
very low expression and negativity of CD27, CD56,
and CD20. Different CD marker positivity intensity is
given in Table 4.
Bone marrow aspiration and biopsy revealed
plasmacytosis between 40 and 90%, with median
plasmacytosis of 70%. These bone marrow aspiration
slides revealed high degree of plasmacytosis with all
having plasmablastic appearance; rest of the cell lines
were markedly suppressed [Figure 5]. Under
immunohistochemistry, cells were per iodic acid Schiff
(P.A.S.), Sudan black stain (S.B.), and myeloperoxidase
Table 2: Laboratory investigation of pPCL patients:
Parameter Minimum
value
Median
value
Maximum
value
HB
gm/dl
8.0 09.2 10.0
TLC(10
3
/μl) 3.5 04.15 10.0
PLT(10
3
/μl) 17 20 40
Plasma cells in PBF/ μl 770 1162 3300
Percentage of plasma cells 22.0 28.0 33
Serum Calcium
mg/dl
7.5 08.29 10.5
Serum Phosphorous
mg/dl
2.4 03.40 4.5
Urea
mg/dl (Normal 15-40)
28 36.0 42
Creatinine
mg/dl (Normal 0.5 -1.5)
1.0 1.30 1.6
ALP (IU/dl)
(Normal 140-300)
190 240 300
ALT (IU/dl)
(Normal 20-40)
35 42 48
Total Bilirubin
mg/dl (Normal 0.5-1)
1.0 1.5 1.9
Serum Na
meq/dl
132 138 148
Serum K
meq/dl
3.4 4.2 4.5
PH 7.30 7.35 7.40
HCO
3 meq/dl
18 23 28
Albumin
g/dl
2.0 2.98 3.5
Protein
g/dl
4.0 4.80 6.0
Gamma globulin
g/dl
0.66 0.78 1.6
LDHU/L
(Normal 150-300)
380 760 950
Figure 1: PBF showing plasma cells with plasma blasts with prominent nucleolus
Figure 2: X-rays showing lytic lesions in both skull and femur
Figure 3: CECT abdomen showing hypoechoic lesions in spleen
Table 3: Multiple myeloma profile -
Parameter Minimum
value
Median
value
Maximum
value
β2 microglobulin
mg/l(Normal 0.7-1.8)
3.5 5.8 7.0
Serum M spike 0.20 0.26 0.75
Urine M spike Not
detected
Not
detected
Not
detected
Serum IgA
mg/dl(Normal 70-400)
55 70 220
Serum IgM
mg/dl(Normal 40-230)
28 33 100
Serum IgG
mg/dl (Normal 700-1600)
550 639 1000
Serum free λ
mg/l (Normal 5.71-26.30)
2600 3250 5500
Serum free Ќ
mg/dl (Normal 3.3-19.40)
6.5 8.5 16.5
Urine Immunofixiation Faint M
spike in λ
region
Faint M
spike in
λregion
Faint M
spike in λ
region
Muzamil, et al.: Clinical profile of plasma cell leukemia at tertiary care hospital
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negative. On conventional cytogenetic karyotype, no
abnormality was noted down. Fluorescence In Situ
Hybridization (FISH) was not conducted due to
financial constraints.
Finally, based on all these parameters, the patients were
diagnosed as primary plasma cell leukemia expressing
lambda light chains exclusively with suppressed rest of
immunoglobulins’and the patients were put on weekly
intravenous borteozomib 2 mg and dexamethasone
40 mg based treatment along with other supportive
treatment in the form of tumor lysis prophylaxis,
antivirals, antimicrobials, and blood products. On
average, 15 weeks of treatment was received, with
longest treatment received being 24 weeks. Our
patients were not transplant candidates on the basis
of general performance. Interim assessment of disease
was done after 8 weeks of treatment with complete
hemogram, PBF, and myeloma profile. There was no
plasma cell seen on PBF examination and serum light
chains were reduced by 80%.
Most of our patients dropped general performance
from ECOG PS II to PS IV. They developed renal
failure and respiratory tract infection, which were
treated with broad-spectrum antibiotics, dialysis
support, and other intensive care support. All our
patients succumbed to different kinds of infection.
The median survival seen was 5 months and the
longest survival was 8 months. There was no
patient available after 8 months for disease
assessment.
So, we conclude that pPCL is a very rare disease in
plasma cell dyscrasias contributing to 1.89% of all
plasma cell dyscrasias, with slight male
predominance and earlier age than MM, and all had
highdiseaseburdenwithhighLDH,β2-microglobulin,
and plasmacytosis. This disease had very aggressive
behavior, especially with light chain lambda disease,
and all patients succumbed within 8 months of
treatment.
Discussion
pPCL is the most aggressive form of the plasma cell
dyscrasias. It is defined by the presence of >2×10
9
/l
peripheral blood plasma cells or plasmacytosis
accounting for >20% of the differential white cell count,
and it does not arise from preexisting MM.
[3,9]
We also used
the same criteria for diagnosis and all our patients had low
median TLC, with median plasma cell of 1160/μl(28%).
pPCL is rare, with only 1–4% of patients with MM
presenting as pPCL.
[1,2,4,11-14]
In addition, <1% of patients
presenting with extreme leukocytosis (>50 × 10
9
/l) are
diagnosed with PCL.
[15]
In our study as well, the total
patients with pPCL were 1.89% among 441plasma cell
dyscrasias which corresponds to other international
studies. None of our patients has TLC more than
10 × 10
3
/dl.
In PCL, tumor cells accumulate in the bone marrow
(BM) but also have an increased capacity to recirculate
in blood, with subsequent egression and formation of
extra-medullary disease. The dissemination of tumor
cells out of the BM is not only related to changes in
expression of adhesion molecules and chemokine
receptors but also to the presence of several
molecular aberrations, which contribute to BM
microenvironment-independent tumor growth,
inhibition of apoptosis, and escape from immune
surveillance. Interestingly, gene expression profiling
identifies pPCL as a distinct molecular entity among
myeloma samples.
[14]
Figure 4: Flow diagram showing plasma cell immunophenotype
Table 4: Immunoflow cytometery in pPCL-
Parameter Minimum
expression
Median
expression
Maximum
expression
CD 38 85.3 % 90.2 % 95.0 %
CD 138 82.5 % 86.2 % 89.9 %
Co expression
CD38/138
80.0 % 83.3 % 86.0 %
CD 45 0.00 % 0.00 % 0.00 %
CD 27 02.0 % 04.0 % 5.80 %
CD 56 0.03 % 0.70 % 0.90%
CD 20 5.00 % 6.80 % 10.0 %
Figure 5: Bone marrow showing immature plasma cells with plasma blasts
Muzamil, et al.: Clinical profile of plasma cell leukemia at tertiary care hospital
98 Journal of Applied Hematology | Vol 7, Issue 3, Jul-Sept 2016
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Compared to MM, tumor cells from patients with pPCL
and secondary plasma cell leukemia (sPCL) have
reduced expression of the adhesion molecules
NCAM (neural cell adhesion molecule/CD56) and
LFA-1 (leukocyte function-associated antigen-1),
which may contribute to the extra-medullary
accumulation of tumor cells in PCL.
[1,16-18]
The absence
of CD56 or LFA-1 is associated with reduced binding of
tumor cells to BM stromal cells.
[19,20]
Furthermore, loss of
CD56 results in increased production of matrix
metalloproteinase-9, which leads to destruction of the
basal membrane and extracellular matrix.
[21]
In our
study, all patients were negative for CD56 and CD27.
Patients with pPCL have a younger age at presentation
compared to patients with MM or sPCL.
[4,11,12,22,23]
However, their performance status at diagnosis is
usually worse,
[1]
which may be related to the more
advanced stage of disease (Durie-Salmon stage III:
∼80–96%; International Staging System stage III:
∼63–80%).
[1,6,7,11,24-26]
Extra-medullary involvement, such
as hepatomegaly, splenomegaly, lymphadenopathy,
leptomeningeal infiltration, or extra-medullary
plasmacytomas, is more frequent in pPCL,
[1,2,4,7,12-
14,23,25-27]
with extensive bone disease being more
common in patients with MM.
[1,4,25]
All our patients
were younger than patients with MM, with median
age being 53 years. Performance of all our patients was
also worse at presentation. However, the stage as per
Durie-Salmon staging system was II, but as per ISS, it
was III. Extra-medullary involvement was very high,
with hepatomegaly in 60%, splenomegaly in 50%, and
lymphadenopathy in 45% and none had central
nervous system (CNS) involvement. Bone
involvement was seen in less than half of the patients.
There are variousparameters which detect tumor burden
in PCL, for exampleplasma cell percentage, LDH, andβ2-
microglobulin. The median percentage of BM plasma
cells is significantly higher in pPCL than in MM
[1,4,26]
as
was seen in our patients as well. We documented bone
marrowplasmacytosisbetween 40and90%, with median
plasmacytosis of 70% and mostly plasmablastic
appearance. In addition, renal failure is more common
in pPCL, which can be partly explained by the higher
incidence of light-chain disease.
[1,4,14,23]
Furthermore,
hypercalcemia, anemia, thrombocytopenia, elevated
plasma cell labeling index, increased LDH, and gene
expression profile (GEP)-defined high-risk disease are
more frequent at presentation in pPCL compared to
MM.
[1,2,4,6,7,14,25,27]
In our series, none of our patients had
renal failure at the beginning but it developed in all
of them over the course of the disease. All our patients
had lambda light chain disease only, with high degree
of thrombocytopenia, moderate anemia and high
LDH.
Peripheral blood examination in pPCL shows circulating
tumor cells and typically a leuko-erythroblastic blood
picture in up to 67% of patients.
[4,25]
BM biopsy typically
demonstrates extensive BM involvement, disrupting
normal hematopoiesis. In some cases, tumor resembles
normal plasma cells, whereas in others, lympho-
plasmacytoid or immature plasma cells predominate.
[28-
30]
Our series also highlighted the presence of plasma
blastic or immature plasma cells both in blood and bone
marrow.
The most striking immune-phenotypic feature is
increased expression of CD20 and CD23, and down-
regulation of CD56 may be related to the high incidence
of t(11;14) in pPCL.
[1,31-33]
Tumor cells are positive for
CD38 and CD138 in both PCL and MM.
[1,16,28]
We also
demonstrated similar results in our series with high
expression of CD38/138 and loss of CD56.
There is a paucity of literature on the treatment of pPCL,
and no randomized trials have been reported exclusively
for patients with pPCL. The prognosis of pPCL after
conventional chemotherapy without novel agents is
poor, with median OS of ∼7months.
[1,4,6,12,23,30,34]
The
introduction of immune-modulatory drugs and
proteasome inhibitors has significantly improved the
survival of patients with MM.
[35,36]
Increasing evidence
suggests that these agents also improve outcome of
pPCL, but the benefit may be less pronounced
compared to classic MM. A retrospective analysis
performed by the Inter-groupe Francophone du
Myélome showed that patients with pPCL treated
with novel agents had a survival of 15 months
compared to 8 months for patients who did not receive
novel agents as part of their treatment.
[37]
Several case
reports and small case series suggest that bortezomib,
alone or in combination with other agents, is effective in
newly diagnosed pPCL and may also be active in
refractory pPCL or sPCL.
[5,34,38-43]
In pPCL, the efficacy of
combinations of novel agents, such as lenalidomide,
bortezomib, and dexamethasone (RVD),
[44]
bortezomib,
thalidomide, and dexamethasone (VTD),
[5,34,37]
or
melphalan, prednisone, bortezomib, and thalidomide
(VMPT),
[5]
appears very promising. In our series, we
treated all patients with borteozomib and
dexamethasone, and all were transplant-ineligible
based on their performance status. For initial 8 weeks
of therapy, all our patients responded evidence by
interim assessment, but subsequently all progressed
fast with deterioration in renal functions and
superadded infections. The median survival we
documented was 5 months and the longest survival of
8months.
There were some peculiarities in our patients. All were
young, and had moderate anemia with critical
Muzamil, et al.: Clinical profile of plasma cell leukemia at tertiary care hospital
Journal of Applied Hematology | Vol 7, Issue 3, Jul-Sept 2016 99
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thrombocytopenia. All had high LDH and β2-
microglobulin with high degree of plasmacytosis in
bone marrow and blood. All our patients had
lambda light chain disease with suppressed other
immunoglobulins’. Response to treatment was very
short-lived and the median survival was lower than
evidenced by modern treatment strategies, partly due
to different genetics in our patients.
Conclusion
Primary plasma cell leukemia is a very aggressive
disease and should be picked up early and treated
aggressively. The authors have recommended that at
least 20% of plasma cells be seen in PBF, so as to
diagnose this condition. As aggressiveness of this
disease is concerned, these criteria need to be revised
and less threshold of monoclonal plasma cells
percentage be seen in PBF for its diagnosis. Further
work needs to be done for classifying this leukemia,
refining its staging and refining its treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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