Clinical Hematology International
Vol. 2(4); December (2020), pp. 133–142
DOI: https://doi.org/10.2991/chi.k.200706.002; eISSN 2590-0048
https://www.atlantis-press.com/journals/chi/
Review
Plasma Cell Leukemia – Facts and Controversies:
More Questions than Answers?
Anna Suska1, David H. Vesole2, Jorge J. Castillo3, Shaji K. Kumar4, Hari Parameswaran5, Maria V. Mateos6,
Thierry Facon7, Alessandro Gozzetti8, Gabor Mikala9, Marta Szostek1, Joseph Mikhael10, Roman Hajek11,
Evangelos Terpos12, Artur Jurczyszyn1,*
1
Department of Hematology, Jagiellonian University Medical College, Kopernika 17, Krakow 31-501, Poland
2
The John Theurer Cancer Center at Hackensack UMC, Hackensack, NJ, USA
3
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
4
Division of Hematology, Mayo Clinic, Rochester, MN, USA
5
Medical College of Wisconsin, Milwaukee, WI, USA
6
Complejo Asistencial Universitario de Salamanca, Instituto de Investigación Biomédica de Salamanca (CAUSA/IBSAL), Salamanca, Spain
7
Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France
8
Division of Hematology and Transplants, University of Siena, Siena, Italy
9
Department of Hematology and Stem Cell Transplantation, South-Pest Central Hospital, Natl. Inst. Hematol. Infectol, Budapest, Hungary
10
Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, Arizona, USA
11
University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
12
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
ARTICLE INFO ABSTRACT
Article History Plasma cell leukemia (PCL) is an aggressive hematological malignancy characterized by an uncontrolled clonal proliferation of
Received 07 April 2020 plasma cells (PCs) in the bone marrow and peripheral blood. PCL has been defined by an absolute number of circulating PCs
Accepted 01 June 2020 exceeding 2.0 × 109/L and/or >20% PCs in the total leucocyte count. It is classified as primary PCL, which develops de novo, and
secondary PCL, occurring at the late and advanced stages of multiple myeloma (MM). Primary and secondary PCL are clinically
Keywords and biologically two distinct entities. After the diagnosis, treatment should be immediate and should include a proteasome
Plasma cell leukemia inhibitor and immunomodulator-based combination regimens as induction, followed by stem cell transplantation (SCT) in
plasma cell dyscrasia transplant-eligible individuals who have cleared the peripheral blood of circulating PCs. Due to the rarity of the condition,
chemotherapy there have been very few clinical trials. Furthermore, virtually all of the myeloma trials exclude patients with active PCL. The
novel agents evaluation of response has been defined by the International Myeloma Working Group and consists of both acute leukemia and
stem cell transplantation MM criteria. With conventional chemotherapy, the prognosis of primary PCL has been ominous, with reported overall survival
clinical trials
(OS) ranging from 6.8 to 12.6 months. The use of novel agents and autologous SCT appears to be associated with deeper response
prognostic index
and an improved survival, although it still remains low. The PCL prognostic index provides a simple score to risk-stratify PCL.
The prognosis of secondary PCL is extremely poor, with OS of only 1 month.
© 2020 International Academy for Clinical Hematology. Publishing services by Atlantis Press International B.V.
This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).
1. INTRODUCTION In general, PCs from patients with PCL overlap in antigenic
expression with those from patients with multiple myeloma
Plasma cell leukemia (PCL) is an aggressive plasma cell dyscrasia (MM). The unique biology of PCL results from the disruption
characterized by an uncontrolled clonal proliferation of plasma cells of the mechanisms crucial for homing of malignant plasma cells
(PCs) in the bone marrow (Figure 1) and peripheral blood (Figure 2) within the bone marrow [4]. A number of adhesion molecules
[1]. The first case was reported by Gluziński and Reichenstein more and chemokine receptors are involved in this process. The most
than a century ago [2]. The definition of PCL has traditionally been important findings in PCL include lower expression of neural cell
based on Kyle’s 1974 criteria [3]. Present diagnostic criteria include adhesion molecule (CD56) and leukocyte function-associated
absolute number of circulating PCs exceeding 2.0 × 109/L and/or antigen-1, which normally enable to anchor PCs to the bone
>20% PCs in the total leucocyte count [4] (Figure 2). marrow stroma [5,6], increased secretion of metalloproteinase-9
leading to the excessive degradation of all components of the
extracellular matrix, and as a consequence, to a weaker myeloma
*
Corresponding author. Email: mmjurczy@cyf-kr.edu.pl cell interaction [7,8], and high expression of very late antigen-4
Peer review under responsibility of the International Academy for Clinical Hematology
(VLA-4) (integrin α4β1) that favors invasiveness of leukemic cells
Data availability statement: Microscope images taken at the Department of
Hematology, the University Hospital in Krakow, are available from the corresponding by causing their extravasation in the way of contact with its ligand
author upon request. in capillary vessel wall [9,10]. All these changes result in the
, 134 A. Suska et al. / Clinical Hematology International 2(4) 133–142
A B 2. CONTROVERSY OVER THE DIAGNOSIS
The current diagnostic criteria which are very restrictive have not
been prospectively evaluated to determine a need for any modifica-
tion. However, such an arbitrary approach might underestimate the
real clinical significance of circulating PCs. In the era of next genera-
tion flow cytometry the definition of PCL is still under debate [18,19].
Conventional microscopic analysis of the peripheral blood sample
should be performed in all MM patients who present with clinical
symptoms suspicious of PCL. If there are more than 20% circulat-
ing PCs and/or an absolute PC count exceeding 2.0 × 109/L, the
C D diagnosis of PCL should be established, according to current crite-
ria [4]. Of note, patients with relapsed/refractory heavily pretreated
MM, and with poor bone marrow reserve commonly have baseline
leukopenia and may not develop significant absolute PCs but may
meet percentage criteria. Therefore, there are some cases in the
literature in which only one criterion was considered sufficient to
establish a diagnosis and start treatment [13,20,21].
Figure 1 | Bone marrow aspirate smears showing immature plasma cells Recent studies have shown that even lower percentages of PCs in
including plasmablasts (A–C) and atypical binucleate plasma cell (D). Obj. peripheral blood may be related to an adverse prognosis in newly
magn. 1000×, Wright’s staining; from the Department of Hematology, the diagnosed MM patients, reflecting the need for re-definition of the
University Hospital in Krakow. diagnostic cut-off [19,22–24]. As it has been proven, the presence
of ≥5% circulating PCs in patients with MM has similar adverse
regression of PCs to the peripheral blood, making PCL a highly prognostic impact as PCL defined traditionally, so that this level
aggressive disease with extremely poor prognosis. may be proposed as a new cut-off point [24]. Interestingly, Rupin
et al. in their small retrospective study stated that, irrespective of
The incidence of PCL in Europe is evaluated at the level of 0.04 quantity, the presence of any PC in the peripheral blood is a poor
cases per 100,000 persons per year [11]. PCL is classified as pri- prognostic indicator [22]. Taking into consideration all the issues
mary (pPCL) when it develops de novo, and secondary (sPCL) when mentioned above, the International Myeloma Working Group
it occurs in patients with previously recognized MM, typically at (IMWG) is working on a new definition of PCL.
a late and advanced stage of the disease [4]. Historically, pPCL
has been reported as more common than sPCL, with their rela- It is also important to state that the presence of a significant
tive incidence estimated at 60–70% and 30–40%, respectively [12]. number of PCs in the peripheral blood, but polyclonal and not
However, in recent years there has been an upward trend in sPCL, at high percentage as in PCL, can be transiently observed in non-
now accounting for about 50% of the cases [13], probably due to malignant conditions, such as severe sepsis, mononucleosis and
improved overall survival (OS) in MM patients. Notably, pPCL serum sickness. Thus, peripheral blood flow cytometry is a useful
and sPCL are two clinically and biologically distinct entities which tool to verify the clonality of the PCs, and it should be a high prior-
only share the features of plasma cells circulating in the peripheral ity in further studies, with a special emphasis on those conducted
blood, unfavorable course and prognosis. in newly diagnosed patients.
The current knowledge on PCL is somewhat controversial, from
the definition of the disease to the treatment algorithms and the 3. PRIMARY PLASMA CELL LEUKEMIA
evaluation of treatment outcomes. This review article underlines
the most important issues, presenting various points of views. 3.1. Clinical and Biological Characteristics
Because of the relative low incidence and prevalence of PCL, most
data concerning clinical features, treatment approaches and results Because of the more aggressive course of the disease, including
come from case reports and retrospective series [12,14–17]. a higher tumor burden and higher proliferative index at diagnosis,
Figure 2 | Peripheral blood smears showing plasma cells and red cells rouleaux formation. Obj. magn. 1000×, Wright’s staining; from the Department of
Hematology, the University Hospital in Krakow.
