Plasma Cell Leukemia
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Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called
plasma cells Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances c ...
. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia,
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.


Signs and symptoms


Primary PCL

The clinical presentation of primary PCL (pPCL) indicates a far more aggressive disease than that of a typical multiple myeloma case with its clinical features being a combination of those found in
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
and
acute leukemia Acute leukemia or acute leukaemia is a family of serious medical conditions relating to an original diagnosis of leukemia. In most cases, these can be classified according to the lineage, myeloid or lymphoid, of the malignant cells that grow uncont ...
. Like multiple myeloma patients, pPCL patients exhibit pathologically high levels of monoclonal plasma cells in their bone marrow plus a malignant plasma cell-secreted circulating monoclonal myeloma protein, either IgG, IgA, a light chain, or none in 28-56%, 4-7%, 23-44%, or 0-12% of cases, respectively. Similar to B cell leukemias, but unlike multiple myeloma, pPCL patients exhibit relative high frequencies of
splenomegaly Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulat ...
,
lymphadenopathy Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In c ...
,
hepatomegaly Hepatomegaly is enlargement of the liver. It is a non-specific sign (medicine), medical sign, having many causes, which can broadly be broken down into infection, hepatic tumours, and metabolic disorder. Often, hepatomegaly presents as an abdomin ...
,
kidney failure Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
, bone marrow failure (i.e.
thrombocytopenia In hematology, thrombocytopenia is a condition characterized by abnormally low levels of platelets (also known as thrombocytes) in the blood. Low levels of platelets in turn may lead to prolonged or excessive bleeding. It is the most common coag ...
,
anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
, and/or, rarely,
leukopenia Leukopenia () is a decrease in the number of white blood cells (leukocytes). It places individuals at increased risk of infection as white blood cells are the body's primary defense against infections. Signs and symptoms Symptoms may include: * s ...
), central nervous system defects, and peripheral neuropathies due to the invasion of these tissues by plasma cells and/or the deposition of their circulating monoclonal immunoglobulin in them. Compared to multiple myeloma patients, pPCL patients also: exhibit 1) high rates of developing a hypercalcemic crisis, i.e. a potentially life-threatening episode of high ionic
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
(Ca2+) levels in the blood due to excess bone re-absorption and/or renal failure; b) higher levels of serum
lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...
and
Beta-2 microglobulin β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by t ...
; and c) lower rates of bone but higher rates of soft tissue plasma cell tumors termed
plasmacytoma Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton. The International Myeloma Working Group lists three types: Plasma cell dyscrasia#Solitary plasmacytoma, solitary plasma ...
s.


Secondary PCL

Secondary PCL (sPCL) is diagnosed in 1-4% of patients known to have had multiple myeloma for a median time of ~21 months. It is the terminal phase of these patients' myeloma disease. sPCL patients typically are highly symptomatic due to extensive disease with malignant plasma cell infiltrations in, and failures of, not only the bone marrow but also other organs. They have failed or broken through one or more treatment regimens and therefore may also show some of the toxic effects of these treatments.


Cause

PCL is caused by the development of an excessively high number of genetic abnormalities in plasma cells or, more particularly, their precursor B cells and plasmablasts (see
plasma cell Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances ca ...
s). This
genetic instability Genome instability (also genetic instability or genomic instability) refers to a high frequency of mutations within the genome of a cellular lineage. These mutations can include changes in nucleic acid sequences, chromosomal rearrangements or an ...
is due to a myriad of acquired abnormalities including
gene mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitosis ...
s;
single nucleotide polymorphism In genetics and bioinformatics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in ...
s; depletions and duplications of parts of a gene, larger portion of a chromosome, or even an entire arm of a chromosome; translocations, deletions, and duplications of entire chromosomes; and increases and decreases in the expression of intact genes due to, e.g. the
methylation Methylation, in the chemistry, chemical sciences, is the addition of a methyl group on a substrate (chemistry), substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replac ...
of gene promotors and various less direct effects. These genetic abnormalities effect the
Wnt signaling pathway In cellular biology, the Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt, pronounced "wint", is a portmanteau created from the ...
, regulation of the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
, RNA metabolism,
protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...
, and
cadherin Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...
-related cell adherence to
extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...
. These effects in turn control plasma cell proliferation, survival,
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, adhesion to bone marrow, genome stability, and secretion of monoclonal immunoglobulins. Secondary plasma cell leukemia (sPCL) results from the comparatively slow development of plasma cell/plasma cell precursor genetic abnormalities which initially create a clone of cells that cause the premalignant condition of
monoclonal gammopathy of undetermined significance Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is u ...
. In a very small percentage of these cases, the progressive development of further genetic abnormalities serially create a clone(s) of plasma cells that cause the more serious but still premalignant disorder of smoldering multiple myeloma, overt myeloma cancer, and ultimately sPCL. In contrast to sPCL, pPCL presents ''de novo'' with a broad range of genetic abnormalities. For example, advanced methods for examining the genome viz., whole-exome sequencing and
gene expression profiling In the field of molecular biology, gene expression profiling is the measurement of the activity (the gene expression, expression) of thousands of genes at once, to create a global picture of cellular function. These profiles can, for example, dis ...
, have identified 166 non-silent gene variants per pPCL patient sample at the time of diagnosis. These abnormalities are similar but not identical to those detected in sPCL while the abnormalities detected in sPCL more closely resemble those detected in multiple myeloma than do those of pPCL: the genetic data support the clinical data in suggesting that sPCL and pPCL are distinct diseases with sPCL among the two PCLs being more closely related to multiple myeloma. Examination of plasma cell
immunophenotype Immunophenotyping is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purpose. This can be done on tissue section (fresh or fixed tissue), cell suspensio ...
by measuring certain of their cell surface antigens, particularly
Cluster of differentiation The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophe ...
. CD markers on plasma cells from patients with pPCL differ from those taken form multiple myeloma or sPCL patients. For example: pPCL plasma cells more often express
CD20 B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule. It is a 33-37 kDa non-glycosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasm ...
antigen, which is considered important in anchoring plasma cells to the bone marrow stroma, than do those on plasma cells taken from myeloma patients (50% vs. 17%); pPCL plasma cells often lack CD56 antigen which is present on the majority of plasma cells taken form multiple myeloma patients; and pPCL plasma cells more frequently express
CD28 CD28 (Cluster of Differentiation 28) is a protein expressed on T cells that provides essential co-stimulation, co-stimulatory signals required for T cell activation and survival. When T cells are stimulated through CD28 in conjunction with the T- ...
than do sPCL plasma cells. Thus, immunophenotyping supports that notion that multiple myeloma, sPCL, and pPCL show critically important fundamental differences that may explain their different clinical presentations, courses, responses to therapy, and prognoses.


Diagnosis

The International Myeloma Working Group has defined the diagnostic criteria for plasma cell leukemia as the presence in blood of >2 billion plasma cells per liter or, alternatively, >20% of nucleated blood cells being plasma cells. More recently, the Group has suggested that values of 0.5 billion or 5%, respectively, may be more appropriate from a therapeutic viewpoint and therefore should be studied as a definitive criterion for the disease. A recent study supported this suggestion in finding that multiple myeloma patients with >5% circulating plasma cells had a prognosis much worse than that for multiple myeloma and similar to that for plasma cell leukemia.
Flow cytometry Flow cytometry (FC) is a technique used to detect and measure the physical and chemical characteristics of a population of cells or particles. In this process, a sample containing cells or particles is suspended in a fluid and injected into the ...
immunophenotyping Immunophenotyping is a technique used to study the protein expressed by cells. This technique is commonly used in basic science research and laboratory diagnostic purpose. This can be done on tissue section (fresh or fixed tissue), cell suspensio ...
of blood cells to detect clonal phenotypes of plasma cells seen in multiple myeloma (e.g. the CD138+,
CD38 CD38 (cluster of differentiation 38), also known as cyclic ADP ribose hydrolase, is a glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B lymphocytes and natural killer cells. CD38 also functions in ...
+,
CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In human ...
, CD45+/- phenotype) may be a more sensitive method to enumerate circulating clonal plasma cells and diagnose plasma cell leukemia.


Treatments

Prior to the use of newly developed drugs and treatment regimens, median survival rates from the time of diagnosis for pPCL and sPCL were 8–11 months and 2–8 months, respectively, even when treated very aggressively with the VAD regimen of
vincristine Vincristine, also known as leurocristine and sold under the brand name Oncovin among others, is a chemotherapy medication used to treat a number of types of cancer. This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin lym ...
,
doxorubicin Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
, and
dexamethasone Dexamethasone is a fluorinated glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive pulmonary disease (COPD), croup, brain swelling, eye pain following eye su ...
or the VCMP regimen of vincristine, carmustine, melphalan, and
prednisone Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...
alternating with vincristine, carmustine, doxorubicin, and prednisone. The treatment of PCL patients, particularly pPCL patients, with newer methods appears to have made modest improvements in survival rates. However, the rarity of these two leukemias has limited individual studies to case reports on a small number of patients or retrospective analyses of patient records.
Randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...
s on these patients have not been reported. One flaw of these methods is patient
selection bias Selection bias is the bias introduced by the selection of individuals, groups, or data for analysis in such a way that proper randomization is not achieved, thereby failing to ensure that the sample obtained is representative of the population inte ...
, i.e. patients selected for treatment with a new regimen may be less ill than average patients with the disease and therefore have an intrinsically less aggressive (i.e. longer overall survival time) disease.


Primary plasma cell leukemia

Recent case report studies suggest that treatment regimens which include a proteasome inhibitor drug, particularly bortezomib, and/or autologous stem-cell transplantation have improved pPCL survival. For example, 28 patients treated with a bortezomib-based induction regimen followed by autologous stem-cell transplantation and then a maintenance regimen of lenaldomide (an
immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system. Classification Immunosuppressive drugs can be classified ...
related to
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
), bortezomib, and dexamethasone (a
corticosteroid Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invo ...
) has a progression free survival rate of 66% at 3 years and an overall survival rate of 73% at 4 years. In one study, patients receiving intensive chemotherapy plus autologous stem-cell transplantation had a median survival of 34 months while those receiving chemotherapy alone had a median survival of 11 months. Two other studies that included bortezomib in their chemotherapy regimens likewise found that the addition of autologous stem-cell transplantation improved results. Current recommendations for treating pPCL often include induction with a three drug regimen such as borezomib-lenalidomide-dexamethasone followed by autologous stem-cell transplantion and consolidation/maintenance with of combination of immunomodulator agents (e.g. thalidomide, lenalidomide, or
pomalidomide Pomalidomide, sold under the brand names Pomalyst and Imnovid, is an anti-cancer medication used for the treatment of multiple myeloma and AIDS-related Kaposi sarcoma. Pomalidomide was approved for medical use in the United States in February ...
) plus a proteasome inhibitor (bortezomib, ixazomib, or carfilzomib.


Secondary plasma cell leukemia

As the end stage of multiple myeloma that has failed or broken through one or more therapeutic regimens, sPCL continues to be highly refractory to various treatment regimens (<50%), very short response times of these regimens, and poor overall survival rates (median survival of 2–8 to months). Patients with sPCL may have short-lived responses to treatment regimens (as communicated in
case report In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an individual patient. Case reports may contain a demographic profile of the patient, but usually describe an unusual or novel occurrenc ...
s) that include bortezomid but there are no established therapeutic regimens that have clearly been shown to improve their overall or median survival.


See also

* Plasma cell dyscrasia *
Multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...


References

;Bibliography * Greer JP, Foerster J, and Lukens JN, "Wintrobe's Clinical Hematology", Lippincott Williams & Wilkins 11th ed., 2003. * Hoffman R, Benz E, Shattil S, Furie B, Cohen H, "Hematology: Basic Principles and Practice", Churchill Livingstone, 4th ed, 2004. * Hoffbrand AV, Catovsky D, and Tuddenham E, "Postgraduate Haematology", Blackwell, 5th ed., 2005. * Hoffbrand AV, Moss PAH, and Pettit JE, "Essential Haematology", Blackwell, 5th ed., 2006.


External links

{{Immunoproliferative immunoglobulin disorders Lymphocytic leukemia Rare cancers