Waldenström macroglobulinemia ( , ) is a type of
cancer
Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
affecting two types of
white blood cell
White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...
s: lymphoplasmacytoid cells and plasma cells (both
B cells
B cells, also known as B lymphocytes, are a type of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasm ...
). It is characterized by having high levels of a circulating antibody,
immunoglobulin M
Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen;
causing it to also ...
(IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" (i.e., one that tends to grow and spread slowly) and a type of
lymphoproliferative disease which shares clinical characteristics with the indolent
non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredn ...
s.
It is commonly classified as a form of
plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to
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 ...
. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more
pre-malignant
A precancerous condition is a condition, tumor or lesion involving abnormal Cell (biology), cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues w ...
phases,
IgM monoclonal gammopathy of undetermined significance and
smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody
isoforms
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
.
Waldenström macroglobulinemia is a rare disease, with only about 1,500 cases per year in the
United States
The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
. It occurs more frequently in older adults. While the disease is incurable, it is treatable. Because of its indolent nature, many patients are able to lead active lives and, when treatment is required, may experience years of symptom-free
remission.
Signs and symptoms
Signs and symptoms of Waldenström macroglobulinemia include
weakness
Weakness is a symptom of many different medical conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, ...
,
fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
,
weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
, and chronic oozing of
blood from the nose and gums.
Peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
occurs in 10% of patients.
Enlargement of the lymph nodes,
spleen
The spleen (, from Ancient Greek '' σπλήν'', splḗn) is an organ (biology), organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter.
The spleen plays important roles in reg ...
, and/or
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
are present in 30–40% of cases.
Other possible signs and symptoms include blurring or loss of vision,
headache
A headache, also known as cephalalgia, is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of Depression (mood), depression in those with severe ...
, and (rarely)
stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
or
coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
.
Causes
Waldenström macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The most commonly associated mutations, based on whole-genome sequencing of 30 patients, are a
somatic mutation
A somatic mutation is a change in the DNA sequence of a somatic cell of a multicellular organism with dedicated reproductive cells; that is, any mutation that occurs in a cell other than a gamete, germ cell, or gametocyte. Unlike germline muta ...
in
MYD88
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the ''MYD88'' gene. originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary resp ...
(90% of patients) and a somatic mutation in
CXCR4 (27% of patients). CXCR4 mutations cause symptomatic
hyperviscosity syndrome and high bone marrow activity characteristic of the disease.
However, CXCR4 mutation is not associated with
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 ...
, high platelet counts, or different response to therapy, questioning the relevance of CXCR4 in treating patients.
An association has been demonstrated with the locus 6p21.3 on
chromosome 6.
There is a two-to-threefold increased risk of Waldenström macroglobulinemia in people with a personal history of
autoimmune disease
An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s with
autoantibodies
An autoantibody is an antibody (a type of protein) produced by the immune system that is directed against one or more of the individual's own proteins. Many autoimmune diseases (notably lupus erythematosus) are associated with such antibodies.
Pr ...
, and a particularly elevated risk associated with
hepatitis
Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
,
human immunodeficiency virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause AIDS, acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of th ...
, and
rickettsiosis.
There are
genetic factors with first-degree relatives of Waldenström macroglobulinemia patients shown to have a highly increased risk of also developing the disease. There is also evidence to suggest that
environmental factors, including exposure to farming, pesticides, wood dust, and organic solvents, may influence the development of Waldenström macroglobulinemia.
Genetics
Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component. A mutation in gene
MYD88
Myeloid differentiation primary response 88 (MYD88) is a protein that, in humans, is encoded by the ''MYD88'' gene. originally discovered in the laboratory of Dan A. Liebermann (Lord et al. Oncogene 1990) as a Myeloid differentiation primary resp ...
has been found to occur frequently in patients. Waldenström macroglobulinemia cells show only minimal changes in
cytogenetic
Cytogenetics is essentially a branch of genetics, but is also a part of cell biology/cytology (a subdivision of human anatomy), that is concerned with how the chromosomes relate to cell behaviour, particularly to their behaviour during mitosis an ...
and
gene expression studies. However, their
miRNA
Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcri ...
signature differs from their normal counterpart. Therefore,
epigenetic
In biology, epigenetics is the study of changes in gene expression that happen without changes to the DNA sequence. The Greek prefix ''epi-'' (ἐπι- "over, outside of, around") in ''epigenetics'' implies features that are "on top of" or "in ...
modifications play a crucial role in the disease.
Comparative genomic hybridization identified the following
chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.
FGFR3 is overexpressed. The following
signalling pathways have been implicated:
*
CD154
CD154, also called CD40 ligand or CD40L, is a protein that is primarily expressed on activated T cells and is a member of the TNF superfamily of molecules. It binds to CD40 on antigen-presenting cells (APC), which leads to many effects dependin ...
/
CD40
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T helper cell, TH cells to CD40 activates antigen presenting cells and i ...
*
Akt
*
ubiquitination
Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 19 ...
,
p53 activation, and
cytochrome c release
*
NF-κB
Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription (genetics), transcription of DNA, cytokine production and cell survival. NF-κB is found i ...
*
Wnt/
beta-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
*
mTOR
*
ERK
*
MAPK
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflamm ...
*
Bcl-2
Bcl-2, encoded in humans by the ''BCL2'' gene, is the founding member of the Bcl-2 family of regulator proteins. BCL2 blocks programmed cell death (apoptosis) while other BCL2 family members can either inhibit or induce it. It was the first a ...
The protein
Src tyrosine kinase is overexpressed in Waldenström macroglobulinemia cells compared with control B cells. Inhibition of Src arrests 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 ...
at phase G
1 and has little effect on the survival of Waldenström macroglobulinemia or normal cells.
MicroRNA
Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
s involved in Waldenström macroglobinemia:
* increased expression of miRNAs-363*, -206, -494, -155, -184, -542–3p.
* decreased expression of miRNA-9*
* microRNA-155 regulates the proliferation and growth of Waldenström macroglobulinemia cells in vitro and in vivo by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.
In Waldenström macroglobulinemia cells,
histone deacetylases and histone-modifying genes are de-regulated. Bone marrow tumor cells express the following antigen targets
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 ...
(98.3%),
CD22
CD22, or cluster of differentiation-22, is a molecule belonging to the SIGLEC family of lectins. It is found on the surface of mature B cells and to a lesser extent on some immature B cells. Generally speaking, CD22 is a regulatory molecule tha ...
(88.3%),
CD40
Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on T helper cell, TH cells to CD40 activates antigen presenting cells and i ...
(83.3%),
CD52 (77.4%),
IgM (83.3%),
MUC1
Mucin short variant S1, also called polymorphic epithelial mucin (PEM) or epithelial membrane antigen (EMA), is a mucin encoded by the ''MUC1'' gene in humans. Mucin short variant S1 is a glycoprotein with extensive O-linked glycosylation of its ...
core protein (57.8%), and 1D10 (50%).
Pathophysiology
Symptoms including blurring or loss of vision, headache, and (rarely)
stroke
Stroke is a medical condition in which poor cerebral circulation, blood flow to a part of the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemor ...
or
coma
A coma is a deep state of prolonged unconsciousness in which a person cannot be awakened, fails to Nociception, respond normally to Pain, painful stimuli, light, or sound, lacks a normal Circadian rhythm, sleep-wake cycle and does not initiate ...
are due to the effects of the
IgM paraprotein
A myeloma protein is an abnormal antibody (immunoglobulin) or (more often) a fragment thereof, such as an immunoglobulin light chain, that is produced in excess by an abnormal monoclonal proliferation of plasma cells, typically in multiple mye ...
, which may cause
autoimmune
In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease" ...
phenomena or
cryoglobulinemia. Other symptoms of Waldenström macroglobulinemia are due to
hyperviscosity syndrome, which is present in 6–20% of patients.
This is attributed to the IgM monoclonal protein molecules increasing the viscosity of the blood by forming aggregates to each other, binding water through their carbohydrate component and by their interaction with blood cells.
Diagnosis
A diagnosis of Waldenström macroglobulinemia depends on a significant monoclonal IgM spike, which is evident in blood tests and
malignant
Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer.
A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
cells consistent with the disease in
bone marrow biopsy
Bone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy (often called trephine biopsy) and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of condit ...
samples.
Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key signs of Waldenström macroglobulinemia. A bone marrow biopsy provides a sample of bone marrow, usually from the lower back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A
pathologist
Pathology is the study of disease. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in the context of modern medical treatme ...
identifies the particular
lymphocytes
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include T cells (for cell-mediated and cytotoxic adaptive immunity), B cells (for humoral, antibody-driven adaptive immunity), and ...
that indicate Waldenström macroglobulinemia.
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 ...
may be used to examine markers on the cell surface or inside the lymphocytes.
[National Cancer Institute]
Waldenström Macroglobulinemia: Questions and Answers
. Retrieved on: 2011-08-14.
Additional tests such as
computed tomography
A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
(CT or CAT) scan may be used to evaluate the chest, abdomen, and pelvis, particularly swelling of the lymph nodes, liver, and spleen. A skeletal survey can help distinguish between Waldenström macroglobulinemia and
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 ...
.
[ ]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 ...
occurs in about 80% of patients with Waldenström macroglobulinemia. A low white blood cell count and low platelet count in the blood may be observed. A low level of neutrophils (a specific type of white blood cell) may also be found in some individuals with Waldenström macroglobulinemia.[
Chemistry tests include ]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 ...
(LDH) levels, uric acid levels, erythrocyte sedimentation rate
The erythrocyte sedimentation rate (ESR or sed rate) is the rate at which red blood cells in anticoagulated whole blood descend in a standardized tube over a period of one hour. It is a common hematology test, and is a non-specific measure of in ...
(ESR), kidney and liver function, total protein levels, and an albumin-to-globulin ratio. The ESR and uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the Chemical formula, formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the meta ...
level may be elevated
An elevated railway or elevated train (also known as an el train or el for short) is a railway with the Track (rail transport), tracks above street level on a viaduct or other elevated structure (usually constructed from steel, cast iron, concre ...
. Creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an impor ...
is occasionally elevated, and electrolytes are sometimes abnormal. A high blood calcium
Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L def ...
level is noted in approximately 4% of patients. The LDH level is frequently elevated, indicating the extent of Waldenström macroglobulinemia–related tissue involvement. Rheumatoid factor, cryoglobulins, direct antiglobulin test, and cold agglutinin titer results can be positive. 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-reactive protein test results are not specific for Waldenström macroglobulinemia. Beta-2 microglobulin is elevated in proportion to tumor mass. Coagulation abnormalities may be present. Prothrombin time
The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the Coagulation#Extrinsic pathway, extrinsic pathway and Coagulation#Common pathway, ...
, activated partial thromboplastin time, thrombin time
The thrombin time (TT), also known as the thrombin clotting time (TCT), is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is ...
, and fibrinogen tests should be performed. Platelet aggregation studies are optional. Serum protein electrophoresis results indicate evidence of a monoclonal spike but cannot establish the spike as IgM. An M component with beta-to-gamma mobility is highly suggestive of Waldenström macroglobulinemia. Immunoelectrophoresis and immunofixation studies help identify the type of immunoglobulin, the light chain's clonality, and the paraprotein's monoclonality and quantitation. High-resolution electrophoresis and serum and urine immunofixation are recommended to help identify and characterize the monoclonal IgM paraprotein. The light chain of the monoclonal protein is usually the kappa light chain. At times, patients with Waldenström macroglobulinemia may exhibit more than one M protein. Plasma viscosity must be measured. Results from characterization studies of urinary immunoglobulins indicate that light chains ( Bence Jones protein), usually of the kappa type, are found in the urine. Urine collections should be concentrated. Bence Jones proteinuria is observed in approximately 40% of patients and exceeds one g/d in approximately 3%. Patients with findings of peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...
should have nerve conduction studies and antimyelin-associated glycoprotein serology.
Criteria for diagnosis of Waldenström macroglobulinemia include:
# IgM monoclonal gammopathy that excludes chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
and mantle cell lymphoma
Mantle cell lymphoma (MCL) is a type of Non-Hodgkin lymphoma, non-Hodgkin's lymphoma, comprising about 6% of cases. It is named for the mantle zone of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffe ...
.
# Evidence of anemia, constitutional symptoms, hyperviscosity, swollen lymph nodes, or enlargement of the liver and spleen that can be attributed to an underlying lymphoproliferative disorder.
Treatment
There is no single accepted treatment for Waldenström macroglobulinemia. There is marked variation in clinical outcomes due to gaps in knowledge of the disease's molecular basis. Objective response rates are high (> 80%), but complete response rates are low (0–15%). The medication ibrutinib
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...
targets the MYD88 L265P mutation induced activation of Bruton's tyrosine kinase
Bruton's tyrosine kinase (abbreviated Btk or BTK), also known as tyrosine-protein kinase BTK, is a tyrosine kinase that is encoded by the ''BTK'' gene in humans. BTK plays a crucial role in B cell development.
Structure
BTK contains five di ...
. In a cohort study of previously treated patients, ibrutinib induced responses in 91% of patients, and at 2 years 69% of patients had no progression of disease and 95% were alive. Based on this study, the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
approved ibrutinib for use in Waldenström macroglobulinemia in 2015.
There are different treatment flowcharts: Treon and mSMART.
Patients with Waldenström macroglobulinemia are at higher risk of developing second cancers than the general population, but it is not yet clear whether treatments are contributory.
Watchful waiting
In the absence of symptoms, many clinicians will recommend simply monitoring the patient; Waldenström himself stated "let well do" for such patients. These asymptomatic cases are now classified as two successively more pre-malignant
A precancerous condition is a condition, tumor or lesion involving abnormal Cell (biology), cells which are associated with an increased risk of developing into cancer. Clinically, precancerous conditions encompass a variety of abnormal tissues w ...
phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. But on occasion, the disease can be fatal, as it was to the French president Georges Pompidou
Georges Jean Raymond Pompidou ( ; ; 5 July 19112 April 1974) was a French politician who served as President of France from 1969 until his death in 1974. He previously served as Prime Minister of France under President Charles de Gaulle from 19 ...
, who died in office in 1974, six years after the discovery of his cancer. Mohammad Reza Shah Pahlavi, the Shah of Iran, also had Waldenström macroglobulinemia, which resulted in his ill-fated trip to the United States for therapy in 1979, leading to the Iran hostage crisis
The Iran hostage crisis () began on November 4, 1979, when 66 Americans, including diplomats and other civilian personnel, were taken hostage at the Embassy of the United States in Tehran, with 52 of them being held until January 20, 1981. Th ...
.
First-line
Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.
In 2002, a panel at the International Workshop on Waldenström's Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting treatment in patients with constitutional symptoms such as recurrent fever
Fever or pyrexia in humans is a symptom of an anti-infection defense mechanism that appears with Human body temperature, body temperature exceeding the normal range caused by an increase in the body's temperature Human body temperature#Fever, s ...
, night sweats
Night sweats or nocturnal hyperhydrosis is the repeated occurrence of excessive sweating during sleep. The person may or may not also perspire excessively while awake.
One of the most common causes of night sweats in women over 40 is the horm ...
, fatigue
Fatigue is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself.
Fatigue (in the medical sense) is sometimes associated wit ...
due to 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 ...
, weight loss
Weight loss, in the context of medicine, health, or physical fitness, refers to a reduction of the total body mass, by a mean loss of fluid, body fat (adipose tissue), or lean mass (namely bone mineral deposits, muscle, tendon, and other conn ...
, progressive symptomatic 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 ...
or spleen enlargement, and 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 ...
due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis
Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. There are several non-specific and vague signs and symptoms associated with amyloidosis. These include fatigue, peripheral edema, weigh ...
, 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 ...
, or symptomatic cryoglobulinemia were also suggested as indications for therapy.
Treatment includes the monoclonal antibody rituximab
Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or 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 ...
or with 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 ...
. 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 ...
s, such as 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 ...
, may also be used in combination. Plasmapheresis
Plasmapheresis (from the Greek language, Greek πλάσμα, ''plasma'', something molded, and ἀφαίρεσις ''aphairesis'', taking away) is the removal, treatment, and return or exchange of blood plasma or components thereof from and to the ...
can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease. Ibrutinib
Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...
is another agent that has been approved for use in this condition. Combination treatment with ibrutinib and rituximab showed significantly higher disease progression-free survival than treatment with rituximab alone.
Autologous bone marrow transplantation
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce a ...
is a treatment option.
Zanubrutinib, another BTK inhibitor, is indicated
In medicine, an indication is a valid reason to use a certain test, medication, procedure, or surgery. There can be multiple indications to use a procedure or medication. An indication can commonly be confused with the term diagnosis. A diagnosis ...
for the treatment of adults with Waldenström macroglobulinemia. For patients experiencing hyperviscosity syndrome, plasmapheresis is used to reduce IgM levels in the blood rapidly.
Salvage therapy
When primary or secondary resistance invariably develops, salvage therapy
Salvage therapy, also known as rescue therapy, is a form of therapy given after an ailment does not respond to standard therapy. The most common diseases that require salvage therapy are HIV and various cancers. The term is not clearly defined; i ...
is considered. Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.
Drug pipeline
As of October 2010, there have been 44 clinical trials on Waldenström macroglobulinemia, excluding transplantation treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenström. A database of clinical trials investigating Waldenström macroglobulinemia is maintained by the National Institutes of Health
The National Institutes of Health (NIH) is the primary agency of the United States government responsible for biomedical and public health research. It was founded in 1887 and is part of the United States Department of Health and Human Service ...
in the U.S..
Patient stratification
Patients with polymorphic variants (alleles
An allele is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.
Alleles can differ at a single position through single nucleotide polymorphisms (SNP), but they can also have insertions and deletions ...
) FCGR3A-48 and -158 were associated with improved categorical responses to rituximab-based treatments.
Prognosis
Current medical treatments result in survival of some longer than 10 years, partly because better diagnostic capabilities mean early diagnosis and treatments. Older age at diagnosis and treatment resulted in published reports of median survival of approximately 5 years from diagnosis. Currently, median survival is 6.5 years. In rare instances, Waldenström macroglobulinemia progresses to 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 International Prognostic Scoring System for Waldenström's Macroglobulinemia is a predictive model to characterise long-term outcomes. According to the model, factors predicting reduced survival are:
* Age > 65 years
* Hemoglobin ≤ 11.5 g/dL
* Platelet count ≤ 100 billion/L
* B2-microglobulin > 3 mg/L
* Serum monoclonal protein concentration > 70 g/L
The risk categories are:
* Low: ≤ 1 adverse variable except for age
* Intermediate: 2 adverse characteristics or age > 65 years
* High: > 2 adverse characteristics
Five-year survival rates for these categories are 87%, 68%, and 36%, respectively. The corresponding median survival rates are 12, 8, and 3.5 years.
The International Prognostic Scoring System for Waldenström's Macroglobulinemia has been shown to be reliable. It is also applicable to patients on a rituximab-based treatment regimen. An additional predictive factor is elevated serum lactate dehydrogenase (LDH).
Epidemiology
Of cancers involving the lymphocytes, 1% of cases are Waldenström macroglobulinemias. A rare disorder, there are fewer than 1,500 cases diagnosed in the United States annually. The median age of onset is between 60 and 65 years, with some cases occurring in late teens. Notable victims of the disease include dancer/choreographer Gower Champion, who died of the disease in 1980, aged 61; and former French president Georges Pompidou
Georges Jean Raymond Pompidou ( ; ; 5 July 19112 April 1974) was a French politician who served as President of France from 1969 until his death in 1974. He previously served as Prime Minister of France under President Charles de Gaulle from 19 ...
.
History
Waldenström macroglobulinemia was first described by Jan G. Waldenström (1906–1996) in 1944 in two patients with bleeding from the nose and mouth, 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 ...
, decreased levels of fibrinogen
Fibrinogen (coagulation factor I) is a glycoprotein protein complex, complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted Enzyme, enzymatically by thrombin to fibrin ...
in the blood (hypofibrinogenemia), swollen lymph nodes, neoplastic plasma cells in bone marrow, and increased viscosity of the blood due to increased levels of a class of heavy proteins called macroglobulins.
For a time, Waldenström macroglobulinemia was considered to be related to 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 ...
because of the presence of monoclonal gammopathy and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new World Health Organization
The World Health Organization (WHO) is a list of specialized agencies of the United Nations, specialized agency of the United Nations which coordinates responses to international public health issues and emergencies. It is headquartered in Gen ...
(WHO) classification, however, places Waldenström macroglobulinemia under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas. Since the 1990s, there have been significant advances in the understanding and treatment of Waldenström macroglobulinemia.
See also
* List of hematologic conditions
* Waldenström hyperglobulinemic purpura
References
{{DEFAULTSORT:Waldenstrom Macroglobulinemia
Hematologic malignant neoplasms
Lymphoma
Rare cancers
Vascular-related cutaneous conditions