Waldenström's macroglobulinemia (WM, also known as lymphoplasmacytic lymphoma) is cancer involving a subtype of white blood cells called lymphocytes. The main attributing antibody is
Immunoglobulin MImmunoglobulin M, or IgM for short, is a basic antibody that is produced by B cells. It is the primary antibody against A and B antigens on red blood cells. IgM is by far the physically largest antibody in the human circulatory system...
(IgM). WM is an "indolent lymphoma," (i.e., one that tends to grow and spread slowly). It is a type of lymphoproliferative disease, which shares clinical characteristics with the indolent
non-Hodgkin lymphomaThe non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....
s.
The disease, named after the Swedish oncologist
Jan G. WaldenströmJan Gösta Waldenström was a Swedish doctor of internal medicine, who first described the disease which bears his name, Waldenström's macroglobulinemia....
, was first identified in 1944. As with other lymphomas, the disease is characterized by an uncontrolled increase of B-cells, i.e., white blood cells formed in the
bone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
and lymph nodes. The proliferation of B-cells interferes with the production of red blood cells, resulting in
anemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
. A unique characteristic of the disease is that the B-cells produce excess amounts of immunoglobulin protein (IgM), thickening the blood, and requiring additional treatment. WM is a rare disease, with only about 1,500 cases per year in the U.S. 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
remissionRemission may refer to:*Remission , the state of absence of disease activity in patients with a chronic illness, with the possibility of return of disease activity*Remission , the reflection or scattering of light by a material...
.
History and classification
WM was first described by
Jan G. WaldenströmJan Gösta Waldenström was a Swedish doctor of internal medicine, who first described the disease which bears his name, Waldenström's macroglobulinemia....
(1906–1996) in 1944 in two patients with bleeding from the nose and mouth,
anemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
, decreased levels of
fibrinogenFibrinogen is a soluble plasma glycoprotein, synthesised by the liver, that is converted by thrombin into fibrin during blood coagulation. This is achieved through processes in the coagulation cascade that activate the zymogen prothrombin to the serine protease thrombin, which is responsible for...
in the blood (hypofibrinogenemia),
swollen lymph nodesLymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
, neoplastic plasma cells in bone marrow, and
increased viscosity of the bloodHyperviscosity syndrome is a group of symptoms triggered by increase in the viscosity of the blood. Symptoms of high blood viscosity include spontaneous bleeding from mucous membranes, visual disturbances due to retinopathy, and neurologic symptoms ranging from headache and vertigo to seizures and...
due to increased levels of a class of heavy proteins called macroglobulins.
For a time, WM was considered to be related to
multiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
due to the presence of
monoclonal gammopathyMonoclonal gammopathy is a synonym for paraproteinemia.- External links :*...
and infiltration of the bone marrow and other organs by plasmacytoid lymphocytes. The new
World Health OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(WHO) classification, however, places WM under the category of lymphoplasmacytic lymphomas, itself a subcategory of the indolent (low-grade) non-Hodgkin lymphomas. In recent years, there have been significant advances in the biology and treatment of WM.
Causes
Waldenström's macroglobulinemia is characterized by an uncontrolled clonal proliferation of terminally differentiated B lymphocytes. The underlying etiology is not yet known but a number of risk factors have been identified. There has been an association demonstrated with the locus 6p21.3 on chromosome 6. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with
hepatitisHepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, human immunodeficiency virus, and
rickettsiosisA rickettsiosis is a disease caused by intracellular bacteria.It has been predicted that global warming may lead to greater incidence.-Examples and causative organisms:Rickettsioses can be divided into a spotted fever group and typhus group ....
.
There are
genetic factorsA genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
, with first-degree relatives shown to have a highly increased risk of also contracting Waldenström's. 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's.
Biochemistry
Although believed to be a sporadic disease, studies have shown increased susceptibility within families, indicating a genetic component. However, genetic involvement is poorly understood. WM cells show only minimal changes in cytogenetic and gene expression studies. Their
miRNAMirna may refer to:geographical entities* Mirna , a river in Istria, Croatia* Mirna , a river in Slovenia, tributary of the river Sava* Mirna , a settlement in the municipality of Mirna in Southeastern Sloveniapeople...
signature however differs from their normal counterpart. It is therefore believed that epigenetic modifications play a crucial role in the disease.
Comparative genomic hybridizationComparative genomic hybridization or Chromosomal Microarray Analysis is a molecular-cytogenetic method for the analysis of copy number changes in the DNA content of a given subject's DNA and often in tumor cells....
identified the following chromosomal abnormalities: deletions of 6q23 and 13q14, and gains of 3q13-q28, 6p and 18q.
FGFR3Fibroblast growth factor receptor 3 is a protein that in humans is encoded by the FGFR3 gene. FGFR3 has also been designated as CD333 .-Structure and function:-Disease linkage:...
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 , which leads to many effects depending on the target cell type...
/CD40
- Akt
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
- ubiquitination, p53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
activation, cytochrome cThe Cytochrome complex, or cyt c is a small heme protein found loosely associated with the inner membrane of the mitochondrion. It belongs to the cytochrome c family of proteins. Cytochrome c is a highly soluble protein, unlike other cytochromes, with a solubility of about 100 g/L and is an...
release
- NF-κB
- WNT
The Wnt signaling pathway is a network of proteins best known for their roles in embryogenesis and cancer, but also involved in normal physiological processes in adult animals.-Discovery:...
/beta-cateninBeta-catenin is a protein that in humans is encoded by the CTNNB1 gene. In Drosophila, the homologous protein is called armadillo...
- mTOR
- ERK
In molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
- MAPK
- Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
The protein
Src tyrosine kinaseProto-oncogene tyrosine-protein kinase Src is an enzyme that in humans is encoded by the SRC gene.Src is a proto-oncogene encoding a tyrosine kinase originally discovered by J. Michael Bishop and Harold E. Varmus, for which they won the 1989 Nobel Prize in Physiology or Medicine. It belongs to a...
is overexpressed in Waldenström macroglobulinemia cells compared with control B cells. Inhibition of Src arrests the
cell cycleThe cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
at phase G
1 and has little effect on the survival of WM or normal cells.
MicroRNAs involved in Waldenström's:
- increased expression of miRNAs-363*, -206, -494, -155, -184, -542–3p.
- decreased expression of miRNA-9*.
MicroRNA-155 regulates the proliferation and growth of WM cells in vitro and in vivo, by inhibiting MAPK/ERK, PI3/AKT, and NF-κB pathways.
In WM-cells,
histone deacetylaseHistone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
s and histone-modifying genes are de-regulated.
Bone marrow tumour cells express the following antigen targets
CD20B-lymphocyte antigen CD20 or CD20 is an activated-glycosylated phosphoprotein expressed on the surface of all B-cells beginning at the pro-B phase and progressively increasing in concentration until maturity....
(98.3%),
CD22CD22 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...
(88.3%), CD40 (83.3%),
CD52CD52 is a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes were derived.It also is found in monocytes and dendritic cells....
(77.4%),
IgMIGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
(83.3%),
MUC1Mucin 1, cell surface associated or polymorphic epithelial mucin is a mucin encoded by the MUC1 gene in humans. MUC1 is a proteoglycan with extensive O-linked glycosylation of its extracellular domain. Mucins line the apical surface of epithelial cells in the lungs, stomach, intestines, eyes and...
core protein (57.8%), and 1D10 (50%).
Epidemiology
Of all
cancers involving the same class of blood cellLymphoproliferative disorders refer to several conditions in which lymphocytes are produced in excessive quantities. They typically occur in patients who have compromised immune systems...
, 1% of cases are WM.
WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. The median age of onset of WM is between 60 and 65 years, with some cases occurring in late teens.
Symptoms
Symptoms of WM include
weaknessWeakness is a symptom represented, medically, by a number of different conditions, including: lack of muscle strength, malaise, dizziness, or fatigue. 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...
,
fatigueFatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...
,
weight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
and chronic oozing of blood from the nose and gums.
Peripheral neuropathyPeripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
can occur in 10% of patients. Lymphadenopathy,
splenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, and/or
hepatomegalyHepatomegaly is the condition of having an enlarged liver. It is a nonspecific medical sign having many causes, which can broadly be broken down into infection, direct toxicity, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdominal mass...
are present in 30-40% of cases. Other possible symptoms include blurring or loss of vision, headache, and (rarely)
strokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or
comaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
.
Pathophysiology
Symptoms blurring or loss of vision, headache, and (rarely)
strokeA stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or
comaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
are due to the effects of the
IgMIGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
paraproteinA paraprotein is an immunoglobulin or immunoglobulin light-chain that is produced in excess by the clonal proliferation of plasma cells. Detection of paraproteins in the urine or blood is most often associated with benign MGUS , where they remain "silent", and multiple myeloma. An excess in the...
, which may cause autoimmune phenomenon or
cryoglobulinemiaCryoglobulinemia is a medical condition in which the blood contains large amounts of cryoglobulins - proteins that become insoluble at reduced temperatures. Cryoglobulins typically precipitate at temperatures below normal body temperature and will dissolve again if the blood is heated...
. Other symptoms of WM are due to the
hyperviscosity syndromeHyperviscosity syndrome is a group of symptoms triggered by increase in the viscosity of the blood. Symptoms of high blood viscosity include spontaneous bleeding from mucous membranes, visual disturbances due to retinopathy, and neurologic symptoms ranging from headache and vertigo to seizures and...
, which is present in 6-20% of patients. This is attributed to the IgM monoclonal protein 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's macroglobulinemia depends on a significant monoclonal IgM spike evident in blood tests and
malignantMalignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
cells consistent with the disease in
bone marrow biopsyBone marrow examination refers to the pathologic analysis of samples of bone marrow obtained by bone marrow biopsy and bone marrow aspiration. Bone marrow examination is used in the diagnosis of a number of conditions, including leukemia, multiple myeloma, lymphoma, anemia, and pancytopenia...
samples. Blood tests show the level of IgM in the blood and the presence of proteins, or tumor markers, that are the key symptoms of WM. A bone marrow biopsy provides a sample of bone marrow, usually from the back of the pelvis bone. The sample is extracted through a needle and examined under a microscope. A pathologist identifies the particular lymphocytes that indicate WM.
Flow cytometryFlow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...
may be used to examine markers on the cell surface or inside the lymphocytes.
Additional tests such as
computed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
(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 WM and
multiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
AnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
is typically found in 80% of patients with WM.
LeukopeniaLeukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....
, and
thrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
may be observed.
NeutropeniaNeutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
may also be found in some patients.
Chemistry tests include lactate dehydrogenase (LDH) levels, uric acid levels, erythrocyte sedimentation rate (ESR), renal and hepatic function, total protein levels, and an albumin-to-globulin ratio.
The ESR and uric acid level may be elevated.
Creatinine is occasionally elevated and electrolytes are occasionally abnormal. Hypercalcemia 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 titre results can be positive.
Beta-2-microglobulin 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, activated partial thromboplastin time, thrombin time, 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 clonality of the light chain, and the monoclonality and quantitation of the paraprotein.
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 1 g/d in approximately 3% of patients.
Patients with findings of peripheral neuropathy should have nerve conduction studies and antimyelin associated glycoprotein serology
Prognosis
Current medical treatments result in survival of some longer than 10 years, in part this is because better diagnostic testing means early diagnosis and treatments. Older diagnosis and treatments resulted in published reports of median survival of approximately 5 years from time of diagnosis. Currently, median survival is 6.5 years. In rare instances, WM progresses to
multiple myelomaMultiple myeloma , also known as plasma cell myeloma or Kahler's disease , is a cancer of plasma cells, a type of white blood cell normally responsible for the production of antibodies...
.
The International Prognostic Scoring System for Waldenström’s Macroglobulinemia (IPSSWM) is a predictive model to characterise long-term outcome.
According to the model, factors predicting survival (n.b. the study quoted conversely refers to them as "5 adverse covariates") are:
- age >65 years;
- hemoglobin ≤11.5 g/dL;
- platelet count ≤100×109/L;
- B2-microglobulin >3 mg/L;
- serum monoclonal protein concentration >70 g/L.
The risk categories are:
- Low: ≤1 adverse variable except 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 IPSSWM 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).
Treatment
There is no single accepted treatment for WM. There is marked variation in clinical outcome due to gaps in knowledge of the disease's molecular basis. Objective
response rateResponse rate in survey research refers to the number of people who answered the survey divided by the number of people in the sample...
s are high (>80%) but complete response rates are low (0-15%).
There are different treatment flowcharts: Treon and mSMART.
WM patients are at higher risk of developing second cancers than the general population, however it is not yet clear whether treatments are contributory.
Watchful waiting
In the absence of symptoms, many clinicians will recommend simply monitoring the patient. But on occasion the disease can be fatal, as it was to its best known sufferer, the former French president
Georges PompidouGeorges Jean Raymond Pompidou was a French politician. He was Prime Minister of France from 1962 to 1968, holding the longest tenure in this position, and later President of the French Republic from 1969 until his death in 1974.-Biography:...
, who died in 1974. Indeed, in 1991, Waldenström himself raised the question of the need for effective therapy.
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 Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent
feverFever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...
, night sweats, fatigue due to
anemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
,
weight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, progressive symptomatic
lymphadenopathyLymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....
or
splenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
, and
anemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
due to marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic
amyloidosisIn medicine, amyloidosis refers to a variety of conditions whereby the body produces "bad proteins", denoted as amyloid proteins, which are abnormally deposited in organs and/or tissues and cause harm. A protein is described as being amyloid if, due to an alteration in its secondary structure, it...
, renal insufficiency, or symptomatic
cryoglobulinemiaCryoglobulinemia is a medical condition in which the blood contains large amounts of cryoglobulins - proteins that become insoluble at reduced temperatures. Cryoglobulins typically precipitate at temperatures below normal body temperature and will dissolve again if the blood is heated...
were also suggested as indications for therapy.
Treatment includes the monoclonal antibody
rituximabRituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
, sometimes in combination with chemotherapeutic drugs such as
chlorambucilChlorambucil is a chemotherapy drug that has been mainly used in the treatment of chronic lymphocytic leukemia...
,
cyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, or
vincristineVincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
or with
thalidomideThalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
.
CorticosteroidCorticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...
s, such as
PrednisonePrednisone is a synthetic corticosteroid drug that is particularly effective as an immunosuppressant drug. It is used to treat certain inflammatory diseases and some types of cancer, but has significant adverse effects...
, may also be used in combination.
PlasmapheresisPlasmapheresis is the removal, treatment, and return of blood plasma from blood circulation. It is thus an extracorporeal therapy...
can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease.
Recently, autologous bone marrow transplantation has been added to the available treatment options.
Salvage therapy
When primary or secondary
resistanceDrug resistance is the reduction in effectiveness of a drug such as an antimicrobial or an antineoplastic in curing a disease or condition. When the drug is not intended to kill or inhibit a pathogen, then the term is equivalent to dosage failure or drug tolerance. More commonly, the term is used...
invariably develops,
salvage therapySalvage therapy is a form of treatment given after an ailment does not respond to standard treatment. The most common diseases that require salvage therapy are HIV and various tumors...
is considered.
Allogeneic stem cell transplantationAllogeneic stem cell transplantation is a procedure in which a person receives blood-forming stem cells from a genetically similar, but not identical, donor. This is often a sister or brother, but could be an unrelated donor...
can induce durable remissions for heavily pre-treated patients.
Drug pipeline
As of October 2010, there have been a total of 44 clinical trials on Waldenstrom's macroglobulinemia, excluding transplantion treatments. Of these, 11 were performed on previously untreated patients, 14 in patients with relapsed or refractory Waldenstrom's. A database of clinical trials investigating Waldenström's macroglobulinemia is maintained by the
National Institutes of HealthThe National Institutes of Health are an agency of the United States Department of Health and Human Services and are the primary agency of the United States government responsible for biomedical and health-related research. Its science and engineering counterpart is the National Science Foundation...
in the US.
Patient stratification
Patients with
polymorphic variantsPolymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
(alleles)
FCGR3ALow affinity immunoglobulin gamma Fc region receptor III-A is a protein that in humans is encoded by the FCGR3A gene. It is also known as CD16a as it is part of the cluster of differentiation cell surface molecules.-Further reading:...
-48 and -158 were associated with improved categorical responses to Rituximab-based treatments.
External links