OVERVIEW
Wahl’s macroglobulinemia is a rare inert lymphoma composed of small B lymphocytes, plasma cell-like lymphocytes and plasma cells, which is mainly characterized by elevated serum monoclonal IgM. The main manifestations of the tumor are infiltration symptoms, hypermucoviscosity, peripheral neuropathy, anemia, etc. Treatment should be based on the condition of the choice of observation, chemoimmunotherapy, targeted therapy, plasma exchange, etc. After effective treatment, most patients can obtain a With effective treatment, most of the patients can have a long survival period, and the prognosis of relapsed and refractory patients is poorer.
Definition
Wahl’s macroglobulinemia (WM) is a rare and inert non-Hodgkin’s lymphoma, the main subtype of lymphoplasmacytic lymphoma.
It is characterized by lymphoplasmacytic lymphoma infiltrating the bone marrow with monoclonal immunoglobulin IgMemia [1-3].
Morbidity
The disease occurs mostly in middle-aged and old age and progresses slowly, with an incidence of 1% ~2% of all hematologic tumors, and is more common in males [1].
Etiology
Causes
The exact etiology of the disease is unknown. It may be related to familial and hereditary factors [1-2].
Some researchers have reported that the prevalence of MYD88 mutations in Wahl’s macroglobulinemia (WM) is up to 95% or more. the CXCR4 mutation rate is 30% to 40% in patients with WM, and almost all patients with CXCR4 mutations have a concomitant MYD88 mutation [4].
Some WM is converted from a precursor disease, IgM monoclonal gammopathy of undetermined significance (MGUS), and the annual conversion rate in individuals with IgM MGUS is approximately 1% to 2%.
Risk and predisposition factors
Individuals with any of the following risk factors are at high risk for WM.
People with a family history of plasma cell lymphoma or other B-cell diseases.
People with a family history of multiple autoimmune diseases (dry syndrome, autoimmune hemolytic anemia).
Pathogenesis
The pathogenesis of WM is unclear. Studies have found that most patients with WM have chromosomal abnormalities, either numerical or structural.
Symptoms
Main Symptoms
Some patients may be asymptomatic at the time of diagnosis, and the main symptoms are caused by tumor infiltration and hyperIgMemia [1-3].
B symptoms
Unexplained fever, nocturnal night sweats and weight loss (10% weight loss within 6 months).
Hyperviscosity
Can be caused by elevated immunoglobulin IgM.
Clinical manifestations include fatigue, headache, blurred vision, mucosal bleeding tendencies, and impaired consciousness to coma.
Peripheral neuropathy
The main manifestation is symmetrical, progressive distal (from feet to knees, from fingers to elbows) numbness and tingling sensation. Weakness and weakness may occur in later stages.
Symptoms related to tumor infiltration
Enlargement of the liver, spleen, and lymph nodes.
Multiple organs and organs may be involved in later stages, with pleural and abdominal fluid in the case of pleural and peritoneal infiltration.
Cold agglutinin disease
Appears as a high concentration of antibodies to red blood cells, which bind to red blood cells when the body temperature is too low, leading to hemolytic anemia, which is manifested by pain and whitening of the fingers and toes when they are cold.
Cryoglobulinemia
Circulating IgM precipitates during hypothermia and obstructs small blood vessels. Clinical manifestations include Raynaud’s phenomenon, cyanosis of the hands and feet, necrosis, ulceration, purpura and cold urticaria.
Anemia
Caused by infiltration of tumor cells into the bone marrow, which may manifest as fatigue, weakness, and pale skin.
Bleeding
Thrombocytopenia leads to bleeding tendencies, skin bruising, and purpura.
Specific organ dysfunction
Aggregation of amorphous monoclonal lgM in the skin, gastrointestinal tract, and kidney can cause specific organ dysfunction. The main manifestations include cutaneous manifestations such as dermatosis herpetiformis and papules on the extremities; gastrointestinal symptoms such as diarrhea, malabsorption, and hemorrhage; and renal manifestations such as mild, reversible proteinuria, which is mostly asymptomatic.
Amyloid fibers (light chain) may cause light chain amyloidosis, with clinical manifestations such as fatigue, weight loss, periorbital purpura, edema, hepatomegaly, and macroglossia.
Complications
The following complications may result from Wahl’s macroglobulinemia (WM):
Bing-Neel syndrome.
This refers to the involvement of tumor cells in the central nervous system; it is a rare complication of WM with an incidence of <1% and consists of two main types: meningeal and mass.
The diagnosis is usually confirmed by cerebrospinal fluid examination (cytology, flow cytometry, and MYD88 mutation testing) or biopsy of the lesion.
Medical Treatment
Department of Medicine
Hematology
Prompt medical attention is recommended when there is painless progressive enlargement of lymph nodes, fatigue, blurred vision and bleeding.
Emergency Department
In the event of an emergency such as a loss of consciousness or even coma, it is recommended to go to the Emergency Department immediately or call the 120 emergency number.
Preparing for a Visit to the Emergency Room
Preparing for the Consultation: Registration, Documentation, Frequently Asked Questions
Tips for Medical Care
Record as much information as possible about the symptoms, duration, and previous treatments to give the doctor more information.
Take photos of skin abnormalities such as purpura, cyanosis, petechiae and papules.
Preparation Checklist for Doctor’s Visit
Symptom list
Particular attention should be paid to the time of symptom onset, special manifestations, etc.
Is there progressive painless enlargement of lymph nodes?
Is there any sign of fatigue, headache, blurred vision?
Is there cyanosis, purpura, petechiae, etc. on the skin?
Is there any bleeding tendency?
Are there any abnormalities such as ataxic gait, double drop foot, etc.?
Are there any aggravating or relieving factors for the above symptoms?
How long have the above symptoms persisted?
Medical History Checklist
Is there a family history of plasma cell lymphoma or other B-cell disease?
Is there a family history of multiple autoimmune (dry syndrome, autoimmune hemolytic anemia) diseases?
Checklist
Test results from the last 6 months to bring with you to your doctor’s appointment
Laboratory tests: routine blood tests, urine tests, bone marrow tests, genetic tests, immunoglobulins, immunofixation electrophoresis.
Imaging tests: relevant CT examination.
Medication list
Medication used in the last 3 months, if available, bring the box or package with you to the doctor’s office.
Monoclonal antibodies: rituximab, abciximab.
Alkylating agents: bendamustine.
Nucleoside analogs: cladribine, fludarabine.
Proteasome inhibitors: bortezomib, carfilzomib.
BTK inhibitors: ibrutinib, zerbutinib.
BCL-2 inhibitors: venetoclax.
Diagnosis
Diagnosis is based on
Medical history
Family history of plasma cell lymphoma or other B-cell disorders.
Family history of multiple autoimmune diseases (dry syndrome, autoimmune hemolytic anemia).
Clinical manifestations
Symptoms
Common symptoms include enlarged lymph nodes, fatigue, anemia, anorexia, peripheral neuropathy, weight loss, fever, and Raynaud’s phenomenon.
Signs
Cyanosis of the hands and feet and reticular cyanosis are seen with anemia.
Signs caused by proliferation and infiltration of abnormal cells such as enlargement of liver, spleen, lymph nodes and ascites in pleural infiltration.
Causes cryoglobulinemia such as cyanosis, necrosis, ulceration, and purpura of the hands and feet.
Produces hemorrhagic tendency with bruising and purpura.
Neuropathy such as ataxic gait, double drop foot.
Laboratory Tests
Routine blood tests
Purpose: To find out the changes in blood cells (red blood cells, white blood cells, platelets) and hemoglobin.
Meaning: Adult male hemoglobin (Hgb) <120g/L, adult female (non-pregnant) Hgb <110g/L, pregnant women Hgb <l00g/L is considered anemia.
Note: Fasting is required before the test.
Urinalysis
Purpose: To assess the condition of urine.
Significance: about 1/3 of patients have elevated urea nitrogen levels and a small amount of light chains in the urine.
Precautions: Prevent contamination when taking urine.
Bone Marrow Examination
Purpose: Bone marrow examination is an important diagnostic indicator of Wharton’s macroglobulinemia (WM) and is recommended for all patients suspected of having symptomatic WM or other IgM-related disorders.
Significance: A bone marrow smear may reveal typical morphology of lymphoplasmacytic cells (cytoplasm resembling a plasma cell, nucleus resembling the nucleus of a lymphocyte) or a bone marrow biopsy may reveal plasma cell-like or plasma cell-differentiated small B-lymphocytes with trabecular space invasion.
Note: The patient should remain cooperative with the test and avoid stress.
Genetic Testing
Purpose: To assist in the diagnosis of WM and may guide therapeutic medications.
Significance: MYD88 and CXCR4 mutations are common genetic abnormalities in patients with WM [4].
Caveat: In all patients undergoing bone marrow evaluation, MYD88 gene status should be assessed using established sensitivity assays.
Immunologic Testing
PURPOSE: The diagnosis of WM emphasizes monoclonal IgM, which needs to be confirmed by serum immunofixation electrophoresis.
SIGNIFICANCE: Lymphoplasmacytic lymphoma may secrete IgA/IgG, which is distinguished from WM by secretion of monoclonal IgM.
Immunoelectrophoresis confirms monoclonal IgM, with IgM-κ more common in WM.
Immunophenotype: CD19(+), CD20(+), sIgM(+), CD22(+), CD25(+), CD27(+), FMC7(+), CD5(+/-), CD10(-), CD23(-), CD103(-).
Note: Elevated serum IgM levels alone are not a therapeutic indication for WM.
Imaging
Cervical, thoracic, and total abdominal CT
Purpose: To help evaluate WM and for pre- and post-treatment efficacy assessment.
Significance: Some patients with WM may have enlarged lymph nodes and enlarged liver and spleen.
Precautions: Patients should be instructed to remove metal objects such as dentures, rings and earrings before the examination.
Diagnostic Criteria
Monoclonal IgM detected in serum.
Plasma cell-like or plasma cell-differentiated small lymphocytes presenting as trabecular gap invasion on bone marrow examination.
Immunophenotype: CD19 (+), CD20 (+), sIgM (+), CD22 (+), CD25 (+), CD27 (+), FMC7 (+), CD5 (+/-), CD10 (-), CD23 (-), CD103 (-). However, 10% to 20% of patients may partially express CD5, CD10, or CD23, so that Wahl’s macroglobulinemia (WM) cannot be excluded on the basis of immunophenotype alone.
Excluding other known types of lymphoma.
MYD88 mutation is an important marker for the diagnosis and differential diagnosis of WM, but is not a specific diagnostic indicator [3,5].
Differential diagnosis
Wahl’s macroglobulinemia should be differentiated from IgM-type monoclonal immunoglobulinemia of undetermined significance, and IgM-associated disorders:
IgM-type monoclonal immunoglobulinemia of undetermined significance
Similarities: both have elevated levels of monoclonal IgM protein.
Differences:
IgM-type monoclonal immunoglobulinemia: no lymphoplasmacytic/plasma cell infiltration in the bone marrow; no evidence of other B-lymphoproliferative disorders; no evidence of associated organ or tissue involvement.
Wahlberg’s macroglobulinemia: plasma cell-like or plasma cell-differentiated small lymphocytes in the bone marrow, which may result in enlarged lymph nodes, liver, and spleen.
IgM-associated diseases
Similarities: both can present with cryoglobulinemia and amyloidosis.
Differences:
IgM-associated disease: associated symptoms due to elevated monoclonal IgM, while there are no lymphoplasmacytic cells in the bone marrow and no evidence of lymphoma.
Wahl’s macroglobulinemia: plasma cell-like or plasma cell-differentiated small lymphocytes in the bone marrow.
Treatment
Treatment aims: inhibit tumor cell proliferation, relieve symptoms, control disease progression, prevent and reduce complications.
Treatment principle: Asymptomatic patients with Wahl’s macroglobulinemia (WM) do not need treatment and can be followed up for observation every 3-6 months. Symptomatic WM patients mainly receive chemoimmunotherapy and targeted therapy. Specific methods need to be evaluated according to the etiology of the patient, the severity of the disease, etc. Patients with symptoms of hyperviscosity and cryoglobulinemia can be treated with plasma exchange, etc. [5-9].
Therapeutic indications
Indications for WM treatment are: B symptoms; symptomatic hyperviscosity; peripheral neuropathy; organomegaly; amyloidosis; cold agglutinin disease; cryoglobulinemia; disease-related anemia and thrombocytopenia; extramedullary lesions, especially in the central nervous system (Bing-Neel syndrome); large lymph nodes; or when there is evidence of disease transformation.
Elevated serum IgM levels alone are not a therapeutic indication for this disease.
If the hematopenia is considered to be due to autoimmune factors, glucocorticoid therapy is preferred, and if glucocorticoid therapy is ineffective, treatment is directed at the primary cause of the disease [3].
Chemoimmunotherapy
Chemotherapeutic agents mainly include nucleoside analogs and alkylating agents; nucleoside analogs combined with rituximab have high activity, with an overall effective rate of 90~95% and a very good partial remission rate (VGPR) of 25%~35%.
Response rates in combination with rituximab for the treatment of Wharton’s macroglobulinemia (WM) typically exceed 80%. The two most commonly used first-line treatment regimens are rituximab and cyclophosphamide combined with dexamethasone (RCD), and rituximab combined with bendamustine (BR).
Monoclonal antibodies
Common drugs include: rituximab.
How the drug works: Rituximab is an antibody against the CD20 antigen.
Precautions: The use of rituximab monotherapy should alert you to the development of a tumor-burning reaction, i.e., a transient increase in blood IgM levels.
Alkylating agents
Commonly used drugs include: bendamustine, cyclophosphamide.
Effects of drugs: Formation of activated carbonyl groups that break DNA molecules leading to cell death.
Cautions: Alkylating agents are slow to take effect and are prone to stem cell damage. Therefore, the use of alkylating agents should be weighed against the need to control the disease as quickly as possible and in patients planning an autologous stem cell transplant.
Nucleoside analogs
Commonly used drugs include: cladribine, fludarabine.
Effects of drugs: Adenosine dehydrogenase inhibitors, interfere with nucleoside metabolism.
Cautions: Long-term use of nucleoside analogs often leads to bone marrow suppression.
Targeted therapy
BTK inhibitors
Commonly used drugs include: Ibrutinib, Zebutinib.
Effects of drugs: irreversibly inhibit BTK activity, inhibit BTK signaling pathway activation.
Cautions: Ibrutinib may increase the risk of neutropenia, bleeding, hypertension and atrial arrhythmias.
Proteasome Inhibitors
Commonly used drugs include: bortezomib, carfilzomib.
Effects of drugs: inhibit proteasome activity, interfere with the original process of cell proliferation, differentiation and apoptosis.
Cautions: Be aware of the neurotoxicity of the drug.
BCL-2 inhibitors
Commonly used drugs include: Venetoclax.
Action of the drug: selective inhibition of B-cell lymphoma-2.
Precautions: common adverse effects include neutropenia, anemia, back pain and constipation.
Plasma Replacement
Patients with symptomatic hyperviscosity and cryoglobulinemia are recommended to undergo plasma exchange 2~3 times before chemotherapy.
It is mainly used for patients with high blood viscosity. Due to the short-lived efficacy, it needs to be repeated every 1~2 months to maintain the efficacy.
Treatment of anemia
Recombinant human erythropoietin or transfusion of red blood cells can be applied to treat anemia.
Infusion of red blood cells should be cautious when the patient has hyperviscosity to avoid increasing blood viscosity and aggravating the symptoms; when the patient has cold agglutinin syndrome, the infused red blood cells should be pre-warmed to 37°C; recombinant human erythropoietin should be used with caution when the patient has a higher risk of thrombosis, poor control of hypertension, and hepatic or renal insufficiency.
Treatment of relapsed refractory patients
Consideration needs to be given to whether there is a therapeutic indication; if there is no indication, observation and follow-up are preferred; if there is an indication, an appropriate clinical trial may be chosen. The indications for autologous hematopoietic stem cell transplantation in Wahl’s macroglobulinemia are unclear.
Prognosis
Cure
The International Prognostic Index for Wahl’s macroglobulinemia (WM), which is currently the more commonly used prognostic judgment system for WM, contains 5 independent prognostic factors: age >65 years, hemoglobin ≤115 g/L, platelets ≤110 × 109/L, β2 microglobulin >3 mg/L, and serum monoclonal immunoglobulin >70 g/L. Each item is assigned 1 point.
Low-risk group: 0 or 1 point and age ≤65 years.
Intermediate-risk group: 2 points or age > 65 years.
High-risk group: >2 points. In addition, the high-risk group with elevated serum lactate dehydrogenase had a worse prognosis.
Although WM cannot be cured, with effective treatment, most patients can achieve a long survival period, and patients with relapsed refractory disease have a poorer prognosis [10].
Daily
Daily management
Dietary management
Eat a light and easily digestible diet, give more nutritious food, consume more fresh fruits and vegetables, and avoid spicy and stimulating, greasy food.
Give high-calorie, vitamin-rich and easy-to-digest food, encourage patients to drink more water, and at the same time, do not eat food that is too hard, too hot, and irritating to the oral mucosa.
Lifestyle management
Maintain good living habits, pay attention to personal hygiene and avoid infection.
During chemotherapy, pay attention to protective isolation, strictly control room entrants, strengthen ward disinfection, and reduce visits to reduce the chance of infection.
Psychological support
Actively communicate with patients so that they can objectively recognize their diseases and help them enhance their confidence in coping with difficulties. Eliminate nervousness and fear.
Disease monitoring
Monitor the patient’s body temperature, observe whether the patient has symptoms such as fatigue, anemia, anorexia, blurred vision, weight loss, etc., and check whether the skin has any abnormalities such as purpura, cyanosis and petechiae on hands and feet.
Follow-up examination
Patients should have regular follow-up examinations so that the doctor can assess the changes in the patient’s condition and adjust the dosage of medication and other treatment options according to the changes in the condition.
The follow-up time should be determined by the specialist according to the patient’s specific condition.
Tests to be done during follow-up: blood routine, blood biochemistry and IgM quantification, and if necessary, bone marrow examination may be required.
Prevention
Enhance the screening of high-risk groups
People with a family history of plasma cell lymphoma or other B-cell diseases.
People with relatives with multiple autoimmune diseases (dry syndrome, autoimmune hemolytic anemia).