Overview of malignant hematologic tumors
A malignant hematologic tumor formed by the clonal proliferation of lymphoid progenitor cells or mature B lymphocytes. Main symptoms include anemia, fever, hemorrhage, bone and joint pain, and enlarged lymph nodes, etc. The cause of the disease is unknown, and it may be related to genetic mutations, hereditary factors, and environmental factors, etc. The treatment is based on chemotherapy, targeted therapy, and in addition to hematopoietic stem cell transplantation.
Definition
Lymphocytic leukemia is a malignant hematologic neoplasm formed by the clonal proliferation of lymphoid progenitor cells or mature B lymphocytes, and is classified as a leukemia.
According to the degree of differentiation and maturation of the leukemic cells and the natural course of the disease, they can be divided into acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). There are significant differences between the two, from their origins, to their clinical manifestations, treatment and prognosis.
Types
Acute lymphoblastic leukemia (ALL)
ALL mainly originates from B- or T-lineage lymphoid progenitor cells, i.e. B-ALL or T-ALL.
Leukemia cells proliferate abnormally in the bone marrow and inhibit the normal hematopoietic function of the bone marrow, leading to a decrease in red blood cells, white blood cells, and platelets in the blood and causing corresponding clinical symptoms.
Leukemia cells can also invade extramedullary tissues and organs, such as liver, spleen, meninges, gonads, thymus, lymph nodes, and bone tissues, leading to corresponding lesions.
ALL is mostly seen in children and is the most common malignant tumor in children. The high incidence is between 1 and 4 years of age, followed by 15 to 25 years of age. 60% of patients are younger than 20 years of age at the time of diagnosis. B-ALL accounts for a higher proportion of childhood ALL.
ALL accounts for about 20% to 30% of adult acute leukemia.
The disease tends to progress rapidly.
Chronic Lymphocytic Leukemia (CLL)
CLL is caused by clonal proliferation of mature B lymphocytes. It is mainly characterized by increased peripheral blood lymphocytes, enlarged liver, spleen and lymph nodes, and can also involve tissues and organs outside the lymphatic system.
Small lymphocytic lymphoma (SLL) and CLL are different manifestations of the same disease, with about 20% of SLL progressing to CLL.The main difference between the two is that CLL tends to involve the peripheral blood and bone marrow, whereas SLL tends to involve the lymph nodes and bone marrow. In this article CLL stands for both CLL and SLL.
CLL is the most common leukemia among adults in Western countries, accounting for 25% to 35% of all leukemias. The annual incidence rate in European and American populations is about (4~5)/100,000 per year. The incidence rate in Asian populations is much lower than that in European and American populations.
It is more common in males, with a male-to-female ratio of about (1.2~1.7):1.
CLL tends to develop in the elderly, with a median age of onset of 72 years in Europe and the United States, while the median age of onset in China is 65 years.
The disease tends to develop slowly [1-4].
Etiology
Causes
The etiology and pathogenesis of lymphoblastic leukemia are not completely clear, and may be related to gene mutation, genetic factors, environmental factors, etc.
Genetic mutations: a variety of genetic abnormalities are thought to be associated with the development of acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL). more than 90% of childhood ALL has clonal chromosomal abnormalities.
Genetic factors: Like other hematologic malignancies, ALL and CLL have been found to run in families, and CLL is considered to be one of the hematologic malignancies with the strongest genetic predisposition, with a family history in about 10% of CLL patients.
Environmental factors: long-term exposure to ionizing radiation or benzene agents, etc.
Others: Infections such as hepatitis C virus are also thought to be associated with the development of CLL. And hematologic disorders such as myelodysplastic syndromes and multiple myeloma can eventually develop into lymphoblastic leukemia [2-4].
Symptoms
Main Symptoms
Main symptoms of acute lymphoblastic leukemia (ALL)
Symptoms due to suppression of bone marrow hematopoiesis
Due to the abnormal proliferation of a large number of B-lineage or T-lineage lymphoid progenitor cells in the bone marrow, the normal bone marrow hematopoietic function is inhibited, and normal red blood cells, platelets and white blood cells decrease, resulting in a series of clinical symptoms.
Red blood cell reduction is mainly manifested as anemia. Anemia symptoms appear early and gradually worsen as the disease progresses. There may also be weakness, dizziness, pallor, shortness of breath, chest tightness and so on.
Thrombocytopenia is mainly characterized by bleeding tendency. There can be bleeding from the skin and mucous membranes, such as skin petechiae and ecchymosis, bleeding gums, nosebleeds, etc.; gastrointestinal bleeding and hematuria; and in severe cases, fundus hemorrhage with blurred vision and intracranial hemorrhage, which is life-threatening.
Leukopenia is mainly characterized by an increased risk of infection. Common infections include respiratory tract infections and gastrointestinal tract infections, often in the gums, mouth, lungs, perianal area, skin and soft tissues, which may be accompanied by fever.
Enlarged liver and spleen, swollen lymph nodes
Hepatosplenomegaly may be accompanied by distension and pain in the right or left lower abdomen, anorexia, weight loss, and in children, abdominal distension may be detected by parents.
Superficial enlarged lymph nodes may be palpable on the surface of the body and may be persistently or progressively enlarged. Typical lymph node enlargement is without tenderness, hard, elastic, and adherent to the surrounding tissues. Enlarged lymph nodes in the mediastinum, mesentery, and retroperitoneum can also be detected by imaging.
Muscle, bone and joint pain
Most commonly seen in pediatric ALL patients. It is caused by infiltration of leukemia cells. Some young children may have claudication or refuse to bear weight due to inability to accurately articulate pain.
Symptoms caused by leukemia cells infiltrating other tissues and organs
Central nervous system: dizziness, headache, vomiting, and in severe cases, neck stiffness, even convulsions and coma.
Testis: mostly painless enlargement of one testis, mostly seen in boys with relapse.
Main symptoms of chronic lymphocytic leukemia (CLL)
In the early stage, there may be no obvious clinical symptoms, and most patients are diagnosed because of lymphocytosis found in routine blood tests.
Some patients may have painless lymph node enlargement, mostly in the neck, supraclavicular and axillary lymph nodes. Hepatosplenomegaly is also common.
Systemic B symptoms of lymphoma, i.e., unexplained fever, night sweats, and weight loss, may be present in 5% to 10% of patients.
Complications
Infection.
Both ALL and CLL are associated with a decrease in white blood cells, especially in ALL. The risk of infection is closely related to a decrease in the number of neutrophils, and as immunity declines, almost any kind of pathogen can lead to infections in the patient, or even lead to sepsis.
Dyspnea.
Most commonly seen in pediatric patients with ALL. Causes superior vena cava syndrome due to rapidly enlarging mediastinal lymph nodes. It manifests as pain, dysphagia, dyspnea, or obstruction of the superior vena cava presenting as swelling of the neck, face, and upper extremities.
Acute tumor lysis syndrome
Most commonly seen in patients with a heavy tumor load that is sensitive to chemotherapy. A large number of tumor cells lysed and necrotic after initial treatment, causing hyperuricemia, hyperphosphatemia, hypocalcemia, hypomagnesemia, and uric acid crystals, which occlude renal tubules and lead to acute renal failure in severe cases [3-9].
Medical treatment
Department of Medicine
Hematology
When unexplained fever, bleeding, anemia, malaise, weight loss, or persistent or progressive lymph node enlargement occurs, prompt hematology consultation is recommended.
Pediatrics
Children with unexplained fever, bleeding, anemia, fatigue, enlarged liver and spleen, persistent or progressive lymph node enlargement, or musculoskeletal and joint pains are advised to consult the Department of Pediatrics.
Preparation
Consultation: Registration, Preparation of Information, Frequently Asked Questions
Tips
Avoid self-medication when the above symptoms occur. Avoid bumps and infections. Avoid exertion.
If symptoms are severe, family or friends should accompany you to the doctor.
Preparation Checklist
Symptom checklist
Pay particular attention to the time of onset of symptoms, specific manifestations, etc.
Is there a feeling of weakness or tiredness? How long does it last?
Is there a fever? How many degrees Celsius?
Are there symptoms associated with anemia, such as pallor, dizziness, etc.?
Is there any bone or joint pain? How long has it lasted?
Is there loss of appetite? How long has it lasted?
Have you lost weight? How much weight has been lost recently?
Are there any bleeding gums or skin petechiae?
Medical History Checklist
Is there a family history of hematologic malignancies?
Is there a history of specific diseases during the mother’s pregnancy?
Is there a history of exposure to ionizing radiation or chemical exposure?
Checklist
Test results of the last 6 months, which can be brought to the doctor’s office
Laboratory tests: routine blood test, blood biochemistry, bone marrow aspiration test, immunological test, cytogenetic test, cerebrospinal fluid test, etc.
Imaging tests: CT, MRI, bone scan, etc.
List of medications used
Medication used in the last 3 months, if you have kept the box or package, please bring it to the doctor.
Chemotherapy drugs: cyclophosphamide, vincristine, hydroxyurea, nitrogen mustard phenylbutyrate, etc.
Immunotherapy drugs: berintuzumab, rituximab, etc.
Targeted therapy drugs: Ibrutinib, Nilotinib, etc.
Diagnosis
Diagnosis is based on
Medical history
History of other hematologic diseases, hereditary diseases, family history of other lymphoproliferative diseases, and history of previous chemotherapy, radiotherapy, etc.
Clinical manifestations
Acute lymphoblastic leukemia (ALL) is characterized by fever, bleeding, anemia, and bone and joint pain. It is more common in children.
Chronic lymphocytic leukemia (CLL) is characterized by fatigue, night sweats, malaise, and low-grade fever, as well as enlarged lymph nodes and liver and spleen. It is common in the elderly.
Laboratory Tests
Routine blood tests
Changes in the number of blood cells and their morphologic distribution can be observed.
Increased peripheral blood leukocyte count and varying numbers of primitive and naïve cells can be seen on blood smear sorting examination, which is mostly seen in ALL.
Bone marrow aspiration or biopsy
To understand the function of the patient’s bone marrow hematopoietic system and to assist in the diagnosis.
ALL is diagnosed by a proportion of ≥20% primitive and naïve lymphocytes.
Significant increase of lymphocytes, accounting for more than 40%, with morphology basically consistent with that of peripheral blood, and rare primitive lymphocytes can suggest CLL.
Blood biochemistry
Understand liver and kidney function, lactate dehydrogenase, electrolyte levels, etc.
Cytogenetic examination
Evaluate whether chromosomal abnormalities have occurred and have guiding value for subsequent treatment decisions and prognosis. For example, Philadelphia (Ph) chromosome t(9;22)(q34.1;q11.2) abnormalities can produce a BCR-ABL1 fusion gene.
The incidence of chromosomal abnormalities varies widely between children and adults.
Immunophenotypic testing
Serial antigen testing, which assists in determining cellular origin, is helpful in typing.
ALL cells may express different antigens depending on whether they are derived from primitive B cells or T cells.
CLL cells mainly express mature B cell-associated antigens, such as CD23+, CD19+, and CD5+.
Cerebrospinal fluid examination
To determine whether there is central nervous system involvement.
Elevated cerebrospinal fluid pressure, increased leukocyte count, and increased proteins may indicate central nervous system involvement.
Imaging examination
Including chest X-ray, abdominal ultrasound, other imaging tests include cardiac ultrasound, head-thorax-abdomen CT and MRI.
Differential Diagnosis
Differential diagnosis of acute lymphoblastic leukemia (ALL)
Acute Mathematical Leukemia (AML)
Similarities: Both may have bone marrow involvement with bleeding, anemia, infection, and extramedullary lymph node enlargement, hepatosplenomegaly, and other manifestations.
Differences: ALL and AML originate from different cells. The primitive cells of AML originate from myeloid, mononuclear, erythroid or megakaryotic lineages, while ALL originates from lymphocytes. Therefore, microscopic observation, immunohistochemistry, and flow cytometry can be used to help differentiate them.
Burkitt’s lymphoma (BL)
Similarities: Both are fast-progressing hematologic malignancies.
Differences: BL mainly presents as a rapidly enlarging mass, such as a jaw or abdominal mass. It can be differentiated by characteristic cellular immunophenotype and chromosome 8 translocation because of its origin from germinal center B cells.
Differential diagnosis of chronic lymphocytic leukemia (CLL)
Sleeve cell lymphoma
Similarity: Both may have enlarged lymph nodes, hepatosplenomegaly and other manifestations.
Differences: The cells of condylomatous lymphoma mostly have strong staining of cell cycle protein D1, high level of SmIg and CD20 expression, and t(11;14) chromosome abnormality.
Infectious mononucleosis
Similarities: both have fever, lymph nodes and hepatosplenomegaly.
Differences: Infectious mononucleosis is an infectious disease, caused by EBV. Typical clinical manifestations include fever, pharyngitis, enlarged lymph nodes, malaise and lymphocytosis. There are no primitive cells in bone marrow and peripheral blood, positive blood heterophilic agglutination test and positive serum EBV antibody [3-9].
Treatment
Aim of treatment: to control the progression of the disease, prevent and reduce complications.
Treatment principle: The treatment of acute lymphoblastic leukemia (ALL) includes induction therapy, post-remission therapy and maintenance therapy.
Childhood ALL is mainly based on the low-risk group, intermediate-risk group and high-risk group determined by prognostic factors, and different intensity of treatment programs are selected. Adult ALL selects different treatments based on Philadelphia (Ph) chromosome positivity or negativity.
Chronic lymphocytic leukemia (CLL) is selected for observation when asymptomatic. Treatment is chosen based on the presence or absence of a del(17p)/TP53 mutation.
Treatment of childhood ALL
Chemotherapy
Chemotherapy regimen
Commonly used induction phase regimens are:
VDLP (vincristine, Zoerythromycin, levomentamide, prednisone) or VDLD (vincristine, Zoerythromycin, levomentamide, dexamethasone) or CVDLD (cyclophosphamide, vincristine, Zoerythromycin, levomentamide, dexamethasone).
Intensive treatment regimens include CAM (cyclophosphamide, cytarabine, 6-mercaptopurine) or CAML (cyclophosphamide, cytarabine, 6-mercaptopurine, pembrolase).
Post-remission consolidation regimens include mM (high-dose methotrexate, calcium tetrahydrofolate), or repeat induction VDLD or CAM.
Maintenance regimens include: 6-mercaptopurine + cyclophosphamide, etc.
Chemotherapy regimen
The total duration of chemotherapy for boys and girls in the low-risk group is 2 years; for girls in the intermediate-risk group, 2 years and boys, 2.5 years; and for both boys and girls in the high-risk group, 2.5 years.
Precautions
Attention needs to be paid to the adverse effects of chemotherapeutic drugs on children. For example, cardiotoxicity of anthracycline, neurotoxicity of cytarabine, and liver and kidney toxicity of many chemotherapeutic drugs. It is necessary to closely monitor the relevant indicators, and adjust the therapeutic dose or stop the drug if necessary.
Targeted therapy
In pediatric ALL patients, the percentage of Philadelphia (Ph) chromosome t(9;22)/BCR-ABL1 positivity is much less than that of adults, and imatinib or dasatinib can be used for treatment of Ph+ patients.
Targeted drugs that target specific antigens on the surface of ALL tumor cells, such as rituximab targeting CD20, alemtuzumab targeting CD52, and eptalizumab targeting CD22, have shown reliable efficacy.
Belintuzumab, a bispecific T-cell engager (BiTE) targeting CD19 and CD3, has been approved in China for the treatment of relapsed or refractory precursor B-cell ALL in adults and children.
Treatment of central nervous system
Intrathecal injection of chemotherapeutic drugs is carried out at the same time with systemic chemotherapy, and the commonly used drugs are cytarabine, methotrexate, dexamethasone.
Hematopoietic stem cell transplantation
Allogeneic hematopoietic stem cell transplantation is an optional treatment option for childhood ALL, especially for Ph+ children.
Some guidelines recommend HSCT as an option for children who fail induction remission therapy; have a bone marrow assessment of minimal residual disease (MRD) level ≥1×10-2 after induction remission therapy; and have a 12-week MRD ≥1×10-4 with t(9;22)/BCR-ABL1, MLL rearrangement, EPT-ALL, and iAMP21.
Radiotherapy
Mainly for children over 2 years old, children with combined testicular leukemia, and unsatisfactory chemotherapy.
Chimeric antigen receptor T cell (CAR-T) immunotherapy
CAR-T immunotherapy extracts some of the patient’s T-cells, adds specific antigens that can recognize tumor cells to the T-cells using genetic engineering technology, cultures and activates the CAR-T in vitro, and then transfuses them back to the patient. It has the advantages of specifically killing tumor cells and controllable adverse reactions.
Supportive therapy
Many pediatric ALL patients require blood transfusion support, antibiotic anti-infection treatment, and correction of metabolic imbalance due to high tumor load after diagnosis. Severe cases may even require blood cell separators to remove excess white blood cells.
Treatment of ALL in adolescents and adults
Treatment of Ph-ALL
Similar to the treatment of childhood ALL, multi-agent chemotherapy is the mainstay. The common chemotherapy regimen for young adult and non-elderly ALL is a regimen based on vincristine such as Vincristine, anthracyclines such as Zorubicin, and glucocorticoids such as Prednisone. Other commonly used chemotherapeutic agents are cytarabine and 6-mercaptopurine.
Patients with B-ALL may be treated with belintuzumab, a bispecific antibody targeting CD19 and CD3, after induction of remission.
Allogeneic hematopoietic stem cell transplantation is recommended for ALL with high white blood cell counts at diagnosis and poor prognostic genetic factors. mostly as soon as possible after consolidation of intensive therapy.
Treatment of Ph+ALL
Combination of tyrosine kinase inhibitor (TKI) imatinib and others on the basis of Ph-ALL treatment regimen [3,5,7,10-13].
Treatment of CLL
Indications for treatment of CLL
Not all patients with CLL require treatment, which is initiated when at least 1 of the following is present.
Progressive bone marrow failure.
Giant spleen or symptomatic splenomegaly.
Giant lymph node enlargement or symptomatic lymph node enlargement.
Progressive lymphocytosis.
Symptomatic organ dysfunction due to disease.
Autoimmune hemolytic anemia and/or immune thrombocytopenia Poor response to corticosteroids.
Weight loss without apparent cause, or severe fatigue, or unexplained persistent fever, or persistent night sweats.
Participation in clinical trials.
Treatment of patients with CLL without del(17p)/TP53 gene mutations
Patients in good physical condition
Preferably ibrutinib, zebrutinib, fludarabine + cyclophosphamide + rituximab (for patients with mutations in IGHV and <60 years of age), bendamustine + rituximab (for patients with mutations in IGHV and ≥60 years of age).
Other regimens: Obrutinib, Vinaclat + rituximab/orthotuzumab, fludarabine + rituximab, fludarabine + cyclophosphamide.
Patients in poor physical status
Prefer ibrutinib, zebrutinib, nitrogen mustard phenylbutyrate + rituximab/otolizumab.
Other treatment options: obrutinib, vinaclat + rituximab/otolizumab, otolizumab, nitrogen mustard phenylbutyrate, rituximab.
Treatment of patients with CLL with del(17p)/TP53 gene mutation
Preferred: ibrutinib, zerbutinib, obrutinib.
Other treatment options: Venegra + rituximab/orthotuzumab, high-dose methylprednisolone + rituximab/orthotuzumab.
Other treatments
Allogeneic hematopoietic stem cell transplantation is the only curative option for CLL and may be considered in refractory patients and in patients with CLL clonally related Richter transformation.
CAR-T therapy has also shown some efficacy in patients with relapsed refractory CLL [8-9,14-16].
Prognosis
Cure.
The 5-year survival rate of pediatric acute lymphoblastic leukemia (ALL) patients can reach about 85%. The prognosis of adult ALL is worse than that of children, but with the use of tyrosine kinase inhibitors, the prognosis of adult ALL has improved in recent years.
The median survival of patients with chronic lymphocytic leukemia (CLL) is about 10 years, but it varies widely among patients.
Prognostic factors
Poor prognostic factors for childhood ALL
Age <1 year or ≥10 years at diagnosis.
Peripheral blood white blood cell (WBC) count ≥50 × 109/L at diagnosis.
Children who have developed central nervous system leukemia or testicular leukemia at diagnosis.
Immunophenotype was T-ALL.
Unfavorable cytogenetic and molecular genetic features such as Ph+, iAMP21, and IKZF deletion.
Bone marrow not in remission at the end of induced remission therapy, or complete remission not achieved in bone marrow at the end of induced remission therapy.
Minor residual disease (MRD) ≥ 10-1 early in induction of remission therapy, MRD ≥ 10-2 after induction of remission therapy, or MRD ≥ 10-4 prior to the start of consolidation therapy.
Poor prognostic factors for CLL
Poor prognosis for patients without mutations in IGHV, with chromosomal complex karyotype abnormalities, del(17p) and/or TP53 gene mutations.
Daily
Daily management
Dietary management
Balanced nutrition, pay attention to vitamin and high protein supplementation, avoid eating raw, cold and hard food, patients should eat cooked and soft food for nearly 1 month after medication.
Before consuming fruits and vegetables, make sure to wash them well.
Loss of appetite may occur during chemotherapy, so eat small and frequent meals.
Life management
Adopt good habits of work and rest, pay attention to personal hygiene, avoid contact with infectious agents and prevent infection.
The living room should be clean and ventilated, maintain air humidity and temperature, and pay attention to keeping warm.
If the patient has fever 7 to 10 days after medication, he/she should seek medical attention for treatment.
Daily activities need to be careful and slow, avoid touching or bumping hard objects that may scratch the skin and increase the risk of bleeding.
Patients who are bedridden for a long time need to massage their lower limbs regularly to avoid muscle atrophy and venous thrombosis of the lower limbs.
Psychological support
In the face of the diagnosis of leukemia or the treatment process, patients are prone to anxiety, depression, resistance, and should communicate with their families and friends in a timely manner to seek psychological support.
Maintain an optimistic and positive attitude and actively cooperate with the treatment.
Disease monitoring
Pay attention to whether there are bleeding symptoms on one’s own skin and mucous membranes.
Monitor the change of body temperature and consult the doctor promptly if there is persistent fever.
Observe whether there is enlargement of testicles, liver and spleen lymph nodes.
For pediatric patients, it is necessary to pay attention to growth and development, and monitor whether there is the occurrence of secondary tumors [3,7].
Follow-up review
In pediatric patients with ALL, routine blood tests were performed approximately every 3 months for two years after discontinuation of the drug, and a comprehensive physical examination was performed annually, focusing on lymph nodes, liver, spleen, and testes. In the third year after stopping the drug, routine blood tests should be performed every 6 months and annual physical examination should be performed. Consultation was performed at any time when symptoms of recurrence appeared.
Regular follow-up of CLL patients should focus on the adverse effects of tyrosine kinase inhibitors in addition to disease monitoring.
Prevention
Regular life and good hygiene habits. Adhere to exercise to enhance immunity.
Avoid long-term exposure to ionizing radiation or benzene, etc.
Regular medical checkups for people with a family history of hematologic malignancies.