Acute lymphoblastic leukemia
Acute lymphoblastic leukemia | |
---|---|
Other names | Acute lymphocytic leukemia, acute lymphoid leukemia |
Prognosis | Children: 90% five-year survival rate[2] Adults: 35% five-year survival[8] |
Frequency | 1 in 1,750 children[4][9] |
Deaths | 111,000 (2015)[10] |
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes.[1] Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain.[1] As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.[11]
In most cases, the cause is unknown.
Acute lymphoblastic leukemia is typically treated initially with
Treatment can also include
Acute lymphoblastic leukemia affected about 876,000 people globally in 2015 and resulted in about 111,000 deaths.
Signs and symptoms
Initial
Central nervous system (CNS) symptoms such as cranial neuropathies due to meningeal infiltration are identified in less than 10% of adults and less than 5% of children, particularly mature B-cell ALL (Burkitt leukemia) at presentation.[20]
The signs and symptoms of acute lymphoblastic leukemia are variable and include:[21]
- Generalized weakness and feeling tired
- Anemia
- Dizziness
- Headache, vomiting, lethargy, neck stiffness,[22] or cranial nerve palsies[23] (CNS involvement)
- Frequent or unexplained fever and infection
- Weight loss and/or loss of appetite
- Excessive and unexplained bruising
- Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity)
- Breathlessness
- Enlarged lymph nodes, liver, and/or spleen
- Pitting edema (swelling) in the lower limbs and/or abdomen
- Petechiae, which are tiny red spots or lines in the skin due to low platelet levels
- Testicular enlargement
- Mediastinal mass
Cause
The cancerous cell in ALL is the lymphoblast. Normal lymphoblasts develop into mature, infection-fighting B-cells or T-cells, also called lymphocytes. Signals in the body control the number of lymphocytes so neither too few nor too many are made. In ALL, both the normal development of some lymphocytes and the control over the number of lymphoid cells become defective.[4][24]
Acute lymphoblastic leukemia emerges when a single lymphoblast gains many
Infant ALL is a rare variant that occurs in babies less than one year old. KMT2A (formerly MLL) gene rearrangements are most common and occur in the embryo or fetus before birth.[4] These rearrangements result in increased expression of blood cell development genes by promoting gene transcription and through epigenetic changes.[25][26] In contrast to childhood ALL, environmental factors are not thought to play a significant role. Aside from the KMT2A rearrangement, only one extra mutation is typically found.[4] Environmental exposures are not needed to help create more mutations.
Risk factors
Genetics
Common inherited risk factors include mutations in
The uneven distribution of genetic risk factors may help explain differences in disease rates among ethnic groups. For instance, the ARID5B mutation is less common in ethnic African populations.[4]
Several genetic syndrome also carry increased risk of ALL. These include:
Rare mutations in ETV6 and PAX5 are associated with a familial form of ALL with autosomal dominant patterns of inheritance.[2]
Environmental
The environmental exposures that contribute to emergence of ALL is contentious and a subject of ongoing debate.[6][4]
High levels of radiation exposure from nuclear fallout is a known risk factor for developing leukemia.[27] Evidence whether lesser radiation, as from x-ray imaging during pregnancy, increases risk of disease remains inconclusive.[6] Studies that have identified an association between x-ray imaging during pregnancy and ALL found only a slightly increased risk.[4] Exposure to strong electromagnetic radiation from power lines has also been associated with a slightly increased risk of ALL. This result is questioned as no causal mechanism linking electromagnetic radiation with cancer is known.[6][4]
High birth weight (greater than 4000 g or 8.8 lbs) is also associated with a small increased risk. The mechanism connecting high birth weight to ALL is also not known.[6]
Evidence suggests that secondary leukemia can develop in individuals treated with certain types of chemotherapy, such as epipodophyllotoxins and cyclophosphamide.[6][28]
Infections
There is some evidence that a common infection, such as influenza, may indirectly promote the emergence of ALL.[6][4] The delayed-infection hypothesis states that ALL results from an abnormal immune response to infection in a person with genetic risk factors. Delayed development of the immune system due to limited disease exposure may result in excessive production of lymphocytes and increased mutation rate during an illness. Several studies have identified lower rates of ALL among children with greater exposure to illness early in life. Very young children who attend daycare have lower rates of ALL. Evidence from many other studies looking at disease exposure and ALL is inconclusive.[6] Some researchers have linked the hygiene hypothesis.[29]
Mechanism
Several characteristic genetic changes lead to the creation of a leukemic lymphoblast. These changes include chromosomal translocations, intrachromosomal rearrangements, changes in the number of chromosomes in leukemic cells, and additional mutations in individual genes.[2] Chromosomal translocations involve moving a large region of DNA from one chromosome to another. This move can result in placing a gene from one chromosome that promotes cell division to a more actively transcribed area on another chromosome. The result is a cell that divides more often. An example of this includes the translocation of C-MYC, a gene that encodes a transcription factor that leads to increased cell division, next to the immunoglobulin heavy- or light-chain gene enhancers, leading to increased C-MYC expression and increased cell division.[2] Other large changes in chromosomal structure can result in the placement of two genes directly next to each other. The result is the combination of two usually separate proteins into a new fusion protein. This protein can have a new function that promotes the development of cancer. Examples of this include the ETV6–RUNX1 fusion gene that combines two factors that promote blood cell development and the BCR-ABL1 fusion gene of the Philadelphia chromosome. BCR–ABL1 encodes an always-activated tyrosine kinase that causes frequent cell division. These mutations produce a cell that divides more often, even in the absence of growth factors.[4][2]
Other genetic changes in B-cell ALL include changes to the number of chromosomes within the leukemic cells. Gaining at least five additional chromosomes, called high hyperdiploidy, occurs more commonly. Less often, chromosomes are lost, called hypodiploidy, which is associated with a poorer prognosis. Additional common genetic changes in B-cell ALL involve non-inherited mutations to PAX5 and IKZF1.[2] In T-cell ALL, LYL1, TAL1, TLX1, and TLX3 rearrangements can occur.[4]
Acute lymphoblastic leukemia results when enough of these genetic changes are present in a single lymphoblast. In childhood ALL, for example, one fusion gene translocation is often found along with six to eight other ALL-related genetic changes.[4] The initial leukemic lymphoblast copies itself into an excessive number of new lymphoblasts, none of which can develop into functioning lymphocytes. These lymphoblasts build up in the bone marrow and may spread to other sites in the body, such as lymph nodes, the mediastinum, the spleen, the testicles, and the brain, leading to the common symptoms of the disease.[2]
Diagnosis
A
-
Acute lymphoblastic leukemia (ALL), peripheral blood of a child, Pappenheim stain, magnification x100
-
Bone marrow smear (large magnification) from a person with acute lymphoblastic leukemia
-
Bone marrow smear from a person with acute lymphoblastic leukemia
Immunophenotyping
In addition to cell morphology and cytogenetics, immunophenotyping, a laboratory technique used to identify proteins that are expressed on their cell surface, is a key component in the diagnosis of ALL. The preferred method of immunophenotyping is through flow cytometry. In the malignant lymphoblasts of ALL, expression of terminal deoxynucleotidyl transferase (TdT) on the cell surface can help differentiate malignant lymphocyte cells from reactive lymphocytes, white blood cells that are reacting normally to an infection in the body. On the other hand, myeloperoxidase (MPO), a marker for the myeloid lineage, is typically not expressed. Because precursor B cell and precursor T cells look the same, immunophenotyping can help differentiate the subtype of ALL and the level of maturity of the malignant white blood cells. The subtypes of ALL as determined by immunophenotype and according to the stages of maturation.[5]
B cell lineage | T cell lineage |
---|---|
pre-pre-B ALL (pro-B-ALL) | precursor T- ALL |
common ALL | mature T-cell ALL |
pre-B ALL | |
mature B-cell ALL (Burkitt leukemia – FAB L3) |
An extensive panel of monoclonal antibodies to cell surface markers, particularly CD or cluster of differentiation markers, are used to classify cells by lineage. Below are immunological markers associated with B cell and T cell ALL.[33]
Immunological markers | B cell Lineage | T cell Lineage |
---|---|---|
B cell lineage | ||
CD19, CD22, CD79a | + | − |
CD10 | − or + (common ALL) | |
cytoplasmic Ig | − or + (pre-B ALL) | |
surface Ig | − or + (mature B-cell ALL) | |
TdT | + | + |
T cell lineage | ||
CD2, CD3, CD4, CD5, CD7, CD8 | − | + |
TdT | + | + |
Cytogenetics
Cytogenetic analysis has shown different proportions and frequencies of genetic abnormalities in cases of ALL from different age groups. This information is particularly valuable for classification and can in part explain the different prognoses of these groups. In regards to genetic analysis, cases can be stratified according to ploidy, a number of sets of chromosomes in the cell, and specific genetic abnormalities, such as translocations. Hyperdiploid cells are defined as cells with more than 50 chromosomes, while hypodiploid are defined as cells with less than 44 chromosomes. Hyperdiploid cases tend to carry a good prognosis while hypodiploid cases do not.[33] For example, the most common specific abnormality in childhood B-ALL is the t(12;21) ETV6–RUNX1 translocation, in which the RUNX1 gene, encoding a protein involved in transcriptional control of hemopoiesis, has been translocated and repressed by the ETV6–RUNX1 fusion protein.[34]
Below is a table with the frequencies of some cytogenetic
Cytogenetic translocation | Molecular genetic abnormality | % |
---|---|---|
cryptic t(12;21) | TEL–AML1 fusion[35] | 25.4%[36] |
t(1;19)(q23;p13) | E2A–PBX (PBX1) fusion[37] | 4.8%[36] |
t(9;22)(q34;q11) | BCR-ABL fusion(P185)[38]
|
1.6%[36] |
t(4;11)(q21;q23) | AF4 fusion[39]
|
1.6%[36] |
t(8;14)(q24;q32) | IGH–MYC fusion[40] | |
t(11;14)(p13;q11) | RBTN2 fusion[41]
|
Classification
French-American-British
Historically, prior to 2008, ALL was classified morphologically using the French-American-British (FAB) system that heavily relied on morphological assessment. The FAB system takes into account information on size, cytoplasm, nucleoli, basophilia (color of cytoplasm), and vacuolation (bubble-like properties).[42][43]
FAB Subtype | Cell Type | Characteristics | Comments |
---|---|---|---|
ALL - L1 | T cell or pre-B cell | Small and homogeneous (uniform) cells | |
ALL - L2 | T cell or pre-B cell | Large and heterogeneous (varied) cells | |
ALL - L3 | B cell | Large and varied cells with vacuoles | Mature B-cell ALL also named Burkitt leukemia. Typically, poor prognosis with standard therapy |
While some clinicians still use the FAB scheme to describe tumor cell appearance, much of this classification has been abandoned because of its limited impact on treatment choice and prognostic value.[44]: 491
World Health Organization
In 2008, the World Health Organization classification of acute lymphoblastic leukemia was developed in an attempt to create a classification system that was more clinically relevant and could produce meaningful prognostic and treatment decisions. This system recognized differences in genetic, immunophenotype, molecular, and morphological features found through cytogenetic and molecular diagnostics tests.[45]: 1531–1535 [33] This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.
The WHO subtypes related to ALL are:[46]
- B-lymphoblastic leukemia/lymphoma
- Not otherwise specified (NOS)
- with recurrent genetic abnormalities
- with t(9;22)(q34.1;q11.2);BCR-ABL1
- with t(v;11q23.3);KMT2A rearranged
- with t(12;21)(p13.2;q22.1); ETV6-RUNX1
- with t(5;14)(q31.1;q32.3) IL3-IGH
- with t(1;19)(q23;p13.3);TCF3-PBX1
- with hyperdiploidy
- with hypodiploidy
- T-lymphoblastic leukemia/lymphoma
- Acute leukemias of ambiguous lineage
- Acute undifferentiated leukemia
- Mixed phenotype acute leukemia(MPAL) with t(9;22)(q34.1;q11.2); BCR–ABL1
- MPAL with t(v;11q23.3); KMT2A rearranged
- MPAL, B/myeloid, NOS
- MPAL, T/myeloid, NOS
Treatment
The aim of treatment is to induce a lasting remission, defined as the absence of detectable cancer cells in the body (usually less than 5% blast cells in the bone marrow) or the absence of minimal residue disease.
Over the past several decades, there have been strides to increase the efficacy of treatment regimens, resulting in increased survival rates. Possible treatments for acute leukemia include
Chemotherapy
Chemotherapy is the initial treatment of choice, and most people with ALL receive a combination of medications. There are no surgical options because of the body-wide distribution of the
Phase | Description[48][49] | Agents[48][49] |
---|---|---|
Remission induction | Aim to:
Must monitor closely for tumor lysis syndrome after initiating therapy Monitoring initial response to treatment is important as failure to show clearance of blood or bone marrow blasts within the first two weeks of therapy has been associated with a higher risk of relapse
Start CNS prophylaxis and administer intrathecal chemotherapy via Ommaya reservoir or multiple lumbar punctures
|
Combination of:
Central nervous system prophylaxis can be achieved via:[50]
In Philadelphia chromosome-positive ALL, the intensity of initial induction treatment may be less than has been traditionally given.[51][52] |
Consolidation/intensification | Use high doses of chemotherapy to further reduce tumor burden | Typical protocols use the following given as blocks (varies from 1–3 blocks depending on person's risk category) in different multi-drug combinations:
Central nervous system relapse is treated with intrathecal administration of hydrocortisone, methotrexate, and cytarabine. |
Maintenance therapy | Kill any residual cell that was not killed by remission induction and intensification regimens
|
Typical protocol would include:
|
Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. Two subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adults with ALL. B-cell ALL is often associated with cytogenetic abnormalities (specifically, t(8;14), t (2;8), and t(8;22)), which require aggressive therapy consisting of brief, high-intensity regimens. T-cell ALL responds to cyclophosphamide-containing agents the most.[49]
Radiation therapy
Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, or as part of the preparations for a
Biological therapy
Selection of biological targets on the basis of their combinatorial effects on the leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.
Blinatumomab is not only a promising add-on to chemotherapy in infant ALL,[55] it is also a promising standalone therapy in children's.[56]
Immunotherapy
CD19 is a molecule found on all B-cells and can be used as a means of distinguishing the potentially malignant B-cell population. In this therapy, mice are immunized with the CD19 antigen and produce anti-CD19 antibodies. Hybridomas developed from mouse spleen cells fused to a myeloma cell line can be developed as a source for the cDNA encoding the CD19 specific antibody.[57] The cDNA is sequenced and the sequence encoding the variable heavy and variable light chains of these antibodies are cloned together using a small peptide linker. This resulting sequence encodes the scFv. This can be cloned into a transgene, encoding what will become the endodomain of the CAR. Varying arrangements of subunits serve as the endodomain, but they generally consist of the hinge region that attaches to the scFv, a transmembrane region, the intracellular region of a costimulatory molecule such as CD28, and the intracellular domain of CD3-zeta containing ITAM repeats. Other sequences frequently included are: 4-1bb and OX40.[58] The final transgene sequence, containing the scFv and endodomain sequences is then inserted into immune effector cells that are obtained from the person and expanded in vitro. In trials these have been a type of T-cell capable of cytotoxicity.[59]
Inserting the DNA into the effector cell can be accomplished by several methods. Most commonly, this is done using a lentivirus that encodes the transgene. Pseudotyped, self-inactivating lentiviruses are an effective method for the stable insertion of a desired transgene into the target cell.[60] Other methods include electroporation and transfection, but these are limited in their efficacy as transgene expression diminishes over time.[medical citation needed]
The gene-modified effector cells are then transplanted back into the person. Typically this process is done in conjunction with a conditioning regimen such as cyclophosphamide, which has been shown to potentiate the effects of infused T-cells. This effect has been attributed to making an immunologic space within which the cells populate.[58] The process as a whole result in an effector cell, typically a T-cell, that can recognize a tumor cell antigen in a manner that is independent of the major histocompatibility complex and which can initiate a cytotoxic response.[medical citation needed]
In 2017,
Relapsed ALL
Typically, people who experience a relapse in their ALL after initial treatment have a poorer prognosis than those who remain in complete remission after induction therapy. It is unlikely that recurrent leukemia will respond favorably to the standard chemotherapy regimen that was initially implemented, and instead, these people should be trialed on reinduction chemotherapy followed by
Low dose palliative radiation may also help reduce the burden of tumor inside or outside the central nervous system and alleviate some symptoms.[medical citation needed]
There has also been evidence and approval of use for dasatinib, a tyrosine kinase inhibitor. It has shown efficacy in cases of people with Ph1-positive and imatinib-resistant ALL, but more research needs to be done on long-term survival and time to relapse.[49]
Side effects
Chemotherapies or stem cell transplantations may require a platelet transfusion to prevent bleeding.[64][65] Moreover, patients undergoing a stem cell transplantation can develop a graft-versus-host disease (GvHD). It was evaluated whether mesenchymal stromal cells can be used to prevent a GvHD. The evidence is very uncertain about the therapeutic effect of mesenchymal stromal cells to treat graft-versus-host diseases after a stem cell transplantation on the all-cause mortality and complete disappear of chronic acute graft-versus-host diseases. Mesenchymal stromal cells may results in little to no difference in the all-cause mortality, relapse of malignant disease and incidence of acute and chronic graft-versus-host diseases if they are used for prophylactic reason.[66]
Supportive therapy
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like ALL may result in little to no difference in mortality, quality of life, and physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect on anxiety and serious adverse events.[67]
Gene therapy
Brexucabtagene autoleucel (Tecartus) was approved for the treatment of adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia in October 2021.[68] [69]
Each dose of brexucabtagene autoleucel is a customized treatment created using the recipient's own immune system to help fight the lymphoma.[70] The recipient's T cells, a type of white blood cell, are collected and genetically modified to include a new gene that facilitates the targeting and killing of the lymphoma cells.[70] These modified T cells are then infused back into the recipient.[70]
Prognosis
Prior to the development of chemotherapy regimens and hematopoietic stem cell transplant, children were surviving a median length of 3 months, largely due to either infection or bleeding. Since the advent of chemotherapy, the prognosis for childhood leukemia has improved greatly and children with ALL are estimated to have a 95% probability of achieving a successful remission after 4 weeks of initiating treatment. People in pediatric care with ALL in developed countries have a greater than 80% five-year survival rate. It is estimated that 60–80% of adults undergoing induction chemotherapy achieve complete remission after 4 weeks, and those over the age of 70 have a cure rate of 5%.[48][71]
However, there are differing prognoses for ALL among individuals depending on a variety of factors:
- Gender: Females tend to fare better than males.
- Ethnicity: Hispanics. However, they also tend to have a better prognosis than non-Caucasians.
- Age at diagnosis: children 1–10 years of age are most likely to develop ALL and to be cured of it. Cases in older people are more likely to result from chromosomal abnormalities (e.g., the Philadelphia chromosome) that make treatment more difficult and prognoses poorer. Older people are also likely to have co-morbid medical conditions that make it even more difficult to tolerate ALL treatment.
- White blood cell count at diagnosis of greater than 30,000 (B-ALL) or 100,000 (T-ALL) is associated with worse outcomes
- Cancer spreading into the central nervous system (brain or spinal cord) has worse outcomes.
- Morphological, immunological, and genetic subtypes
- Person's response to initial treatment and longer length of time required (greater than 4 weeks) to reach complete remission
- Early relapse of ALL
- Minimal residual disease
- Genetic disorders, such as Down syndrome, and other chromosomal abnormalities (aneuploidy and translocations)[72]
Factor | Unfavorable | Favorable |
---|---|---|
Age | <2 or >10 years | 3–5 years |
Sex | Male | Female |
Race | Black | Caucasian |
Organomegaly | Present | Absent |
Mediastinal mass | Present | Absent |
CNS involvement | Present | Absent |
Leukocyte count | B-ALL >30,000mm3 T-ALL >100,000mm3 | Low |
Hemoglobin concentration | >10g/dl | <10g/dl |
Cell type | Non Lymphoid | Lymphoid |
Cell lineage | Pre B cell +
T-ALL (children) |
Early Pre B cell |
Karyotype | Translocation | Hyperdiploidy |
Response to treatment | Slow
>1 week to clear blasts from blood |
Rapid
<1 week to clear blasts from blood |
Time to remission | >4 weeks | <4 weeks |
Minimal residual disease | Positive at 3 – 6 months | Negative at 1 month (children) or 3 months (adults) |
Cytogenetics, the study of characteristic large changes in the
- Person with t(9,22) positive-ALL (30% of adult ALL cases) and other Bcr-abl-rearranged leukemias are more likely to have a poor prognosis, but survival rates may rise with treatment consisting of chemotherapy and Bcr-abl tyrosine kinase inhibitors.[49]
- A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.[medical citation needed]
Cytogenetic change | Risk category |
---|---|
Philadelphia chromosome | Poor prognosis |
t(4;11)(q21;q23) | Poor prognosis |
t(8;14)(q24.1;q32) | Poor prognosis |
Complex karyotype (more than four abnormalities) | Poor prognosis |
Low triploidy
|
Poor prognosis |
Deletion of chromosome 7 | Poor prognosis |
Trisomy 8 | Poor prognosis |
High hyperdiploidy (trisomy 4, 10, 17) | Good prognosis |
del(9p) | Good prognosis |
- Hyperdiploidy (>50 chromosomes) and t(12;21) are good prognostic factors and also makeup 50% of pediatric ALL cases.
Prognosis | Cytogenetic findings |
---|---|
Favorable | Hyperdiploidy > 50 ; t (12;21) |
Intermediate | Hyperdiploidy 47–50; Normal(diploidy); del (6q); Rearrangements of 8q24 |
Unfavorable | Hypodiploidy-near haploidy; Near tetraploidy; del (17p); t (9;22); t (11q23) |
Unclassified ALL is considered to have an intermediate prognosis risk,[77] somewhere in-between the good and poor risk categories.
Epidemiology
Acute lymphoblastic leukemia affected about 876,000 people and resulted in 111,000 deaths globally in 2015.[14][10] It occurs in both children and adults with highest rates seen between the ages three and seven years. Around 75% of cases occur before the age of 6 with a secondary rise after the age of 40.[48] It is estimated to affect 1 in 1500 children.[9]
Accounting for the broad age profiles of those affected, ALL newly occurs in about 1.7 per 100,000 people per year.[5] Acute lymphoblastic leukemia represents approximately 20% of adults and 80% of childhood leukemias, making it the most common childhood cancer.[5] Although 80 to 90% of children will have a long term complete response with treatment,[45]: 1527 it remains the leading cause of cancer-related deaths among children.[78] 85% of cases are of B-cell lineage and have an equal number of cases in both males and females. The remaining 15% of T-cell lineage have a male predominance.
Globally, ALL typically occurs more often in Caucasians, Hispanics, and Latin Americans than in Africans.[79]: 1617 [80] In the US, ALL is more common in children from Caucasian (36 cases/million) and Hispanic (41 cases/million) descent when compared to those from African (15 cases/million) descent.[81]
Pregnancy
Leukemia is rarely associated with pregnancy, affecting only about 1 in 10,000 pregnant women.
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