Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruising, enlarged lymph nodes, or bone pain.[rx] As an acute leukemia, ALL progresses rapidly and is typically fatal within weeks or months if left untreated.[rx]
Acute Lymphoblastic Leukemia (ALL)/lymphoblastic lymphoma (LBL) is a clonal hematopoietic stem cell disorder of B or T cell origin. The World Health Organization (WHO) 2017 classification system categorizes these disease entities under precursor lymphoid neoplasm. The WHO 2017 classification of precursor lymphoid neoplasm includes 4 distinct entities: B-ALL/LBL not otherwise specified (NOS); B-ALL/LBL with recurrent genetic abnormalities; T-ALL/LBL; and NK-ALL/LBL. Lymphoblasts are the characteristic cells of this disease entity. The lymphoblasts are usually small to medium-sized with scant cytoplasm, moderately condensed to dispersed chromatin and inconspicuous nucleoli. The lymphoblasts traditionally involve the bone marrow (BM) and/or blood in ALL and involve the lymph nodes in LBL. The diagnosis is of ALL is rendered when the blast count exceeds 20%. Occasionally, patients present with primary lymph node involvement of nodal or extranodal sites (LBL). Sometimes, there is an overlap between ALL and LBL, and it has been widely accepted to render a combined diagnosis. NK-ALL/LBL is a currently a provisional entity in the WHO 2017 classification. It is a rare entity, and diagnosis often overlaps with T-ALL/LBL. ALL is one of the earliest neoplasms where chemotherapeutic treatment showed a favorable outcome. It has also been one of the earliest neoplastic disease entities where the understanding of biology has led to direct changes in the management of patients.[rx][rx]
Types of Acute Lymphoblastic Leukemia
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).[rx][rx]
| 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 limited impact on treatment choice and prognostic value.[rx]: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.[rx]:1531–1535[rx] This subtyping helps determine the prognosis and the most appropriate treatment for each specific case of ALL.
The WHO subtypes related to ALL are:[rx]
- 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
Pathophysiology
B-ALL arises in either a hematopoietic stem cell or a B-cell progenitor. B-ALL shows various chromosomal abnormalities. Chromosomal abnormalities are thought to be an early initiating event in leukemogenesis and usually involve genes regulating cell signaling, tumor-suppressor functions, and/or lymphoid differentiation. Chromosomal abnormalities encountered include aneuploidy (changes in chromosome number), chromosomal rearrangements/translocations, genetic deletions/gains, and genetic mutations.
Generally, translocations are classified into 2 main classes. The first class involves the translocation of oncogenes to regulatory gene regions. The second class of translocations involves 2 genes and result in a chimeric protein. ALL show many distinct translocations showing both functional classes of translocations.[rx]
B-ALL is classified into 2 distinct entities:
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B-ALL not otherwise specified (NOS)
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B-ALL with recurrent genetic abnormalities
The B-ALL/LBL (NOS) should only be rendered when all other entities have been excluded. B-ALL is classified into multiple entities based on distinct chromosomal abnormalities as follows[rx][rx]:
B-Lymphoblastic Leukemia/Lymphoma (NOS)
Should only be rendered after the exclusion of all ALL with recurrent genetic abnormalities and Burkitt lymphoma/leukemia.
B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities
This entity is classified into 9 different entities based on distinct chromosomal abnormalities as follows:
B-ALL/LBL with t(9;22)(q34;q 112); BCR; ABL1 – This entity is relatively more common in adults than children. The translocation can either lead to a p190 BCR-ABL1 fusion protein (common in children) or p210 BCR-ABL1 fusion protein (common in adults). Overall, t(9;22) B-ALL cases have an unfavorable outcome compared to other ALL entities. Patients who are responsive to tyrosine kinase inhibitors tend to have a more favorable outcome than others.
B-ALL/LBL with t(v;11q23.3); KMT2A rearrangement – This entity shows a translocation between the KMT2A (MLL) gene at band 11q23 and up to 100 different fusion partners. This entity usually presents with a pro-B immunophenotype. ALL with KMT2A rearrangements is by far more common in infants younger than 1 year and tends to present more often with leukocytosis and central nervous system (CNS) involvement compared to other entities. The most common fusion partner gene is AF4 on chromosome 4q21. Overall, B-ALL with KMT2A rearrangements cases has an unfavorable outcome compared to other ALL entities.
B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1 – This entity is common and accounts to up to 25% of childhood B-ALL. The entity has a unique immunophenotype that includes positive CD19, CD10, and CD34 and negative CD9, CD20, and CD66c. The ETV6-RUNX1 translocation results in a fusion protein that inhibits the RUNX1 function. B-ALL/LBL with t(12;21) also shows a unique genetic signature and overall shows a favorable overall prognosis.
B-lymphoblastic leukemia/lymphoma with hyperdiploidy – Hyperdiploidy in B-ALL/LBL is characterized by more than 50 and fewer than 66 chromosomes without other structural abnormalities. Common chromosomes include 21, X, 14, and 4. This entity is common and accounts for to up to 25% of childhood B-ALL. Lymphoblasts show the following immunophenotype: CD19+, CD10-, CD34+, and CD45-. B-ALL/LBL with hyperdiploidy shows a favorable overall prognosis although the outcome may vary based on certain trisomies present. For instance, the most favorable outcome is identified in patients with simultaneous trisomies 4, 10, and 17.
B-lymphoblastic leukemia/lymphoma with hypodiploidy – Hypodiploidy with B-ALL/LBL includes the following subtype: near-haploid ALL (23 to 29 chromosomes), low haploid ALL (33 to 39 chromosomes), high hypodiploid (40 to 43 chromosomes), near-diploid (44 to 45 chromosomes). In addition to the chromosome loss, structural abnormalities can also be identified in B-ALL with hypodiploidy. The entity usually demonstrates a B-cell precursor immunophenotype. Low haploid ALL usually shows a distinctive genetic signature that includes loss of function mutation of TP53 or RB1. Overall, B-ALL with hypodiploidy cases has an unfavorable outcome with near-haploid ALL having the worst prognosis of the 4 subtypes.
B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3) IL3-IGH – This entity is a relatively rare ALL entity. The translocation between the IL3 gene and IGH gene results in the constitutive overexpression of IL3. Patients can present similar to other ALL patients, however, presenting with asymptomatic eosinophilia is possible. The unusual increase in eosinophils in ALL with t(5;14) is characteristic of this entity, however, is not related to the leukemic clone and has no clear cause. The prognosis of ALL with t(5;14) is usually favorable.
B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 – This entity is relatively common in children. There is no unique clinical presentation in these patients. The immunophenotype of lymphoblasts in these patients shows a pre-B with CD19, CD10, and cytoplasmic mu positivity. Although this disease entity shows a distinct genetic and immunophenotypic signature, the management of this entity is not different from other ALL (NOS) patients. Therefore, the identification of this entity is not mandatory.
B-lymphoblastic leukemia/lymphoma with BCR-ABL1-like[rx]: This entity has been introduced as a provisional entity in the WHO 2017. It is a relatively common subtype of B-ALL, representing 7% to 25% of B-ALL patients.
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The entity is more common in Down syndrome patients and uniquely show CRLF2 translocation. It is a diagnosis of exclusion. After exclusion of distinct entities. Gene expression profiling is the “gold standard” for diagnosis of BCR-ABL1-like B-ALL. FISH and karyotyping may be helpful in ruling out other entities.
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Some specialized labs currently offer multiplex FISH testing for some of the common genes
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Similar to other ALL with recurrent genetic abnormalities this entity shows no unique presentation, microscopic presentation or immunophenotypic profile.
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This entity is characterized by a pattern of gene expression similar to that of B-ALL with the BCR-ABL1 translocation but lacks the BCR-ABL1 fusion protein.
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This entity harbors a large number of kinase-activating gene rearrangements primarily involving the ABL class, JAK/STAT and/or Ras pathway associated signaling pathways.
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Common genes involved include ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3 PDGFRb, JAK1/2/3, FLT3, IL7R, and SH2B3, IKZF1.
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Many cases of B-ALL with BCR-ABL1-like may additionally show other deletions or mutation that have a clear role in leukemogeneses such as IKZFA and CDKN2A/B.
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The prognosis of ALL with BCR-ABL1-like is unfavorable.
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Identifying patients with B-ALL with BCR-ABL1-like can influence the management of the patient. For instance, patients with PDGFFB translocation can benefit from TKI inhibitors, while patients with JAK translocations may benefit from JAK inhibitors. Adult patients tend to have a poor outcome even with high-intensity chemotherapy regimens.
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B-lymphoblastic leukemia/lymphoma with iamp21[rx] – This is a relatively rare B-ALL entity predominately in older children. B-ALL with iAMP21 is diagnosed by identifying 3 or more RUNX1 signals on one marker chromosome.
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Similar to the majority of B-ALL with recurrent genetic abnormalities this entity shows no unique presentation, immunophenotypic profile or microscopic finding. Diagnosis can only be rendered through genetic studies.
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B-ALL with iAMP21 can show variable cytogenetic features that include gains of an X chromosome, abnormalities of chromosome 7, deletions of RB1 and/or ETV6, and rearrangements of the CRLF2 gene.
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The prognosis of ALL with iAMP21 is unfavorable.
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Causes of Acute Lymphoblastic Leukemia
There is solid evidence that ALL/LBL has a genetic component. This is evidenced by many distinct translocations associated with the disease and a higher prevalence of the disease in monozygotic twins. Research has shown that polymorphic variants in GATA3, CEBPE, ARID5B, IKZF1, and CDKN2A have also been associated with ALL. ALL incidence has also been found to be higher in patients with immunodeficiency disorders such as Down syndrome, neurofibromatosis type 1, Bloom syndrome, and ataxia-telangiectasia.[rx][rx]
ALL results from either an acquired or a genetic injury to the DNA (genetic material) of a developing stem cell in the bone marrow.
- Stem cells form blood cells (white cells, red cells and platelets).
- Although ALL starts in a stem cell in the bone marrow, it can spread to other areas such as the central nervous system, the lymph nodes and, more rarely, the testes
This dmaged cell becomes a leukemic cell and multiplies uncontrollably into billions of cells called leukemic lymphoblasts.
- Leukemic lymphoblasts
- Do not function normally
- Block the production of normal cells
- Grow and survive better than normal cells
As a result, the number of healthy blood cells (red cells, white cells and platelets) is usually lower than normal.
- Anemia is a condition when there is a low number of red cells in the blood which can cause fatigue and shortness of breath.
- Neutropenia is a condition when there is a low number of white cells so that the immune system can’t effectively guard against infection due to a lack of neutrophils (a type of white cell).
- Thrombocytopenia is a condition when there is a low number of platelets which can cause bleeding and easy bruising with no apparent cause.
- Low numbers of all three blood cell counts is called pancytopenia.
Research is going on all the time into possible causes of this damage, and certain factors have been identified that may put some people at an increased risk. These include exposure to:
- very high doses of radiation either accidentally (nuclear accident) or therapeutically (to treat other cancers)
- industrial chemicals like benzene, pesticides, and certain types of chemotherapy used to treat other cancers
- certain types of viral infections and the way in which the immune system reacts may play a role in the development of some types of ALL
- people with certain genetic disorders like Down’s syndrome and Fanconi’s anaemia may have a higher than average risk of developing ALL.
Symptoms of Acute Lymphoblastic Leukemia
- Anemia – Leukemia frequently causes anemia (low red blood cell count) because the bone marrow becomes too crowded with leukemia cells to produce normal red blood cells. Your child may appear tired and pale, and she may breathe faster to compensate for the decrease in her cells’ ability to carry oxygen.
- Bone and joint pain – Your child may experience pain in his bones and joints. This pain is usually a result of the bone marrow being overcrowded and “full.” Many children experience lower back pain or develop a limp.
- Bruising or petechiae – When the marrow is too crowded to allow platelets to be produced, your child may bruise more easily. You might notice petechiae, or tiny red dots, on the skin if your child has a low number of platelets. These are very small blood vessels that have “leaked” or bled. While these symptoms pose no immediate risk, they do indicate the possibility of a more serious underlying problem. A blood count will show an abnormally low number of platelets.
- Fever – Many children with ALL have fevers that are not related to a specific infection, though sometimes fever at the time of diagnosis can be a sign of infection.
- Recurrent infections – Although there may be an unusually high number of white blood cells on your child’s blood count, these white blood cells aren’t mature and don’t fight infection. Your child may have had several viral or bacterial infections over the past few weeks and may show symptoms of an infection, such as a fever, runny nose, and cough.
- Abdominal pain – Stomachaches also may be a symptom of leukemia. Leukemia cells can collect in your child’s kidney, liver, and spleen, causing these organs to become enlarged. Pain in the abdomen may cause your child to lose her appetite and lose weight.
- Swollen lymph nodes – Your child also may have swelling in the lymph nodes under the arms, or in the groin, chest, and neck. Leukemia cells may collect in the nodes, causing swelling.
- Dyspnea (difficulty breathing) – In some cases of ALL, leukemia cells tend to clump together and form a mass in the middle of the chest. This chest mass can cause pain and difficulty breathing in your child. Wheezing, coughing, and/or painful breathing requires immediate medical attention.
Symptoms of Acute Lymphoblastic Leukemia ALL include
- Anemia due to a lack of red cells. Anemia can cause persistent tiredness, dizziness, paleness, or shortness of breath when physically active.
- frequent or repeated infections and slow healing, due to a lack of normal white cells, especially neutrophils
- Frequent infections
- Fever
- Easy bruising
- Weakness or feeling tired
- Easy bruising or bleeding
- Bleeding under the skin
- Shortness of breath
- Weight loss or loss of appetite
- Pain in the bones or stomach
- Pain or a feeling of fullness below the ribs
- Painless lumps in the neck, underarm, stomach, or groin
- Bleeding that is hard to stop
- Flat, dark-red skin spots (petechiae) due to bleeding under the skin
- Pain in the bones or joints
- Lumps in the neck, underarm, stomach or groin
- Pain or fullness below the ribs
- Weakness, fatigue
- Paleness
- Loss of appetite
Diagnosis of Acute Lymphoblastic Leukemia
History and Physical
Diagnosis of ALL/LBL patients is generally based on clinical, morphologic, immunophenotyping, molecular features. Molecular studies are essential for diagnosis, prognosis, classification, and treatment. The main challenge in the diagnosis of ALL is that the disease is difficult to distinguish from common, self-limited diseases of childhood. B-ALL usually represents as symptoms of bone marrow (BM) suppression by lymphoblasts. Patients can present with anemia, leucopenia or thrombocytopenia, or a combination of these. Symptoms include bruising or bleeding due to thrombocytopenia, pallor, and/or fatigue due to anemia, and recurrent infections caused by neutropenia/leucopenia and/or bone pains. Patients may also frequently present with lymphadenopathy (greater than 10 mm in a single dimension of the lymph node), hepatomegaly, and/or splenomegaly. Patients with relapse usually present with persistent peripheral blood cytopenias. While B-ALL patients present with symptoms that usually render an investigation work-up; B-LBL patients are usually asymptotic. B-LBL most commonly involves the skin, bone-soft tissue, and lymph nodes. Mediastinal involvement is uncommon [rx]
The presentation of B- and T-cell LBL is different. T-LBL commonly involves the mediastinum (thymus), other possible sites include skin, tonsils, and spleen. Since T-LBL is more common than T-ALL, a presentation with mediastinal masses with rapid growth is common. [rx] T-lymphoblasts cannot be differentiated from B-lymphoblasts based on morphology, immunohistochemistry (IHC0, and flow cytometry are essential to render a diagnosis.[rx]
Evaluation
The diagnosis of ALL/LBL is based on clinical, morphologic, immunophenotyping, and molecular features. Workup for ALL cases usually also includes a complete blood count (CBC) with smear evaluation, PT, PTT, comprehensive metabolic panel (CMP), baseline viral titers for cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, and varicella-zoster virus. A peripheral blood smear may show lymphoblasts, especially in ALL cases. Bone marrow involvement with more than 20% of blasts is diagnostic and necessary for diagnosis and future follow-up. The lymphoblasts vary in size from small-medium and show scant cytoplasm, condensed nuclear chromatin, and indistinct nucleoli. It is crucial not to misinterpret hematogenous with lymphoblasts. Some cases may need a flow-cytometry assessment to confirm the preliminary findings. In B-LBL, lymphoblasts may show a diffuse or a paracortical pattern of the lymph node.
- Bone marrow biopsy – To confirm a diagnosis of acute lymphoblastic leukemia, the hematologist will take a small sample of your bone marrow to examine under a microscope. The hematologist will use a local anesthetic to numb the skin over a bone – usually the hip bone – before removing a sample of bone marrow using a needle. You may experience some pain once the anesthetic wears off and some bruising and discomfort for a few days afterward. The procedure takes around 30 minutes and you should not have to stay in the hospital overnight. You will have a dressing over the area of your body where the bone marrow was removed. You will need to keep this dressing on for 24 hours. The bone marrow will be checked for cancerous cells and, if any are found, the type of acute leukemia will be determined at the same time. Some people with acute lymphoblastic leukemia will need to have a bone marrow assessment to check for cancerous cells every 3 months for at least 2 years during maintenance treatment, or after having a bone marrow transplant
- Cytogenetic testing – Cytogenetic testing involves identifying the genetic make-up of the cancerous cells in a sample of blood, bone marrow, or other types of tissue. Specific genetic variations can happen during leukemia and knowing what these variations are can have an important impact on treatment.
- Immunophenotyping – Immunophenotyping is a test to help identify the exact type of acute lymphoblastic leukemia. A sample of blood, bone marrow, or another type of fluid is studied. This testing is important as treatments may be slightly different for each type of acute lymphoblastic leukemia.
- Polymerase chain reaction (PCR) – A polymerase chain reaction (PCR) test can be done on a blood sample. PCR can help diagnose and monitor the response to treatment. The blood test is repeated every 3 months for at least 2 years after starting treatment, then less often once remission is achieved.
- Lymph node biopsy – If you’ve been diagnosed with acute lymphoblastic leukemia, further biopsies may be done on any enlarged lymph nodes you have. These will establish how far leukemia has spread.
- CT scans – If you have acute lymphoblastic leukemia, a CT scan may be used to assess how far leukemia has spread and to check that your organs, such as your heart and lungs, are healthy.
- Chest X-ray – You may have an X-ray of your chest to check for any swollen lymph nodes.
- Lumbar puncture – A lumbar puncture may be done if there’s a chance that acute leukemia has spread to your nervous system. A needle is inserted into the lower part of your spine to extract a small sample of the fluid that surrounds and protects your spine (cerebrospinal fluid), which is tested for cancer cells.
- Chromosome analysis – Samples of blood and bone marrow can be sent to a special laboratory to look for certain changes in the chromosomes of the leukemia cell. For example, in ALL, part of one chromosome may be moved to another chromosome, or there may be too many or too few chromosomes. The results of chromosome tests may help to determine the way the leukemia is treated.
T-ALL/LBL – can only be differentiated from B-ALL/LBL based on IHC and/or flow cytometry. However, some morphological features are common in T-ALL/LBL, for example, increased mitotic index and capsular involvement of the lymph node. Lymphoblasts in T-ALL/LBL are positive for CD3 , CD99, TdT, CD7 and variable expression of other T cell markers (CD1a, CD2, CD4, CD5, CD8), CD34, CD10, CD4/CD8; and negative for CD19, CD20, HLA-DR, surface immunoglobulin, CD22, CD25. Stages of intrathymic differentiation in T-ALL/LBL has based on the cells immunophenotype and is as follows:
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Pro-T: cCD3+, CD7+, CD2-, CD1a-, CD34+/-, double negative CD4 / CD8
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Pre-T: cCD3+, CD7+, CD2+, CD1a-, CD34+/-, double negative CD4 / CD8
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Cortical T: cCD3+, CD7+, CD2+, CD1a+, CD34-, double positive CD4 / CD8
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Medullary T: cCD3+, CD7+, CD2+, CD1a-, CD34-, surface CD3+, either CD4+ or CD8+
Genetics studies for T-ALL/LBL show clonal TCR gene rearrangements and abnormal karyotypes in the majority of cases, most commonly involving 14q11.2 (a/d TCR loci), 7q35 (beta) and 7p14-15.
Treatment of Acute Lymphoblastic Leukemia
Combination chemotherapy has been an effective treatment modality for ALL since the 1950s. Combination chemotherapy is usually administered in distinct three phases (induction, consolidation, and maintenance) and should include intrathecal treatment which is directed to the central nervous system (CNS). Chemotherapy protocols vary; however, the multi-drug induction phase (8 weeks) and the consolidation phase (4 to 8 months) have become the standard of care for most of the patients. The maintenance phase usually lasts 30 to 42 months, therapeutic drugs used include mercaptopurine (6-MP), methotrexate, vincristine, and prednisone. Despite the favorable outcome of management in the majority of ALL/LBL patients, major life-threatening adverse events are possible and include tumor lysis syndrome, thrombosis, major bleeding, and sepsis. The management of ALL patients should include antibiotics, BM stimulants, and antiemetics among others based on the side effects that the patients endure.[rx][rx][rx]
Therapeutic drugs used in Induction therapy include glucocorticoid, vincristine, and asparaginase preparation, anthracycline, and intrathecal chemotherapy. Therapeutic drugs used in the consolidation phase include cytarabine, methotrexate, anthracycline (daunorubicin, doxorubicin), alkylating agents (cyclophosphamide, ifosfamide), and epipodophyllotoxins (etoposide, etopophosphamide). T
Risk stratification of ALL patients classifies patients into low 15, average 36, high 25, very high 24, and special groups. There are guidelines for the management of each group, and the guidelines differ based on the national recommendations. ALL distinct entities such as t(9;22)/BCR-ABL1 translocation will require the addition of tyrosine kinase inhibitors to the standard regimens. Patients with ALL relapse require aggressive reinduction therapy and intensification depending on the risk stratification. Induction failure, is a form of treatment resistance and is defined as the persistence of lymphoblasts post the induction phase and is generally considered as an indication for allogeneic hematopoietic-cell transplantation. Allogeneic, hematopoietic cell transplantation is the preferred mode of treatment for patients who relapse or who are resistant to therapy.[rx][rx][rx][rx]
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 malignant cells. In general, cytotoxic chemotherapy for ALL combines multiple antileukemic drugs tailored to each person. Chemotherapy for ALL consists of three phases: remission induction, intensification, and maintenance therapy.
| Phase | Description[rx][rx] | Agents[rx][rx] |
|---|---|---|
| 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 2 weeks of therapy has been associated with 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:[rx]
In Philadelphia chromosome-positive ALL, the intensity of initial induction treatment may be less than has been traditionally given.[rx][rx] |
| 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
|
A typical protocol would include:
|
Due to presence of CNS involvement in 10–40% of adult with ALL at diagnosis, most providers start Central nervous system (CNS) prophylaxis and treatment during the induction phase, and continue it during the consolidation/intensification period.
Adult chemotherapy regimens mimic those of childhood ALL; however, are linked with a higher risk of disease relapse with chemotherapy alone. It should be known that 2 subtypes of ALL (B-cell ALL and T-cell ALL) require special considerations when it comes to selecting an appropriate treatment regimen in adult 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.[rx]
As the chemotherapy regimens can be intensive and protracted, many people have an intravenous catheter inserted into a large vein (termed a central venous catheter or a Hickman line), or a Portacath, usually placed near the collar bone, for lower infection risks and the long-term viability of the device.Males usually endure a longer course of treatment than females as the testicles can act as a reservoir for cancer.
Radiation therapy
Radiation therapy (or radiotherapy) is used on painful bony areas, in high disease burdens, or as part of the preparations for a bone marrow transplant (total body irradiation). In the past, physicians commonly utilized radiation in the form of whole-brain radiation for central nervous system prophylaxis, to prevent the occurrence and/or recurrence of leukemia in the brain. Recent studies showed that CNS chemotherapy provided results as favorable but with fewer developmental side-effects. As a result, the use of whole-brain radiation has been more limited. Most specialists in adult leukemia have abandoned the use of radiation therapy for CNS prophylaxis, instead of using intrathecal chemotherapy.[rx][rx]
Biological therapy
The selection of biological targets on the basis of their combinatorial effects on leukemic lymphoblasts can lead to clinical trials for improvement in the effects of ALL treatment.[rx] Tyrosine-kinase inhibitors (TKIs), such as imatinib, are often incorporated into the treatment plan for people with Bcr-Abl1+ (Ph+) ALL. However, this subtype of ALL is frequently resistant to the combination of chemotherapy and TKIs and allogeneic stem cell transplantation is often recommended upon relapse.[rx]
Blinatumomab, a CD19-CD3 bi-specific monoclonal murine antibody, currently shows promise as a novel pharmacotherapy. By engaging the CD3 T-cell with the CD19 receptor on B cells, it triggers a response to induce the release of inflammatory cytokines, cytotoxic proteins and proliferation of T cells to kill CD19 B cells.[rx][rx]
Remission induction
The remission induction stage of treatment is done in a hospital or at a specialist center. You’ll probably need regular blood transfusions because your blood will not contain enough healthy blood cells. You’ll also be vulnerable to infection, so it’s important you’re in a sterile environment where your health can be carefully monitored and any infections can be treated quickly. Antibiotics may also be given to help prevent infection.
Steroid therapy
You may also be given steroid (corticosteroid) injections or tablets to help improve the effectiveness of chemotherapy.
Targeted therapies
If you have a type of leukemia called Philadelphia chromosome-positive acute lymphoblastic leukemia (which affects around 20 to 30% of people with acute lymphoblastic leukemia), you’ll also be given a medicine called imatinib. Imatinib is a targeted therapy that blocks signals in the cancerous cells that cause them to grow and reproduce. This kills the cancerous cells.
Imatinib comes as a tablet. The side effects are usually mild and should improve over time.
They include:
- feeling or being sick
- swelling in the face and lower legs
- muscle cramps
- skin rash
- diarrhoea
Depending on how well you respond to treatment, the remission induction phase can last from 2 weeks to several months. Sometimes you may be able to leave hospital and receive treatment on an outpatient basis if your symptoms improve.
If other treatments do not work, your cancer comes back or you have a certain type of acute lymphoblastic leukaemia, you may be given a different targeted therapy. The 2 alternative medicines used are:
- dasatinib
- ponatinib
These come as a table and cause similar side effects to imatinib.
Want to know more about targeted therapies?
- Cancer Research UK – imatinib
- Cancer Research UK – dasatinib
- Cancer Research UK – ponatinib
Consolidation
The aim of consolidation treatment is to ensure that any remaining leukemia cells are killed. The consolidation phase involves regular injections of chemotherapy medicine. This is usually done on an outpatient basis, so you will not have to stay in the hospital overnight. But you may need some short stays in hospital if your symptoms suddenly get worse or you get an infection. The consolidation phase lasts several months.
Maintenance
The maintenance phase is a further step to help ensure the leukaemia does not come back. It involves taking regular doses of chemotherapy medicine while having regular check-ups to monitor your treatment. The maintenance phase can often last for 2 years.
Other treatments
As well as chemotherapy, steroids, and targeted therapies, other treatments are sometimes used.
Radiotherapy
Radiotherapy is where high doses of controlled radiation are used to kill cancerous cells.
It’s usually used to treat acute lymphoblastic leukaemia when:
- acute lymphoblastic leukaemia has spread to the nervous system or brain
- the body needs to be prepared for a bone marrow transplant
Side effects of radiotherapy include:
- hair loss
- feeling sick
- fatigue
These side effects should pass after your course of radiotherapy has finished.
Your skin may be very sensitive to the effects of light for several months after treatment has finished. If this happens, avoid sunbathing or exposure to artificial sunlight, such as sunbeds, for several months. Many young children treated with radiotherapy will go on to have restricted physical growth during puberty. A small number of people develop cataracts several years after having radiotherapy. Cataracts are cloudy patches in the transparent structure at the front of the eye (the lens) that can make your vision blurred or misty.
Stem cell and bone marrow transplants
A stem cell and bone marrow transplant is an alternative treatment option if you not respond to chemotherapy.
A transplant of bone marrow and stem cells is usually more successful if the donor has the same tissue type as you, so the ideal donor is usually a brother or sister. Before a transplant can happen, the person receiving the transplant will need to have high-dose chemotherapy and radiotherapy to destroy any cancerous cells in their body.
This can put a big strain on the body, so transplants are usually only successful when they’re done in:
- children and young people
- older people who are in good health
- when there’s a suitable donor, such as a brother or sister
Recent research has shown it’s possible for people over the age of 40 to have a reduced-intensity stem cell transplant. This is where lower than normal doses of chemotherapy and radiotherapy are used before the transplant, which places less strain on the body.
Immunotherapy
Chimeric antigen receptors (CARs) have been developed as promising immunotherapy for ALL. This technology uses a single-chain variable fragment (scFv) designed to recognize the cell surface marker CD19 as a method of treating ALL.
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.[rx] 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.
In 2017 tisagenlecleucel was approved by the FDA as a CAR-T therapy for people with acute B-cell lymphoblastic leukemia who did not respond adequately to other treatments or have relapsed.[rx] In a 22-day process, the “drug” is customized for each person. T cells purified from each person are modified by a virus that inserts genes that encode a chimeric antigen receptor into their DNA, one that recognizes leukemia cells.[rx]
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 allogeneic bone marrow transplantation. These people in relapse may also receive blinatumomab, as it has shown to increase remission rates and overall survival rates, without increased toxic effects.[rx]
Low dose palliative radiation may also help reduce the burden of the tumor inside or outside the central nervous system and alleviate some symptoms.
Recently, 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.[rx]
Stem cell transplant
A stem cell (or bone marrow) transplant is a treatment that is rarely used to treat ALL except for:
- Certain unusual subtypes of ALL
- Relapsed leukemia – if leukemia comes back (relapse) after initial treatment with chemotherapy
Stem cells are a specific type of cell from which all blood cells develop. They can develop into red blood cells to carry oxygen, white blood cells to fight disease and infection and platelets to aid in blood clotting. Stem cells are found primarily in bone marrow, but some also circulate in the bloodstream.
In acute lymphoblastic leukemia, the cells for a stem cell transplant come from donors (other people). These donated cells are used to replace your child’s stem cells after particularly intense treatment with chemotherapy and/or radiation.
KYMRIAH CAR T-Cell Therapy
CAR (chimeric antigen receptor) T-cell therapy is a promising new treatment for relapsed or refractory B-cell ALL. It works by modifying the body’s T-cells, a type of immune system cell that hunts and destroys abnormal cells, such as cancer cells.
What is sanctuary therapy?
In children with ALL, leukemia cells travel everywhere in the body, including into the brain and spinal fluid. Not all chemotherapy drugs that are given by mouth, by vein, or in the muscle can get into the brain effectively to treat any leukemia that is “hiding” there.
However, it is important to treat the leukemia cells hiding in the brain and spinal fluid to prevent leukemia from coming back. To treat leukemia hiding in the brain and spinal fluid, your child will receive:
- Intrathecal chemotherapy: chemotherapy drugs delivered directly into the spinal canal to kill off cancerous cells that may hide in the central nervous system (CNS)
Your child may also receive:
- Cranial radiation therapy: radiation treatment to the head to destroy leukemia cells that may have moved into the CNS
Supportive therapy
Adding physical exercises to the standard treatment for adult patients with hematological malignancies like ALL may result in little to no difference in the 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 of anxiety and serious adverse events.[rx]
Clinical trials
In the UK, clinical trials are currently being done to find the best way of treating types of acute leukaemia.
These studies are using new techniques to see how well they work in treating and possibly curing acute leukaemia. It’s important to be aware of new studies so you can choose which treatments to have. But there’s no guarantee the techniques being studied in the clinical trial will be more effective than current treatments. Your care team will be able to tell you whether there are any clinical trials available in your area and can explain the benefits and risks involved.
Differential Diagnosis
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Myeloid leukemia
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Diffuse large B-cell lymphoma
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Burkitt lymphoma
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Neuroblastoma: Rosettes and neuroendocrine marker positivity
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Ewing Sarcoma: CD99 positivity
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Osteosarcoma, small cell variant: Osteoid
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Mesenchymal chondrosarcoma: Chondroid differentiation, S100+
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Juvenile idiopathic arthritis
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Osteomyelitis
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Epstein-Barr virus infection
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Immune thrombocytopenia (ITP)
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Pertussis, parapertussis infection
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Aplastic anemia
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Acute infectious lymphocytosis
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Hypereosinophilic syndrome
Complications–Acute Lymphoblastic Leukemia
Tell your care team or GP immediately if you have any symptoms of infection because prompt treatment may be needed to prevent serious complications.
Symptoms of infection may include:
- high temperature
- headache
- aching muscles
- diarrhea
- tiredness
Avoid contact with anyone who has an infection, even if it’s a condition you were immune to in the past, such as chickenpox or measles. This is because your previous immunity to these conditions will probably be lower. It’s important to go outside regularly for exercise and for your wellbeing, but you should avoid crowded places and using public transport during rush hour. Also, make sure all your vaccinations are up to date. Your GP or care team will be able to advise you about this.
You will not be able to have any vaccine containing “live” viruses or bacteria such as the:
- measles, mumps and rubella (MMR) vaccine
- polio vaccine
- oral typhoid vaccine
- BCG vaccine (used to vaccinate against tuberculosis)
- yellow fever vaccine
Bleeding
If you have acute leukemia, you’ll bleed and bruise more easily because of the low levels of platelets (clot-forming cells) in your blood. Although heavy bleeding is uncommon, you need to be aware of the symptoms that can happen in different parts of the body.
Bleeding can happen:
- inside the skull (intracranial hemorrhage)
- inside the lungs (pulmonary hemorrhage)
- inside the stomach (gastrointestinal hemorrhage)
All 3 types of heavy bleed (hemorrhage) are medical emergencies.
Symptoms of intracranial hemorrhage are:
- severe headache
- stiff neck
- being sick
- change in mental state, such as confusion
Common symptoms of a pulmonary hemorrhage are:
- coughing up blood from your nose and mouth
- breathing difficulties
- a bluish skin tone (cyanosis)
Common symptoms of a gastrointestinal hemorrhage are:
- vomiting blood
- poo that is very dark or tar-like
Infertility
Many of the medicines used to treat acute lymphoblastic leukemia can cause infertility.
People who are particularly at risk of becoming permanently infertile are those who’ve received high doses of chemotherapy and radiotherapy in preparation for a stem cell and bone marrow transplant.
It may be possible to guard against any risk of infertility before you begin your treatment. For example, men can store sperm samples. Similarly, women can have fertilized embryos stored, which can be put into their womb following treatment.
Psychological effects of leukemia
Being diagnosed with leukemia can be very distressing, particularly if a cure is unlikely. At first, the news may be difficult to take in.
It can be particularly difficult if you do not currently have any leukemia symptoms, but you know that it could cause a serious problem later on. Having to wait many years to see how leukemia develops can be very stressful and can trigger feelings of anxiety and depression.
If you’ve been diagnosed with leukemia, talking to a counselor or a doctor who specializes in treating mental health conditions (psychiatrists) may help you combat feelings of depression and anxiety. Antidepressants or medicines that help reduce feelings of anxiety may also help you cope better.
You may find it useful to talk to other people living with leukemia. Your GP or multidisciplinary team may be able to provide you with details of local support groups.
References
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