Acute Lymphoblastic Leukemia (ALL)

In other words, Acute Lymphoblastic Leukemia (ALL) is characterized by the clonal expansion of precursor cells involved in the formation of B- or T-lymphocytes. Specific chromosomal abnormalities are common and hold significant clinical importance.

The disease typically presents as leukemia with bone marrow involvement but can also manifest as lymphoblastic lymphoma (tumors consisting of lymphoblasts, with less than 20% lymphoblasts in the bone marrow).

Leukemia involving more mature B-lymphoblasts, known as Burkitt leukemia, is rare. Previously referred to as mature B-ALL (L3-type ALL), it has been reclassified under the 2008 WHO classification alongside Burkitt lymphoma. These cases are managed with intensive combination chemotherapy.

ALL arises due to acquired genetic alterations in hematopoietic stem cells or early precursors within lymphopoiesis. The identified DNA damage may consist of a single specific abnormality or clones with multiple DNA defects. Evidence suggests that more than one genetic alteration is typically necessary for the clinical presentation, as documented in studies of identical twins where one sibling developed acute lymphoblastic leukemia.

Epidemiology and Incidence

Acute lymphoblastic leukemia is a rare disease but is the most common cancer in children. In the United States, approximately 5,000 new cases of ALL are diagnosed annually, with around 60% occurring in individuals under 20 years old. Among adults, the incidence is approximately 1.7 cases per 100,000 people annually. While the disease primarily affects children, its incidence increases slightly with age in adults, though it is far less common than acute myeloid leukemia (AML) in older populations.

The median age of diagnosis is 5 years in children and 35-50 years in adults. Acute lymphoblastic leukemia, particularly T-ALL, is somewhat more common in males than females.

Acute Lymphoblastic Leukemia Symptoms at Onset

When Acute Lymphoblastic Leukemia (ALL) first develops, symptoms can be subtle and nonspecific, often masquerading as common illnesses. Initially, patients may experience fatigue, weakness, or a general feeling of being unwell, which can be attributed to a viral infection or exhaustion. As the disease progresses, more distinctive symptoms emerge, such as frequent or recurring infections, like bronchitis or tonsillitis, due to the compromised immune system. Some individuals may notice easy bruising or bleeding, particularly on the skin or gums, while others may experience bone or joint pain, which can be mistaken for growing pains in children. Swollen lymph nodes, often in the neck, armpits, or groin, can be a visible sign of the disease. In some cases, acute lymphoblastic leukemia may cause anemia, leading to pale skin, shortness of breath, or dizziness, while others may experience weight loss, loss of appetite, or abdominal discomfort.

The initial symptoms of ALL are often nonspecific and may include:

• Fatigue
• General malaise
• Fever

Additional signs and findings include:

• Lymphadenopathy and hepatosplenomegaly
• Bone or joint pain and central nervous system (CNS) symptoms
• Skin involvement (more common in relapse)
• Occasionally, bleeding or infections

Abnormal blood counts are typical and may include:

• Anemia and thrombocytopenia, though not always severe
• Variable white blood cell counts, ranging from very low to very high
• High white blood cell counts often show blasts on peripheral blood smear microscopy

Urgent Referral

Patients with suspected acute leukemia should be referred immediately to a hematology or pediatric oncology specialist without delay.

Acute Lymphoblastic Leukemia diagnostics

The diagnosis of Acute Lymphoblastic Leukemia (ALL) typically begins with a physical examination and medical history to identify potential signs of the disease, such as swollen lymph nodes or an enlarged spleen. A complete blood count (CBC) and peripheral blood smear are then performed to examine the blood cells and identify abnormal lymphoblasts. A bone marrow biopsy is usually necessary to confirm the diagnosis, as it provides a detailed view of the bone marrow’s cell production and abnormalities. Genetic testing, including chromosomal analysis and molecular studies, is also conducted to determine the specific subtype of ALL and predict treatment responses. You may also need imaging studies like CT scans or X-rays may be used to assess organ involvement and check for potential complications.

Bloodwork with Differential Count (B-Cells and Microscopy of Blood Smear)

• Blasts and Immature Lymphoid Cells: Frequently detected but not always.

Bone Marrow Aspiration

This is the most critical diagnostic procedure, typically performed from the posterior iliac crest.

• Flow Cytometry: Essential for analysis, particularly in patients with significant leukocytosis and blast presence in the blood. In some cases, flow cytometry can be performed directly on blood samples.
• Bone Marrow Characteristics: Often hypercellular with an increased presence of monoclonal lymphatic blasts.
• Chromosomal Analysis: A vital component of diagnosis, complemented by molecular studies and/or fluorescence in situ hybridization (FISH) based on specific investigative protocols. It is recommended to preserve blood smears and cryopreserve viable bone marrow cells or blasts for future supplementary analyses.

Biopsy and Imaging

• Evaluation of lymphadenopathy and hepatosplenomegaly, with palpation of the testicles.
• Imaging: Chest X-ray or CT scans of the chest and abdomen.
• Lumbar Puncture: Conducted for cytological analysis of cerebrospinal fluid (CSF) with mandatory intrathecal chemotherapy administration. Neurological symptoms warrant additional imaging, such as MRI.

Additional Evaluations

• Infection and Coagulation: Assessment for infections and coagulation impact.
• Laboratory Tests: Monitoring of sodium (Na), potassium (K), ionized calcium (Ca), creatinine, uric acid, and lactate dehydrogenase (LD) levels to assess the risk of tumor lysis syndrome.
• HLA Typing: Considered for potential donor searches in case of future stem cell transplantation.
• Fertility Preservation: For patients desiring children, consult fertility specialists regarding sperm cryopreservation or the possibility of freezing eggs or ovarian tissue before initiating treatment.

Acute Lymphoblastic Leukemia Classification (WHO 5th Edition)

B-Lymphoblastic Leukemia/Lymphoma

• B-ALL/LBL, not otherwise specified (NOS)
• B-ALL/LBL with high hyperdiploidy
• B-ALL/LBL with hypodiploidy
• B-ALL/LBL with intrachromosomal amplification of chromosome 21 (iAMP21)
• B-ALL/LBL with BCR::ABL1 fusion
• B-ALL/LBL with BCR::ABL1-like alterations
• B-ALL/LBL with KMT2A rearrangement
• B-ALL/LBL with ETV6::RUNX1 fusion
• B-ALL/LBL with ETV6::RUNX1-like alterations
• B-ALL/LBL with TCF3::PBX1 fusion
• B-ALL/LBL with IGH::IL3 fusion
• B-ALL/LBL with TCF3::HLF fusion
• B-ALL/LBL with other defined genetic abnormalities

T-Lymphoblastic Leukemia/Lymphoma

• T-ALL/LBL, not otherwise specified (NOS)
• Early T-precursor lymphoblastic leukemia

Acute Lymphoblastic Leukemia Treatment

Treatment for Acute Lymphoblastic Leukemia (ALL) typically involves a combination of chemotherapy, targeted therapy, and supportive care. The primary goal of treatment is to achieve complete remission, where no signs of leukemia are detectable in the body. Chemotherapy is the mainstay of ALL treatment, with multiple agents administered in a specific sequence to target and eliminate cancer cells. The treatment process is often divided into several phases, including induction, consolidation, and maintenance, each with its own set of medications and treatment goals. In some cases, targeted therapies like tyrosine kinase inhibitors or monoclonal antibodies may be added to the treatment regimen to specifically target cancer cells with certain genetic mutations. Additionally, stem cell transplantation, either from a donor or the patient’s own stem cells, may be considered for certain patients, particularly those with high-risk disease or those who have relapsed after initial treatment. Supportive care measures, such as blood transfusions, antibiotics, and anti-nausea medications, are also very important to manage treatment side effects and prevent complications.

Treatment is always administered according to meticulously designed protocols extending over several months, combining the following medications:

• Steroids: Prednisolone or dexamethasone (e.g., betamethasone).
• Vincristine (Oncovin)
• An Anthracycline: Such as daunorubicin (Cerubidin), doxorubicin, idarubicin (Zavedos), amsacrine (Amekrin), or mitoxantrone.
• Cyclophosphamide (Sendoxan)
• Cytarabine (ara-C)
• High-Dose Methotrexate
• Asparaginase: Pegylated asparaginase (Oncaspar) or Erwinase.

Selection of Treatment Protocols

The choice of a specific treatment regimen for acute lymphoblastic leukemia (ALL) is determined by the leukemia subtype (B-ALL or T-ALL), patient age, and risk assessment, which includes genetic abnormalities. For Philadelphia chromosome-positive ALL (BCR::ABL1 hybrid gene detected), cytostatic treatment is supplemented with a tyrosine kinase inhibitor (e.g., imatinib).

Treatment Protocols

Younger adults (under approximately 40 years old) with Philadelphia-negative B-ALL or T-ALL are typically treated using U.S.-based regimens such as CALGB 10403, adapted from pediatric protocols. For patients aged 40–60 years, dose-adjusted regimens are often used. CNS prophylaxis includes repeated intrathecal injections of methotrexate or triple therapy with methotrexate, cytarabine, and steroids. High-dose intravenous methotrexate and/or cytarabine are also administered to penetrate the cerebrospinal fluid. In cases of CNS disease, intrathecal therapy is intensified, and radiation may be considered in select cases.

Monitoring Treatment Response

Treatment outcomes are evaluated with repeated bone marrow tests and analysis of measurable residual disease (MRD). This sensitive measure detects residual leukemia cells at levels as low as 1 in 10,000 bone marrow cells using flow cytometry and/or molecular techniques. The presence of MRD indicates a higher relapse risk and may warrant intensified treatment, including possible allogeneic stem cell transplantation.

Maintenance Therapy

Following induction and consolidation therapy, maintenance treatment typically includes daily oral 6-mercaptopurine and weekly oral methotrexate for 2–2.5 years. Dosages are adjusted based on blood counts, with periodic reinduction therapies included in the protocol. For high-risk patients (e.g., poor response to initial therapy or Philadelphia-positive ALL), stem cell transplantation may be considered as part of the initial treatment strategy, provided no contraindications exist.

Allogeneic stem cell transplantation is performed with an HLA-identical sibling donor when available. If no related donor exists, an unrelated HLA-matched donor is sought through international donor registries.

Relapse and Refractory Disease

In cases of relapse after completed treatment, intensive chemotherapy can often achieve a second remission, though remission duration is typically shorter for adults. Allogeneic stem cell transplantation is recommended when feasible. For children, specific relapse protocols are available, and stem cell transplantation is considered if needed. Treatment options for refractory disease or post-transplant relapse are limited but may include nelarabine for T-ALL or monoclonal antibody therapies such as blinatumomab or inotuzumab ozogamicin as a bridge to transplantation.

CAR-T Cell Therapy

Immunotherapy with CAR-T cells has shown promising results in relapsed/refractory ALL. Tisagenlecleucel (Kymriah) is FDA-approved for patients under 25 years old with refractory disease or second relapse. For adults, therapies targeting CD19 or CD22 are under investigation, with FDA approval expanding for some treatments.

Acute Lymphoblastic Leukemia Prognosis and Outcomes

Almost all patients under 65 years old achieve complete remission after one to two months of intensive induction therapy. Long-term survival rates for children have improved dramatically, from under 10% in the 1960s to over 90% today. In adults under 40 years, long-term survival exceeds 60%, but outcomes remain poorer for older patients. Advances in targeted therapies, including tyrosine kinase inhibitors for Philadelphia-positive ALL, have significantly improved outcomes across age groups.

Prognostic Factors

Key prognostic factors include:

• Cytogenetic abnormalities
• Patient age
• MRD status post-induction

Favorable Prognostic Indicators:

• Age 1–10 years
• B-ALL subtype
• Hyperdiploidy (>50 chromosomes)
• TEL/AML1 (ETV6–RUNX1) fusion gene
• Low leukocyte count at diagnosis
• Less than 5% blasts on day 14
• MRD negativity at day 28

Unfavorable Prognostic Indicators:

• Philadelphia chromosome t(9;22)(q34;q11.2) (BCR::ABL1 hybrid gene), particularly in older patients
• Hypodiploidy or certain translocations, such as t(4;11) (MLL-AF4 fusion)
• High MRD levels during therapy (≥0.1% or ≥0.01%, depending on the protocol)
• Older age, particularly over 60 years

Key Takeaways: Acute Lymphoblastic Leukemia (ALL)

1. ALL develops rapidly when bone marrow starts producing abnormal white blood cells instead of healthy ones. These malignant cells multiply quickly, flood the bloodstream, and crowd out normal cells—leading to infections, bleeding problems, and severe anemia.
2. Children respond better to treatment than adults, with childhood ALL cure rates reaching 90%. Treatment typically spans 2-3 years, combining chemotherapy phases that target cancer cells throughout the body.
3. Early symptoms often mimic common illnesses: unexplained bruising, frequent infections, bone pain, and unusual fatigue. This makes blood tests essential for proper diagnosis since waiting for obvious symptoms can delay life-saving treatment.