Basics
Description
- Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy that results from malignant proliferation of immature WBC (B cells and T cells).
- Risk group classification:
- Infant ALL: age less than 1 year
- Standard risk ALL: age 1 to younger than 10 years; initial WBC count <50,000/μL
- High risk ALL: age 10 years or older; WBC ≥50,000/μL
- Further risk stratification done based on multiple factors including National Cancer Institute (NCI) criteria (age and WBC count), biologic, cytogenetic characteristics, and response to initial therapy. This classification determines the intensity of therapy and prognosis.
- Low-risk ALL: NCI standard risk group
- Favorable cytogenetic changes (hyperdiploidy, trisomies of 4, 10, and 17; t[12;21]);
- Pre B lymphoblasts and negative minimal residual disease (MRD) at end of induction
- Average risk ALL: NCI standard risk group
- Noncontributory cytogenetics
- Negative MRD at end of induction
- No extramedullary (CNS or testicular) involvement
- Negative MRD at end of induction
- High-risk ALL: NCI high-risk group
- Age >10 years regardless of WBC count, extramedullary (CNS or testicular) involvement
- T-cell phenotype
- No or very low MRD at end of induction
- Very high-risk ALL
- Unfavorable cytogenetics (t[9;22] Philadelphia positive ALL)
- Hypodiploidy
- MLL gene rearrangement
- Induction failure (>25% lymphoblasts in bone marrow at end of induction)
- Positive MRD at the end of induction
Epidemiology
- ALL is the most common childhood malignancy.
- Accounts for approximately 30% of cancer diagnosis in children younger than 15 years of age
- More common in Caucasians and males
- ALL incidence: 3-4 cases per 100,000 per year
- Peak incidence is between ages 2 and 5 years.
Risk Factors
- Prior cancer therapy (chemotherapy or radiation)
- Twin with ALL
- Genetic syndrome listed in the following sections
Genetics
- Increased risk of leukemia, higher with monozygotic twin
- Associated genetic syndromes
- Trisomy 21 (Down syndrome)
- Fanconi anemia
- Bloom syndrome
- Shwachman-Diamond syndrome
- Ataxia telangiectasia
- Neurofibromatosis type 1
- Li-Fraumeni syndrome p53 (familial cancer syndrome)
- Congenital immunodeficiencies (Wiskott-Aldrich syndrome)
Pathophysiology
Leukemia arises from lymphoid progenitor cells that have sustained multiple specific genetic damages that lead to malignant transformation and proliferation, lack of cell maturation, and resistance to normal cell death processes (apoptosis). This lymphoblastic proliferation replaces the normal bone marrow precursor cells, causing ineffective hematopoiesis and infiltration of lymphatic tissue and end organs. �
Diagnosis
- Clinical features due to direct invasion of the bone marrow:
- Pancytopenia: anemia, thrombocytopenia, leukopenia, or neutropenia
- Anemia: irritability, fatigue, anorexia, headache, pallor
- Thrombocytopenia: bleeding is usually mild and manifests as petechiae, bruising, gingival oozing, epistaxis
- Fever: may be a sign of presumed cytokine release or underlying infection due to neutropenia and immunosuppression
- Bone pain
- Typically long bones
- Could be due to direct leukemic infiltration of the periosteum or expansion of marrow cavity by leukemic cells
- Pathologic fractures, leukemic lines on plain radiographs, or T2-weighted changes on MRI
- Testicular involvement (2-5 % of the boys), unilateral or bilateral painless testicular enlargement
- CNS involvement (2-5% of patients on presentation for B cell, 10-15% for T-cell ALL)
- Increased intracranial pressure (morning headache, vomiting, lethargy, visual changes, seizures, CN VI palsy, diplopia, and esotropia)
- Superior vena cava (SVC) syndrome (due to a mediastinal mass)
- Swelling of the face, neck, chest, and, rarely, upper arms with or without visual venous distension, cough, dyspnea, dysphagia
- Leukostasis (large number of deformable blasts plugging the microcirculation)
- Respiratory symptoms: dyspnea, hypoxia
- Neurologic symptoms: visual changes, headache, dizziness, tinnitus, lethargy
- Rare symptoms including renal insufficiency, priapism, acute limb ischemia
- Spinal cord compression (due to a chloroma, an extramedullary collection of lymphoblasts): extremity weakness, numbness, and tingling
Physical Exam
- Pallor (anemia)
- Tachycardia/murmurs (anemia)
- Lymphadenopathy (leukemic infiltration)
- Hepatosplenomegaly (leukemic infiltration)
- Testicular enlargement (leukemic infiltration)
- Bone: tenderness, fracture (marrow infiltration)
- Skin: bruises, petechiae, rash in form of subcutaneous nodules (leukemia cutis, most commonly seen in infants)
- Papilledema (CNS involvement)
- Focal neurologic signs (CNS involvement, chloroma)
Diagnostic Tests & Interpretation
- CBC
- Increased or decreased WBC (50% present with WBC <10,000/μL and 20% present with WBC ≥50,000/μL)
- Anemia: Hgb <10 g/dL (80% of cases)
- Thrombocytopenia (platelets <100,000/μL in 75% at presentation)
- Peripheral smear: may see circulating lymphoblasts, especially with high WBC
- Serum chemistry
- Signs of tumor lysis: elevated uric acid, hyperkalemia, hyperphosphatemia (with secondary hypocalcemia), elevated lactate dehydrogenase (LDH)
- Elevated liver enzymes (leukemic infiltrate)
- Elevated creatinine (due to uric acid/calcium phosphate crystal deposition in renal tubules or leukemic infiltrates)
Imaging
- CXR: mediastinal mass (5-10% of cases)
- Plain films of long bones in case of bone pain/tenderness may show leukemic lines.
Diagnostic Procedures/Other
- Bone marrow aspirate and biopsy (presence of more than 25% blasts consistent with diagnosis of leukemia). Immunophenotyping and cytochemistry is then used to differentiate ALL from acute myeloid leukemia (AML) and identify T-cell or B-cell phenotype.
- Lumbar puncture is also performed for CSF analysis for lymphoblasts.
- Immunophenotyping
- B cell: CD 10+, 19+, 20+, 22+, TdT+
- Pre T cell: CD 3+. 5+, 7+, TdT+
- Myeloid markers: CD 13+, 33+, 34+ (in minority)
- CNS I: No detectable blasts
- CNS 2: <5 WBC/μL, blasts present
- CNS 3: ≥5 WBC/μL, and blasts or symptoms of CNS leukemia)
Differential Diagnosis
- Infectious: infectious mononucleosis, Epstein-Barr virus (EBV), pertussis, parapertussis, parvovirus; cytomegalovirus (CMV), acute infectious lymphocytosis
- Juvenile rheumatoid arthritis
- Hematologic: immune thrombocytopenic purpura (ITP), aplastic anemia, Evans syndrome (ITP and autoimmune hemolytic anemia)
- Malignant disorders: round blue cell tumors with bone marrow involvement (neuroblastoma, rhabdomyosarcoma, Langerhans cell histiocytosis, lymphoma, retinoblastoma), myelodysplastic syndrome, AML, chronic myeloid leukemia (CML)
Treatment
- Patient suspected with ALL must be referred to a pediatric oncologist as soon as possible for further evaluation and management.
- Initial emergent stabilization may be required in case of
- Hyperleukocytosis, defined as a WBC ≥100,000 μ/L
- Tumor lysis syndrome with renal insufficiency
- Spinal cord compression
- Mediastinal mass causing SVC syndrome
- Therapy is aimed at inducing permanent biologic and clinical remission and is divided into various phases. Many children and adolescents are enrolled on clinical trials through the Children's Oncology Group or local institution. Treatment is standardized by prognostic indicators and provided by highly specialized teams with expertise in childhood cancer.
- Induction (first 28-35 days). Typically includes the following drugs:
- A glucocorticoid (prednisone or dexamethasone)
- Vincristine
- L-asparaginase
- Anthracycline (in high-risk patients only)
- Intrathecal chemotherapy (initial dose of cytarabine; subsequent treatment with methotrexate)
- Consolidation: focuses on CNS prophylaxis; weekly intrathecal chemotherapy with
- Low/average-risk patients: weekly vincristine, oral 6-mercaptopurine (6-MP), L-asparaginase, intensified with cyclophosphamide and cytarabine in certain subsets of patients
- High-risk patients: more intensive systemic therapy with cyclophosphamide, cytarabine, methotrexate, vincristine, and L-asparaginase
- Patients with initial involvement of the CNS or testes may receive radiation during this phase.
- Interim maintenance: similar to maintenance therapy but more intensified
- Vincristine, methotrexate, L-asparaginase
- Intrathecal methotrexate
- Delayed intensification: (reintensification and reconsolidation)
- Combination of intensive therapy similar to induction and consolidation
- Maintenance: continuation of therapy (lasts for 2-3 years)
- Daily 6-MP, weekly oral methotrexate, pulse glucocorticoids, and vincristine with periodic intrathecal chemotherapy
- Ph+ patients t(9;21) receive continuous tyrosine kinase inhibitors (imatinib or dasatinib)
- Patients with CNS and testicular involvement get prophylactic and therapeutic radiation therapy.
- Patients with Down syndrome and ALL have increased treatment-related morbidity and mortality and require some treatment modifications.
- Very high-risk patients may be treated with bone marrow transplant, following remission induction.
- Length of treatment from 2 to 3.25 years, depending on protocol and gender
Ongoing Care
Follow-up Recommendations
- Early intensification has led to an increase in relapse-free survival.
Patient Monitoring
After completion of therapy: �
- CBC, complete metabolic panel with LDH, liver and renal function tests every month for the 1st year, every 2 months for the 2nd year, then every 3 months for the 3rd year, every 6 months for the 4th year, and yearly thereafter
- Cardiac evaluation every year, dependent on cumulative dose of anthracycline and possible radiation scatter
- Endocrine evaluation close to puberty, especially in children who have received cranial or testicular radiation
- Monitor for late effects in cancer survivors clinic.
Prognosis
- Long-term survival
- Overall: approaches 90%
- Low-risk patients: 90-95%
- Standard risk group: 85%
- High-risk group: 60-75%
- Very high-risk group: ~20-50%
- Infant group: 50%
Complications
- Bone marrow suppression (anemia and thrombocytopenia requiring transfusion support, possible transfusion-related infection or iron overload)
- Neutropenia leading to increased risk of infection
- L-asparaginase: anaphylaxis, pancreatitis, thrombosis, stroke
- Anthracyclines (daunorubicin and doxorubicin): cardiac toxicity, secondary AML
- Intrathecal methotrexate: neurotoxicity (frequently reversible)
- Steroids: avascular necrosis of bone, decreased bone density
- Cranial radiation: secondary brain tumors, growth retardation, learning difficulties and/or cognitive impairment
- Testicular radiation: lack of pubertal development, sterility
- Relapse
- Approximately 10-30% of children and adolescents with ALL will relapse, usually within 5 years of diagnosis.
- If relapse occurs while the patient is receiving therapy, outcomes are poor (<20%) even with systemic retreatment and possible bone marrow transplant (BMT).
- If relapse occurs >36 months from diagnosis or is isolated to an extramedullary site such as the CNS or testis, survival is improved to 40-70% with systemic chemotherapy and possible focal radiation therapy.
Additional Reading
- Borowitz �MJ, Devidas �M, Hunger �SP, et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a Children's Oncology Group study. Blood. 2008;111(12):5477-5485. �[View Abstract]
- Hunger �SP, Loh �ML, Whitlock �JA, et al. Children's Oncology Group's 2013 blueprint for research: acute lymphoblastic leukemia. Pediatr Blood Cancer. 2013;60(6):957-963. �[View Abstract]
- Hunger �SP, Lu �X, Devidas �M, et al. Improved survival for children and adolescents with acute lymphoblastic leukemia between 1990 and 2005: a report from the children's oncology group. J Clin Oncol. 2012;30(14):1663-1669. �[View Abstract]
- Lo Nigro �L. Biology of childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2013;35(4):245-252. �[View Abstract]
- Pui �CH, Robison �LL, Look �AT. Acute lymphoblastic leukaemia. Lancet. 2008;371(9617):1030-1043. �[View Abstract]
Codes
ICD09
- 204 Acute lymphoid leukemia without mention of having achieved remission
- 204.01 Acute lymphoid leukemia, in remission
- 204.02 Acute lymphoid leukemia, in relapse
ICD10
- C91.00 Acute lymphoblastic leukemia not having achieved remission
- C91.01 Acute lymphoblastic leukemia, in remission
- C91.02 Acute lymphoblastic leukemia, in relapse
SNOMED
- 277571004 B-cell acute lymphoblastic leukemia (disorder)
- 277575008 T-cell acute lymphoblastic leukemia (disorder)
- 91856007 Acute lymphoid leukemia in remission
- 427642009 T-cell acute lymphoblastic leukemia in remission (disorder)
FAQ
- Q: Can a child on treatment for ALL go to school or leave the house?
- A: Yes. Most centers encourage the child to live a normal life, including school, activities, and travel.
- Q: Will hair fall out and will the child be sick for ALL 3 years on chemotherapy?
- A: The hair usually falls out within a few weeks of initiating therapy and grows back when maintenance therapy begins (6-8 months). Most children feel relatively well during therapy, especially maintenance chemotherapy, and can resume a lot of normal activities.
- Q: Does the child need to be isolated from other children?
- A: The most serious infections a child on chemotherapy gets come from bacteria that the child is already colonized with, not community-acquired viruses. That being said, the child should be isolated from any child who has varicella or other known symptomatic infection.