Childhood Leukemia
Summary of Key Points
Incidence
• Leukemia is the most common childhood cancer.
• The most common subtype, acute lymphoblastic leukemia (ALL), accounts for 75% to 80% of all cases of childhood leukemia, whereas acute myeloid leukemia (AML) comprises approximately 20%.
• Chronic myelogenous leukemia (CML), myelodysplastic syndrome (MDS), and myeloproliferative disorder (MPD) are less frequent.
Epidemiology
• Males are generally affected by leukemia slightly more often than females in all age groups except infants.
• In developed countries, the incidence of ALL is highest between ages 2 and 5 years.
• The incidence of AML is relatively constant during childhood, with slight peaks in the first 2 years of life and in late adolescence.
• MDS typically occurs after 5 years of age and juvenile myelomonocytic leukemia (JMML) occurs nearly always before 5 year of age.
Clinical Findings
• Physical signs and symptoms of thrombocytopenia and anemia are common.
• Neutropenia may lead to severe infection.
• Bone pain and arthralgia caused by leukemic infiltration is more common in ALL than AML and may be especially severe in young children.
• Common sites of extramedullary involvement in ALL include liver, spleen, thymus, and lymph nodes.
• Skin, gums, and the head and neck area are typical sites of extramedullary disease in AML Infiltration of the central nervous system can be found in both ALL and AML.
Differential Diagnosis
• The acute onset of petechiae, ecchymoses, and bleeding may suggest idiopathic thrombocytopenic purpura.
• Both acute leukemia and aplastic anemia may present with pancytopenia and complications associated with bone marrow failure.
• Infectious mononucleosis and other viral infections can be confused with ALL.
• Bone pain, arthralgia, and occasionally arthritis may mimic juvenile rheumatoid arthritis, rheumatic fever, other collagen diseases, or osteomyelitis.
• Childhood ALL should also be distinguished from pediatric small round cell tumors that involve the bone marrow.
Therapy
• Patients with ALL undergo a relatively brief remission-induction phase followed by intensification (consolidation) therapy and then prolonged continuation treatment.
• All patients require treatment for subclinical central nervous system (CNS) involvement, which should be initiated early in the form of intrathecal chemotherapy.
• Most protocols for AML include remission induction and 3 to 4 courses of consolidation therapy.
• Autologous hematopoietic stem cell transplantation is not usually recommended.
• At present, ALL with remission failure, high levels (≥1%) of minimal residual disease (MRD) and/or persistent MRD postremission induction or early hematologic relapse are clear indications for allogeneic transplantation.
• Allogeneic transplantation appears to improve overall survival in AML, although the indications for this procedure during first remission are debated.
Prognosis
• Five-year event-free survival estimates for children with newly diagnosed ALL are now over 80%.
• Hypodiploidy with less than 44 chromosomes, and early T-cell precursor status are unfavorable prognostic indicators, whereas hyperdiploidy with more than 50 chromosomes and the ETV6-RUNX1 gene fusion in B-lineage ALL and NOTCH/FBXW7 mutations in T-cell ALL are associated with a favorable outcome. The prognosis associated with the Philadelphia chromosome/BCR-ABL1 abnormality has improved with the availability of tyrosine kinase inhibitors.
• Event-free survival for infant ALL with 11q23/MLL rearrangement remains only 20% to 35% and has not been improved by allogeneic transplantation.
• In AML, patients with Down syndrome or acute promyelocytic leukemia have a favorable prognosis with optimal therapy, whereas those with acute megakaryoblastic leukemia without the t(1;22)/OTT-MAL have significantly worse outcomes than others.
• Early bone marrow relapse and treatment-related AML carry a dismal prognosis.
• Patients with MDS, AML arising from MDS, AML with monosomy 7, or AML with internal tandem duplication of the FLT3 gene often have resistant disease.
• Slow response to remission induction therapy and persistent minimal residual disease are associated with a higher risk of relapse in both ALL and AML.
1. Subtypes of childhood acute lymphocytic leukemia (ALL) with a favorable prognosis include those with:
2. Subtypes of childhood acute myelogenous leukemia (AML) associated with a favorable prognosis include those with:
3. In the treatment of childhood leukemia, prophylactic cranial irradiation:
A Is essential to prevent central nervous system relapse
B Should be performed in all patients with T-ALL
C Can be omitted in all patients in the context of effective risk-adapted intrathecal and systemic chemotherapy
D Should be performed in all patients with leukocyte count above 100 × 109/L
E Should be performed in patients with precursor B-cell ALL and leukocyte count above 100 × 109/L
4. Genetic abnormalities of childhood ALL cells at relapse are:
A Always identical to those identified at diagnosis
B Always different from those identified at diagnosis
C Often identical to those found in a minor clone at diagnosis
1. Answer: D. Childhood ALL with ETV6-RUNX1 or hyperdiploidy >50 chromosomes generally have an excellent prognosis. By contrast, early T-cell precursor ALL is associated with a poor outcome with current chemotherapy.
2. Answer: A. AML with t(8;21)/RUNX1-ETO and AML with inv(16)/CBFB-MYH11 have favorable prognosis. By contrast, FLT3-ITD, M7 without the t(1;22)/OTT-MAL, and treatment-related AML are adverse prognostic features.
3. Answer: C. Prophylactic cranial irradiation has neurotoxicity and can cause brain tumors. Recent trials have shown that it can be safely omitted in all patients with either ALL or AML in the context of effective risk-adapted intrathecal and systemic chemotherapy without jeopardizing outcome and without increasing CNS relapse. The presence of leukemic cells in cerebrospinal fluid at diagnosis of ALL and T-cell ALL with initial leukocyte count above 100 × 109/L are associated with increased risk of CNS relapse, and are indications for intensive triple intrathecal therapy. However, prophylactic cranial irradiation is still used in some clinical trials for patients with T-cell ALL and leukocyte count >100 × 109/L and those with overt CNS leukemia (CNS3 status; >5 leukocyte count/mm3 of cerebrospinal fluid with blasts).
4. Answer: C. Genome-wide studies of paired diagnosis/relapse samples showed that the predominant clone at relapse was often present as minor clone at diagnosis. Mutations of CREBBP, which encodes the transcriptional coactivator and histone acetyltransferase CREB-binding protein, are found in 18% of cases.
5. Answer: E. MRD is the strongest prognostic factor in both ALL and AML. MRD studies by flow cytometry or PCR amplification of antigen-receptor genes provide strong prognostic information in patients with ALL. In AML, flow cytometric measurements of MRD are prognostic.
