Basics
Description
- Acute myeloid leukemia (AML) results from a block in differentiation and unregulated proliferation of myeloid progenitor cells.
- AML is classified according to the World Health Organization (WHO) classification (2008).
- Formerly classified by French-American-British (FAB) classification
- WHO classification is based on genetic alterations, whereas FAB is based on morphology.
Epidemiology
- AML is the 7th most common pediatric malignancy.
- Leukemia that occurs in first 4 weeks of life is usually AML.
- Ratio of AML to acute lymphoblastic leukemia (ALL) throughout childhood is 1:5.
- Boys and girls are equally affected.
- Rates are highest in Asian and Pacific Islanders followed by Hispanics, Caucasians, and African Americans.
Incidence
- AML incidence peaks in infants younger than 1 year of age and again in children 10-14 years of age.
- Around 500 children/year in the United States
Risk Factors
Genetics
- 20-30% of pediatric blasts have normal karyotype versus 40-50% in adults.
- 60% of abnormal karyotypes fall into known subgroups.
- Translocations or duplications of the MLL gene at 11q23 or monosomy 7 carry a poor prognosis.
- These genetic abnormalities are found in many cases of therapy-induced AML.
- FLT3-ITD with high allelic ratio, a drug targetable lesion, has been recently shown to carry a poor prognosis.
- Translocations t(8;21), t(15;17), and inv(16), as well as NPM and CEPBα mutations carry a good prognosis.
- AML associated with Down syndrome has an excellent prognosis.
- Certain congenital syndromes that carry an increased risk of AML:
- Fanconi anemia
- Bloom syndrome
- Neurofibromatosis type I
- Down syndrome
- Severe congenital anemia (i.e., Kostmann disease treated with granulocyte colony-stimulating factor)
- Diamond-Blackfan anemia
- Paroxysmal nocturnal hemoglobinemia
- Li-Fraumeni syndrome
- Shwachman-Diamond syndrome
- Dyskeratosis congenita
- Noonan syndrome (RASopathies)
Pathophysiology
- Principal defect is a block in the differentiation of primitive myeloid precursor cells.
- 2 mechanisms predominate:
- Defect at the level of transcriptional activation
- Defects in the signaling pathway of hematopoietic growth factors. For example, the proto-oncogene Ras is mutated in up to 1/3 of patients with AML.
Etiology
- Exact cause unknown in most cases.
- Acquired risk factors include the following:
- Exposure to benzene
- Exposure to ionizing radiation
- Therapy induced, from chemotherapy for a prior malignancy
- Alkylating agents such as cyclophosphamide, nitrogen mustard, chlorambucil, and melphalan (typically presents several years after therapy)
- Epipodophyllotoxins such as VP16, VM26 (typically occurs within 2 years after therapy and is characterized by rearrangements involving 11q23)
Diagnosis
History
Children with AML can present with very few symptoms or with life-threatening sepsis or hemorrhage. Common symptoms include the following: �
- Fever: 30-40%
- Pallor: 25%
- Weight loss/anorexia: 22%
- Fatigue: 19%
- Bleeding (i.e., cutaneous, mucosal, menorrhagia): 33%
- Bone or joint pain: 18%
Physical Exam
- Signs of anemia:
- Pallor
- Fatigue
- Headache
- Dyspnea
- Systolic flow murmur
- Signs of thrombocytopenia:
- Petechiae
- Bruising
- Epistaxis
- Gingival bleeding
- Signs of infection:
- Fever
- Bacterial infections of lung, sinuses, gingiva, perirectal area, skin
- Other exam findings:
- Hepatomegaly
- Splenomegaly
- Lymphadenopathy
- Gingival hyperplasia
- Papilledema, cranial nerve palsies (rare)
- Colorless or slightly purple subcutaneous nodules: "blueberry muffin"� lesions of leukemia cutis (more commonly seen in neonates)
- Chloroma is an extramedullary collection of leukemic cells that can present as a mass
Diagnostic Tests & Interpretation
Techniques such as fluorescence in situ hybridization, flow cytometry Southern blotting, and reverse transcriptase-polymerase chain reaction are used to diagnose and classify AML. �
Lab
- CBC
- Anemia, thrombocytopenia, elevated or low total WBC peripheral smear
- Circulating myeloblasts may be seen.
- Prothrombin time (PT)/partial thromboplastin time (PTT), fibrin spit products
- Elevated in some cases, especially with acute promyelocytic leukemia (M3)
- Can have severe, life-threatening disseminated intravascular coagulation (DIC)
- Electrolytes (abnormalities associated with tumor lysis syndrome)
- Hyperkalemia
- Hypocalcemia
- Hyperphosphatemia
- Hyperuricemia
- CSF analysis for cell count and cytology:
- >5 WBC/μL is suggestive of CNS disease.
- 5-15% of cases have CNS involvement at diagnosis.
Diagnostic Procedures/Other
Bone marrow aspirate: �
- >20% myeloblasts is typically seen.
- To differentiate between AML with low blast count and myelodysplastic syndrome, serial bone marrow aspirates and biopsies are required as well as detailed cytogenetic analysis.
- At diagnosis, morphology, cytochemistry, immunophenotyping, and molecular and cytogenetics of the bone marrow aspirate are required.
Pathologic Findings
- Immunophenotyping
- Precursor stage: CD34, CD117
- Myelomonocytic markers: CD11B, CD11C, CD13, CD14, CD15, CD33, CD64, CD65, i-lysozyme
- Lymphoid markers: T and B cell markers may be present on 30-60% of pediatric blasts.
- CD41, CD42, and CD61 (megakaryocytic): particularly prevalent in patients with Down syndrome
- Morphology
- Large blasts with low nuclear/cytoplasmic ratio
- Multiple nucleoli and cytoplasmic granules
- Cytochemistry
- Blasts are positive for myeloperoxidase and Sudan Black and usually negative for periodic acid-Schiff (PAS) and terminal deoxynucleotide transferase (TdT).
Differential Diagnosis
- Myeloid blast crisis of chronic myeloid leukemia (Philadelphia chromosome positive)
- Transient myeloproliferative disorder of the newborn (in Down syndrome)
- ALL
- Leukemoid reaction
- Exaggerated leukocytosis
- Myelodysplastic syndrome
Treatment
Medication
- Patients are treated with 6-9 months of intensive chemotherapy given in cycles.
- The most effective drugs for remission induction in AML combine anthracyclines (e.g., doxorubicin, daunorubicin, daunomycin, and mitoxantrone) and cytarabine (Ara-C).
- Other agents sometimes used in combination chemotherapy include etoposide (VP-16), gemtuzumab (anti-CD33 monoclonal antibody), fludarabine, dexamethasone, L-asparaginase, and 6-thioguanine.
- Patients with acute promyelocytic leukemia can be cured with all-trans-retinoic acid and arsenic.
- Intrathecal Ara-C for CNS prophylaxis
- FLT3 inhibitors including sorafenib are being used in some patients with FLT3-ITD.
- Hematopoietic stem cell transplant is recommended for patients with high-risk cytogenetics (monosomy 7, monosomy 5, 5q-, FLT3-ITD) or those whom not in remission following 2 courses of induction therapy
Additional Therapies
General Measures
- Hydration, alkalization, and allopurinol during induction
- Consider rasburicase in patients with marked elevations in uric acid and renal compromise (contraindicated in patients with G6PD deficiency).
- Blood product support
- Avoid products from family members as sensitization can lead to poor engraftment after allogeneic bone marrow transplant.
- Broad-spectrum antibiotics and antifungal therapy for fever and neutropenia
- Prophylactic trimethoprim-sulfamethoxazole for Pneumocystis infection
Additional Therapies
Allogeneic bone marrow transplant is recommended for high-risk AML in first remission. �
Inpatient Considerations
Initial Stabilization
Children with suspected AML should have immediate evaluation with physical exam, history, and laboratory data including CBC, PT/PTT, electrolytes, calcium, phosphorus, uric acid, and creatinine. �
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- Blood counts monthly for 1st year, every 4 months for the 2nd year, and every 6 months thereafter
- Liver and kidney function tests every 3-6 months
- Cardiac function every 12 months.
- Endocrine function should be tested in pubertal children.
Prognosis
- 85% achieve remission with intensive chemotherapy.
- ~60-70% achieve long-term survival (>5 years after diagnosis).
- Factors associated with poor prognosis:
- WBC count >100,000/μL
- Monosomy 7, monosomy 5 or del(5q)
- Secondary AML or prior myelodysplastic syndrome
- FLT3-ITD
- Presence of multiple other genetic translocation events or mutations
- Poor initial response to therapy (induction failure or presence of >0.1% minimal residual disease [MRD] in the bone marrow at the end of induction)
- MRD testing measures quantities of residual leukemia not seen on morphologic exam using flow cytometry or standard cytogenetics.
Complications
- Bleeding (usually secondary to thrombocytopenia)
- DIC occurs in some types of AML, including acute promyelocytic leukemia (M3).
- Treat bleeding aggressively with fresh frozen plasma and platelets.
- Other cytopenias require blood product support.
- Infection
- 40% of patients are febrile at diagnosis.
- Empiric antibiotic therapy must be started after blood cultures are obtained.
- Leukostasis
- Intravascular clumping of blasts causing hypoxia, infarction, and hemorrhage
- Usually occurs when WBC >200,000/μL
- Brain and lung are commonly affected.
- Leukapheresis or exchange transfusion may be indicated for patients who are symptomatic with extremely high blast counts.
- Tumor lysis syndrome
- Refers to the metabolic consequences from the release of cellular contents of dying leukemic cells
- Hyperuricemia can lead to renal failure.
- Hyperkalemia, hyperphosphatemia, and secondary hypocalcemia can be life threatening.
- Patients should be hydrated with fluid containing bicarbonate and given allopurinol.
Additional Reading
- Creutzig �U, van den Heuvel-Eibrink �M, Gibson �B, et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood. 2012;120(16):3187-3205. �[View Abstract]
- Kersey �JH. Fifty years of studies of biology and therapy of childhood leukemia. Blood. 1997;90(11):4243-4251. �[View Abstract]
- Pui �CH, Carroll �WL, Meshinchi �S, et al. Biology, risk stratification, and therapy or pediatric acute leukemias: an update. J Clin Oncol. 2011;29(5):551-565. �[View Abstract]
- Puumala �S, Ross �J, Aplenc �R, et al. Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 2013;60(5):728-733. �[View Abstract]
- Rubnitz �JE, Gibson �B, Smith �FO. Acute myeloid leukemia. Hematol Oncol Clin North Am. 2010;24(1):35-63. �[View Abstract]
- Vardiman �JW, Thiele �J, Arber �DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951. �[View Abstract]
Codes
ICD09
- 205 Acute myeloid leukemia, without mention of having achieved remission
- 205.01 Acute myeloid leukemia, in remission
- 205.02 Acute myeloid leukemia, in relapse
ICD10
- C92.00 Acute myeloblastic leukemia, not having achieved remission
- C92.01 Acute myeloblastic leukemia, in remission
- C92.02 Acute myeloblastic leukemia, in relapse
SNOMED
- 91861009 Acute myeloid leukemia, disease (disorder)
- 91860005 Acute myeloid leukemia in remission (disorder)
FAQ
- Q: Is an indwelling line required for therapy?
- A: Always
- Q: Are repeated hospitalizations likely?
- A: Repeated hospitalizations are needed for chemotherapy and infectious complications.