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Acute Myeloid Leukemia, Pediatric

Basics

Description

- 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 CEPBО± 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)

- 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.

- 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)

- Signs of thrombocytopenia: - Petechiae - Bruising - Epistaxis - Gingival bleeding

- Other exam findings: - Hepatomegaly - Splenomegaly - Lymphadenopathy - Gingival hyperplasia - Papilledema, cranial nerve palsies (rare) - Colorless or slightly purple subcutaneous nodules: "blueberry muffin"пїЅ lesions of leukemia cutis (more commonly seen in neonates) - Chloroma is an extramedullary collection of leukemic cells that can present as a mass

- CBC - Anemia, thrombocytopenia, elevated or low total WBC peripheral smear - Circulating myeloblasts may be seen.

- 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

- Leukostasis - Intravascular clumping of blasts causing hypoxia, infarction, and hemorrhage - Usually occurs when WBC >200,000/ОјL - 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.

  • 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 CEPBО± 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 anemiaBloom syndromeNeurofibromatosis type IDown syndromeSevere congenital anemia (i.e., Kostmann disease treated with granulocyte colony-stimulating factor)Diamond-Blackfan anemiaParoxysmal nocturnal hemoglobinemiaLi-Fraumeni syndromeShwachman-Diamond syndromeDyskeratosis congenitaNoonan 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 activationDefects 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 benzeneExposure to ionizing radiationTherapy induced, from chemotherapy for a prior malignancyAlkylating 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: пїЅ

  • 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:PallorFatigueHeadacheDyspneaSystolic flow murmur
  • Signs of thrombocytopenia:PetechiaeBruisingEpistaxisGingival bleeding
  • Signs of infection:FeverBacterial infections of lung, sinuses, gingiva, perirectal area, skin
  • Other exam findings:HepatomegalySplenomegalyLymphadenopathyGingival hyperplasiaPapilledema, cranial nerve palsies (rare)Colorless or slightly purple subcutaneous nodules: "blueberry muffin"пїЅ 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. пїЅ

Lab

  • CBCAnemia, thrombocytopenia, elevated or low total WBC peripheral smearCirculating myeloblasts may be seen.
  • Prothrombin time (PT)/partial thromboplastin time (PTT), fibrin spit productsElevated 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)HyperkalemiaHypocalcemiaHyperphosphatemiaHyperuricemia
  • CSF analysis for cell count and cytology:>5 WBC/ОјL is suggestive of CNS disease.5-15% of cases have CNS involvement at diagnosis.

Diagnostic Procedures/Other

Bone marrow aspirate: пїЅ

  • >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

  • ImmunophenotypingPrecursor stage: CD34, CD117Myelomonocytic markers: CD11B, CD11C, CD13, CD14, CD15, CD33, CD64, CD65, i-lysozymeLymphoid 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
  • MorphologyLarge blasts with low nuclear/cytoplasmic ratioMultiple nucleoli and cytoplasmic granules
  • CytochemistryBlasts 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 supportAvoid 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. пїЅ

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. пїЅ

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/ОјLMonosomy 7, monosomy 5 or del(5q)Secondary AML or prior myelodysplastic syndromeFLT3-ITDPresence of multiple other genetic translocation events or mutationsPoor 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.
  • Infection40% of patients are febrile at diagnosis.Empiric antibiotic therapy must be started after blood cultures are obtained.
  • LeukostasisIntravascular clumping of blasts causing hypoxia, infarction, and hemorrhageUsually occurs when WBC >200,000/ОјLBrain and lung are commonly affected.Leukapheresis or exchange transfusion may be indicated for patients who are symptomatic with extremely high blast counts.
  • Tumor lysis syndromeRefers to the metabolic consequences from the release of cellular contents of dying leukemic cellsHyperuricemia 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 пїЅU, van den Heuvel-Eibrink пїЅM, Gibson пїЅB, 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. пїЅ[View Abstract]
  • Kersey пїЅJH. Fifty years of studies of biology and therapy of childhood leukemia. Blood. 1997;90(11):4243-4251. пїЅ[View Abstract]
  • Pui пїЅCH, Carroll пїЅWL, Meshinchi пїЅS, et al. Biology, risk stratification, and therapy or pediatric acute leukemias: an update. J Clin Oncol. 2011;29(5):551-565. пїЅ[View Abstract]
  • Puumala пїЅS, Ross пїЅJ, Aplenc пїЅR, et al. Epidemiology of childhood acute myeloid leukemia. Pediatr Blood Cancer 2013;60(5):728-733. пїЅ[View Abstract]
  • Rubnitz пїЅJE, Gibson пїЅB, Smith пїЅFO. Acute myeloid leukemia. Hematol Oncol Clin North Am. 2010;24(1):35-63. пїЅ[View Abstract]
  • Vardiman пїЅJW, Thiele пїЅJ, Arber пїЅDA, 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. пїЅ[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.