Acute Myeloid Leukemia
Acute Myeloid Leukemia (AML) is a malignant proliferation of myeloblasts in the blood and bone marrow. The hematopoietic precursors are arrested in an early stage of development. Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow. The disease is commonest in the middle-aged and elderly.
Although the onset is usually acute there is a smouldering or “preleukemic” phase in about 15% of cases.
The presenting features of AML, as in ALL, are generally those of bone marrow failure:
Anemia with weakness and lethargy.
Leucopenia with recurrent infections.
Thrombocytopenia with purpura and bleeding. Bleeding may be particularly severe in acute promyelocytic leukemia (APL/M3) in which disseminated intravascular coagulation (DIC) is a feature.
Hepatosplenomegaly but not lymphadenopathy is common.
Infiltration of the gums and perineum is a feature of AML, particularly M4 and M5.
- FBC & Blood film.
- Coagulation profile.
- Biochemistry profile including U&Es, LFTs, Bone, LDH, Uric Acid and hematinics.
- CT scan neck, thorax, abdomen and pelvis.
- Cultures, in particular blood cultures.
- Bone marrow aspirate, trephine, cell markers and cytogenetics.
Anemia is usually present. Anisocytosis and poikilocytosis are common.
The total leucocyte count is usually raised with myeloblasts the predominant cell type. The neutrophil count is usually reduced.
The platelet count is usually low.
The bone marrow is hypercellular and aspiration may be difficult. Blast cells predominate. Features of dyserythropoiesis and dysgranulopoiesis are seen.
In the “preleukemic phase” there is depression of one or more cell lines in the blood with few if any blast cells present. In the marrow, there is usually marked dyshematopoiesis and there may or may not be a modest increase in blast cells. Ringed sideroblasts may be seen on iron stains.
Morphology is the gold standard for blast enumeration with a blast percentage of 20% defining AML in the WHO classification system. Of note, a blast percentage of 30% was used by the FAB classification.
Myeloblasts vary in size but are usually intermediate or large cells with relatively abundant blue cytoplasm. The nuclear chromatin is finely dispersed with often more than two nucleoli per cell. The finding of “Auer Rods” is pathognomonic of AML.
Monoblasts are usually large cells with voluminous cytoplasm which may contain azurophil granules. The nucleus is often folded and contains 3-5 nucleoli.
It is difficult in some cases to differentiate myeloblasts from lymphoblasts and cytochemistry and immunophenotyping may then be helpful.
Myeloblasts are typically Sudan black and Myeloperoxidase positive and PAS negative. They are often diffusely positive for non-specific esterase (NSE).
Cytogenetic studies performed on bone marrow provide important prognostic information. They are useful for confirming a diagnosis of APL, which bears the t(15;17) chromosome abnormality (PML/RARa) and is treated differently.
Chromosomal abnormalities are seen in the majority of cases; t(15;17), inv(16) and t(8;21) are good prognostic features whereas trisomy 8, monosomy 7 and monosomy 5 are poor prognosis disease.
Fluorescence in situ hybridization (FISH) studies can be used to get a faster overview of cytogenetic abnormalities than traditional cytogenetic studies. FISH does not replace cytogenetics.
Molecular Marrow Evaluation:
Several molecular abnormalities that are not detected with routine cytogenetics have been shown to have prognostic importance in patients with AML. The bone marrow should be evaluated at least with the commercially available tests. Patients with APL should have their marrow evaluated for the PML/RARa genetic rearrangement. When possible, the bone marrow should be evaluated for Fms-like tyrosine kinase 3 (FLT3) and nucleophosmin (NPM1) mutations.
FLT3 is the most commonly mutated gene in persons with AML and is constitutively activated in one-third of AML cases. Internal tandem duplications (ITDs) in the juxtamembrane domain of FLT3 exist in 25% of AML cases. In other cases, mutations exist in the activation loop of FLT3. Most studies demonstrate that patients with AML and FLT3 ITDs have a poor prognosis. Analysis of FLT3 is commercially available.
Mutations in NPM1 are associated with increased response to chemotherapy in patients with a normal karyotype.
Treatment of AML:
Includes transfusion for anemia, treatment of infections, platelets for bleeding, and social and psychological support. Patients should receive leucodepleted, irradiated blood products to reduce the risk of transfusion-associated graft versus host disease, cytomegalovirus (CMV) transmission, and febrile transfusion reactions. Patients usually receive packed red cells when the hemoglobin level falls below 8 g/dL, those with significant respiratory and cardiac disease might require transfusion at a higher hemoglobin level. Patients receive platelet transfusions when the platelet count is <10,000/mm3. Patients with active bleeding will be transfused to a platelet count of 50,000/mm3; patients with CNS hemorrhage should be transfused to a platelet count of 100,000/mm3. If disseminated intravascular coagulation (DIC) is present (M3) large numbers of platelets and clotting factor replacement therapy are required.
Initial therapy attempts to induce remission and differs most from ALL in that AML responds to fewer drugs. The basic induction regimen includes cytarabine (ara-C) by continuous IV infusion or high doses for 5 to 7 days; daunorubicin or idarubicin is given IV for 3 days during this time. Some regimens include 6-thioguanine, etoposide, vincristine, and prednisone, but their contribution is unclear. Treatment usually results in significant myelosuppression, with infection or bleeding. There is significant latency before marrow recovery. During this time, meticulous preventive and supportive care is vital.
In APL and some other cases of AML, disseminated intravascular coagulation (DIC) may be present when leukemia is diagnosed and may worsen as leukemic cell lysis releases procoagulant. APL is a particularly important subtype, representing 10 to 15% of all cases of AML, striking a younger age group (median age 31 years) and particular ethnicity (Hispanics), in which the patient commonly presents with a coagulation disorder. In APL with the translocation t(15;17), all- trans retinoic acid (ATRA/tretinoin) corrects the DIC in 2 to 5 days; combined with daunorubicin or idarubicin, this regimen can induce remission in 80 to 90% of patients and bring about long-term survival in 65 to 70%. Arsenic trioxide is also very active in APL.
Patients who have not responded to treatment and younger patients who are in remission but who are at high risk of relapse (generally identified by high-risk molecular or chromosomal abnormalities) may be given high-dose chemotherapy and stem cell transplantation. Extramedullary sites are infrequently involved in isolated relapse. When relapse occurs, additional chemotherapy for patients unable to undergo stem cell transplantation is less effective and often poorly tolerated. Another course of chemotherapy is most effective in younger patients and in patients whose initial remission lasted > 1 year.
Remission induction rates range from 50 to 85%. Long-term disease-free survival occurs in 20 to 40% of patients and increases to 40 to 50% in younger patients treated with intensive chemotherapy or stem cell transplantation.
Prognostic factors help determine treatment protocol and intensity; patients with strongly negative prognostic features are usually given more intense forms of therapy because the potential benefits are thought to justify the increased treatment toxicity. An important prognostic factor is the leukemia cell karyotype. The specific chromosomal rearrangements of the different forms of AML affect the outcome.
Three clinical groups have been identified: favorable, intermediate, and poor. Patients who have the cytogenetic findings of t(8;21), t(15;17), and inv(16) typically have a favorable response to therapy, durable remission, and improved survival. Patients with a normal karyotype have an intermediate prognosis, and patients with a poor prognosis are those with a deletion of chromosome 5 or 7, trisomy 8, or a karyotype with > 3 abnormalities.
Molecular genetic abnormalities are becoming more important in refining prognosis and therapy in AML. Mutations in FLT3 kinase in particular indicate a poorer prognosis and are targets for additional therapy. Other negative factors include increasing age, a preceding myelodysplastic phase, secondary leukemia, high WBC count, and absence of Auer rods. Except in APL, the FAB or WHO classification alone does not predict response.
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