AML is a clonal malignancy of myeloid bone marrow precursors in which poorly differentiated cells accumulate in the bone marrow and circulation.
Signs and symptoms occur because of the absence of mature cells normally produced by the bone marrow, including granulocytes (susceptibility to infection) and platelets (susceptibility to bleeding). In addition, if large numbers of immature malignant myeloblasts circulate, they may invade organs and rarely produce dysfunction. There are distinct morphologic subtypes (Table 66-1 AML Classification Systems) that have largely overlapping clinical features. Of note is the propensity of pts with acute promyelocytic leukemia (APL) (FAB M3) to develop bleeding and disseminated intravascular coagulation, especially during induction chemotherapy, because of the release of procoagulants from their cytoplasmic granules.
Incidence and Etiology
In the United States about 19,520 cases occurred in 2018. AML accounts for about 80% of acute leukemias in adults. Etiology is unknown for the vast majority. As we age, mutations may occur in normal stem cells that convey a proliferative advantage and establish so-called clonal hematopoiesis. In the setting of clonal hematopoiesis, the relative risk for developing acute leukemia increases but the absolute risk is still very small. Three environmental exposures increase the risk: chronic benzene exposure, radiation exposure, and prior treatment with alkylating agents (especially in addition to radiation therapy) and topoisomerase II inhibitors (e.g., doxorubicin and etoposide). Chronic myeloid leukemia (CML), myelodysplasia, and myeloproliferative syndromes may all evolve into AML. Certain genetic abnormalities are associated with particular morphologic variants: t(15;17) with APL, inv(16) with eosinophilic leukemia; others occur in a number of types. Chromosome 11q23 abnormalities are often seen in leukemias developing after exposure to topoisomerase II inhibitors. Chromosome 5 or 7 deletions are seen in leukemias following radiation plus chemotherapy. The particular genetic abnormality has a strong influence on treatment outcome. Expression of MDR1 (multidrug resistance efflux pump) is common in older pts and adversely affects prognosis.
Clinical and Laboratory Features
Initial symptoms of acute leukemia have usually been present for <3 months; a preleukemic syndrome may be present in some 25% of pts with AML. Signs of anemia, pallor, fatigue, weakness, palpitations, and dyspnea on exertion are most common. White blood cell count (WBC) may be low, normal, or markedly elevated; circulating blast cells may or may not be present; with WBC >100 × 109 blasts per liter, leukostasis in lungs and brain may occur. Minor pyogenic infections of the skin are common. Thrombocytopenia leads to spontaneous bleeding, epistaxis, petechiae, conjunctival hemorrhage, gingival bleeding, and bruising, especially with platelet count <20,000/μL. Anorexia and weight loss are common; fever may be present.
Bacterial and fungal infection are common; risk is heightened with total neutrophil count <5000/μL, and breakdown of mucosal and cutaneous barriers aggravates susceptibility; infections may be clinically occult in presence of severe leukopenia, and prompt recognition requires a high degree of clinical suspicion.
Hepatosplenomegaly occurs in about one-third of pts; leukemic meningitis may present with headache, nausea, seizures, papilledema, cranial nerve palsies.
Metabolic abnormalities may include hyponatremia, hypokalemia, elevated serum lactate dehydrogenase (LDH), hyperuricemia, and (rarely) lactic acidosis. With very high blast cell count in the blood, spurious hyperkalemia and hypoglycemia may occur (potassium released from and glucose consumed by tumor cells after the blood was drawn).
| TREATMENT | ||
Acute Myeloid LeukemiaLeukemic cell mass at time of presentation may be 1011 -1012 cells; when total leukemic cell numbers fall below ∼109 , they are no longer detectable in blood or bone marrow and pt appears to be in complete remission (CR). Thus, aggressive therapy must continue past the point when initial cell bulk is reduced if leukemia is to be eradicated. Typical phases of chemotherapy include remission induction and postremission therapy, with treatment lasting about 1 year. Figure 66-1. Flowchart for the Therapy of Newly Diagnosed Acute Myeloid Leukemia (AML) outlines a treatment algorithm. Supportive care with transfusions of red cells and platelets (from cytomegalovirus [CMV]-seronegative donors, if pt is a candidate for bone marrow transplantation) is very important, as are aggressive prevention, diagnosis, and treatment of infections. Colony-stimulating factors offer little or no benefit; some recommend their use in older pts and those with active infections. Febrile neutropenia should be treated with broad-spectrum antibiotics (e.g., ceftazidime 1 g q8h); if febrile neutropenia persists beyond 7 days, a broad spectrum antifungal agent should be added. About 60-80% of pts will achieve initial remission when treated with cytarabine 100-200 (mg/m2 )/d by continuous infusion for 7 days, and daunorubicin (45 [mg/m2 ]/d) or idarubicin (12-13 [mg/m2 ]/d) for 3 days. Addition of etoposide may improve CR duration. Half of treated pts enter CR with the first cycle of therapy, and another 25% require two cycles. About 10-30% of pts achieve 5-year disease-free survival and probable cure. Pts achieving a CR who have low risk of relapse (cells contain t[8;21] or inv[16]) receive 3-4 cycles of cytarabine. Those at high risk of relapse may be considered for allogeneic bone marrow transplantation. Response to treatment after relapse is short, and prognosis for pts who have relapsed is poor. In APL, arsenic trioxide plus trans-retinoic acid (tretinoin) induces differentiation of the leukemic cells and molecular CRs. A fraction of pts may develop pulmonary symptoms from the sludging of differentiated neoplastic granulocytes in the lung. Glucocorticoids may speed recovery from this syndrome. Bone marrow transplantation from identical twin or human leukocyte antigen (HLA)-identical sibling is effective treatment for AML. Typical protocol uses high-dose chemotherapy ± total-body irradiation to ablate host marrow, followed by infusion of marrow from donor. Risks are substantial (unless marrow is from identical twin). Complications include graft-versus-host disease, interstitial pneumonitis, opportunistic infections (especially CMV). Comparison between transplantation and high-dose cytarabine as postremission therapy has not produced a clear advantage for either approach. Up to 30% of otherwise end-stage pts with refractory leukemia achieve probable cure from transplantation; results are better when transplant is performed during remission. Results are best for children and young adults. Many new therapies are in development including agents that target kinases in important cellular pathways (e.g., FLT3, KIT, Aurora, and Polo-like kinases), epigenetic modulators (histone deacetylase, DNA methyltransferase, and isocitrate dehydrogenase inhibitors), chemotherapy agents (nucleosides), BCL2 inhibitors, and immunotherapies (CAR T cells, antibodies, immune checkpoint inhibitors). |
Section 6. Hematology and Oncology