Acute Myeloid Leukemia (AML) is the most common of the four types of leukemia, with an estimated 12,000 new cases diagnosed in the United States in 2006. AML may occur at any age, but the incidence of the disease increases as individuals get older, with the average age at diagnosis being approximately 60 years. If untreated, the average survival of patients is approximately 2 months, but with appropriate treatment, many patients can now be cured of their disease.
Biology and Classification
Like other forms of leukemia, AML is caused by alterations in the genes of an early blood forming cell causing excess growth and decreased maturation of the cell and its progeny. In many cases of AML, the genetic alternation can be identified either by cytogenetic testing or by other molecular tests. Cytogenetic and molecular testing of AML are the most important tests for determining the correct form of therapy and are performed on a bone marrow specimen. The most important chromosomal abnormalities in AML are listed in Table 1 along with their incidence and implications.
Table 1 Common Cytogenetic Abnormalities in AML
| Abnormality | Incidence | Significance |
| t(8;21) | 6% | Favorable risk |
| inv(16) | 5% | Favorable risk |
| t(15;17) | 10% | APL, favorable risk, different treatment |
| 11q23 | 5% | Intermediate risk |
| -7/-7q | 7% | Unfavorable risk |
| -5/-5q | 4% | Unfavorable risk |
Additional testing may reveal mutations in key genes that can’t be identified by routine cytogenetic testing. The two most important in AML are abnormalities of a gene called “FLT3” and a gene called “NPM1”. Mutations in FLT3 are seen in approximately 30% of cases, while mutations in NPM1 occur with a similar frequency. Although cytogenetic and molecular testing are by far the most important methods of classifying AML, historically physicians also classified AML by how it looks under a microscope, using the so-called “FAB” (French-American-British) system that divided AML into 8 classes from M0 to M7. While this nomenclature is still sometimes used, it is of little clinical or scientific significance.
Causes of AML
In the vast majority of cases of AML, no reason can be found for the mutational events that result in the disease. Patients with Down syndrome, Fanconi anemia and a few other uncommon genetic diseases have an increased incidence of AML. Patients treated with chemotherapy and radiation therapy for other malignancy are at increased risk as well. Exposure to tobacco smoke and benzene has been linked to a greater chance for the development of AML. Although in the large majority of cases AML is not hereditary, there are rare families that carry a gene that increases susceptibility to AML. AML is not contagious.
Signs and Symptoms of AML
The most common signs and symptoms of AML are due to the lack of normal marrow function. Lack of red cell production causes anemia, which results in pallor, headache, fatigue, shortness of breath with exertion, and dizziness. The lack of normal functioning white cells leads to recurrent infections, and a lack of platelets leads to easy bruising, gum bleeding and petechiae. Leukemic blasts may accumulate in the gums causing swelling, in the skin causing multiple small raised lesions, or in the liver and spleen leading to enlargement of these organs and vague discomfort in the right and left upper abdomen. The symptoms of AML generally develop over a period of several weeks, but slower or more rapid onset is sometimes seen.
Diagnosis of AML
The diagnosis of AML is usually first suggested by the finding of an abnormality in the number or appearance of peripheral blood cells. Confirmation of the diagnosis usually requires examination of the bone marrow.
Treatment of AML
Once AML is diagnosed, it is important to begin treatment relatively promptly. In some cases, AML may evolve more slowly and a delay in therapy of some days or even weeks is possible, but in most cases, AML evolves rapidly, and a delay of even a few days can be dangerous. Because of differences in treatment approaches, the following discussion is separated into three major sections – treatment for AML in patients less than age 60, treatment for patients over age 60, and treatment of acute promyelocytic leukemia.
Treatment of AML in Patients Less than Age 60
Remission Induction
Without treatment, AML is generally fatal in an average of about 2 months. The first goal of therapy is to obtain a complete remission of the disease. A complete remission (abbreviated as CR), is defined as elimination of all leukemic blasts from the peripheral blood, reduction in the blast count in the marrow to less than 5%, and recovery of marrow cell function so that peripheral red, white and platelet counts recover to normal levels. Standard initial therapy of AML involves the administration of a combination of two chemotherapeutic agents, cytarabine and an anthracycline (usually either daunomycin or idarubicin). Various doses and schedules of these two agents have been studied, and sometimes additional agents are added, but there is as yet little evidence that one combination is superior to all others. A commonly used approach is daunomycin 60 mg/m2 i.v. on days 1, 2 and 3, along with cytarabine 200 mg/m2 i.v. on days 1-7. Patients are usually hospitalized when these agents are given. The chemotherapeutic agents preferentially kill leukemia cells, but also affect normal cells, so that shortly after therapy, most patients will develop a profound drop in their normal blood counts, making them susceptible to bleeding and infection, they may loose their hair and may develop sores in their mouth (oral mucositis). These side effects are temporary, and if the therapy is successful, within two or three weeks of starting chemotherapy mouth sores heal, counts begin to recover, and a remission is achieved. In order to document a remission, a repeat bone marrow is required. If leukemia blasts persist in the bone marrow, a second round of induction may be needed. With standard chemotherapy, approximately 75% of patients less than age 60 will achieve a complete remission. Approximately 10% may die of infection, bleeding or other complications during the induction attempt and in 15% of cases, the leukemia will persist despite chemotherapy. Achievement of a complete remission is not synonymous with cure, and if further therapy is not given, the leukemia will regrow in virtually every case. Thus, some form of post-induction therapy is required.
Post-induction Therapy
There are three forms of post-induction therapy that are commonly used in patients less than age 60 with AML in first remission – further chemotherapy, allogeneic hematopoietic cell transplantation (HCT) or autologous HCT. The therapy of choice is influenced by the subtype of leukemia, the availability of an appropriate donor and patient and physician choice. Standard post transplant chemotherapy generally involves administering three or four cycles of chemotherapy very similar to that used for initial induction chemotherapy. There is evidence that the use of higher doses of cytarabine during consolidation is of some advantage. [1] With standard consolidation chemotherapy, approximately 40% of patients with AML who achieved a first remission can expect to be cured. The leukemia will recur (or relapse) in the remainder. The vast majority of relapses occur anytime within 3 years of diagnosis. Approximately 30% of patients will have a brother or sister who is HLA matched with them. HLA is a marker found on white cells that determines whether a hematopoietic cell transplant is possible or not. Hematopoietic cell transplantation involves treating the patient with very high dose chemotherapy or chemo-radiotherapy and transplanting hematopoietic stem cells obtained from the bone marrow or peripheral blood of the matched sibling. The procedure is complex but results in cure in approximately 60-65% of patients with AML transplanted in first remission. Approximately 20-25% may die of the procedure, while relapse can still occur in 10-20%. Autologous HCT involves collecting hematopoietic stem cells from the bone marrow or peripheral blood of the patient and freezing them. The patient is then treated with very high dose chemotherapy or chemo-radiotherapy, following which the stem cells are reinfused. A number of prospective randomized trials have been conducted comparing chemotherapy versus allogeneic transplantation versus autologous transplantation for patients with AML in first remission. Because results have been somewhat inconsistent, investigators have performed “meta-analyses” of these studies, a process in which the results of many studies are combined. The most recent meta-analyses show that there is a survival advantage for allogeneic HCT compared to chemotherapy or autologous transplantation. [2, 3] However, the relative benefits of allogeneic transplantation depend on the subtype of leukemia, with no advantage seen for patients with favorable risk disease, only a modest benefit for patients with intermediate risk disease and considerable benefit for patients with unfavorable risk disease. [4] Some investigations suggest that the intermediate risk patients can be further subdivided into two groups – those with mutations in the NPM1 gene but without mutations in FLT3, who do almost as well as the favorable risk patients, and the remainder who do not have as favorable a prognosis. [5]
Recurrent Disease
Patients who recur with AML after initial therapy can sometimes achieve a second remission with further chemotherapy. Because the prospects for cure with further chemotherapy are poor, HCT should be strongly considered if the patient did not have a transplant as part of their initial therapy.
Treatment of AML in Patients Age 60 or Older
Remission Induction
AML in older patients is more difficult to treat for two reasons. [6] Older patients often have other illnesses that make it harder for them to tolerate the toxic effects of chemotherapy. Further, for reasons that are not well understood, AML in older individuals is less sensitive to chemotherapy. An initial decision that must be made in considering treatment in the older patient is whether exposure to standard induction chemotherapy is likely to benefit the patient. For patients over age 70 or 75, and particularly those with other significant illnesses (such as heart failure, renal failure or chronic obstructive lung disease), intensive induction chemotherapy may cause more harm than good, and many physicians will choose to treat such patients with low-dose cytarabine, or withhold chemotherapy and treat with antibiotics and transfusion support. [6] For patients age 60-75 who are otherwise healthy, standard chemotherapy can be expected to result in complete remission in 40-65% of cases, depending on other risk factors.
Post-induction Therapy
As in the case of younger patients, some form of therapy is warranted in older patients who have achieved a complete remission. However, older patients may have difficulty tolerating high dose cytarabine, and so most physicians will chose several cycles of less intensive chemotherapy as post-induction therapy.