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Acute myeloid leukemia (AML) is a quickly progressing disease in which too many immature white blood cells (not lymphocytes) are found in the blood and bone marrow. Learn about acute myeloid leukemia and find information on how we support and care for people with AML before, during, and after treatment.
Acute myelogenous leukemia (AML) is the most common acute leukemia affecting adults — and Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) is one of the world's most experienced programs in treating people like you who are fighting this disease. Our Adult Leukemia Program includes a team of knowledgeable, compassionate specialists who aren't just experts in treating cancer; they are global leaders in treating leukemia — and in treating your type of leukemia, in particular.
Exceptional Care for Patients with Acute Myelogenous Leukemia
World-class care from a full array of specialists — including medical and radiation oncologists, infectious disease specialists, nursing professionals, physician assistants, psychologists, and social workers — with years of expertise in caring for patients with AML.
Development of the personalized treatment plan that's best for you — with options ranging from standard supportive care to intensive chemotherapy, as needed.
Access to both conventional and innovative treatments, including bone marrow/stem cell transplantation, combination chemotherapy, radiation therapy, and immune-based therapies and vaccines.
Close collaboration with you and your family as key members of the treatment team.
Partnership with your referring physician at each stage of your treatment, including follow-up care that's closer to your home.
Comprehensive support services for you and your family, including patient and caregiver education and survivorship programs to help you live well beyond cancer.
The full expertise of two renowned medical centers: Brigham and Women's Hospital and Dana-Farber Cancer Institute.
To schedule a consultation or request a second opinion from our multidisciplinary team, please contact us at 617-632-6028 or 617-632-5138 or fill out our secure online form.
Adult acute myeloid leukemia (AML) is a cancer of the blood and bone marrow. This type of cancer usually gets worse quickly if it is not treated. It is the most common type of acute leukemia in adults. AML is also called acute myelogenous leukemia, acute myeloblastic leukemia, acute granulocytic leukemia, and acute nonlymphocytic leukemia.
Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell.
A myeloid stem cell becomes one of three types of mature blood cells:
In AML, the myeloid stem cells usually become a type of immature white blood cell called myeloblasts (or myeloid blasts). The myeloblasts in AML are abnormal and do not become healthy white blood cells. Sometimes in AML, too many stem cells become abnormal red blood cells or platelets. These abnormal white blood cells, red blood cells, or platelets are also called leukemia cells or blasts. Leukemia cells can build up in the bone marrow and blood so there is less room for healthy white blood cells, red blood cells, and platelets. When this happens, infection, anemia, or easy bleeding may occur. The leukemia cells can spread outside the blood to other parts of the body, including the central nervous system (brain and spinal cord), skin, and gums.
This summary is about adult AML. See the following PDQ summaries for information about other types of leukemia:
Most AML subtypes are based on how mature (developed) the cancer cells are at the time of diagnosis and how different they are from normal cells.
Acute promyelocytic leukemia (APL) is a subtype of AML that occurs when parts of two genes stick together. APL usually occurs in middle-aged adults. Signs of APL may include both bleeding and forming blood clots.
Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Possible risk factors for AML include the following:
The early signs and symptoms of AML may be like those caused by the flu or other common diseases. Check with your doctor if you have any of the following:
The following tests and procedures may be used:
The prognosis (chance of recovery) and treatment options depend on:
It is important that acute leukemia be treated right away.
The extent or spread of cancer is usually described as stages. In adult acute myeloid leukemia (AML), the subtype of AML and whether the leukemia has spread outside the blood and bone marrow are used instead of the stage to plan treatment. The following tests and procedures may be used to determine if the leukemia has spread:
The disease is described as untreated, in remission, or recurrent.
Untreated adult AML
In untreated adult AML, the disease is newly diagnosed. It has not been treated except to relieve signs and symptoms such as fever, bleeding, or pain, and the following are true:
Adult AML in remission
In adult AML in remission, the disease has been treated and the following are true:
Recurrent Adult AML
RecurrentAML is cancer that has recurred (come back) after it has been treated. The AML may come back in the blood or bone marrow.
Different types of treatment are available for patients with adult acute myeloid leukemia (AML). Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.
The 2 treatment phases of adult AML are:
Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid (intrathecal chemotherapy), an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). Intrathecal chemotherapy may be used to treat adult AML that has spread, or may spread to the brain and spinal cord. Combination chemotherapy is treatment using more than one anticancer drug. The way the chemotherapy is given depends on the subtype of the cancer being treated and whether it has spread to the brain and spinal cord.
See Drugs Approved for Acute Myeloid Leukemia for more information.
Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.
Stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells that are abnormal or destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Stem Cell Transplant
Stem cell transplant (Step 1). Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm.
Stem cell transplant (Step 2). The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown).
Stem cell transplant (Step 3). The patient receives stem cells through a catheter placed into a blood vessel in the chest.
Arsenic trioxide and all-trans retinoic acid (ATRA) are anticancer drugs that kill leukemia cells, stop the leukemia cells from dividing, or help the leukemia cells mature into white blood cells. These drugs are used in the treatment of a subtype of AML called acute promyelocytic leukemia.
This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.
Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibody therapy is one type of targeted therapy being studied in the treatment of adult AML.
Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.
For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.
Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.
Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.
Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.
Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.
Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.
Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.
Standard treatment of untreated adult acute myeloid leukemia (AML) during the remission induction phase depends on the subtype of AML and may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
Standard treatment of adult AML during the remission phase depends on the subtype of AML and may include the following:
One of the treatments being studied in clinical trials for adult AML in remission is arsenic trioxide.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia in remission. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
There is no standard treatment for recurrent adult AML. Treatment depends on the subtype of AML and may include the following:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute myeloid leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.
For more information from the National Cancer Institute about adult acute myeloid leukemia, see the following:
For general cancer information and other resources from the National Cancer Institute, see the following:
This information is provided by the National Cancer Institute.
This information was last updated on June 6, 2014.
Estimated new cases and deaths from acute myeloid leukemia (AML) in the United States in 2014:
Advances in the treatment of AML (also called
acute myelogenous leukemia, acute nonlymphocytic leukemia [ANLL]) have resulted in substantially improved
complete remission (CR) rates. Treatment should be sufficiently aggressive to
achieve CR because partial remission offers no substantial
survival benefit. Approximately 60% to 70% of adults with AML can be expected
to attain CR status following appropriate induction therapy.
More than 25% of adults with AML (about 45% of those who attain CR) can be expected to survive 3 or more years and may be cured.
Remission rates in adult AML are inversely related to age, with an expected
remission rate of more than 65% for those younger than 60 years.
Data suggest that once attained, duration of remission may be shorter in older
patients. Increased morbidity and mortality during induction appear to be
directly related to age. Other adverse prognostic factors include central
nervous system involvement with leukemia, systemic infection at diagnosis,
elevated white blood cell count (>100,000/mm3),
treatment-induced AML, and history of myelodysplastic syndromes or another antecedent hematological disorder. Patients with leukemias that
express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene
product) have an inferior outcome.
AML associated with an internal tandem duplication of the FLT3 gene (FLT3/ITD mutation) has an inferior outcome that is attributed to a higher relapse rate.
Cytogenetic analysis provides some of the strongest prognostic information
available, predicting outcome of both remission induction and postremission
therapy, as seen in a trial from the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group (ECOG) (E-3489). Cytogenetic abnormalities that indicate a good prognosis include
t(8; 21), inv(16) or t(16;16), and t(15;17). Normal cytogenetics portend average-risk AML.
Patients with AML that is characterized by deletions of the long arms or
monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome
3, t(6; 9), t(9; 22); or by abnormalities of chromosome 11q23 have particularly
poor prognoses with chemotherapy. These cytogenetic subgroups, as seen in the trial from the Medical Research Council (MRC-LEUK-AML11), predict clinical
outcome in older patients with AML as well as in younger patients. The
fusion genes formed in t(8; 21) and inv(16) can be detected by
reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), which will indicate
the presence of these genetic alterations in some patients in whom standard
cytogenetics was technically inadequate. RT–PCR does not appear to identify
significant numbers of patients with good-risk fusion genes who have normal
The classification of AML has been revised by a group of pathologists and clinicians under the auspices of the World Health Organization (WHO). While elements of the French-American-British classification have been retained (i.e., morphology, immunophenotype, cytogenetics and clinical features), the WHO classification incorporates more recent discoveries regarding the genetics and clinical features of AML in an attempt to define entities that are biologically homogeneous and that have prognostic and therapeutic relevance. Each criterion has prognostic and treatment implications but, for practical purposes, antileukemic
therapy is similar for all subtypes.
A long-term follow-up of 30 patients who had AML that was in remission for at least 10 years has demonstrated a 13% incidence of secondary malignancies. Of 31 younger-than-40-years, long-term, female survivors of AML or acute lymphoblastic leukemia, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, 2 congenital problems occurred.
The differentiation of AML from acute lymphocytic leukemia has important
therapeutic implications. Histochemical stains and cell
surface antigen determinations aid in discrimination.
American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
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Geller RB, Zahurak M, Hurwitz CA, et al.: Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: the significance of the stem-cell glycoprotein CD34 (My10) Br J Haematol 76 (3): 340-7, 1990.
Campos L, Guyotat D, Archimbaud E, et al.: Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79 (2): 473-6, 1992.
Kottaridis PD, Gale RE, Frew ME, et al.: The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials. Blood 98 (6): 1752-9, 2001.
Yanada M, Matsuo K, Suzuki T, et al.: Prognostic significance of FLT3 internal tandem duplication and tyrosine kinase domain mutations for acute myeloid leukemia: a meta-analysis. Leukemia 19 (8): 1345-9, 2005.
Slovak ML, Kopecky KJ, Cassileth PA, et al.: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood 96 (13): 4075-83, 2000.
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Mrózek K, Prior TW, Edwards C, et al.: Comparison of cytogenetic and molecular genetic detection of t(8;21) and inv(16) in a prospective series of adults with de novo acute myeloid leukemia: a Cancer and Leukemia Group B Study. J Clin Oncol 19 (9): 2482-92, 2001.
Brunning RD, Matutes E, Harris NL, et al.: Acute myeloid leukaemia: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 77-80.
Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol 33 (4): 451-8, 1976.
Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8 (5): 813-9, 1990.
Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
The World Health Organization (WHO) classification of acute myeloid leukemia (AML) incorporates and interrelates morphology, cytogenetics, molecular genetics, and immunologic markers in an attempt to construct a classification that is universally applicable and prognostically valid. In the older French-American-British (FAB) criteria, the classification of AML is solely based upon morphology as determined by the degree of differentiation along different cell lines and the extent of cell maturation.
Under the WHO classification, the category “acute myeloid leukemia not otherwise categorized” is morphology-based and reflects the FAB classification with a few significant modifications. The most significant difference between the WHO and FAB classifications is the WHO recommendation that the requisite blast percentage for the diagnosis of AML be at least 20% blasts in the blood or bone marrow. The FAB scheme required the blast percentage in the blood or bone marrow to be at least 30%. This threshold value for blast percentage eliminated the category “refractory anemia with excess blasts in transformation” (RAEB-t) found in the FAB classification of myelodysplastic syndromes (MDS), where RAEB-t is defined by a marrow blast percentage between 20% and 29%. In the WHO classification, RAEB-t is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as “AML with multilineage dysplasia following a myelodysplastic syndrome.”
Although this lowering of the blast threshold has been met with some criticism, several studies indicate that survival patterns for cases with 20% to 29% blasts are similar to survival patterns for cases with 30% or more blasts in the bone marrow. The diagnosis of AML in itself does not represent a therapeutic mandate. The decision to treat should be based on other factors including patient age, previous history of MDS, clinical findings, disease progression, in addition to the blast percentage, and most importantly, patient preference.
Several groups have begun to investigate the use of gene expression profiling (GEP) using microarrays to augment current diagnostic and prognostic studies for AML. Distinct subsets can be identified using GEP that correspond to known cytogenetic and molecular abnormalities. The positive predictive value appears to be sufficiently powerful to be clinically useful only for patients with the t(8;21) and inv(16) (now referred to as core-binding factor [CBF] leukemias) and acute promyelocytic leukemia (APL) with the t(15;17). GEP identified several cases of CBF leukemias that were not diagnosed using conventional cytogenetics.
In the following outline and discussion, the older FAB classifications are noted where appropriate.
This category is characterized by characteristic genetic abnormalities and frequently high rates of remission and favorable prognoses with the notable exception of those with 11q23 abnormalities. The reciprocal translocations t(8; 21), inv(16) or t(16;16), t(15; 17), and translocations involving the 11q23 breakpoint are the most commonly identified genetic abnormalities. These structural chromosome rearrangements result in the formation of fusion genes that encode chimeric proteins that may contribute to the initiation or progression of leukemogenesis. Many of these translocations are detected by reverse transcriptase–polymerase chain reaction (RT–PCR) or fluorescence in situ hybridization (FISH), which has a higher sensitivity than cytogenetics. Other recurring cytogenetic abnormalities are less common and described below in AML not otherwise categorized.
Acute myeloid leukemia with t(8; 21)(q22; q22); (AML/ETO)
AML with the translocation t(8; 21)(q22; q22) (occurring most commonly in FAB classification M2) is one of the most common genetic aberrations in AML and accounts for 5% to 12% of cases of AML and 33% of karyotypically abnormal cases of acute myeloblastic leukemia with maturation. Myeloid sarcomas (chloromas) may be present and may be associated with a bone marrow blast percentage of less than 20%.
Common morphologic features include the following:
AML with maturation (FAB classification M2) is the most common morphologic type correlating with t(8; 21). Rarely, AML with this translocation presents with a bone marrow blast percentage less than 20%.
The translocation t(8; 21)(q22; q22) involves the AML1 gene, also known as RUNX1, which encodes CBF-alpha, and the ETO (eight-twenty-one) gene. The AML1/ETO fusion transcript is consistently detected in patients with t(8; 21) AML. This type of AML is usually associated with a good response to chemotherapy and a high complete remission (CR) rate with long-term survival when treated with high-dose cytarabine in the postremission phase as in the Cancer and Leukemia Group B (CLB-9022 and CLB-8525) trials. Additional chromosome abnormalities are common, for example, loss of a sex chromosome and del(9)(q22). Expression of the neural-cell adhesion molecule (CD56) appears to be an adverse prognostic indicator.
Acute myeloid leukemia with inv(16)(p13; q22) or t(16; 16)(p13; q22); (CBFβ/MYH11)
AML with inv(16)(p13; q22) or t(16; 16)(p13; q22) is found in approximately 10% to 12% of all cases of AML, predominantly in younger patients. Morphologically, this type of AML is associated with acute myelomonocytic leukemia (FAB classification M4) with abnormal eosinophils (AMML Eo). Myeloid sarcomas may be present at initial diagnosis or at relapse.
Most cases with this genetic abnormality have been identified as AMML Eo, but occasional cases have been reported to lack eosinophilia. As is found in rare cases of AML with t(8; 21), the bone marrow blast percentage in this AML is occasionally less than 20%.
Both inv(16)(p13; q22) and t(16; 16)(p13; q22) result in the fusion of the CBF-beta (CBFβ) gene at 16q22 to the smooth muscle myosin heavy chain (MYH11) gene at 16p13, thereby forming the fusion gene CBFβ/MYH11. The use of FISH and RT–PCR methods may be necessary to document this fusion gene because its presence cannot be reliably documented by traditional cytogenetics banding techniques. Patients with this type of AML may achieve higher CR rates when treated with high-dose cytarabine in the postremission phase.
Acute promyelocytic leukemia [AML with t(15; 17)(q22; q12); (PML/RARA) and variants] (FAB Classification M3)
APL AML with t(15; 17)(q22; q12) is an AML in which promyelocytes predominate. APL exists as two types, hypergranular or typical APL and microgranular (hypogranular) APL. APL comprises 5% to 8% of cases of AML and occurs predominately in adults in midlife. Both typical and microgranular APL are commonly associated with disseminated intravascular coagulation (DIC). In microgranular APL, unlike typical APL, the leukocyte count is very high with a rapid doubling time.
Common morphologic features of typical APL include the following:
Common morphologic features of microgranular APL include the following:
In APL, the RARA) gene on 17q12 fuses with a nuclear regulatory factor on 15q22 (promyelocytic leukemia or PML gene) resulting in a PML/RARA gene fusion transcript. Rare cases of cryptic or masked t(15;17) lack typical cytogenetic findings and involve complex variant translocations or submicroscopic insertion of the RARA gene into PML gene leading to the expression of the PML/RARA fusion transcript. FISH and/or RT–PCR methods may be required to unmask these cryptic genetic rearrangements.
APL has a specific sensitivity to treatment with all-trans retinoic acid (ATRA, tretinoin), which acts as a differentiating agent. High CR rates in APL may be obtained by combining ATRA treatment with chemotherapy. In approximately 1% of the cases of APL, variant chromosomal aberrations may be found in which the RARA gene is fused with other genes. Variant translocations involving the RARA gene include: t(11;17)(q23; q21), t(5;17)(q32; q12), and t(11; 17)(q13; q21).
Acute myeloid leukemia with 11q23 (MLL) abnormalities
AML with 11q23 abnormalities comprises 5% to 6% of cases of AML and is typically associated with monocytic features. This AML is more common in children. Two clinical subgroups of patients have a high frequency of AML with 11q23 abnormalities: AML in infants and therapy-related AML, usually occurring after treatment with DNA topoisomerase inhibitors. Patients may present with DIC and extramedullary monocytic sarcomas and/or tissue infiltration (gingiva, skin).
Common morphologic features of this AML include the following:
11q23 abnormalities are associated frequently with acute myelomonocytic, monoblastic, and monocytic leukemias (FAB classifications M4, M5a and M5b, respectively) and occasionally with AML with and without maturation (FAB classifications M2 and M1, respectively).
The MLL gene on 11q23, a developmental regulator, is involved in translocations with approximately 22 different partner chromosomes. Genes other than MLL may be involved in 11q23 abnormalities. FISH may be required to detect genetic abnormalities involving MLL. In general, risk categories and prognoses for individual 11q23 translocations are difficult to determine because of the lack of studies involving significant numbers of patients; however, patients with t(11; 19)(q23; p13.1) are reported to have poor outcomes.
Activating mutations of FLT3 (FMS-like tyrosine kinase-3), present at diagnosis in 20% to 30% of de novo AML, represent the most frequent molecular abnormality in this disease. The most common type of mutation (23%) is an internal tandem duplication mutation (FLT3/ITD) localized to the juxtamembrane region of the receptor, while point mutations in the kinase domain are less common (7%). Common clinical features of patients with FLT3/ITD AML are:
Patients with FLT3/ITD mutations, and possibly those with FLT3 point mutations, are consistently reported to have an increased relapse rate and reduced overall survival (OS). The CR rate for patients with FLT3-mutant AML is generally reported to be no different than that for patients with AML with nonmutant FLT3, but most studies examining this clinical parameter used results from patients treated with intensive chemotherapy regimens, and some data are available to suggest that the conventional 7+3 regimen leads to a reduced remission rate in this group of patients.[Level of evidence: 3iiiDiv]
One study from the German-Austrian Acute Myeloid Leukemia Study Group examined data on 872 patients with cytogenetically normal AML treated with intensive induction and postremission regimens over an 11-year period.[Level of evidence: 3iiiA] The study group found that patients with a mutant CCAAT/enhancer binding-protein alpha (CEBPA) or a nucleophosmin mutation (NPM1) without fms-related tyrosine kinase 3-internal tandem duplication (FLT3-ITD) had higher complete response rates, disease-free survival (DFS) rates, and OS rates (with a 4-year OS rate of 62% and 60%, respectively) than other cytogenetically normal AML patients (who had a 4-year OS rate of between 25% and 30%). As yet, no clear strategy exists for improving patient outcome in FLT3-mutant AML, or in patients with abnormalities other than CEBPA or the NPM1 without the FLT3-ITD, but small molecule FLT3 inhibitors are in development, and the role of allogeneic transplant is being considered.
Note: In the WHO classification, refractory anemia with excess blasts in transformation (RAEB-t) is no longer considered a distinct clinical entity and is instead included within the broader category “AML with multilineage dysplasia” as one of the following:
AML with multilineage dysplasia is characterized by 20% or more blasts in the blood or bone marrow and dysplasia in two or more myeloid cell lines, generally
including megakaryocytes. To make the diagnosis, dysplasia must be present in 50% or more of the cells of at least two lineages and must be present in a pretreatment bone marrow specimen. AML with multilineage dysplasia may occur de novo or following MDS or a myelodysplastic and myeloproliferative disorder (MDS and MPD). (Refer to the PDQ summaries on Myelodysplastic Syndromes Treatment/ Myelodysplastic/ Myeloproliferative Neoplasms for more information.) The diagnostic terminology “AML with multilineage dysplasia evolving from a myelodysplastic syndrome” should be used when an MDS precedes AML.
This category of AML occurs primarily in older patients. Patients with this type of AML frequently present with severe pancytopenia.
The differential diagnosis of AML with multilineage dysplasia includes acute erythroid-myeloid leukemia and acute myeloblastic leukemia with maturation (FAB classifications M6a and M2). Some cases may overlap two morphologic types.
As evidenced in several Southwest Oncology Group studies, such as SWOG-8600 and NCT00023777, the numerous chromosome abnormalities observed in AML with multilineage dysplasia were similar to those found in MDS and frequently involved gain or loss of major segments of certain chromosomes, predominately chromosomes 5 and/or 7. The probability of achieving a CR has been reported to be affected adversely by a diagnosis of AML with multilineage dysplasia.
This category includes AML and MDS that arise secondary to cytotoxic chemotherapy and/or radiation therapy. The therapy-related (or secondary) MDS are included because of their close clinicopathologic relationships to therapy-related AML. Although these therapy-related disorders are distinguished by the specific mutagenic agents involved, a recent study suggests this distinction may be difficult to make because of the frequent overlapping use of multiple potentially mutagenic agents in treating cancer.
Alkylating agent-related acute myeloid leukemia and myelodysplastic syndromes
The alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes typically occur 5 to 6 years following exposure to the mutagenic agent, with a reported range of approximately 10 to 192 months. The risk for occurrence is related to both the total cumulative dose of the alkylating agent and the age of the patient. Clinically, the disorder commonly presents initially as an MDS with evidence of bone marrow failure. This stage is followed by dysplastic features in multiple cell lineages with a blast percentage that is usually less than 5%. In the MDS phase, approximately 66% of cases satisfy the criteria for refractory cytopenia with multilineage dysplasia (RCMD), with approximately 33% of these cases exhibiting ringed sideroblasts in excess of 15% (RCMD-RS). (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) Another 25% of cases satisfy the criteria for refractory anemia with excess blasts 1 or 2 (RAEB-1; RAEB-2). The MDS phase may evolve to a higher grade MDS or AML. Although a minority of patients may present with acute leukemia, a substantial number of patients succumb to the disorder in the MDS phase.
Cases may correspond morphologically to AML with maturation, acute monocytic leukemia, AMML, erythroleukemia,
or acute megakaryoblastic leukemia (FAB classifications M2, M5b, M4, M6a, and M7, respectively).
Cytogenetic abnormalities have been observed in more than 90% of cases of therapy-related AML or MDS and commonly include chromosomes 5 and/or 7. Complex chromosomal abnormalities (≥3 distinct abnormalities) are the most common finding. Therapy-related AML is usually refractory to antileukemia therapy. Median survival after diagnosis of these disorders is approximately 7 to 8 months.
Topoisomerase II inhibitor-related acute myeloid leukemia
This type of AML occurs in patients treated with topoisomerase II inhibitors. The agents implicated are the epipodophyllotoxins etoposide and teniposide and the anthracyclines doxorubicin and 4-epi-doxorubicin. The mean latency period from the time of institution of the causative therapy to the development of AML is approximately 2 years. Morphologically, there is a significant monocytic component. Most cases are categorized as acute monoblastic or myelomonocytic leukemia. Other morphologies reported include APL, myelodysplastic syndromes, and acute megakaryoblastic leukemia.
As with alkylating agent/radiation-related acute leukemias and myelodysplastic syndromes, the cytogenetic abnormalities are often complex. The predominant cytogenetic finding involves chromosome 11q23 and the MLL gene. Current data are insufficient to predict survival times.
Cases of AML that do not fulfill the criteria for AML with recurrent genetic abnormalities, AML with multilineage dysplasia, or AML and MDS, therapy-related, fall within this category. Classification within this category is based on leukemic cell features of morphology, cytochemistry, and maturation.
Acute myeloblastic leukemia, minimally differentiated (FAB Classification M0)
This AML shows no evidence of myeloid differentiation by morphology and light microscopy cytochemistry. The myeloid nature of the blasts is demonstrated by immunophenotyping and/or ultrastructural studies. Immunophenotyping studies must be performed to distinguish this acute leukemia from acute lymphoblastic leukemia (ALL). AML, minimally differentiated, comprise approximately 5% of cases of AML. Patients with this AML typically present with evidence of marrow failure, thrombocytopenia, and neutropenia.
Morphologic and cytochemical features include the following:
Immunophenotyping reveals blast cells that express one or more panmyeloid antigens (CD13, CD33, and CD117) and are negative for B and T lymphoid-restricted antigens. Most cases express primitive hematopoietic-associated antigens (CD34, CD38, and HLA-DR). The differential diagnosis includes ALL, acute megakaryoblastic leukemia, biphenotypic/mixed lineage acute leukemia, and, rarely, the leukemic phase of large cell lymphoma. Immunophenotyping studies are required to distinguish these disorders.
Although no specific chromosomal abnormalities have been found in AML, minimally differentiated point mutations of the AML1 gene have been observed in approximately 25% of cases. This mutation appears to correlate clinically with a higher white blood cell count and greater marrow blast involvement. Mutation of FLT3, a receptor tyrosine kinase gene, occurs in approximately 25% of cases and has been associated with short survival. The median OS is approximately 10 months.
Acute myeloblastic leukemia without maturation (FAB Classification M1)
AML without maturation is characterized by a high percentage of bone marrow blasts with little evidence of maturation to mature neutrophils and comprises
approximately 10% of cases of
AML. Most patients are adults. Patients usually present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
Common morphologic and cytochemical features include the following:
Immunophenotyping reveals blasts that express at least two myelomonocytic antigens (CD13, CD33, CD117) and/or MPO. CD34 is often positive. The differential diagnosis includes ALL in cases of AML without maturation with no granules and a low
percentage of MPO positive blasts, and AML with maturation in cases of AML with maturation with a high percentage of blasts.
Although no specific chromosomal abnormality has been identified for AML without maturation, mutation of the FLT3 gene has been associated with leukocytosis, a high percentage of bone marrow blast cells, and a worse prognosis.
Acute myeloblastic leukemia with maturation (FAB Classification M2)
AML with maturation is characterized by 20% or more myeloblasts in the blood or bone marrow and 10% or more neutrophils at different stages of maturation. Monocytes constitute less than 20% of bone marrow cells. This AML comprises approximately 30% to 45% of cases of AML. While it occurs in all age groups, 20% of patients are younger than 25 years and 40% of patients are aged 60 years or older. Patients frequently present with anemia, thrombocytopenia, and neutropenia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
Morphologic features include the following:
With immunophenotyping, the blasts typically express one or more myeloid-associated antigens (CD13, CD33, and CD15). The differential diagnosis includes: RAEB in cases with a low blast percentage, AML without maturation when the blast percentage is high, and AMML in cases with increased monocytes.
Approximately 33% of karyotypically abnormal cases of AML with maturation are associated with t(8; 21)(q22;q22). (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) Such cases have a favorable prognosis. Rare cases with t(6; 9)(q23; q34) are reported to have a poor prognosis.
(Refer to the Acute promyelocytic leukemia (FAB Classification M3) section of the Acute Myeloid Leukemia With Characteristic Genetic Abnormalities section of this summary for more information.)
Acute myelomonocytic leukemia (FAB Classification M4)
Acute myelomonocytic leukemia (AMML) is characterized by the proliferation of neutrophil and monocyte precursors. Patients usually present with anemia and thrombocytopenia. (Refer to the PDQ summary on Fatigue for more information on anemia.) This classification of AML comprises approximately 15% to 25% of cases of AML, and some patients have a previous history of chronic myelomonocytic leukemia (CMML). (Refer to the PDQ summary on Myelodysplastic/ Myeloproliferative Neoplasms for more information.) This type of AML occurs more commonly in older individuals.
Morphologic and cytochemical features include the following:
Immunophenotyping generally reveals monocytic differentiation markers (CD14, CD4, CD11b, CD11c, CD64, and CD36) and lysozyme. The differential diagnosis includes AML with maturation and acute monocytic leukemia.
Most cases of AMML exhibit nonspecific cytogenetic abnormalities. Some cases may have a 11q23 genetic abnormality. Cases with increased abnormal eosinophils in the bone marrow associated with a chromosome 16 abnormality have a favorable prognosis. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.)
Acute monoblastic leukemia and acute monocytic leukemia (FAB classifications M5a and M5b)
Acute monoblastic and acute monocytic leukemia are AMLs in which 80% or more of the leukemic cells are of a monocytic lineage. These cells include monoblasts, promonocytes, and monocytes. These two leukemias are distinguished by the relative proportions of monoblasts and promonocytes. In acute monoblastic leukemia, most monocytic cells are monoblasts (usually ≥80%). In acute monocytic leukemia, most of the monocytic cells are promonocytes. Acute monoblastic leukemia comprises 5% to 8% of cases of AML and occurs most commonly in young individuals. Acute monocytic leukemia comprises 3% to 6% of cases and is more common in adults. Common clinical features for both acute leukemias include bleeding disorders, extramedullary masses, cutaneous and gingival infiltration, and central nervous system involvement.
Morphologic and cytochemical features of acute monoblastic leukemia include the following:
Morphologic and cytochemical features of acute monocytic leukemia include the following:
The extramedullary lesions of these leukemias may be predominantly monoblastic or monocytic or an admixture of the two cell types. Immunophenotyping
of these leukemias may reveal expression of the myeloid antigens CD13, CD33, CD117, CD14 ( + ), CD4, CD36, CD 11b, CD11c, CD64, and CD68. The differential diagnosis of acute monoblastic leukemia includes AML without maturation, minimally differentiated AML, and acute megakaryoblastic leukemia. The differential diagnosis of acute monocytic leukemia includes AMML and microgranular APL.
An abnormal karyotype has been observed in approximately 75% of cases of acute monoblastic leukemia while approximately 30% of cases of acute monocytic leukemia are associated with an abnormal karyotype. Almost 30% of cases of acute monoblastic leukemia and 12% of cases of acute monocytic leukemia are associated with 11q23 genetic abnormalities involving the MLL gene. (Refer to the Acute myeloid leukemia with characteristic genetic abnormalities section of the Classification section of this summary for more information.) Mutation of FLT3, a receptor tyrosine kinase gene, has been observed in about 30% of cases of acute monocytic leukemia (approximately 7% in acute monoblastic leukemia). The translocation t(8;16)(p11; p13) (strongly associated with acute monocytic leukemia, hemophagocytosis by leukemic cells, and a poor response to chemotherapy) fuses the MOZ gene (8p11) with the CBP gene (16p13). Median actuarial
DFS for acute
monocytic leukemia has been reported to be approximately 21 months.
Acute erythroid leukemias (FAB classifications M6a and M6b)
The two subtypes of the acute erythroid leukemias, erythroleukemia and pure erythroid leukemia, are characterized by a predominant erythroid population and, in the case of erythroleukemia, the presence of a significant myeloid component. Erythroleukemia (erythroid/myeloid; M6a) is predominantly a disease of adults, comprising approximately 5% to 6% of cases of AML. Pure erythroid leukemia (M6b) is rare and occurs in all age groups. Occasional cases of chronic myeloid leukemia (CML) may evolve to one of the acute erythroid leukemias. Erythroleukemia may present de novo or evolve from an MDS, either RAEB or RCMD-RS or RCMD. (Refer to the PDQ summary on Myelodysplastic Syndromes Treatment for more information.) The clinical features of these acute leukemias include profound anemia and normoblastemia. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and cytochemical features of erythroleukemia include the following:
Morphologic and cytochemical features of pure erythroid leukemia include the following:
Immunophenotyping in erythroleukemia reveals erythroblasts that react with antibodies to glycophorin A and hemoglobin A and myeloblasts that express a variety of myeloid-associated antigens (CD13, CD33, CD117, c-kit, and MPO). Immunophenotyping in acute erythroid leukemia reveals expression of glycophorin A and hemoglobin A in differentiated forms. Markers such as carbonic anhydrase 1, Gero antibody against the Gerbich blood group, or CD36 are usually positive. The differential diagnosis for erythroleukemia includes RAEB and AML with maturation with increased erythroid precursors and AML with multilineage dysplasia (involving ≥50% of myeloid or megakaryocyte-lineage cells). If erythroid precursors are 50% or more and the nonerythroid component is 20% or more, the diagnosis is erythroleukemia, whereas, if the nonerythroid component is less than 20%, the diagnosis is RAEB. The differential diagnosis for pure erythroid leukemia includes megaloblastic anemia secondary to vitamin B12 or folate deficiency, acute megakaryocytic leukemia, and ALL or lymphoma.
No specific chromosome abnormalities are described for these AMLs. Complex karyotypes with multiple structural abnormalities are common. Chromosomes 5 and 7 appear to be affected frequently. One study indicates that abnormalities of chromosomes 5 and/or 7 correlate with significantly shorter survival times.
Acute megakaryoblastic leukemia (FAB Classification M7)
Acute megakaryoblastic leukemia, in which 50% or more of blasts are of the megakaryocyte lineage, occurs in all age groups and comprises approximately 3% to 5% of cases of AML. Clinical features include cytopenias; dysplastic changes in neutrophils and platelets; rare organomegaly, except in children with t(1; 22); lytic bone lesions in children; and association with mediastinal germ cell tumors in young adult males.
Morphologic and cytochemical features include the following:
Immunophenotyping reveals megakaryoblast expression of one or more platelet glycoproteins: CD41 (glycoprotein IIb/IIIa) and/or CD61 (glycoprotein IIIa). Myeloid markers CD13 and CD33 may be positive; CD36 is typically positive. Blasts are negative with the anti-MPO antibody and other markers of myeloid differentiation. In bone marrow biopsies, megakaryocytes and megakaryoblasts may react positively to antibodies for Factor VIII. The differential diagnosis includes minimally differentiated AML, acute panmyelosis with myelofibrosis, ALL, pure erythroid leukemia, and blastic transformation of chronic myeloid leukemia or idiopathic myelofibrosis and metastatic tumors in the bone marrow (particularly in children). (Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information on chronic myeloid leukemia or idiopathic myelofibrosis).
No unique chromosomal abnormalities are associated with acute megakaryoblastic leukemia in adults. In children, particularly infants, a distinct clinical presentation may be associated with t(1:22)(p13; q13). The prognosis for this type of acute leukemia is poor.
Variant: Acute myeloid leukemia/transient myeloproliferative disorder in Down syndrome
Individuals with Down syndrome (trisomy 21) have an increased disposition to acute leukemia, primarily the myeloid type. The primary subtype appears to be acute megakaryoblastic leukemia. In cases in which the leukemia remits spontaneously, the process is referred to as transient myeloproliferative disorder or transient leukemia. Clinical features include presentation in the neonatal period (10% of newborn infants with Down syndrome),
marked leukocytosis, blast percentage in the blood greater than 30% to 50%, and extramedullary involvement.
Immunophenotyping reveals markers that are generally similar to those of other cases of childhood acute megakaryoblastic leukemia.
In addition to trisomy 21, some cases may show other clonal abnormalities, particularly trisomy 8. Spontaneous
remission occurs within 1 to 3 months in transient cases. Recurrence followed by a second spontaneous remission or persistent disease may occur. Treatment outcomes for pediatric patients with Down syndrome and persistent disease may be better than those for pediatric patients with acute leukemia in the absence of trisomy 21.
Acute basophilic leukemia
Acute basophilic leukemia is an AML that exhibits a primary differentiation to basophils. This acute leukemia is relatively rare, comprising less than 1% of all cases of AML. Clinical features include bone marrow failure, circulating blasts, cutaneous involvement, organomegaly, occasional osseous lytic lesions, and symptoms secondary to hyperhistaminemia.
Immunophenotypically, the blasts express the myeloid markers CD13 and CD33 and the early hematopoietic markers CD34 and class-II HLA-DR. The differential diagnosis includes: blast crisis of CML, other AML subtypes with basophilia such as AML with maturation (M2) associated with abnormalities of 12p or t(6;9), acute eosinophilic leukemia, and, rarely, a subtype of ALL with prominent coarse granules.
No consistent chromosome abnormality has been identified for acute basophilic leukemia. Because of its rare incidence, little information regarding survival is available.
Acute panmyelosis with myelofibrosis
Acute panmyelosis with myelofibrosis (also known as acute myelofibrosis, acute myelosclerosis, and acute myelodysplasia with myelofibrosis) is an acute panmyeloid proliferation associated with fibrosis of the bone marrow. This disorder is very rare and occurs in all age groups. The disorder may occur de novo or after treatment with alkylating-agent chemotherapy and/or radiation (Refer to the Acute myeloid leukemias and myelodysplastic syndromes, therapy related section of this summary for more information). Clinical features include constitutional symptoms such as weakness and fatigue. (Refer to the PDQ summary on Fatigue for more information.)
Immunophenotypically, blasts may express one or more myeloid-associated antigens (CD13, CD33, CD117, and MPO). Some cells may express erythroid or megakaryocytic antigens. The major differential diagnosis includes acute megakaryoblastic leukemia, acute leukemias with associated marrow fibrosis, metastatic tumor with a desmoplastic reaction, and chronic idiopathic myelofibrosis. (Refer to the PDQ summary on Chronic Myeloproliferative Neoplasms Treatment for more information.)
No specific chromosomal abnormalities are associated with acute panmyelosis with myelofibrosis. This AML is reported to respond poorly to chemotherapy and to be associated with a short survival.
Myeloid sarcoma (also known as extramedullary myeloid tumor, granulocytic sarcoma, and chloroma) is a tumor mass that consists of myeloblasts or immature myeloid cells, occurring in an extramedullary site; development in 2% to 8% of patients with AML has been reported. Clinical features include occurrence common in subperiosteal bone structures of the skull, paranasal sinuses, sternum, ribs, vertebrae, and pelvis; lymph nodes, skin, mediastinum, small intestine, and the epidural space; and occurrence de novo or concomitant with AML or a myeloproliferative disorder.
Morphologic and cytochemical features include the following:
Immunophenotyping with antibodies to MPO, lysozyme, and chloroacetate are critical to the diagnosis of these lesions. The myeloblasts in granulocytic sarcomas express myeloid-associated antigens (CD13, CD33, CD117, and MPO). The monoblasts in monoblastic sarcomas express acute monoblastic leukemia antigens (CD14, CD116, and CD11c) and usually react with antibodies to lysozyme and CD68. The main differential diagnosis includes non-Hodgkin lymphoma of the lymphoblastic type, Burkitt lymphoma, large-cell lymphoma, and small, round-cell tumors, especially in children (e.g., neuroblastoma, rhabdomyosarcoma, Ewing/primitive neuroectodermal tumors, and medulloblastoma).
No unique chromosomal abnormalities are associated with myeloid sarcoma. AML with maturation and t(8; 21)(q22; q22) and AMML Eo with-in (16)(p13; q22) or t(16;16)(p13; q22) may be observed and monoblastic sarcoma may be associated with translocations involving 11q23. The presence of myeloid sarcoma in patients with the otherwise good-risk t(8; 21) AML may be associated with a lower CR rate and decreased remission duration. Myeloid sarcoma occurring in the setting of MDS or MPD is equivalent to blast transformation. In the case of AML, the prognosis is that of the underlying leukemia. Although the initial presentation of myeloid sarcoma may appear to be isolated, several reports indicate that isolated myeloid sarcoma is a partial manifestation of a systemic disease and should be treated with intensive chemotherapy.
Acute leukemias of ambiguous lineage (also known as acute leukemias of undetermined lineage, mixed
phenotype acute leukemias, mixed
lineage acute leukemias, and hybrid acute leukemias) are types of acute leukemia in which the morphologic, cytochemical, and immunophenotypic features of the blast population do not allow classification in myeloid or lymphoid categories; or the types have morphologic
immunophenotypic features of both myeloid and lymphoid cells or both B and T lineages (i.e., acute bilineal leukemia and acute biphenotypic leukemia). These rare leukemias account for less than 4% of all cases of acute leukemia and occur in all age groups but are more frequent in adults. Clinical features include symptoms and complications caused by cytopenias, i.e., fatigue, infections, and bleeding disorders. (Refer to the PDQ summary on Fatigue for more information.)
Morphologic and immunophenotypic features of these acute leukemias include the following:
The differential diagnosis includes myeloid antigen-positive ALL or lymphoid-positive AML (from which biphenotypic acute leukemia should be distinguished) and minimally differentiated AML (from which undifferentiated acute leukemia must be distinguished).
Cytogenetic abnormalities are observed in a high percentage of bilineal and biphenotypic leukemias. Approximately 33% of cases have the Philadelphia chromosome, and some cases are associated with t(4; 11)(q21; q23) or other 11q23 abnormalities. In general, the prognosis appears to be unfavorable, particularly in adults; the occurrence of the translocation t(4; 11) or the Philadelphia chromosome are especially unfavorable prognostic indicators.
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Panagopoulos I, Isaksson M, Lindvall C, et al.: Genomic characterization of MOZ/CBP and CBP/MOZ chimeras in acute myeloid leukemia suggests the involvement of a damage-repair mechanism in the origin of the t(8;16)(p11;p13). Genes Chromosomes Cancer 36 (1): 90-8, 2003.
Fenaux P, Vanhaesbroucke C, Estienne MH, et al.: Acute monocytic leukaemia in adults: treatment and prognosis in 99 cases. Br J Haematol 75 (1): 41-8, 1990.
Cigudosa JC, Odero MD, Calasanz MJ, et al.: De novo erythroleukemia chromosome features include multiple rearrangements, with special involvement of chromosomes 11 and 19. Genes Chromosomes Cancer 36 (4): 406-12, 2003.
Domingo-Claros A, Larriba I, Rozman M, et al.: Acute erythroid neoplastic proliferations. A biological study based on 62 patients. Haematologica 87 (2): 148-53, 2002.
Olopade OI, Thangavelu M, Larson RA, et al.: Clinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia. Blood 80 (11): 2873-82, 1992.
Bernstein J, Dastugue N, Haas OA, et al.: Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14 (1): 216-8, 2000.
Nichols CR, Roth BJ, Heerema N, et al.: Hematologic neoplasia associated with primary mediastinal germ-cell tumors. N Engl J Med 322 (20): 1425-9, 1990.
Carroll A, Civin C, Schneider N, et al.: The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a Pediatric Oncology Group Study. Blood 78 (3): 748-52, 1991.
Dastugue N, Lafage-Pochitaloff M, Pagès MP, et al.: Cytogenetic profile of childhood and adult megakaryoblastic leukemia (M7): a study of the Groupe Français de Cytogénétique Hématologique (GFCH). Blood 100 (2): 618-26, 2002.
Pagano L, Pulsoni A, Vignetti M, et al.: Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16 (9): 1622-6, 2002.
Athale UH, Razzouk BI, Raimondi SC, et al.: Biology and outcome of childhood acute megakaryoblastic leukemia: a single institution's experience. Blood 97 (12): 3727-32, 2001.
Zipursky A, Brown EJ, Christensen H, et al.: Transient myeloproliferative disorder (transient leukemia) and hematologic manifestations of Down syndrome. Clin Lab Med 19 (1): 157-67, vii, 1999.
Zipursky A, Thorner P, De Harven E, et al.: Myelodysplasia and acute megakaryoblastic leukemia in Down's syndrome. Leuk Res 18 (3): 163-71, 1994.
Kounami S, Aoyagi N, Tsuno H, et al.: Additional chromosome abnormalities in transient abnormal myelopoiesis in Down's syndrome patients. Acta Haematol 98 (2): 109-12, 1997.
Yamauchi K, Yasuda M: Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 94 (6): 1739-46, 2002.
Byrd JC, Weiss RB, Arthur DC, et al.: Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. J Clin Oncol 15 (2): 466-75, 1997.
Hayashi T, Kimura M, Satoh S, et al.: Early detection of AML1/MTG8 fusion mRNA by RT-PCR in the bone marrow cells from a patient with isolated granulocytic sarcoma. Leukemia 12 (9): 1501-3, 1998.
Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Ann Intern Med 123 (5): 351-3, 1995.
Brunning RD, Matutes E, Borowitz M: Acute leukaemias of ambiguous lineage. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 106-7.
Hanson CA, Abaza M, Sheldon S, et al.: Acute biphenotypic leukaemia: immunophenotypic and cytogenetic analysis. Br J Haematol 84 (1): 49-60, 1993.
Legrand O, Perrot JY, Simonin G, et al.: Adult biphenotypic acute leukaemia: an entity with poor prognosis which is related to unfavourable cytogenetics and P-glycoprotein over-expression. Br J Haematol 100 (1): 147-55, 1998.
Matutes E, Morilla R, Farahat N, et al.: Definition of acute biphenotypic leukemia. Haematologica 82 (1): 64-6, 1997 Jan-Feb.
Sulak LE, Clare CN, Morale BA, et al.: Biphenotypic acute leukemia in adults. Am J Clin Pathol 94 (1): 54-8, 1990.
Carbonell F, Swansbury J, Min T, et al.: Cytogenetic findings in acute biphenotypic leukaemia. Leukemia 10 (8): 1283-7, 1996.
Pane F, Frigeri F, Camera A, et al.: Complete phenotypic and genotypic lineage switch in a Philadelphia chromosome-positive acute lymphoblastic leukemia. Leukemia 10 (4): 741-5, 1996.
Killick S, Matutes E, Powles RL, et al.: Outcome of biphenotypic acute leukemia. Haematologica 84 (8): 699-706, 1999.
There is no clear-cut staging system for this disease.
Untreated adult acute myeloid leukemia (AML) is defined as newly diagnosed leukemia with no previous treatment. The patient exhibits the following features: abnormal bone marrow with at least 20% blasts and signs and symptoms of the disease, usually accompanied by an abnormal white blood cell count and differential, an abnormal hematocrit/hemoglobin count, and an abnormal platelet count.
AML in remission is defined as a normal peripheral blood cell count (absolute neutrophil count >1,000/mm3 and platelet count >100,000/mm3)  and normocellular marrow with less than 5% blasts in the marrow and no signs or symptoms of the disease. In addition, no signs or symptoms are evident of central nervous system leukemia or other extramedullary infiltration. Because the vast majority of AML patients meeting these criteria for remission have residual leukemia, modifications to the definition of complete remission have been suggested, including cytogenetic remission, in which a previously abnormal karyotype reverts to normal, and molecular remission, in which interphase fluorescence in situ hybridization (FISH) or multiparameter flow cytometry are used to detect minimal residual disease. Immunophenotyping and interphase FISH have greater prognostic significance than the conventional criteria for remission.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
Cheson BD, Bennett JM, Kopecky KJ, et al.: Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. J Clin Oncol 21 (24): 4642-9, 2003.
Bacher U, Kern W, Schoch C, et al.: Evaluation of complete disease remission in acute myeloid leukemia: a prospective study based on cytomorphology, interphase fluorescence in situ hybridization, and immunophenotyping during follow-up in patients with acute myeloid leukemia. Cancer 106 (4): 839-47, 2006.
Successful treatment of acute myeloid leukemia (AML) requires the control of
bone marrow and systemic disease and specific treatment of central nervous
system (CNS) disease, if present. The cornerstone of this strategy includes
systemically administered combination chemotherapy. Because only 5% of
patients with AML develop CNS disease, prophylactic treatment is not
Treatment is divided into two phases: remission induction (to attain remission) and
postremission (to maintain remission). Maintenance therapy for AML was
previously administered for several years but is not included in most current
treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission
section of this summary for more information.) Other studies have used more intensive
postremission therapy administered for a shorter duration of time after which
treatment is discontinued. Postremission therapy appears to be effective
when given immediately after remission is achieved.
Since myelosuppression is an anticipated consequence of both the leukemia and
its treatment with chemotherapy, patients must be closely monitored during
therapy. Facilities must be available for hematologic support with multiple
blood fractions including platelet transfusions and for the treatment
of related infectious complications. Randomized trials have shown similar
outcomes for patients who received prophylactic platelet transfusions at a
level of 10,000/mm3 rather than 20,000/mm3. The incidence of platelet alloimmunization was similar among
groups randomly assigned to receive pooled platelet concentrates from random
donors; filtered, pooled platelet concentrates from random donors; ultraviolet
B-irradiated, pooled platelet concentrates from random donors; or filtered
platelets obtained by apheresis from single random donors.
Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF)
and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been
studied in an effort to shorten the period of granulocytopenia associated with
leukemia treatment. If used, these agents are administered after completion
of induction therapy. GM-CSF was shown to improve survival in a randomized
trial of AML in patients aged 55 to 70 years (median survival was 10.6 months
vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF
or placebo following demonstration of leukemic clearance of the bone marrow;
however, GM-CSF did not show benefit in a separate similar randomized trial in
patients older than 60 years. In the latter study, clearance of the marrow
was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of
G-CSF given following induction therapy to patients older than 65 years, complete
response was higher in patients who received G-CSF because of a decreased
incidence of primary leukemic resistance. Growth factor administration did not
impact on mortality or on survival. Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.
The administration of GM-CSF or other myeloid growth factors before and during
induction therapy, to augment the effects of cytotoxic therapy through the
recruitment of leukemic blasts into cell cycle (growth factor priming), has
been an area of active clinical research. Evidence from randomized studies of
GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF
priming during conventional induction and postremission therapy showed no
difference in outcomes between patients who received GM-CSF and those who did
not receive growth factor priming.[Level of evidence: 1iiA] In
contrast, a similar randomized placebo-controlled study of GM-CSF priming in
patients with AML aged 55 to 75 years showed improved disease-free survival (DFS)
in the group receiving GM-CSF (median DFS for patients who
achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall
survival (2-year survival was 39% vs. 27%, P = .082) for patients aged 55 to 64
years.[Level of evidence: 1iiDii]
Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia--results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992.
Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992.
Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996.
Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995.
Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995.
Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995.
Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998.
Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997.
Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998.
The two-drug regimen of daunorubicin given in conjunction with cytarabine will
result in a complete response rate of approximately 65%. Some physicians opt
to add a third drug, thioguanine, to this regimen, although little
evidence is available to conclude that this three-drug regimen is better therapy. One study suggested that the addition of etoposide during induction therapy may improve
response duration. The choice of anthracycline and the dose-intensity of anthracycline may influence the survival of patients with acute myeloid leukemia (AML). Idarubicin appeared to be more effective than
daunorubicin, particularly in younger adults, although the doses of idarubicin and daunorubicin may not have
been equivalent. No significant survival difference between daunorubicin and
mitoxantrone has been reported.
In patients aged 60 years and younger, outcomes for those receiving daunorubicin (90 mg/m2/dose, total induction dosing at 270 mg/m2) were superior to those receiving more traditional dosing (45 mg/m2/dose; total dose = 135 mg/m2). Complete remission (CR) rate was 71% versus 57% (P < .001), and median survival was 24 months versus 16 months (P = .003). No randomized comparison data between daunorubicin at 270 mg/m2 and daunorubicin at 180 mg/m2, nor between daunorubicin at 270 mg/m2 and idarubicin, are available. However, two studies examined when idarubicin (36 mg/m2) versus daunorubicin (180 mg/m2 or 240 mg/m2) were administered to elderly patients. While overall survival (OS) was not impacted by the choice of anthracycline, the percentage of long-term disease-free survivors in a mixed-cure model did appear to be impacted (hazard ratio [HR], 0.8; 0.65–0.98). The addition of the CD33-directed immunotoxin gemtuzumab ozogamicin to cytarabine plus anthracycline or clofarabine plus anthracycline in patients aged 51 to 79 years led to a small increase in median survival (25% vs. 20%; HR, 0.87; 95% confidence interval [CI], 0.76–1.00; P = < .05). In contrast, gemtuzumab did not improve the 1-year survival rate of elderly patients receiving low-dose cytarabine, although the CR rate increased from 17% to 30% (odds ratio [OR], 0.48 (0.32–0.73); P = .006).
The role of high-dose cytarabine in induction therapy is controversial;
randomized trials have shown prolongation of DFS  or no
effect  compared with conventionally dosed cytarabine-based induction
chemotherapy. Post hoc analyses of two negative trials suggested potential
benefit for the intensified therapy in subsets of patients at high risk for
treatment failure; however, an analysis of a subset of patients with
complex cytogenetic abnormalities treated in a randomized multicenter trial in
Germany showed improvement in CR rate with minimal improvement
in event-free survival (EFS) (CR, 56% vs. 23%; P = .04; median EFS, 1
month vs. 2 months; P = .04).[Level of evidence: 1iiDii]
AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy
has a lower rate of remission than de novo AML. A retrospective analysis of
patients undergoing allogeneic bone marrow transplantation (BMT) in this setting
showed that the long-term survival for such patients was identical regardless
of whether or not patients had received remission induction therapy
(DFS was approximately 20%). These data suggest that
patients with these subsets of leukemia may be treated primarily with
allogeneic BMT if their overall performance status is
adequate, potentially sparing patients the added toxic effect of induction
chemotherapy.[Level of evidence: 3iiiDii]
Older adults who decline intensive remission induction therapy or are considered unfit for intensive remission induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks. The CR rate using this regimen was 18% compared with 1% for patients treated with hydroxyurea (P = .006). Survival with low-dose cytarabine was better than survival was with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = .009).[Level of evidence: 1iiA]
Supportive care during remission induction treatment should routinely include
red blood cell and platelet transfusions when appropriate. Empiric
broad spectrum antimicrobial therapy is an absolute necessity for febrile
patients who are profoundly neutropenic. Careful instruction in
personal hygiene, dental care, and recognition of early signs of infection are
appropriate in all patients. Elaborate isolation facilities (including
filtered air, sterile food, and gut flora sterilization) are not routinely
indicated but may benefit transplant patients. Rapid marrow ablation
with consequent earlier marrow regeneration decreases morbidity and mortality.
Prophylactic oral antibiotics may be appropriate in patients with expected
prolonged, profound granulocytopenia (<100/mm3 for 2
weeks). Norfloxacin and ciprofloxacin have been shown to decrease the
incidence of gram-negative infection and time to first fever in randomized
trials. The combination of ofloxacin and rifampin has proven superior to
norfloxacin in decreasing the incidence of documented granulocytopenic
infection. Serial surveillance cultures may be helpful in such patients
to detect the presence or acquisition of resistant organisms.
A long-term follow-up of 30 patients who had AML that was in remission for at least 10 years has demonstrated a 13% incidence of secondary malignancies. Of 31 long-term female survivors of AML or acute lymphoblastic leukemia younger than 40 years, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.
Special consideration must be given to induction therapy for acute
promyelocytic leukemia (APL). Oral
administration of tretinoin (all-trans-retinoic acid [ATRA]); 45 mg/mm2/day) can induce remission in 70% to 90% of patients with M3
AML. (ATRA is not effective in patients with AML that resembles M3
morphologically but does not demonstrate the t(15;17) or typical PML-RARA gene rearrangement.) ATRA induces terminal differentiation of the
leukemic cells followed by restoration of nonclonal hematopoiesis.
Administration of ATRA leads to rapid resolution of coagulopathy in most patients, and heparin administration is not required in patients
receiving ATRA. However, randomized trials have not shown a reduction in
morbidity and mortality during ATRA induction when compared with chemotherapy.
Administration of ATRA can lead to hyperleukocytosis and a syndrome of
respiratory distress now known as the differentiation syndrome. Prompt
recognition of the syndrome and aggressive administration of steroids can
prevent severe respiratory distress. The optimal management of
ATRA-induced hyperleukocytosis has not been established; neither has the
optimal postremission management of patients who receive ATRA induction.
However, two large cooperative group trials have demonstrated a statistically
significant relapse-free and OS advantage to patients with M3 AML
who receive ATRA at some point during their antileukemic management.
randomized study has shown that the relapse rate was reduced in patients
treated with concomitant ATRA and chemotherapy compared with ATRA induction
followed by chemotherapy given in remission (relative risk [RR] of relapse at 2
years, 0.41; P = .04).[Level of evidence: 1iiDii] This trial also showed a
DFS benefit to maintenance therapy, which consisted of either
6-mercaptopurine plus methotrexate (RR of relapse, 0.41),
intermittent ATRA (RR of relapse, 0.62), or a combination of all
three drugs. The use of 6-mercaptopurine and methotrexate also produced an
improvement in OS (RR of relapse, 0.36; P = .005). Two
concurrent clinical trials separately conducted in Italy and Spain included
ATRA plus anthracycline induction followed by three cycles of postremission and
maintenance therapy. The two treatment protocols differed only in the addition
of nonanthracycline drugs during postremission therapy cycles in the Italian study;
doses of anthracyclines were identical between the two trials. Essentially
identical relapse-free survival suggests that the nonanthracycline drugs
(i.e., cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to
the outcome of patients with acute promyelocytic leukemia induced with ATRA
plus anthracycline.[Level of evidence: 3iiiDii]
In contrast, a trial randomly assigned low-risk patients (age <60 years, white blood cell count [WBC] < 10,000/mm3) to receive ATRA and daunorubicin as induction therapy, followed by daunorubicin consolidation and ATRA plus mercaptopurine plus methotrexate as maintenance therapy. Patients were randomly assigned to receive cytarabine in the induction and consolidation modules, or not. The trial was stopped at an early interim analysis following randomization of 172 patients. The cytarabine group demonstrated a superior 2-year relapse rate (4.7% vs. 15.9%, P = .011), 2-year EFS (93.3% vs. 77.2%, P = .002), and 2-year OS (97.9% vs. 89.6%, P = .007).[Level of evidence: 3iiiA] The latter study used a different chemotherapy platform than the one used by the Italian and Spanish groups, which reported no benefit to cytarabine.
Studies are beginning to examine the inclusion of arsenic trioxide (ATO) in the management of previously untreated patients. In one trial, 85 newly diagnosed patients were treated with ATRA plus ATO until remission; hydroxyurea or idarubicin and cytarabine were added if the WBC was greater than 10,000/mm3. This was followed by three cycles of consolidation (ara-C plus daunorubicin, plus cytarabine, and ara-C plus homoharringtonine) and maintenance with five cycles of sequential ATRA (1 month), ATO (1 month) and 6-mercaptopurine plus methotrexate (1 month). Eighty patients achieved remission with five induction deaths. Four relapses developed between 8 months and 39 months following remission attainment, all of which were in the central nervous system (CNS). Five-year event-free survival (EFS) was 89%.
In another trial, investigators used an ATO-based regimen, which included gemtuzumab ozogamicin (GO) as the only cytotoxic drug. Patients received ATRA plus ATO induction; patients also received a dose of GO if the WBC was greater than 10,000/mm3 on presentation or rose to over 30,000/mm3 during induction. Patients in remission received alternating months of ATO and ATRA for a total of seven cycles; GO was substituted if either ATO or ATRA were discontinued as a result of toxicity. Eighty-two patients were treated; seven patients died during induction, the remainder achieved remission. Three patients relapsed and four patients died during remission; thus EFS was approximately 76%.
Presence of the unique fusion transcript PML-RARA (measured in bone marrow
by polymerase chain reaction) in patients who achieve CR may
indicate those who are likely to relapse early. In addition, a
retrospective review of randomized trials from the Southwest Oncology Group suggested that the dose-intensity of daunorubicin administered in induction and
postremission chemotherapy may significantly impact on remission rate,
DFS, and OS in patients with M3 AML.
Although most patients currently receive ATRA in their induction therapy, for
patients who do not, careful management of coagulopathy is required.
Coagulopathy is occasionally a problem in patients undergoing induction with
ATRA plus chemotherapy. This coagulopathy can lead to catastrophic
intracranial bleeding but can be well controlled with low-dose heparin
infusion (in the setting of clotting) or with aggressive replacement of platelets and clotting factors.
Treatment options for remission induction therapy:
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Bishop JF, Lowenthal RM, Joshua D, et al.: Etoposide in acute nonlymphocytic leukemia. Australian Leukemia Study Group. Blood 75 (1): 27-32, 1990.
Wiernik PH, Banks PL, Case DC Jr, et al.: Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79 (2): 313-9, 1992.
Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group Study. J Clin Oncol 10 (7): 1103-11, 1992.
Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77 (8): 1666-74, 1991.
Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. A multicentric study from the Italian Co-operative Group GIMEMA. Eur J Cancer 27 (6): 750-5, 1991.
Arlin Z, Case DC Jr, Moore J, et al.: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL). Lederle Cooperative Group. Leukemia 4 (3): 177-83, 1990.
Fernandez HF, Sun Z, Yao X, et al.: Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med 361 (13): 1249-59, 2009.
Gardin C, Chevret S, Pautas C, et al.: Superior long-term outcome with idarubicin compared with high-dose daunorubicin in patients with acute myeloid leukemia age 50 years and older. J Clin Oncol 31 (3): 321-7, 2013.
Burnett AK, Russell NH, Hills RK, et al.: Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol 30 (32): 3924-31, 2012.
Burnett AK, Hills RK, Hunter AE, et al.: The addition of gemtuzumab ozogamicin to low-dose Ara-C improves remission rate but does not significantly prolong survival in older patients with acute myeloid leukaemia: results from the LRF AML14 and NCRI AML16 pick-a-winner comparison. Leukemia 27 (1): 75-81, 2013.
Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87 (5): 1710-7, 1996.
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Weick JK, Kopecky KJ, Appelbaum FR, et al.: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood 88 (8): 2841-51, 1996.
Büchner T, Hiddemann W, Wörmann B, et al.: Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group. Blood 93 (12): 4116-24, 1999.
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Anderson JE, Gooley TA, Schoch G, et al.: Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 89 (7): 2578-85, 1997.
Burnett AK, Milligan D, Prentice AG, et al.: A comparison of low-dose cytarabine and hydroxyurea with or without all-trans retinoic acid for acute myeloid leukemia and high-risk myelodysplastic syndrome in patients not considered fit for intensive treatment. Cancer 109 (6): 1114-24, 2007.
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Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
Karp JE, Merz WG, Hendricksen C, et al.: Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 106 (1): 1-7, 1987.
Prevention of bacterial infection in neutropenic patients with hematologic malignancies. A randomized, multicenter trial comparing norfloxacin with ciprofloxacin. The GIMEMA Infection Program. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. Ann Intern Med 115 (1): 7-12, 1991.
Bow EJ, Mandell LA, Louie TJ, et al.: Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. National Cancer Institute of Canada Clinical Trials Group. Ann Intern Med 125 (3): 183-90, 1996.
Huang ME, Ye YC, Chen SR, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72 (2): 567-72, 1988.
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Although individual patients have been reported to have long disease-free
survival (DFS) or cure with a single cycle of chemotherapy, postremission therapy
is always indicated in therapy that is planned with curative intent. In a
small randomized study conducted by the Eastern Cooperative Oncology Group (ECOG), all
patients who did not receive postremission therapy experienced a relapse after
a short median complete remission (CR) duration. Current approaches to
postremission therapy include short-term, relatively intensive chemotherapy
with cytarabine-based regimens similar to standard induction clinical trials
(postremission chemotherapy), postremission chemotherapy with more
dose-intensive cytarabine-based treatment, high-dose chemotherapy or
chemoradiation therapy with autologous bone marrow rescue, and high-dose
marrow-ablative therapy with allogeneic bone marrow rescue. While older
studies have included longer-term therapy at lower doses (maintenance), no convincing evidence is available with acute myeloid leukemia (AML) that maintenance therapy provides prolonged
DFS beyond shorter-term, more dose-intensive approaches, and
few current treatment clinical trials include maintenance therapy.
Nontransplant postremission therapy using cytarabine-containing regimens has
treatment-related death rates that are usually less than 10% to 20% and have
yielded reported long-term DFS rates from 20% to 50%. A large,
randomized trial that compared three different cytarabine-containing
postremission therapy regimens showed a clear benefit in survival to patients younger
than 60 years who received high-dose cytarabine. Intensification of
cytarabine dose or duration of postremission chemotherapy with conventionally dosed cytarabine did not improve DFS or OS in patients aged 60 years or older, as evidenced in the Medical Research Council (MRC-LEUK-AML11) trial. The duration of postremission therapy has
ranged from one cycle  to four or more cycles. The optimal doses,
schedules, and duration of postremission chemotherapy have not been determined.
Therefore, to address these issues, patients with AML should be included in
clinical trials at institutions that treat large numbers of such patients.
Dose-intensive cytarabine-based chemotherapy can be complicated by severe
neurologic  and/or pulmonary toxic effects  and should be administered
by physicians experienced in these regimens at centers that are equipped to
deal with potential complications. In a retrospective analysis of 256 patients
who received high-dose bolus cytarabine at a single institution, the most
powerful predictor of cytarabine neurotoxicity was renal insufficiency. The
incidence of neurotoxicity was significantly greater in patients treated with
twice daily doses of 3 g/m2/dose when compared with 2
Allogeneic bone marrow transplantation (BMT) results in the lowest incidence of
leukemic relapse, even when compared with BMT from an
identical twin (syngeneic BMT). This has led to the
concept of an immunologic graft-versus-leukemia effect, similar to (and related
to) graft-versus-host disease. The improvement in freedom from relapse using
allogeneic BMT as the primary postremission therapy is
offset, at least in part, by the increased morbidity and mortality caused by
graft-versus-host disease, veno-occlusive disease of the liver, and
interstitial pneumonitis. The DFS rates using allogeneic
transplantation in first complete remission (CR) have ranged from 45% to 60%.
The use of allogeneic BMT as primary postremission
therapy is limited by the need for a human leukocyte antigen (HLA)-matched
sibling donor and the increased mortality from allogeneic BMT of patients who are older than 50 years. The mortality
from allogeneic BMT that uses an HLA-matched sibling
donor ranges from 20% to 40%, depending on the series. The use of matched,
unrelated donors for allogeneic BMT is being evaluated
at many centers but has a very substantial rate of treatment-related mortality,
with DFS rates less than 35%. Retrospective analysis of
data from the International Bone Marrow Transplant Registry suggests that
postremission chemotherapy does not lead to an improvement in DFS or
OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[Level of evidence: 3iiiA]
A common clinical trial design used to evaluate the benefit of allogeneic transplant as consolidation therapy for AML in first remission is the so-called donor-no donor comparison. In this design, newly diagnosed AML patients who achieve a CR have one or more siblings, and are deemed medically eligible for allogeneic transplant, undergo HLA typing. If a sibling donor is identified, the patient is allocated to the transplantation arm. Analysis of outcome is by intention to treat; that is, patients assigned to the donor arm who do not receive a transplant are grouped in the analysis with the patients who did actually receive a transplant. Relapse-free survival (RFS) is the usual endpoint for this type of trial. Overall survival (OS) from the time of diagnosis is less frequently reported in these trials. Results of these trials have been mixed, with some trials showing a clear benefit across all cytogenetic subgroups, and others showing no benefit.
Investigators attempted to address this issue with a meta-analysis using data from 18 separate prospective trials of AML patients using the donor-no donor design, with data from an additional six trials included for sensitivity analysis. The trials included in this meta-analysis enrolled adult patients aged 60 and younger during the years 1982 to 2006. Median follow-up ranged from 42 months to 142 months. Preparative regimens were similar among the different trials. Allogeneic transplant was compared with autologous transplant (6 trials) or with a variety of consolidation chemotherapy regimens, with high-dose cytarabine being the most common.
Treatment-related mortality ranged from 5% to 42% in the donor groups compared with 3% to 27% in the no-donor group. Of 18 trials reporting RFS across all cytogenetic risk groups, the combined hazard ratio (HR) for overall RFS benefit with allogeneic transplant was 0.80, indicating a statistically significant reduction in death or relapse in a first CR. Of the 15 trials reporting OS across all cytogenetic risk groups, the combined HR for OS was 0.90, again indicating a statistically significant reduction in death or relapse in a first CR.
In subgroup analysis according to cytogenetic risk category, there was no RFS or OS benefit of allogeneic transplant for patients with good-risk AML (RFS: HR, 1.07; 95% confidence interval [CI], 0.83–1.38; P = .59; OS: HR, 1.06; 95% CI, 0.64–1.76; P = .81). However, a transplant benefit was seen for patients with intermediate (RFS: HR, 0.83; 95% CI, 0.74–0.93; P < .01; OS: HR, 0.84; 95% CI, 0.71–0.99; P = .03) or poor-risk cytogenetics (RFS: HR, 0.73; 95% CI, 0.59–0.90; P < .01; OS: HR, 0.60; 95% CI, 0.40–0.90; P = .01). The conclusion from this meta-analysis was that allogeneic transplant from a sibling donor in a first CR is justified on the basis of improved RFS and OS for patients with intermediate- or poor-risk, but not good-risk, cytogenetics.[Level of evidence: 2A]
An important caveat to this analysis is that induction and postremission strategies for AML among studies included in the meta-analysis were not uniform; nor were definitions of cytogenetic risk groups uniform. This may have resulted in inferior survival rates among chemotherapy-only treated patients. Most U.S. leukemia physicians agree that transplantation should be offered to AML patients in first CR in the setting of poor-risk cytogenetics and should not be offered to patients in first CR with good-risk cytogenetics.
The use of matched,
unrelated donors for allogeneic BMT is being evaluated
at many centers but has a very substantial rate of treatment-related mortality,
with DFS rates less than 35%. Retrospective analysis of
data from the International Bone Marrow Transplant Registry suggests that
postremission chemotherapy does not lead to an improvement in DFS or
OS for patients in first remission undergoing allogeneic BMT from an HLA-identical sibling.[Level of evidence: 3iiiA]
Autologous BMT yielded DFS rates
between 35% and 50% in patients with AML in first remission. Autologous BMT has also cured a smaller proportion of patients in second
remission. Treatment-related mortality rates of patients who have had
autologous peripheral blood or marrow transplantation range from 10% to 20%.
Ongoing controversies include the optimum timing of autologous stem cell
transplantation, whether it should be preceded by postremission chemotherapy,
and the role of ex vivo treatment of the graft with chemotherapy, such as
4-hydroperoxycyclophosphamide (4-HC)  or mafosphamide, or monoclonal
antibodies, such as anti-CD33. Purged marrows have demonstrated delayed
hematopoietic recovery; however, most studies that use unpurged marrow grafts
have included several cycles of postremission chemotherapy and may have
included patients who were already cured of their leukemia.
In a prospective trial of patients with AML in first remission, City of Hope
investigators treated patients with one course of high-dose cytarabine
postremission therapy, followed by unpurged autologous BMT
following preparative therapy of total-body radiation therapy, etoposide, and
cyclophosphamide. In an intent-to-treat analysis, actuarial DFS was approximately 50%, which is comparable to other reports of
high-dose postremission therapy or purged autologous transplantation.[Level of evidence: 3iiDii]
A randomized trial by ECOG and the Southwest
Oncology Group (SWOG) compared autologous BMT using
4-HC-purged bone marrow with high-dose cytarabine postremission therapy.
No difference in DFS was found between patients treated with
high-dose cytarabine, autologous BMT, or allogeneic
BMT; however, OS was superior for
patients treated with cytarabine compared with those who received BMT.[Level of evidence: 1iiA]
A randomized trial has compared the use of autologous BMT in first CR with postremission chemotherapy, with
the latter group eligible for autologous BMT in second
CR. The two arms of the study had equivalent survival.
Two randomized trials in pediatric AML have shown no advantage of autologous
transplantation following busulfan/cyclophosphamide preparative therapy and
4HC-purged graft when compared with postremission chemotherapy, including
high-dose cytarabine. An additional randomized Groupe Ouest Est d'etude des Leucemies et Autres Maladies du Sang trial (NCT01074086) of autologous BMT versus intensive postremission chemotherapy in adult
AML, using unpurged bone marrow, showed no advantage to receiving
autologous BMT in first remission. Certain subsets of AML may specifically benefit from autologous BMT in first remission. In a retrospective analysis of 999
patients with de novo AML treated with allogeneic or autologous BMT in first remission in whom cytogenetic analysis at diagnosis
was available, patients with poor-risk cytogenetics (abnormalities of
chromosomes 5, 7, 11q, or hypodiploidy) had less favorable outcomes following
allogeneic BMT than patients with normal karyotypes or
other cytogenetic abnormalities. Leukemia-free survival for the patients in
the poor-risk groups was approximately 20%.[Level of evidence: 3iiiDii]
An analysis of the SWOG/ECOG (E-3489) randomized trial of postremission therapy
according to cytogenetic subgroups suggested that in patients with unfavorable
cytogenetics, allogeneic BMT was associated with an
improved relative risk of death, whereas in the favorable cytogenetics group,
autologous transplantation was superior. These data were based on analysis of
small subsets of patients and were not statistically significant. While
secondary myelodysplastic syndromes have been reported following autologous
BMT, the development of new clonal cytogenetic
abnormalities following autologous BMT does not
necessarily portend the development of secondary myelodysplastic syndromes or
AML.[Level of evidence: 3iiiDiv] Whenever possible, patients should be
entered on clinical trials of postremission management.
Because BMT can cure about 30% of patients who
experience relapse following chemotherapy, some investigators suggested that
allogeneic BMT can be reserved for early first relapse
or second CR without compromising the number of patients who
are ultimately cured; however, clinical and cytogenetic information can
define certain subsets of patients with predictable better or worse prognoses
using postremission chemotherapy. Good-risk factors include t(8; 21),
inv(16) associated with M4 AML with eosinophilia, and t(15; 17) associated with
M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6; 9),
t(9; 22), and a history of myelodysplasia or antecedent hematologic disorder.
Patients in the good-risk group have a reasonable chance of cure with intensive
postremission therapy, and it may be reasonable to defer transplantation in that group
until early first relapse. The poor-risk group is unlikely to be cured with
postremission chemotherapy, and allogeneic BMT in first CR is a reasonable option for patients with an HLA-identical
sibling donor. However, even with allogeneic stem cell transplantation, the
outcome for patients with high-risk AML is poor (5-year DFS
of 8% to 30% for patients with treatment-related leukemia or
myelodysplasia). The efficacy of autologous stem cell transplantation in
the poor-risk group has not been reported to date but is the subject of active
clinical trials. Patients with normal cytogenetics are in an intermediate-risk
group, and postremission management should be individualized or, ideally,
managed according to a clinical trial.
The rapid engraftment kinetics of peripheral blood progenitor cells
demonstrated in trials of high-dose therapy for epithelial neoplasms has led to
interest in the alternative use of autologous and allogeneic peripheral blood
progenitor cells as rescue for myeloablative therapy for the treatment of AML.
One pilot trial of the use of autologous transplantation with unpurged
peripheral blood progenitor cells in first remission had a 3-year DFS rate of 35%; detailed prognostic factors for these patients were not
provided. This result appears inferior to the best results of chemotherapy
or autologous BMT and suggests that the use of
peripheral blood progenitor cells be limited to clinical trials.
Allogeneic stem cell transplantation can be performed using stem cells obtained from a bone marrow harvest or a peripheral blood progenitor cell harvest. In a randomized trial of 175 patients undergoing allogeneic stem cell transplantation, with either bone marrow or peripheral blood stem cells, for a variety of hematologic malignancies using methotrexate and cyclosporine to prevent graft-versus-host disease, the use of peripheral blood progenitor cells led to earlier engraftment (median neutrophil engraftment, 16 vs. 21 days; median platelet engraftment, 13 vs. 19 days). The use of peripheral blood progenitor cells was associated with a trend toward increased graft-versus-host disease but comparable transplant-related death. The relapse rate at 2 years appeared lower in patients receiving peripheral blood progenitor cells (hazard ratio [HR], 0.49; 95% CI, 0.24–1.00); however, OS was not significantly increased (HR for death within 2 years, 0.62; 95% CI, 0.38–1.02).
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with adult acute myeloid leukemia in remission. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Vaughan WP, Karp JE, Burke PJ: Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer 45 (5): 859-65, 1980.
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Goldstone AH, Burnett AK, Wheatley K, et al.: Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. Blood 98 (5): 1302-11, 2001.
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Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplant 2 (3): 243-58, 1987.
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Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65 (5): 1191-6, 1985.
Busca A, Anasetti C, Anderson G, et al.: Unrelated donor or autologous marrow transplantation for treatment of acute leukemia. Blood 83 (10): 3077-84, 1994.
Tallman MS, Rowlings PA, Milone G, et al.: Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission. Blood 96 (4): 1254-8, 2000.
Koreth J, Schlenk R, Kopecky KJ, et al.: Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA 301 (22): 2349-61, 2009.
Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide--initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81 (2): 319-23, 1993.
Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81 (2): 311-8, 1993.
Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. J Clin Oncol 11 (9): 1661-7, 1993.
Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. J Clin Oncol 11 (2): 314-9, 1993.
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Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75 (8): 1606-14, 1990.
Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79 (9): 2229-36, 1992.
Stein AS, O'Donnell MR, Chai A, et al.: In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. J Clin Oncol 14 (8): 2206-16, 1996.
Cassileth PA, Harrington DP, Appelbaum FR, et al.: Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 339 (23): 1649-56, 1998.
Zittoun RA, Mandelli F, Willemze R, et al.: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 332 (4): 217-23, 1995.
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No standard regimen exists for the treatment of patients with relapsed acute myeloid leukemia (AML), particularly in patients with a first remission duration of less than 1 year.
A number of agents have activity in recurrent AML. A combination of
mitoxantrone and cytarabine was successful in 50% to 60% of patients who
experienced relapse after initially obtaining a complete remission (CR). Other
studies using idarubicin and cytarabine or high-dose etoposide and
cyclophosphamide reported similar results. Mitoxantrone, etoposide, and cytarabine (MEC) demonstrated a CR induction rate of 55% in a population including 30 patients with relapsed AML, 28 patients with primary refractory AML, and 16 patients with secondary AML.[Level of evidence: 3iiiDiv] However, in a phase III Eastern Cooperative Oncology Group (ECOG) (E-2995) trial of MEC with or without PSC388, a multidrug resistance modulator, complete response (CR) was only 17% to 25% in a population including relapse at less than 6 months after first complete remission (CR), relapse after allogeneic or autologous bone marrow transplantation (BMT), second or greater relapse, primary induction failures, secondary AML, and high-risk myelodysplastic syndromes.[Level of evidence: 1iiDiv] Thus, treatments with new agents under clinical evaluation remain appropriate in eligible patients with recurrent AML.
The immunotoxin gemtuzumab ozogamicin has been reported to have a 30% response
rate in patients with relapsed AML expressing CD33. This included 16% of
patients who achieved CRs and 13% of patients who achieved a CRp, a new
response criteria defined for this trial. CRp refers to clearance of leukemic
blasts from the marrow, with adequate myeloid and erythroid recovery but with
incomplete platelet recovery (although platelet transfusion independence for at
least 1 week was required). Unclear is whether the inadequate platelet
recovery is the result of megakaryocyte toxic effects of gemtuzumab or subclinical
residual leukemia. The long-term outcomes of patients who achieve CRp
following gemtuzumab are not yet known. Gemtuzumab induces profound bone
marrow aplasia similar to leukemia induction chemotherapy and also has
substantial hepatic toxic effects, including hepatic venoocclusive
disease. The farnesyltransferase inhibitor tipifarnib (R115777) demonstrated a 32%
response rate in a phase I study in patients with relapsed and refractory acute
leukemia (two CRs and six partial responses in 24 patients treated)
and has entered phase II trials. Clofarabine, a novel purine nucleoside analogue, induced CR in 8 out of 19 patients in first relapse as a single agent  and in seven out of 29 patients when administered in combination with intermediate-dose cytarabine.[Level of evidence: 3iiiDiv]
A subset of relapsed patients treated aggressively may have extended
disease-free survival (DFS); however, cures in patients following a relapse are
thought to be more commonly achieved using BMT.[Level of evidence: 3iDii] A
retrospective study from the International Bone Marrow Transplant Registry
compared adults younger than 50 years with AML in second CR who received HLA-matched sibling transplantation versus a variety of
postremission approaches. The chemotherapy approaches were heterogeneous;
some patients received no postremission therapy. The transplantation regimens
were similarly diverse. Leukemia-free survival appeared to be superior for
patients receiving BMTs for two groups: patients older than
30 years whose first remission was less than 1 year; and patients
younger than 30 years whose first remission was longer than 1 year.[Level of evidence: 3iDii]
Allogeneic BMT from an HLA-matched donor in early first relapse or in second
CR provides a DFS rate of approximately
30%.[Level of evidence: 3iiiA] Transplantation in early first relapse potentially avoids the toxic effects of
reinduction chemotherapy. Allogeneic BMT can
salvage some patients whose disease fails to go into remission with intensive
chemotherapy (primary refractory leukemia). Nine of 21 patients with primary refractory AML were alive and disease free at 10 years following allogeneic BMT.[Level of evidence: 3iiiA] Randomized trials testing the efficacy of this approach are not available. Autologous BMT is an option for patients in second CR, offering a DFS that may be comparable to autografting in first CR.
Patients who relapse following an allogeneic BMT may undergo an infusion of lymphocytes from the donor (donor lymphocyte infusion or DLI), similar to the therapy patients with relapsing chronic myelogenous leukemia (CML) undergo. (Refer to the Relapsing Chronic Myelogenous Leukemia section of the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.) There are no published studies of any prospective trials examining the role of DLI for patients with AML who relapsed following allogeneic BMT. A retrospective study of European patients found that, out of 399 patients who relapsed after an allogeneic BMT, 171 patients received DLI as part of their salvage therapy. A multivariate analysis of survival showed a significant advantage for the 171 DLI recipients, who achieved a 2-year overall survival from the time of relapse of 21%, compared to 9% for the 228 patients who did not receive DLI (P < .04; RR, 0.8; 95% confidence interval, 0.64–0.99).[Level of evidence: 3iiiA] The strength of this finding is limited by the retrospective nature of the study, and the possibility that much of the survival advantage could have been the result of selection bias. Furthermore, the remission rate of 34% reported in this study was considerably less than the 67% to 91% reported for CML. Therefore, even if the survival advantage conferred by DLI is real, the fraction of relapsed AML patients who might benefit from this therapy appears to be quite limited.
Arsenic trioxide, an agent with both differentiation-inducing and apoptosis-inducing
properties against acute promyelocytic leukemia (APL) cells, has a high rate of
successful remission induction in patients with relapsed APL. Clinical CRs have been reported in 85% of
patients induced with arsenic trioxide, with a median time to clinical CR of 59 days. Eighty-six percent of evaluable patients tested negative
for the presence of PML-RARA transcript after induction or postremission therapy
with arsenic trioxide. Actuarial 18-month relapse-free survival was 56%.
Induction with arsenic trioxide may be complicated by APL differentiation
syndrome (identical to ATRA syndrome), prolongation of QT interval, and
Arsenic trioxide is now being incorporated into the postremission treatment strategy of de novo APL patients in clinical trials.
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent adult acute myeloid leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
Ferrara F, Palmieri S, Mele G: Prognostic factors and therapeutic options for relapsed or refractory acute myeloid leukemia. Haematologica 89 (8): 998-1008, 2004.
Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69 (3): 744-9, 1987.
Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76 (3): 473-9, 1990.
Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1 (7): 565-7, 1987.
Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. Eur J Cancer Clin Oncol 23 (7): 1041-5, 1987.
Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. J Clin Oncol 7 (1): 45-9, 1989.
Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. J Clin Oncol 9 (9): 1570-4, 1991.
Spadea A, Petti MC, Fazi P, et al.: Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia. Leukemia 7 (4): 549-52, 1993.
Greenberg PL, Lee SJ, Advani R, et al.: Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995). J Clin Oncol 22 (6): 1078-86, 2004.
Estey E, Plunkett W, Gandhi V, et al.: Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leuk Lymphoma 9 (4-5): 343-50, 1993.
Sievers EL, Larson RA, Stadtmauer EA, et al.: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 19 (13): 3244-54, 2001.
Giles FJ, Kantarjian HM, Kornblau SM, et al.: Mylotarg (gemtuzumab ozogamicin) therapy is associated with hepatic venoocclusive disease in patients who have not received stem cell transplantation. Cancer 92 (2): 406-13, 2001.
Karp JE, Lancet JE, Kaufmann SH, et al.: Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase 1 clinical-laboratory correlative trial. Blood 97 (11): 3361-9, 2001.
Kantarjian H, Gandhi V, Cortes J, et al.: Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood 102 (7): 2379-86, 2003.
Faderl S, Gandhi V, O'Brien S, et al.: Results of a phase 1-2 study of clofarabine in combination with cytarabine (ara-C) in relapsed and refractory acute leukemias. Blood 105 (3): 940-7, 2005.
Gale RP, Horowitz MM, Rees JK, et al.: Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10 (1): 13-9, 1996.
Clift RA, Buckner CD, Appelbaum FR, et al.: Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. J Clin Oncol 10 (11): 1723-9, 1992.
Meloni G, De Fabritiis P, Petti MC, et al.: BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission. Blood 75 (12): 2282-5, 1990.
Chopra R, Goldstone AH, McMillan AK, et al.: Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: the British autograft group experience. J Clin Oncol 9 (10): 1840-7, 1991.
Gorin NC, Labopin M, Meloni G, et al.: Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. European Co-operative Group for Bone Marrow Transplantation (EBMT). Leukemia 5 (10): 896-904, 1991.
Schmid C, Labopin M, Nagler A, et al.: Donor lymphocyte infusion in the treatment of first hematological relapse after allogeneic stem-cell transplantation in adults with acute myeloid leukemia: a retrospective risk factors analysis and comparison with other strategies by the EBMT Acute Leukemia Working Party. J Clin Oncol 25 (31): 4938-45, 2007.
Dazzi F, Szydlo RM, Craddock C, et al.: Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95 (1): 67-71, 2000.
Soignet SL, Frankel SR, Douer D, et al.: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 19 (18): 3852-60, 2001.
Shen ZX, Chen GQ, Ni JH, et al.: Use of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia (APL): II. Clinical efficacy and pharmacokinetics in relapsed patients. Blood 89 (9): 3354-60, 1997.
This information was last updated on March 28, 2014.
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
If you are dealing with the death of a loved one, grief can be a lonely and isolating experience. The Bereavement Program provides support to bereaved family members and friends following the death of a patient.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Expressive Arts Therapy program, sponsored by the Leonard P. Zakim Center for Integrative Therapies, provides adult patients, family members, and caregivers with a variety of options to support well-being during cancer treatment. From live music meditation to painting technique workshops, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Friends' Place provides personal consultations to help cancer patients of all ages cope with changes in physical appearance that result from cancer treatment. Our experienced, compassionate team provides fittings for compression garments or breast prostheses, helps with wigs and other head coverings, and offers make-up and skincare advice.
The Friends' Corner Gift Shop, located on the first floor of the Yawkey Center for Cancer Care, offers a wide selection of unique gifts and everyday items for patients, families and staff.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
Every year, thousands of patients with cancer from around the world come to Dana-Farber for their care. We provide a wide array of logistical and other services for individuals who live outside the United States.
Dana-Farber provides interpreting services for patients whose first language is not English. Interpreters may be requested for any activity, including registration, booking appointments, attending treatments and exams, support groups, and meetings with doctors and other members of your health care team.
Our nutritionists are registered dietitians who can assist you in planning an optimal diet during any stage of your cancer journey, cope with any side effects you may experience, and answer your questions about the latest findings on cancer and nutrition.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
Patients websites help friends and family members stay up-to-date on their loved ones' condition and write messages of support and encouragement.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
In this video, Dr. Corey Cutler talks about his work in the Hematologic Oncology Treatment Center at Dana-Farber/Brigham and Women's Cancer Center.