Acute Myelogenous Leukemia Phoebe San Diego Laila Rivera.

Acute Myelogenous Leukemia

Phoebe San DiegoLaila Rivera

Acute Myelogenous Leukemia

• A malignant disease of the bone marrow in which hematopoietic precursors are arrested in an early stage of development.

• Most AML subtypes are distinguished from other related blood disorders by the presence of more than 20% blasts in the bone marrow. (WHO criteria)

WHO Classification of AMLAcute myeloid leukemia with recurrent genetic abnormalities    Acute myeloid leukemia with t(8;21)(q22;q22), (AML1/ETO)

    Acute myeloid leukemia with abnormal bone marrow eosinophils and inv(16)(p13q22) or t(16;16)(p13;q22), (CBF/MYH11)

    Acute promyelocytic leukemia with t(15;17)(q22;q12), (PML/RAR) and variants    Acute myeloid leukemia with 11q23 (MLL) abnormalities  Acute myeloid leukemia with multilineage dysplasia    Following MDS or MDS/MPD

    Without antecedent MDS or MDS/MPD, but with dysplasia in at least 50% of cells in 2 or more myeloid lineages

  Acute myeloid leukemia and myelodysplastic syndromes, therapy related    Alkylating agent/radiation-related type

    Topoisomerase II inhibitor-related type (some may be lymphoid)    Others  Acute myeloid leukemia, not otherwise categorized    Classify as:      Acute myeloid leukemia, minimally differentiated      Acute myeloid leukemia without maturation      Acute myeloid leukemia with maturation      Acute myelomonocytic leukemia      Acute monoblastic/acute monocytic leukemia

      Acute erythroid leukemia (erythroid/myeloid and pure erythroleukemia)      Acute megakaryoblastic leukemia      Acute basophilic leukemia      Acute panmyelosis with myelofibrosis      Myeloid sarcoma

FAB ClassificationFAB

subtype Name% of adult AML

patients

M0Undifferentiated acute myeloblastic leukemia 5%

M1Acute myeloblastic leukemia with minimal maturation 15%

M2Acute myeloblastic leukemia with maturation 25%

M3 Acute promyelocytic leukemia 10%

M4 Acute myelomonocytic leukemia 20%

M4 eosAcute myelomonocytic leukemia with eosinophilia 5%

M5 Acute monocytic leukemia 10%

M6 Acute erythroid leukemia 5%

M7 Acute megakaryoblastic leukemia 5%

Pathophysiology

• Pathophysiology consists of a maturational arrest of bone marrow cells in the earliest stages of development.

• Mechanism involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.

Pathophysiology

• 2 Disease Processes: 1.) Production of normal blood cells markedly decreases, which results in varying degrees of anemia, thrombocytopenia, and neutropenia. 2.)Rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death (apoptosis), results in their accumulation in the bone marrow, blood, and, frequently, the spleen and liver.

Mortality/Morbidity

• In 2007, an estimated 8990 deaths from acute myelogenous leukemia (AML) occurred in the United States. Of these, 5020 occurred in men and 3970 occurred in women.

• In adults, treatment results are generally analyzed separately for younger (18-60 y) and older (>60 y) patients with acute myelogenous leukemia (AML).

• With current standard chemotherapy regimens, approximately 30-35% of adults younger than 60 years survive longer than 5 years and are considered cured.

• Results in older patients are more disappointing, with fewer than 10% of surviving over the long term.

Incidence

• More common in men than in women. • Some have proposed that the increased

prevalence of acute myelogenous leukemia (AML) in men may be related to occupational exposures.

• Prevalence of increases with age • The median age of onset is approximately 70

years.

History

• Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia. – The most common symptom of anemia is fatigue– Other symptoms of anemia include dyspnea upon

exertion, dizziness, and, in patients with coronary artery disease, anginal chest pain. In fact, myocardial infarction may be the first presenting symptom of acute leukemia in an older patient.

– Patients often have decreased neutrophil levels despite an increased total white blood cell (WBC) count.

History

– Often present with fever, which may occur with or without specific documentation of an infection. Patients with the lowest absolute neutrophil counts (ANCs) (ie, <500 cells/µL, especially <100 cells/µL) have the highest risk of infection.

– (+) history of upper respiratory infection symptoms that have not improved despite empiric treatment with oral antibiotics.

History

– Patients present with bleeding gums and multiple ecchymoses probably secondary to thrombocytopenia, coagulopathy that results from DIC.

– Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.

History

– The most common sites of infiltration include the spleen, liver, gums, and skin.

– Splenomegaly = note fullness in the left upper quadrant and early satiety.

– Gingivitis due to neutropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.

History

– Patients with markedly elevated WBC counts (>100,000 cells/µL) can present with symptoms of leukostasis (ie, respiratory distress and altered mental status).

– Patients with a high leukemic cell burden may present with bone pain caused by increased pressure in the bone marrow.

Signs of AML

• anemia: pallor, cardiac flow murmur• Fever and other signs of infection can occur,

including lung findings of pneumonia.• Thrombocytopenia: petechiae, particularly on the

lower extremities, areas of dermal bleeding or bruises (ie, ecchymoses) that are large or present in several areas may indicate a coexistent coagulation disorder such as DIC, purpura

Signs of AML

• Signs relating to organ infiltration with leukemic cells: hepatosplenomegaly, lymphadenopathy, skin rashes (leukemia cutis), chloromata are extramedullary deposits of leukemia.

• Signs relating to leukostasis include respiratory distress and altered mental status.

Risk Factor

– MDS is a disease of the bone marrow of unknown etiology that occurs most often in older patients and manifests as progressive cytopenias that occur over months to years.

– Patients with low-risk MDS (eg, refractory anemia with normal cytogenetics findings) generally do not develop acute myelogenous leukemia (AML), whereas patients with high-risk MDS (eg, refractory anemia with excess blasts-type 2) frequently do develop AML.

Risk Factor

Familial syndromes – Germ-line mutations in the gene AML1 (RUNX1, CBFA2)

occur in the familial platelet disorder with predisposition for myelogenous leukemia (AML)

– Mutation of CEBPA (the gene encoding CCAAT/enhancer binding protein, alpha; a granulocytic differentiation factor and member of the bZIP family) was described in a family with 3 members affected by myelogenous leukemia (AML).

– Some hereditary cancer syndromes, such as Li-Fraumeni syndrome, can manifest as leukemia

Risk Factor

• Environmental exposures – Several studies demonstrate a relationship

between radiation exposure and leukemia.– Early radiologists (before the use of appropriate

shielding) were found to have an increased likelihood of developing leukemia.

– Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk of leukemia.

– Survivors of the atomic bomb explosions in Japan were at a markedly increased risk for the development of leukemia.

Risk Factor

– Persons who smoke have a small but statistically significant (odds ratio, 1.5) increased risk of developing myelogenous leukemia (AML). In several studies, the risk of AML was slightly increased in people who smoked compared with those who did not smoke.

– Exposure to benzene is associated with aplastic anemia and pancytopenia. These patients often develop AML. Many of these patients demonstrate M6 morphology.

Risk Factor

• Previous exposure to chemotherapeutic agents for another malignancy – Patients with a previous exposure to alkylating agents,

with or without radiation, often have a myelodysplastic phase before the development of myelogenous leukemia (AML)

– Patients with a previous exposure to topoisomerase-II inhibitors do not have a myelodysplastic phase.

– The typical latency period between drug exposure and acute leukemia is approximately 3-5 years for alkylating agents/radiation exposure, but it is only 9-12 months for topoisomerase inhibitors.

Laboratory Studies

• Complete blood cell (CBC) count with differential demonstrates – anemia and thrombocytopenia to varying degrees.

• Peripheral blood smear – Circulating blasts are usually seen.– Schistocytes are occasionally seen if DIC is

present.

Laboratory Studies

• Prothrombin time (PT) / activated partial thromboplastin time (aPTT) / fibrinogen / fibrin degradation products – The most common abnormality is DIC, which results in

an elevated prothrombin time, a decreasing fibrinogen level, and the presence of fibrin split products.

• Chemistry profile – Most patients with acute myelogenous leukemia (AML)

have an elevated lactic dehydrogenase (LDH) level and, frequently, an elevated uric acid level.

– Liver function tests and blood urea nitrogen (BUN)/creatinine level tests are necessary before the initiation of therapy.

Laboratory Studies• Bone marrow aspiration

– presence of more than 30% blasts in the bone marrow

– In the newer World Health Organization (WHO) classification: presence of greater than 20% blasts in the marrow.

– Evaluation of the degree of dysplasia in all cell lines.

• Flow cytometry (immunophenotyping) – can be used to help distinguish acute myelogenous

leukemia (AML) from acute lymphocytic leukemia (ALL) and further classify the subtype of AML.

Imaging Studies

• Fluorescence in situ hybridization (FISH) studies– used to get a faster overview of cytogenetic

abnormalities than traditional cytogenetic studies. FISH does not replace cytogenetics.

• Chest radiographs – help assess for pneumonia and signs of cardiac

disease

Treatment of acute myelogenous leukemia (AML) (excluding acute promyelocytic leukemia)

Induction therapy:• "3 and 7"

– 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin 12 mg/m2/d or daunorubicin 45-60 mg/m2/d ) or anthracenedione (mitoxantrone 12 mg/m2/d ), combined with 100 mg/m2 of arabinosylcytosine (ara-C) as a 24-hour infusion daily for 7 days

– These regimens require adequate cardiac, hepatic, and renal function.

– approximately 50% of patients achieve remission with one course. Another 10-15% of patients enter remission following a second course of therapy.

Other immune therapies

• Lintuzumab– a humanized monoclonal antibody that targets CD33– It induces antibody-dependent cellular cytotoxicity,

complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis.

– Early studies demonstrated activity, although randomized studies of lintuzumab given after chemotherapy did not show a benefit. However, a phase I study of lintuzumab as a single agent in patients with acute myelogenous leukemia (AML) demonstrated a response rate of 28%.

Treatment of relapsed AML

• Initial complete response duration of less than 1 year or with no initial complete response had a 14% complete response rate with initial salvage therapy.

• Patients with an initial complete response duration of less than 1 year (or no initial complete response) who had no response to first-salvage therapy and received a second or subsequent salvage therapy had a response rate of 0%.

Treatment of relapsed AML

• Chances of obtaining a second remission with chemotherapy correlate strongly with the duration of the first remission.

• Patients with an initial complete response duration of longer than 2 years had a 73% complete response rate with initial salvage therapy.

• Patients with an initial complete response duration of 1-2 years had a complete response rate of 47% with initial salvage therapy.

Supportive Care

• Replacement of blood products – Patients with acute myelogenous leukemia (AML)

have a deficiency in the ability to produce normal blood cells and, therefore, need replacement therapy.

– The addition of chemotherapy temporarily worsens this deficiency. All blood products should be irradiated to prevent transfusion-related graft versus host disease that is almost invariably fatal.

Supportive Care

• Packed red blood cells – for hemoglobin level of less than 7-8 g/dL or at a higher

level if the patient has significant cardiovascular or respiratory compromise

• Platelets– For platelet less than 10,000-20,000 cells/µL– Patients with pulmonary or gastrointestinal hemorrhage

should receive platelet transfusions to maintain a value greater than 50,000 cells/µL

– Patients with CNS hemorrhage should be transfused until they achieve a platelet count of 100,000 cells/µL

– Patients with APL should have their platelet count maintained at more than 50,000 cells/µL, at least until evidence of DIC has resolved.

Supportive Care

• Fresh frozen plasma• For patient with significantly prolonged

prothrombin time• Cryoprecipitate

• given if the fibrinogen level is less than 100 g/dL.

Antibiotics

• Intravenous antibiotics should be given to all febrile patients.

• should include broad-spectrum coverage such as that provided by a third-generation cephalosporin with or without vancomycin.

• Patients with persistent fever after 3-5 days of antibacterial antibiotics should receive antifungal antibiotics. – Patients with fever but without a focus of infection

received amphotericin at a dose of 0.5 mg/kg. – Lipid-preparation amphotericins (Abelcet and AmBisome),

newer azoles (voriconazole and posaconazole), and the echinocandins (caspofungin, anidulafungin, and micafungin).

Antibiotics

• Prophylactic antibiotics are usually used in nonfebrile patients undergoing intensive chemotherapy. A commonly used regimen is ciprofloxacin, fluconazole, or itraconazole, and acyclovir or valacyclovir.

Diet and Activity

• Patients with acute myelogenous leukemia (AML) should be on a neutropenic diet (ie, no fresh fruits or vegetables). All foods should be cooked. Meats should be cooked completely, well done.

• Patients should limit their activity to what is tolerable, with no strenuous activities (eg, lifting, exercise).

PROGNOSIS OF AML

FAB subtype

Name % of adult AML patients

Prognosis compared to

average for AML

M0Undifferentiated acute myeloblastic leukemia 5% Worse

M1Acute myeloblastic leukemia with minimal maturation 15% Average

M2Acute myeloblastic leukemia with maturation 25% Better

M3 Acute promyelocytic leukemia 10% Best

M4Acute myelomonocytic leukemia 20% Average

M4 eosAcute myelomonocytic leukemia with eosinophilia 5% Better

M5 Acute monocytic leukemia 10% Average

M6 Acute erythroid leukemia 5% Worse

M7Acute megakaryoblastic leukemia 5% Worse

Prognosis

Favorable abnormalities:• translocation between chromosomes 8 and 21 (seen most often in

patients with M2)• inversion of chromosome 16 (seen most often in patients with M4

eos)• translocation between chromosomes 15 and 17 (seen most often in

patients with M3)

Unfavorable abnormalities:• deletion (loss) of part of chromosome 5 or 7 (no specific AML type)• complex changes involving several chromosomes (no specific AML

type

PrognosisAge• Older patients (over 60) generally do not fare as well as

younger patients. Some of this may be because they are more likely to have unfavorable chromosome abnormalities. It is also harder to treat them with more intense chemotherapy regimens.

White blood cell count• A high white blood cell count (>100,000) at the time of

diagnosis is linked to a worse outlook.Prior blood disorders or cancers• Having a prior blood disorder such as a myelodysplastic

syndrome or having AML that develops after treatment for another cancer tends to lead to a worse prognosis, as these types of AML are often harder to treat

Reference

• Seiter, K., “Acute Myelogenous Leukemia”, Jun 22, 2010. http://emedicine.medscape.com/article/197802-overview

• Fauci, Braunwald, Kasper et.al. “Harrison’s Principles of Internal Medicine”, 17th ed., McGrall-Hill Company, ©2008

• “Detailed Guide: Leukemia - Acute Myeloid (AML)How Is Acute Myeloid Leukemia (AML) Classified?”. American Cancer Society. Last Revised: 08/06/2009. http://www5.cancer.org/docroot/CRI/content/CRI_2_4_3x_How_Is_Acute_Myeloid_Leukemia_AML_Classified.asp

THANK YOU!