1. Acute Myelogenous Leukemia
Jim Czarnecki, D.O.
The First in a Four-Part Series

2. Introduction

3. Background
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 30% blasts in the blood, bone marrow, or both.

4. Pathophysiology
Consists of a maturational arrest of bone marrow cells in the early stages of development.
The mechanism is currently under investigation and research, however it is known that it involves the activation of abnormal genes through chromosomal translocations and other genetic abnormalities.

5. Pathophysiology
The developmental arrest results in 2 disease processes:
A marked decrease in the production of normal blood cells, resulting in varying degrees of anemia, thrombocytopenia, and neutropenia.
The rapid proliferation of these cells, along with a reduction in their ability to undergo programmed cell death. This results in their accumulation in various organs, most commonly the liver and spleen.

6. Frequency
US: Estimates indicated that 10,100 new cases would be diagnosed in 1999 (latest stat data).
Internationally: AML is more commonly diagnosed in developed countries.

7. Mortality / Morbidity
In 1999, approximately 6,900 people in the US died from AML.
With current chemotherapy regimens, approximately 25-30% 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 patients surviving.

8. Race
AML is more common in whites than in other populations.

9. Sex AML is more common in men than in women.
Some researchers have proposed that the increased prevalence of AML in men may be related to occupational exposures.

10. Age
Prevalence increases with age. The median age of onset is 65 years.
However, this disease affects all age groups.

11. Clinical

12. History
Patients present with symptoms resulting from bone marrow failure, organ infiltration with leukemic cells, or both. The time course is variable.
Some patients can present with acute symptoms over a few days to 1-2 weeks
Others have longer course, with fatigue or other symptoms lasting from weeks to months.

13. History
Symptoms of bone marrow failure are related to anemia, neutropenia, and thrombocytopenia.
The most common symptom is fatigue from the anemia.
Other symptoms from anemia include dyspnea upon exertion, dizziness, and in patient with coronary artery disease, anginal chest pain.
In fact, myocardial infarction may be the first presenting symptom of acute leukemia in the older patient.

14. History
Patients often have decreased neutrophil levels despite an increased total WBC count.
They present with fever, which may occur with or without specific documentation of an infection.
Patients often have a history of upper respiratory infection symptoms that have not improved despite appropriate oral antibiotic treatment.
Patients present with bleeding gums and multiple ecchymoses.

15. History
Potentially life-threatening sites of bleeding include the lungs, gastrointestinal tract, and the central nervous system.
Symptoms may be the results of organ infiltration with leukemic cells.
Most common sites include the spleen, liver, and gums.
Infiltration most commonly occurs in those patients with monocytic subtypes of AML.

16. History
Patients with splenomegaly note fullness in the left upper quadrant and early satiety.
Patients with gum infiltration often present to their dentist first. Gingivitis due to neuropenia can cause swollen gums, and thrombocytopenia can cause the gums to bleed.
Patient’s with elevated WBC counts (> 100,000) can present with symptoms of leukostasis (respiratory and altered mental status). This is a medical emergency.

17. Gum Hypertrophy

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

19. Physical
Signs of anemia, include pallor and cardiac flow murmur, are frequently present.
Fever and other signs of infection can occur, including lung findings of pneumonia
Patients with thrombocytopenia usually demonstrate petechiae, particularly on the lower extremities

20. Physical
Signs relating to organ infiltration with leukemic cells include hepatosplenomegaly and, to a lesser degree, lymphadenopathy.
Patients may have skin rashes due to infiltration of the skin with leukemic cells (leukemia cutis).
Signs relating to leukostasis include respiratory distress and altered mental status.

21. Leukemia Cutis

22. Causes
Although several factors have been implicated in the causation of AML, most patients who present with de novo AML have no identifiable risk factor.

23. Causes Antecedent hematologic disorders (AHD)
The most common is MDS – 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 do not generally develop AML.
Other AHDs that predispose patients to AML include aplastic anemia, myelofibrosis, paroxysmal nocturnal hemoglobinuria, and polycythemia vera.

24. Causes Congenital disorders
Usually, these patients will develop AML during childhood; although rarely, some may present in young adulthood.
Disorders include Bloom syndrome, Down syndrome, congenital neurtropenia, Fanconi anemia and neurofibromatosis.

25. Causes Familial syndromes
Rare cases of familial erythroleukemia (a subtype of AML), have been described.
These families tend to present with a preleukemic picture or acute leukemia in the sixth or seventh decades.
Inheritance appears to be autosomal dominant with variable penetrance.

26. Causes Environmental exposures
Several studies demonstrate a relationship between radiation exposure and leukemia.
Early radiologists (prior to appropriate shielding) were found to have an increased likelihood of developing anemia.
Patients receiving therapeutic irradiation for ankylosing spondylitis were at increased risk.
Exposure to benzene is associated with aplastic anemia andpancytopenia. These patients often develop AML.

27. Causes
Prior exposure to chemotherapeutic agents for another malignancy.

28. Differentials

29. Differentials Acute Lymphoblastic Leukemia
Agnogenic Myeloid Metaplasia With Myelofibrosis
Agranulocytosis
Anemia
Aplastic Anemia
Bone Marrow Failure

30. Differentials Chronic Myelogenous Leukemia Lymphoma, B-Cell
Lymphoma, Lymphoblastic
Myelodysplastic Syndrome

31. Workup

32. Lab Studies
CBC count with differential demonstrates anemia. Patients with AML can have high, normal, or low WBC counts.
Prothrombin time/fibrinogen products
Most common is DIC
Acute promyelocytic leukemia (APL), also known as M3, is the most common subtype of AML associated with DIC.

33. Lab Studies Peripheral blood smear
Review of peripheral blood smear confirms the findings of the CBC count.
Circulating blasts are usually seen.
Schistocytes are occasionally seen if DIC is present.

34. Schistocytes

35. Schistocytes

36. Lab Studies Chemistry profile
Most patients will have an elevated lactic dehydrogenase level, and frequently, an elevated uric acid level.
Liver function tests and BUN/Creatinine level tests are necessary prior to the initiation of therapy.
Hypokalemia, hypocalcemia, hypomgnesemia may develop because of renal losses seen in acute monocytic leukemia (M5) and acute myelomonocytic leukemia (M4).

37. Lab Studies
Appropriate cultures should be obtained in patients with fever or signs of infection, even in the absence of fever.
Cytogenetic studies performed on bone marrow provide important prognostic information and are useful to confirm a diagnosis of APL.

38. Lab Studies Bone marrow aspiration
This enables a blast count to be performed.
Also allows an evaluation of the degree of dysplasia in all cell lines and the number of platelet precursors present
The disease can then be classified into any of 7 subtypes (M1 – M7) based on cytochemical stains.

39. Imaging Studies
Chest radiographics help assess for pneumonia and signs of cardiac disease.
Multiple gated acquisition (MUGA) scan is needed once the diagnosis is confirmed because many of the chemotherapeutic agents used in the treatment of AML are cardiotoxic.

40. Other Tests
Electrocardiography should be performed prior to treatment.

41. Procedures
Bone marrow aspiration and biopsy are the definitive diagnostic tests.
Aspiration slides should be stained for morphology with either Wright or Giemsa stain.
Bone marrow samples should also be sent for cytogenetics testing and flow cytometry.

42. Histologic Findings M0 – Undifferentiated leukemia
M1 – Myeloblastic without differentiation
M2 – Myeloblastic with differentiation
M3 – Promyelocytic
M4 – Meylomonocytic
M4eo – Myelomonocytic with eosinophilia

43. Histologic Findings M5 – Monoblastic leukemia M6 – Erythroleukemia
M5a – Monoblastic without differentiation
M5b – Monocytic with differentiation
M6 – Erythroleukemia
M7 – Megakaryoblastic leukemia

44. RECOGNIZABLE BONE MARROW PRECURSOR CELL
Hematopoiesis
PLURIPOTENT
STEM CELL
MIXED PROGENITOR CELL
COMMITTED
PROGENITOR
CELL
RECOGNIZABLE BONE MARROW PRECURSOR CELL
MATURE BLOOD CELL
BFU-E/CFU-E
pronormoblast
red cell
myeloblast
monoblast
neutrophil
monocyte
CFU-GM
CFU-Eos
eosinophil
myeloid
progenitor
cell
CFU-Baso
basophil
CFU-Meg
megakaryocyte
platelet
pluripotent
stem cell
pre-T
lymphoblast
T-cell
pre-B
lymphoblast
B-cell
lymphoid
progenitor
cell
& plasma cell

45. Myeloid Maturation MATURATION myeloblast promyelocyte myelocyte
metamyelocyte
band
neutrophil
MATURATION

46. Acute Myelogenous Leukemia

47. Acute Myelogenous Leukemia

48. Acute Myelogenous Leukemia

49. AML – Auer Rods

50. Treatment

51. Medical Care
Current standard chemotherapy regimens cure only a minority of patients.
As a result, all patients should be evaluated for entry into well-designed clinical trials.
If a clinical trial is not available, patients can be treated with standard therapy.

52. Induction Therapy Does not treat acute promyelocytic leukemia
Most common approach is “3 and 7”, which is 3 days of a 15- to 30-minute infusion of an anthracycline (idarubicin or daunorubicin) or anthracenedione (mitoxantrone) combined with arabinosylcytosine (araC), 100 mg/m2 as a 24-hour infusion daily for 7 days.

53. Induction Therapy
Idarubicin is given at a dose of 12 mg/m2/d for 3 days, daunorubicin at mg/m2/d for 3 days, or mitoxantrone at 12 mg/m2/d for 3 days.
These regimens require adequate cardiac, hepatic, and renal function.
Using these regimens, approximately 50% of patients achieve remission with one course. Another 10-15% enter remission following a second course of therapy.

54. Consolidation Therapy
In order to define the best post-remission therapy for young patients, several large, randomized studies comparing allogeneic bone marrow transplant (BMT), autologous BMT, and chemotherapy without BMT have been performed.
Unfortunately, the results of the studies are conflicting.

55. Consolidation Therapy
The following recommendations can be followed:
Patients with good-risk AML, and inversion of chromosome 16, have a good prognosis following consolidation with high-dose araC and should be offered such therapy. Transplantation should be reserved for patients who relapse.

56. Consolidation Therapy
Patient’s with high-risk cytogenetics findings are rarely cured with chemotherapy and should be offered transplantation in first remission
However these patients are also at high risk for relapse following transplantation.

57. Consolidation Therapy
The best approach for patients with intermediate-risk cytogenetics findings is controversial.
Some oncologists refer patients for transplantation in first remission, whereas others give consolidation chemotherapy with high-dose araC for 4 courses and reserve transplantation for patient who relapse.

58. Consolidation Therapy
For older patients:
The best post-remission therapy for elderly patients has yet to be determined.
Most patients are ineligible for standard allogeneic BMT.
Some patients may be candidates for autologous BMT; however, the effectiveness of autologous BMT in this patient population is unclear.

59. Consolidation Therapy
The most commonly used regimen is araC at 100 mg/m2 daily for 5 days combined with 2 days of anthracycline, for 2 courses.
Newer approaches under investigation include monoclonal antibodies and allogeneic transplantaion following nonmyeloablative chemotherapy (minitransplants).

60. Relapsed AML
Patients with relapsed AML have an extremely poor prognosis.
Most patients should be referred for investigational therapies.

61. Supportive Care Replacement of blood products
Patients with AML have a deficiency in the production of normal blood cells, therefore need replacement. All blood products should be irradiated to prevent graft-versus-host disease, which is almost invariably fatal.
PRBCs are given to patients with a hemoglobin level of less than 7-8 g/dL, or at a higher level if the patient has cardiovascular or respiratory compromise.

62. Supportive Care
Platelets should be transfused if the level is less than 10,000 to 20,000 cells/uL.
Fresh frozen plasma should be given to patients with a significantly prolonged prothrombin time, and cryoprecipitate should be given if the fibrinogen level is less than 100 g/dL.

63. Supportive Care Antibiotics Should be given to all febrile patients.
At minimum, should include broad-spectrum coverage, such as a third-generation cephalosporin, usually with an aminoglycoside.
For patients receiving antibiotics with persistant fever of no focus, should also receive amphotericin at a dose of 0.5 mg/kg.
Allopurinol at 300 mg should be given 1-3 times a day during induction therapy until clearance of blasts and resolution of hyperuricemia.

64. Follow-up

65. Further Inpatient Care
Patients require readmission for consolidation therapy or for the management of toxic effects of chemotherapy.

66. Further Outpatient Care
Patients should come to the office for monitoring of disease status and chemotherapy effects.

67. Deterrence / Prevention
While receiving chemotherapy, patients should avoid exposure to crowds and people with contagious illnesses, especially children with viral infections.

68. Complications
The most common complication is failure of the leukemia to respond to chemotherapy.
The prognosis for these patients is poor because they usually do not respond to other chemotherapy regimens.

69. Prognosis Relies on several factors:
Increasing age is an adverse factor because older patients more frequently have cormorbid medical conditions that compromise the ability to give full doses of chemotherapy.
Cytogenetic analysis of the bone marrow is one of the most important prognostic factors. Patients with t(8;21), t(15;17) or inversion 16 have the best prognosis, with long-term survival rates of approximately 65%.

70. Patient Education
Patients should be instructed to call immediately if they are febrile or have signs of bleeding.

71. Competency Exam

72. Question One 1) Acute Myelogenous Leukemia (AML) is defined as:
5% blasts in bone marrow
12% blasts in bone marrow
25% blasts in bone marrow
30% blasts in bone marrow
75%+ blasts in bone marrow

73. Question One 1) Acute Myelogenous Leukemia (AML) is defined as:
5% blasts in bone marrow
12% blasts in bone marrow
25% blasts in bone marrow
30% blasts in bone marrow
75%+ blasts in bone marrow

74. Question Two
2) All of the following cytogenetic analysis indicators have the best prognosis, except:
t(8;21)
t(15;17)
Inversion 16
11q23

75. Question Two
2) All of the following cytogenetic analysis indicators have the best prognosis, except:
t(8;21)
t(15;17)
Inversion 16
11q23

76. Question Three
3) Acute promyelocytic leukemia can be treated with induction therapy, as well as combination therapy.
True
False

77. Question Three
3) Acute promyelocytic leukemia can be treated with induction therapy, as well as combination therapy.
True
False

78. Thank you for your attendance.
End of Lecture
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