AML

Question 1

What is basic pathogenesis of AML?

Answer 1

Acute myeloid leukemia (AML) is a group of aggressive blood cell cancers that arise from clonal expansion of malignant hematopoietic precursor cells in the bone marrow. When the total amount of blast cells in the bone marrow increases, the amount of normal cell elements decreases. As a result, there is an accumulation of leukemic blasts or immature forms in the bone marrow, peripheral blood, and occasionally in other tissues, with a variable reduction in the production of normal red blood cells, platelets, and mature granulocytes. The increased production of malignant cells, along with a reduction in these mature elements.

Affects the group of cells that arise from the common myeloid progenitor cells. The common myeloid precursor includes erythrocytes, thrombocytes, granulocytes (neutrophils, eosinophils, and basophils), and monocytes.

Question 2

What is the epidemiology of AML?

Answer 2

AML is the most common acute leukemia in adults and accounts for approximately 80 percent of cases in this age group.

In adults, the median age at diagnosis is approximately 65 years. The male:female ratio is approximately 5:3.

Question 3

What are some risk factors of AML?

Answer 3

→ There is no identifiable cause or risk factors in most cases.

Pre-existing hematopoietic disorder (most common identifiable cause):

• Myelodysplastic syndromes (bone marrow failure)
• Aplastic anemia
• Myeloproliferative disorders: proliferation of malignant hematopoietic stem cells of the myeloid cell lineage.

Environmental factors:

• Alkylating chemotherapy
• Ionizing radiation
• Benzene exposure
• Tobacco

Some immunosuppression medication.

Human T-cell leukemia-lymphoma virus (HTLV-1 / HTLV-2)

Genetic or chromosomal factors:

• Down syndrome, the risk of AML is 10–20 times higher in patients with Down syndrome compared with the general population.
• Fanconi anemia

Question 4

How can you classify AML?

Answer 4

The French-American-British (FAB) classification distinguishes between eight subtypes of AML, according to the histopathological appearance of the cells.

M0: Acute myeloblastic leukemia without maturation
M1: Acute myeloblastic leukemia with minimal granulocyte maturation
M2: Acute myeloblastic leukemia with granulocyte maturation
M3: Acute promyelocytic leukemia (APL)
M4: Acute myelomonocytic leukemia
M5: Acute monocytic leukemia
M6: Acute erythroid leukemia
M7: Acute megakaryoblastic leukemia

Question 5

What are the clinical manifestations of AML?

Answer 5

Anemia, thrombocytopenia, neutropenia. Think about that.

• Fatigue is present in the majority of patients.
• Pallor and weakness (anemia)
• Bone pain is infrequent in adults with AML (but may be present)
• Fever is possible, due to infection (neutropenia).
• Skin can show pallor secondary to anemia, petechiae or ecchymoses secondary to thrombocytopenia or disseminated intravascular coagulation.
• Eyes, careful examination of the ocular fundus reveals hemorrhages and/or whitish plaques in most patients. The conjunctiva may be pale due to anemia.
• CNS involvement. The incidence is unknown. May be asymptomatic or complain of headache, cranial nerve palsies, or visual changes.
• Oropharynx. May show oral candidiasis, or herpetic lesions.
• Organomegaly. Palpable adenopathy is uncommon. Similarly, hepatomegaly and splenomegaly are present in approximately 10 percent of cases.

Question 6

How do you diagnose AML?

Answer 6

The diagnosis of AML requires both of the following:

1. Documentation of bone marrow infiltration – Blast forms must account for at least 20 percent of the total cells of the bone marrow aspirate. Whether or not a blast percentage can be determined in the bone marrow (eg. due to fibrosis), the presence of 20 percent or more blasts in the peripheral blood is also diagnostic of AML.
2. The leukemic cells must be of myeloid origin as demonstrated by either the presence of Auer rods, cytochemical positivity for myeloperoxidase, or presence of sufficient myeloid/monocytic markers recognized by immunophenotyping (see below).

–> The first diagnostic steps include a complete blood count and peripheral blood smear to determine the WBC count and the presence of blasts. Bone marrow biopsy or aspiration with subsequent cytogenetic analysis and immunophenotyping confirm the diagnosis.

1. Initial test: CBC and peripheral blood smear.
   - Leukocytes: The WBC may be elevated, normal, or low. Important to remember is the leukemic hiatus (a gap in the differentiation of WBC in which there is a high number of blast cells and mature leukocytes but no intermediate forms, only in AML)
   - Thrombocytopenia.
   - Anemia. Normocytic, normochromic anemia that can vary in severity.
   - Blood smear: ↑ Myeloblasts. Some types have Auer rods, these are also myeloperoxidase positive (see below).
2. Confirmatory test.
   Bone marrow biopsy or aspiration with subsequent cytogenetic analysis and immunophenotyping confirm the diagnosis. Confirmatory diagnostic tests: > 20% myeloblasts in the bone marrow.

• Histochemistry: A myeloperoxidase reaction determine if the blasts are myeloid. Will be positive.
• Immunophenotyping: by flow cytometry of the peripheral blood or marrow aspirate can identify circulating myeloblasts in the majority of patients by characteristic patterns of surface antigen expression. Looking for CD receptor (eg. CD13).
• Cytogenetics: Looking for translocations (eg. Philadelphia translocation).

Additional laboratory studies:

• Coagulation studies: rule out DIC
• Electrolytes and metabolic markers: ↑ PO43-, ↓ Ca2+, ↑ K+, ↑ LDH, and ↑ uric acid indicate increased cell lysis.

Further tests:
- Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis.

• Chest x-ray: mediastinal mass in the case of thymic infiltration (occurs primarily in T-cell ALL) or mediastinal lymphadenopathy.
• Abdominal ultrasound: organ enlargement (especially the liver and/or spleen).

Question 7

What is treatment of AML? Do not name any chemotherapy agents.

Answer 7

A. Aggressive chemotherapy is the mainstay of treatment. It also includes supportive treatment and preventive CNS treatment in some cases (see below).

1. Induction therapy (goal: massive reduction of tumor cell count).
   - Duration: 4–6 weeks
   - High-dose chemotherapy.
   - Bone marrow and blood analysis must be controlled after the end of aplasia period. REMISSION – blast cells < 5% of all bone marrow cells, which contain a nucleus.
2. Re-induction therapy (goal: massive reduction of tumor cell count). Only indicated in case of relapse or failure of primary induction therapy.
   - Duration: 4–6 weeks
3. Consolidation therapy (goal: destruction of remaining tumor cells). Begin after complete remission is achieved. Always indicated, even if no tumor cells are detected after induction therapy. Duration: several months. Medium doses.
4. Maintenance therapy (goal: maintaining remission).Duration: up to 24 months. Low doses.

B. Preventive (prophylaxis) CNS treatment. Only indicated after diagnostic measures have confirmed CNS involvement.

• Intrathecal chemotherapy.
• CNS radiotherapy: only if the intrathecal chemotherapy is not working.

C. Allogeneic stem cell transplantation.
Indication: poor prognostic factors (e.g., unfavorable cytogenetics) or patients who do not achieve remission through chemotherapy.

D. Supportive treatment:

• Neutropenia+fever=antibiotics
• PCP (Pneumocystis jirovecii) prophylaxis with TMP-SMX in all neutropenic patients.
• Mucositis prophylaxis with local antimycotics.
• Herpes simplex prophylaxis with acyclovir.
• Colony-stimulating factor administration can be considered for febrile neutropenia.
• Moreover, anemia and thrombocytopenia must also be compensated by RBC transfusion and PLT transfusion if indicated.

Question 8

Name some common chemotherapy agents?

Answer 8

Standard regimen includes:
Cytarabine
Anthracyclines (e.g., daunorubicin)
Addition of ATRA (all-trans-retinoic acid) in APL (promyelocytic leukemia)

Question 9

What is prognosis of AML?

Answer 9

5 year survival rate:
∼ 30%, but it varies according to the patient’s age. The survival time has increased more recently due to improvements in treatment.

Question 10

What are some complications of both AML and ALL?

Answer 10

Oncological emergencies:

1. Mediastinal or thymic infiltration (primarily in T-cell ALL) → SVC syndrome, airway compromise. SVC syndrome is superior vena cava syndrome, a condition caused by obstruction of blood flow in the superior vena cava (e.g., by a thrombus or external compression). This impairs venous backflow to the right atrium and results in upper venous congestion. Features include a feeling of fullness in the head, dyspnea, edema of the upper extremities, and distention of the superficial veins of the chest, face, and upper extremities.
2. Febrile neutropenia. Neutropenic fever is an oncologic emergency common in patients receiving chemotherapy Empiric antibiotic therapy should be started within the first hour of onset to minimize mortality risk.

Leukostasis: ↑ blood viscosity caused by an excessive number of leukocytes (usually > 150,000/mm3 in patients with AML and > 400,000/mm3 in patients with ALL). → increased risk of vascular obstruction → cerebral and pulmonary complications, DIC.

Tumor lysis syndrome: tumor cell lysis → release of intracellular components (e.g., K+, PO43-, nucleic acid) into the bloodstream. Can be prevented with for example good hydration and allopurinol.