Acute myeloid

leukemia
Dr Bhuwan Thapa
1st year resident
KUSMS Dhulikhel Hospital
2019/11/11
Introduction
• Leukemia: hematological neoplasm with widespread involvement of
bone marrow and ( usually but not always) pheripheral blood.

• According to clinical presentation:

1. Acute leukemia's: appearance of clinical features early in the course
with fatal outcomes in couple of years if left untreated.

2. Chronic leukemia's: insidious onset of symptoms with realtively longer

expected survival, terminating in blast crisis.
• Lymphoid neoplasm:
 It include a diverse group of tumors of B-cell, T-cell, and NK-cell origin.

 Phenotype of the neoplastic cell may closely resembles that of a particular stage of normal
lymphocyte maturation.

 Lymphoma is used for proliferations that arise as discrete tissue masses.

• The histiocytoses are uncommon proliferative lesions of macrophages and dendritic

cells in connective tissues.

• Plasma cell neoplasms: These most often arise in the bone marrow and only
infrequently involve lymph nodes or the peripheral blood.
• Myeloid neoplasms: arise from early hematopoietic progenitors.
 Acute myeloid leukemias: immature progenitor cells accumulate in the
bone marrow;

 Myelodysplastic syndromes: associated with ineffective hematopoiesis

and resultant peripheral blood cytopenias and

 Chronic myeloproliferative disorders: increased production of one or

more terminally differentiated myeloid elements (e.g., granulocytes)
usually leads to elevated peripheral blood counts.
Acute myeloid leukemia (AML)
• Definition: AML is a neoplasm characterized by infiltration of the blood,
bone marrow, and other tissues by proliferative, clonal, poorly
differentiated( immature myeloid blast) cells of the hematopoietic
system.
• Replacement of the marrow with blasts produces marrow failure and
complications related to anemia, thrombocytopenia, and neutropenia.
• Most common acute leukemia in older patients.

• Occurs at all ages peaking after 60 years of age.

• Incidence: 1.2% of all cancer cases.

Etiology and risk factors
• Most cases are idiopathic.

• Genetic predisposition, radiation, chemical/other occupational

exposures, and drugs may be implicated in the development of AML.

• Typically occur sporadically in adults; inherited predisposition is

rare.

• Anticancer drugs are the leading cause of therapy-associated AML.

• Preceding MDS or myeloproliferative disease.

• Exposure to DNA damaging agent

 Ionizing radiation
 Chemicals(benzene)
 Cytotoxic agents : alkylating agent (cyclophosphamide, chlorambucil,melphalan)
and topoisomerase II inhibitors (etoposide, anthracyclines)

• Genetic factors
 Identical twins have hogher rates pf leukemia
 In patients with
 Downs syndrome, Bloom syndrome, Fanconi anemia, ataxia-telangiectasia and
Klinefelters syndrome
Clinical presentation
• Usually presents with non specific symptoms as a consequences of anemia,
leukocytsis/leukopenia or thrombocytopenia.
• Fatigue is frequent first symptom.
• Others
 anorexia,
 Weight loss
 Fever
 Bleeding/easy bruising
 Bone pain
 Lymphadenopathy
 Non specific cough
 Headache
 Diaphoresis

• Rarely may present with symptoms of myeloid sarcoma.

Physical findings
Bone pain,
splenomegaly, May present with
Fever, infection hepatomegaly features of
• and
. and complications like
hemorrhage- lymphadenopat lukostasis(stroke/me
commonly found ntal status change,
hy may be
at the time of CHF, MI, pulmonary
present. congestion), tumor
diagnosis.
lysis syndrome or
1. Hemorrhagic DIC
complication's-- m/c in APL.
2. APL patients often present
with DIC-associated minor
hemorrhage/sometimes with
significant
bleeding/sometimes with
thrombosis.
• Infiltration of the gingiva, skin, soft tissues, or meninges with
leukemic blasts--characteristic of the monocytic subtypes.

• Retinal hemorrhage may occur in 15% cases.

Diagnosis
• Depends on identification of myeloblast in PBS or bone marrow
preparation.

• PBS may vary from pancytopenia without circulating blast to

marked leukocytosis with blast predominance.
Hematologic findings
High or low leukocyte
Anemia Platelets
count
• Normocytic • 25-40% have <5000 • 75% have <100000 and
normochromic or • 20% have >10000 25% may have <25000
macrocytic • Auer rods may be • Morphological and
• Not severe present which are functional abnormality
• Usually present at myeloperoxidase+ may occur.
diagnosis
• Decreased reticulocyte
count
PBS
• Myeloblast and monoblast are seen.

• Cytoplasm_ primary non specific granules

• Nucleus- fine, lacy chromatin with one or more nucleoli

characteristic of immature cells.
• Blast cells more than 10%.
• Auer rods: cytoplasmic inclusions of aggregated lysosomes if present
are pathognomic of AML
Bone marrow
• Hypercellular

• Blast cells >20%

• Usually completely replaced by blasts cells

Electrolytes
 There may be hyperkalaemia, hyperphosphetemia or
hyperuricemia due to tumor lysis syndrome
Immunophenotyping findings
• Immunophenotype can be studied by multiparameter flow cytometer.

• This can be important in quickly distinguishing AML from ALL.

• Can identify subtypes of AML.

• Myeloid specific CDs are CD13, CD117

 Management and treatment
• Pretreatment evaluation:
 Functional integrity of the major organ system.

 Evaluation of factors that have prognostic significance.

 Leukemic cells should be obtained from all patients and cryopreserved for
future use.

 Evaluation for infection.

 Replacement of blood component if indicated.

 Management of hyperuricemia.
Treatment
• Divided into two phases:
 Induction and

 Post remission management(consolidation).

Initial goal- to induce complete remission (CR)

CR obtained
Further therapy to prolong survival and achieve cure

Both phases of treatment are chosen based on patient’s age, overall fitness, and
cytogenetic/molecular risk.
Initial induction treatment
• M/C inducton regimen (except in APL) : cytarabine + anthracyclines( e.g.
daunorubicin/idarubicin).

• Cytarabine 100-200mg/m2 continuous iv infusion for 7 days along with

daunorubicin (60-90mg?m2) or idarubicin(12mg/m2) iv on day 1, 2 and 3.

• Patients failing remission after one induction : reinduction with same or slightly
modified therapy.

• In older patients (age 60-65years ) outcome is poor.

•

• Older patients and those with adverse-risk genetics: lower intensity therapy
with a hypomethylating agent (decitabine or azacitidine), clofarabine.

• Fit younger patients with primary refractory disease have ~15–20% cure rates
with allogeneic HCT.

•
Post remission therapy
• Postremission therapy is designed to eradicate residual (typically undetectable)
leukemic cells.

• Therapy is selected in individual patient based on age, fitness, and

cytogenetic/molecular risk.

• ELN recommendation: Cytarabine at 1–1.5 g/m2, every 12 h, on days 1–3, as the

optimal postremission chemotherapy approach for favorable and intermediate-risk
younger patients, for two to four cycles.

• Intermediate- and adverse-risk patients should be considered for allogeneic HCT

CR1 when feasible
• In older patients ELN recommends relatively attenuated cytarabine doses (0.5–
1g/m2, every 12 h, on days 1–3) in favorable-risk older patients.

Treatment of relapse
• Length of first CR is predictive of response to salvage chemotherapyhe treatment.

• Patients who eventually achieve a second CR and are eligible for allogeneic HCT
should be transplanted.

• No consensus on optimal treatment for patients who relapse after allogeneic HCT.

• Patients who relapse rapidly after achievement of first CR (<12 months)and those
lacking HLA-compatible donors or who are not candidates for allogeneic HCT
should be considered for innovative approaches on clinical trials.
Hematopoietic stem cell transplantation in AML
• Allogeneic HCT is the best relapse-prevention strategy currently available for
AML.

• Allogeneic HCT is probably best understood as an opportunity for immunotherapy

due to graft vs leukemia reaction.

• Allogeneic HCT in CR1 is a favored strategy.

• Recommended in patient <75 years without favorable risk disease and with ALA
matched donor.

• Recommanded in CR1 for patients with intermediate-risk disease.

Supportive treatment
• Multilumen CVP should be inserted as soon as diagnosis is confirmed.

• Adequate and prompt blood bank support.

• Platelet transfusion to keep platelets >10000 (higher in febrile patients and with
DIC)

• RBC transfusion to keep Hb >7-8gm/dl (high in DIC,CHF,actibe bleeding).

• In neutropenic patients antibacterial (with gram negative and broad spectrum
coverage) and antifungal (i.e., posaconazole) prophylaxis should be given.
Treatment of acute promyelocytic
leukemia
• APL is highly curable AML subtype.

• ATRA/ATO was superior and is the new standard of care for low risk APL patients.

• High risk patients are treated with ATRA plus concurrent idarubucin chemotherapy.

• APL syndrome with ATRA.

• Assessment of residual disease by RT-PCR amplification of the t(15;17) chimeric

gene product PML-RARA following the final cycle of treatment is important.
• Patients in molecular, cytogenetic, or clinical relapse should be salvaged with
ATO with or without ATRA.

• ATO remains the preferred reinduction therapy for patients who relapse.

• Achievement of CR2 should be followed by consolidation with autologous HCT

(for patients who achieve RT-PCR negative status).

• If not achieved negative RT-PCR or who realpse allogenic HCT may be

potentially curative.
Prognostic indicators
• Worse prognostic factors
 Age>60years

 Poor performance status

 Therapy re;ated AML (secondary to prior chemotherapy)

 AML arisig from another marrow disorder (MDS/myeloproliferative disease)

 WBC count >100000/ml (hyperleukocytosis)

 FLT3-ITD mutation
References
1. Harrisons principle of internal medicine 20 th edition
2. Davidsons principle and practice of internal medicine 23 rd edition
3. Internal medicine board review
4. Washington manual of medical therapeutics 35 th edition
Thank you