This document discusses acute myeloid leukemia (AML), including its causes, pathogenesis, diagnosis, risk stratification, treatment options, and key messages. AML is a neoplastic disease characterized by infiltration of blood, bone marrow, and other tissues by proliferative, clonal myeloid cells. Risk factors include hereditary conditions, radiation/chemical exposure, and certain drugs. Treatment is chosen based on risk assessment and may include intensive or non-intensive chemotherapy, hematopoietic stem cell transplantation, supportive care, or clinical trials. The document emphasizes tailoring treatment to individual risk profiles and age.
1. Dr ANKUR NANDAN VARSHNEY
Senior Resident
Department of Medical Oncology
Safdurjung Hospital
2. Acute Myeloid Leukemia
neoplastic disease characterized by infiltration of the
blood, bone marrow, and other tissues by proliferative,
clonal undifferentiated cells of the hematopoietic
system.
incidence increases with age, median age at diagnosis
is 67 years.
3. Etiology
Hereditary: Down’s Syndrome
Defective DNA repair, e.g., Fanconi anemia,
Bloom Syndrome
Ataxia telangectasia
Radiation
Chemical: Chemical , Plastic , Rubber, Petroleum
Drugs: Alkylating agents (4–6 years after exposure, aberrations in
chromosomes 5 and 7).
Topoisomerase II (1–3 years after exposure, involving
chromosome 11q23).
Chloramphenicol, phenylbutazone, chloroquine and
methoxypsoralen
4. Pathogenesis
AML is a result of distinct but co-operating genetic
mutations resulting in
Proliferative & survival advantage to the myeloid
precursor cells
Impaired differentiation & apoptosis of myeloid
precursor cells
Rubnitz JE et al. Hematol Oncol Clin N Am 24 (2010) 35–63
5. Pathogenesis
Proliferative & survival advantage to the myeloid
precursor cells
FLT3, ALM, oncogenic Ras mutations
BCR/ABL and TEL/PDGFbR gene fusions
Impair differentiation & apoptosis of myeloid
precursor cells
Mutations in CEBPA, CBF, HOX family members,
CBP/P300, and co-activators of TIF1
AML/ETO and PML/RARa fusions
Rubnitz JE et al. Hematol Oncol Clin N Am 24 (2010) 35–63
6. Clinical presentation
Signs & symptoms due to pancytopenia
Pallor, fatigue due to anemia
Fever & infections due to neutropenia
Bleeding due to thrombocytopenia
Infiltration of extramedullary sites
Lymphadenopathy
Hepatosplenomegaly
Granulocytic sarcoma
Leukemia cutis
Testicular involvement
Disseminated Intravascular Coagulation
7. Diagnostic evaluation
Diagnosed by bone marrow examination.
The standard test battery for bone marrow samples
currently includes
cytomorphological and cytochemical studies
flow cytometry
cytogenetic analysis
molecular studies for the detection of mutations that
affect prognosis, including Flt3 and nucleophosmin
mutations
9. WHO classification
Blast cutoff for a diagnosis of AML is 20% in the WHO
classification and 30% in the FAB.
Specific chromosomal rearrangements, i.e.,
1. t(8;21)(q22;q22),
2. inv(16)(p13.1q22),
3. t(16;16)(p13.1;q22)
4. t(15;17)(q22;q12),
define AML even with <20% blasts.
10. AML with recurrent Cytogenetic abnormality.
AML with myelodysplasia related changes
AML, therapy related
Myeloid Sarcoma
Myeloid Proliferation associated with down Syndrome
Blastic plasmacytoid dendritic cell neoplasm
AML, not otherwise specified
15. High dose daunorubicin ( 90 mg/m2)
1. Favorable and intermediate risk cytogenetics
2. Younger < 50 years
No significance difference with Idarubicin
Some studies quote lower remission failure rate but no
over all survival
16. Addition of Cladribine (DAC) was beneficial in
1. High risk Karotype
2. WBC count > 50,000
3. < 50 years.
HIDAC was beneficial in
1. High-risk cytogenetic abnormalities
2. FLT 3- ITD
3. Secondary AML
4. Age < 45 years
22. Patients > 60 years age
Poor Outcome
Disease Related
1. Favorable CBF translocations decreases
2. Unfavorable karyotypes and mutation decreases
3. Secondary AML increases
4. Increased multidrug resistance protein
Patient related
1. Significant co-morbidities
2. Increased treatment related mortality
23.
24. HOVON study
Escalated dose daunorubicin increased OS in patients < 65
years of age and CBF translocation
ALFA study
Standard idarubicin has better cure rates than High dose
daunorubicin in patients < 65 years. (p <0.49)
No significant in patients > 65 years
Gemtuzumab ozogamicin produces conflicting results. Not
approved.
25. Clofarabine can be used in patients unfit for intensive
therapy but not FDA approved ( approved in relapsed
ALL) as monotherapy. Phase 3 trial undergoing
Decitabine and Azacytidine ( approved for MDS) are
not approved By USFDA but approved in european
countries. Increased incidences of cytopenias
Low dose cytarabine ( 20mg sc BD X 10 days)
29. Allogeneic HSCT was associated with a lower risk of
relapse and superior OS relative to autologous HSCT.
Myeloablative HSCT did not provide survival benefit
in first CR due to increased incidence of non-relapse
mortality.
Reduced Intensity conditioning is preferred in patients
> 60 years of age and an available donor.
1. As post remission therapy after CR
2. Treatment of induction failure in patients with low
volume disease.
30. Surveillance
Complete Blood Counts and peripheral film X 1-3
monthly X 2 years
3-6 monthly X 5 years
Bone marrow is done
1. Persistent Cytopenias
2. Abnormal peripheral Smears
31. MRD
Not recommended
Flow cytometry has sensitivity of 1 in 10000 while
RTPCR has sensitivity of 1 in 1000.
Lack of standardization
Widely used in APL
38. Key Messages
Treatment is chosen on the basis of risk factors that
are easy to assess, which are derived from
Standard diagnostic evaluation
Specific prognostic scores
Geriatric assessment.
Selected older patients are suitable candidates for
intensive chemotherapy of the same type offered to
younger patients, possibly including HSCT with
reduced-dose conditioning treatment
39. Patients who are not candidates for intensive
chemotherapy can be treated non-intensively with
chemotherapeutic drugs such as azaciti dine or low-
dose cytarabine
Patients who are not suitable candidates for intensive
chemotherapy with bone marrow blast ≥30% can be
given
purely supportive care
Participation in a therapeutic trial
Key Messages