AML

INTRODUCTION:
  • Clonal expansion of myeloid precursor cells with reduced capacity to differentiate
  • As opposed to ALL/CLL, it is limited to the myeloid cell line differentiated from ALL based on morphology, cytogenetics, cytochemical analysis, cell surface markers
 ETIOLOGY:
  1. Hereditary - Down syndrome, Klinefelter syndrome, Patau syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, Kotsman syndrome.
  2. Radiation
  3. Chemical and other exposure
  4. Benzene, smoking, ethylene oxide, paint, herbicide and pesticides.
  5. Drugs
  6. Aplastic anemia
  7. Polycythemia vera
  8. Alkalating agents, Topoisomerase II inhibitors, Chloramphenicol, phenylbutazone and less commonly chloroquine, methoxypsoralen can result in bone marrow failure that may result in AML.
CLINICAL SYMPTOMS:
  • Due to the excessive proliferation of myeloid precursor cells in bone marrow, certain symptoms/lab findings are expected (e.g. as a result of pancytopenia) 
  1. 1.Functional neutropenia – fever, chills (INFECTION)
  2. 2.Thrombocytopenia – bleeding, bruising
  3. 3.Anemia – weakness, fatigue
  • Other findings:bone pain (sternum, lower extremities) – infrequent but thought to be secondary to expansion of medullary cavity
PHYSICAL FINDINGS:
  • Gingival involvement (especially in the monocytic variants (M4 or M5))
  • Rare hepatosplenomegaly or LAD
  • Pallor, petechiae, ecchymoses
  • Hepatosplenomegaly(M4)
  • Bone tenderness
  • Retinal hemorrhage
  • CNS infiltration (more common in M4 and M5)
  • DIC (Disseminated Intravascular Coagulation)
  • Seen in AML M3 (promyelocytic)
  • Skin, soft tissue infiltration
  • Chloromas (granulocytic sarcomas or myeloblastomas) are localize masses composed of myeloblasts in the absence of marrow or peripheral blood involvement.
 DIAGNOSIS:
  • Previously >30% blasts on BM aspirate (per FAB criteria)
  • MPO positive blasts are quite specific for acute myeloid leukemia (AML)
  • Recently changed to > 20% blasts on BM aspirate (per WHO criteria)
  1. patients with certain cytogenic abnormalities are considered to have AML regardless of blast percentage
  2. t(8;21)(q22;q22), inversion (16)(p13q22)
  3. t(16;16)(p13;q22), and t(15;17)(q22;q12)
  • The diagnosis of AML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow.
  1. Myeloblasts are myeloperoxidase (peroxidase positive)
  2. Auer rods (represent abnormal azurophilic granule) are also present in myeloblasts and their presence is taken to be definitive evidence of myeloid differentiation.
  3.  In some AMLs, blast cells exhibit differentiation of other myeloid stem cell line (other than myeloblast), e.g.,
  • Monoblast –3 Lack auer rods, peroxidase negative, but nonspecific esterase positive.
  • Megakaryocytic differentiation
  • Erythroblast
FAB Classification of AML:
  1. M0 undifferentiated acute myeloblastic leukemia (5%)
  2. M1 AML with minimal maturation (20%)
  3. M2 AML with maturation (30%)
  • t(8;21)
  • M3 Acute promyelocytic leukemia (5%)
  • t(15;17)
  1. M4 Acute myelomonocytic leukemia (20%)
  2. M4 eos Acute myelomonocytic leukemia with eosinophilia (5%)
  • inv (16)
  1. M5 Acute monocytic leukemia (10%)
  • t(9;11)
  1. M6 Acute erythroid leukemia (3%)
  2. M7 Acute megakaryoblastic leukemia (3%)
WHO CLASSIFICATION:
  • AML with certain genetic abnormalities
  1. t(8;21), t(16), inv(16), chromosome 11 changes
  2. t(15;17) as usually seen with AML M3
  • AML with multilineage dysplasia (more than one abnormal myeloid cell type is involved)
  • AML related to previous chemotherapy or radiation
  • AML not otherwise specified
  1. undifferentiated AML (M0)
  2. AML with minimal maturation (M1)
  3. AML with maturation (M2)
  4. Acute promyelocytic leukaemia (AML—M3) includes Hyper granular and micro granular type 
  5. acute myelomonocytic leukemia (M4)
  6. acute monocytic leukemia (M5)
  7. acute erythroid leukemia (M6)
  8. acute megakaryoblastic leukemia (M7)
  9. acute basophilic leukemia
  10. acute panmyelosis with fibrosis
  11. myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
  • Undifferentiated or biphenotypic acute leukemias (leukemias that have both lymphocytic and myeloid features. Sometimes called ALL with myeloid markers, AML with lymphoid markers, or mixed lineage leukemias.)
TREATMENT:
  • Remission induction therapy
  1. Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine → (“3+7 regimen”)
  2. Cytarabine has ample CNS penetration so no need for prophylactic intrathecal chemotx (also, ↓ risk in patients with AML compared to ALL)
  3. 60-80% achieve complete remission
  • Postremission therapy
  1. Consolidation
  2. longer survival than maintence alone
  3. typically high dose cytarabine
  4. Maintenance – continue chemotx monthly for 4-12 months
  5. nonmyelosuppressive doses
  • Increasingly, hematopoietic cell transplantation is used in patients with AML after 1st remission in those with poor/intermediate prognostic factors.Supportive care G-CSF
  1. platelet transfusions
  2. PRBCs (leukodepleted, irradiated)
  3. Prophylactic antibiotics
  4. fluconazole (candidiasis)
  5. acyclovir (HSV, VZV
PROGNOSIS:
Favourable prognostic factors Unfavourable prognostic factor s Miscellaneous prognostic factors
Age < 40 yrs
AML without antecedent MDS/ MPD
Blast cells with Auer rods
TLC < (25 x 109/L)
t (15;17) in AML - M3- PMURARA +ve
t (8;21) in AML-M
,Inv (16) in AML- M4Eo
FAB subtype - AML- M2, M3, M4
del (7q) MONOSOMY 5 OR 7dui (5q)
11q23 -
MLL +ve3q21
Expression of MDR-1 gene (Multidrug resistance gene) 3q26
Complex karyotypes:
Karyotypes include monosomy chromosome 5 or chromosome 7 have 78% of relapse rate
.High WBC count > 100 x 109/LAML with preceeding MDS/ PMD
Extremes of age55 years
FLT-3 mutation -7/7q
Extramedullary disease in AML-m5
Presence of CNS involvement
FAB subtype AML -MO, M6, M7
In recent years,with availability of markers on bone marrow trephine sections,
it has been possible to study antiogenesis,proliferative index, apoptosis and other parameters
Exam Question
  • DIC is seen most commonly seen in M3
  • Bad prognosis in AML is indicated by Monosomy
  • AML with gum infiltration, hepatosplenomegaly M4
  • Aplastic anemia can progress to AML
  • Non specific esterase is present in AML
  • T (15,17) is the chromosomal translocation in AML M3
  • Chloroma is due to AML
  • AML is characterized by Auer rods
  • Acute promyelocytic leukaemia (AML—M3) includes Hyper granular and micro granular type
  • Hereditary - Down syndrome, Klinefelter syndrome, Patau syndrome, Fanconi anemia, Bloom syndrome, Ataxia telangiectasia, Kotsman syndrome.
  • Polycythemia vera may cause AML
Don't Forget to Solve all the previous Year Question asked on AML