AML

M3 REF: Wintrobe’s Clinical Hematology 11′ ed chapter 3 1/4

Acute Promyelocytic Leukemia (AML t15;17) (q22;q12) Acute promyelocytic leukemia (APL) is diagnosed in less than 10% of all AML cases. A variant of APL is known as microgranular M3 (or hypogranular) because the granulation is significantly less than in the traditional M3. Accurate diagnosis of APL is important because of the danger of potentially fatal disseminated intravascular coagulation, which can be initiated by procoagulants contained in the granules. 

M4 [Ref Robbins 7^th/e p 693, Harrison 17^th/e p 6801

In acute leukemias the clinical features are primarily seen because of:-

(i) Replacement of normal cells of bone marrow by leukemic cells resulting in anemia, thrombocytopemia, neutropenia

(ii)Infiltration of leukemic cell in various extramedullary organs causing, hepalomegaly, splenomegaly, Gum hypertrophy due to infiltration of gums by leukemic cells is one such feature. It is characteristically associated with AML-Mg and AML-M i.e. (acute monocytic leukemia).

Prognostic factors of acute myeloid leukemia (AML):

• Advancing age is associated with a poorer prognosis, in part because of its influence on the patient’s ability to survive induction therapy.
• The leukemic cells in elderly patients more commonly express the multidrug resistance 1 (MDR1) efflux pump that conveys resistance to natural product–derived agents such as the anthracyclines.
• Patients with t(15;17) have a very good prognosis, and those with t(8;21) and inv(16) a good prognosis, while those with no cytogenetic abnormality have a moderately favorable outcome.
• Patients with a complex karyotype, t(6;9), inv(3), or -7 have a very poor prognosis.
• Among patients with hyperleukocytosis (>100,000/L), early central nervous system bleeding and pulmonary leukostasis contribute to poor outcome with initial therapy.
• Karyotypes include monosomy chromosome 5 or chromosome 7 have 78% of relapse rate.

Monosomy 7 is known to be associated with poor prognosis, while trans-location 15/17(t15;17) have good prognosis.

Disseminated intra vascular coagulation is most commonly associated with acute promyelocytic leukemia(M3).

Ans. is ‘a’ i.e., AML; ‘b’ i.e., Myelodysplastic anemia; ‘c’ i.e., Paroxysmal nocturnal hemoglobinuria

Aplastic anemia can progress to : –

Paroxysmal nocturnal hemoglobinuria, Myelodysplastic anaemia, Rarely acute leukemia.

Ans. is ‘d’ i.e., AML

Acute myelogenous leukemia (AML)

o AML is a cancer of myeloid line of WBCs, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells.

o AML is the most common acute leukemia affecting adults.

o The diagnosis of AML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow. o Myeloblasts are mveloperoxidase (peroxidase positive)

o Auer rods (represent abnormal azurophilic granule) are also present in myeloblasts and their presence is taken to be definitive evidence of myeloid differentiation.

o In some AMLs, blast cells exhibit differentiation of other myeloid stem cell line (other than myeloblast), e.g.,

(i)       Monoblast –3 Lack auer rods, peroxidase negative, but nonspecific esterase positive.

(ii)     Megakaryocytic differentiation

(iii)    Erythroblast

Ans. is ‘b’ i.e., T(15,17)

Ans. is ‘a’ i.e., AML

Clinical features ofAML

o The clinical findings in AML are similar to those in ALL i.e., suppression of normal hematopoiesis in the marrow that results in ‑

(i)        Anemia                                    Fatigue, Pallor

(ii)      Neutropenia              —->       Infection, Fever

(iii)    Thrombocytopenia —›         Spontaneous mucosal and cutaneous bleeding. This the most striking clinical feature.

Others

o Cells with multiple Auer rods are called “Faggot cells” are seen in M₁ type of AML.

o Tumor cells in acute promyelocytic leukemia (M₃) release procoagulant and fibrinolytic factors that cause disseminated intravascular coagulation (DIC).

o Monocytic differentiation type (M₄ and M₃) may present with infiltration of skin (leukemia cutis) and gingival hypertrophy.

o Chloromas (granulocytic sarcomas or myeloblastomas) are localize masses composed of myeloblasts in the absence of marrow or peripheral blood involvement.

o Lymphodenopathy, Hepatosplenomegaly, CNS involvement and testicular involvement are less common than AML.

Ans. is ‘d’ i.e., M₄

• In acute leukemias the clinical features are primarily seen because of :

(i)         Replacement of normal cells of bone marrow by leukemic cells resulting in anemia, thrombocytopenia, neutropenia.

(ii)       Infiltration of leukemic cell in various extramedullary organs causing, hepalomegaly, splenomegaly. Gum hypertrophy due to infiltration of gums by leukemic cells is one such feature. It is characteristically associated with AML-M5 and AML-M4 i.e. (acute monocytic leukemia).

Ans. is ‘d’ i.e., M4

• See above explanation.

Ans. is ‘b’ i.e., Promyelo cytic (M3)

o Tumor cells in acute promyelocytic leukemia (M₃) release procoagulant and fibrinolytic factors that cause disseminated intravascular coagulation (DIC).

Ans. is ‘b’ i.e., Auer rods

Ans. is ‘d’ i.e., Monosomy 7

GOOD PROGNOSIS

• Age < 40 years
• M₂, M₃, M₄forms of AML
• Blast cell with Auer rods o TLC < 25 x 109/L
• 415;17), t (8;21), inv 16
• Leukemia without preceeding MDS

BAD PROGNOSIS

J Age < 2 years or > 55 years o M_o, M₆,M₇ forms of AML

o Complex karyotypes

o TLC > 100 x 109/L

o Deletions 5q, 7q

o AML with preceding MDS or anticancer drug exposure

Following molecular prognostic markers ofAML have been added in 18″ /e of Harrison

Marker                                                 Location                                Prognostic impact

NPM1 mutation                                     5g35                                           Favourable

CEBPA mutation                                    19q 13.1                                    Favourable

FLT3-I ID                                             13q12                                         Adverse

WT-1 mutation                                     11p13                                         Adverse

KIT mutation                                        4q llq 12                                     Adverse

BAALC overexpression                           8g22.3                                        Adverse

ERG overexpression                              21q22.3                                     Adverse

MN I overexpression                              22q12.1                                     Adverse

EVI1 overexpression                              3q26                                          Adverse

Ans. is ‘b’ i.e., M3

o Tumor cells in acute promyelocytic leukemia (M₃) release procoagulant and fibrinolytic factors that cause disseminated intravascular coagulation (DIC).

Ans. is ‘c’ i.e., Hyper granular and micro granular type

Ans. is ‘d i.e., AML

Acute Myelogenous leukemia (AML)

o AML is a cancer of myeloid line of WBCs, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells.

o AML is the most common acute leukemia affecting adults.

o The diagnosis of AML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow.

o Myeloblasts are mveloperoxidase (peroxidase) positive.

o Auer rods (Represent abnormal azurophilic granule) are also present in myeloblasts and their presence is taken to be definite evedence of myeloid defferentiation.

o In some AMLs, blast cells exhibit differentiation of other myeloid stem cell line (other than myeloblast), e.g., i) Monoblast Lack auer rods, peroxidase negative, but nonspecific esterase positive.

Megakaryocytic differentiation

Erythroblast

Ans. is ‘d’ i.e., M₆

o FAB classification divides AML into eight types M ₀ to M7.

o This scheme takes into account : ‑

i)    The degree of maturation (MO to M3)

ii)   The lineage of leukemic blast (M4 to M7).

Class                                                                                              Blast cells

o Myeloperoxidase negative                                        M_o minimally differentiatedAML                                

                                                                               o Auer rods negative

                                                                               o Express myeloid lineage antigen

                                                                               o 3 % blasts myeloperoxidase positive M 

AML without differentiation                                           o Auer rods positive

                                                                               o Full range of myeloid maturation

M_Z AML with maturation                                              o Myeloperoxidase positive o Auer rods positive

Ans. is ‘None’

Treatment of AML

o The most commonly used chemotherapy regimen is combination of cytarabine (cytosine arabinoside) and anthrocycline (Doxorubian or daunorubicin). 3-4 cycles are given.

o Patients who fails to attain complete remission after two induction courses, Should immediately proceed to an allogenic stem cell transplant (SCT).

Ans. is ‘D’ i.e., Turner’s syndrome

Risk Factors of AML:

• Genetic disorders :Down syndrome ,Klinefelter syndrome ,Patau syndrome ,Ataxia telangiectasia, Shwachman syndrome ,Kostman syndrome, Neurofibromatosis ,Fanconi anemia ,Li-Fraumeni syndrome
• Physical and chemical exposures: Benzene Drugs such as pipobroman, Pesticides ,Cigarette smoking, Embalming fluids. Herbicides.
• Radiation exposure :Nontherapeutic, therapeutic radiation
• Chemotherapy :Alkylating agents ,Topoisomerase-II inhibitors, Anthracyclines, Taxanes

Ans. is ‘a’ i.e., AML; ‘b’ i.e., CML & ‘c’ i.e., ALL

o Down’s syndrome predisopse to —> AML, ALL, Juvenile type of CML, Transient myeloproliferative disorder, Myelodysplasia.

Answer is A (Monosomy)

Monosomy is consistently associated with an unfavorable or poor prognosis.

Monosomy is associated with a poor prognosis

Monosomy especially those involving chromosome 7 (monosomy 7) and chromosome 5 (monosomy 5) are consistently associated with poor prognosis in both adults and children with AML

Deletion of X or Y chromosome is associated with a favorable / intermediate prognosis

‘Monosomy of the X chromosome in a female patient (loss of the Y chromosome) is the most common whole chromosome loss identified in pediatric patients with AML. This numeric abnormality is usually associated with t(8; 21) translocation and AML M2 which carry a good prognosis’ – ‘Childhood Leukemias’ by Puri 2″d/253

`Loss of Y and X chromosomes are most frequently observed in patients with t(8; 21) which carries a favourable prognosis’ – ‘Blood: Principles and Practice of Hematology’ 2″d/108

Answer :A.)AML-M0

Auer Rods and Acute Myeloid Leukemia (AML)

• Auer rods are clumps of azurophilic granular material that form elongated needles seen in the cytoplasm of myeloid leukemic blasts. They can be seen in the leukemic blasts of acute myeloid leukemia with maturation and acute promyelocytic leukemia and in high grade myelodysplastic syndromes and myeloproliferative syndromes. They are composed of fused lysosomes/primary neutrophilic granules and contain peroxidase, lysosomal enzymes, and large crystalline inclusions.
• Auer rods, the higher percentage being in FAB types M2 and M4 and lower in M1, M3, and M5B, with none in M5A.

Answer is D (Monosomy 7)

Cytogenic studies are most powerful prognostic factors (CMDT)

The answer is D (Monosomy 7)

Patients with a complex karyotype, inv (3), or -7 (monosomy) have a poor prognosis. 

Answer is C (M3-AML)

DIC or DI VC may occur in any subgroup of AML but is especially common in Acute Promyelocytic Leukemia or M3- .4,VIL of FAB classification.

Ans. B i.e. AML

Polycythemia vera

• It is a stem cell disorder characterized as a panhyperplastic, malignant, and neoplastic marrow disorder.
• The most prominent feature of this disease is an elevated absolute red blood cell mass because of uncontrolled red blood cell production.
• This is accompanied by increased white blood cell (myeloid) and platelet (megakaryocytic) production, which is due to an abnormal clone of the hematopoietic stem cells with increased sensitivity to the different growth factors for maturation
• Progression to acute myeloid leukemia/ myelodysplastic syndromes (AML/MDS) is a possible evolution of polycythemia vera (PV)

Ans. B: AML

Ans. C: Both of the above

Children with trisomy 21 have a 10-20 fold increased risk of developing acute leukemia.

Both AML and ALL can occur.

AML, most commonly, is acute megakaryoblastic leukemia.

Ans. A: AML

Gingival hyperplasia is secondary to infiltration of the gingival tissue with leukemia cells.

Gingival hyperplasia was observed in acute myelogenous leukemia (AML) with a frequency of 3% to 5%.

Gingival hyperplasia is most commonly seen with the AML subtypes acute monocytic leukemia (M5), acute myelomonocytic leukemia (M4), and acute myelocytic leukemia (M1, M2).

Tumors with monocytic differentiation often infiltrate the skin (leukemia cutis) and gingiva; this probably reflects the normal tendency of the monocytes to extravasate into tissues.

Ans. ‘a’ i.e., t(8,21)

Monsomies (eg. -5 or -7) carry poor prognosis.

Prognostic factors of AML

• There are many prognostic factors for AML of particular note are : –
• Age : – Age greater than 65 years or less than 2 years has been associated with poor prognosis independent of cytogenetics.
• AML evolving from prior myelodysplastic syndrome (MDS) is associated with poor prognosis.
• Leukocytosis and/or an elevated peripheral blast count are associated with poor prognosis.
• Cytogenetics : – AML prognosis is currently separated into three broad categories based on cytogenic results:- o Favourable : inv (16), t (15:17), t (8 : 21).
• Intermediate : Normal, + 8, + 21, +22, del (7q), del (9q), Abnormal 11 q23.
• Unfavorable : – -5, -7, complexes with 5 chromosomes involved, del (5q), abnormal 3q, abnormal 17p.

Ans. is ‘b’ i.e., M3 AML

Acute myelogenous leukemia (AML)

• AML is a cancer of myeloid line of WBCs, characterized by the rapid proliferation of abnormal cells which accumulate in the bone marrow and interfere with the production of normal blood cells.
• AML is the most common acute leukemia affecting adults.
• The diagnosis ofAML is based on finding that myeloid blasts make up more than 20% of the cells in the marrow.
• Myeloblasts are myeloperoxidase (peroxidase positive)

Ans. is ‘c’ i.e., Acute promyeloblastic leukemia (M.3)

Acute promycloblastic leukemia

• Also known as M-3
• Associated with t(15:17)
• DIC, chloromas common
• Very responsine to retinoic acid combined with anthracylines.
• M.7 (acute megakaryocytic leukemia) mostly seen in down syndrome.
• French-American-British (FAB) Classification of Acute Myelogenous Leukemia