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Questions and Answers
Which classification does NOT provide prognostic information for AML?
Which classification does NOT provide prognostic information for AML?
- WHO classification
- WHO-5 classification
- ICC classification
- FAB classification (correct)
Acute Promyelocytic Leukemia (APML) is classified under the WHO classification as having a bad prognosis.
Acute Promyelocytic Leukemia (APML) is classified under the WHO classification as having a bad prognosis.
False (B)
What type of cell abnormality requires a minimum of 20% blasts for diagnosis in the context of poor prognosis AML?
What type of cell abnormality requires a minimum of 20% blasts for diagnosis in the context of poor prognosis AML?
t(BCR; ABL)
AML defined by differentiation falls under the ______ classification.
AML defined by differentiation falls under the ______ classification.
Match the following recurrent genetic abnormalities with their prognosis:
Match the following recurrent genetic abnormalities with their prognosis:
Which of the following diagnostic methods is NOT part of the 5-point diagnosis of a hematological disorder?
Which of the following diagnostic methods is NOT part of the 5-point diagnosis of a hematological disorder?
Hyperviscosity is present in acute myeloid leukemia (AML).
Hyperviscosity is present in acute myeloid leukemia (AML).
What is the most common cell type found in myeloblastic leukemia?
What is the most common cell type found in myeloblastic leukemia?
In general, leukemia is characterized by the clonal proliferation of cells of the _____ lineage in marrow or blood.
In general, leukemia is characterized by the clonal proliferation of cells of the _____ lineage in marrow or blood.
Match the hereditary conditions to their associated risks for acute myeloid leukemia (AML):
Match the hereditary conditions to their associated risks for acute myeloid leukemia (AML):
Which of the following features is NOT associated with Fanconi's anemia?
Which of the following features is NOT associated with Fanconi's anemia?
Shwachman-Diamond syndrome is characterized by ribosomopathy.
Shwachman-Diamond syndrome is characterized by ribosomopathy.
What are the common causes of acquired aplastic anemia?
What are the common causes of acquired aplastic anemia?
Dyskeratosis Congenita involves a defect in __________ repair.
Dyskeratosis Congenita involves a defect in __________ repair.
Match the following conditions with their associated features:
Match the following conditions with their associated features:
Which of the following is a congenital cause of pure red cell aplasia?
Which of the following is a congenital cause of pure red cell aplasia?
MDS and MPN overlap is known as chronic myelomonocytic leukemia.
MDS and MPN overlap is known as chronic myelomonocytic leukemia.
What is the most common symptom associated with pancytopenia?
What is the most common symptom associated with pancytopenia?
The condition characterized by sudden reticulocytopenia due to parvovirus B19 infection is called __________.
The condition characterized by sudden reticulocytopenia due to parvovirus B19 infection is called __________.
Match the following blood parameters with their significance:
Match the following blood parameters with their significance:
What does a 5q deletion indicate in terms of prognosis?
What does a 5q deletion indicate in terms of prognosis?
The presence of Dohle bodies in the WBC indicates a good prognosis.
The presence of Dohle bodies in the WBC indicates a good prognosis.
Name one treatment option for trilineage bone marrow failure syndromes.
Name one treatment option for trilineage bone marrow failure syndromes.
The presence of ____ bodies is commonly associated with toxic granulation in white blood cells.
The presence of ____ bodies is commonly associated with toxic granulation in white blood cells.
Match the following diagnostic features with their corresponding prognostic outcomes:
Match the following diagnostic features with their corresponding prognostic outcomes:
What is the most common hematological abnormality seen at birth?
What is the most common hematological abnormality seen at birth?
Environmental factors such as radiation and benzene can increase the risk of hematological diseases.
Environmental factors such as radiation and benzene can increase the risk of hematological diseases.
What mutation is associated with transient abnormal myelopoiesis?
What mutation is associated with transient abnormal myelopoiesis?
Myelodysplastic syndromes (MDS) can progress to acute myeloid leukemia (AML) when there are at least _____ blast cells.
Myelodysplastic syndromes (MDS) can progress to acute myeloid leukemia (AML) when there are at least _____ blast cells.
Match the following inherited syndromes with their associated hematological condition:
Match the following inherited syndromes with their associated hematological condition:
What percentage of acute leukemias in adults is Acute Myeloid Leukemia (AML)?
What percentage of acute leukemias in adults is Acute Myeloid Leukemia (AML)?
In acute leukemia, children and adolescents show a predominance of Acute Myeloid Leukemia (AML).
In acute leukemia, children and adolescents show a predominance of Acute Myeloid Leukemia (AML).
What is the time frame for the short history of acute leukemia symptoms?
What is the time frame for the short history of acute leukemia symptoms?
Acute Myeloid Leukemia (AML) is characterized by the complete arrest of differentiation of _______ in the bone marrow.
Acute Myeloid Leukemia (AML) is characterized by the complete arrest of differentiation of _______ in the bone marrow.
Match the precursor cells with their associated leukemia types:
Match the precursor cells with their associated leukemia types:
What is the most common cause of Aplastic Anemia?
What is the most common cause of Aplastic Anemia?
Myelodysplastic syndrome (MDS) is characterized by hypocellular marrow.
Myelodysplastic syndrome (MDS) is characterized by hypocellular marrow.
What age group is primarily affected by inherited Aplastic Anemia?
What age group is primarily affected by inherited Aplastic Anemia?
Pancytopenia with hypercellular marrow is a characteristic of __________.
Pancytopenia with hypercellular marrow is a characteristic of __________.
Match the following conditions with their associated features:
Match the following conditions with their associated features:
Which of the following drugs is associated with dose-dependent aplastic anemia?
Which of the following drugs is associated with dose-dependent aplastic anemia?
Bleeding is the most common clinical presentation of aplastic anemia.
Bleeding is the most common clinical presentation of aplastic anemia.
Name two drugs that can cause aplastic anemia in a dose-independent manner.
Name two drugs that can cause aplastic anemia in a dose-independent manner.
The most common clinical presentation of aplastic anemia is __________.
The most common clinical presentation of aplastic anemia is __________.
Match the following drugs with their classification as dose-dependent or dose-independent in causing aplastic anemia:
Match the following drugs with their classification as dose-dependent or dose-independent in causing aplastic anemia:
Which of the following is the most common complication of acute myeloid leukemia (AML)?
Which of the following is the most common complication of acute myeloid leukemia (AML)?
Meningeal involvement is a common presentation in acute myeloid leukemia (AML).
Meningeal involvement is a common presentation in acute myeloid leukemia (AML).
What is a common site for myeloid sarcoma in patients with acute myeloid leukemia?
What is a common site for myeloid sarcoma in patients with acute myeloid leukemia?
Acute myeloid leukemia can lead to _____ pain, although it is rare.
Acute myeloid leukemia can lead to _____ pain, although it is rare.
Match the following presenting features of acute myeloid leukemia with their descriptions:
Match the following presenting features of acute myeloid leukemia with their descriptions:
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Study Notes
AML Classification
- FAB classification (Does not give prognosis):
- m2: myeloblast
- m3: Promyelocyte
- m4: myelomonocyte
- m5: monocyte
- m6: erythroid
- m7: megakaryocyte
- WHO classification (2016):
- AML with recurrent genetic abnormalities (Blasts ≥ 20%): Poor prognosis
- AML - MDS related
- AML - therapy related (m6)
- AML - not otherwise specified (m2, m3, m4): Poor prognosis
- myeloid sarcoma
- Recurrent genetic abnormalities:
- Good prognosis:
- t(15; 17) / t(PML; RARα): Acute Promyelocytic Leukemia (APML)
- t(8; 21) / t(RUN X1; RUN X1)
- t(16; 16) / Inversion 16: Involves CBFB (core-binding factor B)
- Mutations:
- Nucleophosmin (NPM)
- CEBPA
- Bad prognosis: t(BCR; ABL) / t(9; 22)
- Very bad prognosis: FLT3-ITD (Inverse tandem duplication of FMS-like tyrosine kinase)
- Good prognosis:
- WHO-5 classification (2023):
- AML with recurrent genetic abnormalities. Blasts ≥ 20% not required except in some cases
- AML-MDS
- AML-therapy related
- AML defined by differentiation (FAB classification)
5 Point Diagnosis of Hematological Disorder
- Morphology
- Cytology/Cytochemistry: of bone marrow/blood cells. Myeloperoxidase/Sudan black
- Immunophenotyping: using Flow cytometry CD markers
- Cytogenetics: Recurrent genetic abnormalities. Inversion/deletion
- Molecular Genetics
AML Definition
- Generalised neoplastic (clonal) proliferation: of immature leucocytes with/without involvement of peripheral blood and non-hematopoietic tissues.
- Leukemia: Clonal proliferation of cells of WBC lineage in marrow/blood.
- Most common cell type: myeloblast (myeloblastic leukemia)
- Median age: 65 years, but seen in all ages.
- Gender Predominance: Male > Female (All acute leukemias)
5-Year Survival Rates of AML
- >75 years: Almost NIL
- >50 years: ~20% with transplant
Risk Factors of AML
- Hereditary Conditions:
- Defective DNA repair
- Bloom syndrome
- Ataxia-telangiectasia
- Inherited cause for pure red cell aplasia: Diamond-Blackfan syndrome
- Inherited causes of aplastic anemia
- Fanconi's anemia
- Dyskeratosis congenita
- Shwachman-Diamond syndrome
- Environmental factors:
- Radiation
- Benzene
- Drug-induced leukemias:
- Alkylating agents (after 5-6 years of therapy)
- Topoisomerase II inhibitors (after 1-3 years of therapy) - etoposide
- Hematological diseases:
- Myeloproliferative neoplasms (MPN)
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocythemia
- Chronic myeloid leukemia (CML)
- Paroxysmal nocturnal hemoglobinuria (PNH)
- Aplastic anemia
- Myeloma
- Myeloproliferative neoplasms (MPN)
- Progression:
- 25% cases of myelodysplastic syndromes (MDS) can progress to acute myeloid leukemia (AML)
- (20% blast cells)
- (10-19% blast cells)
Aplastic Anemia
- Inherited:
- Fanconi's anemia:
- Defect: Autosomal recessive FANCA gene mutation > FANCB, FANCC
- Features:
- Short stature
- Cafe au lait macules
- Gonadal dysgenesis
- Increased risk of AML & SCC (Head & neck)
- Esophageal atresia
- Fanconi's anemia:
- Acquired:
- Dyskeratosis Congenita:
- Defect: DKC, mutation, Telomere repair, Complex defect
- Features:
- Reticular skin pigmentation
- Dystrophic nails
- Pancreatic exocrine insufficiency
- Metaphyseal dysplasia
- Shwachman-Diamond syndrome:
- Features:
- Pancreatic exocrine insufficiency
- Metaphyseal dysplasia
- Ribosomopathy
- Features:
- Dyskeratosis Congenita:
Acquired Aplastic Anemia
- Causes:
- Idiopathic
- Drugs
- Toxins: Benzene
- Virus: Non A, B, C hepatitis virus
- Others: PNH (Paroxysmal nocturnal hemoglobinuria)
- Autoimmune: Eosinophilic fasciitis (Scleroderma mimic)
Hematology
- Germline susceptibility:
- Very minimal familial inheritance
- Germline CEBPA mutation
- Germline GATA2 mutation
- Inherited syndromes:
- Kostmann syndrome (congenital agranulocytosis)
- Noonan syndrome
- Down syndrome
- Transient abnormal myelopoiesis:
- Most common hematological abnormality
- Seen at birth and resolves spontaneously within 2-3 months
- Mutation in GATA-1
- Acute myeloid leukemia (AML):
- Occurs in approximately 20% of cases
- Typically develops within 4 years of age
- Megakaryocytic (M7) subtype
- Better prognosis than in children without this subtype
Bone Marrow Failure Syndromes
-
Other conditions:
- Howell Jolly body: Post splenectomy
- Basophil stippling: 5' nucleotidase deficiency
-
WBC:
- Blasts cells 5-19%
- Pseudo pelger huet (2 lobes)
- Hypersegmented
- Toxic granules
- Dohle bodies
- Platelet:
- Pawn ball (multiple nuclear lobes)
- Binucleate megakaryocyte
PROGNOSTIC SCORING for Bone Marrow Failure Syndromes
| Diagnostic Features | Prognosis | Gene |
|---|---|---|
| Pancytopenia: > 10%; dysplastic cells | Poor | Tq deletion, monosomy 7 |
| Cytogenic abnormality | Good | 5q deletion, 20q deletion |
| No AML | Best | 11q deletion |
| No other cause |
TREATMENT for Bone Marrow Failure Syndromes
- Single lineage:
- 5q deletion →Â
- Trilineage:
- Bone marrow transplantation → Hypomethylating agent → Azacytidine → Decitabine
- Present: Lenalidomide
- Absent: Erythropoietin
- Luspatercept: SMAD signaling inhibitor
PURE RED CELL APLASIA
- Causes:
- Diamond blackfan syndrome (Congenital)
- Thymoma/CLL (Acquired)
- Transient aplastic crisis:
- Seen in hereditary spherocytosis d/t parvovirus B19 infection.
- Sudden reticulocytopenia.
- Smear: Giant pronormoblasts.
- Rx: IVIG.
- Post EPO administration → D/t anti-EPO antibodies.
Myelodysplastic Syndrome
- AKA myeloid neoplasm
- Terminal mature cell proliferation: myeloproliferative neoplasm.
- Dysplasia + Ineffective erythropoiesis: myelodysplastic syndrome.
- MDS + MPN overlap: Chronic myelomonocytic leukemia.
- Myeloblast proliferation (Immature myeloid cell): Acute myeloid leukemia.
Presentation of Myelodysplastic Syndrome
- Global:
- 70 yrs
- m > F
- Single/multilineage disease
- India:
- 40-60 yrs (D/t sq deletion)
- Female predominance
- RBC lineage disease
- Lenalidomide (Good response)
- Pancytopenia:
- Hypercellular (80%), hypocellular (20%)
- Progresses to AML (25%)
- No extramedullary hematopoiesis
- m/c symptom: Fatigue
BLOOD PARAMETERS of Myelodysplastic Syndrome
- RBC:
- Anemia (m/c presentation)
- Ringed sideroblasts (SF3B mutation MDS)
- Oval macrocytes (m/c)
- Megaloblasts, nucleated RBC
- Howell Jolly body, basophil stippling, cabots ring
Acute Leukemia
- Classification:
- Adults: 80% AML, 20% ALL
- Children/Adolescents: 90% ALL, 10% AML
Acute Myeloid Leukemia (AML) Pathogenesis
- Involves:
- Clonal proliferation of myeloid precursors:
Precursor Cell Leukemia Type Percentage of Leukemias Myeloblast (m/c) Myeloblastic leukemia (70-80%) Monoblast Monoblastic/myelomonocytic leukemia RBC precursor Erythro-leukemia Platelet precursor Megakaryocytic leukemia - Complete arrest of differentiation: Myeloblast takes over the marrow.
- Clonal proliferation of myeloid precursors:
Clinical Presentation of AML
- Short history (2-3 months)
- Acute presentation:
- No involvement of CNS/testes/organs (Spleen/liver/lymph nodes)
- Pancytopenia manifesting as bleeding
- High turnover: Leaks out into blood when marrow is completely replaced.
- Blood blasts: Increased blood blast counts (poor prognosis).
- CNS involvement (late stages): Decreased blood blast counts (possible prognosis).
Bone Marrow Failure Syndromes
- Diseases:
- Aplastic Anemia
- Myelodysplastic syndrome/neoplasia (MDS)
- Pure red cell aplasia
- Myelophthisis (Secondary myelofibrosis)
Approach to Pancytopenia
-
Bone marrow aspiration + biopsy
-
Cellularity of marrow:
-
Hypercellular Marrow:
- 1.Acute Leukemia (unless proven otherwise)
- (In adults: AML (80%), ALL (20%))
- 2.Myelodysplastic syndrome (MDS)
- 3.Primary myelofibrosis (PMF)
- 4.Hairy cell leukemia (Good prognosis)
- 5.Megaloblastic anemia (Good prognosis)
- 6.Paroxysmal nocturnal hemoglobinuria (PNH)
- 7.Systemic: SLE, HIV, TB, brucellosis, leishmaniasis, sarcoidosis
- 1.Acute Leukemia (unless proven otherwise)
-
PMF: Pancytopenia + Fibrosis
-
Hairy cell leukemia: Pancytopenia + massive splenomegaly
-
Aplastic Anemia
- Pancytopenia with hypercellular marrow.
- Bimodal age distribution (Inherited < 20 years, acquired > 60 years).
- Most common cause: Drug dependent (Good prognosis).
- Most common infection: Non A, non-B hepatitis.
- Poor prognosis.
- Hypocellular Marrow + Pancytopenia:
- Aplastic anemia (20% of MDS cases)
- Aleukemic leukemia
- Copper deficiency
- Lymphoma
- Q fever
- Legionella
- Anorexia
- TB
-
Drugs Causing Aplastic Anemia
- Dose-Dependent:
- Anticancer drugs
- Fluorouracil
- Mercaptopurine
- Daunorubicin
- Cyclophosphamide
- Busulfan
- Anticancer drugs
- Dose-Independent:
- Chloramphenicol
- Sulfonamides
- Gold
- Acetazolamide
- Propylthiouracil (PTU)
- d-Penicillamine
Clinical Presentation of Aplastic Anemia
- Bleeding (most common)
- Anemia
- Infection
- Features against diagnosis of aplastic anemia: Hepatomegaly, splenomegaly, lymphadenopathy, fever.
Investigation for Aplastic Anemia
- Blood Counts: Hb: #
Clinical Features of AML
Presenting Features
- Acute presentation (3 month history)
- Pancytopenia
- m/c complication: Abnormal bleeding d/t prominent thrombocytopenia
- Bruising
- Petechiae
- Epistaxis
- Gingival bleeds
- Excess menstrual bleeding
- m/c complication: Abnormal bleeding d/t prominent thrombocytopenia
- Anemia: Pallor, fatigue, weakness, palpitation
- Absolute Neutrophil Count (ANC): Normal → Only minor infection/pustules.
- No fever (No cytokine production)/lymphadenopathy
- No hepatosplenomegaly
- Bone pains (Rare, m/c in ALL)
- Life-threatening hemorrhage (in acute promyelocytic leukemia)
- Meningeal, cardiac, urogenital involvement: Rare
- Complex infections in:
- Aplastic anemia (Profound neutropenia)
- Hairy cell leukemia (Neutropenia, monocytopenia)
Other Manifestations
- Myeloid sarcoma/Chloroma:
- D/t extramedullary blast proliferation
- Uncommon
- m/c site: Orbit
- Can occur independent of bone marrow involvement
- Associated translocation: t(8; 21)
- Also seen in children
- m/c causative cells: myeloblast/monoblast (m4/m5) → Infiltrate
- Chloroma:
- Gingiva → Gum hypertrophy/gingivitis
- Liver → Hepatomegaly
- Spleen → Splenomegaly
- Dental abscess
- Proctitis
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