Acute Leukemias

Question 1

Acute Leukemies

Answer 1

a clonal, neoplastic proliferation of hematopoietic cells, usually immature, presenting as a rapidly progressive diease.

Question 2

2 basic categories of acute leukemia

Answer 2

AML – Acute myeloid leukemia – leukemic cells resemble cells of one or more myeloid lineages
ALL – Acute lymphoblastic leukemia –leukemic cells resemble precursor (immature) lymphocytes

Question 3

Etiology of leukemias

Answer 3

Majority of acute leukemias have chromosomal abnormalities, detectable by cytogenetic tests. IN additional, many contain more subtle abnormalities requiring molecular tests for detection. Abnormalities include 1) block in the ability to differentiate, 2) increased autonomy of growth-signalling pathways.

Question 4

Acute Leukemias - Risk Factors

Answer 4

1) MAJOR: Previous chemotherapy, ESPECIALLY
DNA alkylating agents and topoisomerase-II
inhibitors
2) MAJOR: Previous exposure of active marrow to ionizing radiation
3)Tobacco smoke
4) Benzene exposure
5) Genetic syndromes, including Down syndrome, Bloom syndrome, Fanconi anemia, and ataxia-telangiectasia

Question 5

Clinical presentation from replacement of normal marrow cells by leukemic cells

Answer 5

1) Signs/symptoms of anemia: fatigue, malaise, pallor, dyspnea
2) Signs/symptoms of thrombocytopenia:
bruising, petechiae, hemorrhage
3) Signs/sympyoms of neutropenia:
fever, infections

Question 6

More rare signs include

Answer 6

Thrombotic events due to increased blood VISCOSITY. DIC events. Direct infiltration of skin, gums, lymph nodes, and/or other tissues by leukemic cells. Sometimes gingiva in the mouth.

Question 7

Acute Lymphoblastic leukemia

Answer 7

Neoplasms of precursor lymphoid cells PREDOMINANTLY manifest as leukemia (ALL); much less commonly they may manifest primarily as a solid mass, referred to as lymphoblastic lymphoma.

Question 8

ALL is divided into 2 types

Answer 8

B-lymphoblastic leukemia (B-ALL), T-lymphoblastic Leukemia (T-ALL)

Question 9

ALL epidemiology

Answer 9

has incidence in 1-5 cases/100k persons/year. 75% of cases of ALL occur in children less than 6 years old

Question 10

ALL diagnosis

Answer 10

1) ALL patients nearly always present with blasts representing a majority of marrow cells (“packed marrow”) so no % of blasts required for diagnosis. 2) perpipheral blood WBC count may be increased, normal, or decreased. 3) determining blast type (myeloblast v lymphoblast) requires immunophenotyping

Question 11

AML Diagnosis markers

Answer 11

Generic markers of immaturity (also on lymphoblasts) = CD34. Common Myeloid Markers (not usually on lymphoblasts) = CD117 and myeloperoxidase

Question 12

Myeloblasts

Answer 12

Myeloblasts typically have the generic appearance of a blast and cannot be definitively differentiated from lymbphoblasts based on morphology alone. Exception is in AML where some myeloblasts contain AUER RODs

Question 13

AML diagnosis

Answer 13

Additionally the presence of certain recurrent cytogenic abnormalities (usually translocations) allows a diagnosis of AML to be made regardless of blast count.

Question 14

AML diagnosis with recurrent cytogenetic abnormalities: t(8:21);RUNX1-RUNX1T1

Answer 14

5% of AML cases. Younger patients. “AML with maturation”. RELATIVELY GOOD PROGNOSIS. Also called a Core Binding Factor needed for transcription of differentiation

Question 15

AML diagnosis with recurrent cytogenetic abnormalities: inv (16) or (t16:16);CBFB-MYH11

Answer 15

5-10% of AML cases, younger patients. associated with presence of abnormal EOSINOPHILIC precursors with abnomal basophilic granules. CBFB encodes beta subunit o core binding factor. RELATIVELY GOOD PROGNOSIS

Question 16

AML diagnosis with recurrent cytogenetic abnormalities: t(15:16); PML-RARA

Answer 16

Probably most important subtype of translocation to know. 5-10% of cases. aka ACUTE PROMYELOCYTIC LEUKEMIA (APL) as leukemic cells are blocked at the promyelocyte stage rather than blast stage. Cells have HYPERGRANULAR morphology. may see multiple AUER rods. Sometimes referred to M3-AML.

Question 17

AML with t(15:17) i.e. acute promyelocytic leukemia) is important to recognize QUICKLY for 2 reasons

Answer 17

1) APL fusion protein functions poorly as a retinoic acid receptor. However, adequate levels of signalling can be obtains with supraphysiologic doses of all-tranns retinoic acit (ATRA). So can treat with ATRA instead of regular chemotherapy.
2) APL is associated with DIC

Question 18

AML t(1:22):RBM 15-MKL1

Answer 18

usually shows megakaryoblastic differentiation

• most often seen in infants with Down syndrome
• relatively good prognosis (in relation to other infantile acute leukemias)

Question 19

AML with abnormalities of 11q23:MLL

Answer 19

• MLL may be rearranged with multiple possible partner genes
• AML with abnormalities of MLL frequently shows some degree of monocytic differentiation
• poor prognosis (similar to cases of ALL with abnormalities of MLL)

Question 20

Therapy-related AML (T-AML)

Answer 20

t-AML is defined as AML arising secondary to DNA damage from a prior therapy. T-AML accounts for 10-20% AML. Damage from alklating agents or topoisomerase.
VERY BAD PROGNOSIS

Question 21

AML - not otherwise specificed (NOS)

Answer 21

includes cases of AML lacking recurrent cytogenetic findings, not known to be due to previous therapy.

Question 22

AML NOS - undifferentiated

Answer 22

leukemic cells are myeloblasts

Question 23

AML NOS - myelomonocytic

Answer 23

leukemic cells are myeloblasts and monocytes

Question 24

AML NOS - monoblastic or monocytic

Answer 24

Leukemic cells are: Monoblasts, promonocytes, and or/monocytes. THINGS TO KNOW: leukemic calls often causes lesion in skin and gums.

Question 25

AML NOS: Megakaryoblastic

Answer 25

Leukemic cells are: megakaryblasts. THINGS TO KNOW: Often associated with significant marrow fibrosis

Question 26

Acute myeloid leukemia therapy/prognosis

Answer 26

- Prognosis is heterogeneous, like AML, with mean survival times ranging from 10 years for patients with favorable risk AML - Approximate complete remission rate of 60% - If patients are healthy enough, hematopoietic stem cell transplant (SCT) is the therapy of choice for younger patients, patients with high risk disease, and patients with relapsed disease

Question 27

Acute lymphoblastic leukemia (ALL) DIAGNOSIS Markers

Answer 27

Generic markers of immaturity = CD34 Common lymphoblast marker = TdT Markers of B cell lineadge = CD19, CD22 Markers of T cell CD3, CD7

Question 28

B-Lymphoblastic Leukemia (B-ALL)

Answer 28

- B-ALL accounts for 80-85% of cases of ALL - Besides expressing B cell-lineage antigens (previous notecard), B-lymphoblasts usually lack markers of mature B cells, such as CD20 and surface immunoglobulin - B-ALL is the typical ALL of childhood

Question 29

B-LYMPHOBLASTIC LEUKEMIA (B-ALL)w/ Recurrent Cytogenetic Findings

Answer 29

- t(9;22) results in a derivative chromosome 22, the so-called Philadelphia chromosome (Ph+ALL). -Seen in 25% cases of adult ALL, but only 2% of cases of childhood ALL. Fusions protein breakpoint is 190, which is smaller than CML.

Question 30

B-ALL with translocations of 11q23: MLL

Answer 30

MLL may be rearranged with any multpile possible partner genes. Frequenctly seen in neonates and young infants Poor prognosis

Question 31

B-ALL with t(12;21); ETV6-RUNX1

Answer 31

Very favorable prognosis. | 25% cases of childhood B-ALL

Question 32

T-LYMPHOBLASTIC LEUKEMIA(T-ALL)

Answer 32

1) T-ALL accounts for only around 25% of cases of ALL 2) When compared to B-ALL….. - T-ALL more frequently occurs in adolescents and young adults. B-ALL more in young children. - T-ALL more frequently presents with a component of -T-lymphoblastic lymphoma (T-LBL), often present as a mediastinal mass (since immature T cells like to hang out in the thymus) - T-ALL is more likely to have a markedly elevated WBC count - T-ALL FAVORS males over females

Question 33

ALL therapy/prognosis

Answer 33

In children, ALL is generally considered a “good prognosis disease,” with… complete remission rates of >95% - cure rates around 80% In adults, the prognosis for ALL is worse than for children, with … complete remission rates of 60-80%, cure rates of <50%

Question 34

ALL prognosis factors that are positive

Answer 34

1-10 years old. B-lymphoblastic Hyperdiploidy.

Question 35

ALL prognosis factors that are negative

Answer 35

Infants, Teens/adults, Very high WBC, T-lymphoblastic hypodiploidy, Slow response to Rx, Minimal residual disease.

Question 36

Acite myeloid leukemia (AML)

Answer 36

AML is a much MORE heterogeneous disease than ALL (many more types) AML is typically a disease of adults: average age at diagnosis of AML: 65. Only ~10% of childhood leukemias are AML AML incidence is around 3 cases per 100K persons per year (similar to ALL)

Question 37

AML diagnosis

Answer 37

Most cases of AML are diagnosed due to the PRESENCE of ≥20% myeloblasts in the marrow and/or peripheral blood. This can be determined by: - Identifying blasts by their morphologic appearance while performing a differential count on marrow aspirate smears or peripheral blood smears - Flow cytometric analysis of marrow aspirate or peripheral blood - Immunohistochemistry performed on a marrow core biopsy

Question 38

Molecular abnormality in AML NOS: FLT3

Answer 38

Internal tandem duplication is a poor prognosis.

Question 39

Molecular abnormality in AML NOS: Nucleophosmin-1 (NPM1)

Answer 39

Prognosis is GOOD (as long as negative for FLT3 ITD)

Question 40

Molecular abnormality in AML NOS::CEBPA Mutation

Answer 40

Prognosis is GOOD (as long as negative for FLT3 ITD)