Acute Leukemias - Definitions and Etiology

Question 1

Compare AML and ALL in respect to patient demographic and prognosis

Answer 1

ALL - acute lymphocytic leukemia. Neoplasms of precursor lymphoid cells, rarely manifest as solid mass.
1-5cases/100Kppl/1yr.
75% of cases in children <6 yrs old.

AML - acute myelocytic leukemia. At level of pluripotent stem cell/committed progenitors.

Question 2

What are leukemic stem cells?

Answer 2

Self-renewing cells, so theres a constant supply of additional diseased cells.

Question 3

Name risk factors for acute leukemias

Answer 3

1. ) Previous chemo (DNA alkylating agents + topoisomerase II inhibitors) MOST IMPORTANT
2. ) Exposure to ionizing radiation
3. ) Tobacco smoke, benzene
4. ) Genetic syndromes

Question 4

Common signs/symptoms of pts w/ acute leukemia

Answer 4

Symptoms often due to LACK of normal cells (general malaise, night sweats, weight loss, etc)

Rarer - Symptoms due to leukemic cells - Thrombic events, increased blood viscosity (leukostasis,) Disseminated intravascular coagulation (DIC)
Sometimes direct infiltation of skin, gums, lymph nodes and other tissues

Question 5

List major markers that would help assign a blast as precursor B, precursor T, or myeloid lineage.

Answer 5

CD34 - positive on all blasts. Confirms that these are immature cells.

TdT - expressed only in lymphoblasts.

CD19, CD22 - B-cell lineage markers

CD3, CD7 - T-cell lineage markers

Question 6

Contrast B-ALL and T-ALL in respect to patient age, sex, manner of manifestation and prognosis

Answer 6

B-ALL - 80-85% of all cases of ALL. Lack markers for mature B-cells (like CD20) and surface immunoglobulin. Typical in childhood.

T-ALL - 25% of all ALL. In adolescents and young adults. Frequently presents w/ component of T-lymphoblastic lymphoma, w/ mediastinal mass. Higher WBC count. Favors males over females.

Question 7

Name the 3 Common cytogenetic abnormalities in B-ALL

Answer 7

1. ) t(9;22); BCR-ABL1 - derivitive chromosome 22. Ph+ ALL, 25% of cases of adult ALL, 2% of childhood ALL. Unfavorable prognosis.
2. ) 11q23; MLL - seen in neonates and young infants. Poor prognosis.
3. ) t(12;21); ETV6-RUNX1 - 25% of bases of childhood B-ALL, favorable prognosis

Question 8

List 5 factors affecting prognosis in ALL

Answer 8

1. ) Age. Much better prognosis in children (80% cure rt, 95% 5 yr remission rt) than adults (50% cure rt, 60-80% remission rt)
2. ) B-lymphoblastic (better) vs T-lymphoblastic (worse)
3. ) Hyperploidic (better) vs Hypoploidic (worse)
4. ) Quick response to drugs (better) vs Slow response to drugs (worse)
5. ) Residual disease absent (better) vs residual disease present (worse)

Question 9

List 2 findings that would allow for AML diagnosis

Answer 9

1. ) >20% myeloblasts in marrow/peripheral blood
2. ) Cytogenetic abnormalities

Also important: Age. Avg age of diagnosis is 65 yrs

Question 10

Auer rods…?!?!?

Answer 10

seen in AML. basically an immature bad granule that looks like a line coming out of the nucleus. this is very definitive of a myeloblast.

Question 11

What are the 5 recurrent cytogenetic abnormalities in AML?

Answer 11

This is a big notecard lol sorry

1. ) t(8;21) RNX1-RNX1T1 - 5% of cases, younger pts. Some mature neutrophils seen. Good prognosis. Diagnostic.
2. )inv(16) or t(16;16) CBFB-MYH11 - 5-10%, younger pts, good prognosis, associated with baso eo cells. Diagnostic.

!!!!! 3.)t(15;17) PML-RARA - 5-10%, known as acute promyelocytic leukemia. Differentiation is blocked. Hypergranular morphology. Multiple Auer rods. Diagnostic.

4. ) t(1;22) RBM12-MLK1 - megakaryoblastic differentiation. Seen often in infants w/ Down Syndrome. Relatively good prognosis.
5. ) 11q23 MLL gene - poor prognosis, some degree of monocytic differentiation.

Question 12

Why is the AML t(15;17) PML-RARA the most important subtype? How does this diagnosis affect treatment?

Answer 12

RARA encodes retinoic acid alpha receptor, which is required to get past promyelocytic stage. Protein function COULD be respored with supraphysiologic doses of all-trans retinoic acid (ATRA)

These pts don’t have to go through traditional chemo! Just ATRA + arsenic salts!

OFTEN associated w/ DIC, clotting and clot lysis. Keep on eye on this.

Question 13

What are the two main categories of therapy related AML?

Answer 13

t-AML = secondary to DNA damage. Is 10-20% of all AML.

Alkylating agents - latency 2-8 yrs. Whole or partial deletions of Chr. 5 and/or 7. Progresses to AML through MDS.

Topoisomerase II - latency 1-2 years. Rearrangements of 11q23;MLL, progresses too quickly to go through MDS stage.

Both have shitty prognosis tbh

Question 14

List 3 molecular markers used to predict prognosis in patients w/ AML w/ normal karyotype (AML NOS)

Answer 14

1. ) FLT3 ITD - positivity for internal tandem dumplications. Bad prognosis. TRUMPS ALL OTHERS
2. ) NPM1 - + for mutation in nucleophosmin-1 gene. Positive prognosis only if FLT3 (-)
3. ) CEBRA - + for mut of CEBRA gene. Positive prognosis if FLT3 (-)

Question 15

What is AML, NOS?

Answer 15

AML not otherwise specified - lacks recurrent cytogenetic findings, not due to previous therapy. Subclassified depending on cell type. Myelomonocytic, Myelokaryocytic, etc etc

Question 16

What is the treatment of choice in AML?

Answer 16

Treatment of choice is def hematopoetic stem cell transplant.

For children, chemo alone CAN be used but adults need the transplant