Intro to Malignant Heme & AML

Question 1

bone marrow failure

Answer 1

*a decrease in the PRODUCT of bone marrow function: a decrease in cell counts -> cytopenias (typically pancytopenias)

Question 2

causes of bone marrow failure - overview

Answer 2

1. bone marrow is empty of hematopoietic precursors = aplastic anemia
2. bone marrow hematopoietic elements are not maturing like they should = myelodysplastic syndrome
3. bone marrow space is replaced with only one type of cell = leukemias

Question 3

acute myeloid leukemia (AML) - overview

Answer 3

a cause of bone marrow failure due to the bone marrow space being replaced by only one type of cell (myeloblasts - immature leukocyte precursors)

Question 4

pathogenesis of leukemia

Answer 4

*a genetic alteration occurs in an immature hematopoietic cell
*resulting in clonality and excess growth
*usually occurs with myeloid or lymphoid cells but can involve other cells, including cells in the erythroid or megakaryocytic lineages

Question 5

“acute” leukemias

Answer 5

*describes which cell is in excess (an IMMATURE blood cell, aka a blast)
*describes when people present (typically very aggressive)
*describes rate of growth
*describes type of treatment

note - maturation does not occur

Question 6

AML - which cell is in excess?

Answer 6

*the MYELOBLAST (most immature cell committed to becoming a neutrophil) is in excess
*in AML, the myeloblasts:
-grow uncontrollably (signal to grow is always on; signal to stop growing or die gets turned off)
-maturation (differentiation) is halted!! [not maturing into neutrophils]
-inhibit growth of normal cells in the marrow
-quickly becomes a life-threatening disease

Question 7

risk factors for AML

Answer 7

*prior chemotherapy [alkylating agents and epipodophyllotoxins]
*prior radiation
*exposure to benzenes
*preceding myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN)
*note - primary risk factor is unknown/idiopathic (random or spontaneous)

Question 8

clinical presentation for AML and other bone marrow failure sydromes

Answer 8

*we recognize AML by the symptoms that develop as a result of not having enough good blood cells:
-fatigue [from anemia]
-dyspnea on exertion [from anemia]
-petechiae/bleeding [from thrombocytopenia]
-persistent infections [from neutropenia]

Question 9

diagnosis of AML

Answer 9

*bone marrow biopsy
*note - must be 20% or more of cells in the bone marrow be MYELOBLASTS to dx AML
*flow cytometry helps us determine lineage - allows us to tell a myeloblast from a lymphoblast (and AML from ALL)

Question 10

basics of treatment for AML

Answer 10

*don’t use surgery
*don’t use radiation
*USE CHEMOTHERAPY - circulates in the blood like the leukemia cells do
-chemo is nonspecific: kills the good cells as well as the bad cells (any cell that is actively dividing)

Question 11

induction chemotherapy as AML treatment - basics

Answer 11

*first tx patients get
*called induction chemo because we are trying to INDUCE a remission (this is our goal)
*standard of care: 7 + 3: cytarabine (or ara-C) on days 1-7 AND daunorubicin on days 1-3
*patient stays in hospital 4-6 weeks for supportive care, antibiotics, pRBC and platelet transfusions, etc

Question 12

induction chemotherapy as AML treatment - how do we know our chemo is working?

Answer 12

*repeat a marrow on day 14
*if no leukemia is visible (relatively hypocellular bone marrow), await count recovery (about another 2 weeks)
*if leukemia is still present, need additional chemo

Question 13

types of supportive care involved during induction chemotherapy for AML

Answer 13

*antibiotics
*pRBC transfusions
*platelet transfusions
*preventing and treating tumor lysis syndrome
*monitoring for side effects of the meds:
-nausea, vomiting, diarrhea, mucositis
-cardiotoxicity, hepatic toxicity, renal dysfunction/failure, etc

Question 14

consolidation treatment for AML

Answer 14

*we need to give additional chemotherapy to consolidate the the remission that we’ve achieved with our induction therapy
*we do this because there is an 85% chance that the leukemia comes back after the induction tx if no addition tx is given
*involves 3 “booster treatments”, including preparing for the myelosuppression expected during booster treatments (antibiotics, supportive care, etc)

Question 15

AML patients with leukostasis

Answer 15

*sometimes, induction chemo won’t work quick enough
*“sludging” symptoms: chest pain, shortness of breath, headaches, blurry vision
-usually occurs when patients have WBCs > 75K with majority of those cells being blasts
-need emergent leukopheresis
-central line is placed and blasts are filtered out of blood by a pheresis machine
-WBC can drop from 300K to 150K

Question 16

bad prognostic factors of AML

Answer 16

*increased age:
-ability to tolerate chemotherapy
-higher incidence of antecedent hematologic disorders (MDS, etc)
*secondary AML
*therapy-related AML (toxin-induced)
*certain genetic and/or molecular abnormalities: -5, -7, Flt-3 mutations
*not obtaining a remission after induction chemo

Question 17

what genetic/molecular abnormalities are considered “bad” prognostic factors of AML

Answer 17

-5, -7, Flt-3 mutations

Question 18

good prognostic factors of AML

Answer 18

*APL (acute promyelocytic leukemia):
-AML FAB M3
*Inv (16) or t(16;16)
*t(8;21)

Question 19

acute promyelocytic leukemia (APL) - overview

Answer 19

*comprises ~10% of AMLs
* t(15;17) is diagnostic!!! (must have this to be APL)
*patients are younger at the time of diagnosis
*associated with risk of DIC:
-high incidence of early fatal hemorrhage
-7% of patients will die of intracranial hemorrhage

Question 20

acute promyelocytic leukemia (APL) - treatment

Answer 20

*we use 2 different drugs:
1. ATRA (all-trans retinoic acid)
2. arsenic trioxide

note - both of these drugs promote promyelocyte differentiation

Question 21

ATRA treatment for acute promyelocytic leukemia (APL)

Answer 21

*retinoic acid promotes promyelocyte differentiation
*when the t(15;17) translocation occurs in PML, supra-physiological doses of retinoic acid are needed to promote differentiation of the promyelocytes - we give that in the form of all-trans retinoic acid (Vitamin A) -> ATRA

Question 22

arsenic trioxide treatment for acute promyelocytic leukemia (APL)

Answer 22

*also thought to help APL by promoting differentiation of promyelocytes
*main side effect: QTc prolongation

Question 23

myeloblasts in AML

Answer 23

• > 20% myeloblasts in the bone marrow is diagnostic for AML
  *myeloblasts:
  1. MPO + (myeloperoxidase +)
  2. TdT + (a marker of immaturity)
  3. have characteristic AUER RODS in their cytoplasm