Acute Leukemia: Clinical Cases and Correlates

Question 1

What is AML?

Answer 1

• Uncontrolled clonal proliferation and accumulation of neoplastic hematopoietic precursor cells of myeloid lineage
• –Inhibition of normal hematopoiesis
• –Defective maturation
• –Dissemination into blood and other tissues
• –20% myeloblasts in BM (WHO) or 30% myeloblasts in BM (FAB)

Question 2

What is the #1 thing to think about with leukemia? (EXAM)

Answer 2

What are the cytogenetics? This drives prognosis and treatment

Question 3

What are you thinking if you see a patient with fever, chills and swollen glands under neck?

Answer 3

Viral illness

Question 4

What are you thinking if you see fever, chills, and diffuse adenopathy (all over body)?

Answer 4

HIV, AML (leukemia) (BAD STUFF)

Question 5

Who is at increased risk for acute myelogenous leukemia? (EXAM)

Answer 5

-Down Syndrome, Ataxia telangiectasia, Fanconi anemia, Li Fraumeni syndrome, Wiskott-Aldrich, familial leukemia, myelodysplasia, PNH

Question 6

What can cause secondary AML (acute myelogenous leukemia)?

Answer 6

Prior chemotherapy, radiation exposure, benzene

Question 7

What is the median age of diagnosis for AML? How many cases in the US?

Answer 7

• Median age: 63 (80% > 15) - mostly adults
• 7,400 deaths in US in 2002
• 10,600 new cases in US in 2002

Question 8

What can AML do the the mouth? (EXAM)

Answer 8

Can cause gums to hypertrophy

Question 9

What are the clinical features associated with AML?

Answer 9

• Pancytopenia (red cells, white cells & platelets reduced)
• –Anemia (often asymtomatic in elderly)
• –Neutropenia
• –Thrombocytopenia
• B symptoms: fever, night sweats, chills, malaise, weight loss
• Extremedullary disease - outside of the blood & bone marrow!
• –Monocytic leukemias are most common (infiltration of leukemia in the gums)
• –Skin, CNS, orbits, bone, lung, kidney, spleen, liver, ovary
• Hyperleukocytosis
• –>100,000 blast count/ml
• –APML, moncytic AML, inv(16), 11q23

Question 10

How should you treat AML?

Answer 10

Promptly with hydroxyurea, leukopheresis, chemotherapy

Question 11

What are the two methods of classification of AML?

Answer 11

FAB

WHO

Question 12

What does AML look like on a blood film?

Answer 12

• Monocytic blast
• Cleft in the nucleus of monocytes
• You’ll also see an auer rod

Question 13

What is the FAB classification?

Answer 13

• > 30% BM myeloblasts
• M0 (undifferentiated myeloid leukemia)
• M1 (acute myeloid leukemia without maturation)
• M2 (acute myeloid leukemia with maturation)
• M3 (acute promyelocytic leukemia)
• M4 (acute myelomonocytic leukemia)
• M5 (acute monocytic leukemia)
• M6 (acute erythroleukemia)
• M7 (acute megakaryocytic leukemia)

Question 14

What is the WHO classification of AML?

Answer 14

• > 20% BM myeloblasts
• AML with recurrent cytogenetic abnormalities
• –ex: t(8;21), t(15;17), t(inv16), 11q23
• AML with multilineage dysplasia
• AML and MDS, therapy-related
• AML not otherwise categorized
• –similar to FAB list
• Acute biphenotypic leukemia

Question 15

What is the MAJOR PROGNOSTIC FACTOR for AML?

Answer 15

CYTOGENETICS - major and most important thing in terms of prognosis and treatment

Question 16

What are favorable features of the AML? (good prognostic indicators)

Answer 16

-Age

Question 17

What are unfavorable features of AML? (poor prognostic indicators)

Answer 17

• Poor risk cytogenetics
• Age >60
• Presence of infection or sepsis
• Poor performance status
• Presence of prior MDS
• Secondary AML
• Extreme leukocytosis
• Extramedullary disease (enlarged lymph nodes all over - adenopathy all over)

Question 18

WHAT IS THE SINGLE MOST IMPORTANT PROGNOSTIC FACTOR FOR AML?

Answer 18

CYTOGENETICS

Question 19

What cytogenetic outcomes have a favorable risk?

Answer 19

t(8;21) (best), t(16;16), t(15;17)

Question 20

What cytogenetic outcomes have an intermediate risk?

Answer 20

(Normal karyotype)

-NPM1+/Flt3- genotype most favorable

Question 21

What cytogenetic outcomes have an unfavorable risk?

Answer 21

del 5, del 7, trisomy 8, 11q23, other complex karyotypes

Question 22

How do you do cytogenetics?

Answer 22

• Undergo tissue assay
• Prepare 20 cells in metaphase
• Pathologist looks at cells under microscope and tells you what’s going on

Question 23

How are most AML cases treated if 60 years or younger?

Answer 23

• Induction chemotherapy with anthracycline (daunorubicin, mitoxantrone, idarubicin) plus cytosine arabinoside. “7 + 3” regimen.
• If remission obtained (60-70% remission rate), then consolidation chemotherapy or transplantation
• If no remission, then especially poor prognostic sign
• –If remission induced with alternative regimen, then consider allergenic transplantation

Question 24

What is the “7 + 3” regimen?

Answer 24

• 7 days of cytosine arabinoside (continuous infusion)
• 3 days of 3 (idarubicin, mitoxantrone, daunorubicin)
• They’re in the hospital for 3 weeks

Question 25

Who should receive consolidation chemotherapy and what is it?

Answer 25

- High-dose cytosine arabinoside x 4 cycles - Good risk cytogenetics (8;21, inv16, 15;17) - Normal karyotype with NPM1+, Flt3- - Intermediate risk cytogenetics w/o matched sibling donor or unwilling/unable to have transplant in 1st CR

Question 26

What determines your eligibility for a stem cell transplant?

Answer 26

Poor risk cytogenetics

Question 27

Why is cord blood so good?

Answer 27

- It is so simple and easy to do | - But it's not good because you have such a limited supply (baby is not identified)

Question 28

When should you do allogenic stem cell transplantation?

Answer 28

- Poor risk cytogenetics - Intermediate-risk cytogenetics with matched sibling donor - Extramedullary disease (chloroma) - 1st or 2nd relapse - Donor sources include siblings, children, parents, MUD-matched unknown donor, umbilical cord blood

Question 29

What is autologous stem cell transplantation used for?

Answer 29

- No proven benefit over consolidation chemotherapy in 1st CR - Consider for patients w/o an allogenic donor

Question 30

What type of transplant is better?

Answer 30

Allogenic

Question 31

How are AML cases treated if older than 60 years?

Answer 31

- USUALLY DON'T DO ALLOGENIC TRANSPLANTS - Induction chemotherapy with anthracycline (daunorubicin, mitoxantrone, idarubicin) plus cytosine arabinoside. "7+3" regimen. - If remission obtained (60% remission rate), then consolidation chemotherapy with reduced intensity cytosine arabinoside - Mylotarg (anti-CD33 moAb) coupled to calicheamicin) for relapsed disease - Consider observation and supportive care in lieu of induction chemotherapy

Question 32

Is GVHD (graft vs. host disease) curable?

Answer 32

NO!

Question 33

What are you thinking if patient has fatigue, malaise, fevers?

Answer 33

-Infection, Lyme's, Tick-borne illness

Question 34

What are you thinking if patient has fatigue, malaise, fevers and nosebleed (epistaxis)?

Answer 34

- Thrombocytopenia, problem with coagulation system (less common) - Tick borne illness can also present with thrombocytopenia

Question 35

What is normal range for WBC count?

Answer 35

In single digits

Question 36

What are normal platelets?

Answer 36

150-200 K

Question 37

If fibrinogen is under 100?

Answer 37

Patient is consuming their factors or they don't have good liver function

Question 38

What is a common drug that can elevate WBCs?

Answer 38

Steroids - cause demargination of neutrophils from the vascular system!

Question 39

What can cause fever, fatigue, malaise and nosebleed? What does it look like on a blood smear?

Answer 39

M3 AML - acute promyelocytic leukemia - You'll see heavily granulated promyelocytes! - Stack of AUER RODS seen in cells - Much mononuclear infiltrate is evident in slides!

Question 40

What should you remember about acute promyelocytic leukemia (M3)? (EXAM)

Answer 40

- t(15;17) translocation | - If they relapse, they get arsenic trioxide

Question 41

What should you know about acute promyelocytic leukemia (M3)?

Answer 41

- Most with t(15;17). Creates fusion gene, PML/RAR-alpha - Poor risk disease with t(11;17) - Induction therapy with ATRA plus anthracycline-based chemotherapy - Consolidation with 2 courses anthracycline-based chemotherapy - 2 years maintenance chemotherapy with ATRA, 6-MP, and methotrexate - Relapse - --Arsenic trioxide

Question 42

What commonly happens with APML - M3?

Answer 42

- Auer rods - DIC a common presentation - --Coagulopathy - --Depressed fibrinogen - --Thrombocytopenia - --Fatal hemorrhage

Question 43

If a patient has M3 and DIC. . .

Answer 43

. . .start ATRA (all-trans retinoic acid) in

Question 44

What can you not 'let the sun set on' or miss?

Answer 44

AML M3

Question 45

What do you think when you hear 50 f, fatigue, headache, blurred vision?

Answer 45

- Electrolyte balance - Dehydration - Needs glasses

Question 46

What does 1 gram of hemoglobin equal?

Answer 46

1 unit of blood

Question 47

What is seen in the blood smear of someone with M4 AML?

Answer 47

Hyperleukocytosis - Too big monocytes with cleft in nucleus - Lymphocytes are too large (much larger than red cells) - --Indicates = bone marrow failure

Question 48

What causes fatigue, headache and blurred vision in a patient with M4 AML?

Answer 48

Hyperleukocytosis --Hyperviscosity --Sludging in vasculature with ischemia and/or infarct Leukopheresis to reduce WBC

Question 49

What happens with automated blood counters?

Answer 49

- Can misdiagnose monocytosis - could actually be leukemia | - Cell counters can confuse blasts and monocytes

Question 50

What can happen with a blood transfusion?

Answer 50

- Patient can have new blood type, the HLA of the donor | - This is called 100% donor chimerism - their cells even use the DNA of the donor

Question 51

What are two new treatment paradigms in AML?

Answer 51

1. Flt-3 receptor tyrosine kinase inhibitors - Quizartinib - Effective (47% response rate ) in relapsed AML - May be effective "bridge to transplant" strategy - Studies underway to combine with conventional induction therapy - Notable side-effects include QTc prolongation 2. CBF (core binding factor) - Dasatinib - C-kit overexertion in CBF+ AML