- 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)

Acute Leukemia: Clinical Cases and Correlates Flashcards by Kayla Schenheit

What is AML?

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)

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

What are the cytogenetics? This drives prognosis and treatment

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

Viral illness

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

HIV, AML (leukemia) (BAD STUFF)

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

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

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What can cause secondary AML (acute myelogenous leukemia)?

Prior chemotherapy, radiation exposure, benzene

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

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

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What can AML do the the mouth? (EXAM)

Can cause gums to hypertrophy

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What are the clinical features associated with AML?

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

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How should you treat AML?

Promptly with hydroxyurea, leukopheresis, chemotherapy

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What are the two methods of classification of AML?

FAB

WHO

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What does AML look like on a blood film?

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

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What is the FAB classification?

> 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)

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What is the WHO classification of AML?

> 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

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What is the MAJOR PROGNOSTIC FACTOR for AML?

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

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

-Age

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

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)

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WHAT IS THE SINGLE MOST IMPORTANT PROGNOSTIC FACTOR FOR AML?

CYTOGENETICS

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What cytogenetic outcomes have a favorable risk?

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

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What cytogenetic outcomes have an intermediate risk?

(Normal karyotype)

-NPM1+/Flt3- genotype most favorable

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What cytogenetic outcomes have an unfavorable risk?

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

How do you do cytogenetics?

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

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

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

What is the “7 + 3” regimen?

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

Who should receive consolidation chemotherapy and what is it?

- 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

What determines your eligibility for a stem cell transplant?

Poor risk cytogenetics

Why is cord blood so good?

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

When should you do allogenic stem cell transplantation?

- 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

What is autologous stem cell transplantation used for?

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

What type of transplant is better?

Allogenic

How are AML cases treated if older than 60 years?

- 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

Is GVHD (graft vs. host disease) curable?

NO!

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

-Infection, Lyme's, Tick-borne illness

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

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

What is normal range for WBC count?

In single digits

What are normal platelets?

150-200 K

If fibrinogen is under 100?

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

What is a common drug that can elevate WBCs?

Steroids - cause demargination of neutrophils from the vascular system!

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

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!

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

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

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

- 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

What commonly happens with APML - M3?

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

If a patient has M3 and DIC. . .

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

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

AML M3

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

- Electrolyte balance - Dehydration - Needs glasses

What does 1 gram of hemoglobin equal?

1 unit of blood

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

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

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

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

What happens with automated blood counters?

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

What can happen with a blood transfusion?

- 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

What are two new treatment paradigms in AML?

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