4 - Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia Flashcards Preview

Oncology > 4 - Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia > Flashcards

Flashcards in 4 - Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia Deck (78):
1

ALL

Acute LymphoBLASTic Leukemia
Focuses on very early immature cells
Aggressive
Requires immediate treatment
Curable

2

CLL

Chronic LymphoCYTic Leukemia
Often indolent
May not need treatment for years
Incurable

3

ALL - Detected but not treated

You could die within days to weeks

4

Malignant lymphocytes mainly in the lymph nodes

Lymphoma

5

Malignant lymphocytes mainly in the blood and bone marrow

Leukemia

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Lymphocytic Leukemia - Arrested a mature state

CLL

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Lymphocytic Leukemia - Arrested at an immature state

ALL

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2 Types of ALL

B Cell
T Cell

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ALL - Incidence

Rare
~1000 cases per year

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ALL - Prognosis

Pediatrics - Curable, even at relapse
Adults - Often fatal

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ALL - Risk Factors

Radiation exposure
Trisomy 21

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ALL - Patient Presentation

Acute complications of cytopenias (Bleeding, Infection, Fatigue, Dyspnea, Dizziness)
Fever
Bone Pain
Rarely lymphadenopathy

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Acute complications of cytopenias

Bleeding
Infection
Fatigue
Dyspnea
Dizziness

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ALL - Microscopic

Large redundant lymphocytes
Open chromatin
Prominent nucleoli
Light purple cytoplasm
No granules

15

ALL - Physical Exam

Signs of anemia
Ecchymosis, petechiae
Lymphadenopathy (rare)
Splenomegaly (rare)
Rash (from an infection)

16

ALL - Diagnosis

Bone Marrow Tests:
Core biopsy
Flow cytometry
Aspirate slides
Cytogenetics

Source for core biopsy: Superior iliac crest (feel through the skin)

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Flow Cytometry

Critical test for all lymphoid malignancies
Less critical for myeloid malignancies

Suck fluid out of bone marrow, or take blood
Label the cells with fluorescent antibodies
Shoot cells down a channel
Hit them with a laser and see what lights up

Therapeutic implications:
Once you know which surface markers are on a cancer cell, you can target those cells using that surface marker.

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B Cell ALL - Diagnosis on Flow Cytometry

TdT
CD19 (can be therapeutic target)
CD22
CD79
Immunoglobulin

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T Cell ALL - Diagnosis on Flow Cytometry

TdT
CD7
CD2
CD3

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CD19

B Cell ALL Marker
Can be therapeutic target

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T Cell ALLs often present with

Large mediastinal mass
When it disappears, it means you've given good chemotherapy and it's worked

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Components of Therapy - ALL

Induction
CNS Therapy
Intensification
Maintenance

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ALL Therapy - Induction

Prednisone
Dexamethasone
Vincristine
Doxorubicin
Cyclophosphamide
Asparaginase

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ALL Therapy - CNS Therapy

Craniospinal irradiation
Intrathecal Methotrexate and Cytarabine

This is important because ALL spreads to the CNS through the CSF

Maybe don't radiate kids though if you can avoid it. Check CSF to see if there's any cancer in there.

25

ALL Therapy - Intensification

Similar to Induction:

Prednisone
Dexamethasone
Vincristine
Doxocubicin
Cyclophosphamide
Asparaginase

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ALL Therapy - Maintenance

Prednisone
Mercaptopurine
Methotrexate

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ALL Therapy - Time Course

2+ years

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Chemotherapy - Dexamethasone

Directly toxic to lymphocytes

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Chemotherapy - Prednisone

Directly toxic to lymphocytes

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Chemotherapy - Vincristine

Inhibits microtubule polymerization

31

Chemotherapy - Doxorubicin

Inhibits Topoisomerase II
Used in lymphoma, leukemia, breast cancer, etc

32

Chemotherapy - Cyclophosphamide

Alkylating agent - Induces bulky DNA lesions

33

Chemotherapy - Asparaginase

Depletes asparagine
ALL cells are particularly sensitive to this.
Most other tumors are not.

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Chemotherapy - Methotrexate

Folate antagonist

35

Complications of ALL

DIC
Tumor Lysis Syndrome

36

DIC Labs

PT ↑
aPTT ↑
Fibrinogen ↓ (sometimes "spuriously" normal)
D-Dimer ↑
Platelets ↓
Schistocytes +/-

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DIC - Treatment

Cryoprecipitate

38

Tumor Lysis Syndrome Labs

K+ ↑ (from lysed cells and reduced renal clearance)
Creatinine ↑ (from acute renal failure due to Uric Acid)
Uric Acid ↑ (from DNA breakdown)
Phosphorous ↑ (from lysed cells)
LDH ↑ (from lysed cells)
Calcium ↓ (it binds to phosphorous)

39

How do you prevent the complications of Tumor Lysis Syndrome?

Allopurinol (prevent Uric Acid formation)
Rasburicase (break down Uric Acid)

40

Allopurinol

Prevents breakdown from xanthine to uric acid
Doesn't help the problem if the patient already has high levels of uric acid.

41

Rasburicase

Recombinant enzyme
Breaks down Uric Acid into Allantoin (white stuff in bird poop)
Costs more than $10,000

42

ALL - Adverse Prognostic Factors

Younger than 1 year old
Older than 10 years old
Adults - Increasing age, especially over 60
WBC > 30K (B-Cell)
WBC > 100K (T-Cell)
Adverse cytogenetics
B-Cell Phenotype
Presence of minimal residual disease

43

Minimal Residual Disease

Detect DNA left over from leukemia cells when in apparent remission
Test: PCR
Indicates likelihood of relapse

44

ALL - Adverse Cytogenetic Risk Factors

t(9;22) "Philadelphia Chromosome" - Poor Prognostic Marker, more common in adults

t(4;11) "Mixed Lineage Leukemia" - Poor Prognostic Marker, more common in infants

Hyperdiploidy - Favorable Prognostic Marker, more common between ages 1 and 10

45

ALL - Allogeneic Bone Marrow Transplant

Young patients with adverse cytogenetics in first remission
Standard treatment for relapsed ALL in young patients

Important factors in other scenarios:
Patient Age
Presence of HLA-matched sibling

46

2 new therapies for ALL

Blinatumomab
CART therapy

47

Blinatumomab

Bispecific T-Cell engaging Ab (BiTE)
Redirects T cells to lyse CD19+ malignant and nonmalignant B cells

It's essentially an adaptor, hooking up T Cells and CD19 B Cells

Effective in patients who have not responded well to standard therapy

Costs $200,000

48

CART Cells

Chimeric Antigen Receptor T Cells

Take T Cells out of the body, transfect them with DNA that causes them to express a novel T Cell receptor specifically looking for CD19

Effective in getting rid of refractory ALL

They may never make antibodies again, though.

49

CLL - Incidence

Most common form of leukemia
Only form of leukemia with NO increased incidence with a-bomb survivors
Disease of the elderly

50

CLL - Microscopic Smear

Small redundant lymphocytes (around the size of an RBC)
Clumped chromatin
Absent nucleoli
Light purple cytoplasm
Smudge cells (not pathognomonic, but frequently seen)

51

CLL - Patient Presentation

Asymptomatic Lymphocytosis
Lymphadenopathy (Common)
Chronic complications of cytopenias (recurrent sino-pulmonary infections, gradual fatigue, dyspnea, dizziness)
Chronic weight loss

52

Chronic complications of cytopenias

Recurrent sino-pulmonary infections
Gradual fatigue, dyspnea, dizziness

53

CLL - Diagnosis on Flow Cytometry

Predominance on lymphocytes of:
CD5
CD19
CD20 (can be therapeutic target)
CD23

Adverse prognosis: High expression of CD38 & ZAP-70

Look for "light chain restriction" meaning only kappa or lambda light chains are expressed, not both (which would indicate normal light chains)

54

CLL Diagnosis

No bone marrow needed. Can do flow cytometry on the blood

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CLL - Cytogenetics order of prognosis (Worst-to-best)

17p Deletion (lose p53)
11q Deletion
12q Trisomy
Normal
13q Deletion as SOLE abnormality

56

CLL - Heavy Chain Hypervariable Region Mutations

If you see mutations in the hypervariable region of the heavy chains on surface Ab, it is a FAVORABLE prognosis.
Wild type hypervariable regions indicate POOR prognosis.

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CLL - Stage 0

Monoclonal lymphocytosis
>6,000/μL

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CLL - Stage 1

Lymphadenopathy

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CLL - Stage 2

Hepatosplenomegaly

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CLL - Stage 3

Hemoglobin

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CLL - Stage 4

Platelets

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If a patient has asymptomatic CLL, when do we treat?

At Stage 3!

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Immune Dysregulation due to CLL

Immune Thrombocytopenic Purpura (ITP)
Autoimmune Hemolytic Anemia (AIHA)
Hypogammaglobulinemia
Pure Red Cell Aplasia (PRCA)
Other auto-immune diseases

64

Venn Diagram of Mechanisms of Thrombocytopenia

ITP (platelets low, out of proportion to the hemoglobin)
Splenic sequestration
Marrow involvement

65

CLL - Indications for treatment

Stage 3/4 CLL
Rapid lymphocyte doubling time (faster than every 6 months)
Symptomatic lymphadenopathy
Fevers, night sweats, weight loss
Transformation to high grade lymphoma

66

CLL Treatment - Agents

Cyclophosphamide (C)
Fludarabine (F)
Rituximab (R)
Bendamustine (B)
Alemtuzumab
Ofatumumab
Chrlorambucil

67

CLL Treatment - Regimens

FCR:
Fludarabine
Cyclophosphamide
Rituximab

FR:
Fludarabine
Rituximab

BR:
Bendamustine
Rituximab

68

Chemotherapy - Fludarabine

Nucleoside Analogue

69

Chemotherapy - Rituximab

Monoclonal Ab to CD20

Partially humanized, but synthesized in mouse ovaries
Opsonizes CLL B Cells

70

Chemotherapy - Ofatumumab

Monoclonal Ab to CD20

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Chemotherapy - Obinotuzumab

Monoclonal Ab to CD20

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Chemotherapy - Alemtuzumab

Monoclonal Ab to CD52

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Chemotherapy - Chlorambucil

Alyklating agent - Induce bulky DNA lesions

74

Chemotherapy - Bendamustine

Aklylating agent - Induce bulky DNA lesions

75

Idelalisib

New Therapy for CLL. Blocks PI3kδ
PO therapy

Small molecular inhibitors of growth pathways in CLL cells

B cell receptors aren't just important in recognizing antigen. They also trigger proliferation. Poison that pathway with these drugs.

76

Ibrutinib

New Therapy for CLL. Blocks BTK
PO therapy

Small molecular inhibitors of growth pathways in CLL cells

B cell receptors aren't just important in recognizing antigen. They also trigger proliferation. Poison that pathway with these drugs.

77

Idelalisib & Ibrutinib

Oral Monotherapy
Highly effective in relapsed CLL
Effective in 17p- Disease
Effective in the infirm
Induce transient lymphocytosis

78

Only cure for CLL

Allogeneic Bone Marrow Transplant
Carries a high mortality rate (10 - 40%)