Leukemia

Question 1

CML Pathophysiology

Answer 1

• uncontrolled production of maturing granulocytes (neutrophils&raquo_space; basophils or eosinophils); inc prolif/ dec apoptosis
• Cytogenetic hallmark - Philadelphia chromosome; translocation b/n chromosomes 9 and 22 (22q11 breaks and fuses w/ 9q34 AKA ABL gene)
• New fusion gene –> BCR/ABL protein –> Abl tyrosine kinase becomes constitutively active —> act downstream kinases –> no apoptosis and inc cell division

Question 2

3 Phases of CML

Answer 2

• Chronic (25+ yrs)- insidious onset (fatigue, malaise, wt loss, splenomegaly –> LUQ pain/ early satiety)
• Less commonly present w/ infection, thrombosis, bleeding from dec platelets or WBCs
• Occasionally present w/ thrombosis due to severe leukocytosis (stroke, MI, venous thrombosis, visual disturbance, pulmonary insufficiency, vaso-occlusive disease)
• Accelerated (4-5 yrs)/Blastic (6-12 mo)- worsening symptoms (fever, inc wt loss, joint/bone pain, bleeding, thrombosis, infection)
• Accelerated may include clonal evolution
• Blastic - extramedullary disease w/ localized immature blasts

Question 3

How do you treat chronic v accelerated CML?

Answer 3

• Chronic - TK inhibitors first like Imatinib (comp inhibitor of ATP binding site of Abl)
  
  • Also, hydroxyurea, interferon, busulfan (alkylating agent)
• Accelerated, blastic or failed TK inhibitor - HSCT (curative)

Question 4

Incidence/Common Age of Onset for Ea Leukemia

Answer 4

CML - 50s/60s

CLL 60-80 (most common leukemia)

AML - incidence inc w/ age

ALL - overall less common than AML but B cell ALL is most common childhood cancer

Question 5

CLL Presentation

Answer 5

• Develop lymphocytosis, anemia, thrombocytopenia, lymphadenopathy, splenomegaly
• Recurrent infections b/c dec B cell function

Question 6

CLL Dx

Answer 6

• Made by flow cytometry (CD 19+, CD20+, CD23+, clonal kappa or lambda, abberant T cell CD5+); must have > 5000 B cells / microL
• Must r/o mantle cell lymphoma, prolymphocytic leukemia and hairy cell leukemia

Question 7

Flow Cytometry of Hairy Cell Leukemia

Answer 7

CD20+, CD103+, CD5-

Question 8

Richter’s Syndrome

Answer 8

-When CLL is transformed to a prolymphocytic leukemia or aggressive lymphoma

Question 9

CLL Prognosis and 3 Complications

Answer 9

Prognosis dep on genetics

• Those that undergo hypermutation - CD38- ZAP70- (better prognosis)
• No hypermutation - CD38+ or ZAP70+ (worse prognosis)

1- Predisposition to developing autoimmune hemolytic anemia and secondary ITP
2- May have leukostasis w/ very high WBC count >50,000 (leuks block vessels)
- Treat w/ leukapharesis or hydroxyurea
3- Inc risk secondary malignancies

Question 10

CLL Tx

Answer 10

• If non-elderly use fludarabine + cyclophosphamide + rituximab (FCR)
• If elderly use chorambucil (alkylating agent) OR bendamustine + rituximab (BR)
• HSCT reserved for 17p- pts and people < 65 (curative)

Question 11

AML Risk Factors

Answer 11

Incidence in w/ age and exposure to DNA damage (radiation, chem, drugs, alkylating agents, benzene) or inherited disease in DNA repair (Fanconi anemia)

Question 12

Prognosis of Various AML Cytogenetics

Answer 12

Favorable

t(15;17)
inv(16)(p13;q22)
t(8:21)

Intermediate

+8 or normal karyotype

Unfavorable

-7
t(6;9)
inv(3)(q21;q26.2)
Complex (>3 abnormalities on karyotype)

Question 13

AML Presentation

Answer 13

Anemia, leukocytosis, neutropenia, thrombocytopenia

Question 14

WHO Classification (4) of AML

Answer 14

• I - AML w/ recurrent genetic abnormalities
• II - AML w/ multilineage dysplasia
• III - AML, therapy -related
• IV - AML, not otherwise specified

Question 15

AML Tx Approach

Answer 15

1- Induction chemo until < 5% blasts in marrow

2- Post-remission

Question 16

Acute Promyelocytic Leukemia

Answer 16

• No maturation beyond promyelocytes (pro have primary granules - for Auer rods on smear- needle-shaped crystals)
  
  • “Faggot cells” - b/c Auer rods like bundle of sticks
• t(15;17) results in PML-RARA fusion protein; RARA causes co-repressor to bind PML rather than retinoic acid (no
  transcription)
• Tx = ATRA (all trans retinoic acid in high conc outcompetes co-repressor for binding on PML –> transcription –> then mature cells die)
• Do not use leukapharesis for leukostasis in these patients

Question 17

ALL (presentation and prognosis)

Answer 17

• Malignancy of pre-B cells (T cells much less common)
• Presentation - cytopenia –> fatigue, pallor, bleeding, infection AND extramedullary (splenomegaly, hepatomegaly, lymphadenopathy, CNS, testicular enlargement)
• Prognosis (dep on age)
  
  • 90% kids cured
  • 40% adults cured
  • 10% elderly cured

Question 18

ALL Tx

Answer 18

*B cells not in cell cycle as much so do not use meds that are cell cycle dep

1- Induction - steroids, asparaginase

2- Post-remission - (dep on risk) if high risk then get intrathecal chemo for CNS/CSF penetration (inc mortality but important to prevent CNS problems)

Question 19

ALL v AML Morphology

Answer 19

ALL

• More variable blast size; generally smaller blasts
• Scant cytoplasm; if any then coarse
• Auer rods in 60-70%
• Fine chromatin
• 1 to 4 nucleoli (often prominent)

AML

• Large, uniform sheets of blasts
• Moderate cytoplasm; frequent granules
• No Auer rods
• Fine or coarse chromatin
• Absent nucleoli; if present then 1 to 2 inconspicuous