Leukemias and Lymphomas

Number of cases of leukemias/non-Hodgkin lymphoma vs. number of deaths of leukemia/non-Hodgkin lymphoma

Greater number of non-hodgkin lymphomas, but greater number of deaths from leukemia

Two main categories of leukemias

Acute and chronic

Acute leukemia types

AML, ALL

AML

acute myelogenous leukemia

ALL

Acute lymphoblastic leukemia

AML comes from what cell line

Myeloid cell line (of the marrow)

Myeloid meaning

derived from bone marrow

ALL comes from what cell line

Lymphoid cell line

Chronic leukemia types

CML, CLL

CML

chronic myelogenous leukemia

CLL

chronic lymphocytic leukemia

Acute (A) meaning in leukemia

Cancer is dividing progenitor cells in the bone marrow

Those with acute leukemia exhibit what?

Pancytopenia

Pancytopenia

deficiency of all types of blood cells —> from bone marrow failure

Get pain where with acute leukemia

Bone pain

Chronic (C) meaning in leukemia

Cancer is dividing circulating cells (more mature form than blasts)

#1 leukemia in adults

AML

#1 leukemia in kids/teens

ALL

#2 leukemia type

CLL

#3 leukemia type

CML

Two types of lymphomas

Non-Hodgkin's Lymphomas (NHL)

Hodgkin Lymphoma (HL)

NHL

non-Hodgkin's lymphoma

abbr.

HL

Hodgkin's lymphoma

Pathogenesis of acute leukemia

1. Mutations (chemo/radiation or sporadic)

2. Cancer fills bone marrow

3. Reduced normal cells —> pancytopenia

4. Cancer cells spill out of marrow

5. Some infiltration of lymph

What symptoms come with the pancytopenia with acute leukemia (and what specific cells that are low are causing this)

-Ecchymosis/hemorrhages —> low platelets

-anemia —> low erythrocytes

-infections —> neutrophils

Dx criteria for acute leukemia

>20% circulating blast cells

Acute leukemia is/isn't inherited

Isn't

Ocular presentation of pancytopenia

-hemorrhages

-infections

-acute onset!

Hemorrhages in the eye for pancytopenia cause what symptoms

Blurry vision/vision loss = retinal hemorrhages

Hyphema = blood in the anterior chamber

AML is what percent of all leukemias

80%

AML is cancer of what

Myeloid blasts

How many subtypes of AML

8

Dx for AML

20% myeloid blasts

TdT negative

Auer rods

Treatment for most AML subtypes takes how long

4-6 weeks

Phases of AML treatment

Phase 1 = wipe out phase —> chemo to try to remove all cells

Phase 2 = keep patient alive (if infected, treat w/ antibiotics; if bleeding give platelet transfusions; if anemia give RBC transfusions or epo)

Phase 3 = allow normal cell repopulation —> may require HSC transplant to repopulate

Phase 4 = booster chemotherapy treatments for a week

People who survive AML are at a high risk for how long

2-3 years

Prognosis for +5yr survival with AML

Poor prognosis 20% survival

Phase 3 of treatment for AML to allow normal cell repopulation may require what

HSC transplant to repopulate

What do you have to worry about with HSC transplant

Graft vs. host rxn

Specific subtype of AML

APL = acute promyelocytic leukemia

APL =

Acute promyelocytic leukemia

APL subtype has what type of mutation

Translocation —> t(15:17)

APL subtype pathogenesis

1. t(15:17) = translocation

2. Causes PML:RAR alpha fusion

3. Binds promoters regulating genes for differentiation

4. Arrest at promyelocytic stage

5. Abnormal accumulation of promyelocytes

PML =

Promyelocytic leukemia gene

RAR alpha =

Retinoic acid receptor alpha

PML and RAR alpha come from what chromosomes

PML from chromosome 15

RAR alpha from chromosome 17

What happens with PML:RAR alpha binds promotors regulating genes for differentation

Repressors bind PML:RAR alpha —> no differentiation genes on

Repressor

A protein that suppresses the transcription of a gene.

APL results in an accumulation of what cells

Promyelocytes

What does PML normally do? What happens in APL

Normally PML is a transcription factor that allows for production of proteins for differentiation of cells

*in APL, RAR alpha is fused on PML so no longer stimulates production of genes responsible for differentiation —> stuck in blast and accumulate promyelocytes

Treatment for APL

1. All trans retinoic acid (ATRA) therapy

2. Chemotherapy (arsenic)

ATRA

All-trans retinoic acid

Retinoic acid is what

Vitamin A

Explain ATRA therapy

Retinoic acid binds PML:RAR alpha

Activators bind

Transcription of differentiation genes

Cells differentiate

Cure rate of APL

90% really good for AML!!

Most common childhood cancer

acute lymphoblastic leukemia

Dx for ALL

Lymphoid blasts (20%)

TdT+

No auer rods

Subtypes of ALL

B-ALL

T-ALL

Most common subtype of ALL

B-ALL

B-ALL peaks at what age

Age 4

B-ALL is heavily associated with what?

Down's syndrome (200x)

B-ALL =

B cell ALL

T-ALL =

T-cell ALL

Least common ALL

T-ALL —> RARE!

T-ALL found in what age group

Adults

If adults do get ALL, get what type

T-ALL

Ocular presentation of ALL

Hemorrhages!

-blurry vision/vision loss = retinal hemorrhages

-hyphema = blood in the anterior chamber

-infections

-acute onset

What is unique to ALL that you don't normally see in AML

Severe lymphadenopathy, splenomegaly, and hepatomegaly

Why do you get lymphadenopathy/splenomegaly/hepatomegaly with ALL and not AML

Because the lymphoblasts like lymph tissues much more than the other myeloid cells

Treatment for ALL takes how long

1.5-2.5 years

Pancytopenia seen in what type of leukemia always

Acute

Tx phases for ALL

Phase 1 = wipe out phase (chemo)

Phase 2 = keep patient alive (infected = treat with antibiotics; bleeding = platelet transfusions; anemia = RBC transfusions)

Phase 3 = allow normal cell repopulation (may require HSC transplant)

Phase 4 = booster chemotherapy treatments for over a year!! (Intrathecal treatments and scrotal treatments)

What is unique to ALL treatment (compared to AML)

Booster chemotherapy treatments for over a year —> intrathecal treatments and scrotal treatments

Intrathecal

In the CSF

Where does ALL really like to hide (and therefore where must you treat to have a successful treatment of ALL)

CSF —> intrathecal treatment

Scrotal tissue —> scrotal treatment

Prognosis of ALL

Good, >90%

Prognosis with ALL relapse

Poor —> gets worse the more you relapse

Intrathecal chemo for ALL since CSF is "____________"

Sanctuary

ALL treatment puts you at risk for what later

CML/AML, other leukemias, etc.

Alternative tx for ALL

CART

CART

Chimeric antigen receptor T cell

What is the CART treatment about

-take a CTL with chimera protein —> Anti-CD19 (on all B cells) - target; triggers TCR to release granzyme and perforin

-targets and kills B cell cancers

Steps of CART treatment

1. Collect naive CTLs

2. Transfect (HIV containing TCR:CD19)

3. Grow cells

4. Transfer cells

5. CTLs attack B cells inducing cancer

What is the chimera protein used in CART

TCR:CD19

Downside to CART tx

-production issues = $ and time

-causes cytokine storm —> get really sick initially: high fever, drop in bp

-requires antibody infusion for the rest of your life because B cells are dead

CART (other than ALL) is also being used to treat what

Non-Hodgen's lymphoma —> all B-cells lymphomas

CML is cancer of what

Myeloid blasts of PMNs, or monocytes

Maturity of CML...what does this mean?

Capable of maturation —> no blasts or pancytopenia

CML usually has what chromosome associated with it

Philadelphia chromosome (Ph+)

Symptoms of CML

Usually asymptomatic

Dx for CML

Found on routine blood work:

-leukocytosis

-may cause cardiovascular problems

CML can convert to what

AML

Leukocytosis

increase in the number of white blood cells

'Normal' signal transduction pathway that regulates gene expression (that goes wrong in CML)

with signaling:

-JAK activated

-phosphorylation of proteins

-genes for cell division made

-cells divide

without signaling:

-no phosphorylation

-no genes-no division

Pathogenesis of CML

1. Philadelphia chromosome produced —> t(9:22) —> BCR-ABL fusion = active oncogene (tyrosine kinase)

2. BCR-ABL protein phosphorylates proteins

3. Stimulates cell division —> cancer

Oncogene associated with Philadelphia chromosome

BCR-ABL

Philadelphia chromosome produced how

Translocation between chromosome 9 and 22

BCR-ABL is what type of protein

Tyrosine kinase

Tyrosine kinase does what

Phosphorylates proteins —> causes activation of genes responsible for cell division and differentiation

Tx for CML

Gleevec (Imantinib)

-inhibits ATP binding —> inhibits tyrosine kinase —> no phosphorylation or cell division