Lesson 6.

Leukemias

Armand B. Hisona Jr., RMT

 History

• Means “white blood” in Greek

• Discovered by Dr. Alfred Velpeau in France,
1827
• Named by pathologist Rudolf Virchow in
Germany, 1845
 Leukemia
• Is a malignant hematologic disorder
characterized by proliferation of abnormal
white cells that infiltrate the bone marrow,
peripheral blood and organs.
• Acute Leukemias
– Blast (precursor) cells
– Rapidly fatal if not treated
• Chronic Leukemias
– More mature cells
– Longer life expectancy
 Classification of leukemias

Acute Chronic

Myeloid Acute Myeloid Chronic Myeloid Leukemia

Leukemia (AML) (CML)
origin

Lymphoid Acute Lymphoblastic Chronic Lymphocytic Leukemia

Leukemia (ALL) (CLL)
origin
 ALL
naïve

B-lymphocytes

Plasma
Lymphoid cells
progenitor T-lymphocytes

AML
Hematopoietic Myeloid Neutrophils
stem cell progenitor

Eosinophils

Basophils

Monocytes

Platelets

Red cells
 Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website

 Pictures of Blood
Platelet Platelet
White Cell Red Cell Red Cell Blasts
White Cell

Normal human blood Blood with leukemia

Sources from beyond2000.com
Sources from Arginine.umdnj.edu
 Acute Lymphoblastic Leukemia

• Proliferation of lymphoblasts
– anemia, thrombocytopenia, increased WBC
– lymphadenopathy/splenomegaly
• B- or T-cell
– flow cytometry
• Most common leukemia of childhood
Acute Lymphoblastic Leukemia
 Acute Myelogenous Leukemia
• Proliferation of myeloblasts
– anemia, thrombocytopenia, increased WBC
• Myeloid, monocytic, RBC, or
megakaryocytic
– flow cytometry
– myeloperoxidase +, TdT-
• Auer rods
• Over age of 20
Acute Myelogenous Leukemia
 Chronic Myelogenous Leukemia

• One of myeloproliferative diseases (PV, ET)

• Proliferation of more mature granulocytes
– normal to increased platelet count
– anemia
• Splenomegaly
• t(9;22) (bcr-abl) (Philadelphia
chromosome)
Chronic Myelogenous Leukemia
 Chronic Lymphocytic Leukemia

• Proliferation of small mature B-

lymphocytes
– flow cytometry (monoclonal Kappa or lambda)
• Lymphadenopathy
– relationship to small lymphocytic lymphoma
• May have Ab production
• 50% 5-year survival
Chronic Lymphocytic Leukemia
 Development of Leukemia in the
Bloodstream

Stage 1- Normal Stage 2- Symptoms Stage 3- Diagnosis

Legend:
Stage 5a- Anemia
White Cell

Red Cell
Platelet Stage 4- Worsening
Blast
Germ Stage 5b- Infection
ACUTE MYELOID LEUKEMIA
(AML)
 ACUTE MYELOID LEUKEMIA (AML)
Clinical Overview

• Acute myeloid leukemia (AML) is one of four types of

leukemia.
• AML is cancer of the blood-forming tissue (bone marrow).
• Normal bone marrow produces red cells, white cells, and
platelets.
• AML causes bone marrow to produce too many immature
white blood cells (blast cells).
• Suppresses normal blood cell production.
– Anemia, leucopenia, thrombocytopenia
Classification of AML

APL, PML
 Signs and Symptoms
• Fatigue
• Shortness of breath on exertion
• Easy bruising
• Petechiae
• Bleeding in the nose or from the gums
• Prolonged bleeding from minor cuts
• Recurrent minor infections or poor healing of minor cuts
• Loss of appetite or weight loss
• Mild fever
 Causation
• Genetic changes in AML
• Chromosomal changes lead to activation of
oncogenes
• Translocation between chromosomes 8 and 12
• Translocation between chromosomes 15 and 17
• Deletion of a segment of chromosome 5 or 7
• Genetic factors that predispose an
individual to AML
• Fanconi’s anemia
• Down syndrome
• Bloom’s syndrome
 Causation
• Environmental factors
• Exposure to ionizing radiation
• Exposure to benzene
• Treatment with alkylating agents or procarbazine
• Treatment with other drugs
• Viral oncogenesis (speculative)
• Age
• Adults are more likely to develop AML
• Smoking
• 20% of AML cases are linked to smoking
• Doubles the risk of disease in people older than 60
t(15;17) translocation in AML
 Clinical Manifestations

• symptoms due to:

– marrow failure
– tissue infiltration
– leukostasis
– constitutional symptoms
– other (DIC)
• usually short duration of symptoms
 Marrow failure
• neutropenia: infections, sepsis
• anemia: fatigue, pallor
• thrombocytopenia: bleeding
Infiltration of tissues/organs
• enlargement of liver, spleen, lymph nodes
• gum hypertrophy
• bone pain
• other organs: CNS, skin, testis, any organ
Gum hypertrophy
Chloromas

C
NEJM 1998
 Laboratory features

• WBC usually elevated, but can be normal or

low
• blasts in peripheral blood
• normocytic anemia
• thrombocytopenia
• neutropenia
• DIC
Auer rods in AML
 Treatments for AML

• Chemotherapy
Phase One – Remission induction therapy
Phase Two – Remission continuation therapy
• Radiation therapy for certain cases
• Bone marrow transplantation
 Treatments
• Chemotherapy
• Induction therapy
• Initial stage of therapy to eradicate systemic and
marrow-localized leukemic cells leading to
remission
• Combination of an anthrocycline antibiotic and a
cytarabine
• Both prevent DNA synthesis thus stopping growth and
leading to their death
• If remission is not achieved with the first round of
induction therapy, another round is begun
 Treatments
• Post-remission therapy
• Consolidation therapy
• Goal is to destroy any undetectable leukemic cells
• Many different approaches all of which involve
short doses of intensive therapy
• Maintenance therapy
• months to years of less intensive therapy to prevent
further recurrence
 Treatments

• Bone marrow transplant

• Used as a last resort if 3 rounds of induction
therapy have been unsuccessful
• Used as or along with post-remission therapy
• Two types of transplants are used
• Autologous
• Allogeneic
• Radiation therapy
• Only used in rare cases where leukemic cells
are centralized in one part of the body
 Goal of treatment: Remission
• Blood cell counts return to normal
• Leukemic cells can no longer be found in blood
or marrow
After remission
• If at any time after remission is achieved a relapse
occurs the initial treatment may be repeated
usually with minor changes in protocol
• If after five years of remission there have been no
new outbreaks of leukemic cells the patient is
considered cured
 Two-hit model of leukemogenesis

Loss of function of Gain of function mutations of

transcription factors tyrosine kinases
needed for differentiation
eg. FLT3, c-KIT mutations
eg. AML1-ETO N- and K-RAS mutations
CBFb-SMMHC BCR-ABL
PML-RARa TEL-PDGFbR

differentiation enhanced Acute

block + proliferation Leukemia
 Leukemic Normal progenitor
progenitor cell BLOOD STEM CELL cell

1% of
leukemic cells

Leukemic
mutation

99% of
leukemic cells

LEUKEMIA
Leukemia stem cells could be targeted with chemo
different from that killing leukemic cell

Conventional
Chemotherapy

Disease recurrence

Stem cell killing True Tumor

involution

Disease
Stem cell killing + remission
Conventional Chemotherapy

Brian J. P. Huntly & D. Gary Gilliland

To understand the difference between leukemic cell
and normal blood cell we shall look into
differentiation related pathways
 common lymphoid
progenitor (CLP)

Lymphoid
cells
Upregulation PU.1

Myeloid
hematopoietic cells
stem cells

CCAAT/enhancer
binding protein- Factor
(C/EBP) α
interplay
upregulation
Downregulation PU.1 fork
Erythroid
common myeloid cells
progenitor (CMP)
 Transcription factors involved in normal
hematopoiesis
AML1

GATA1

PU.1

(C/EBP)α

(C/EBP)β

(C/EBP)ε
1. Signaling event changes the ratio of PU.1 and GATA proteins in a stem
cell.

2. GATA protein inhibit PU.1 blocking its interaction with c-JUN

3. PU.1 inhibitions GATA function
through inhibition of GATA DNA binding.

4.
GM–CSF
and EPO
facilitate
differentiation
along either
the myeloid
or erythroid
pathways

Nature Cancer Review

 Lymphoid
cells
Upregulation PU.1

+ PU.1 Myeloid
- GATA = Myeloid cells

- PU.1
Downregulation PU.1 + GATA =Erythroid
Erythroid
cells
 PU.1 factor
DUAL ROLE OF PU.1 factor

development of a development of
lymphoid monocytes/
precursor macrophages
Degradation

Basal
transcription C-Jun positive
factors GATA1, C/EBP
negative

PU.1 regulates almost every myeloid gene, including GM-CSF

receptor, macrophage M-CSF, granulocyte G-CSF
 The Future
• Clinical trials
• New drug treatments
• Vaccines
• Immunotherapy
• Leukemia type-specific therapy
• Gene therapy
– Block encoding instructions of an oncogene
– Target the oncoprotein
• Blood and marrow stem cell transplantation
– Bone marrow transplantation provides long-term, disease-free
survival among patients in remission
~Thank you~